PhLE MODULE 4 – PHARMACOLOGY

CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

COMMON MAJOR PATHOPHYSIOLOGIC MECHANISMS

INTRODUCTION Causes nerve excitability →
CNS Stimulation
seizures → brain damage
TOXICOLOGY Loss of airway protective reflexes
CNS Depression and respiratory drive →
respiratory depression
• Study of poison, its mechanism of action,
Diarrhea
and its management Urination
• Study of adverse effects / events of Parasympathomimetic
Miosis, muscle fasciculations
Bronchoconstriction, bradycardia
physical / chemical agents in humans, Effects (DUMBBELS)
Emesis
other organisms, and environment Lacrimation
Salivation, sweating
POISONS Mydriasis
Agitation
Sympathomimetic
• Has deleterious effects; may cause Effects (MATHS)
Tachycardia
Hypertension
physical injuries or death Seizure, sweating
• Sola dosis facit venenum – the dose makes Heart: Cardiac arrhythmias
the poison Vasculature:
Cardiovascular Effects
‣ Vasodilation → hypotension
• Toxin – natural source ‣ Vasoconstriction → hypertension
• Toxicants – man-made / artificial source Respiratory Effects Aspiration → bronchospasm
Interference with O2 transport and
Cellular Hypoxia
Side Effects – related to therapy utilization
Muscle breakdown with
Musculoskeletal
Adverse Effects – deleterious / toxic effects myoglobinuria → renal failure,
Effects
lactic acidosis, hyperkalemia
✓ Immune-mediated: hypersensitivity rxn
✓ Receptor-related: idiosyncrasy, tolerance,
RISK ASSESSMENT
or desensitization
✓ Others: teratogenicity Estimate potential effect on human health and
FDA PREGNANCY CATEGORIES
environmental significance of various types of
CATEGORY HUMANS ANIMALS chemical exposure
A (-) (-)
No human studies (-) Hazard – ability of a chemical agent to cause injury
B
(-) (+) in a given situation or setting
C No human studies (+)
D (+) Benefit > Risk Risk – expected frequency of the occurrence of an
E/X (+) Risk > Benefit
undesirable effect arising from exposure to a
chemical or physical agent
TERATOGENIC DRUGS
ACEi Renal dysgenesis AREAS OF TOXICOLOGY
Fetal alcohol syndrome
✓ Facial anomalies 1. Mechanistic – mechanism of toxicity
Alcohol ✓ Growth retardation
✓ Neuro-developmental 2. Descriptive – direct toxicity testing
defects
Carbamazepine Neural tube defect 3. Regulatory – decision making process using
Clear cell cervical carcinoma of the
Diethylstilbestrol information from: mechanistic and descriptive
vagina or cervix
Lithium Ebstein’s Anomaly (assess safety or if a substance possess a risk)
Methimazole Aplasia cutis
Phenytoin Fetal hydantoin syndrome SPECIALIZED AREAS OF TOXICOLOGY
Retinoids Heart and brain abnormalities
8th cranial nerve (vestibulocochlear) 1. Clinical Toxicology
Streptomycin
damage
Tetracycline Teeth discoloration, bone problems • Study of adverse effects in humans caused
Thalidomide Phocomelia, amelia by incidental/accidental overdose
Valproic Acid Spina bifida / neural tube defect
Nasal hypoplasia / fetal warfarin • Mechanistic + descriptive toxicology
Warfarin
syndrome

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 PhLE MODULE 4 – PHARMACOLOGY
CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

2. Environmental Toxicology 2. According to Duration

• Deals with the harmful effects of chemicals • Acute – ↑ dose in short period of time (<
to the environment / organisms 24 hours)
• Regulatory + descriptive toxicology • Subacute – less than 1 month
• Chronic – ↓ dose in longer period of time
3. Forensic Toxicology
(> 3 months)
• Medicolegal aspects of poisoning • Subchronic – duration is 1-3 months
• Mechanistic + regulatory
3. According to Onset
TOXICOKINETICS • Immediate – seen after single
administration
ABSORPTION • Delayed – seen after a lapse of time

• Parameters: BIOAVAILABILITY (F) – rate 4. Reversible vs Irreversible

and extent of absorption; extent / fraction
of drug that enters systemic circulation • Reversible – reversed by administration of
• Affected by: the antidote
o Physical Properties – lipid soluble • Irreversible – permanent damage,
= ↑ extent; water soluble = ↓ carcinogenic, and teratogenic effects
extent FACTORS THAT INFLUENCE EFFECTS OF POISON
o Gastric Emptying Rate – ↓ GER =
↓ absorption ROUTE
o Health of GIT
• Oral
o First pass effect – hepatic
o Most common or important
metabolism
o ↑A = lipid soluble
DISTRIBUTION o ↓GER = delay absorption (ex.
anticholinergic)
• Parameter: VOLUME OF DISTRIBUTION • Dermal
(Vd) o lipid soluble = ↑ damage
• Affected by: Protein binding – ↑ PB = ↓ o ↑ absorption – (ex. phenol)
VD • Inhalation – gases/particle < 0.5μm;
𝑑𝑜𝑠𝑒 systemic or local effect
𝑉𝑑 = • IV
𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
• IM
METABOLISM AND EXCRETION • Rectal
• Parameter: CLEARANCE – rate by which a Concentration – ↑ conc = ↑ toxicity
known volume of plasma is cleared by drug
• Affected by: Liver and kidney function – PATIENT-RELATED FACTOR
specially in pediatric and geriatric px
Age (Pediatric)
POISONS • Child Inutero
✓ 1-2 weeks – conception /
EFFECTS OF POISONS implantation; abortion
✓ 3-8 weeks – embryogenesis
1. According to Extent / Location
period; morphologic change (ex.
• Local – Ex. Phenol ACEi)
• Remote – Ex. Paraquat → Pulmonary ✓ > 8 weeks – minor physiologic
fibrosis changes
• Systemic – Ex. Metabolic acidosis

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

• Examples: PRIMARY SURVEY

✓ Tetracycline – teeth discoloration
AIRWAY
and bone problems
✓ ACEi – renal dysgenesis • Should be cleared of any obstruction or
✓ Diethylstilbestrol (DES) – uterine any vomitus
/ cervical cancer to daughter • Optimize airway position
✓ Thalidomide – phocomelia → • Place the neck and head in “sniffing”
limb deformities position
Age (Geriatric) – ↓ liver/kidney function; ↓ muscle • Apply the jaw-thrust maneuver
mass; ↑ fat deposition • Place the patient in a head-down, left-
sided position
• Tolerance / Tachyphylaxis – increase dose • CAUTION: Do not perform neck
to get same effect (Ex. Nitrates, Morphine) manipulation if neck injury is suspected
✓ Dispositional Tolerance – ↓ amt • Management:
of chemical agent reaching the ✓ Remove any obstruction
circulation ✓ Administer / provide artificial
✓ Desensitization – ↓ response of airway via insertion of oral airway
receptors to an agent or insertion of endotracheal tube
• Idiosyncrasy and Pharmacogenetics
✓ G6PD Deficiency – triggers: sulfa BREATHING
drugs, antimalarials, analgesics,
• Assess O2 saturation – using pulse
acetanilide, antibiotics (nalidixic
oximeter
acid), INH, nitrofurantoin
• NORMAL: 95-100% O2
• RR: 12-21 breathes/min
• ABG: For determination of acidosis /
alkalosis; NORMAL: 7.40-7.45
• Management:
✓ O2 supplementation if O2 sat is
✓ Pseudocholinesterase Deficiency <95%
– ex. Succinylcholine → malignant ▪ Nasal cannula – 90-94%
hyperthermia ▪ O2 face mask – 80-89%
✓ NAT2 Polymorphism – ex. INH → ▪ Non-rebreather O2
fast acetylators: Asians; slow: mask – 70-80%
Caucasians ✓ Perform intubation and manual /
mechanical ventilation if O2 sat is
MANAGEMENT OF POISONED PATIENT < 70%
BREATHING PROBLEMS
Paralysis of Ventilatory Muscles:
Primary Survey (ABCDE)
‣ Flaccid Paralysis: NMBs, Botulinum toxin
‣ Spastic Paralysis: Tetanospasmin,
Ventilatory strychnine, saxitoxin, tetrodotoxin
History and Physical Examination Failure
CNS Depression: Alcohols, sedative-
hypnotics, opioids, antidepressant,
antipsychotics
Decontamination ‣ Inert Gases: CO2, methane, propane,
nitrogen
‣ Cellular Hypoxia: methemoglobinemia,
Hypoxia
Antidotal Therapy CO, cyanide, H2S
‣ Sulfahemoglobinemia Pneumonia:
Aspiration of gastric contents
Beta-blocker, hydrocarbon aspiration,
Toxin Elimination Bronchospasm
organophosphates, and carbamates

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

CIRCULATION MANAGEMENT – diagnostics and therapeutics

• Assessment: DECONTAMINATION
✓ BP; NORMAL: >90/60 mmHg
INGESTION
✓ Pulse rate: 65-100 bpm
• Management: 1. Lavage
✓ For HTN:
▪ Give 200mL PNSS IV • Passage of tube via mouth or nose down
bolus to consume 1L to stomach followed by sequential
▪ Check breath sounds administration of warm saline solution and
✓ Pulseless / bradycardic: removal of small volume of liquids
▪ Start chest compression • Used for massive ingestion
▪ Initial: 30 comp/min • Contraindications:
o Unconscious patients
DEPRESSED MENTAL STATUS o Ingestion of corrosive substances
o Ingestion of SR and enteric-
• Assessment:
coated tablets
✓ Check for responsiveness (tap /
sternal rub) 2. Dilution / Neutralization – CI in alkali and acids
✓ Check for capillary blood glucose;
NORMAL: 70-200 g/dL 3. Emesis (Syrup of Ipecac / Apomorphine) – toxin
• Differential Diagnosis: does not cause rapid onset coma / convulsion →
✓ Hypoglycemia – Mgt. Dextrose aspiration
50/50 Contraindications (4C’s)
✓ Alcohol intoxication – Mgt. Vit B1
100mg IV (for the prevention of ✓ Children <6 yrs old – underdeveloped
Wernicke Korsakoff Syndrome) airway protection mechanism
✓ Opioid Toxicity – Mgt. Naloxone ✓ Agents which may cause comatose –
0.4-2mg IV alcohol; short acting barbiturates;
✓ Sedative/hypnotic toxicity – nonbarbiturates; hypnotics; TCA
Mgt. Flumazenil or urine ✓ Agents causes rapid onset convulsions – β
alkalinization using NaHCO3 blockers; CCBs; chloroquine; camphor;
codeine; TCA; mefenamic acid;
DEGREE OF DISABILITY organophosphate; strychnine;
EYES VERBAL MOTOR
phencyclidine (angel’s dust)
(+6) Obey
commands ✓ Agents that are corrosives and
(+5) Oriented
(+4) Spontaneous
(+4) Confused
(+5) Localizing hydrocarbons
(+3) To sound (+4) Normal flexion
(+3) Words
(+2) To pressure (+3) Abnormal 4. Activated charcoal – adsorbs toxin
(+2) Sounds
(+) None flexion
(+1) None
(+2) Extension
(+1) None
• Dose: ratio of Activated charcoal to the
toxin by weight is 10:1
• CI:
EXPOSURE o Unconscious patients
o Poorly absorbed substances: Fe,
Remove clothing for better evaluation
Li, K, F, cyanide, alcohol, acids,
SECONDARY SURVEY (MAPLE) alkali, ethylene glycol
• GI Dialysis – repeated dose of charcoal;
• Medication creates concentration gradient between
• Allergy intestinal lumen and plasma
• Past Medical History / Pregnancy
• Last Meal
• Events or Environment Related to Injury

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

5. Cathartics – saline cathartics DERMAL EXPOSURES

• Contraindications: • Remove exposed clothes

o Absence of bowel sounds • Rinse with copious H2O and soap for 30
o Evidence of intestinal obstruction minutes
o Pre-existing electrolyte
TOPICAL AGENTS FOR CHEMICAL EXPOSURE TO THE SKIN
imbalance Hydrofluoric Acid Calcium Soaks
o Renal dysfunction Oxalic Acid Mineral Oil
o GI bleeding Phenol Isopropyl Alcohol
White Phosphorous 1% Copper SO4
• Indication (FFED):
o Foreign bodies
o Fe tablets OCULAR EXPOSURES
o Enteric coated tablets
o Illicit drug packet/fillers Irrigate with saline solution for 15-20 minutes with
eyelids retracted
6. Whole Bowel Irrigation – administer with PEG
with electrolytes until completely cleansed EXTRACORPOREAL METHODS

1. Hemodialysis – passing of blood through a semi-

• ENDGOAL: Effluent is same color of
permeable membrane with counter current
infuscate
dialysate flow, allowing passage of solute
• Indication:
o Substances that are poorly Dialyzable Toxins:
absorbed (ex. Li, Fe, Pb)
o Slow-release preparations ✓ Water-soluble
o Late presentation (takes 2-4 ✓ Low Vd - <1L/kg
hours) ✓ Protein binding – <50%
✓ Low MW – <500 Daltons
7. Diuresis / pH Manipulation
Supportive Measure (AEIOU)
• Kidneys → filtration, reabsorption,
secretion • Acid-base disturbances that are
• Examples: unresponsive (Severe)
o Salicylates + NaHCO3 (alkalizer) • Electrolyte disturbances that are
o Amphetamine + Vit C or NH4Cl unresponsive (Refractory hyperkalemia)
(acidifier) • Intoxication (Salicylates, lithium,
methanol, ethylene glycol)
DRUG / TOXIN BINDING AGENTS
• Overhydration / Overload (Volume)
Calcium Cellulose Na PO4
Chlorinated • Uremia (Bleeding, altered mental status)
Cholestyramine
hydrocarbons
Heavy Metals Egg white, milk (demulcents) 2. Hemoperfusion – blood through an adsorbent
Iron Na bicarbonate (charcoal)
Na polystyrene sulfonate
Lithium, Potassium
(Kayexalate®) Indications:
Paraquat Fuller’s Earth, Bentonite
Thallium Prussian Blue ✓ Highly protein bound
✓ High Vd
INHALATION ✓ Lipid soluble

• Remove from hazardous environment 3. Peritoneal Dialysis – least invasive because it

• (+) 100% humidified O2 does not require anticoagulation; 10-15% as
effective as hemodialysis
• Assisted ventilation
• Bronchodilators

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

COMMON MAJOR PATHOPHYSIOLOGIC Cyanide

MECHANISMS (+)
Amyl Nitrate /
INTERFERENCE WITH O2 UTILIZATION NaNO2

Respiration → O2 transport → Cellular respiration Methemoglobin + CN

Energy Production:
Glycolysis → Kreb’s → ETC → O2, ATP, CO2
Cyanomethemoglobin
1. Carbon Monoxide (+)

• Product of incomplete combustion Na thiosulfate

• MOT: Inhibits cytochrome oxidase

• Presentation: pallor, headache, vertigo, Thiosulfate
(Excreted)
cherry red skin (postmortem)
• CO + Hgb → methemoglobin (↑affinity to
✓ Hydroxycobalamin (B12) – binds
O2) = hypoxia
with CN → cyanocobalamin
Management:
✓ Methylene Blue – high dose to
✓ O2 supplementation
produce methemoglobin
✓ Hyperbaric oxygen (100% O2)
4. Nitrites / Nitrates
2. Hydrogen Sulfide
• Inorganic Nitrates – Preservatives: KNO3
• MOT: Blocks cytochrome → blocks O2
(Salt Peter), NaNO3 (Chile saltpeter)
utilization
• Organic Nitrates – ISDN, glyceryl trinitrate
• Rotten egg odor; hot springs
• Inorganic Nitrites – NaNO2
• Highly toxic, colorless gas
• MOT: Methemoglobin Formation
• Irritation of mucous membrane →
↑ cGMP → desphosphorylate myosin light
respiratory depression
chain → smooth muscle relaxation →
• Methemoglobin + Sulfide Ion →
vasodilation
Sulfmethemoglobin + hypertonic O2
• Clinical Effects: Cyanosis, dizziness, HA,
• Management
lightheadedness, N&V, diarrhea
✓ Amyl nitrite (inhalation)
• Treatment: Methylene blue – ↓ doses 1-2
✓ NaNO2 (IV)
mg/kg
✓ Hyperbaric O2 (100% O2)
DEPRESSION OR STIMULATE CNS
3. Cyanide
CAUSING COMA / CONVULSION
• Found in Prunus spp. (wild blackberry,
• Depression – coma; (Ex. OH, sedative,
bitter almond, apricot), cassava, lima
hypnotics)
beans, silver jewelry cleaner
• Stimulate – convulsions; (Ex. Cocaine,
• Clinical Effects:
sympathomimetics)
✓ CNS disturbances & hypotension;
death from seizure and central AFFECT THE ANS, PARASYMPATHETIC (ACh),
respiratory depression SYMPATHETIC (NE/E), ENTERIC NS
✓ Triad: hypotension, seizure,
respiratory depression Organophosphate + Carbamates – insecticides
• Treatment: • Organophosphate
✓ Step 1 → 2 o Malathion, Parathion
• Carbamates
o Edrophonium, Physostigmine
• MOT: Inhibit acetyl cholinesterase

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

o Irreversibly (OP) SPECIFIC TOXICANTS

o Reversibly (Carbamates)
o Muscarinic – increase cholinergic INDUSTRIAL + HOUSEHOLD TOXICANTS
activity (DUMBBELS)
o Nicotinic – muscle weakness + SOLVENTS
fasciculations, adrenal medulla =
↑ epinephrine activity, • Examples: OH, glycol, aldehydes,
tachycardia, cramping, HTN hydrocarbons
• Treatment: • ↑ lipophilicity = ↑ chances of CNS
✓ Atropine – anticholinergic; disturbances
counteracts effects of OP • Aldehydes – generally irritating
poisoning • Amides – sensitizers → allergic rxn
✓ Pralidoxime • Halogenated HC – cytotoxic, mutagenicity
▪ Early poisoning (24–36h) • Alcohol – CNS depression
▪ Reverse bond between
1. Ethylene Glycol – anti-freeze preparation
AChE and OP by forming
an oxime phosphate
bond to release AChE
▪ Done before aging into a
covalent bond

AFFECTS VASCULATURE AND HEART

• HTN / Cardiac arrhythmia (Ex. NTG)

• ↑ cGMP → relax smooth muscle →
vasodilation

AFFECTS LUNGS EITHER SYSTEMICALLY OR

LOCALLY

• Paraquat – systemically
• Aspiration – locally
• Clinical Presentation:
LOCAL DAMAGE o 1st Stage – transient excitation →
CNS depression → coma → EtOH
Phenol (Carbolic Acid)
intoxication
• Component of industrial paint removers o 2nd Stage – cardiopulmonary sx,
• Once widely used as an antiseptic (Joseph tachypnea, tachycardia,
Lister) metabolic acidosis
• MOT: Denatures protein o 3rd Stage – renal stone formation
• Presentation: Burning sensation, tingling, • Treatment:
numbness, leaves a burn mark ✓ EtOH – competes with OH
• Treatment: Castor oil / PEG / Mineral Oil dehydrogenase
(Dilute) ✓ Thiamine / Pyridoxine –
facilitates conversion to α-
DELAYED EFFECTS ON LIVER AND KIDNEY hydroxy-β-ketoadipate
✓ Leucovorin – facilitates
Example: Acetaminophen, heavy metals
conversion of formate → CO2
✓ Fomepizole (4-methylpyrazole) –
OH dehydrogenase inhibitor

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

2. Methanol (Wood Alcohol) – colorless liquid • MOT: Aspiration associated with

volatile at room temp increasing volatility but decreasing
viscosity = ↑ irritation to the lungs
METHANOL (Non-toxic) → metabolites (formic acid); toxic • Clinical Presentation:
METHANOL –[o]-> Formaldehyde –[o]-> Formic Acid
✓ Burning sensation
✓ Choking
• Formic Acid – inhibits cytochrome oxidase ✓ Coughing
in optic nerve blindness ✓ Gagging
• Clinical Presentation: ✓ Atelectasis, bronchopneumonia
o Metabolic Acidosis ✓ CNS manifestation
✓ Hyperventilation – • Treatment:
compensation; pale + ✓ Respiratory O2 support
clammy skin ✓ Selective β2 agonist –
✓ Confusion / lethargy – bronchospasm
decrease intracerebral ✓ Mineral oil – ↑ viscosity ↓
pH aspiration
✓ Hypotension – H+
(negative inotrope); ACIDS AND ALKALIS
myocardial depression
MOT:
✓ Arrhythmia – H+ → K+
shifts outside cells ✓ ACIDS – coagulation necrosis – eschar
o Blindness (protective) → deeper layer (protects)
✓ Treatment: EtOH – ✓ BASES – liquefactive necrosis → deeper
competes with OH penetration
dehydrogenase
Treatment:
3. Formaldehyde – colorless liquid with pungent
odor; embalming liquid; snowstorm ✓ Supportive
✓ Surgery – perforation
Clinical Effects: ✓ Avoid neutralization and dilution
✓ Local Effects – mucosal irritation, oral, HEAVY METALS
oropharyngeal, conjunctiva
✓ Metabolic acidosis Common MOT: Binds sulfhydryl groups of enzymes
causing inactivation; treated with chelators
Treatment: Ammonium salts
FOOD ADDITIVES
4. Hydrocarbons and Petroleum Distillates
1. Tartrazine (FD & C 5)
• Hydrocarbons – organic compounds of H
and C • MOT: Anaphylaxis vs Anaphylactoid (not
• Distillates – mixture of aromatic and IgE mediated)
aliphatic HC • Presentation:
✓ Hives
Physical Properties: ✓ Difficulty of breathing
High volatility,
✓ Shock
Simple gases such as methane and
minimal • Treatment: Epinephrine, Antihistamines
butane
viscosity
Intermediate 2. Monosodium Glutamate
volatility, low Gasoline and turpentine
viscosity • MOT: Anaphylaxis vs Anaphylactoid (not
Low volatility,
low viscosity
Petroleum spirits, kerosene IgE mediated)
Minimal • Presentation: Chinese Restaurant
volatility, high Lubricating oil, mineral oil Syndrome
viscosity

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

✓ Difficulty of breathing CALCIUM EDTA (Ca EDTA)

✓ Facial flushing
✓ Tachycardia • Binds both divalent and trivalent metals
• Treatment: Epinephrine, Antihistamines • ROA: IV, IM
• Forms H2O soluble complex → kidneys
CHELATOR PHARMACOLOGY • Used for Cd, Co, Cu, Zn, Pb poisoning
• Initial antidote of choice for Pb poisoning
Substances that have a lone pair of electrons (-NH, (Ca EDTA + BAL)
-SH, -OH)
HEAVY METALS
DEFEROXAMINE (Desferal®)
• COMMON MOT: Binds to -SH groups of
• DOC for Fe poisoning
enzymes → inactivation
• ROA: IV, IM, SC
• Treated with the use of chelators /
• Complexes with ferric iron → hexadentate
chelating agents
complex ferrioaxime → urine
• Forms water-soluble complexes with
• Does not bind with Hgb, cytochrome
heavy metals → easily excreted
DIMERCAPROL (BAL)
ARSENIC
• Arsenic gas
• Lewisite metal; Salvarsan, Arsphenamine,
• First commercially available chelator; As,
Compound 606, Magic Bullet
Au, Hg
• Clinical Presentation:
• ROA: IM (Peanut oil)
✓ ACUTE
• Adjunct with severe Pb poisoning (Ca
▪ Garlic odor breath
EDTA)
▪ Diarrhea, dehydration
• Forms stable dimercaptide (dimercaprol
▪ CNS: Delirium, seizure,
[2:1] metal)
coma
• Most toxic among all chelators ✓ CHRONIC: Aldrich Mee’s Line
• Median lethal dose is 1 mmcl/kg ▪ White lines on nails
• Indication: Acute poisoning ONLY ▪ Milky + rosy complexion
• Side Effects: ▪ Abnormal weight gain
o ↑ systolic + diastolic BP by 50 ▪ Keratosis
mmHg ▪ Hair loss
o Pain in injection site • Treatment:
• Contraindication: ✓ BAL
✓ Chronic poisoning – may cause ✓ BAL + Penicillamine (Severe)
redistribution of As from the
tissues to the brain LEAD
✓ Cd, Se, Tc, Fe, Organomercurials
• Leaded gasoline, paint, newspapers,
– increases tissue uptake
earthenware, automobile exhaust
DIMERCAPTOSUCCINIC ACID / SUCCIMER / DMSA • Kinetics:
– water-soluble form of BAL; orally taken; used in ✓ T½ (Bones) – 32 years
chronic poisoning ✓ T½ (Kidneys) – 7 years
• MOT: Interferes with heme synthesis →
D-PENICILLAMINE (Cuprimine®) cytochrome production → anemia with
• Oral chelator, monothiol basophilic stippling and Burton’s Line
• DOC for Cu toxicity (Wilson’s Dx) Heme Synthesis:
• ROA: PO
• Bind Fe, Hg, Pb, Zn, As (1) Prevents incorporation of Fe into
• CI: Penicillin allergy protoporphyrin IX

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

(2) Inhibits ferrochelatase and ALA ✓ Pink palm and soles

dehydratase ✓ Photophobia
✓ Triad: Madhatter’s Disease
Basophilic Stippling – MOT: Inhibition of 3'5-
▪ Erethism – neuro
pyrimidine nucleotidase
psychiatric disorder
• Clinical Presentation: ▪ Gingivostomatitis
✓ Peripheral neuropathy – wrist / ▪ Tremor
foot drop • Treatment:
✓ Anemia o BAL – inorganic acute
✓ Encephalopathy – ataxia, o Penicillamine – low level Hg
delirium, coma, ↓ IQ o Na Formaldehyde sulfoxinate –
✓ Renal toxicity leading to saturnine most useful antidote
gout
IRON
✓ GIT – Burton’s Line
• Treatment: • Caused by ingestion of Fe tablets among
✓ CaNa2 EDTA + BAL – initial mgt: children
NMT 5 days • Clinical Presentation: GI hemorrhage
✓ Succimer • Treatment: Deferoxamine
✓ DMSA
✓ DMPs COPPER

CADMIUM • Probably binds to hepatic enzymes → free

radicals → hepatic injury and renal tubular
Causes Itai-itai Dx injuries; causes Wilson’s disease (Kaiser-
Fleischer ring on eye)
• MOT: Displaces Ca2+ in bones
• Clinical Presentation:
• Clinical Presentation:
✓ Acute kidney / liver injury –
✓ Osteomalacia, fracture, renal
kidney/liver failure
abnormalities – Fanconi-like
✓ Kaiser-Fleischer rings – copper
syndromes
deposits of limbs of cornea
✓ Fanconi Syndrome
• Treatment: D-penicillamine – water-
▪ Proteinuria
soluble analog of penicillin
▪ Aminoaciduria
▪ Glucosuria
INSECTICIDES
▪ ↓ PO4 reabsorption
✓ Gait disturbances
Includes organophosphates + carbamates
• Treatment: EDTA
CHLORINATED HYDROCARBONS
MERCURY
• Lidocaine, chlordane, DDT, neurotoxin
• Aka Quicksilver
• MOT: After Na+/K+ flux (myocardial
• Causes Minamata Disease
irritation) → CNS hyperexcitability
• MOT: Inhibition of MAO
• Clinical Presentations:
• Types:
o CNS Excitations – tremors, HA,
o Elemental Hg – thermometers,
agitation, seizures,
amalgam
disorientation, coma
o Inorganic Hg – HgCl2 (corrosive
o Respiratory depression
sublimate); Hg2Cl2 (calomel)
o Nausea and vomiting
o Organic Hg – thimerosal
(Merthiolate); methyl mercury PYRETHOIDS
• Clinical Presentation: Arcodynia / Pink
Disease • More commonly used in insecticides
• 1000x more toxic to insects than man

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

• MOT: ↑ Na conductance; ↓ Cl MEDICAL TOXICOLOGY

conductance
• Clinical Presentations: ANALGESICS
✓ Dizziness
✓ Headache 1. Aspirin (Lethal Dose: > 200 mg/kg)
✓ Fatigue
• Reye’s Syndrome – fatty liver + hepatic
✓ Seizure / coma
encephalopathy due to ASA in children
after viral infection
RODENTICIDES
• Mechanism of Toxicity:
(1) Direct effect on CNS
COUMARIN DERIVATIVES
o Respiratory alkalosis +
• MOT: Inhibits vitamin K dependent bicarbonaturia
clotting factors o Severe: CNS respiratory center →
• Treatment: Vitamin K (Phytonadione) respiratory acidosis
(2) Uncoupling of oxidative
PHOSPHORUS phosphorylation → hyperthermia
• Yellow – waxy, fat-soluble, highly (3) Inhibition of aminotransferase in Kreb’s
poisonous cycle → metabolic acidosis
• Red – granular, non-absorbed, non- (4) Salicylic acids → metabolic acidosis
poisonous • Clinical Presentation:
• Clinical Presentations: ✓ Mild (Salicylism)
✓ Luminous vomitus or stool with ▪ Tinnitus
garlic odor ▪ Hyperventilation
✓ Hypocalcemia ▪ Headache
✓ Severe
✓ Cardiac arrhythmia
✓ Coma ▪ Hallucinations
✓ Cardiac arrest ▪ Acid-base balance
disturbances
• Treatment:
▪ fever
o CuSO4
✓ Fatal – respiratory depression
o Lavage
o BZD – for seizure • Treatment:
o Activated charcoal
HERBICIDES o Forced alkaline diuresis
o Gastric lavage
BIPYRIDYL HERBICIDES o Emesis
o Ice blanket (hyperthermia)
• MOT: Inhibition of superoxide mutase o NaHCO3 solution (acidosis)
• Paraquat
TOXIC DOSE EFFECTS
✓ Pulmonary fibrosis
Salicylism
✓ Hemorrhage 50 – 80 mg/kg
Hyperventilation
✓ Edema
Metabolic acidosis
• Diquat 80 – 110 mg/kg
Hyperthermia
✓ Burning pain in mouth, throat, Vascular collapse
chest, upper abdomen 110 – 160 mg/kg
Hypoprothrombinemia
✓ Pulmonary edema Renal and respiratory
✓ Pancreatitis > 160 mg/kg failure that may lead
✓ Renal damage to death
✓ CNS effects

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

2. Acetaminophen (Paracetamol) DRUGS OF ABUSE

OPIOIDS AND OPIATES

• MOT: Hepatic injury

• Clinical Presentation:
o Non-specific: N&V, abd pain
o Jaundice
• Treatment: N-acetylcysteine (Fluimucil®) –
replenish GSH stores • MOT: Stimulation of opioid receptors
• Clinical Presentation:
ISONIAZID
o Pinpoint pupils
• Isoniccotinylhydrazide (INH) o Coma
• MOT: Inhibits pyridoxal phosphokinase o Respiratory depression
• Clinical Presentation: • Treatment: Naloxone – antidote;
✓ Signs of liver failure competitive opioid antagonist
✓ Irritability SEDATIVE HYPNOTICS
✓ seizure
• Isoniazid metabolites – toxic (hepatic) • BZDs / Barbiturates
• Treatment: Pyridoxine / Vit B6 (1:1) • Clinical Presentation:
✓ Drowsiness
DIGOXIN ✓ Ataxia
• From Digitalis lanata / purpurea ✓ Somnolence
• MOT: Inhibits Na+-K+ ATPase ✓ Confusion
• Factors Affecting Toxicity: • Treatment: BZD (Flumazenil)
o Hypercalcemia HALLUCINOGENS
o Hypokalemia
o Chronic antibiotic use 1. Lysergic Acid Diethylamide (LSD)
o Concomitant quinidine
• Ergot derivative
administration
• MOT: Targets 5HT2a receptors →
• Clinical Presentation:
hallucination
o Confusion, hallucination
• Clinical Presentation:
o Xanthopsia (yellow / green color
✓ HTN
blindness)
✓ Tremors
o Fatal arrhythmia (ventricular
✓ Vomiting
tachycardia) – d/t stimulation of
✓ Profound mydriasis
automatic cardiac cells, SA nodes,
AV nodes, bundle of His, and 2. Amphetamine + Related Compounds
ventricular muscle
• Ecstasy – MDMA, Cocaine
• MOT: Stimulates adrenergic receptors →
releases NE
• Clinical Presentation:
✓ Bruxism (teeth grinding)

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CLINICAL TOXICOLOGY
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✓ Hyperthermia (most toxic) ✓ Hyperthermia

✓ HTN ✓ Hypoglycemia
• Treatment: Labetalol, Na nitroprusside • Treatment:
o Vit B1 + Glucose – Wernicke-
3. Phencyclidine
Korsakoff Sx
• Angel dust o Hemodialysis – severe cases
• Ketamine-like → dissociative anesthesia o IV fluid, supportive –
• Clinical Presentation: dehydration
✓ Disorganized thought process ERGOT ALKALOIDS
✓ Nystagmus
✓ HTN • From Claviceps purpurea
• Related Drugs:
4. Marijuana o Ergotamine – acute migraine
• Hashish, hashoids o Ergonovine, methysergide – post
• ΔTHC → delta-9-tetrahydrocannabinoids partum bleeding, abortifacient
(active) • Clinical Presentation:
• Most commonly used illegal drug o Convulsive: Painful seizures &
• MOT: Stimulates cannabinoid receptors spasms
o Gangrenous: Excessive
• Clinical Presentation:
vasoconstriction → poorly
✓ Tachycardia
vascularized distal structures
✓ Rhinitis
(toes, fingers) → dry gangrene
✓ Increase appetite
✓ Impaired short-term memory • Treatment: Vasodilators (Tolazoline, Na
Nitroprusside)
✓ Impaired rxn time
✓ Acute psychosis
FUNGAL / ANIMAL TOXINS
✓ Bizarre behavior
✓ Motor disturbances
AFLATOXIN
ALCOHOL
• From Aspergillus flavus
• MOT: CNS depressant – rostral to caudal • Found in improperly dried peanuts and
progression grains
• GABA-ergic • Clinical Presentation:
• Acid-base disturbances o Adults: ↑ Tolerance –
• Respiratory acidosis = ↓ CNS respiratory asymptomatic
center o Children: Acute hepatic necrosis
• Metabolic alkalosis = ↑ vomitus → liver cirrhosis → liver cancer
• Metabolic lactic acidosis – lactic acid • Treatment: Supportive (IV fluids,
electrolytes)

SAXITOXIN

• From Dinoflagellates
• Causes red tide poisoning, paralytic
shellfish poisoning (PSP)
• MOT: Na+ channel blocker (important for
muscle depolarization → contraction) →
flaccid paralysis
• Complication: respiratory depression →
• Clinical Presentation: death
✓ Metabolic acidosis • Treatment: airway support (intubation)
✓ Coma

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CLINICAL TOXICOLOGY
TRANS BY MLVGA, RPh

AMATOXIN ANTIDOTES
• From Amanita phalloides (destroying
angel) Antidotes are any agent (physical or chemical) that
• MOT: inhibits RNA polymerase II in the counteract the effect of the poison
liver → ↓ protein synthesis → TYPES OF ANTIDOTES
hepatotoxicity
• Treatment: 1. Physiologic Antidotes – agents that have
o Supportive (IV fluids, electrolytes) different physiologic action with that of the poison
o Benzylpenicillin (Penicillin G):
Examples:
competitively inhibits amatoxin in
its liver receptors (theoretical) • Epinephrine – anaphylaxis
• Physostigmine – atropine toxicity
LATROTOXIN
• Diazepam – INH toxicity
• From Latrodectus mactans (black widow)
2. Pharmacological Antidotes – agents that have
• MOT: Causes presynaptic release of ACh
the same action or binding site with that of the
• Clinical Presentation:
poison
o Parasympathomimetic effects:
DUMBELS 3. Chemical Antidotes – alters the chemical nature
o Conjunctivitis of the poison to make the poison more polar hence
o Restlessness increasing its excretion
o Hypertension
• Treatment: Antivenom 4. Mechanical Antidotes – physically removes the
poison out of the systemic circulation
TETRODOTOXIN
ANTIDOTES POISON
N-acetylcysteine Acetaminophen
• From Amphibians, mollusks (snails,
Organophosphates
octopus), pufferfish (Japan) Atropine Carbamates
• MOT: Na+ channel blocker Mushroom poisoning
Fluoride toxicity
• Clinical Presentation: Ca gluconate
Ca channel blockers
o Perioral numbness Deferoxamine Iron toxicity
o Flaccid paralysis Digoxin Immune FAB
Digoxin toxicity
Cardiac glycosides
• Treatment: Airway support (intubation)
Methylxanthines
Esmolol Alkaloids
TOXIN ANIMAL Metaproterenol
Bufotoxin Bullfrogs Methanol
Ethanol
Clupeotoxin Oysters Ethylene glycol
Flumazenil BZD
Gemblid Mackerel
Fomepizole Alcohol toxicity
Venerupin Sardines Glucagon Beta blocker toxicity
Saurine Tuna Glucose Hypoglycemics
Hydroxycobalamin Cyanide poisoning
Naloxone Opioid
Oxygen CO poisoning
AIR POLLUTANTS Physostigmine Atropine
Membrane-depressant
• CO, NO, SO2 + O3 Sodium Bicarbonate cardiotoxic drugs (e.g.
quinidine, TCAs)
• Airway irritation; pulmonary edema Atropine & Pralidoxime Organophosphates
• Chronic – gradual Protamine sulfate Heparin
Normal Saline Silver Nitrate
• Lung damage – chronic cardiopulmonary
disease

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TRANS BY MLVGA, RPh

PHARMACOLOGY Toxicology – branch that deals with the undesirable

effects of chemical on living systems, from
Study of substances that interact with living individual cells to complex ecosystems
systems through chemical processes, especially by
binding to regulatory molecules and activating or CLASSIFICATION OF DRUGS
inhibiting normal processes BASED ON GENERAL USE

DEFINITION OF TERMS FUNCTIONAL MODIFIERS

Medical Pharmacology – area of pharmacology Drugs that alter certain physiologic functions and
concerned with the use of chemicals in the biochemical activities of cells in the body
prevention, diagnosis, and treatment of disease,
especially in humans • Anxiety (HR; palpitations) → β-blockers to
modify HR
Drugs
• Pain Perception → NSAIDs / Analgesics;
• Article recognized in the official USP, local and general anesthetics
official Homeopathic Pharmacopeia of the • Fever (Mediated IL-1 = lowering fever
US or the official NF, or any supplements threshold) → Antipyretics
to any of them • Neovascularization → Vascular
• Articles for use in the diagnosis, cure, endothelial growth factor inhibitors (VEGF
mitigation, treatment, or prevention of inh); ex. Bevacizumab (Avastin)
disease in man or other animals
• Articles, other than food, intended to NOTES:
affect the structure or any function of the Neovascularization – process of producing new
body of man or other animals blood vessels; hallmark of diabetic retinopathy
• Substances that act on biological systems
at the chemical/molecular level and other High sugar → block capillaries in the eye → low
their functions blood flow → retina becomes hypoxic
Pharmacodynamics
REPLENISHERS
• What the drug does to the body
• Branch of pharmacology that focuses on Replaces or replenishes endogenous substances
the study of biochemical and physiological that are lacking / deficient / absent
effects of drugs and the mechanisms by • DM Type 1 → Exogenous insulin
which they produce such effects • Diarrhea → ORS
• Deals with interaction of drugs with • Pernicious Anemia → Exogenous Vit B12
receptor → molecular consequences →
biological effect NOTES:
• Study of biochemical and physiologic
T1DM – absolute insulin deficiency; B-cells of
effects of drugs in a biological system
pancreas do not secrete insulin
Pharmacokinetics T2DM – relative insulin deficiency; normal
secretion
• What the body does to the drug Pernicious Anemia – autoimmune disease
• Quantitative measurement of drug
when immune system produces antibodies that
absorption, distribution, elimination, and
target parietal cells of the stomach that leads in
includes the rate processes for drug
inhibiting / decreasing HCl and intrinsic factor of
movement into the body, within the body,
and out of the body castle which are important in Vit B12
• Examines the moment of drug over time absorption
through the body
B12 & B9 helps in maturation of RBCs = high
Pharmacotherapeutics – rational use of drugs in immature RBCs characterized by low function
the management of diseases of D2 = megaloblastic anemia (def vit b9 & b12)

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PHARMACOLOGY
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NOTES:
Dobutamine – inotropic agent
Megaloblastic Anemia
B12 Deficiency
(Cyanocobalamin) Dipyridamole – PDE inhibitor
Myocardial Ischemia – low O2; cells are still
(+) neurologic symptoms = viable
impaired position and vibration Myocardial Infarction – no O2 supply; cells are
sensation dead (necrosis)
B9 Deficiency (Folic Acid) Myasthenia Gravis – autoimmune disorder that
(-) inactivates or targets ACh receptors
• Initial: Droopy eyelids during the
afternoon
• Terminal: Paralysis of diaphragm
NOTES: • Tensilon Test – used to help diagnose
Other causes of Vit B12 Deficiency: or differentiate the muscle weakness
✓ Diphyllobothrium latum (Fish caused by myasthenia gravis from
Tapeworm) – competes with the other causes / underlying disease
absorption of Vit B12
✓ Chronic use of PPIs & H2 blockers – CHEMOTHERAPEUTIC AGENTS
always give with PO Vit B12; low acid
Agents used to kill / inhibit growth cells considered
in the stomach; extension effect
as foreign to the body
✓ Use of metformin – S/E: weight loss,
lactic acidosis • Anti-infectives
✓ Diet: Low intake of Vit B12 • Antimicrobials
(gastrectomy, iliectomy) • Antineoplastics
• Anti-cancer
DIAGNOSTIC AGENTS
PHARMACODYNAMICS
Drugs that are used to confirm diagnosis of certain
diseases TARGET PROTEIN MEDIATED

• Dobutamine, Dipyridamole, Adenosine – • Biologic site of action, “action site” or

MI through pharmacologic stress test “active site”
• Radiopharmaceuticals • Targets a physiologic action
o I-131 Thyroid Scan – thyroid gland • Ex: Structural Proteins, Regulatory
o Sestamibi MI perfusion scan – Proteins
heart
STRUCTURAL PROTEINS
• Tc 99m Stratum (Thallium 201) – for
myocardial ischemia and myocardial • Proteins that make up the cytoskeleton or
infarction cell framework
• Barium Meal (BaSO4) – to detect GIT • Tubulin – basic unit of the structural
obstruction / abnormalities proteins
• Histamine – diagnosis of bronchial asthma • Microtubules – made of alpha and beta
through pulmonary challenge test units of tubulin
• Dobutamine – ischemia Function:
• Tensilon Test (Edrophonium) – used in the ✓ Keeps organelles in place (in
diagnosis of myasthenia gravis eukaryotic cells)
✓ Chemotaxis – cell movement via
chemical stimulus
✓ Axonal release of NT
✓ Mitosis / cell division
(metaphase)

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DRUGS THAT INHIBIT MICROTUBULES II III IV

Bepridil
1. Griseofulvin
Bretylium
• Antifungal agent for dermatophytosis Propranolol
Ibutilide Diltiazem
(tinea / ringworm) Esmolol
Dofetilide Verapamil
• Management of dermatomycosis Acebutolol
Amiodarone
(infection of skin and appendages) Sotalol
• Arrest fungal mitosis
• Enzyme inducer
• ↑ absorption w/ fatty foods NOTES:
2. Colchicine Class IA – most notorious for inducing Torsades
de Pointes (fatal arrhythmia; ↑ QRT)
• 1st line treatment for acute gout Sotalol – ↑↑↑ risk of TDP
• Inhibits chemotaxis of immune cells that
causes inflammation ✓ Local Anesthetics
• S/E: Diarrhea
ESTER TYPE AMIDE TYPE
3. Antimitotic Drugs (Chemo Drugs) Procaine Lidocaine
• Taxanes: Paclitaxel, Docetaxel, Cabazitaxel Cocaine Bupivacaine
• Vinca Alkaloids: Vincristine, Vinblastine, Short-acting Long-acting
Vinorelbine, Vindesine
o Vincristine – neurotoxic ✓ Anticonvulsants
• Estramustine – estrogen ester used in the • Phenytoin – blocks Na (↑) and K
tx of prostate CA channels
• Epothilone – novel drug in CA • Carbamazepine
chemotherapy with similar action with
taxanes 2. Voltage-gated K Channels – blocked by:
✓ Class III Anti-arrhythmics
4. Benzimidazole • BBIDAS – “bibida bida”
• Thiabendazole, Albendazole, • Bepridil, Bretylium, Ibutilide,
Mebendazole Dofetilide, Amiodarone, Sotalol
• Treatment for roundworm infections ✓ Insulin Secretagogues – high risk of
hypoglycemia
REGULATORY PROTEINS
1ST GEN SFU 2ND GEN SFU GLINIDES
Regulates biochemical or physiologic cell activity or Glyburide
Tolbutamide Repaglinide
function Gliclazide
Chlorpropamide Nateglinide
Glimepiride
CHANNELS
K will stay
• Conduct changes in electrical signals INSULIN Inhibit K
outside of the
SECRETAGOGUES Channels
• Present in all cells cells

1. Voltage-gated Na Channels – blocked by:

Pancreatic β-
✓ Class I Anti-arrhythmics Inside will stay
Generation of
cells stimulated
action
depolarized to release
potential
IA IB IC insulin
Tocainamide Moricizine
Disopyramide
Mexiletine Flecainide 3. Ca Channel Blockers
Quinidine
Lidocaine Propafenone ✓ Dihydropyridines – “–dipines”
Procainamide
Phenytoin Encainide • Nicardipine, Clevidipine,
Prolongs Shortens No effect on Amlodipine, Nimodipine
action action action • Nicardipine – vasoselective
potential potential potential (arteries)
• S/E: Reflex tachycardia

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✓ Non-DHP Class IV Antiarrhythmics

• Heart and arteries
• L type Ca channels
• Verapamil – cardioselective tx for
arrhythmia; selective Ca2+
blocker in the heart
• Diltiazem – heart and blood
vessels (intermediated effect);
balance Ca2+ blocker in the heart
and arteries
• CI: Patients with heart failure
(inefficient force of contraction of
the heart)
CARRIERS
Voltage gated Arteries
Blockade by
Ca2+ channel Relaxation
in arteries
DHP
(Vasodilation) Cell membrane proteins with specific binding sites
that undergo conformational change thus enabling
transport against concentration gradient
S/E: High HR,
Homeostatic
Low BP
Mechanism
reflex Pump – involved in active transport
tachycardia
1. Na-K-ATPase Pump (NKAP)
✓ Ethosuximide – DOC for absence seizure • Found in the cardiac myocytes
(T-type Ca channel) • Responsible for Ca extrusion
• Activation of Na+/Ca2+ Exchange (NCX) is
NOTES: dependent on NKAP activation
Cells at rest are (-) or polarized, once excited, • Inhibited by cardiac glycosides
cell becomes less negative or (+), it will become o Digoxin
depolarized and repolarizes (-) to each ▪ Digitalis lanata
equilibrium. Hyperpolarization of cells renders ▪ Inotropic – heart
the cell more negative (-) or less excitable. contractility
o Digitoxin
Dominant anions / cations: ▪ Digitalis purpurea
• PISO (K, Na)
2. H/K-ATPase Pump / Proton Pump
• MICO (Mg, Ca)
• PIChlO (PO4, Cl) • Seen in parietal cells at the stomach
• Mediates release of gastric acid (acid
Importance of Ions: production)
• Na, Cl – for tonicity • ACh, gastrin, histamine in parietal cells of
the stomach → triggers release of HCl
• Ca – structural component in bones,
• Prostaglandin → decrease acid production
muscle contraction, release of
• Inhibited by:
neurotransmitters from the pre-
✓ Proton Pump Inhibitors (PPIs)
synapse
o -prazoles
• Mg or MgSO4 (Epsom Salt) o Omeprazole (most
o Natural CCB, used for effective in
eclampsia hyperacidity),
o IV/IM: Anticonvulsant Pantoprazole
o PO: Cathartic o Except: Aripiprazole –
o Competes with Ca at binding atypical antipsychotic
sites ✓ H2 Receptor Antagonists
o -tidine
o Cimetidine, Ranitidine,
Famotidine

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ENZYMES 3. Angiotensin-Converting Enzyme (ACE)

• Synonyms: Kinase II or Dipeptidyl
Enzymes catalyze the reaction decarboxypeptidase
1. Eicosanoid Pathway • Inhibited by ACEi (-prils) for HTN; S/E:
• Phospholipase A2 (PLA2) – Inhibitor: Cough
Corticosteroids (Ex. Prednisone) 4. Monoamine Oxidase (MAO A, MAO B)
• Cyclooxygenase (COX) – Inhibitor: NSAIDs,
Aspirin, -coxibs • MAO A – metabolizes NE, Epi, 5-HT
• 5-lipoxygenase (5-LOX) – Inhibitor: • MAO B – metabolizes Dopa
Zileuton (Anti-asthma) • Clinical Depression: ↓ 5-HT, NE
• Phospholipids – precursor for Arachidonic • Parkinsonism: ↓ Dopa
Acid, in turn giving prostaglandin and
leukotriene (eicosanoids) with the action MAOIs
of COX and LOX respectively Selective Selective
Non-selective
o Prostaglandin – cytoprotection, MAO A MAO B
pain, and inflammation; derived Phenelzine
Selegiline
from semen Moclobemide Isocarboxazid
Rosagiline
o Leukotrienes – Tranylcypromine
bronchoconstriction
5. Acetylcholinesterase (AChE) – inhibitor:
Edrophonium

6. Phosphodiesterase (PDE)

• Responsible for conversion of CAMP →

inactive metabolite / ATP
• PDE-5 Inhibitors
o Sildenafil, Tadalafil
o Erectile dysfunction → secondary
to vasodilation
• PDE-3 Inhibitors
o Milrinone, Amrinone
2. Cyclooxygenase (COX) o For heart failure
• COX-1 – constitutive enzyme; gastric 7. Catechol-o-methyltransferase (COMT) –
protection inhibited by COMTIs (-capones); Tolcapone,
• COX-2 – inducible enzyme; responsible for Entacapone
inflammation
o New Study: Constitutive enzyme RECEPTORS
responsible for inhibition of
platelet aggregation Structural or functional macromolecular
o Rofecoxib – withdrawn in the component of a cell wall with a specific
market due to MI stereochemical configuration which a ligand
• Inhibited by NSAIDs, Aspirin, -coxibs interacts, usually in a lock and key fashion
• NSAIDs TYPE I (IONOTROPIC)
o Non-selective COX inhibitor
o S/E: GI bleeding secondary to • Location: Cell membrane
COX-1 inhibitions • Onset: Milliseconds (ms)
o -profens • Mechanism: Binding of ligand to receptors
• Aspirin – irreversible COX inhibitor • Associated with ion channels (ligand gated
• -coxibs channels)
o Selective COX-2 inhibitor
o S/E: Thrombolic events – ↑ risk 1. GABA Receptor Complex
of MI and stroke • Associated with Cl- channels
o Rofecoxib, Vioxx • Inhibitory NT

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• Facilitates influx of Cl- ions = G-RECEPTORS

hyperpolarization Gs Gi Gq
• Stimulants: BZP, Barbiturates β1, β2 α2 α1
✓ BZP – increases frequenZy of Cl- H2, V2 M2 M1
channel opening Dopa 1 Dopa 2 H1, V1
✓ Barbiturates – prolongs duration QISS & QIQ till you’re SIQ of SQS
of Cl- channel opening “Kiss and kick till you’re sick of sex”
Q α1 Q M1 S D1 S H2
I α2 I M2 I D2 Q V1
S β1 Q M3 Q HI S V2
S β2
OTHERS
H3
H4
I
5-HT1D
(-triptans) → for migraine
Q 5-HT2 – ergot alkaloids
Ligand
5-HT3 – where (-setrons) bind to
gated ion
Anti-emetics
channel
S 5-HT4
NOTES:
Barbiturates and benzodiazepines enhance
Secondary Messengers
GABA-A receptor binding with GABA. Hence,
opening of Cl channels, influx of Cl, resulting to • cAMP, cGMP
hyperpolarization of the cell. (CNS Depression) o Cyclic adenosine monophosphate
o Cyclic guanosine monophosphate
2. Nicotinic Receptors o Utilize same signaling cascades
o Intestinal mucosa and BV
• Associated with Na+ channels (ACh • IP3 – inosine triphosphate
receptors) • DAG – diacylglycerol
• Nn (neural / neuronal)
• Nm (neuromuscular) – skeletal muscle Types of G-proteins
• Stimulants: Nicotine, Lobeline, Varenicline
• Gs
• Inhibitors: NMBs (Nm), ganglionic
o Stimulates adenylyl cyclase (AC)
blockers (Nn)
→ increase in cAMP → stimulates
adrenergic responses
NOTES:
o Ex: Beta receptors
Glycine Blocker: Strychnine o Stimulants: Epi, NE
Serotonin Blocker: (-setron); Ex: Ondansetron – o Inhibitors: Beta-blockers (-olols)
tx for CA-induced nausea
NOTES:
TYPE II (METABOTROPIC) β1 Receptors ( )
• Location: Cell membrane • (+) ino, dromo, chromo
• Onset: Seconds (secs) • Stimulants: Dobutamine, Dopamine
• Mechanism: Signal transduction and • Inhibitors: β-blockers
involves the generation of secondary β2 Receptors ( )
messengers (cAMP, IP3, DAG) • Bronchodilation
• G-protein linked, coupled receptors • Stimulants:
• 7-transmembrane spanning receptors ✓ SABA: Albuterol, Salbutamol,
Terbutaline
✓ LABA: Salmeterol, Formoterol

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• Gi SYMPATHETIC: PARASYMPATHETIC:
o Inhibits adenylyl cyclase → ADRENERGIC CHOLINERGIC
decrease cAMP NT: Catecholamines
NT: Acetylcholine
o Pre-synaptic α2 receptors (Norepinephrine)
▪ Stimulation leads to Receptors: α, β Receptors: N, M
opposite adrenergic
effects
▪ Stimulants: TYPE III (ENZYME LINKED)
✓ Clonidine
• Location: Cell membrane
✓ Methyldopa
• Onset: Minutes (mins)
✓ Guanfacine
• Mechanism: Direct binding of ligand to
✓ Guanabenz
particular receptors)
▪ Inhibitor: Yohimbine
o Pre-synaptic 5-HTIA receptors Examples:
▪ Stimulant: Buspirone
o M2 receptors 1. Insulin Receptors
• Gq
• Tyrosine kinase linked
o Stimulates phospholipase C (PLC)
• Increase phosphorylation → decrease
o α1 receptors
blood glucose; upon binding to receptor →
▪ Blood vessels (smooth
activation of glucokinase (glycolysis)
muscle)
▪ Agonist: 2. ANP Receptor – atrial natriuretic peptide
Vasoconstriction
✓ Epi 3. GLUT (Glucose Transporter)
✓ NE
• GLUT 1
✓ Phenylephrine
✓ Oxymetazoline • GLUT 2 – liver, pancreatic β-cells
▪ Antagonist: • GLUT 3 – brain / CNS
Vasodilation • GLUT 4 – skeletal muscles, cardiac tissues,
✓ Prazosin adipose tissue / adipocytes
✓ Tamsulosin TYPE IV (NUCLEAR)
✓ Terazosin
o M1, M3 receptors • Location: Cytoplasm / nucleus
o Post-synaptic α2 receptors • Onset: Hours (hrs)
• Mechanism: Modulates gene transcription
NOTES: • Synonyms: Gene-transcription linked,
Phospholipase C stimulates the formation of IP3 intracellular receptors
and DAG from phosphatidylinositol 4,5- • Ex: Sex hormones, thyroid hormones, Vit
biphosphate (PIP2) D, steroidal hormones

NON-TARGET PROTEIN MEDIATED

PIP2

Phospholipase C 1. Colligative Mechanism / Mass Effect

IP3 & DAG • Colligative Properties – dependent on the

number of solute particles in a solution
(Ex. VP lowering, BP elevation, FP
Increase IP3 and
DAG
depression, osmotic pressure)
• Mannitol
o Osmotic diuretic
Increase
intracellular Ca+2 o Osmosis – area of high water
conc to low water conc (low salt
to high salt)
Contraction o MOA (IV): Inhibits water
reabsorption in the water
permeable regions in the renal

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tubules (PCT, descending LoH) by o Inverse Agonist – Affinity + IA (↓)

increasing osmotic pressure • Basal / Constitutive Activity – ability of a
o MOA (PO): Osmotic laxative receptor to generate a response or effect
o Used in the treatment of cerebral with or without a bound ligand
edema
• Lactulose PROPERTIES OF RECEPTORS

2. Chemical Antagonism / Direct Chemical • Saturability – a finite number of receptors

Interaction per cell, or per weight of tissue or protein
is present as revealed by a saturable
Acid-Base Neutralization (Acid + Base) binding curve
• Specificity
• Local Antacids o Lock and key fashion of drug-
o Neutralization reaction receptor interaction
o Ex: Mg(OH)2, Al(OH)3, CaCO3 o Drugs should be structurally
• Systemic Antacids complementary to the receptor
o NaHCO3 – metabolic acidosis • Reversibility
o NH4Cl – metabolic alkalosis o The drug should bind to receptors
• Protamine Sulfate – for heparin toxicity then dissociate in its non-
Chelation / Complexation metabolized form
(Heavy Metal + Antidote) o This distinguishes receptor-drug
interaction from enzyme-
• Dimercaprol (BAL) – IM for As, Hg, Pb substrate interactions
(peanut oil as vehicle)
• Penicillamine (Cuprimine®) – for Wilson’s
Disease (Cu poisoning)
• Deferoxamine (Desferal®) – for Fe3+ or
hemochromatosis
• EDTA – emergency tx for hypercalcemia,
control of ventricular arrhythmia due to
digitalis

3. Counterfeit / Incorporation Mechanism

• Affects gene transcription

• Ex: Antimetabolites
• Full, Partial Agonist – enhance the basal
o Purine and pyrimidine base
activity of receptors; (+) IA
analogues (also used as
• Antagonist – receptor will maintain its
anticancer drugs)
constitutive activity; zero IA
▪ Flucytosine
▪ 5-FU – cornerstone in • Inverse Agonist – reduce the basal activity
colon CA chemotherapy of receptors; (-) IA
o NRTIs AGONIST

DRUG-RECEPTOR INTERACTION • Favor the active form of the receptor

• Binds and causes a response
DEFINITION OF TERMS • Responses resembles the effect of the
endogenous ligands
• Ligand – substance that binds to receptor
• Interact with specific cellular constituents,
• Affinity – ability of a ligand to bind to a
known as receptors, and elicit and
receptor
observable biological response
• Intrinsic Activity – ability of a ligand to
• Have both affinity for the receptor and IA
generate a series of biological events
leading to an effect
o Agonist – Affinity + IA (↑)
o Antagonist – Affinity + no IA

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TYPES OF AGONISTS ANTAGONISTS

1. Full Agonist • Favors an equilibrium of the active and

inactive form of receptor
• Produces all the effects of the receptor • Lack intrinsic activity and produce effects
• 100% effect by competitively and non-competitively
• Ex: Morphine – mu receptor inhibiting the action of the endogenous
2. Partial Agonist molecules of the receptors
• A drug that binds without activating its
• Have no intrinsic activity but has affinity receptor and thereby prevents activation
• Produces some of the effects of the by an agonist
receptor
TYPES OF ANTAGONISTS BASED ON MECHANISM
• Has a mixed agonist and antagonist action
• IA > 0 but < 1 1. Functional / Physiologic Antagonism
• Examples:
✓ Nalbuphine • Produces opposite effects by binding to
o Mixed (Anta, Ago) different receptors
o Acts as a full antagonist • 2 ligands acting on different receptors,
in the presence of a full producing opposite effects
agonist (Morphine) • Ex: Epinephrine in the management of
✓ Tamoxifen anaphylaxis
o Partial agonist of
estrogen with allosteric
site (full agonist is
endogenous estrogen)
o Management of
estrogen receptor in
breast CA

NOTES:
A partial agonist in the presence of a full agonist
will act as an antagonist.
NOTES:
Ex: Morphine + Nalbuphine An allergic reaction would trigger IgE and mast
cell production, which in turn would release
Morphine is a full agonist to mu receptors while your histamine. Binding of histamine to your H1
Nalbuphine is a partial agonist for the same receptors will cause bronchoconstriction, and
receptor. When taken together, the result is vasodilation of blood vessels → anaphylactic
reduction of analgesia. shock (↓ BP)

Allosteric Site – site other than the agonist Epinephrine would bind to the following
binding site receptors to produce these corresponding
Allosteric Agonism – increases the binding of effects:
an agonist, while an allosteric antagonist • α1 – vasoconstriction
inhibits its binding • β2 – bronchodilation

3. Inverse Agonist 2. Pharmacologic / Receptor Antagonism

• Favors the inactive form of the receptor • Produces opposite effects by binding to
• Reduces basal activity of receptors same or similar receptors
• Ligand which produces an effect opposite • Examples:
to that of an agonist occupying the same o Histamine in allergic reactions –
receptor using antihistamines like
• Ex: All antihistamines Diphenhydramine (first

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generation antihistamine) will THEORIES

inhibit binding of your histamine
o Epinephrine and β-blockers – Epi Lock and Key Hypothesis – states that the drug
is a beta agonist molecules must fit into a receptor like a key fit into
▪ NE/Epi – tachycardia a lock
▪ BB – bradycardia Induced-fit Theory
▪ Epinephrine – DOC for
anaphylaxis • Postulated a complementary relationship
between the drug molecules and its active
3. Chemical Antagonism site
• Protamine Sulfate • Provides for mutual conformational
o Used for the management of changes between the drug and its receptor
heparin (acidic) toxicity Hypothesis of Clark
o MOA: Neutralization reaction
• Percentage of receptors occupied
TYPES OF ANTAGONISTS BASED ON INTERACTION
• Maximum effectiveness / effect of a drug
1. Reversible Antagonism can be obtained if all the receptors are
occupied
• Temporary – Duration of Interaction
(DOI): <24 hours Hypothesis of Paton
• Non-covalent bonds – weak forces of • Rate Theory
attraction like VDW, H-bond
• Effectiveness does not depend on binding
2. Irreversible Antagonism to a receptor, but upon obtaining the
proper stimulus
• As long as the receptor is viable, effects are
still present Hypothesis of Ariens and Stephenson
• Permanent – DOI: days to weeks • Occupation Theory
• Covalent bond • Pharmacologic effects of drug remain as
• Ex: Aspirin long as receptors are occupied
o Antiplatelet
o MOA: Irreversibly acetylates the DOSE RESPONSE GRAPHS
COX in platelet

TYPES OF ANTAGONISTS BASED ON GRADED DOSE RESPONSE CURVE

SURMOUNTABILITY • Shows the relationship between the
1. Competitive / Surmountable degree of response with dose
• Plot: Degree of Response vs Dose / Log
Completely overcomes the effect of the antagonist Dose
by increasing the dose of the agonist; quantity • Log dose (sigmoidal), dose (hyperbolic)
based
PARAMETERS

EFFICACY

• Capacity to produce an effect

• Represents the ability of a drug to
accomplish a specified effect
• Ceiling effect – maximum achievable
2. Non-competitive / Non-surmountable response
• Ceiling dose – smallest dose that produces
the maximum effect (maximum available
dose; limit dose)

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• Competitive Antagonist – shifts to the

right, with the same height for efficacy
• Non-competitive Antagonist – increases
amount of agonist and non-competitive
antagonist, but never reaching max
efficacy

QUANTAL DOSE RESPONSE CURVE

• Shows how a population responds

(quantal event) to a given dose
• Ex: Prevention of convulsion, arrhythmia,
or death
NOTES: • Plot: Cumulative number of px vs Log Dose
ED50 is inversely proportional to potency
• ↑ ED50 ↓ potency PARAMETERS
• ↓ ED50 ↑ potency • Median Effective Dose (ED50) – Dose that
produces the beneficial response in 50% of
POTENCY the study population
• Median Toxic Dose (TD50)
• Measure of drug activity expressed in o Dose that produces the toxic
terms of the amount required to produce response in 50% of the study
an effect of given intensity population
• Reflects the amount of drug (the dose) o NOTE: LD50 is used in death
required to cause an effect responses in pre-clinical trials (ex.
SLOPE in animals)
• Therapeutic Index (TITE) – relative
measure of safety; wider TI, safer drug
𝑻𝑫𝟓𝟎
𝑻𝑰 =
𝑬𝑫𝟓𝟎
• Margin of Safety

• Degree of change in response with a

change in the dose
• Steep Slope
o Drastic response
o Start low, go slow
o Small increases in dose of the
drug lead to large changes in
response REGULATION OF RECEPTORS
• Slow Rising Slope
Down Regulation
o Dose can be adjusted
o Small increases in dose of the • Aka Desensitization, Refractoriness
drug lead to small increases in • Development of tolerance to drugs
response • May be homologous (receptor itself) or
APPLICATIONS heterologous (downstream proteins that
participate in the signaling)
• Efficacy vs Potency
Up Regulation / Supersensitivity – antagonist
• Full, Partial, and Inverse Agonists
bound for a long time = counters the effects of
antagonist

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PHARMACOKINETICS o Surface area and rate

o Diffusion coefficient and rate –
• What the body does to the drug property of the drug in relation to
• The actions of the body on the drugs, the property of the membrane
including absorption, distribution, o Membrane thickness and rate
metabolism, and elimination (indirect)
• Study of the processes a drug undergoes • Diffusion coefficient is determined by:
as it reaches and leaves the site of action ✓ Indirect: particle size & diffusion
• Processes Involved: (TLADMER) partition coefficient
✓ Transportation ✓ Direct: lipophilicity & diffusion
✓ Liberation partition coefficient
✓ Absorption o Degree of Dissociation /
✓ Distribution Ionization
✓ Metabolism
LUNA HIPE
✓ Excretion (Elimination)
Lipophilic Hydrophilic
✓ Response
Unionized Ionized
• Biopharmaceutics
Non-polar Polar
o Bio – bioavailability
Absorbed Excreted
o Pharmaceutics – dosage forms,
physicochemical properties of a
o Partition Coefficient –
drug (pKa, pH, etc.), routes of
increased K, increased
administration (PO, IV, IM, etc.)
diffusion
𝐶𝑜𝑖𝑙
TRANSPORTATION 𝐾=
𝐶𝑤𝑎𝑡𝑒𝑟
• Movement through the cell membrane
NOTES:
• Basic Requirement: Drug must be in
aqueous solution EXCEPT in pinocytosis • kB = base dissociation constant
where drug is in micelle form • kA = acid dissociation constant
• pKa = -logkA (increased pKa favors
PASSIVE DIFFUSION diffusion)
• Dominant, most common chemical
process CARRIER MEDIATED TRANSPORT
• Slowest process – inversely proportional
Selectivity / Stereospecificity
to the membrane thickness
• Important process for small lipophilic • Carriers recognize specific molecular
molecules configurations that will only allow
• No energy requirement transport of molecules that have
• Along concentration gradient (high to low) configuration that fit into the carrier
• Governed by Fick’s Law of Diffusion binding site
𝑃𝐴 (𝐶1 − 𝐶2) • Ex: Levodopa – crosses the BBB because of
𝐽=
𝑡ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠 a L-amino acid transporter (LAAT)
Where:
▪ J = rate of diffusion Subject to Competition
▪ P = permeability (LUNA, high oil
• Digoxin and Quinidine (same transporter
water coefficient)
for excretion, increase plasma level of
▪ A = surface area (increase surface
Digoxin)
area)
▪ C1 – C2 = concentration gradient • Levodopa – given after meals
(increase gradient) Subject to Saturability
▪ Thickness = inversely
proportional to rate of diffusion • Follows saturable kinetics (Michaelis-
• Factors Affecting Passive Diffusion: Menten, non-linear kinetics, capacity
o Concentration gradient and rate limited)

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• Basis is limited number of carriers ION PAIR TRANSPORT

• First Order – elimination is dependent on
drug concentration • Important for movement or transport of
large ions
• Zero Order – drug clearance is on a
constant rate; independent of drug • Enters the cell via passive transport
concentration because there is no charge
• Ex: (+) Tertiary Amine + (-) Mucin → makes
TYPES OF CARRIER-MEDIATED TRANSPORT use of a combination or neutralization
reaction first before passive diffusion
1. Active Transport
PINOCYTOSIS / PHAGOCYTOSIS
• Energy-requiring
• Moves against concentration gradient • Pinocytosis – cell drinking
(uphill; low to high) • Phagocytosis – cell eating
• Fastest transport process • Preferred mechanism for the transport of
• Important for polar molecules lipophilic drugs
• Ileum sac of guinea pig – used for testing • Energy requiring
of active transport • Requirements:
• Primary Transport – creates the gradient ✓ Micelle form of drug
• Secondary Transport – follows the ✓ Vesicle mediated
gradient ✓ ATP
o Symport – same direction • Ex: Griseofulvin, Fat soluble vitamins
o Antiport – different direction (ADEK)
• Ex: Na-K-ATPase Pump
NOTES:
2. Facilitated Transport Body Surfactants:
• No energy required Bile which is produced in the liver and
• Movement along concentration gradient stored in the gall bladder. The contraction of
(high to low) the gallbladder is stimulated by cholecystokinin
• Passive diffusion with carrier (pancreatic enzyme) which is on the other
• Ex: Vit B12 (Cyanocobalamin), glucose hand, stimulated by fatty food.
uptake
Micelle – oil globules stabilized by surfactants
CONVECTIVE TRANSPORT / BULK FLOW

• Movement through water-filled pores LIBERATION

• Only paracellular transport mechanisms
• Drug molecules dissolved in aqueous • Release of drug from the dosage form
medium at the absorption site moves • End Product / Goal: Drug in aqueous form
along with the solvent through the pore or solution
• Factors Affecting Transport: • Dissolution (RLS)
✓ Pore size – diameter is 7-10 A; • Highly modifiable process (e.g. controlled
allows passage of substances release dosage forms)
with MW around 150 – 400 (small • Exemptions: True Solutions
substances only) • Affected by pharmacotechnical
✓ Charge of the pore lining – only properties:
opposite charges can pass ✓ Formulation
through ✓ Quality
✓ Movement is along concentration ✓ Hardness
gradient (no ATP) ✓ Thickness
✓ Movement is by solvent-drug ✓ Disintegration rate
✓ Dissolution rate
✓ Friability

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ABSORPTION 5. Gastric Emptying Time

• Time it takes the stomach to empty its

• From site of administration to systemic contents into the small intestine
circulation
• Normal: 2-3 hours
• Physiologic: rate and extent of drug
• Faster emptying, faster absorption, lower
disappearance from the site of
GET
administration
• Goals:
o Examples:
✓ Decrease GET
▪ Tablet PO
✓ Increase GER
▪ GIT to bloodstream
• Important because the stomach has a
(portal circulation)
small surface area, degree of perfusion
• Pharmacokinetic: rate and extent of drug
and thick mucous membrane making it
entry into the systemic circulation
inefficient for absorbing drugs
o Ex: Peripheral → liver → systemic
DECREASE GET / INCREASE GET /
FACTORS AFFECTING ABSORPTION
INCREASE GER DECREASE GER
1. Dose size and rate and extent (direct) – ↑ dose (GERMSPD) (SHALL)
= ↑ rate and extent Gastrectomy
Extremes of temp Stress
2. pH of absorption site – stomach: ASA [WA] & Right lying Heavy exercise
EtOH, upper segment of small intestine Mild exercise Antimotility drugs
Spicy foods Left lying
STOMACH SMALL INTESTINE
DRUG Promotility drugs Large meal
(Acidic) (Basic)
Diabetes mellitus
Weak Acid Absorbed Excreted
Weak Base Excreted Absorbed
NOTES:
3. Surface Area Promotility Drugs:
✓ Metoclopramide
• ↑ SA = ↑ Rate and extent ✓ Cholinergics
• SI > Stomach
✓ Erythromycin
• Lungs > SI > Stomach
Antimotility Drugs:
✓ Opioids
NOTES:
✓ Anticholinergics
The small intestine’s surface area is 120 sq. m.
making it the main site of drug absorption. The
BIOAVAILABILITY (BA / F)
small intestine has villi and microvilli that
increases its surface area. 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒓𝒆𝒂𝒄𝒉𝒊𝒏𝒈 𝒔𝒚𝒔 𝒄𝒊𝒓𝒄
𝑭=
𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈
4. Degree of Perfusion
Methods:
• ↑ Blood supply = ↑ Rate and extent
✓ Cumulative urinary excretion data
• Lungs (100%)
✓ Drug plasma concentration vs Time graph
• Kidneys and liver (25%)
• Bones (<1%)
• Local anesthetics / vasoconstrictors
(Epinephrine)
✓ To minimize systemic absorption
✓ To minimize systemic toxicity
✓ Prolong duration of action of local
ones
✓ Minimize bleeding

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PARAMETERS ‣ Same API

‣ Maximum plasma concentration ‣ Same dosage form
achieved after PO administration ‣ Same salt or esters
Pharmaceutical
Cmax ‣ Measures both rate and extent of ‣ Same route of administration
Equivalence
absorption ‣ Same strength / concentration
‣ Most variable ‣ Ex: Chlordiazepoxide HCl 5 mg
‣ Time it takes to reach Cmax capsule (branded) → generic
Tmax ‣ Measures rate only ‣ Process of dispensing pharmaceutical
‣ Least important alternatives
‣ Area under the curve ‣ Examples:
Pharmaceutical
AUC ‣ Measures extent only ✓ Ampicillin suspension and
Substitution
‣ Most important ampicillin capsules
✓ Nifedipine 5mg cap and
nifedipine 20mg GITS tab
TYPES OF BIOAVAILABILITY ‣ Different API
Therapeutic ‣ Same therapeutic effect or
Alternatives pharmacologic class
1. Absolute Bioavailability
‣ Ex: Ibuprofen → Aspirin
• Same dose, different routes ‣ Pharmaceutical equivalents that
contain certain identical amounts of
• Systemic availability of a drug after Therapeutic
the same API in the same dosage form
Equivalence
extravascular administration (ex. oral, and route of administration
rectal, SQ, transdermal) compared to IV ‣ Similar bioavailability
dosing Therapeutic Process of dispensing a therapeutic
Substitution alternative
• Comparison of the AUC of a test drug to an
IV

𝑨𝑼𝑪𝒏𝒐𝒏−𝑰𝑽 DISTRIBUTION
𝑭𝒂𝒃𝒔 =
𝑨𝑼𝑪𝑰𝑽 • Reversible transfer of a drug from the
2. Relative Bioavailability systemic circulation to the site of action
and to the other compartments
• Same dose, same route (particularly PO) • Goal: Reach the biological site of action
• Comparison of the AUC of a test drug
against the AUC of standard PHYSIOLOGIC FACTORS AFFECTING DISTRIBUTION
• Availability of the drug from a drug 1. Cardiac Output
product as compared to a recognized
standard 𝑪𝑶 = 𝑯𝑹 𝒙 𝑺𝑽

𝑨𝑼𝑪𝒏𝒐𝒏−𝑰𝑽 • Volume of blood pumped by the heart per

𝑭𝒓𝒆𝒍 = minute is directly related to the extent of
𝑨𝑼𝑪𝒏𝒐𝒏−𝑰𝑽
distribution (↑ CO ↑ Vd)
BIOEQUIVALENCE • Normal: 2.2 – 3.5 L/min/sqm
• Stroke Volume – amount of blood that
• Similarity of bioavailability of generic and returns to the heart
innovator or standard drug
• AUC Ratio, Cmax Ratio, Tmax Ratio 2. Regional Blood Flow
• Requirements: The FDA considers two
• Fraction of the CO that reaches a specific
products BE if the 90% Cl of the relative
organ or tissue
mean Cmax, AUC(0-t), and AUC(0-x) of the
• Organs with high RBF:
test to reference should be within 80% —
✓ Lungs – 100%
125% at 90% confidence interval in the
✓ Liver, kidney – 25%
fasting state
• Organs with low RBF:
PHILIPPINE NATIONAL DRUG FORMULARY LIST B ✓ Bones, adipose tissue – <1%
‣ Same therapeutic moiety / API
‣ Different salts, esters, or complexes
Pharmaceutical ‣ Different dosage forms
Alternatives ‣ Different strength
‣ Ex: Tetracycline PO4 250mg →
Tetracycline HCl 250mg

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NOTES: 2. Protein Binding – only free / unbound drugs can

elicit effect
That’s why a lung infection would only take 7-
10 days to treat while a bone infection would • Consequences of CHON binding:
take longer (at least 6 weeks) ✓ Long duration of action
✓ Limited access to certain body
PHARMACOKINETIC FACTORS AFFECTING compartments
DISTRIBUTION ✓ Potential for drug plasma
displacement interaction (ADR)
1. Volume of Distribution • Drugs that undergo extensive protein
• Hypothetical / apparent volume of body binding: (WANMS)
✓ Warfarin
fluid that is necessary to dissolve a given
✓ NSAIDs (Phenylbutazone)
amount of drug to a concentration equal
✓ Midazolam
to that achieved in the blood
✓ Sulfa drugs
• Ratio of the amount of drug in the body to
the drug concentration in the plasma or BLOOD PROTEINS
blood ‣ Albumin – most abundant;
• If high Vd (Intracellular): Structure for weak acids
✓ Atropine Non-Selective ‣ Alpha-1-acid Glycoprotein –
✓ Β-blockers for weak bases
✓ Chloroquine Structure
• If low Vd (Extracellular): ‣ Globulins – for hormones
Selective
✓ Warfarin
✓ Midazolam
• Applications: METABOLISM / BIOTRANSFORMATION
✓ To estimate the loading dose
✓ To estimate the actual Goal: Convert drugs to less active, inactive
distribution of drugs in the body – metabolite, polar, water soluble, hydrophilic form
significant in the management of
toxicities / drug overdose EXCEPTIONS
• Unit: Liters
1. Inactive (Prodrugs) to Active Form
𝑨𝒃 (𝒅𝒐𝒔𝒆)
𝑽𝒅 = 𝑳𝑫 = 𝑽𝒅 × 𝑪𝒕𝒂𝒓𝒈𝒆𝒕 • Phenacetin → APAP
𝑪𝒑
• Prontosil → Sulfadiazine
Where: • Malathion → Malaoxon
• All ACEi EXCEPT Captopril, Lisinopril,
• Vd – volume of distribution Enalaprilat (active form for Enalapril)
• Cp – plasma concentration
• LD – loading dose 2. Active to Active Metabolites
• Ctarget – target concentration
• Hydroxyzine (Iterax®) → Cetirizine
Total Body Fluid: 60% of body weight • Diazepam → Nordiazepam → Oxazepam –
inactive glucuronidation
• Intracellular Compartment – 40% • Atracurium → Laudanosine
• Extracellular Compartment – 20% • Eserine → Rubreserine
o Interstitial – 15% • Codeine (Methylmorphine) → Morphine –
o Intravascular – 5% N-demethylation
• Allopurinol → Alloxanthine

3. Formation of Toxic Metabolites

• APAP → NAPQI – oxidation; AD: NAC

(Fluimucil®, Exflem®)
• Malathion → Malaoxon

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NOTES: Caffeine
Liver – main organ for metabolism N-dealkylation Morphine
Theophylline
Other metabolizing organs:
Codeine
✓ Kidneys (excretion)
O-dealkylation Dextromethorphan
✓ Intestines (absorption)
Indomethacin
✓ Lungs Meperidine
✓ Placenta N-oxidation Acetaminophen
✓ Aqueous humor of the eyes Nicotine
Chlorpromazine
FIRST PASS EFFECT Cimetidine
S-oxidation
Thioridazine
• Aka Pre-Systemic Metabolism Omeprazole
• For PO drugs (decreases oral BA) Amphetamine
• Hepatic FPE – may occur following PO and Deamination
Diazepam
deep rectal administration; may be OXIDATION (CYP450 INDEPENDENT)
avoided using sublingual and buccal routes Reaction Types Typical Drug Substrates
of administration Amine Oxidation (MAO) Epinephrine
• Pulmonary FPE – cannot be avoided by IV, Aldehyde
SL, and buccal routes Chloral hydrate
• Drugs with extensive FPE (high ER): Carbonyl
Ethanol
✓ Propranolol Reduction
Olefins
✓ Catecholamines (NE, Epi, Dopa) Aromatic
✓ Opiates (natural) and opioids
(synthetic)
✓ Felodipine 1. CYP Mediated – CYP 450
✓ Pentazocine
✓ Lidocaine CYP 1A2 APAP, Theophylline, Caffeine
CYP 2C9 S-warfarin, Phenytoin
PHASE I METABOLISM CYP 2C19 PPIs, Clopidogrel, Propranolol
Codeine, Tamoxifen,
• Functionalization / Asynthetic Phase
CYP 2D6 Some antipsychotics, anti-
• Reactions that convert the parent drug to
depressants, β-blockers
a more polar (water-soluble) or more
Azole antifungals, CCBs,
reactive product by unmasking or inserting
Macrolides, Antivirals (HIV),
a polar functional group such as -OH, -SH, CYP 3A4,
Tyrosine kinase inhibitors
or -NH2 3A5, 3A7
(anti-cancer), Amiodarone,
• Oxidation (most dominant), Reduction,
Cortisol, Grapefruit juice
Hydrolysis

OXIDATION
2. Non-CYP Mediated
• CYP enzymes
• Monoamine oxidase (MAO) – for
• Most of drugs undergo this reaction
catecholamines
• Most dominant among phase I reactions
• Aldehyde dehydrogenase – facilitates this
OXIDATION (CYP450 DEPENDENT) process: OH → Acetaldehyde → Acetic
Reaction Types Typical Drug Substrates Acid
Phenobarbital REDUCTION
Propranolol
Hydroxylation
Phenytoin • Addition of H, removal of O
(Aromatic)
Warfarin • Nitro Reduction – Chloramphenicol (S/E:
Ethinyl estradiol Aplastic Anemia)
Pentobarbital • Carbonyl Reduction – Naloxone,
Hydroxylation
Chlorpromazine Methadone
(Aliphatic)
Ibuprofen • Azo Reduction – Prontosil

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HYDROLYSIS • Drugs that undergo glucuronidation:

✓ Acetaminophen
• Local anesthetics, Aspirin, ACh ✓ Diazepam
• Esters: Aspirin, Clofibrate, Procaine, ACEi, ✓ Digoxin
Succinylcholine ✓ Morphine
• Amides: Indomethacin, Procainamide, ✓ Sulfamethoxazole
Lidocaine ✓ Chloramphenicol

NOTES: ACETYLATION
Propranolol – inhibits the formation of T3 to T4
• Enzyme: N-acetyltransferase
Suicide Inhibitors – drugs that are metabolized
• Substrates: (HIPSS)
to products that irreversibly inhibit the ✓ Hydralazine
metabolizing enzyme: ✓ Isoniazid
✓ Ethinyl estradiol ✓ Procainamide
✓ Norethindrone ✓ Sulfonamide
✓ Spironolactone ✓ Sulfanilamide
✓ Secobarbital • Subject to genetic polymorphism (more
✓ Allopurinol than 1% of the population)
✓ Fluroxene o Extensive metabolizers – normal
✓ Propylthiouracil o Ultra metabolizers – increased
enzyme activity
PHASE II METABOLISM o Poor metabolizers – decreased
enzyme activity
• Conjugation / Synthetic Phase • Drugs that undergo acetylation:
• Addition of a polar functional group, ✓ Clonazepam
increase water solubility by the ✓ Dapsone
conjugation of the drug molecule with a ✓ Isoniazid
polar moiety such as glucuronate, acetate, ✓ Mescaline
or sulfate ✓ Sulfonamides
• Almost always involved in the inactivation ✓ Hydralazine
of drug and formation of its polar form ✓ Procainamide
• Allows attachment to small, polar, and
GENETIC POLYMORPHISM
ionizable endogenous compounds
• Allow the termination or attenuation of a • Variation in the DNA sequences that is
biologic activity present at an allele frequency of 1% or
• Serve to protect the body against greater in a population
chemically reactive compounds or • Variation in expression of enzymes (rapid /
metabolites slow acetylators, CYP polymorphism)
GLUCURONIDATION 1. CYP 2D6 Polymorphism
• Dominant phase II metabolism in adults • Increased risk of cardiotoxicity
• Enzyme is efficiently expressed • Thioridazine and antidepressants
• Neonates: Sulfation (underdeveloped • Most studied CYP family
glucuronidation reaction)
• Enzyme: Uridine 5’Diphosphoglucoronosyl 2. NAT2 Polymorphism
transferase; glucoronosyl transferase
• Fast Acetylators: Asians, Eskimos – EM
• Responsible for functional groups that can
• Slow Acetylators: Caucasians – PM
combine enzymatically with glucuronic
acid 3. Acetylation (HIPS)
• Require an active center as the site of
conjugation • Causes SJS → SLE
• Expression of glucuronosyl transferase is • Isoniazid – peripheral neuropathy; toxicity
inducible (Phenobarbital) treated with Vit B6
• Available source of D-glucuronic acid

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NOTES: ✓ Inactivation – decrease efficacy

✓ Activation of prodrug – increases
Regioselectivity – denotes the selective
efficacy and toxicity
metabolism of two or more similar functional
✓ Formation of toxic metabolite –
groups, or two or more similar atoms that are increases toxicity
positioned in different regions of molecules
ENZYME INDUCERS (O-CRAP-GPTS)
SULFATION Omeprazole Griseofulvin
Carbamazepine, char-
• Only phase II reaction present in neonates broiled foods, Phenobarbital
(only well-developed metabolic pathway cruciferous vegetables
in neonates) Rifampicin Tolbutamide
• Drugs that undergo sulfation: (MATAP) Alcohol (Chronic) St. John’s Wort
Phenytoin
✓ Methyldopa
✓ Acetaminophen / Paracetamol
✓ Terbutaline Enzyme Inhibitors
✓ Albuterol
✓ Phenacetin • Inhibition of enzyme activity; competitive
inhibition
METHYLATION • Consequences:
• Enzyme: Methyltransferase ✓ No enzyme present to inactivate
• Important in the biosynthesis of many drug increasing its efficacy and
endogenous substances like epinephrine toxicity
and melatonin ✓ No enzyme to activate prodrug
• Constitutes only a minor pathway for rendering it less efficient
conjugating drugs or xenobiotics ENZYME INHIBITORS (SICK FACES [Link])
• Ex: COMT Sodium valproate / Erythromycin (except
• Drugs that undergo methylation: Valproic Acid Azithromycin)
✓ Dopamine Isoniazid Sulfonamides
✓ Epinephrine Cimetidine Diltiazem
✓ Histamine Ketoconazole Grapefruit
✓ Norepinephrine Fluoroquinolones Disulfiram
✓ Thiouracil Alcohol (Acute),
Quinidine / Quinine
Antivirals (Protease Inh)
GLUTATHIONE CONJUGATION Ciprofloxacin Chloramphenicol

• Neutralizes chemically reactive substances

• Back-up mechanism for paracetamol ELIMINATION
toxicity
• Drugs that undergo conjugation: • Final loss of drug from the body
✓ Ethacrynic Acid • Requirements:
✓ Reactive phase I metabolite of ✓ Polar
APAP ✓ Water soluble
✓ Free radicals ✓ MW <400
• Routes of Excretion:
GLYCINE CONJUGATION
✓ Renal
Deoxycholic acid, Nicotinic Acid (Niacin), Salicylic ✓ Biliary
Acid, Carboxylic Acid, Benzoic Acid ✓ Lungs
✓ Skin
ENZYME INDUCTION AND INHIBITION ✓ Mammary
Enzyme Inducers ✓ Intestinal

KIDNEYS / RENAL EXCRETION

• Stimulate the release of CYP 450,
enhancing or stimulating enzyme activity • Main excretory organ
• Consequences: • Urine

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• Requirement: Polar, low MW <400-600 biological effectiveness of a drug upon

• Processes Involved: administration
✓ Glomerular filtration
✓ Tubular secretion BIOPHARMACEUTICS CLASSIFICATION SYSTEM
CLASS I
GLOMERULAR FILTRATION CLASS II Chloroquine
Carbamazepine Metoprolol
• Passive process Ketoconazole Propranolol
• Major excretory mechanism Danazol Theophylline
• CrCl = approximate GFR Glibenclamide Diltiazem
𝟏𝟒𝟎−𝑨𝒈𝒆 (𝒊𝒏 𝒚𝒓𝒔) ×𝒘𝒕 (𝒊𝒏 𝒌𝒈) Nifedipine Verapamil
𝑪𝒓𝑪𝒍 = = 𝒎𝑳/𝒎𝒊𝒏 Phenytoin
𝑺𝒆𝒓𝒖𝒎 𝑪𝒓 (𝒎𝒈/𝒅𝑳) × 𝟕𝟐
Mefenamic Acid
• If female, x 0.85 ↓ Solubility ↑ Solubility
• Normal GFR: 125 – 130 mL/min ↑ Permeability ↑ Permeability
TUBULAR SECRETION
Dissolution limited Dissolves rapidly and
• Active (carrier) and well-absorbed well-absorbed
• Peripheral capillaries to lumen of renal CLASS IV CLASS III
tubules Coenzyme A Atenolol
• Ex: Digoxin, Quinine, Penicillin, Probenecid Cyclosporin A Cimetidine
Ellagic Acid Metformin
BILIARY EXCRETION Ritonavir Acyclovir
Saquinavir Captopril
• Stool
Taxol Neomycin B
• Requirements: polar, high MW
Ranitidine
• Limitations:
↓ Solubility
✓ Biliary recycling / enterohepatic ↑ Solubility
↓ Permeability
circulation (reabsorption of ↓ Permeability
drugs)
Difficult in formulating
✓ May undergo metabolism on its Permeability limited
a drug product
way into the small intestine
rendering drugs less polar,
entailing reabsorption
AUTONOMIC NERVOUS SYSTEM
✓ Biliary recycling (enterohepatic
recycling) increases the toxicity
Subdivision of efferent peripheral NS (neurons
• Drugs that undergo enterohepatic
outside the CNS)
recycling:
✓ OCPs • Afferent: Stimuli
✓ Doxycycline • Efferent: Motor, responses (flow of
✓ Ampicillin information)
✓ Nafcillin
✓ Cefoperazone
✓ Ceftriaxone

MISCELLANEOUS

• Lungs – non-polar volatile drugs

• Sweat gland – sweat
• Mammary gland – milk

BIOPHARMACEUTICS

Deals with the physical and chemical properties of

the drug substance, the dosage form, and the

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Central Nervous System Synaptic Cleft

Composed of brain • Metabolizing enzyme containing
and spinal cord
• Responsible for inactivating NTs
• Facilitates
Afferent Neurons reuptake of NTEfferent Neurons

Post Synapse
Effector Organs
• Primary location of receptors
• Metabolizing enzymes
• (+) Stimulatory
ANS
Somatic NS 2 neuron set-up
PROCESS OF SYNAPTIC NEUROTRANSMISSION
1 neuron set-up Presence of ganglia
No ganglia Involuntary control 1. Impulses enter the pre-synapse
Voluntary control Innervates almost all 2. Depolarization of pre-synaptic membrane
Found on skeletal muscle smooth muscle, exocrine,
and cardiac 3. Increased permeability of Ca2+ into the
pre-synapse
4. Ca2+ influx trigger the release of
neurotransmitters
5. Binding of neurotransmitters on the post-
synaptic receptors
6. Generate new impulses

SYMAPTHETIC PARASYMPATHETIC
SympaShortPre ParaLongPre
Anatomy
SYNAPTIC NEUROTRANSMISSION
STL PCSO
• Mechanism of impulse transport across a Thoracolumbar Craniosacral
Origin / Roots
synapse T1 – T12 CN 3,7,9,10
• Synapse – communication between 2 L1 – L5 S1 – S4
Length of
nerves or a neuron and target organ preganglionic Shorter Longer
fiber
PARTS OF SYNAPTIC NEUROTRANSMISSION Length of
postganglionic Longer Shorter
fiber
Presynapse
Location of Near the spinal Near the
ganglion cord / CNS target organ
• Synthesis, storage, and release of
NEUROTRANSMITTERS
neurotransmitters Preganglionic ACh
ACh
• (-) Inhibitory Postganglionic NE, Epi, Dopa
• Autoreceptors / presynaptic receptors – RECEPTORS
for modulation or regulation of NT release Adrenergic Cholinergic
Ganglion Nn Nn
• Metabolizing enzymes (ex. MAO)

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Target Organ α, β, D M, N o Adrenal medulla

FUNCTIONAL RESPONSES
SYMPATHETIC PARASYMPATHETIC STEPS OF BIOSYNTHESIS
STRESS BASAL
General
Fight, flight, fright Rest and digest
1. Active uptake of tyrosine
Mydriasis (Dilation) Miosis (Constriction)
Pupils
Contraction of Contraction of 2. Conversion of tyrosine –(tyrosine hydroxylase)→
radial muscle ciliary muscle L-DOPA (Dihydroxyphenylalanine)
Bronchi Bronchodilation Bronchoconstriction
Heart Tachycardia Bradycardia
• Rate limiting step
Relaxation (Ileus; loss Contraction
GIT (Wall)
of peristalsis) (Bowel movement) • Inhibitor: Metyrosine
GIT (Sphincter) Contracted (Closure) Relaxed (Opening)
Bladder Wall
Relaxation Contraction 3. Formation of the first catecholamine
(Urinary retention) (Urination)
Bladder
L-DOPA –(DOPA decarboxylase)→ Dopamine
Sphincter and Contracted (Closure) Relaxed (Opening)
Trigone • Inhibitor: Carbidopa
Apocrine / Local Eccrine (Diffuse,
(Palm and sole generalized sweating) 4. Vesicular storage and uptake of Dopamine
Sweat Glands sweating) for thermoregulation

Increased sweating Increased sweating • Prevents premature metabolism of

Blood Vessels
Vasodilation,
----
dopamine
vasoconstriction
M: Ejaculation
• Carrier: Vesicular monoamine transporter
Genitalia M: Erection (VMAT)
F: Uterine relaxation
Skeletal Muscle Dilation ---- • Inhibitor: Reserpine – indole alkaloid from
Skin, Mucous
Membrane
Constriction Stimulation of tears Rauwolfia reserpina
Copious, watery
Lacrimal Gland ----
secretion 5. Formation of NE inside the vesicle
Thick, viscous DA –(dopamine-β-hydroxylase)→ Norepinephrine
Salivary Gland
secretion
Adrenal Secretion of NE and (Phenylethanolamine)
----
Medulla Epinephrine
Kidney
Secretion of Renin: 6. Formation of Epinephrine at the adrenal medulla
↑ β1 ↓ α2
Norepinephrine –(PENMT)→ Epinephrine
SYMPATHETIC PARASYMPATHETIC
Alice in Wonderland DUMBBELSS • Phenylethanolamine methyltransferase
Dry as a bone: Anhydrosis, (PENMT)
dry mouth
7. Exocytotic release of neurotransmitters into the
Hot as hell: Hyperthermia,
synaptic cleft
decrease sweating Diarrhea
Urination
Red as a beet: Miosis • Requires Ca ion
Vasodilation, flushing, Bradycardia • Inhibitors:
tachycardia Bronchial spasm ✓ Guanethidine
Emesis
✓ Guanadrel
Blind as a bat: Cycloplegia Lacrimation
(blurring of vision), Salivation ✓ Bretylium
mydriasis, glaucoma Sweating • Stimulants: (TAAAE)
✓ Tyramine
Mad as a hatter: CNS
✓ Amphetamine
(agitation, confusion,
psychosis) ✓ Angiotensin II
✓ α-latrotoxin – from black widow
spider; explosive release of
SYMPATHETIC / ADRENERGIC DRUGS catecholamines
✓ Ephedrine / pseudoephedrine
BIOSYNTHESIS OF CATECHOLAMINES
FATE OF NT IN THE SYNAPTIC CLEFT
• Precursor: Tyrosine
1. Binding on the post-synaptic receptors –
• Site:
(+) effect
o Post ganglionic sympathetic
2. Metabolized by MAO / COMT – (-) effect
nerves
3. Reuptake into the synapse
o Brain / CNS

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• Major mechanism for ✓ TCAs (NE > 5-HT)

termination of activity (70%) via ✓ Cocaine – causes
transporters in the pre-synapse vasoconstriction
• Prevents premature metabolism ✓ NE Reuptake Inh – ex.
• (-) effect Reboxetine
• Carrier: NE Transporter / Uptake- ✓ Sibutramine
1 Transporter ✓ Atomoxetine
• Inhibitors:
RECEPTORS
Secondary
G-CHON Location Major Function
Messengers
Effector Tissues
↑ Ca2+ (↑BP), contraction, secretion
Smooth muscle, gland
Smooth Muscles Contraction
Vascular SM: Cutaneous
Vasoconstriction
splanchnic
Females: Sphincter, bladder,
trigone Urinary retention (↑ closure of internal
α1 Gq ↑ IP3, DAG Males: Prostatic smooth sphincter, contraction of the bladder)
muscles
Radial muscle of iris (eyes) Contraction = mydriasis (dilation of pupil)
Ciliary muscles Cycloplegia
Pilomotor smooth muscles
Contraction (Piloerection) = goosebumps
(skin)
Peripheral NS Increased peripheral resistance
Autoregulation (-) release of NE; anti-
sympathetic

Central: Sedation, depression

Presynapse
Gi Peripheral: Vasodilation (NE release; ACh;
↓ cAMP Central NS / Vasomotor Center
α2 insulin)
↓ IP3, DAG
NOTE: Vasomotor Center – responsible for
maintaining blood pressure (baroreceptors)
Post-synapse
Gq Vasoconstriction
Blood Vessels
Tachycardia
(+) Inotropism – increase contractility
Cardiac Muscle
(+) Dromotism – increase conduction velocity
β1 (+) Chronotropism – increase heart rate
Juxtaglomerular Apparatus
↑ Renin release = ↑ BP
(Kidney)
Bronchi Smooth Muscle Relaxation (bronchodilation)
Blood Vessel (supplies to SM) Vasodilation
Gs ↑ cAMP Contraction (intracellular / uptake movement of
Skeletal Muscle
K = hypokalemia)
Glycogenolysis (increase release of glucagon,
β2 Liver
increase glucose level)
Heart Tachycardia (HR, force)
Lungs Bronchodilation
Uterus Uterine relaxation / tocolysis
Peripheral NS Slightly decrease peripheral resistance
β3 Adipose Cells ↑ Lipolysis (weight loss)
Peripheral
Renal Vasculature
D1 Gs ↑ cAMP Vasodilation (↑ GFR – diuresis) = ↓ BP
Splanchnic Blood Vessels

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↓ GIT motility (loss of peristalsis / ileus)

D2 Gi Gastrointestinal Tract
Constipation
Central
D2 Behavioral changes
D3 Gs ↑ cAMP Central Nervous System Perception regulation
D4 Modulation of motor activities

NOTES: ▪ Can be used to diagnose

pheochromocytoma (CA of
TCAs + MAOIs → Hypertensive Crisis
adrenal medulla)
• Accumulation of catecholamines
Dopamine – homovanillic acid
• TCAs – inh reuptake
• MAOIs – inh metabolism EPINEPHRINE / ADRENALINE

• 1st line cardiac stimulant

ADRENERGIC AGONISTS • 1st line for anaphylaxis and anaphylactic
shock
• Direct Acting – the drug binds directly to • Local vasoconstrictor (+ Lidocaine)
adrenergic receptors to elicit effect • Management of glaucoma
• Indirect Acting – increases concentration ▪ Dipivefrin – pivalic ester of Epi
of catecholamines in the cleft used in glaucoma
✓ Increases sympathetic effect
✓ Increases exocytosis of NE NOTES:
✓ Inhibits reuptake of NE Anaphylaxis – IgE mediated
• Mixed Acting – DA + IA Anaphylactoid Reaction
• Centrally Acting – CNS; habit-forming ‣ Non-IgE; drug induced
DIRECT ACTING: NON-SELECTIVE ‣ Guanethidine, Tubocurarine, Morphine
‣ HIS release = vasodilation,
• Stimulates more than one type of receptor bronchoconstriction (low BP / hypotension)
(α, β, Dopa) Anaphylactic Shock – due to allergy
• Natural Catecholamines: NE, Epi, Dopa

PHARMACODYNAMICS NOREPINEPHRINE / NORADRENALINE

• Higher affinity at β receptors than α • Aka Levarterenol

o ↓ Dose: β effect • 1st line inotropic agent for septic shock
o ↑ Dose: α effect may manifest • Septic Shock – type of hypotension
• Norepinephrine: β1 > α1 induced by an infection
• Epinephrine: β2 = β1 > α1
DOPAMINE
• Dopamine: D1 > β1 > α1
• IV infusion (mcg/kg/min)
PHARMACOKINETICS
• Dose-dependent response
• Undergo extensive first pass effect • Uses:
o Decreased oral BA ✓ Mgt of septic shock
o Acid / labile ✓ Mgt of cardiogenic shock
o Unstable in gastric acid ✓ Mgt of acute heart failure,
• Routes: IV, SQ, inhalation complicated by oliguria or anuria
• Metabolism by MAO and COMT o Oliguria – < 500 mL/day
Norepinephrine and Epinephrine o Anuria – < 50 mL/day
▪ 3-methoxy-4-hydroxy mandelic • Adverse Effects: (Overstimulation)
acid / vanillyl mandelic acid α1: Peripheral vasoconstriction → digital
(VMA) necrosis; Tx: Phentolamine
β1: Tachyarrhythmias; Tx: β-blockers

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DOSE RECEPTOR EFFECT • Ex: Apraclonidine, Brimonidine

Renal vasodilator
1-3 D1 activation Antihypertensive
↑ GFR
(+) Ino, chromo, • (+) autoregulation = ↓ NE (vasodilation)
2-5 β1 activation
dromo • Ex: Clonidine (Catapres®), Methyldopa
>5 α1 activation Vasoconstriction (Aldomet®), Guanfacine, Guanabenz

CLONIDINE
DIRECT-ACTING: SELECTIVE
Phases of Effects
Stimulates only one type of receptor
• Initial: Vasoconstriction
SELECTIVE α1 AGONISTS ▪ Transient, ↑ BP
▪ Post-synaptic α2 activation
• Effects: Vasoconstriction, urinary
retention • Final: Vasodilation
▪ Inhibition of NE release /
• Drugs:
reuptake of NE
✓ Phenylephrine – decongestant
▪ Pre-synaptic activation
✓ Methoxamine
▪ Lasting effect
✓ Propylhexedrine
✓ Tetrahydrozoline Clinical Uses:
✓ Oxymetazoline
✓ Naphazoline ✓ Alt. for HTN; DOC for HTN in patients
• Clinical Uses: undergoing hemodialysis
✓ Mgt of hypotension ✓ Alt. for ADHD – physiologic antagonism
✓ Mgt of nasal congestion (sedation)
▪ Oxymetazoline ✓ Mgt of Clonidine withdrawal-induced HTN
(Drixine®) / rebound HTN – reinstate Clonidine or
✓ Local vasoconstrictors with local give the px Labetalol or Nitroprusside
anesthetic effect ✓ Mgt of hypertensive urgency – SL form
▪ Tetrahydrozoline ✓ Mgt of glaucoma – Apraclonidine,
(EyeMo Red) Brimonidine (more preferred)
✓ Mgt of arrhythmia ✓ Anti-HTN for pregnant patients (HLMN):
▪ Methoxamine – causes ▪ Hydralazine
reflex bradycardia ▪ Labetalol (JNC 7)
• Side Effects (Local / Intranasal) ▪ Methyldopa (not JNC)
o Rebound congestion / rhinitis ▪ Nifedipine
medicamentosa
METHYLDOPA
o Use NMT 3 days
• Side Effects (Systemic) • Prodrug
o Exacerbation of hypertension • Upon entering the body, it will be
o Precipitation of urinary retention converted to alpha-methyl NE / pseudoNT
in patients with BPH • Looks like NE but does not bind to β
o Tolerance – increases risk of receptors, binds to α2 receptors
toxicity; use α1 for NMT 5 days • Use: Mgt of HTN in pregnant patients
SELECTIVE α2 AGONISTS • Side Effects:
o Sedation (most common)
• Binds to pre-synaptic α2 receptors in o Hepatotoxicity – Methyldopa is a
general prodrug (> 2g/day)
• Anti-glaucoma and antihypertensive drugs o (+) Coombs Test – used in
• S/E: Sedation, depression hemolytic anemia

Anti-glaucoma

• ↓ IOP = inhibits synthesis of aqueous

humor

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SHORT ACTING BETA AGONISTS (SABA)

α-methyldopa
• 1st line reliever for bronchial asthma
Dopa decarboxylase • Routes: PO, inhalational, SQ (Terbutaline)
• Albuterol (US) / Salbutamol (UK) –
α-methyldopamine Ventolin®
• Terbutaline, Metaproterenol, Picoterol,
Dopamine-β-hydroxylase Pirbuterol

LONG ACTING BETA AGONISTS (LABA)

α-methylnorepinephrine
• Controllers in bronchial asthma with
NON-SELECTIVE BETA AGONISTS inhaled corticosteroids
• Salmeterol – slow onset of action
• Drug: Isoproterenol / Isoprenaline • Formoterol – fast onset of action
• Clinical Uses: • Bambuterol (PO)
✓ Alt. inotropic IV infusion during • Indacaterol – for COPD
shock states
✓ Alt. for mgt of acute heart failure TOCOLYTICS
✓ Historically used for the mgt of • Agents that induce uterine relaxation to
bronchial asthma prevent premature labor
• Ritodrine
NOTES:
• Isoxsuprine (Duvadilan®) – most common
Mgt of bronchial asthma with Isoproterenol:
• Terbutaline (SQ) – Off label use
Can cause tachyphylaxis or the rapid o Used in the tx of symptomatic
development of tolerance to β2 effects that bradycardia
also leads to the stimulation of β1 receptors → o Has more β1 effects than other
development of tachyarrhythmias tocolytics

SELECTIVE D1 AGONISTS
SELECTIVE β1 AGONISTS
• Renal blood vessels
• Cardioselective
• ↑ diuresis ↑ vasodilation
• Drug: Dobutamine
• Drug: Fenoldopam (IV) – used in
• Clinical Uses:
hypertensive crisis
✓ 1st line for cardiogenic shock
✓ Mgt of AHF (+) inotrope • S/E: Diuresis
✓ Diagnostic agent; pharmacologic INDIRECT ACTING ADRENERGIC AGONISTS
stress test (also Dipyridamole,
Adenosine) • Releasers
• Reuptake inhibitors
SELECTIVE β2 AGONISTS
RELEASERS
• Clinical Uses:
✓ Mgt of bronchial asthma and • Increases / stimulates the release of
COPD catecholamines (exocytosis)
✓ Mgt of pre-term labor • TEAAA: Tyramine, Ephedrine,
✓ Adjuncts in the management of Amphetamine, Angiotensin II, α-latrotoxin
hyperkalemia – β2 has • Modafinil – 1st line for narcolepsy
hypokalemic effects • Methylphenidate – alt. for ADHD
• Side Effects: • Phenmetrazine – anorexiant
o Tachycardia
o Palpitations Ephedrine
o Hypokalemia
• From Ma Huang (Ephedra sinica)
o Tremors
• Alkaloidal amine
o Tolerance
• Has mixed action

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o Directly activates α, β, and Dopa ADRENERGIC ANTAGONISTS

receptors
o Indirectly increases the release of ALPHA BLOCKERS
NE from the pre-synapse
• Clinical Uses: • Non-selective: Phenoxybenzamine,
✓ Mgt of hypotension Phentolamine
✓ Mgt of nasal congestion (α1) • Selective: Prazosin, Doxazosin, Terazosin,
✓ Mgt of bronchial asthma (β2) Tamsulosin, Rauwolscine, Yohimbine
• C/I: MAOI → HTN crisis • General Clinical Uses:
• Side Effects: ✓ Mgt of Raynaud’s Syndrome
o Exacerbation of HTN
NON-SELECTIVE α BLOCKERS
o Urinary retention (BPH px)
o Ventricular arrhythmias PHENOXYBENZAMINE
REUPTAKE INHIBITORS • Irreversible, non-competitive
• TCAs, Cocaine, NERIs (Reboxetine) • Blocks α1, histamine, and 5-HT receptors
o α1: used for pheochromocytoma
• Cocaine – only vasoconstrictor LA
as pre-surgical treatment
• Atomoxetine – mgt of ADHD
o Histamine: for mastocytosis
• Sibutramine – mgt of obesity
o 5-HT: for carcinoid tumor
(enterochromaffin cells)

MIXED ACTING ADRENERGIC AGONISTS • Clinical Uses:

✓ Mgt of HTN secondary to
• Phenylpropanolamine (PPA) – nasal
pheochromocytoma / increased
decongestant
Epi levels
o Risk: Hemorrhagic stroke
✓ DOC in the mgt of carcinoid’s
• Mephentermine, Metaraminol – mgt of
syndrome
hypotension
• Ephedrine PHENTOLAMINE
CENTRALLY ACTING ADRENERGIC AGONISTS • Reversible, competitive
• Antidote in the tx of sympathomimetics
• Drugs: (PPPAM)
poisoning
✓ Phentermine
• Clinical Uses:
✓ Phenmetrazine
✓ Mgt of erectile dysfunction –
✓ Phenylpropanolamine
direct injection to penile shaft
✓ Amphetamine
✓ For pheochromocytoma during
✓ Methylphenidate
surgery
• Side Effects:
o Increased risk of addiction;
Amphetamine – most addicting
o Risk of hemorrhagic stroke in
young women – PPA
o Risk of pulmonary HTN –
Phentermine
• Clinical Uses:
✓ Mgt of ADHD
1st line: Methylphenidate
Alt: Amphetamine
✓ Appetite suppressant /
anorexiant (Phentermine,
Phenmetrazine, PPA)
✓ Mgt of narcolepsy
(Amphetamine, Phentermine)

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NOTES: • No therapeutic value

Pheochromocytoma – tumor / hyperplasia in • Yohimbine – CNS stimulant, local
anesthetic, FDA approved aphrodisiac
adrenal medulla; causes hypersecretion of
• Rauwolscine
catecholamines
• SSX: Agitation, confusion, tachycardia, BETA BLOCKERS
palpitation, paroxysmal HTN
Default MOA: β1 antagonism; (-) Ino, chrono,
• Diagnosis: VMA Assay (Vanillyl
dromo = cardiac depression
mandelic acid) in serum / urine or
imaging studes (MRI, CT) Clinical Uses:
• Treatment:
✓ Alt. in the mgt of HTN
o Initial control: α, β blockers
✓ Mgt of Chronic Stable Angina Pectoris
o Surgical incision (CSAP)
Carcinoid’s Syndrome – neuroendocrine ✓ Mgt of stable heart failure
condition associated with malignancy affecting o Bisoprolol
enterochromaffin cells (secretes 90% of 5-HT) o Metoprolol
• SSX: Watery diarrhea, flushing, HA o Carvedilol
• Tx: Phenoxybenzamine (DOC) o Nebivolol
Raynaud’s Syndrome – digital vasospasm in ✓ Mgt of arrhythmia – Class 2 (PEAce)
response to stress / cold environment; o Propranolol
vasoconstriction causes necrosis o Esmolol
o Acebutolol
• Treatment:
✓ Mgt of glaucoma – decreases aqueous
o α blockers (DOC)
humor secretion / production
o CCBs (Alt.) o Timolol
o Betaxolol
SELECTIVE α1 BLOCKERS
Clinical Uses: (Propranolol)
FOR HYPERTENSION
✓ Mgt of sympathetic symptoms of
• Prazosin, Doxazosin, Terazosin hyperthyroidism through the inhibition of
• Vasodilators the peripheral conversion of T4 to T3
• S/E: ✓ Prophylaxis of migraine headache
o Reflex Tachycardia ✓ Tx of stage fright
o First Dose Phenomenon –
orthostatic hypotension and Side Effects:
syncope • Bronchospasm (non-selective)
• Extension Effect: Bradycardia → heart
▪ Triggers: block (with CCBs especially Verapamil)
✓ Initial dose
• Hyperlipidemia
✓ Big dose
• Hyperuricemia
✓ Use of another
• Rebound HTN and tachycardia
anti-HTN
(withdrawal)
▪ Remedies:
o Remedy: Taper the dose over 10-
• Give 1st dose at
14 days before completely
bedtime
stopping the treatment
• Give ½ or ¼ of
• Erectile dysfunction
usual dose
• Masking of SSX of hypoglycemia – not CI in
FOR BENIGN PROSTATIC HYPOPLASIA DM patients; monitor blood sugar level
(CBG)
• Alfuzosin, Tamsulosin
• Used to shrink enlarged prostate gland Contraindications:
• Relief of urinary retention
• Px > 65 years old
SELECTIVE α2 BLOCKERS • Px with HR < 60 bpm (Normal: 80-100)

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• Px with pre-existing heart block ✓ Penbutolol

• Px with unstable HF ✓ Acebutolol
• Px with reduced exercise tolerance ✓ Labetalol
• Not given concomitantly with non-DHP ✓ Metoprolol
CCBs – can enhance the (-) ino, chrono,
dromo effect of β blockers NOTES:
o Verapamil – more cardioselective These drugs CANNOT BE administered through
o Diltiazem – mixed eyedrops because of disabling the blink
responses leading to loss of the protective
BASED ON SELECTIVITY
mechanism of the eye that may lead to corneal
NON-SELECTIVE injury

• β1 and β2 blockade
BETA BLOCKERS WITH ALPHA BLOCKING EFFECT
• The rest of the -olols and -alols
• Drugs: (NSTP) • Mixed action
✓ Nadolol – longest acting • Causes vasodilation aside from cardio
✓ Sotalol – Class III Antiarrhythmics effects
✓ Timolol – antiglaucoma • Drugs: (CLN)
✓ Propranolol (Inderal®) – ✓ Carvedilol
prototype ✓ Labetalol – causes rebound effect
✓ Nebivolol
SELECTIVE

• Cardioselective (β1) blockers PARASYMPATHETIC / CHOLINERGIC DRUGS

• Less likely to cause bronchospasm; can be
used safely in px with asthma BIOSYNTHESIS OF ACETYLCHOLINE
• Drugs: (CBBEAMN) Sites:
✓ Celiprolol
✓ Betaxolol ✓ Preganglionic fiber
✓ Bisoprolol ✓ Parasympathetic post-ganglionic fibers
✓ Esmolol – shortest T½; given IV ✓ Central nervous system
✓ Atenolol / Acebutolol ✓ Somatic nerves
✓ Metoprolol
STEPS OF BIOSYNTHESIS
✓ Nebivolol – most cardioselective
1. Active uptake of choline into the pre-synapse
BASED ON INTRINSIC
SYMAPTHOMIMETIC ACTIVITY (ISA) • Rate limiting step
• Has partial β2 agonistic effect • Inhibitor: Hemicholinium
• Less likely to cause rebound hypertension 2. Formation of ACh from Acetyl CoA + Choline
when withdrawn
o Cold Turkey – abrupt withdrawal • Enzyme: Choline acetyltransferase (CAT)
o Warm Turkey – tapering of dose • Transfer of acetate from Acetyl CoA
before withdrawal
3. Vesicular storage / uptake of ACh
• Alternative in patients with asthma
• Drugs: (CLAP) • Carrier: Vesicle associated transporter
✓ Carteolol, Caliprolol (VAT)
✓ Labetalol • Inhibitor: Vesamicol
✓ Acebutolol
✓ Penbutolol, Pindolol 4. Quantal release of ACh into the synaptic cleft
(Exocytosis)
BASED ON MEMBRANE STABILIZING EFFECT
• Quantal – all or none release
• Has local anesthetic effect • Inhibitor: Botulinum toxin – causes flaccid
• Drugs: (PPALM) paralysis
✓ Propranolol • Stimulant: α-latrotoxin

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FATES OF ACETYLCHOLINE

1. Bind to receptors (M, N)

2. Metabolism by AChE – inhibited by AChE
inhibitors
3. Reuptake into the synapse
• Acetylcholinesterase (AChE) –
RBCs; true cholinesterase
• Butylcholinesterase (BuChE) –
pseudocholinesterase
(metabolizes all esters, non-
specific); plasma ChE

RECEPTORS
G-CHON Location Major Function
Gastric gland in the parietal cells ↑IP3, DAG cascade, hyperacidity
M1 Gq
(nerve that supplies GIT) (+) Proton pump = HCl secretion
Heart, atria (nerve that supplies ↓cAMP, activates K+ channels
M2 Gi
the heart) Bradycardia, (-) Dromotism
Effector Cells: Smooth muscles,
↑IP3, DAG cascade
glands, endothelium
Smooth Muscles
Circular muscles (eyes) Contraction; miosis
Ciliary muscles (eyes) Contraction; accommodation (cytoplasm)
Lungs Bronchospasm / bronchoconstriction
Exocrine Glands
Lachrymal glands Increased secretion (thermoregulatory
Salivary glands sweating, lacrimation, salivation, bronchial
M3 Gq Sweat glands (eccrine) secretion, gastrointestinal glands)
Gastric
GIT walls Contraction = bowel movement
GIT sphincter Relaxation = diarrhea
Gut Walls Contraction
Gut Sphincter Opening
Urinary Bladder Urination / micturition
Detrusor Contraction and opening
Trigone Relaxation; voiding; urination
Complex stimulatory effects, for example,
nicotine (elevation of mood, alerting,
IONOTROPIC – (+) STIMULATORY
addiction), physostigmine (convulsions);
excessive concentrations may cause coma
Ion Channel
Neutral – ANS Stimulation:
(stimulate by
Nn Ganglion: Synaptic transmission • Parasympathetic neurons
opening inward
Adrenal Medulla: Epi release • Sympathetic neurons
Na Channel)

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Muscular – Somatic
Neuromuscular end plate Depolarizes, evokes action potential
Nm Ion Channel
(skeletal muscles) Skeletal muscle contraction
Ganglion

CHOLINERGIC AGONISTS o Resistant to AChE

• Methacholine
DIRECT ACTING CHOLINERGIC AGONISTS o Used in the diagnosis of asthma
o Pulmonary challenge test –
• Parasympathomimetics provocative test
• Stimulates cholinergic receptors (N, M) o Causes bronchoconstriction
o Resistant to AChE
Carbachol
Demecarium Mgt of glaucoma
SELECTIVE
Echothiopate
Neostigmine Mgt of atropine toxicity
• Bethanechol (Urecholine®)
Physostigmine Mgt of non-obstructive ileus
Pilocarpine (reduced peristalsis) o M selective
Bethanechol Mgt of urinary retention o Mgt of urinary retention (due to
Varenicline
For smoking cessation bladder contraction of M3 =
Nicotine urination)
Methacholine Pulmonary challenge test
Physostigmine Mgt of GI atony
o Mgt of bladder and bowel atony
(after surgery or spinal cord
injury; bowel movement of M3)
CHOLINE ESTERS (ABCM)
CHOLINERGIC ALKALOIDS
NON-SELECTIVE
NON-SELECTIVE
• Binds to both receptors (N, M)
• Binds to both receptors (N, M)
• Acetylcholine
o Prototype • Arecoline – from betel nut (Areca catechu)
o No clinical use due to widespread SELECTIVE
effects and rapidly hydrolyzed by
AChE • Pilocarpine
o Primary transmitter at cholinergic o M selective
nerve endings o Causes contraction of ciliary
• Carbachol muscle fiber → opens the
o For glaucoma

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trabecular meshwork to enhance INTERMEDIATE ACTING ANTICHOLINESTERASE

aqueous humor outflow
o From Pilocarpus jaborandi • Reversible inhibitor (-stigmines)
o Mgt of glaucoma • DOA: 2 – 8 hours (< 24 hours)
o Mgt of GI atony • Structure: Carbamates / carbamyl esters
• Muscarine with quaternary / tertiary ammonium
o M selective groups
o From mushrooms (Amanita • Physostigmine / Eserine
muscaria) o Tertiary amine
• Nicotine o More lipophilic
o N selective o Reversal of severe atropine
o From Nicotiana tabacum poisoning (IV)
o Overdose: convulsion, paralysis, o Used in acute glaucoma (topical)
coma • Neostigmine
• Lobeline, Varenicline o Quaternary amine
o N selective o Poorly absorbed
o Lobeline: From Lobelia inflata o Little to no CNS effect
o For smoking cessation o Antidote for tubocurarine
poisoning
INDIRECT ACTING CHOLINERGIC AGONISTS o Treatment for myasthenia gravis
• Pyridostigmine
• Increase concentration of ACh in the cleft
• Demecarium – for glaucoma
• MOA: Inhibition of AChE
• Ambenomium
• Reversible – safe
• Irreversible – toxic LONG ACTING ANTICHOLINESTERASE
• CNS-acting – Anti-ALZ
• Structure: Organophosphates
Side Effects: (DUMBBELSS) • Duration of Action (DOA):
o < 24-48h – potentially reversible
• Diarrhea inhibition
• Urination o ≥ 48h – irreversible inhibition
• Miosis because of aging (covalent
• Bradycardia bonding of OP with the serine
• Bronchial spasm residue of AChE)
• Emesis • Drugs:
• Lacrimation ✓ Echothiopate – medically useful;
• Salivation for glaucoma
• Sweating ✓ Isofluorophate
✓ Malathion – prodrug → Malaoxon
Management of Cholinergic Toxicities:
✓ Parathion
• Principal / 1st line – Atropine ✓ Sarin, Tabun, Soman – nerve
(Antimuscarinic) gases
• Pralidoxime – ChE reactivator; mgt of OP DRUGS FOR ALZHEIMER’S DISEASE
poisoning with 24-48 hours of exposure
• Diacetyl monoxime – ChE reactivator • Only counteracts the symptoms but DO
NOT cure the disease; the disease has no
SHORT-ACTING ANTICHOLINESTERASE cure as of the moment
Edrophonium (Tensilon Test) • ALZ is considered to be Type 3 Diabetes
• MOA: CNS-acting cholinesterase inhibitor
• Reversible inhibitor • Drugs: (TAClesa at GALANTe si DONya
• Amplifier of endogenously released ACh RIVA)
• DOA: 15 – 30 minutes (average of 20 mins) ✓ Tacrine
• Structure: Aminoalcohol ✓ Galantamine
• Diagnostic agent for myasthenia gravis ✓ Donepezil
✓ Rivastigmine

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✓ Memantine (NMDA Agonist) • Increase intraocular pressure (glaucoma)

o CI: Narrow-angle glaucoma (over
DRUGS FOR MYASTHENIA GRAVIS production of aqueous humor)
• Autoimmune condition where antibodies • Bronchi: Bronchodilation
are targeting ACh receptors • GIT: Ileus and constipation
• Targets Nm • Bladder: Urinary retention
• Signs and Symptoms: • Exocrine Glands: Decrease secretions
o Initial: Late afternoon muscle • Managed by AChE inhibitors
weakness, ptosis
2. Dry as a bone
o Final: Diaphragmatic muscle
weakness • Anhidrosis (decreased sweating)
• Diagnosis: • Hyperthermia
o Progressive symptoms • Managed by AChE inhibitors
o Serologic Test: Anti-ACR
antibodies 3. Hot as hell
o Imaging Studies: Thymoma
• Cutaneous vasodilation
o Tensilon Test – to differentiate
cholinergic and myasthenic crisis • Managed by AChE inhibitors
• Treatment: 4. Red as a beet
o 1st line: Immunosuppression with
Prednisone • Flushing
o AChE Inhibitors: Neostigmine, • Managed by AChE inhibitors
Pyridostigmine, Ambenonium –
for improvement of muscle 5. Mad as a hatter
strength • CNS effects: agitation, seizure, confusion,
o Non-pharma: Thymectomy psychosis
• Managed by BZDs
CHOLINERGIC ANTAGONISTS
MISCELLANEOUS ANTICHOLINERGICS
ANTI-MUSCARINIC DRUGS
CNS-ACTING
Prototype: Atropine – inhibits M1, M2, M3
• BBTS
ATROPINE • Benztropine (Congentin®), Biperiden
(Akineton®), Trihexyphenidyl (Artane®)
Effects:
o Mgt of Parkinson’s Disease
• M1 Block: decreased acid secretion o Mgt of EPS (Pseudoparkinsonism,
• M2 Block: vagolytic effect; tachycardia akathisia, acute dystonia)
• M3 Block: mydriasis • Scopolamine
• Cycloplegia – loss of near vision due to o Mgt of motion sickness
increase intraocular pressure (failure to o Sedative
drain aqueous humor); can last up to 72h o + Morphine = twilight sleep
(combination of analgesia and
Clinical Uses: anesthesia)

✓ Mgt of symptomatic bradycardia MYDRIATIC / CYCLOPEGIC

✓ Mgt of cholinergic overdose
✓ Atropine + Diphenoxylate (Lomotil®) • Mydriatic – for eye exam
o Additive effect • Cycloplegics – for eye injury
o Anti-diarrheal • Drugs: (ATCH)
o Diphenoxylate – addicting ✓ Anisotropine
✓ Tropicamide
Side Effects: (Alice in Wonderland Syndrome) ✓ Cyclopentolate
✓ Homatropine
1. Blind as a bat
BRONCHODILATORS

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• Acts on bronchi o Final: Desensitization Phase;

• Ipratropium, Oxitropium (SAMA) muscle fatigue; muscle paralysis
• Tiotropium (LAMA) • Side Effects:
• 1st line relievers in COPD o Use with inhalational anesthetics
• Alt relievers in bronchial asthma causes malignant hyperthermia
(Tx: Dantrolene) and acute
NOTES: tubular necrosis
Drugs for COPD and chronic asthma: o Rhabdomyolysis (skeletal muscle
✓ LABAs breakdown), myositis, myalgia
o Hyperkalemia (terminal: acute
✓ Inhaled corticosteroids
kidney failure), myoglobinemia
✓ Anticholinergics
(toxic to renal tubule,
myoglobinuria)
SELECTIVE M1 BLOCKERS o Hypersecretion of Ca ions by the
sarcoplasmic reticulum (muscle
• Acts on gastrointestinal tract
rigidity) – Tx: Ryanodine
• Prenzepine
• Telenzepine – adjunct in the management NON-DEPOLARIZING NMBs
of hyperacidity
• Curare derivatives
SELECTIVE M3 BLOCKERS • MOA: Reversibly blocks Nm receptors =
immediate skeletal muscle relaxation
• Acts on gastrointestinal tract and urinary
• Isoquinoline (-curium): Atracurium,
bladder
Cisatracurium, Mivacurium
• Hyoscine-n-butylbromide, Dicycloverine,
Clidinium, Glycopyrrolate
NOTES:
• Clinical Uses:
S/E for Tubocurarine: Tubocurarine-induced
✓ Spasmolytics – renal and biliary
colic anaphylactoid reaction (same with anaphylactic
✓ Hypermotility disorder reaction but not caused by mast cells) – DOC:
✓ Urinary incontinence Epinephrine

ANTI-NICOTINIC DRUGS
• Steroidal (-curonium): Pancuronium,
• Nn – inhibited by ganglionic blockers Rocuronium, Vecuronium
o Hexamethonium, Trimetophan, • Effect:
Mecamylamine o No initial muscle contraction
o Unpredictable (anticholinergic o Direct / immediately cause
and vasodilation) paralysis
o Used historically in hypertensive • Clinical Uses:
crisis; obsolete ✓ Skeletal muscle relaxant during
surgery
• Nm – inhibited by neuromuscular blockers ✓ Used in patients with spastic
o S/E: Respiratory / diaphragmatic disorder (cerebral palsy)
paralysis
Tx: Edrophonium, Neostigmine CENTRAL NERVOUS SYSTEM
Non-drug: Mechanical ventilation
• Command center of the body
DEPOLARIZING NMBs • Neurotransmitters – chemical compounds
that are transmitted via synapse
Succinylcholine (Suxamethonium)
o EPSP – excitatory
• MOA: Irreversibly stimulates Nm o IPSP – inhibitory
receptors • Termination of NT:
• Non-competitive ✓ Reuptake
• Effects: ✓ Metabolism by COMT & MAO
o Initial: Depolarizing Phase; ✓ Diffusion (Passive)
muscle contraction; tremors

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Neurotransmitters: ‣ Hallucination (Auditory) – perception like

• 5-HT (Serotonin) experiences without external stimulus
Trp → 5-HT → Melatonin ‣ Delusions (False Belief)
• Glutamate – major excitatory NT • Paranoia / persecutory
o NMDA • Grandiose
EPSP
o AMPA • Referential
• Acetylcholine • Erotomania
• Norepinephrine – β1 > α1 ‣ Disorganized thoughts / speech
• Epinephrine – β1 > β2 > α1 ‣ Bizarre behavior
Uncommon; harder to treat symptoms
Activation of ionotropic receptor = Na+ channel
opening = ↑ Na+ (i) = Depolarization ‣ Alogia – low verbal output
Neurotransmitters: ‣ Anhedonia – unable to feel pleasure
• NEGATIVE
GABA (Brain) ‣ Avolition – lack of motivation / drive
o GABA-A: BZDs, Barbs; Cl- SYMPTOMS
‣ Associality – loss of interest in social
ch opening; brain activities
o GABA-B: Baclofen; K+ ch ‣ Flattening of affect – monotonous voice /
opening, Ca2+ ch closing; one facial expression
IPSP
spinal cord
• Glycine (Spinal cord) – inhibited by
Strychnine = excitatory
ANTIPSYCHOTICS / NEUROLEPTICS /
Activation of ionotropic receptor = Cl- channel MAJOR TRANQUILIZERS
opening = ↑ Cl- = Hyperpolarization
Neurotransmitter:
• Dopamine (D2) – major NT Goal: Decrease Dopa, 5-HT, Glutamate
BOTH FIRST GEN / TYPICAL ANTIPSYCHOTICS
D1 – renal and splanchnic BV → vasodilation
D2 – GIT → ileus and relaxation
– CNS → mood regulation and mood control • Aka Traditional / Classical Antipsychotics
• Addressed DA Theory

• Ions – charged particles Mechanism of Action (MOA):

o Major Cations (+):
▪ PISO – 1st • D2 blockade – major
▪ MICO – 2nd • Anti-HAM – minor
o Major Anions (-): o Histamine (H1) – sedation
▪ PhIClO – 1st o Alpha (α1) – vasodilation → ↓BP;
orthostatic hypotension
CHANNEL INTRACELLULAR CELL EXCITATORY o Muscarinic (M1, M3) – atropine-
(OPEN) IONS CHARGE INHIBITORY
like effects; urinary retention
Na+ ↑ Na+ +
Excitatory
Ca2+ ↑ Ca2+ +
Potency:
K+ ↓ K+ -
Inhibitory
Cl- ↑ Cl- - 𝑫𝟐 𝑎𝑓𝑓𝑖𝑛𝑖𝑡𝑦
𝑯𝑨𝑴 𝑎𝑓𝑓𝑖𝑛𝑖𝑡𝑦

• ↑ Potency ↑ D2 affinity ↓ HAM

PSYCHOSIS • ↑ D2 affinity = EPS, hyperprolactinemia
• Butyrophenones = Piperazines >
• General Term: Breakdown of personality Piperidines ≥ Thioxanthines > Aliphatic
• ↑ Dopa, 5-HT, glutamate
• Tx of psychotic disorder: Schizophrenia NOTES:
• Types: D2 Blockade Effects:
o Schizophrenia – ↑ Dopa, 5-HT, ‣ Mesolimbic System → Antipsychotic → (+) Sx
glutamate ‣ Tuberoinfundibular System (Prolactin) → ↓
o Affective disorder – mania, DA → ↑ PRL release (hyperprolactinemia)
depression ‣ Nigro-Striatal System → EPS
POSITIVE More obvious symptoms
SYMPTOMS PHENOTHIAZINES (-azines)

Aliphatic (-promazine)

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• Ex: Chlorpromazine -PERIDONE

• Causes corneal deposits
• Risperidone
• Doesn’t cause blindness
o First line
Piperazines (-phenazine) o Does not have muscarinic effects
o Equal effect on D4 and 5-HT
• Ex: Fluphenazine blockade
o S/E: Hyperprolactinemia
Piperidines (-ridazine)
• Paliperidone – S/E: QT Prolongation
• Ex: Thioridazine (ThioRETINA) • Ziprasidone
• Causes retinal deposits
OTHERS
• Can cause blindness
• Weight neutral antipsychotic drugs (AMA)
BUTYROPHENONES
• Aripiprazole, Molindone, Amisulpride
• (-peridol)
ADVERSE EFFECTS
• Haloperidol, Droperidol
Dopamine receptor blockade, weight gain (↓ DA
THIOXANTHINES
level = ↑ ACh effects)
• (-thix-)
EXTRAPYRAMIDAL SYNDROME (EPS)
• Thiothixene
• Movement disorders due to cholinergic
SECOND GEN / ATYPICAL ANTIPSYCHOTICS
stimulation
• Addressed 5-HT Theory • 1st line tx: centrally acting anticholinergics
• Mechanism of Action: Blocks D4 and 5- ✓ Benztropine
HT2A receptors > D2 receptors ✓ Biperiden
• Advantage: Low EPS effects ✓ Trihexyphenidyl
• Efficacy: AKATHISIA
o Tx of (+) Sx: 1st Gen = 2nd Gen
o Tx of (-) Sx: 2nd Gen > 1st Gen • Uncontrolled restlessness
• Most difficult to treat
NOTES: • Only EPS that is not treated with
D4 Receptors – less likely associated with anticholinergics
extrapyramidal syndrome (EPS) • Mgt: BZD, β-blockers (Propranolol)

DYSTONIA
-ZAPINES
• Aka Retrocollis / Torticollis / Twisting of
• Clozapine
Neck
o Prototype 2nd gen antipsychotic
• 1st EPS seen
o ↓ Risk of suicidality
• Easier to treat but can be fatal
o No EPS
o Never given as 1st line because of • Management:
SAM (seizures, agranulocytosis, o IV Diphenhydramine
myocarditis) effects ▪ 1st gen antihistamine
o Highest risk of seizure ▪ Antimuscarinic effects
o Requires WBC monitoring every o CNS Anticholinergics (BBT)
week for the 1st 6 months of PSEUDOPARKINSONISM
therapy and every 3 weeks
thereafter • Parkinson-like syndrome
• Olanzapine – S/E: Weight gain • Due to severe depletion of Dopamine
• Quetiapine – used to induce sedation • SSX: (TRAP)
✓ Tremors
-XAPINES ✓ Rigidity
• Loxapine ✓ Akinesia – limited movement
✓ Postural instability / imbalance

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• Mgt: CNS Anticholinergics Mood Regulation: 5-HT, NE, Dopamine

TARDIVE DYSKINESIA

• Potentially irreversible
• Toxic effect of 1st gen antipsychotics
• Due to hypersensitivity of D2 receptors
• Tic-like motion; repetitive involuntary
Mood Stabilizers
movement
• Management: • Increase NE, 5-HT, Dopamine
o Best: Discontinue the drug • MOA: Reuptake inhibition, inhibit MAO
o Reduce dose enzyme, α2 presynaptic blockade
o Switch to Clozapine or Quetiapine
o Tx with Diazepam TRADITIONAL ANTIDEPRESSANTS

HYPERPROLACTINEMIA All antidepressants have equal efficacy, they only

differ in safety
• Increased prolactin in the blood
• Dopamine – prolactin inhibiting hormone TRICYCLIC ANTIDEPRESSANTS (TCAs)
• Patient manifests galactorrhea along with
• Drugs ending in:
the ff:
o (-tryptiline): Amitryptiline
✓ Amenorrhea
o (-pramine): Despiramine,
✓ Gynecomastia
Imipramine, Clomipramine,
✓ Impotence
Doxepine
NEUROLEPTIC MALIGNANT SYNDROME (NMS) • Mechanism of Action:
o Inhibition of NE >> 5-HT
• Malignant Hyperthermia o HAM Blockade
• Succinylcholine – Depolarizing ▪ Histamine
NMB ▪ Alpha
• Inhalational anesthetics ▪ Muscarinic
• Management: • Clinical Uses:
o Dantrolene (Ca antagonist, ✓ Mgt of neuropathic pain
muscle relaxant) ✓ Mgt of enuresis
o Bromocriptine (D2 agonist) ▪ Bed wetting / urine
incontinence
OTHER EFFECTS
▪ DOC: Imipramine – used
• Seizure – all anti-psychotics can lower because of its
seizure threshold, highest with Clozapine antimuscarinic effects;
• Weight Gain – common to 2nd generation IHIpramine
antipsychotics EXCEPT AMA ✓ Mgt of insomnia
• Increased Risk of DM – ↑↑ with ✓ Mgt of anxiety disorders
Olanzapine ✓ Mgt of OCD – Clomipramine
• Agranulocytosis • Side Effects:
o Low basophil, neutrophil, o Narrow TI – 3C’s
eosinophil count ▪ Coma
o Neutropenia Effect: bacterial ▪ Convulsion
infection ▪ Cardiotoxicity
• Cardiac Effects o Weight gain
o Myocarditis: Clozapine o ECG abnormalities
(Idiosyncratic) ▪ QT prolongation (TdP) →
o QT Prolongation: Ziprasidone, arrhythmia
Sertindole, Thioridazine, ▪ Request 12-lead ECG
Quetiapine prior to treatment
o Extension Effect: (HAM)
DRUGS FOR MOOD DISORDERS ▪ Sedation

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▪ Orthostatic hypotension SELECTIVE SEROTONIN REUPTAKE INHIBITOR

▪ Anticholinergic effects
• MOA: Inhibits reuptake of 5-HT
TETRACYCLIC ANTIDEPRESSANTS • Drugs:
✓ Citalopram
• MOA: Inhibits reuptake of NE and 5-HT ✓ Escitalopram – prodrug of
• Drugs: (MaAmMia) Citalopram
✓ Maprotiline ✓ Fluoxetine
✓ Amoxapine ✓ Fluvoxamine
✓ Mianserin ✓ Paroxetine
MONOAMINE OXIDASE INHIBITORS ✓ Sertraline
• Pharmacokinetics: (Inhibitors)
• MOA: Inhibits MAO – enzyme that o CYP 2D6: Fluoxetine, Paroxetine
degrades catecholamines o CYP 1A2 & 3A4: Fluvoxamine
o MAO-A: NE, Epi, 5-HT, Dopa • Clinical Uses:
o MAO-B: Dopamine ✓ 1st line mgt of depression in
• Non-Selective Drugs: (PIT) children and young adults
✓ Phenelzine ✓ Mgt of bulimia nervosa –
✓ Isocarboxazid Fluoxetine
✓ Tranylcypromine ✓ Mgt of OCD – Fluoxetine,
• Selective Drugs: (MS) Fluvoxamine
✓ Moclobemide – MAO-A; RIMA ✓ Mgt of premenstrual dysphonic
(Reversible inhibitor of MAO-A) disorder (PDD) – Fluoxetine,
✓ Selegiline – MAO-B Sertraline
• Clinical Uses: Mgt of atypical depression – • Side Effects:
has psychotic features (+ sx) o Serotonin Syndrome
o Hallucination ▪ Agitation, tremors, fever
o Delusions ▪ Mgt: Cyproheptadine (5-
o Disoriented speech HT blocker)
o Bizarre behavior o Sexual disturbances
• Drug Interaction: Hypertensive Crisis o Sleep disturbances
o Tyramine → Tyrosine – parent o Hyperthermia / hypothermia
compound of catecholamines ▪ Mgt: Better choice –
o Food rich in Tyr: Cheese, wine, Paroxetine, Sertraline
meat products, fermented fish, (sedative; beneficial)
pickled vegetables, chicken liver • Contraindications:
o Px with serotonin syndrome
o Combination of TCAs and MAOI
• BLACK BOX WARNING: Fluoxetine
2ND GEN / ATYPICAL ANTIDEPRESSANTS (Prozac®) – increased suicidal tendency
Amoxapine
NOTES:
• D2 blocker All are Category C (no human studies, (+)
• MOA: Inhibits reuptake of NE >> 5-HT animals), EXCEPT Paroxetine – Category D
(benefit > risk)
Trazodone, Nefazodone
Generally given a 2-week drug holiday EXCEPT
• 5-HT2 blockers Fluoxetine which is given a 4-week drug holiday
• MOA: Inhibition of 5-HT reuptake; due to active metabolite (Norfluoxetine) that is
inhibition of 5-HT2A and 2C receptors long-acting
• Withdrawn; causes severe hepatotoxicity
(Nor-) – underwent demethylation
Mirtazapine – 5-HT3 and α2 blocker

NEWER GENERATION OF ANTIDEPRESSANTS SEROTONIN NOREPINEPHRINE

REUPTAKE INHIBITOR
• SSRI, SNRI, NaRI, NASSA, NDRI

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• Similar MOA to TCA, however, TCAs have o Eskalith® – capsule

effect on HAM o Lithase® – tablet
• No effect on HAM receptors o Quilonium SR® – modified release
• Atomoxetine – mgt of ADHD tablet
• Venlafaxine
o Less affinity to NE reuptake
o More selective to 5-HT reuptake
o Mgt of chronic pain
o S/E: ↑ Risk of cardiotoxicity
• Duloxetine – S/E: ↑ Risk of hepatotoxicity
• Desvenlafaxine

NORADRENALINE REUPTAKE INHIBITOR

NOTES:
• Reboxetine IP3, DAG – products of PIP2, classified as a
• Clinical Uses: secondary messenger, which is essential for
✓ Mgt of depression – alt to SSRI neurotransmission
✓ Mgt of back and muscle pain
• Side Effect: Sexual dysfunction
• Side Effects:
NORADRENALINE DOPAMINE o Nausea and vomiting
REUPTAKE INHIBITOR o Polyuria, polydipsia – secondary
to nephrogenic DI
• Bupropion o Tremor – common even at
• Advantage: Does not cause sexual normal doses
dysfunction / disturbance • Idiosyncratic Reactions:
• Clinical Use: Smoking cessation o Nephrogenic DI – due to
• S/E: Psychotic features vasopressin deficiency
o Thyroid abnormalities
DRUGS FOR BIPOLAR DISORDERS o Goiter
o Ebstein’s Anomaly (Teratogenic)
Goal: Decrease 5-HT, NE, Dopamine – insufficient development of
tricuspid valve = backflow of
Anxiety D/O: (Goal: Inhibit stimulatory effects)
blood
• General anxiety disorder • Drugs that DECREASE Li excretion
• Panic disorder (↑Na↓Li):
• Obsessive compulsive disorder ✓ Acetazolamide
• Post-traumatic disorder / Warshock ✓ Xanthine diuretics
Syndrome ✓ Osmotic diuretics
✓ Na supplements
GABA Receptors (Allosteric Sites) ✓ Urine alkalinizers
• Drugs that INCREASE Li excretion
• BZPs, Barbs
(↓Na↑Li):
• Binding of drug to above receptors
✓ Thiazide diuretics
agonizes the binding of GABA to the
✓ ACE inhibitors
receptors, making the membrane
✓ NSAIDs
hyperpolarized (more negative)
✓ Na loss
LITHIUM ✓ Fluoxetine
✓ Renal disorder
• DOC: Mania
• MOA: Unknown SODIUM VALPROATE / VALPROIC ACID
o Proposed: Inhibits membrane • For rapid cycling bipolar disorder
phosphoinositide (ex PIP2)
• Better safety profile than Lithium
recycling
• S/E: Hepatotoxicity
• Not for rapid cycling (> 4 cycles per year)
• Dosage Forms: CARBAMAZEPINE (Tegretol®)

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• For acute mania • CNS Depression – dose dependent

• Prophylaxis for depressive phase of bipolar Tranquilizer → sedative → hypnotic →
disorder respiratory depression → coma → death
• Anterograde Amnesia
ATYPICAL ANTIPSYCHOTICS o Partial / temporary loss of
• Quetiapine, Olanzapine memory
o Use in surgery is acceptable
ANXIOLYTICS / SEDATIVE-HYPNOTICS / o Flunitrazepam (Rohypnol®) – aka
Roofies; date-rape drug
MINOR TRANQUILIZERS
• Cross-tolerance
• Physical / psychological dependence
• Low dose – sedative
o May lead to withdrawal
• High dose – hypnotic
symptoms
• Benzodiazepines: Increase the frequenZy
o Remedy: Taper the dose slowly
of opening of Chloride channels
when terminating treatment
• Barbiturates: Increase the duration of
• Paradoxical reaction – BZPs can induce
opening of Chloride channels
anxiety attacks
• MOA of BZPs and Barbs:
o Bind to their respective active BARBITURATES
sites at GABA-A receptors
(Ionotropic receptor → Cl- • More toxic than BZPs
channel) • Steeper dose-response
o ↑ GABA binding at GABA-A • Phenobarbital
receptor = opening of Cl- o From Primidone
channels = hyperpolarization o Enzyme inducer (for
(inhibitory) hyperbilirubinemia)

BENZODIAZEPINES

• (-zepam), (-zolam) EXCEPT Chlorazepate,

Chlordiazepoxide
SHORT ACTING Midazolam, Triazolam
Alprazolam, Lorazepam,
INTERMEDIATE
Temazepam, Oxazepam,
ACTING (ALTOE)
Estazolam
The rest of BZDs represented by
LONG ACTING Diazepam (Valium®),
Chlordiazepoxide, Chlorazepate

o CI: Disorders associated with

• Prodrugs with active metabolites
porphyrin
✓ Diazepam to Nordiazepam
o Tox: Neutralization
✓ N-desmethyldiazepam
• No active metabolites: (COLA) – Short and Thiopental, Thiamylal, Methohexital
intermediate acting BZPs
‣ Very lipid-soluble, lipophilic, with
✓ Clonazepam short duration of action
✓ Oxazepam ULTRA SHORT
‣ Thiol-containing (-SH)
ACTING
✓ Lorazepam ‣ Clinical Uses:
✓ Alprazolam ✓ Preferred for induction of
anesthesia
Clinical Uses: ✓ Tranquilizer
567: Pentobarbital, Hexobarbital,
✓ Mgt of anxiety disorders Secobarbital
SHORT ACTING
✓ Mgt of insomnia Clinical Use: Sedative
✓ Mgt of seizures Amobarbital, Butabarbital
INTERMEDIATE
✓ Pre-adjunct in anesthesia ACTING
Clinical Use: Hypnotic
Side Effects: LONG ACTING Phenobarbital, Barbital

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o Full body convulsion, urination

Clinical Use: Anticonvulsant, mgt of and defecation (uncontrolled)
neonatal hyperbilirubinemia
o DOC: Valproic Acid
• Absence Seizure (Petit Mal)
OTHER DRUGS o Sudden onset and abrupt
cessation
Ramelteon o Involves a brief, abrupt, and self-
limiting loss of consciousness
• Novel drug
o Blank stares, lip smacking, rapid
• MOA: Melatonin agonist
eye blinking
Buspirone o Common in children
o DOC: Ethosuximide
• MOA: 5-HT1A partial agonist o Alt: Valproic Acid
• Advantage over BZP and Barbs: • Atonic Seizure (Drop Seizure)
✓ No potential for abuse o Loss of muscle tone
✓ No euphoric effects o DOC: Clonazepam
✓ No dependence o Alt: Valproic Acid, Topiramate,
✓ No muscle relaxant effect Lamotrigine
• Myoclonic Seizure
Zaleplon, Zolpidem, Eszopiclone
o Muscle jerking
• Same MOA with BZPs o DOC: Valproic Acid
• Advantage: Less likely to affect sleeping • Febrile Seizure
patterns than BZPs o Consists of GTC convulsions of
short duration
DRUGS FOR SEIZURE DISORDERS o Develops in children (3 mos – 5
years)
Seizure – abnormal firing of neurons leading to o Accompanied by high fever
excitability o DOC: Phenobarbital
o Alt: Primidone
All anticonvulsants are enzyme inducers EXCEPT
Valproic Acid – extensive enzyme inhibitor STATUS EPILEPTICUS

TYPES OF SEIZURE • Recurrent seizure episodes without

regaining consciousness
✓ Partial / Focal Seizure • New DOC: Clonazepam
✓ Generalized Seizure
• Old DOC: Diazepam → Lorazepam
✓ Status Epilepticus
CLASSICAL ANTISEIZURE DRUGS
PARTIAL / FOCAL SEIZURE
Na Channel Ca Channel
↑ GABA
• Only affects one hemisphere of the brain Blockade Blockade
• Simple: Jacksonian Epilepsy, repetitive Carbamazepine ✓
jerking, no loss of consciousness Phenytoin ✓
Valproic Acid ✓ ✓ ✓
• Complex: Psychomotor Epilepsy, ↓ level Lamotrigine ✓
of consciousness, automatism behavioral Phenobarbital ✓
changes, hallucinations ✓
Ethosuximide
• Drugs (1st Line): Carbamazepine, (T-type)

Phenytoin
• Alt: Lamotrigine, Oxcarbazepine, Valproic CARBAMAZEPINE
Acid
• MOA: Na channel blocker
GENERALIZED SEIZURE • Enzyme inducer and capable of
• Involves both hemispheres autoinduction (induces its own
• Loss of consciousness metabolism)
• Tonic-Clonic Seizure (Grand Mal) • Clinical Uses:
✓ DOC for trigeminal neuralgia

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✓ 1st line in partial / focal seizure • Black Box Warning: ↑ Suicidal ideation
• S/E: (Dose Related)
o Diplopia – double vision; 1st sign OTHER DRUGS
of toxicity; requires dose Ethosuximide
adjustment
o Ataxia – loss of control of • MOA: T-type Ca channel blocker
voluntary movement • NOTE: L-type is for periphery ANS
o Teratogenic: Neural tube defect /
spina bifida – use Folic Acid / Vit Topiramate – MOA: Na and Ca channel blocker
B9 for prevention NEWER AGENTS
PHENYTOIN (DIPHENYLHYDANTOIN)
• Vigabatrin – Irreversible inhibitor of
• MOA: Block conductance of Na, K, and Ca GABA-T / GABA Aminotransferase = ↑
• Enzyme inducer GABA
• Fosphenytoin – phenytoin derivative; can • Felbamate – NMDA (Excitatory) receptor
be given IV/IM blocker = ↑ GABA
• Phenytoin (IV) – if given IM, erratic • Gabapentin – analog of GABA but does not
absorption and tissue necrosis act on GABA receptors; unknown
• S/E: mechanism
o Nystagmus – horizontal eye • Pregabalin – analog of Gabapentin;
movement unknown MOA
▪ Most common S/E • Tiagabine – inhibits GABA uptake = ↑
▪ Doesn’t require dose GABA
adjustment; not dose • Lamotrigine – Na and Ca channel blocker;
related ↓ Glutamate conc = inhibitory effect
o Dose Related: Diplopia, Ataxia –
requires dose adjustment DRUGS FOR PARKINSONISM
o Cosmetic Changes: Gingival
hyperplasia, hirsutism Parkinson’s Disease
o Teratogenic: Fetal hydantoin • Neurodegenerative disorder
syndrome – craniofacial • Substantia nigra (stores DA) cell death = ↓
abnormalities Dopamine
• Idiosyncratic Reactions: • ↓ Dopamine ↑ ACh (responsible for
o SJS-TEN tremors and rigidity)
o Hemolytic anemia
• SSX (TRAPS):
o Tremors
VALPROIC ACID AND VALPROATE o Rigidity
o Akinesia / bradykinesia
• Mechanism of Action: o Postural imbalance
✓ Increases GABA concentration by o Shuffling gait
stimulating glutamic acid
decarboxylase (enzyme for GABA
synthesis)
✓ Blocks Na and Ca conductance
• Side Effects:
o Hepatotoxicity – should not be
given to < 2 years old
o Teratogenic: Neural tube defect /
spina bifida – use Folic Acid / Vit
B9 for prevention

LAMOTRIGINE (Lametal®) • ACh – potentiates inhibition of GABA

• Muscles (in periphery)
• MOA: Na channel blocker
o Absence of movement
• Safest in pregnancy

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o Rigidity, akinesia, tremors • S/E: Emesis

LEVODOPA OTHER DRUGS

• Does not bind to dopamine receptors • MAO-B Inh: Selegiline, Rasagiline

• Exogenous dopamine • COMT Inh: Tolcapone, Entacapone
• Dopamine precursor; DA cannot enter BBB L-DOPA –(COMT)→ 3-o-methyldopa (IA)
• L-DOPA –(DOPA decarboxylase)→ DA • Anticholinergics (BBT) – for tremor and
• Carrier: L-amino acid transporter (LAAT) rigidity (↓ ACh)
• Levodopa + Carbidopa (Sinemet®)
o Potentiation effect ANESTHETICS
o Carbidopa – peripheral DOPA
decarboxylase inhibitor Cortical
‣ Analgesia – loss of pain perception
o Peripheral DOPA decarboxylase STAGE 1 ‣ From administration of agent up to loss of
may prematurely metabolize L- consciousness
DOPA to DA = S/E and cannot Delirium / Emergence Phenomenon
enter BBB STAGE 2 ‣ Excitation of neurons
‣ ↑ BP, HR, and sympathetic tone
• Side Effects:
Surgical / Anesthetized / Optimal Stage
o Nausea and vomiting ‣ Ideal stage to do surgery
▪ Caused by ileus (D2) STAGE 3 ‣ Respiratory relaxation
▪ Effect when L-DOPA is ‣ Skeletal muscle relaxation
prematurely converted Medullary
STAGE 4 ‣ Respiratory depression = fatal
▪ Can be minimized by
Carbidopa
o Wearing off phenomenon / on- GENERAL ANESTHETICS
off phenomenon – due to the
very short T½ of L-DOPA • Inhalational or intravenous (IV)
o Transient agranulocytosis –
idiosyncratic reaction INHALATIONAL GENERAL ANESTHETICS

MOA: ↑ GABA-A and Glycine, K+ channels open

DOPAMINE AGONISTS
✓ Nitrous Oxide
• Can be used as monotherapy or adjunct to ✓ Desflurane
Levodopa ✓ Sevoflurane
• Non-Ergot: Pramipexole, Ropinirole ✓ Isoflurane
• Ergot: Bromocriptine, Cabergoline, ✓ Enflurane
Pergolide ✓ Halothane
✓ Methoxyflurane
AMANTADINE (Simmetrel®) • Nitrous Oxide /
Laughing Gas (N2O) – highest MAC; weak
• Antiviral; used primarily in the mgt of
anesthetic, potent analgesic
Influenza A
• Desflurane to Methoxyflurane – volatile
• Mechanism of Action:
liquids
✓ Increases the release of DA
• Methoxyflurane – lowest MAC; most
✓ Decreases the reuptake of DSA
potent as anesthetic; weak analgesic; used
• Side Effects:
during labor, OBSOLETE
o 4-8 wks of treatment may lead to
tachyphylaxis (duration-induced)
NOTES:
o Livido reticularis / fishnet
appearance (idiosyncratic rxn) Minimum Alveolar Concentration (MAC) – amt
of inhalational anesthetic that needs to be
APOMORPHINE absorbed in the circulation and elicit anesthetic
effect (↑ MAC = ↓ anesthetic potency)
• D2 agonist activity
• Mimics dopamine in the body
• Adjunct during off phenomenon of L-DOPA INTRAVENOUS GENERAL ANESTHETICS

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• Short Acting BZP – Midazolam, Triazolam

• Ultra Short Acting Barbs – Thiopental
• Etomidate (GABA Mimetic)
o Non-barbiturate hypnotic (ultra
short acting)
o Causes sedation but no analgesia
• Propofol
o Lowest risk for emergence
phenomenon 1. Aromatic Ring – Na channel blockade
o 1% white / milk emulsion
o Administered through IV infusion 2. Ester / Amide
o Side Effects: 3. Tertiary Amino Alkyl Group – responsible for
▪ Hypotension formation of water-soluble salts
▪ Respiratory depression
▪ Seizures AUTACOIDS
▪ ↑ arrhythmogenicity of
Epinephrine • Localized hormone
• Ketamine • Endogenous compounds – produced by all
o Similar to Phencyclidine aka cells, no need for systemic distribution
Angel Dust (Schedule 1 Drug) • Site of Action: Within area of secretion
o S/E: Dissociative anesthesia – out • Examples (BESH): Bradykinin, Eicosanoids,
of body like feeling Serotonin, Histamine

NOTES: HISTAMINE
Schedule 1 Drugs – drugs with no currently
accepted medical use and a high potential for BIOSYNTHESIS
abuse
• Location: Mast cells, basophils, stomach
(enterochromaffin cells), brain / CNS
• Opioids – analgesia, sedation
• Step: 1-Histidine undergoes (Histidine
• Combination Therapy
decarboxylase) decarboxylation to
✓ Neuroleptanalgesia: Fentanyl +
produce Histamine
Droperidol
✓ Neuroleptanesthesia: Fentanyl + RELEASE: DEGRANULATION
Droperidol + Nitrous Oxide
• Anaphylaxis – IgE mediated degranulation
/ Ca2+ dependent
• Anaphylactoid – Non-IgE mediated
LOCAL ANESTHETICS degranulation; Ca2+ independent
• MOA: Na channel blockade – induced by RECEPTORS – EFFECTS
aromatic ring
‣ Gq coupled
• Esters (One “i"): Procaine, Benzocaine
‣ Vascular Smooth Muscles / Blood
• Amide (Two “i"): Lidocaine (Xylocaine®), Vessels: Vasodilation
Bupivacaine (most cardiotoxic) ‣ Extravascular Smooth Muscles:
• S/E: Seizures • GIT: Contraction of walls
• Bronchi: Bronchospasm /
• All are vasodilators EXCEPT Cocaine – H1 Receptors Constriction = DOB
MOA: Inhibit reuptake of catecholamines ‣ Sensory Nerve Endings: Tingling or pain;
• PABA – Derivative ester-type causes pruritus / itch; wheal or flare (reflex
`hypersensitivity reaction vasodilation of cutaneous vessels)
‣ Endothelial Cells (Capillaries):
• 5% EMLA®: 2.5% Lidocaine + 2.5%
Contraction
Prilocaine ‣ CNS: Alertness / wakefulness
‣ Gs coupled receptor
STRUCTURE OF LOCAL ANESTHETICS ‣ Gastric Glands: Basal gastric acid
H2 Receptors
secretions (peaks at the height of sleep)
‣ Mast Cells: Stimulate histamine release

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‣ Presynaptic (inhibitory effect) Summary of Effects: Anti-allergy, Anti-muscarinic

H3 Receptors
‣ Inhibits further release of histamine
‣ Inflammation 1ST GENERATION / CLASSICAL
H4 Receptors ‣ Found in inflammatory cells (neutrophils)
= chemotaxis • Sedating antihistamines
• Lipophilic; can pass through BBB
• Central anticholinergic effects –
NOTES: Ethanolamine, Ehylenediamines
Triple Response of Lewis – elicited by stroking
the skin, or intradermal injection of Histamine ETHANOLAMINE
• Localized redness (red dot) • Has atropine-like effects
• Spreading erythema • Drugs:
• Swelling ✓ Diphenhydramine (Benadryl®,
Unisom® soft gel capsule)
HISTAMINE RECEPTOR AGONISTS o Antral, highest
antimuscarinic effect
• Histamine, Betahistine o Mgt of Parkinsonism and
some forms of EPS
HISTAMINE
(Pseudoparkinsonism,
• OBSOLETE; diagnostic agent Dystonia)
• Used in pulmonary function / challenge o DOC for acute dystonic
test; NEW: Methacholine crisis (dystonia)
• Diagnosis of airway hyperresponsiveness o Route: IV
(AHR) ✓ Dimenhydrinate – salt of
• Determine adequacy of gastric acid Diphenhydramine
secretion in achlorhydria ✓ Carbinoxamine
o Achlorhydria – absence of HCl ✓ Doxylamine (Unisom® tablet)
o Mgt: Dilute HCl (10%) o Sleeping aid
o Most sedating
NOTES: o Most effective H1
blocker
Most diluted acids are 10% in concentration,
EXCEPT Acetic Acid with 6% concentration ETHYLENEDIAMINE

• Not commonly used

BETAHISTINE (Serc®)
• Causes GI upset and mild sedation
• Mechanism of Action: • Drugs: Pyrilamine, Tripelennamine
✓ H3 central antagonist – leads to
the vasodilation of middle ear =
resorption of endolymph ALKYLAMINES
✓ H1 agonist
• Clinical Uses: • Brompheniramine, Chlorpheniramine
✓ For the management of vertigo • Use: Components of cold medication
(Meniere’s Syndrome)
✓ For endolymph (presence of fluid PIPERAZINES
in ear with vertigo) • Cyclizine, Meclizine (Bonamine®) – for
HISTAMINE RECEPTOR ANTAGONISTS motion sickness
• Hydroxyzine (Iterax®) – prodrug; active
• Physiologic: Epinephrine form is Cetirizine (2nd gen antihistamine)
• Pharmacologic:
✓ H1 Antagonists / Antihistamines PHENOTHIAZINES
✓ H2 Antagonists / Antacids • Promethazine (Phenergan®)
• Release Inhibitors: Nedocromil, Cromolyn • Clinical Uses:
Sodium ✓ Induce preoperative sedation
H1 ANTAGONISTS / ANTIHISTAMINES

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✓ Anesthetic adjunct – additional o Non-sedating but it can enhance

MOA: blocks Na+ channels depression effects of CNS drugs
✓ Minimize stage 2 anesthesia o Headache – most common
(excitation) o Rhinitis
✓ Minimize emergence
phenomenon NOTES:
• S/E: EPS Only 2nd gen-antihistamines are allowed to be
used by pilots. 2nd generation is less effective
PIPERIDINES
for allergic rhinitis compared to 1st generation
• Cyproheptadine 1st generation is more potent than 2nd
• Additional MOA: generation.
✓ 5-HT Antagonist – blocks 5-HT2
and 5-HT1 receptors H2 ANTAGONISTS / ANTACIDS
✓ Blocks antimuscarinic-1
• Clinical Use: Mgt of 5-HT syndrome • Drugs:
(muscle rigidity, hyperthermia) ✓ Cimetidine (Tagamet®)
o Imidazole – 5C aromatic
2ND GENERATION ring with 2N atom
o Prototype
PIPERAZINE
o Least potent
• Less sedating ✓ Ranitidine (Zantac®)
• Drugs: o Furan – 5C aromatic with
✓ Cetirizine (Virlix®, Zyrtec®, Alnix®) 1 Oxygen atom
– product of hydroxyzine ✓ Famotidine (H2-Bloc®)
✓ Levocetirizine (Allerzet®) o Thiazole – 5C aromatic
o Zykast®, Co-Altria® - with 1N and 1S atom
Levocetirizine + o Most potent
Montelukast ✓ Nizatidine (Axid®)
o Thiazole
PIPERIDINE o Has almost 100% oral BA
• Clinical Uses:
• Non-sedating
✓ Mgt of acid peptic diseases:
• Drugs:
o Mild GERD
✓ Loratadine (Claritin®, Allerta®)
o Mild dyspepsia
✓ Desloratadine
o Acute GI ulcer bleeding
✓ Fexofenadine
✓ Alt in the mgt of PUD
✓ Note: Time of administration is at
bedtime (adjunct anti-allergy)

NEWER DRUGS

• Bilastine (Bilaxten®) • Side Effects:

• Ebastine + Betamethasone (Co-Aleva®) o Cimetidine – anti-androgenic
▪ M: Gynecomastia, loss
MISCELLANEOUS 2ND GEN ANTIHISTAMINE of libido, sterility
▪ F: Infertility, loss of
Ketotifen
libido
• Additional MOA: Mast cell stabilizer – ▪ Enzyme inhibitor
inhibits the release of histamine from mast o All H2 Blockers – risk of Vit B12
cells (from food) deficiency
• Clinical Use: Seasonal allergic rhinitis (4-6
weeks before allergy season)
• Side Effects: ▪ Pepsin – degrades CHON
to absorbable form

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SEROTONIN 5-HT 1A PARTIAL AGONIST

• Drug: Buspirone
BIOSYNTHESIS
• Effect: Decrease 5-HT release in the CNS
• Location: Enterochromaffin cells (SI: • Clinical Use: Anxiolytic
>90%), CNS brainstem, platelets, GIT
5-HT 1B/1D FULL AGONISTS
• Steps: L-tryptophan undergoes:
(1) Decarboxylation, and • Drugs: (-triptans)
(2) Hydroxylation to form 5- ✓ Sumatriptan – PO, SC, intranasal
hydroxytryptamine aka 5-HT → ✓ Naratriptan – PO
Melatonin ✓ Zolmitriptan – PO
• Bioavailability:
SUMMARY OF EFFECTS
o Naratriptan – most BA (70%)
Central Effects o Sumatriptan – least BA (20%)
• Metabolism: MAO – all EXCEPT
• Mood regulation Naratriptan which is metabolized by CYP
• BP, temperature regulation • Clinical Use: Mgt of acute migraine attacks
• Appetite • Side Effects:
• Nausea and vomiting` o Increase blood pressure
o Angina pectoris
Peripheral Effects: Vasoconstriction – all blood
o Muscle pain (peripheral vascular
vessels EXCEPT a normal coronary artery and
occlusive disease / claudication)
normal skeletal muscle arteries
5-HT2
Other Effects
5-HT 2A AGONISTS
• Increase peristalsis
• Platelet aggregation • Drugs: Ergots – St. Anthony’s Fire;
Claviceps purpurea
RECEPTORS
✓ Ergotamine – PO, SL, rectal
All are G-coupled receptors EXCEPT 5-HT3, which is ✓ Ergonovine – uteroselective
ligand gated ✓ Dihydroergotamine (DHEA) – IM,
SQ, intranasal
5-HT EFFECTS
• Can be combined with caffeine to improve
‣ Location: Presynaptic (CNS / Brain)
1A
‣ Inhibits serotonin release from storage sites
absorption
‣ Location: Vascular smooth muscle • Rectal – most effective route
1B / 1D
‣ Vasoconstriction • Clinical Uses:
‣ Location: ✓ Mgt of migraine but a maximum
• Smooth muscle (vasoconstriction) of 2 doses per week
• Platelets (aggregation)
2A
• Uterine (contraction)
✓ Mgt of duster headache – can be
‣ GIT: Peristalsis given daily
‣ Bronchi: Bronchospasm ✓ Mgt of migraine headache –
‣ Location: Ergotamine
• Brain – area postrema ✓ Mgt of post-partum bleeding and
3
• CTZ – chemoreceptor trigger zone
migraine headache – Ergonovine
‣ Vomiting center, emesis
4 ‣ GIT: Peristalsis
NOTES: Risk of rebound headache if given more
than 2 doses a week
NOTES:
• 5-HT1, 5-HT4 – Agonist • Side Effects:
• 5-HT2, 5-HT3 – Antagonist o Ergotism
o Triad: Paresthesia, HTN,
digital vasospasm
SERATONERGIC DRUGS
(necrosis)
5-HT1

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o Mgt: Vasodilatory for ✓ Cisapride

24h – Na nitroprusside • Drugs: (Full Agonist)
(IV) ✓ Prucalopride
o GI discomfort – most common • Clinical Use: Mgt of irritable bowel
o Nausea and vomiting syndrome and predominant constipation
o Retroperitoneal Fibrosis – (IBS-C)
development of mass at the back
(area of kidney) EICOSANOIDS
5-HT 2C AGONIST SYNTHESIS
• Drugs:
✓ Lorcaserin – FDA approved for
obesity
✓ Fenfluramine – older drug
✓ Dexfenfluramine – older drug;
obsolete; withdrawn due to
pulmonary HTN; cardiotoxic
• Fen-Phen (Fenfluramine + Phentermine) –
weight loss products

5-HT2 ANTAGONISTS

• Drugs:
✓ Ketanserin
✓ Ritanserin
• Clinical Uses:
✓ Prevents platelet aggregation • Arachidonic Acid
✓ Used as anti-HTN agents o 5,8,11,14-eicosatetraneoic acid
o Parent compound
5-HT3 • COX-1 – constitutive; cytoprotection
• COX-2 – inducible/constitutive enzyme;
ANTAGONISTS
causes pain and inflammation; risk of clot
• Drugs: (-setrons) • Leukotrienes – SRSA (Slow Reacting
✓ Ondansetron Substances of Anaphylaxis)
✓ Granisetron o LTD4 – humans
✓ Ramosetron o LTC4 – animals
✓ Palonosetron o LTB4 – chemotactic factor
✓ Alosetron – not used as anti-
emetic; used in the mgt of IBS-D
• Routes: EFFECTS
o PO: All EXCEPT Palonosetron
Blood ‣ Vasoconstriction: TXA2, PGF2D, PGF2a
▪ Given as a single IV dose
Vessels ‣ Vasodilation: PGI2 (Prostacycline), PGI
▪ Effects lasts for around 5 Inflammation:
days • PG12 – increase blood flow
Injured
o IV – All Tissues
• PGE2 – increase blood flow;
o ID Patch: Granisetron (Sancuso®) bradykinin
• LTB4 – chemotaxis
▪ Effects 2-7 days
‣ Bronchospasm: SRSA (LTD4, LTC4), TXA2,
▪ Given 24 hours before Bronchi PGF2a
scheduled chemo ‣ Bronchodilation: PGE series, PGF, PGI2
‣ Contraction
5-HT4 Uterus
‣ Oxytocic, Dysmenorrhea: PGE, PGF2a, PGD
‣ Aggregation (Clot): TXA2
AGONISTS Platelets
‣ Inhibit Aggregation (Bleeding): PGI2
Eyes Lowering of IOP: PGF2a, PGE
• Drugs: (Partial Agonist) GIT Cytoprotection: PGE series, PGI2
✓ Tegaserod

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ANALOGS AND RELATED DRUGS PURINE –(Xanthine oxidase)→ URIC ACID

–(Uricase)→ ALLANTOIN
MEDAL: Misoprostol, Epoprostenol, Dinoprostone,
Alprostadil, Latanoprost Diagnosis: Synovial Fluid Analysis – (+) strongly
negatively birefringent needle-shaped crystals of
MISOPROSTOL monosodium
• Cytotec® Pillars of Inflammation:
• PGE1 analog – cytoprotection
• Clinical Uses: ✓ Rubor – redness
✓ Mgt of NSAID-induced peptic ✓ Calor – heat
ulcers (due to the inhibition of ✓ Dolor – pain
COX) ✓ Tumor – swelling
✓ Off Label: ✓ Function laesa – loss of function
o Ripening of cervix –
labor induction
o Renal protectant
o Abortifacient

EROPROSTENOL

• PGI2 analog – vasodilators

• Clinical Use: Acute management of
symptoms of primary pulmonary HTN

DINOPROSTONE

• PGE2 analog
• Clinical Use: Induce abortion – FDA-
approved abortifacient
STAGES OF GOUTY ARTHRITIS
ALPROSTADIL
• Asymptomatic hyperuricemia
• PGE1 analog – vasodilators • Acute gouty arthritis
• Clinical Uses: • Intercritical gout – in between episodes
✓ Mgt of erectile dysfunction • Chronic gouty arthritis
✓ Maintain potency of ductus
arteriosus

NOTES: ASYMPTOMATIC HYPERURICEMIA

Ductus Arteriosus Uric Acid
• Directs blood away from the lungs
• Should be closed • M: > 7 mg/dL
• F: > 6 mg/dL
• Indomethacin – used in its closure
Treatment: Lifestyle changes
LATANOPROST
• Diet – do not take alcohol, fruit juice and
• Xalatan® red meat
• PGF2a analog – lower IOP • Exercise
• Clinical Use: Mgt of glaucoma
ACUTE GOUTY ARTHRITIS
DRUGS FOR GOUTY ARTHRITIS Monoarthritis
GOUTY ARTHRITIS • Usually the big toe is affected
• 1st metatarsophalangeal joint – podagra
Increase in uric acid (product in purine metabolism)
of gout
and inflammation of joints

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• Initial episode / exacerbation of chronic o Management: Urinary alkalinifier

gout (NaHCO3), Hydration

Treatment: DRUGS FOR RHEUMATOLOGIC DISORDERS

✓ Colchicine
o MOA: Targets microtubules • Musculoskeletal Systems: Muscles, joints,
o Dosing: bones, ligaments, tendons
▪ 2 tablets now, after 1h, • DMARDs, Glucocorticoids, Analgesics
take another
▪ Ff day: 1 tab 2x a day DISEASE MODIFYING ANTIRHEUMATIC DRUGS
o S/E: Diarrhea
• DMARDs
✓ Pain Relievers
o NSAIDs • Drugs that can retard disease progression
o Indomethacin, Etoricoxib (more • SAARDs (Slow Acting Anti-rheumatic
common) Drugs) – 2 weeks to 6 months before
o Short acting, lipophilic clinical benefit is evident
✓ Glucocorticoids NON-BIOLOGICAL DMARDs
o If unable to tolerate NSAIDs
o If pain is severe Small molecular weight drugs
o Short course only
o Prednisone for 5 days METHOTREXATE
✓ Non-Pharmacological: Ice compress • 1st line DMARD
CHRONIC GOUTY ARTHRITIS • Mechanism of Action:
✓ Inhibits pyrimidine synthesis by
• Gouty nephropathy inhibiting 2 enzymes:
• Chronic tophaceous gout – (+) Tophi: ▪ Thymidylate synthase
subcutaneous deposits of monosodium ▪ AICAR transformylase
urate ✓ (For CA) Inhibition of
dihydrofolate reductase (folic
Treatment: acid synthesis)
✓ Colchicine – until symptom-free or as • Dosing:
advised o 7.5 – 25 mg/week (DMARD)
✓ Hypouricemic Agents – Xanthine Oxidase o 100 mg/day (Anti-CA)
Inhibitors • Side Effects:
o Mucositis – most common
o Hepatotoxicity – dose-
Allopurinol dependent; Mgt: Folinic Acid
o 1st line (100 mg → 300mg) (Leucovorin®)
o Irreversible
ANTI-MALARIALS
o Renal metabolism
o May cause SJS, cataract • Drugs:
o Prophylaxis for tumor lysis ✓ Chloroquine
syndrome ✓ Hydroxychloroquine
Febuxostat • 2nd line DMARDs
o Alternative • Mechanism of Action:
o Reversible ✓ Inhibit T-cell response to
o Hepatic metabolism mitogens that inhibit mitosis
✓ Uricosuric Agents thereby inhibiting immune cells
o Uric acid → urine → out that are normally functioning
o Sulfinpyrazone, Probenecid, ✓ Inhibit chemotaxis
Penicillamine ✓ Inhibit DNA and RNA synthesis
o For underexcreters of uric acid • Side Effects:
(uric acid stone) o Cinchonism – tinnitus, HA

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o Optic neuritis, retinal toxicity – ✓ Mgt of px with contraindications

annual eye examination to with DMARDs
monitor • Side Effects:
o Increased risk of serious
SULFASALAZINE infections
• Prodrug o Hypersensitivity (premedication
• Metabolites: with antihistamine w/ or w/o
o Sulfapyridine – active DMARD glucocorticoids)
o 5-aminosalicylate / Mesalamin – INTERLEUKIN INHIBITORS
anti-inflammatory only; for IBD
• Side Effects: • Drugs:
o GI Disturbances ✓ Tocilizumab – IL-6 inhibitor
o Sulfonamide associated toxicities ✓ Anakinra – IL-1 inhibitor
▪ Blood: Hemolysis
▪ Skin: SJS, dermatitis, OTHER DRUGS
rashes • Abatacept – T-cell activation inhibitor
LEFLUNOMIDE • Rituximab – β-cell depleting agent

• Prodrug GLUCOCORTICOIDS
• Metabolite: A77-1726
• MOA: Inhibits dihydroorotate • Drugs:
dehydrogenase (pyrimidine synthesis) ✓ Prednisone
✓ Methylprednisolone
MYCOPHENOLATE MOFETIL ✓ Dexamethasone
• Systemic Administration
• Metabolite: Mycophenolic Acid
o Mgt of RA and SLE
• MOA: Inhibits the enzyme Inosine-5’-
o For life-threatening SLE: Use
Monophosphate dehydrogenase
Methylprednisolone IV at
GOLD COMPOUNDS 1000mg intermittent
• Local Administration: For treatment of
• Drugs: osteoarthritis – every 4-6 months
✓ Auranofin – PO
✓ Aurothioglucose – IM
✓ Aurothiomalate – IM
• MOA: Inhibits chemotaxis; modifies the
morphology / function of phagocytes
• Side Effects:
o Increased risk of hypersensitivity ANALGESICS
o Nephrotic syndrome – massive
albuminuria • Drugs that can cause analgesia – loss of
pain perception
BIOLOGICAL DMARDS
• Types of Analgesics:
Large, products of recombinant DNA technology o Narcotic: Morphine and related
Agents
TNF-α INHIBITORS o Non-Narcotic: NSAIDs, COX Inh
• Drugs: NARCOTIC ANALGESICS
✓ Adalimumab – fully human
✓ Infliximab – chimeric Narcosis – manifested at stupor and insensibility
✓ Certolizumab – humanized GENERAL PROPERTIES
✓ Etanercept
• Clinical Uses: Sources:
✓ Management of RA refractory /
unresponsive to DMARDs • Papaver somniferum – Morphine;
prototype narcotic analgesic

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• Papaver bracteatum – Thebaine • Respiratory Depression – greatest threat

in narcotic poisoning
Mechanism of Action: • Tolerance – unresponsiveness to a given
✓ Stimulate the release and mimic the action dose of a drug after continuous use
of endogenous peptides: o 2-3 weeks of chronic use
o Endorphins • Physical Dependence / Addiction
o Dynorphin o Withdrawal Sx / Abstinence
o Endomorphin Syndrome:
o Len- & met- enkephalins ▪ Frequent yawning
✓ Interact with Mu receptor = Mu activation ▪ Rhinorrhea
▪ Hyperventilation
Pharmacologic Effects: ▪ Mydriasis
▪ Hostility
• CNS Effects: Analgesia, euphoria,
o Precipitants:
sedation, respiratory depression, miosis,
▪ Abrupt D/C after chronic
addiction, truncal rigidity
use; onset: 2-3 days
• Peripheral Effects: ▪ Administration of an
o Cardiovascular opioid antagonist;
▪ Cardiac: Bradycardia onset: minutes
EXCEPT Meperidine ▪ Delivery of a baby by a
▪ Vascular: Venodilation chronic opioid user
(relaxation of veins)
o Biliary Contraindications:
▪ Contraction of the biliary
tract (sphincter of Oddi) • Pregnancy
EXCEPT Meperidine • Head trauma (or any condition that
▪ CI: Acute pancreatitis – increases intracranial pressure or ICP)
backflow of pancreatic • Do not give full agonists with partial
enzymes, bile, etc. agonists (makes the partial agonist act as
o Gastrointestinal Tract full antagonist; cancellation of effects)
▪ Constipation ‣ For severe pain
▪ Tx: Laxative (Lactulose) Strong Full ‣ Morphine, Heroin, Hydromorphone,
o Mast Cells – anaphylactoid rxn Agonist Oxymorphone, Methadone, Meperidine,
o Uterus – relaxation (tocolysis) Levorphanol, Fentanyl
Mild to ‣ For mild to moderate pain
Moderate ‣ Codeine, Hydrocodone, Oxycodone,
Agonist Tramadol
‣ DI with full agonist – reduction of
analgesia
Partial Agonist
Clinical Uses: ‣ Nalbuphine, Butorphanol, Pentazocine,
Buprenorphine
✓ Mgt of pain (analgesia) ‣ Antidotes for narcotic poisoning
o Tramadol – mild ‣ Naloxone, Naltrexone, Nalorphine,
Nalmiphene, Levallorphan
o Codeine – moderate Full Agonist
o Morphine – severe ‣ Naloxone – narcotic antagonist that
✓ Mgt of acute pulmonary edema has a long duration of action
o Accumulation of fluid in lung
tissues and air spaces = impaired
gas exchange NATURAL AGENTS (OPIATES)
o Morphine – peripheral Morphine, Codeine, Thebaine
venodilation
✓ Mgt of diarrhea – Diphenoxylate, MORPHINE
Loperamide
✓ Anesthetic adjuncts – Fentanyl • Standard of comparison for analgesics
✓ Antitussive – Codeine • Low oral bioavailability (25-30%)
• Oral dose is 4x IV dose
Toxic Effects: • Has 2 active metabolites:

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o M3G: Causes convulsions METHADONE

o M6G: Active analgesic
• Metabolites normally do not cross the • Same analgesia with morphine
BBB, unless the patient has renal • Good oral bioavailability
insufficiency or renal failure (may cause • Longer duration of action
seizures) • Less rapid development of tolerance
• Used to wean off patients that are
CODEINE addicted to morphine and heroin
• 3-methylmorphine MEPERIDINE
• Standard of comparison for anti-tussives
• Product of methylation of morphine • Same activity as morphine
• Less active compared to morphine • No cardiovascular and biliary effects
• Metabolized by CYP2D6 via oxidation → • Metabolite: Normeperidine – convulsions
Morphine • Used for acute pain only

THEBAINE FENTANYL

• Precursor in the synthesis of Naloxone • Also Alfentanil, Sufentanil, Remifentanil

• Commonly used as anesthetic adjuncts
SEMI-SYNTHETIC (OPIOIDS) • Same activity as morphine
Heroin, Apomorphine, Oxymorphone, • Fentanyl – 100x more potent than
Hydromorphone, Oxycodone, Hydrocodone morphine

HEROIN LEVORPHANOL

• Diacetylmorphine / diamorphine • 5-7x more potent than morphine

• Derivative of morphine • D-isomer: Dextromethorphan – anti-
tussive
• Same efficacy with morphine
• Drug of abuse / recreational drug LOPERAMIDE, DIPHENOXYLATE
APOMORPHINE • Antidiarrheals
• Diphenoxylate (Rx) – crosses the BBB
• NOT an analgesic
• Loperamide (DOC)
• Derivative of morphine
• Lomotil® – Diphenoxylate + Atropine
• MOA: D2 agonist, D2 reuptake inhibitor =
increase DA level
• Clinical Use: Used in the mgt of PENTAZOCINE
parkinsonism
• S/E: Emesis – Tx: Trimethobenzamide • Partial kappa agonist

OXYMORPHONE & HYDROMORPHONE TRAMADOL

• Semi-synthetic morphine derivatives • Weak opioid agonist

• Same activity as morphine • Derivative of codeine
• 8-12x more potent than morphine • Used for mild pain

OXYCODONE & HYDROCODONE NON-NARCOTIC ANALGESICS

• Semi-synthetic codeine derivatives NON-STEROIDAL ANTI-INFLAMMATORY

• Same activity as codeine DRUGS (NSAIDs)
• 8-12x more potent than codeine
CHEMISTRY
SYNTHETIC (OPIOIDS)
ALL are weak acids EXCEPT Nabumetone
Methadone, Meperidine, Fentanyl, Loperamide,
Diphenoxylate, Levorphanol, Pentazocine, WEAK ACIDS WEAK BASE
Tramadol Absorbed Acidic Basic

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Excreted Basic Acidic

MECHANISM OF ACTION

✓ Inhibition of COX (Cyclooxygenase)

Pharmacodynamics (4A)

• Anti-inflammatory
o 3.2 – 4g/day
o MOA: Inhibit COX = ↓PG
• Analgesic
o < 600mg/day
COX-1 COX-2
o MOA: Inhibition of the synthesis
Previously an inducible
Constitutive enzyme enzyme, studies showed it of peripheral PG
is a constitutive enzyme • Antipyretic
EFFECT: AA → PG
EFFECT: ↓ O2 delivery = o 0.3 – 1.2 g/day
can lead to ischemia
↑ mucus, ↑ HCO3 vs. gastric o Fever: 37.2 (AM), 37.7 (PM)
BRAIN: Stroke/brain attack
acid – cytoprotective
HEART: MI/heart attack o MOA: Inhibition of the
If inhibited, ↓ PG = ↓ mucus conversion of arachidonic acid to
If inhibited, ↓ PG ↑ TXA2
and HCO3 which leads to an
(Proaggregant) PGE2
increase in the risk for PUD
PUD main causes:
1. H. pylori
NOTES:
2. NSAIDs Fever (E2 and para sa lagnat)
Diagnosis of PUD: Endoscopy • Always think of an infection
Complications of PUD: (PBO)
Perforation, Bleeding, and • Promotes the release of cytokines and
Obstruction PGE2 which acts on the hypothalamus,
NON-SELECTIVE NSAIDs resulting to an ↑ of thermoregulatory
setpoint = fever
Disadvantage: Increased risk in gastritis

ASPIRIN / ASA & SALICYLATES

Pharmacokinetics
• Antiplatelet
• Absorption: Stomach (partial), upper o < 325 mg/day
small intestine (primary site) o MOA: Irreversible (covalent
• Metabolism: Hydrolysis bond) acetylation of COX in
Aspirin –[H]→ Acetic Acid platelets, leading to decreased
• Excretion: TXA2
o < 600 mg/day (first order) o D/C 7 days before surgery
o ≥ 600 mg/day (zero order) Side Effects

Gastrointestinal Tract

• Causes peptic ulcer disease (PUD)

• High Risk for PUD:

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✓
Immunocompromised patients
(HIV/AIDS, chemo and steroids
use) Respiratory Tract
✓ Geriatrics – multiple comorbids • Aspirin-induced Bronchial Asthma
associated with multiple drugs o Bronchoconstriction → dyspnea
✓ Use of multiple NSAIDs o Use LT Antagonist: Montelukast –
✓ History of ulcer theoretical only
• To Avoid: • Aspirin Syndrome – (+) nasal polyps,
o Take NSAIDs after meals chronic sinusitis = ASA allergy
o Use mucosal protectants
▪ Misoprostol – not used Reye’s Syndrome
anymore; abortifacient
▪ Rebamipide (Mucosta®) • Viral infection in children + ASA
– increases mucus and • Liver failure, encephalopathy
bicarbonate PYRAZOLONE DERIVATIVES
Urinary Tract
• Drugs:
• Increases serum urate level ✓ Phenylbutazone
o Hyperuricemia: <2 g/day ASA ✓ Dipyrone
o Uricosuric: > 3g/day ASA ✓ Oxyphenbutazone
• Decreases glomerular filtration rate ✓ Sulfinpyrazone – gouty arthritis
(reversible) • Power anti-inflammatory and analgesics
o Afferent Arteriole: dilated by PG • Not used anymore because of side effects
(use of NSAIDs inhibit de novo
Side Effects (4A)
synthesis of PG = constriction)
• Hematotoxic
o Aplastic Anemia
▪ Hypocellular bone
marrow
▪ Absent lahat
o Agranulocytosis
▪ Decrease granulocytes
(BEN), ↑ agranulocytes
▪ ↑ risk of infection
▪ Fever, sore throat, oral
ulcers
o Pancytopenia – decrease RBC,
o If AA dilates = ↑GFR WBC, platelets
o PG = ↑AA dilation = ↑GFR o Thrombocytopenia
o NSAIDs = ↓PG = ↓GFR (acute • Hepatotoxic
kidney injury) – ↑Crea ↓CrCl, • Nephrotoxic
GFR o Acute Kidney Injury
CNS Effects
o Albuminuria
SERUM LEVEL EFFECTS ▪ Albumin: plasma CHON;
‣ Salicylism (hearing, tinnitus, vertigo) macromolecule
50–80 mg/dL ‣ Hyperventilation (↓ CO2) – give brown
▪ Appear as frothy urine,
bag
‣ Hyperthermia
edema, and anasarca
‣ Dehydration (generalized edema)
‣ Metabolic acidosis
80–110 mg/dL
• Dx: Arterial Blood Gas (ABG)
• Acidosis: ↓ HCO3 ↑ CO2
• Alkalosis: ↑HCO3 ↓ CO2
110–160 mg/dL Hypoprothrombinemia – risk: bleeding
> 160 mg/dL Renal and respiratory failure

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TEN) – 10-30% of BSA; give

steroids
▪ SJS – rashes affecting
<10% of BSA
▪ TEN – rashes affecting
>30% of BSA
• Nabumetone
o Only NSAID that is not a weak
organic acid
o Acetic acid derivative (active
▪ Glomerulus is negatively metabolite)
charged • Ketorolac
▪ Albumin is also (-) o Mgt of post-op pain (acute pain)
charged so it should NOT o Use NMT 5 days
be excreted o S/E: Nephrotoxicity
PYROLLE ALKANOIC ACID DERIVATIVES PROPIONIC ACID DERIVATIVES
• Drug: Tolmetin • Drugs:
• CI: Px with gout – causes hyperuricemia ✓ Ibuprofen
✓ Ketoprofen
INDOLE DERIVATIVES
✓ Naproxen
• Drug: Indomethacin ✓ Flurbiprofen
• Mechanism of Action • Anti-inflammatory, antipyretic, analgesic
✓ Inhibits COX (COX1 > COX2) • Naproxen – used in the mgt of fever
✓ ↓PG = closes the ductus malignancy / tumor fever
arteriosus o Naproxen Test: No lowering of
• Clinical Use: temp with APAP / ASA; suspected
✓ Mgt of pain for gouty arthritis CA
✓ For patent ductus arteriosus • S/E: Peptic ulcer disease
o Patency of connection is
FENAMIC ACID DERIVATIVES
maintained by PG

OXICAM DERIVATIVES • Drugs:

✓ Mefenamic Acid
• Drug: Piroxicam o 250 mg (OTC)
• MOA: Inhibits COX (COX1 >>>>> COX2) o 500 mg (Rx)
• Highest risk of gastritis (PUD) ✓ Meclofenamic Acid
• Used as analgesic in mild to moderate pain
PHENYLACETIC DERIVATIVES • Not intended for long term use – may
predispose px to acute kidney injury and
• Drugs:
peptic ulcer disease
✓ Sulindac
✓ Diclofenac – anti-inflammatory, SELECTIVE NSAIDs
analgesic, antipyretic
✓ Ketorolac • Coxibs, APAP
✓ Etidolac
SELECCTIVE / SPECIFIC COX-2 INHIBITORS
✓ Alclofenac
✓ Nabumetone – not a weak acid • Drugs:
✓ Meloxicam (Mobic®) – selective
• Sulindac ✓ Celecoxib (Celebrex®)
o Prodrug ✓ Etoricoxib (Arcoxia®)
o Gives rise to an active sulfide ✓ Rofecoxib (Vioxx®) – obsolete
metabolite associated with SJS because of MI
o S/E: Stevens Johnson Syndrome – • Used as analgesic for moderate to severe
Toxic Epidermal Necrolysis (SJS- pain

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• S/E: High risk of stroke and myocardial • Product: Secondary Hemostasis / Red
infarction Thrombus (Stable)

PARACETAMOL (BP) / ACETAMINOPHEN (USP) 3. Regulatory Mechanisms

• Historical: Phenacetin – causes renal • Antithrombin III – endogenous

papillary necrosis anticoagulant; inhibits IIA
• Currently: P-aminophenol • Protein C & S – endogenous anticoagulant
• MOA: Inhibition of COX – ↓PG without • Plasmin – serine protease; activated from
anti-inflammatory effect plasminogen via tPA
• Clinical Use: Analgesic, antipyretic
• Therapeutic Dose: HEMOSTASIS THROMBOSIS
o Children – 10-15 mg/kg/dose Physiologic Pathologic
o Adults – 500 mg q4h Maintain the blood in
Abnormal formation
▪ 3000mg/3g per day a fluid state but able
even if no injury
▪ Toxic: 4g/day to form clots in case of
occurred
▪ Lethal: 15g/day an injury
• S/E: Hepatotoxicity
o N-acetylparabenzoquinone imine HEMOSTASIS
(NAPQI)
o AD: NAC (Fluimucil®) Primary Hemostasis

HEMATOLOGIC DISORDERS • Platelets

• Endothelin (+) = reflex vasoconstrict
PHYSIOLOGY OF CLOT FORMATION • Steps:
o Platelet binds via GPIb to the
Triggers: Von-Willebrand Factor
o Conformational change
✓ Endothelial injury
o Granules → pro-aggregants
✓ Blood stasis
(ADP, TXA2, 5-HT)
✓ Presence of foreign material
o Interplatelet binding via GPIIb
PROTEIN AND CELLULAR EVENTS IN CLOT and GPIIIa
FORMATION • Result: Primary platelet plug (white
thrombus)
1. Platelet Migration and Aggregation – End
Product: Platelet Plug / White Thrombus (Unstable) Secondary Hemostasis

• Pro-Aggregants • Clotting factors

o TXA2, ADP, 5-HT • Recall: Coagulation cascade
o Platelet-derived o Intrinsic: XII, XI, IX, X
• Anti-Aggregants o Extrinsic: III, VII, X
o PGE1, PGE2 (Prostacyclin), cAMP
Factor I Fibrinogen
o Endothelial cell derived Factor II Prothrombin
• Receptors Factor III Tissue Thromboplastin / Factor
o GPIa – binding of platelets to Factor IV Calcium
collagen Factor V Labile Factor
Factor VII Stable Factor
o GPIb – binding to Von Willebrand
Factor VIII Anti-hemophilic Factor
Factor (VWF) Factor IX Christmas Factor
o GPIIb / GPIIa – for interplatelet Factor X Stuart Prower Factor
binding through fibrinogen bridge Factor XI Plasma Thromboplastin
Factor XII Hageman Factor
2. Activation of Blood Coagulation Cascade Factor XIII Fibrin Stabilizing Factor

• Goal: Activate Factor I (Fibrinogen) to form

Factor 1a (Fibrin) which is its stable form
• 2 Pathways: Extrinsic, Intrinsic

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✓ Bivalirudin
✓ Argatroban
✓ Dabigatran

LEPIRUDIN (IV)

• Recombinant form of Hirudin

• Less associated with hypersens reactions
• Clinical Use: 1st line for HIT (Heparin-
induced thrombocytopenia)

HIRUDIN, BIVALIRUDIN, ARGATROBAN (IV)

• Hirudin (IV) – from Hirudo medicinalis

(medicinal leech)
• Bivalirudin (IV) – used in the mgt of acute
thrombosis post-angioplasty
• Argatroban (IV) – alt to Lepirudin for HIT

• Result: Secondary platelet plug (red DABIGATRAN (PO)

thrombus); 6-12 hours • Clinical Uses:
• Regulatory Mechanisms: o For prophylaxis versus venous
• Plasminogen –(tPA)→ Plasmin (destroys thromboembolism
fibrin) o Alt to Warfarin for the ff
conditions:
NOTES: ▪ Stroke prophylaxis,
Clotting factors are produced in the liver except prevention in px with
for FVIII and Von Willebrand Factor atrial fibrillation
▪ Mgt of vascular
THROMBOSIS thromboembolic events
▪ Deep vein thrombosis
• Abnormal blood clotting • Advantage:
• No dugo o No PT-INR monitoring required
• Virchow’s Triad: (VESH) o No significant drug-food
✓ Endothelial injury interaction
✓ Stasis • S/E: Hemorrhage
✓ Hypercoagulability
• Hypercoagulable State: INDIRECT THROMBIN INHIBITORS
o Pregnancy
• MOA: Destroys the clotting factor that
o Oral contraceptive pills
activates prothrombin (FII)
o Protein C and S deficiency
• Drugs:
o Factor 5 Leiden Mutation
✓ Heparin (IV/SQ)
o Infection
✓ Warfarin (PO)
✓ Dicumarol (PO)
ANTICOAGULANTS
✓ Indanedione (PO)
✓ Apixaban (PO)
• Inhibits clotting factors
✓ Rivaroxaban (PO)
DIRECT THROMBIN (2a) INHIBITORS
HEPARIN (IV/SQ)
• MOA: Directly inactivates F(IIa), impeding
Acidic; Mixture of sulfated mucopolysaccharides
the activation of F(I) to Fibrin
Prothrombin (II) –[Xa]→ Thrombin (IIa) Clinical Uses:
Fibrinogen (I) –[IIa]→ Fibrin (Ia)
• Drugs: (Luh, HuBAD) ✓ Antiphospholipid Antibody Syndrome
✓ Lepirudin (APAS) – recurrent abortion (3x)
✓ Hirudin

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✓ For pulmonary embolism (+) dyspnea, o Requires monitoring of aPTT q6h

tachycardia – Remedy: Give caval filter until target 60-85 second delay is
(temporary) reached
✓ Used in pregnancy (LMWH) • SQ: 5000 – 15,000 units OD
✓ Mgt of acute coronary syndrome (ACS)
✓ Dialysis Monitoring for IV infusion:
✓ When initiating anticoagulation therapy • aPTT – Activated Partial Thromboplastin
with warfarin Time
✓ Prophylaxis for deep vein thrombosis
• Goal: 60 – 85 sec delay
(DVT) and venous thromboembolism (VTE)
• < 40 = underdose
Side Effects: • > 40 = overdose

• Hemorrhage / bleeding – Tx: Protamine LOW MOLECULAR WEIGHT HEPARIN

SO4 (AD for heparin toxicity)
• MOA: Inhibits Xa
• Heparin-induced Thrombocytopenia (HIT)
• Drugs:
o Immune-mediated response
✓ Enoxaparin (Clexane®)
o Decreased platelet count =
✓ Dalteparin
thrombosis
✓ Tinzaparin
o Tx: Lepirudin, Hirudin,
• Route: SQ; usually available in pre-filled
Argatroban
syringes
• Osteoporosis
o Ex: Enoxaparin – 1mg/kg; 0.4
• Alopecia
units (0.6 to 0.8)
Contraindications: Thrombocytopenia, active • Monitoring: None required to monitor
bleeding aPTT; if needed = Factor Xa Assay

WARFARIN (PO)

Historical

• Warfarin: Wisconsin Alumni Research

Foundation (Arin = Coumarin)
• Bishydroxycoumarin (Dicumarol)
o From spoiled sweet clover
o 1st oral anticoagulant
o S/E: Bleeding
o Current Use: Rodenticide
• Indanedione
o Anisindione, Phenindione
o S/E: Thrombocytopenia,
Hypersensitivity
HIGH MOLECULAR WEIGHT HEPARIN • Phenprocoumon
o Very long T½
• Aka Unfractionated / Regular Heparin o S/E: Bleeding
• 1500 – 3000 Daltons
Mechanism of Action (Warfarin):
• MOA: Forms an active complex with ATIII
(Anti-thrombin III) by 1000-fold → ✓ Inhibits Vit K Epoxide Reductase Complex
inactivation of IXa, Xa, XIa, XIIIa (VKERC)
• Effect: Within 6 hours

Administration:

• Thromboembolism: 80 units/kg then 80

units/kg/hr infusion
• Acute Coronary Syndrome: 50 units/kg
then 15 units/kg/hr

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✓ Inhibition of hepatic synthesis of Vit K Drug Interactions

dependent clotting factors (II, VII, IX, X) –
↑ PT-INR (Hemorrhage) ↓ PT-INR (Thrombosis)
1972 Enzyme inducer, green leafy
✓ Inhibits Protein C & S (endogenous Enzyme inhibitor, Aspirin,
vegetables, Cholestyramine,
Heparin, Cirrhosis
anticoagulants / anti-clotting factors) hypothyroidism

Effects
NOVEL ANTICOAGULANTS (NoAC)
• Initial: Inhibition of Protein C and S (T½ =
6-24 hours) – Procoagulation • Rivaroxaban, Apixaban
• Final: Inhibition of Vit K dependent clotting • MOA: Inactivates Factor Xa
factors (T½ = 6-60 hours) • No monitoring required

Bridging Anticoagulation – Heparin then Warfarin ANTIPLATELETS

because Warfarin only inhibits new clotting factors
Acts against primary hemostasis
HALF-LIFE DAY/S
7 ½ day TXA2 INHIBITORS
9 1 day
10 2 days Aspirin
2 3 days
• MOA: Irreversibly acetylates the COX in
the platelets
Monitoring (Usual 1-2 mg): PT-INR • Low TXA2 = inhibit platelet aggregation
• Duration: Entire lifespan of platelets (8-10
• Caucasians: 5 mg daily days)
• Asians: 1-2 mg daily • Clinical Uses:
• PT-INR: Prothrombin Time – International ✓ 1st line antiplatelet
Normalized Ratio: 2-3 ✓ For primary and secondary
o PWET IN PHITT prevention of acute thrombotic
▪ Warfarin: Extrinsic, PT event (stroke, MI)
▪ Heparin: Intrinsic, PTT • Side Effects:
o ↑ INR = dugo o Bleeding
o ↓ INR = no dugo o PUD
o Acute kidney injury
Clinical Uses: Chronic conditions requiring
anticoagulation EXCEPT pregnancy: ADP INHIBITORS
✓ Heart failure = stasis (clot formation) • Thienopyridines: (Irreversible)
✓ Chronic atrial fibrillation ✓ Ticlopidine
✓ Prosthetic heart valve ✓ Clopidogrel
✓ Rheumatic heart disease • Non-Thienopyridine: (Reversible)
✓ DVT, VTE ✓ Ticagrelor
Side Effects: TICLOPIDINE (Ticlid®)
• Hemorrhage – Tx: Vit K1 • 250 mg BID
• Cutaneous necrosis due to procoagulant • Full effect is seen in 11 days
effect – Remedy: Co-administration with • Clinical Uses:
Heparin ✓ For transient ischemic attack
• Purple Toe Syndrome – 2-3 weeks use of o (+) neurologic deficit >
Warfarin 60 mins
• Teratogenic Effects o (-) infarct on imaging
o 1st Trimester: Hypoplastic nose ✓ Alt to ASA in stroke prophylaxis
o 3rd Trimester: Hemorrhagic • Side Effects:
disease of the newborn, o Thrombocytopenia – purpura /
necrotizing enterocolitis rashes
o Neutropenia

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CLOPIDOGREL (Plavix®) ✓ Tirofiban

• Clinical Use: Mgt of acute thrombus post-
• 75 mg OD angioplasty
• Replaced Ticlopidine • S/E: Hemorrhage
• Prodrug; metabolized by CYP 2C19 to its
active form FIBRINOLYTIC AGENTS
• Advantage: Not associated with
neutropenia and thrombocytopenia • MOA: Accelerates the activation of
• Clinical Uses: Plasminogen to Plasmin (destroys fibrin)
✓ Alt to ASA in stroke prophylaxis • DO NOT give if px has the ff:
✓ Dual antiplatelet therapy (ASA + ✓ Bleeding
Clopidogrel) ✓ Head trauma
o 2 wks if STE-ACS ✓ Brain tumor
o 12 months if non-STE- ✓ Brain hemorrhage
ACS ✓ Vascular anomalies
PHOSPHODIESTERASE INHIBITORS STREPTOKINASE
• MOA: Inhibits PDE; increase cAMP = • From Streptococcus pyogenes
increase anti-aggregant = antiplatelet • Clinical Use: Fibrinolytic for ACS
• S/E: Hypersensitivity Reaction (ensure 2-
year interval)

RECOMBINANT tPA

• Plasminogen –[tPA]→ Plasmin

o tPA: 0.9mg/kg
• Drugs:
✓ Alteplase – natural
✓ Reteplase – recombinant
• Golden Period: Last seen normal (ictus) to
time of injection – IV: 3h; IA: 6h
• Drugs:
• Brain Attack:
✓ Dipyridamole
o Ischemic (FAST)
✓ Cilostazol
▪ Facial asymmetry
DIPYRIDAMOLE ▪ Arm weakness
▪ Slurring of speech
• MOA: Inhibits PDE5 ▪ Time
• Used in pharmacologic stress test o Hemorrhagic – ruptured BV; (+)
• Alternative antiplatelet HA
• S/E: Coronary steal phenomenon
(vasodilation) OTHERS

CILOSTAZOL • Anistreplase – Anisoylated Plasminogen

Streptokinase Activator Complex (APSAC)
• MOA: Inhibits PDE3 • Urokinase – from mammalian urinary
• For peripheral arterial occlusive disease epithelium (kidneys)
(PAOD)
o (+) Intermittent claudication – PROTHROMBIC AGENTS
pain in the leg while walking
o Risk Factors: DM, Smoking VITAMIN K

GLYCOPROTEIN IIB/IIIA INHIBITORS • MOA: Vitamin K = Increase 1972

• Types:
• Drugs: o Vit K1 (Phylloquinone /
✓ Eptifibatide Phytonadione) – plants; clinically
✓ Abciximab useful

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o Vit K2 (Menaquinone) – ✓ Preload

synthesized by colonic bacteria; o Aka End Diastolic Volume /
flora Venous Return (blood that
o Vit K3 (Menadione) – water- returns to the heart)
soluble; used in assays o Volume in the heart prior to
• Clinical Use: contraction or end
✓ For hemorrhagic disease of the o Factors:
newborn ▪ Tone of the veins
✓ Tx of bleeding associated with Vit (pressure) / capacitance
K deficiency → Venodilators
▪ Fluid content of the
EPSILON AMINOCAPROIC ACID ANALOG blood (increased Na and
• Drug: Tranexamic Acid (Hemostan®) H2O increases preload)
→ Aldosterone antag,
• MOA: Inhibits plasminogen activation
Diuretics
• Clinical Use: For mild to moderate
bleeding (post-op dental surgery,
NOTES:
hemoptysis)
Arteries – carries blood away from the heart;
SERINE PROTEASE INHIBITOR greatest pressure
Veins – carries blood towards the heart; least
• Drug: Aprotinin
pressure; IVALIK
• MOA: Inhibits serine protease (plasmin)
• Clinical Use: Mgt or to minimize bleeding
in px undergoing CABG (Coronary Artery SYSTEMIC VASCCULAR RESISTANCE /
Bypass Graft) TOTAL PERIPHERAL RESISTANCE /
PERIPHERAL VASCULAR RESISTANCE
CARDIOVASCULAR DRUGS • Pressure required by the blood to be
ejected from the heart
BLOOD PRESSURE CONTROL AND REGULATION
• Factors Affecting Afterload:
BP = CO x SV o Tone of the arteries (pressure /
resistance) – Ex. Arteriolar
CARDIAC OUTPUT (CO) vasoconstriction, narrow
diameter (↑ SVR, BP)
CO = HR x SV (vol/min)
COMPENSATORY MECHANISM OF BP CONTROL
• Volume of blood pumped out by the hear
per minute • Baroreceptor Reflex
• HR = chronotropy (bilis ng pagtakbo ng • Renin-Angiotensin-Aldosterone System
puso); ↑ CO ↑ BP
o HR – affected by drugs that bind BARORECEPTOR REFLEX
to β1, M1
• For short term BP control and rapid BP
• Inotropy – contraction
regulation
• Dromotropy – conduction
• Sensory Organs: Carotid Sinus, Aortic Arch
Stroke Volume – volume of blood pumped out by • Stimulus: Change in arterial pressure
the heart per contraction or beat; directly
proportional with cardiac output

Factors:

✓ Strength of Myocardial Contraction

o Inotropy – affected by drugs that
bind to β1
o Direct relationship with SV, CO, • CN IX: Glossopharyngeal Nerve
BP • CN X: Vagus Nerve
o ↑ Inotropy = ↑ SV, CO, BP • Efferent: ↓ HR, BP, Inotropy

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HTN Crisis ≥ 180 mmHg ≥ 120 mmHg

NOTES: Baroreceptor Reflex Components
• Baroreceptors – carotid sinus, aortic
arch TYPES OF HYPERTENSIONS
• Afferent Pathways (Baroreceptor →
Primary / Essential HTN – no identifiable cause
Control Center) – CN IX, CN X
• Control Center – Vasomotor Center Secondary HTN – with identifiable cause
• Efferent Pathways – Responses
Special Types of HTN
• Effector Organ – Heart
• Gestational HTN / HTN in Pregnancy
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM o Renal hypertension at the
beginning of pregnancy
• Effect: Increase BP o Albuminuria
• For long term BP regulation o Pre-eclampsia, eclampsia (+)
• Triggers: (Renin Release) seizure – Tx: MgSO4 / Epsom Salt
✓ β1 activation (heart and o Drugs for Mgt: (HLMN)
juxtaglomerular apparatus) ✓ Hydralazine
✓ Renal hypotension – marked ✓ Labetalol
reduction of BP in the kidneys ✓ Methyldopa
✓ Renal hypoperfusion – low blood ✓ Nifedipine
supply in the kidneys • Hypertensive Crisis
o Hypertensive Urgency
▪ DBP ≤ 120 mmHg
Angiotensinogen RENIN ▪ Asymptomatic
Angiotensin I
(Liver)
(Kidney) ▪ No target organ damage
▪ Tx: Rapid acting HTN
drugs (PO/SL/IV)
PO/SL: Captopril /
ACE / KININASE II (Lungs)
Clonidine / Nifedipine
1. AT1 & AT2 Receptors IV: Nicardipine (Bolus)
Gq coupled → Vasoconstriction
Angiotensin II o Hypertensive Emergency
2. ↑ Sympathetic Activity ▪ Malignant HTN
Increased exocytosis of NE
▪ Symptomatic with target
3. ↑ Release of Aldosterone organ damage – caused
Increased H2O & Salt Retention by low blood perfusion
= ↑ fluid content of blood = ↑
Preload, SV, CO, BP due to vasoconstriction
▪ SSX: Encephalopathy,
4. Stimulates the release of
ADH
AHF, ARF, Papilledema
H2O Retention = ↑ fluid (swelling of optic arcs or
content of blood = ↑ Preload, discs)
SV, CO, BP
▪ Tx: Anti-HTN (IV inf)
BLOOD PRESSURE CATEGORIES THERAPEUTIC GOALS
JNC 7 SYSTOLIC BP DIASTOLIC BP
Pharmacologic:
Normal < 120 mmHg AND < 80 mmHg
Pre-HTN 120 – 139 mmHg OR 80 – 89 mmHg
• Lower BP by altering CO, SVR, and BV
HTN Stage 1 140 – 159 mmHg OR 90 – 99 mmHg
HTN Stage 2 ≥ 160 mmHg OR ≥ 100 mmHg • Delay or limit subsequent organ pathology
JNC 8 BP GOAL • Drugs:
< 60 years old < 140 / < 90 mmHg ✓ Diuretics: ↓ BV
≥ 60 years old < 150 / <90 mmHg ✓ Sympathoplegics: ↓CO (β), SVR
AHA (Recent
Guidelines)
SYSTOLIC BP DIASTOLIC BP (α)
Normal < 120 mmHg AND < 80 mmHg ✓ Vasodilators: ↓ SVR
Pre-HTN 120 – 129 mmHg AND < 80 mmHg ✓ CCBs: ↓CO, SVR
HTN Stage 1 130 – 139 mmHg OR 80 – 89 mmHg ✓ Angiotensin Antagonist: ↓ BV,
HTN Stage 2 ≥ 140 mmHg OR ≥ 90 mmHg SVR

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Non-Pharmacologic: Lifestyle Modifications 3. Thick Ascending Limb (TAL)

• Na restriction • Reabsorption of Na, K, and Cl ions

• Increase K intake • Secondary reabsorption of Mg, Ca
• Smoking cessation (divalent ions)
• Moderate alcohol consumption • Water impermeable
o Females: 1 glass/day • Drug: Loop Diuretics
o Males: 2 glasses/day
• Exercise 4. Distal Convoluted Tubule (DCT)

• Reabsorption of Na, Cl
DIURETICS • Reabsorption of Ca (mediated by PTH)
• Water impermeable
• Increase urinary excretion of Na
• Drug: Thiazide Diuretics
(natriuresis) and H2O (aquaresis) = diuresis
(↓ BV = ↓ BP) 5. Collecting Duct (CD)
• Site of Action: Kidney Tubule
• Reabsorption of Na
• Secretion of K
• Drug: Potassium Sparing Diuretics

CARBONIC ANHYDRASE INHIBITORS

• MOA: Inhibits carbonic anhydrase in the

PCT (kidneys), eyes, and brain
• Site of Action: Proximal Convoluted
Tubule (PCT)
• Sulfonamide-like compounds
• Active Moiety: Sulfamoyl (SO2 – NH2)
• Drugs: (-zolamides)
✓ Acetazolamide (Diamox®)
✓ Dorzolamide
✓ Brinzolamide
PARTS OF THE KIDNEY TUBULE ✓ Dichlorphenamide

1. Proximal Convoluted Tubule (PCT)

• Main site of HCO3- reabsorption

• Reabsorption of Na ions (minimal amount)
• Water permeable
• Drugs: (COMA)
✓ Carbonic Anhydrase Inhibitors
(CAIs)
✓ Osmotic Diuretic (Mannitol)
✓ Methylxanthine (Caffeine)
✓ Acidifying salts (NH4Cl)

2. Thin Descending Limb (TDL)

• Water permeable
• Drug: Osmotic Diuretic (Mannitol)
EFFECTS
• NOTE: Mannitol is an aquaretic (H2O
excretion) = water permeable PCT and TDL 1. Proximal Convoluted Tubule

• Inhibits Na+ reabsorption = ↓ in blood Na

(short-lived natriuretic effect that lasts for
NMT 3 days) – NOT Anti-HTN

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• Inhibits HCO3 reabsorption = ↓ blood • Site of Action: Thick Ascending Limb (TAL)
HCO3 (continuous) – metabolic acidosis • Drugs:
✓ Sulfonamide-like Compounds
2. Eyes (Ciliary Bodies) – inhibit aqueous humor o Furosemide (Lasix®)
production = lower IOP – Anti-glaucoma o Bumetanide
3. Brain (Choroid Plexuses) – inhibit production of ✓ Sulfonylurea: Torsemide
CSF = reduction of head size ✓ Phenoxyacetate: Ethacrynic Acid

CLINICAL USES

✓ First line in the mgt of open angle

glaucoma
✓ For urinary alkalinization (↑ urine HCO3)
during acidic drug poisoning =
neutralization
✓ Useful as presurgical treatment in acute
angle closure glaucoma
✓ Mgt of metabolic alkalosis
✓ Mgt of acute mountain sickness (inhibit
CSF production)
✓ Mgt of catamenial seizure (in women;
seizure during menstruation) —
EFFECTS
Acetazolamide

SIDE EFFECTS • Decreased serum Na, K, Cl, Ca, Mg (↓↓)

• Furosemide – vasodilating effect
• Increased risk of metabolic acidosis due to
HCO3 wasting CLINICAL USES
• Sulfonamide-associated S/E: Dermatitis Edematous:
or rashes (SJS-TEN)
• Hematologic: Hemolytic anemia, aplastic ✓ Adjuncts in the mgt of pulmonary
anemia, neutropenia congestion in CHF
• Hypersensitivity reaction ✓ Acute pulmonary edema – Furosemide

CONTRAINDICATIONS Non-Edematous:

• Px with COPD (px are already acidotic) ✓ Mgt of oliguric and anuric ARF
• Px with Chronic Liver Disease (↑↑ ✓ Mgt of anion poisoning
ammonia by-product in the urine) = ✓ Mgt of hyperkalemia and hypercalcemia
encephalopathy SIDE EFFECTS

• Electrolyte imbalance
• Sulfonamide-associated S/E: SJS-TEN,
hemolytic anemia
• Ototoxicity – increased when combined
with Aminoglycosides, Cisplatin; highest
risk: Ethacrynic Acid
LOOP / HIGH-CEILING DIURETICS • Metabolic-associated S/E: (HyperGLU)
o Hyperglycemia
• Has a dose-dependent effect (↑ Dose = ↑ o Hyperlipidemia
Diuresis) o Hyperuricemia
• Mechanism of Action:
✓ Inhibits Na-K-2Cl (NK2Cl) Co- THIAZIDE DIURETICS
transporter in TAL
• One of the first line drugs in the tx of HTN
✓ Inhibits Na-K Pump – highly
efficacious natriuretic • MOA: Inhibits Na-Cl Co-transporter in the
✓ Inhibits K-2Cl Co-transporter DCT

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• Site of Action: Distal Convoluted Tubule POTASSIUM SPARING DIURETICS

(DCT)
• Drugs: • Site of Action: Collecting Duct
✓ Benzothiadiazides / True • Aldosterone Antagonists
Thiazides o Higher DOA
o Hydrochlorothiazide o Natriuresis
(HCTZ) o Drugs:
o Chlorothiazide ✓ Spironolactone
✓ Thiazide- like (lacks the Thiazide ✓ Eplerenone
ring) • Epithelial Na+ Channel Blockers
o Indapamide o Lower DOA
o Metolazone o Drugs:
o Chlorthalidone ✓ Amiloride
✓ Sulfonamide-like compounds ✓ Triamterene

EFFECTS CLINICAL USES

• Phase 1: Diuretic Effect / Natriuresis – 2 Alternative agent in:

weeks only ✓ Prevention / treatment of diuretic-induced
• Phase 2: Vasodilation (> 2 weeks of use) hypokalemia
• Activate COX2 = ↑ PGE2 = greater diuresis ✓ Adjuncts in the mgt of CHF
• Enhance PTH activity = enhances Ca2+
reabsorption (Hypercalcemia) Management of: (Spironolactone)

CLINICAL USES ✓ Hyperaldosteronism-induced HTN

✓ Polycystic ovary syndrome (PCOS) – anti-
✓ First line for HTN (ABCD) androgenic
o < 55 years old – ACEi / ARBs ✓ DOC for px with hepatic cirrhosis (↑↑
o > 55 years old – Thiazide Diuretics Aldosterone); Loop and Thiazide Diuretics
& CCBs are ineffective
✓ Adjuncts in the mgt of CHF (excessive H2O ✓ DOC in resistant HTN
retention)
✓ Mgt of nephrogenic DI – vasopressin SIDE EFFECTS
imbalance
• Hyperkalemia
✓ Mgt of nephrolithiasis (causes
• Spironolactone:
hypocalcemia)
o Anti-androgenic
o Gynecomastia and decreased
NOTES:
libido in men
There is hypocalcemia in nephrolithiasis (Ca
o Hirsutism and infertility in
oxalate in kidney stones), one of the effects of women
thiazide is hypercalcemia • Triamterene: Increased risk of renal stone
formation
SIDE EFFECTS
MANNITOL (Aquaretic/Osmotic Diuretic)
• Electrolyte imbalance (all HYPO EXCEPT
Ca) • MOA: Creates osmotic gradient
• Sulfonamide-associated S/E (movement of water from low to high
• Metabolic-associated S/E (HyperGLU) concentration) in water-permeable
o CI: Gout, ACEi regions (PCT, TDL) of the kidney tubule
• DI: NSAIDs = COX (Antagonistic) • Site of Action: PCT, TDL
• Clinical Use:
✓ Mgt of increased intracranial
pressure (ex. cerebral edema)
✓ IV: Diuretic
✓ PO: Osmotic Laxative
• S/E: Dehydration, hypovolemia, hyperNa

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SYMPATHOPLEGICS HYDRALAZINE (IV)

• MOA: Increase levels of Nitric Oxide

Paralysis of the sympathetic NS = decrease
(endogenous vasodilator) = increase cGMP
sympathetic outflow (vasodilation, bradycardia)

CENTRALLY ACTING NOTES: When there is increased NO, there will

also be an increase in cGMP. NO interacts with
• ↓ CO, SVR guanylate cyclase. GTP is thus converted to
• Site of Action: Vasomotor Center cGMP, which dephosphorylates MLC-PO4 /
• Drugs: (α2 Agonists) myosin light chain phosphate (responsible for
✓ Clonidine
vasoconstriction) causing a vasodilating effect
✓ Methyldopa
✓ Guanfacine
✓ Guanabenz • Clinical Uses:
✓ Mgt of HTN specifically in
PERIPHERALLY ACTING pregnant patients with HTN crisis
✓ Adjunct in the mgt of CHF (with
• α blockers – ↓ BP, SVR (vasodilation) ISDN) in African American px
• β blockers – ↓ CO, BP • S/E: Systemic Lupus Erythematosus (SLE)
• Adrenergic Neuronal Blockers • CI: Px with ischemic heart disease
o Alters the physiology in the pre-
synapse (storage in vesicles, MINOXIDIL
exocytosis)
o Reserpine: inhibits vesicular • MOA: Induce the opening of K channels in
storage of Dopamine the vascular / arteriolar smooth muscles
o Bretylium, Guanethidine, • Clinical Use:
Guanadrel: inhibits the release of ✓ Most efficacious but alt only for
NE via exocytosis HTN crisis
• Ganglionic Blockers – obsolete because of ✓ Off Label (Topical): Regeneration
its unpredictable effects of hair, for alopecia
o Nn blockers • S/E: Hirsutism, hypertrichosis
o Trimethaphan
o Hexamethonium NOTES: Opening of K+ channels, hyperpolarizes
o Mecamylamine the cell (overly negative) = relaxation /
vasodilation
VASODILATORS
DIAZOXIDE
PURE ARTERIOLAR VASODILATORS
• MOA: Same with Minoxidil
• 1st line in HTN emergency • Clinical Uses:
• Pure = Arteries only ✓ Alt for HTN crisis
• Common Toxic Effects: (Monotherapy) ✓ Mgt of hypoglycemia secondary
o All arteriolar vasodilators cause to insulinoma
reflex tachycardia (compensatory • Side Effects:
effect) o Hyperglycemia – inhibits insulin
o Peripheral edema (leakage of release
H2O into the tissue) o Metabolic associated: HyperGLU
• Combinations to prevent T/E:
✓ β-blockers: For reflex tachycardia MIXED ARTERIOLAR / VENODILATOR
✓ Diuretics & ACEi/ARBs: Edema
Sodium Nitroprusside

• Cyanide-containing
• MOA: Increase levels of Nitric Oxide
(endogenous vasodilator) = increase cGMP
• Clinical Use: 1st line in HTN emergency

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• S/E: Accumulation of CN (inhibits • Diltiazem

cytochrome oxidase = cellular respiration o Intermediate action
is inhibited) o Acts on the heart and blood
o Management: vessels
▪ Cyanide Antidote Kit o Dose: 30 mg, 60 mg
• Amyl nitrate
BASED ON DURATION OF ACTION
• Na nitrite
• Na thiosulfate • Intrinsically Short-Acting
▪ Hydroxocobalamin or • Intrinsically Long Acting
hydroxycobalamin • Modified Long Acting
▪ High dose of methylene
blue INTRINSICALLY SHORT ACTING

NOTES: Sodium Nitroprusside must be freshly • All DHPs EXCEPT LAL:

✓ Lercanidipine
prepared and used within 24 hours as it is prone
✓ Amlodipine
to photodegradation.
✓ Lacidipine
• All non-DHPs
CALCIUM CHANNEL BLOCKERS (CCBs) • Side Effects:
o Reflex tachycardia (use w/ β
• Site of Action: Heart, Arterial SM blockers)
• MOA: Block L-type Ca channels (Muscle o Peripheral edema (use w/ ACEi,
contraction) ARBs or diuretics)
• Clinical Uses:
INTRINSICALLY LONG ACTING
✓ 1st line for HTN
✓ Anti-angina • LAL: Lercanidipine, Amlodipine, Lacidipine
✓ Anti-arrhythmic (Class IV) • NOT associated with reflex tachycardia
• Potency: DHP >> Diltiazem > Verapamil and peripheral edema
BASED ON STRUCTURE MODIFIED LONG ACTING
• Dihydropyridines • Intrinsically short-acting but have been
• Non-dihydropyridines made available as modified release
DIHYDROPYRIDINES • Adalat GITS® – Nifedipine MR
• NOT associated with reflex tachycardia
• Dose: 5 mg, 10 mg and peripheral edema
• Drugs: (-dipines)
✓ Amlodipine (Norvasc®) ANGIOTENSIN ANTAGONISTS
✓ Nifedipine (Adalat®)
✓ Nicardipine (Cardine®) • Inhibits synthesis and action of ATII
• Vasoselective CCBs (Arteries) • Synthesis: ACEi, Aliskiren (Renin Inhibitor)
• S/E: Reflex tachycardia, peripheral edema • Action: ARBs

NON-DIHYDROPYRIDINES ANGIOTENSIN CONVERTING ENZYME INHIBITORS

• Verapamil • MOA: Prevents formation of Angiotensin II

o Most cardioselective • Effects:
o Greatest depressant effect in the ✓ Decrease ATII, BV, SVR
heart amongst all CCBs ✓ ↑ Bradykinin = ↓ SVR
o Dose: 80 mg, 160 mg, 240 mg • All (-prils) are prodrugs EXCEPT Acute ACEi
o Side Effects: where their parent molecules are already
▪ AV Block (w/ β blockers) active:
▪ Constipation ✓ Captopril
✓ Lisinopril
✓ Enalaprilat (IV)

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• Clinical Uses: • Contraindications:

✓ 1st line in HTN o Pregnancy (Teratogenic: Renal
✓ Base treatment in patients with Dysgenesis, Oligohydramnios)
CHF o SBP <100mmHg
✓ 1st line in the mgt of HTN in px o Pre-existing hyperkalemia
with CKD w/ or w/o DM
✓ 1st line in the mgt of albuminuria RENIN INHIBITOR (ALISKIREN)
• Side Effects: • Clinical Use: Add on to ACEi and ARBs
o Dry Cough – due to bradykinin; do • S/E: Dry cough, rashes, angioedema
not shift immediately; lower the
dose or stop therapy DRUGS FOR ANGINA PECTORIS
o Angioedema – shift to ARBs
o Hyperkalemia Angina Pectoris aka Coronary Artery Disease (CAD)
o Interstitial nephritis / Coronary Heart Disease / Ischemic Heart Disease
o Hypotension – characteristic chest pain due to insufficiency of
• Contraindications: oxygenated blood reaching the myocardium
o Pregnancy (Teratogenic: Renal
Dysgenesis, Oligohydramnios) CAUSES
o SBP <100mmHg
• Atherosclerosis – hardening of arterial
o Pre-existing hyperkalemia
walls
• Thrombosis – stationary clot
• Embolism – mobile clot
• Vasospasm / Arteriolar Vasoconstriction

CONSEQUENCES

• Ischemia – low oxygenation of

myocardium; cells still viable
NOTES: Effects include increasing serum • Infarction – absence of oxygenation;
bradykinin (an autocoid) which induces the death of myocardial cells
release of NO and PGI2 (prostacyclin) causing PATHOPHYSIOLOGY
vasodilation
O2 supply (coronary arteries) – demand (heart)
ANGIOTENSIN RECEPTOR BLOCKERS / mismatch
ANGIOTENSIN II ANTAGONISTS
Acute Coronary Syndrome (ACS)
• MOA: Prevents the action of ATII by
• Chest pain lasts for 15-20 minutes
blocking the binding of ATII to its receptor
• Cannot be relieved by resting or by taking
• Drugs: (-sartans)
SL nitrates
✓ Losartan – 50mg, 100 mg
✓ Valsartan Chronic Stable Angina Pectoris / Effort Angina
✓ Candesartan (CSAP)
✓ Eprosartan
✓ Olmesartan • Precipitated by physical exertion or
• Clinical Uses: emotional stress (taking exercise)
✓ 2nd line in HTN • Lasts for 2-5 minutes
✓ 1st line in the mgt of HTN in px • Can be relieved by resting or by taking SL
with CKD w/ or w/o DM nitrates (low dose)
✓ 1st line in the mgt of albuminuria • Increased myocardial O2 demand
• Side Effects: • Goal: Decrease O2 demand
o Hyperkalemia
o Interstitial nephritis
o Hypotension

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Prinzmetal / Vasospastic / Variant Angina Pectoris CALCIUM CHANNEL BLOCKERS

• Persistent coronary artery vasospasm • Non-DHP – alt maintenance for CSAP

• Low O2 supply • Long Acting and Modified Long Acting –
• Goal: Increase O2 supply alt for Prinzmetal

NITROVASODILATORS / ORGANIC NITRATES DRUGS FOR HEART FAILURE

• MOA: NO stores induce the formation of
Heart Failure
cGMP which is responsible for vasodilation
• Drugs: • Pump / mechanical failure / systolic heart
o Very Short Acting (< 5-10 mins) failure
✓ Amyl nitrate (inhalation) • Left Sided: Pulmonary Edema
o Short Acting (15-20 mins) • Right Sided: Peripheral Edema
✓ Isosorbide dinitrate (SL)
✓ Nitroglycerin (SL) Signs and Symptoms:
o Intermediate Acting (5-8 hours)
✓ Dyspnea on exertion (DOB)
✓ Isosorbide dinitrate (PO)
✓ Orthopnea – DOB when lying plain in bed
✓ Nitroglycerin (SR PO)
✓ Paroxysmal Nocturnal Dyspnea
o Long Acting (10-24 hours)
✓ Presence of 3rd heart sound (S3)
✓ ISDN (SR PO)
o S1, S2 – normal heart sounds
✓ NTG Transdermal Patch
✓ Edema
✓ ISMN (PO)
✓ Cardiomegaly – irreversible
• Effects: (Dose-Dependent)
o Low Dose (SL): Venodilation (Tx NEW YORK HEART ASSOCIATION (NYHA)
for CSAP); ↓ preload, SV, Classification of HF Patients
workload = ↓ O2 demand Class I No limitation of physical activity
Class II Slight limitation of physical activity
o High Dose (IV): Arteriolar Class III Marked limitation of physical activity
(coronary artery) = Vasodilation = Class IV At rest, symptoms are experienced
↑ O2 supply (Tx for Prinzmetal) AMERICAN COLLEGE OF CARDIOLOGY /
• Clinical Uses: AMERICAN HEART ASSOCIATION (ACC / AHA)
Stage A No HF; high risk
✓ Tx of angina pectoris
With structural heart disease;
✓ Mgt of acute pulmonary edema Stage B
w/o signs and symptoms
✓ Alt in the mgt of HTN crisis With structural heart disease;
Stage C
✓ Adjunct in the mgt of CHF (ISDN with signs and symptoms
w/ Hydralazine) Stage D Refractory HF
✓ Mgt of CN Poisoning – Amyl
nitrite
Therapeutic Goals:
• Side Effects:
o Hypotension – DI: PDE5 Inh ✓ Increase the force of myocardial
(Sildenafil, Tadalafil, Vardenafil) = contraction with the use of inotropic
Fatal Hypotension agents
o Vascular / Throbbing HA ✓ Decrease the workload of the heart via
o Tolerance – Monday Disease unloader medication (afterload and
o Methemoglobinemia – Amyl preload unloaders, anti-HTN)
Nitrite
INOTROPIC AGENTS
BETA BLOCKERS
Digoxin, Beta Agonists, Bipyridines
• 1st line maintenance treatment of CSAP
(Decrease O2 demand) DIGOXIN
• Given with high dose nitrates to prevent • Cardiac glycoside from Digitalis purpurea
reflex tachycardia • MOA: Inhibits Na-K-ATPase Pump for
• B1 Blockers – has no effect on blood extrusion of Ca from the myocardiocyte
vessels; exacerbates Prinzmetal Angina • Endpoint: Increase Ca in the cell = increase
contraction

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• Effects:
o Mechanical Effect: Increase
intracellular Ca ions (inotropism)
o Autonomic Effect:
▪ Parasympathetic effect
in the atria – bradycardia
▪ M2 activation (increased
sensitivity to M2) UNLOADER MEDICATIONS
▪ (-) Chronotropy
▪ (+) Inotropy 1. Angiotensin Antagonists (ACEi/ARBs)
o Electrical Effect: In the ventricles • Base treatment component in HF px
– tachycardia • Decreases preload and afterload (arteries)
• Clinical Use: Adjunct in the mgt of HF
particularly in patients with atrial 2. Diuretics
fibrillation
• Side Effects: • Decreases preload (veins, blood volume)
o Cardiac: Bradycardia in atria; • Loop and/or Thiazide
tachycardia in ventricle – DOC: • Alt: K-sparing (K wasting is prevented)
Lidocaine 3. Vasodilators
o Extracardiac: N&V (vomiting is
most common); Xanthopsia • Decreases afterload
(yellow-green discoloration of • Hydralazine + ISDN: HZN decrease
vision) afterload, ISDN decrease preload
• Nesiritide: brain natriuretic peptide
NOTES: Digoxin has a narrow therapeutic index. analog, increases cGMP, diuresis
Its toxic effects are enhanced by the ff: • Bosentan, Tezosentan: endothelium
• Hypokalemia antagonists (vasoconstrictor)
• Hypomagnesemia
• Hypercalcemia DRUGS FOR ARRHYTHMIA
• Hypoxia
VAUGHAN – WILLIAMS CLASSIFICATION
Class I Na Channel Blockers
BETA (B1) AGONISTS
Class II β-blockers
• MOA: B1 activation in the heart = increase Class III K Channel Blockers
cAMP = (+) inotropy Class IV Ca Channel Blockers
• Drugs:
✓ Dobutamine (B1)
• Could be bradycardia / tachycardia
✓ Dopamine (B1 depending on
• Therapeutic Goals:
dose: 2-5 mcg/kg/min)
✓ Block Na channels (Class I)
• Clinical Uses:
✓ Block sympathetic activities
✓ Alt for AHF
(Class II)
✓ Mgt of CHF with acute
✓ Prolong effective refractory
exacerbation
period (by blocking K channels,
BIPYRIDINES Class III)
✓ Block Ca channels (Class IV)
• MOA: Inhibit PDE3 (inactivates the
degradation of cAMP to AMP) CLASS I ANTI-ARRHYTHMICS
• Drugs:
Class IA: Moderate Na Channel Blockers
✓ Inamrinone
✓ Milrinone • Prolongs the duration of action potential
• Clinical Use: Management of acute heart • Drugs: (Double Quarter Pounder)
failure & exacerbation of CHF ✓ Disopyramide – anticholinergic
• S/E: Thrombocytopenia, Hypersensitivity, effect (dry mouth, urinary
Hepatotoxicity, Arrhythmia retention)

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✓ Quinidine – causes Cinchonism CLASS IV ANTI-ARRHYTHMICS

(tinnitus, dizziness, HA)
✓ Procainamide – SLE Verapamil

Class IB: Weak Na Channel Blockers • Cardioselective CCB

• Clinical Use: Mgt of chronic paroxysmal
• Shortens the duration of action potential supraventricular tachycardia (SVT)
• Drugs: (To Make Love Please) • S/E: Constipation
✓ Tocainide
✓ Mexiletine MISCELLANEOUS AGENTS
✓ Lidocaine – DOC for Digoxin- 1. Digoxin – for atrial fibrillation
induced ventricular tachycardia;
SVA associated with acute MI 2. Adenosine
✓ Phenytoin
• Mgt of acute paroxysmal supraventricular
Class IC: Strong Na Channel Blockers tachycardia (SVT)
• S/E: Bronchoconstriction – pretreat px
• No effect on the duration of action with β2 agonists
potential
• Drugs: (More Fries, Papa Enchong) 3. Magnesium Sulfate (IV) – mgt of Torsades de
✓ Moricizine Pointes (QRS)
✓ Flecainide
✓ Propafenone
✓ Encainide

CLASS II ANTI-ARRHYTHMICS

• All β blockers EXCEPT Sotalol

• Drugs: (PEAce)
✓ Penbutolol
✓ Esmolol
✓ Acebutolol

CLASS III ANTI-ARRHYTHMICS

• Drugs:
✓ Amiodarone – 32% by weight
Iodine
✓ Sotalol
✓ Bretylium
• P – atrial contraction
✓ Ibutilide
• R, T – ventricular contraction
✓ Dofetilide
✓ Dronedarone – no Iodine cmpd
DRUGS FOR DYSLIPIDEMIA
• Clinical Uses:
✓ 1st line in ventricular tachycardia Dyslipidemia / Hyperlipidemia – abnormality in
✓ Mgt of atrial fibrillation blood lipid levels
• Side Effects:
o Hepatotoxicity DIETARY LIPIDS
o Pulmonary fibrosis
o Wolff-Chaikoff Effect – initially 1. Triglycerides / Triacylglycerols
(<10-14 days) hypothyroidism, • Hydrolysable
final (>14 days) reaction is • TG –(Lipases)→ FFA (3) + Glycerol
hyperthyroidism
• Hypertriglyceridemia / hyperlipemia – ↑
TG in blood

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2. Cholesterol NOTES: Empty Stomach: 1h before meal or 2hrs

• Non-hydrolysable after meal
• Precursor in the synthesis of bile acids in
the liver CLASSIFICATION ACCORDING TO DOA
• Hypercholesterolemia – ↑ cholesterol in
1) Short-Acting Statins
blood

IMPORTANT LIPOPROTEINS • T½ of 1-3 hours

• Taken at night
Lipoproteins – lipids + transport proteins • Majority of statins are short-acting,
EXCEPT Atorvastatin and Rosuvastatin
1. Endogenous Lipoproteins – from the liver
2) Long-Acting Statins
• VLDL – triglycerides are dominant
• IDL • Can be taken any time of the day
✓ Triglycerides are dominant • Atorvastatin (Lipitor) – T½ of 14 hours
✓ Lower concentration than VLDL • Rosuvastatin (Crestor)
• LDL o T½ of 19 hours
✓ Cholesterol is dominant o Most effective in the mgt of
✓ Liver → tissues hypercholesterolemia
• HDL
✓ Cholesterol is dominant NICOTINIC ACID
✓ Tissues → liver Form of B3 (Niacin)
✓ ↓ Risk of causing atherosclerosis
✓ Good cholesterol • Nicotinic Acid – has a hypolipidemic effect
• Niacinamide
2. Exogenous Lipoproteins – from the small
intestine MECHANISM OF ACTION

• Chylomicrons – triglycerides are dominant ✓ Activates lipoprotein lipase

o TG –(LL)→ FFA = ↓ TG
HMG-CoA REDUCTASE INHIBITORS (STATINS) ✓ Inhibits synthesis and release of VLDL = ↓
• MOA: Inhibition of HMG-CoA Reductase VLDL
• De Novo Cholesterol Biosynthesis – ✓ HDL catabolism = ↑ HDL (most effective)
process of self-production of cholesterol ✓ Inhibits lp(a) lipoproteins = ↓ lp(a) – bad
by the liver; usually happens at night lipoprotein; contributes to the
precipitation of angina pectoris
• Other Effects of Statins: ↑HDL, ↓ LDL
• Statins in general: CLINICAL USES
o Statins are taken with food
EXCEPT Pravastatin – should be ✓ Most effective agent in increasing HDL
taken on an empty stomach ✓ Alternative agent in hyperlipemia
o Statins are generally teratogenic, ✓ Mgt of lp(a) hyperlipoproteinemia
thus CI in pregnancy
SIDE EFFECTS
• Clinical Uses:
✓ 1st line agents in the mgt of • Hepatotoxicity
hypercholesterolemia • Erythema (Flushing) – due to PG
✓ For stabilization of atheromatous
plaque formation
• Side Effects:
o Myalgia
o Myositis
o Rhabdomyolysis
o Hepatotoxicity – monitor liver
function tests (AST, ALT)

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BOARD EXAM QUESTION: • Clinical Use: Add-ons to statins

What treatment is used when the patient o Ex: Simvastatin + Ezetimibe
becomes red due to nicotinic acid? (Vytorin®)

ENDOCRINE PHARMACOLOGY
A: NSAIDs such as ASA / Ibuprofen to block
COX; redness or flushing occurs due to
ENDOCRINE SYSTEM
prostaglandins
• Ductless system
FIBRIC ACID DERIVATIVES (FIBRATES) • Composed of distant or remote systems
• Responsible in the synthesis and release of
• MOA: Peroxisome Proliferator Activated
Receptor-α PPAR-α Agonists endocrine hormones
✓ Activates lipoprotein lipase ENDOCRINE GLANDS (ORGANS)
TG –(LL)→ FFA = ↓ TG
✓ Activates ApoAI and ApoAII • Central Nervous System
proteins – important parts of HDL ✓ Hypothalamus (Mother / master
= ↑ HDL gland)
✓ Decreased expression of ApoIII –
✓ Pituitary Gland
important part of VLDL = ↓ VLDL
o Anterior
• Drugs:
o Posterior
✓ Fenofibrate
✓ Clofibrate • Peripheral (PEG)
✓ Gemfibrozil ✓ Thyroid Gland
• Clinical Uses: ✓ Adrenal Gland
✓ 1st line agents in the mgt of ✓ Pancreas
hyperlipemia ✓ Ovaries
✓ Mgt of metabolic syndrome ✓ Testes
• Side Effects:
o Rhabdomyolysis ENDOCRINE HORMONES
o ↑ Risk of bile stone formation
• Produced by specific cells
o ↑ Risk of hepatobiliary cancer
• Distributed systemically
BILE ACID BINDING RESINS (SEQUESTRANTS) • Incorporated in the blood ready for
circulation
• MOA: Inhibition of biliary recycling; ↓ BA
= ↓ Cholesterol PEPTIDE / PROTEIN HORMONES
• Drugs:
✓ Cholestyramine • From gene (portion of DNA) expression
✓ Colestipol (transcription, translation)
✓ Colesevelam • Ex: Insulin, Glucagon
• Clinical Uses:
✓ Add-ons to statins
✓ Used in the treatment of certain
oral poisoning such as:
▪ Warfarin poisoning
▪ Digoxin poisoning
• Side Effects:
o Steatorrhea – fatty stool
o ↑ Risk of bile stone formation
o Malabsorption of ADEK vitamins

EZETIMIBE AMINE HORMONES

• MOA: Inhibition of Niemann-Pick C1-like 1 • From Tyrosine

Transporter – cholesterol absorption • Ex: Norepinephrine, Epinephrine

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STEROIDAL HORMONES REGULATION OF HORMONE SECRETION

• From Cholesterol ✓ Feedback Mechanism

• Examples: ✓ Local Control
✓ Glucocorticoids – D: Cortisol ✓ Circadian Rhythm
✓ Mineralocorticoids – D:
FEEDBACK MECHANISM
Aldosterone
✓ Sex Hormones (Gonads) Negative Feedback
o Estrogens – Estradiol
o Progestins – • Prevents further hormone secretion once
Progesterone a set point is achieved
o Androgens – • Ex: Thyroid Gland
Testosterone
Positive Feedback
PHYSIOLOGY OF ENDOCRINE SYSTEM
• Support response
ANTERIOR ORGAN / • Uncommon/rare
HYPOTHALAMIC PITUITARY PERIPHERAL PERIPHERAL
HORMONES GLAND ENDOCRINE HORMONES • Only happens in menstrual cycle
HORMONES GLAND
Thyrotropin / Thyroid
Thyrotropin RH T3, T4
TSH Gland
Corticotropin Corticotropin Adrenal
Cortisol
RH / ACTH Cortex
Follicle
Stimulating
Ovaries Estrogen
Hormone
Gonadotropin
(FSH)
RH (GnRH)
Luteinizing Ovaries Progesterone
Hormone
Testes Testosterone
(LH)
Growth Somatotropin
Somatomedin
Hormone (Growth Liver
C
(GHRH) Hormone)
Growth
Hormone
Inhibiting
Hormone
(GHIH) /
Somatostatin
LOCAL CONTROL

Wolf – Chaikoff Effect

• T3 – Triiodothyronine – active
• T4 – Thyroxine • For thyroid hormones
• ACTH – Adrenocorticotropic Hormone • Excess iodides inhibit active uptake of
• GHRH – Binds to type III receptors iodine and organification of iodine which
• Somatomedin-C – Insulin-like growth ultimately leads to decreased production
factor 1 (IFG1) of T3 and T4
• Somatostatin – inhibits release of GH and • Duration: 10-14 days; after this duration,
TSH any excess iodides = increase T3 and T4

CIRCADIAN RHYTHM / DIURNAL / SLEEP-WAKE

Secretion of hormone is patterned with the sleep-

wake cycle (24 hours); hormone release = entrained
to sleep

• Growth Hormone – secretion peaks during

deep sleep
• Cortisol – secretion occurs upon waking
up; important in the metabolism of CHO,
CHONS, and lipids

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HYPOTHALAMIC – PITUITARY
HORMONES AND AGENTS

HYPOTHALAMIC HORMONES: GnRH ANALOGUES

• Drugs:
✓ Gonadorelin
✓ Buserelin
✓ Goserelin
✓ Leuprolide
✓ Nafarelin
✓ Triptorelin
✓ Histrelin Effects:
• Effects: ✓ Lactation
o Physiological: seen in ✓ Breast development
intermittent / pulsatile serum ✓ Inhibition of ovulation
GnRH; stimulatory effects in FSH / ✓ Inhibit spermatogenesis
LH
o Pharmacological: seen in Conditions: (Deficit, Exccess)
sustained serum GnRH levels;
• Hypoprolactinemia – inhibited lactation
inhibitory effects on FSH / LH
• Hyperprolactinemia – caused by:
• Clinical Uses:
o Prolactinomas (tumor)
✓ Intermittent: Management of
o Drug-induced (1st gen
hypothalamic hypogonadism (↓
antipsychotics – inhibit DA)
estrogen, progesterone)
o S/Sx: Galactorrhea, amenorrhea,
✓ Sustained: Management of
infertility
hormone sensitive diseases:
o Tx: Bromocriptine (D2 Agonist)
o Endometriosis
o Breast CA GROWTH HORMONE (Somatotropin)
o Prostate CA
• Side Effects: Regulation:
o Intermittent:
▪ F: Masculinizing Effect
▪ M: Feminizing Effect
o Continuous
▪ F: Menopausal Sx
✓ Flushing
✓ Irritability
✓ Osteoporosis
▪ M: Gynecomastia

PITUITARY HORMONES

Anterior Pituitary Gland / Adenohypophysis

Effects:
• Follows the axis
• Ex: Prolactin, Growth Hormone ✓ Muscles: CHON synthesis
✓ Adipose: Lipolysis (TG Hydrolysis) = weight
PROLACTIN (PRL) loss due to shrinkage of adipose because
of hydrolysis
Regulation:
✓ Liver: Increase somatomedin (IGF-1)
• Increase lean body mass

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• Increase organ size Cadaveric GH

• Increase linear body growth
• From animals
✓ Other Cells: Inhibition of glucose uptake =
• Obsolete
hyperglycemia
• S/E: Creutzfeldt – Jakob Disease
DEFICIENCY (Spongiform brain)
Onset: Recombinant GH

• Childhood: Pituitary dwarfism • Drugs:

• Adulthood: ↑ risk of cardiovascular ✓ Somatotropin
morbidity and mortality ✓ Somatrem® - Somatotropin +
o Fatigue, weakness, hypoglycemic Methionine
effects • S/E (Extension Effects):
o Hyperglycemia
NOTES: Hormones that can increase blood o Peripheral edema
glucose levels: o Myalgia
✓ Fast-Acting: Glucagon, Epinephrine o Arthralgia
✓ Slow-Acting: Cortisol, Growth Mecasermin
Hormone
• Complexed recombinant human IGF-1
Diagnosis • S/E: Hypoglycemia

EXCESS
Measure baseline GH
levels Onset:
Test: Insulin-induced hypoglycemia
• Childhood: Pituitary gigantism
Reason: GH should increase blood • Adulthood: Acromegaly (Fatal:
sugar and return to normal
Cardiomegaly)
Measure GH
levels AGENTS FOR GH EXCESS

Increase GH from No change from Somatostatin and Analogues

baseline (normal) baseline
• MOA: Inhibits GH release, insulin,
NO GH DEFICIENCY GH DEFICIENCY
glucagon, gastrin, and TSH
Give GHRH
• Drugs: (Analogues) – more preferred
✓ Octreotide
Measure GH
✓ Lancreotide
levels • Somatostatin – more active; short T½
• Clinical Uses:
Increase GH levels ✓ Acromegaly (inhibit GH release)
No Change
Dx: APG Defect
Dx: Hypothalamic ✓ Tumors = hypersecretion
Defect
✓ Insulinoma
✓ Glucagonoma
✓ Zollinger-Ellison Disease
✓ Mgt of bleeding esophageal
Treatment – depends on the defective gland varices (vasoconstriction)
• S/E: GI Disturbances
• Hypothalamic Defect: GHRH
• Pituitary Defect: Dopamine Agonists
o GH – 1st line
o Somatotropin

AGENTS FOR GH DEFICIENCY

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• MOA: Inhibit GH release associated with DEFICIENCY (DIABETES INSIPIDUS)

hyperprolactinemia by agonizing DA
Signs and Symptoms:
(prolactin-inhibiting hormone)
• Drugs: • Polyuria
✓ Bromocriptine • Polydipsia
✓ Cabergoline • Hypovolemia (low blood volume)
✓ Pergolide • Hypernatremia
Pegvisomant • Diluted / hypo-osmolar urine

Forms:
• Pegylated somatropin antagonist (GH
receptor antagonist) • Central Diabetes Insipidus
• Reduce clearance and overall improve o True DI; true deficiency of ADH
effectiveness o Mgt: Desmopressin / Vasopressin
Posterior Pituitary Gland / Neurohypophysis o Desmopressin – more preferred;
selective V2 receptor agonist
• Do not follow an axis • Nephrogenic Diabetes Insipidus
• Ex: Oxytocin, Vasopressin o Normal levels of ADH (sometimes
• Hypothalamus (Synthesis) → PPG above normal) but V2 receptors
(Storage, Release) → Cells are non-responsive
o Mgt: Thiazide Diuretic (1st line) +
OXYTOCIN Potassium Sparing Diuretics –
Effects: paradoxical mechanism
o Thiazide – HypoK; K Sparing –
✓ Uterine contraction (oxycytosis) counteracts hypoK
✓ Stimulation of milk letdown – natural
stimulators: suckling of nipples EXCESS (SIADH)

Clinical Uses: SIADH – Syndrome of Inappropriate ADH Secretion

✓ Nasal Spray: stimulate milk letdown Signs and Symptoms:

✓ IV Infusion: tx of post-partum hemorrhage • Hypervolemia (increase blood volume)
✓ Labor induction (1h infusion only) • Hypertension
Side Effect: Uterine rupture / uterine tetany • Hyponatremia
• Concentrated / hyperosmolar urine
• Mgt: Atosiban
o Oxytocin receptor antagonist Management:
o Used in preventing premature
• Acute SIADH – infusion of hypertonic
labor
saline
VASOPRESSIN / ANTIDIURETIC HORMONE • Chronic SIADH
o Demeclocycline – 1st line;
Effects: tetracycline but NOT used as
antibiotic; most photosensitizing
• V1 Receptor – found in blood vessels =
tetracycline
vasoconstriction

• V2 Receptor o Vasopressin Receptor

o Located on kidney distal tube = Antagonist
translocation of aquaporins ▪ Conivaptan – non
o Located on cell membrane = H2O selective; risk of
reabsorption hypotension

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▪ Tolvaptan – V2 selective ▪ > 14d = (+) active uptake

= ↑ T3, T4
CRITERION DEFICIENCY EXCESS
Syndrome of o Inhibitor: Inorganic Anions
Diabetes
Disease
Insipidus
Inappropriate • Peroxidase-catalyzed reactions
ADH Secretion o Peroxidation of iodine products:
Agonist Antagonist
Drugs molecular iodine and periodate
(-pressin) (-vaptan)
Non-Selective Vasopressin Conivaptan o Organification / Iodination:
Selective Desmopressin Tolvaptan addition of I2 to the tyrosine
residues of thyroglobulin;
products:
THYROID HORMONES ▪ Monoiodotyrosyl
thyroglobulin (MIT)
Thyroid Gland
▪ Diiodotyrosyl
• Requires iodine to synthesize thyroid thyroglobulin (DIT)
hormones o Coupling Reaction
• Secretes thyroid hormones (T3, T4) – ▪ T3 → MIT + DIT – TG
Function: Regulate metabolic rates; ▪ T4 → DIT + DIT – TG
essential for growth and development o Inhibitor: Thionamides
• Follicular Cells – main cells / main • Proteolysis of thyroglobulin with the use of
producers of hormones (secretes T3 and proteases
T4) • Release of T3 and T4 into the systemic
• Parafollicular Cells – supporting cells circulation
(Calcitonin) o Ratio: T3 (1 part) : T4 (4 parts)
o T3 (Triiodothyronine): T½ of 1-3
REGULATION OF THYROID HORMONES days; 10x more potent
o T4 (Thyroxine): T½ of 7-10 days
• Peripheral conversion of T4 → T3 with the
use of deiodinase
o Inhibitors:
▪ Propranolol
▪ Radiocontrast dyes
▪ Dexamethasone
▪ Iodinated radiocontrast
media

THYROID DISORDERS

• Hypothyroidism
• Hyperthyroidism
BIOSYNTHESIS OF T3 AND T4
HYPOTHYROIDISM
Site: Thyroid follicular cells (FCs)
Raw Material: Iodine → Iodide (I-) • Insufficient, low levels of T3 and T4
Steps:
TYPE TRH TSH T3, T4
• Active uptake of iodide in the systemic
Primary (TG) ↑ ↑ ↓
circulation via the Na-I symporter Secondary (APG) ↑ ↓ ↓
o NOTE: Local Regulation Tertiary (H) ↓ ↓ ↓
o Stimulus: ↑ I- (blood) • Causes:
o Duration: (Wolf-Chaikoff Effect) o Iodine deficiency
▪ < 10-14d = (-) active o Post-procedural (thyroidectomy,
uptake = ↓ T3, T4 radiation)
o Drug-induced
▪ Amiodarone: < 10-14d

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▪ Anti-thyroid drugs ✓ Inhibits peripheral conversion of

o Autoimmune (Hashimoto’s) T4 to T3 – PTU only
• SSX: Hypometabolic, Hyposympathetic • Drugs:
o Weight gain ✓ Propylthiouracil (PTU)
o Constipation ✓ Methimazole
o Slowness in movement ✓ Carbimazole – prodrug of
o Increased sleeping time Methimazole
o Cold intolerance • Pregnancy: Use PTU; Methimazole and
• Management: (Supplementation) Carbimazole causes aplasia cutis
✓ Thyroxine (T4) • Side Effects:
o Dextro – 4% activity of o Liver dysfunction
Levo ▪ Reversible hepatitis –
o Levo (Euthyrox®) – prep PTU
of choice; maintenance ▪ Cholestatic jaundice –
treatment Methimazole
✓ Liothyronine – 3-4x more potent o Agranulocytosis (↓ BEN)
than Levothyroxine; emergency ▪ Increased risk of
situation (myxedema coma) infection
▪ Red Flags:
HYPERTHYROIDISM / THYROTOXICOSIS
✓ Fever
• Causes: ✓ Oral ulcers
o Autoimmune Disease (Grave’s) ✓ Sore throat
▪ Photophobia o Hypoprothrombinemia
▪ Dermopathy o Hypothyroidism (extension
▪ Ophthalmopathy effect)
(Exophthalmos) PROPERTY PTU METHIMAZOLE
o Solitary hyperfunctioning nodule DOA Short Long
o Thyroiditis Use Emergency Maintenance
Safety Teratogenic:
o Drug-induced (Pregnancy)
✓
Aplasia cutis
▪ Amiodarone: >14d Toxicity Reversible hepatitis Cholestatic jaundice
▪ Liothyronine
▪ Levothyroxine
• SSX: Hypermetabolic, Hypersympathetic INORGANIC ANIONS
o Weight loss • MOA: Inhibit uptake of Iodide via Na-I
o Diarrhea transporter
o Tachycardia • Drugs:
o Tremors ✓ Thiocyanate
o Heat intolerance ✓ Pertechnetate
o Profused sweating ✓ Perchlorate
o Increased irritability • Clinical Use: DOC for Amiodarone-induced
ANTI-THYROID DRUGS hyperthyroidism
• S/E: Increased risk of aplastic anemia
Thionamides, Inorganic Anions, Iodides, RAI (bone marrow destruction)
Therapy, β-blockers, Radiocontrast Dyes,
Dexamethasone, Iodinated Contrast Media IODIDES

THIONAMIDES • MOA: Inhibit organification of iodine and

thyroid hormone release
• Mechanism of Action: • Drugs:
✓ Inhibits peroxidase enzyme ✓ Lugol’s Solution (Strong Iodide
Solution) – 5% Iodine in H2O w/ KI

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✓ KI Saturated Solution (KISS) o Clinical Use: For rapid reduction

• Clinical Use: Pre-operative agents of T3 levels during thyrotoxicosis
• S/E: Iodism – conjunctivitis, rhinitis,
sialadenitis; Antidote: Starch ADRENOCORTICAL HORMONES AND AGENTS
• CI: Pregnancy and lactation
Location: Adrenal Cortex
RAI THERAPY
• Zona Glomerulosa: Mineralocorticoids
• MOA: Emits beta particles that cause (Aldosterone)
oxidation of the thyroid follicular cells = • Zona Fasciculata: Glucocorticoids
mutations = cell death (Cortisol)
• Drugs: • Zona Reticularis: Sex Hormones /
✓ 131-I: Treatment Androgens (Testosterone)
✓ 135-I: Diagnostics
• Clinical Use: 1st line treatment for
hyperthyroidism induced by Grave’s
disease and solitary hyperfunctioning
nodule
• S/E: Hypothyroidism

NOTES: RAI should be freshly prepared and the

patient should be quarantined 48-72 hours
prior to the procedure

BETA BLOCKERS

• Mechanism of Action:
✓ Inhibit peripheral conversion of
T4 to T3
Regulation of Hormone Secretion
✓ Inhibit sympathetic symptoms
• Clinical Uses: 1. RAAS – Aldosterone
✓ Adjunct for RAI therapy for the 2. Circadian Rhythm and HPA (Hypothalamic
management of symptomatic – Pituitary – Adrenal) Axis – Cortisol
hyperthyroidism especially in
cases of thyroid storm / GLUCOCORTICOIDS
thyrotoxicosis
Endogenous: Cortisol / Hydrocortisone /
✓ Can be given alone for thyroiditis
Compound F
OTHER DRUGS
Physiological Effects:
• Radiocontrast Dyes
• Seen in < 20 mg/day Cortisol
o MOA: Inhibition of peripheral
• Important in the metabolism of fats and
conversion of T4 to T3
proteins
o Drugs: Ipoate, Iopanoic Acid
• Enhancement of smooth muscle response
• Dexamethasone
to catecholamines
o MOA: Inhibition of peripheral
• Cardiovascular function, immunity, growth
conversion of T4 to T3
o Clinical Use: Hyperthyroidism Pharmacological Effects:
caused by Grave’s Disease
• Iodinated Radiocontrast Media • Seen in > 20 mg/day Cortisol
o MOA: Inhibition of peripheral • Anti-inflammatory
conversion of T4 to T3 • Immunosuppressant
• Catabolism of bones and joints

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• Inhibition of cell division (mitosis) • Increased risk of infection (extension

effect)
Additional Effect: Mineralocorticoid Activity = salt
• Hypertension (secondary to fluid
and water retention
retention)
Drugs: • Poor wound healing activity
• Hypokalemia (mineralocorticoid effect)
• Short Acting • Proximal myopathy
✓ Prednisone • Hyperglycemia
✓ Prednisolone
• Bone growth retardation
✓ Meprednisone
• Osteoporosis
✓ Meprednisolone
• HPA Axis Suppression (> 10-14 days)
✓ Hydrocortisone
o Addison’s Disease / Adrenal Crisis
✓ Cortisone
o Abrupt due to withdrawal (HTN,
• Intermediate Acting
abd pain, death)
✓ Fluocinolone
o Remedy: Taper the dose slowly
✓ Triamcinolone
✓ Paramethasone MINERALOCORTICOIDS
• Long Acting
Endogenous: Aldosterone
✓ Betamethasone
Effects: Physiologic = Pharmacologic
✓ Dexamethasone – highest anti-
inflammatory activity • Retention of sodium, water, bicarbonate
Clinical Uses: • Excretion of K, Cl, Hydrogen

✓ Adrenal Diseases Drugs:

o Diagnosis and treatment of ✓ Fludrocortisone
disturber adrenal function o Most commonly prescribed salt
o Dexamethasone – diagnostic for retaining agent
Cushing’s Syndrome o For the mgt of mineralocorticoid
▪ Deficiency: Addison’s deficiency
▪ Excess: Cushing’s ✓ Deoxycorticosterone acetate
✓ Non-Adrenal Diseases
o Allergy Hyperaldosteronism
o Collagen vascular disorder (SLE)
• Na and H2O retention = HTN
o Eye disorders
• Hypernatremia, hypervolemia
o Hematologic disorders
• Hypochloremic metabolic alkalosis
o GIT disorders
o Respiratory disorders • Hypokalemia
o Systemic inflammation Hypoaldosteronism
o Infections
✓ Stimulation of lung maturation in fetus • Hyponatremia, hypovolemia =
hypotension
Side Effects: • Hyperchloremic metabolic acidosis
• Cushing’s Syndrome (Type C ADR) • Hyperkalemia
o Moon facies
o Buffalo hump PANCREATIC HORMONES
o Easy bruising
Insulin
o Truncal obesity
o Skin thinning • Synthesized, stored (hexamer), and
o Cushing’s ulcer released (monomer) by the pancreatic β
• Fluid retention / edema cells

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• Effects: (+) Stimulus – increase blood o Oral anti-diabetic agents (OADs)

glucose (fed) = anabolic o Oral hypoglycemic agents (OHAs)
o Liver: o Insulin for control
(+) stimulate glycogenesis
Type III DM – secondary with identifiable causes
(glucose to glycogen), lipogenesis
(TG synthesis) • Cushing’s Syndrome
(-) block gluconeogenesis (non- • Chronic pancreatitis
sugar to glucose), glycogenolysis • Pancreatectomy
o Muscles: (+) Stimulate
glycogenesis, CHON synthesis Type IV DM – gestational DM
o Adipose: (+) Lipogenesis
• Occurs during pregnancy
o Other Cells: (+) Glucose uptake
• Resolved after giving birth but increase risk
Glucagon of acquiring type II DM

• From pancreatic α cells DIAGNOSIS OF DIABETES MELLITUS

• Effects: (+) Stimulus – fasted = catabolic
Symptomatic:
o (+) Glycogenolysis
o (+) Gluconeogenesis • RBS ≥ 200 mg/dL + DM
• 3P’s: Polyuria, polydipsia, polyphagia
DIABETES MELLITUS
• Weight loss
• Metabolic disorder characterized by
Asymptomatic:
chronic hyperglycemia
• Retinopathy, neuropathy, nephropathy • FBS ≥ 126 mg/dL + DM
TYPES OF DIABETES MELLITUS • Fasting – no food, no drink for 8 hours
• At least 2 determinations in separate
Type I DM – absolute lack of insulin due to occasions
destruction of β cells to the pancreas
Oral Glucose Tolerance Test
• Old Term: Insulin dependent DM
o 1A – autoimmune disease • 75g anhydrous glucose
o 1B – idiopathic • 2 hrs post prandial RBS ≥ 200 mg/dL + DM
• Age of Diagnosis: < 3 years old (juvenile HbA1C (Glucosylated/ Glycosylated / Glycated
DM) Hgb)
• Patient is NOT obese at the onset of
diagnosis • Assess blood sugar levels for 1-3 months
• Mgt: Exogenous insulin for survival • ≥ 6.5% + DM

PRE-DIABETES

Type II DM – relative lack of insulin • FBS: ≥ 100 – 126 mg/dL

• RBS: ≥ 140 – 200 mg/dL
• Decrease insulin secretion • Mgt: Lifestyle modification, Metformin
• Decrease insulin sensitivity / increase
insulin resistance INSULIN
• Increase hepatic glucose production –
• Hormone secreted by the pancreatic β
gluconeogenesis
cells
• Old Term: Non-insulin dependent DM
• Co-secreted by Amylin – roles:
• Age of Diagnosis: > 35 years old
o Decrease glucagon secretion
• Patient is already obese at the onset of
o Increase incretin (endogenous
diagnosis
anti-diabetic secreted by GIT)
• Management:

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o Increase peripheral tissue • Basal Insulin

response to insulin o Controls blood sugar levels for 24
• Storage Form: Hexamer hours
• Active Form: Monomer o Long acting and intermediate
• Effects: acting agents
✓ Stimulates enzyme glucokinase
BASED ON DURATION OF ACTION
✓ Translocation of glucose
transporters such as GLUT2 (liver) Ultra Rapid Acting Agents
and GLUT4 (muscle) into the cell
membrane • Drugs: (LAG) – already in monomer form
• Clinical Use: ✓ Lispro
✓ Mgt of Type I DM ✓ Aspart
✓ Adjunct in Type II DM ✓ Glulisine (Apidra)
• Side Effects: • Onset: 5 minutes
o Hypoglycemia: coma, tremors, • Peak: 0.5 – 1.5 hours
sweating, tachycardia; Tx: • Duration: 1-3 hours
glucose administration • Timing: Right before or after each meal
o Lipodystrophy: atrophy (SQ fatty • Route: SQ
tissues); Remedy: rotate injection
Rapid Acting / Short Acting Agent
sites
o Immunopathology – insulin • Drug: Regular Insulin (Hexamer)
allergy • Onset: 30 minutes
BASED ON SOURCE • Peak: 1.5-3 hours
• Duration: 3-4 hours
• Animal Sourced – bovine, porcine; more • Timing: 30 mins before each meal
immunogenic • Route: SQ and IV (only insulin that can be
• Recombinant Sourced – less immunogenic administered through IV)

BASED ON STRUCTURE Intermediate Acting

Native Insulin • Drugs: (Protamine Containing)

✓ Lispro (Humalog)
• No modification on endogenous insulin (51
✓ Aspart (Novolog)
AA sequence)
• Onset: 1-3 hours
• Examples:
• Peak: 3-4 hours
✓ Regular Insulin
• Duration: 10 hours
✓ NPH / Isophane Insulin
• Timing: BID; 2/3 pre-breakfast, 1/3 pre-
✓ Insulin-Zinc Suspension
dinner
Modified Insulins • Route: SQ

• Addition of AA sequence / fatty acids Long Acting Agents

• Examples:
• Drugs:
✓ Insulin lispro, aspart, glulisine
✓ Glargine (Lantus)
✓ Protamine lispro, aspart
✓ Degludec (Tresiba)
✓ Insulin glargine, degludec,
✓ Detemir (Levemir)
detemir (+ myristic acid)
• Onset: 1-2 hours
BASED ON USE • Peak: Peak less (Glargine)
• Duration: 24 hours
• Demand Insulin
• Timing: OD
o Controls post prandial hypergly
• Route: SQ
o Short acting agents

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Mixed Insulins – 60 (Intermediate) / 40 (Short ✓ Acetohexamide

Acting)
2nd Generation – more potent; ↓ dose = ↓ S/E
ORAL ANTI-DIABETIC DRUGS
✓ Glibenclamide
Used in the management of Type II DM ✓ Glipizide
✓ Gliclazide
INSULIN SECRETAGOGUES
✓ Glimepiride

MEGLITINIDES

• Duration of Action: 1-2 hours

• Drugs:
✓ Repaglinide
✓ Nateglinide
✓ Mitiglinide

BIGUANIDES

• MOA: Activate AMP-activated protein

NOTES: ↑ K (i) = Ca channel opening = (+) cell kinase (AMP-k) pathway
depolarization = exocytosis (release) • Drugs:
✓ Metformin
• Mechanism of Action: ✓ Phenformin – withdrawn due to
✓ Block potassium ion channels in lactic acidosis
the beta cells • Effects: Increase glucose utilization
✓ Stimulation of the release of o Fat oxidation, inhibit glucose
insulin from the beta cells absorption, (+) glucose uptake
• Drugs: o Stimulate glycolysis
✓ Sulfonylureas o Decrease gluconeogenesis
✓ Biguanides o Decrease glycogenolysis
• Clinical Use: Control of post-prandial • Clinical Uses:
hypoglycemia ✓ 1st line management of type II
• Dosing: Take 30 mins before breakfast DM especially in obese patients
• Side Effects: ✓ Only drug for pre-diabetes
o Hypoglycemia ✓ Euglycemic Agent – blood glucose
o Weight gain to normal
o Disulfiram-like rxns (erythema) • Side Effects:
o Diarrhea (most common) relieved
with chronic use
SULFONYLUREAS (SFUs) o Weight loss (beneficial)
o Risk of lactic acidosis
1st Generation – less potent; ↑ dose = ↑ S/E ▪ Risk factor: CHF, liver
✓ Chlorpropamide cirrhosis, renal
o Longest acting (60 hours) insufficiencies
o Use with caution in patients with o Megaloblastic anemia due to
kidney and liver disorders decreased Vit B12 absorption
✓ Tolbutamide • NOTE: Biguanides DOES NOT cause
o Shortest acting (6-12 hours) hypoglycemia
o Most cardiotoxic when
THIAZOLIDINEDIONES (PPAR-γ Agonists)
accumulated
o Preferred for geriatrics • MOA: Activates peroxisome-proliferator
✓ Tolazamide activated gamma to convert adipose fats

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into smaller globules which are more ✓ Exenatide (Byetta®)

sensitive to insulin (insulin sensitizers) ✓ Lixisenatide
• Drugs: ✓ Liraglutide
✓ Pioglitazone (Prialta®) • Route: SQ
o Increased risk of bladder
Dipeptidyl Peptidase IV Inhibitors
cancer
✓ Rosiglitazone (Avandia®) • Drugs:
o Withdrawn due to ✓ Sitagliptin (Januvia®)
cardiotoxicity ✓ Saxagliptin (Onglyza®)
• Side Effects: ✓ Linagliptin (Trajenta®)
o Edema ✓ Vildagliptin (Galvus®, Proglin®)
o Hepatotoxicity ✓ Teneligliptin (Glipten®)
o Cardiotoxicity • S/E: Weight loss, hypoglycemia, N&V
• CI: Px with CHF
NA-GLUCOSE CO-TRANSPORTER 2 INHIBITORS
ALPHA-GLUCOSIDASE INHIBITORS
• SGLT-2 – found in the renal proximal
• MOA: Complex CHO –(α-glucosidase)→ tubule; 90% reabsorbed glucose into the
Simple Sugar circulation
o NOTE: If α-glucosidase is inh, CHO • MOA: Inhibit SGLT-2 → inhibit glucose
will not be absorbed, goes to reabsorption → increase excretion in the
colon, bacteria will thrive with urine
the sugar = CO2 gas • Drugs:
• Drugs: Taken after first bite of a meal ✓ Dapagliflozin (Forxiga®)
✓ Acarbose ✓ Canagliflozin
✓ Voglibose ✓ Empagliflozin
✓ Miglitol • Clinical Uses: Mgt of T2DM
• S/E: Flatulence / bloating ✓ Monotherapy: Dapagliflozin
✓ SGLT-2 Inh + Metformin
AMYLIN ANALOGUE
o Dapagliflozin + Met
• Amylin – hormone; satiety effect, (Xigduo®)
anorexiant, slows down GET ✓ SGLT-2 Inh + DPP4 Inh
• Drug: Pramlintide (SQ) o Empagliflozin +
• Clinical Use: T1DM, T2DM Linagliptin (Glyxambi®)
• S/E: Hypoglycemia, weight loss, N&V • Side Effects:
o Pain in urination; risk of UTI
o Oral thrush

INCRETIN MIMETICS GONADAL HORMONES

• Incretins – hormones that are released in Receptor: Type IV
the GIT in response to food intake
o IN – increase ESTROGEN
o RE – release of
Forms of Estrogen
o tINS – insulin
• Effects: Increase insulin secretion, slow • Natural:
down GET, anorexiant o E1 – Estrone
• Examples: Glucagon-like-peptide 1 (GLP1), o E2 – Estradiol
Gastric insulinotropic polypeptide (GIPO) o E3 – Estriol
GLP-1 Agonist

• Drugs:

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Side Effects: Increased risk of thromboembolic

Cholesterol events

Contraindications:

• Women > 35 years old

Androstenedione
(Androgen) • Chronic smoking
• History of breast cancer (ER)
• Obesity

PROGESTIN
Estrone (E1) Testosterone
Forms of Progestin
AROMATASE AROMATASE
• Natural: Progesterone
Estradiol (E2) • Synthetic:
Estriol (E3) Most potent
Major estrogen form Progesterone Derivative Medroxyprogesterone acetate
Dimethylsterone
Testosterone Derivative
Highly androgenic
• Synthetic:
Levonorgestrel, Norethindrone
o Steroidal 19-Nortestosterone
Highly androgenic
▪ Mestranol 13-ethyl-17-
Desogestrel, Norgestimate
nortestosterone
▪ Ethinyl estradiol Less androgenic
Derivative
▪ Quinestrol
o Non-steroidal
▪ Diethylstilbestrol – Effects:
teratogenic;
✓ Ovulation
adenocarcinoma
✓ Thickening of endometrium
▪ Dienestrol
✓ Development of secondary sexual
▪ Chlorotrianisene
characteristics
▪ Methallenestril
✓ Thermogenic
NOTES: Increased estrogen in females = at risk Clinical Uses:
of developing endometrial cancer
✓ For contraception
Effects: ✓ For correction of hormonal imbalance

✓ Sexual Effects: Side Effects: Acne, hirsutism

o Egg cell maturation
o Shedding of endometrium =
periodic bleeding
o Development of secondary sexual
CONTRACEPTION
characteristics
✓ Metabolic Effects: MOA: Negative feedback mechanism
o Inhibit bone resorption
o ↑ HDL, TG ↓ LDL
✓ Hematologic Effects:
o Increase synthesis of clotting
factors (thrombosis)

Clinical Uses:

✓ For contraception
✓ For hormonal replacement therapy (HRT)

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Forms of Contraceptives • Inhibits negative feedback mechanism of

1. Combined Oral Contraceptives estrogen
• Partial estrogen receptor agonist
• Estrogen + Progesterone (< 50 mg/day)
• Increase FSH = increase follicular
• Types:
maturation of the egg cell
o Monophasic – constant conc
• Clinical Use: For primary / secondary
o Biphasic – 2 sets of conc
infertility, women with PCOS
o Triphasic – 3 sets of conc
• S/E: Multiple Birth
2. Progestin Only Contraceptives
2. Menopausal Gonadotropin
• Oral
• Source: Urine of menopaused women
o Minipills – Norethindrone
• Forms:
o Ex. Norgestimate
✓ Menotropins – FSH and LH
o Frequency: Daily
✓ Urofollitropins – FSH
• Injectable
• Clinical Use: Add-on to Clomiphene
o IM Depo-Provera
o Medroxyprogesterone acetate 3. Chorionic Gonadotropin
o Frequency: Every 1 month, every
3 months • Source: Urine of pregnant women
• Implantable • Form: Beta-HCG (Beta Human Chorionic
o Intradermal imbalance Gonadotropin)
o Ex: Norplant® (Levonorgestrel), • Clinical Use: Add-on to Clomiphene
Implanon® (Etonorgestrel)
ANDROGENS
o Frequency: Every 3 years
• Intrauterine Device (IUD) Examples:
o Ex: Mirena (Levonorgestrel)
o Frequency: Every 5 years ✓ Androstenedione
✓ Testosterone (Major)
3. Emergency Contraceptives ✓ Dihydrotestosterone – more effective than
Testosterone
• For unprotected sexual intercourse
• Taken within 72 hours post-coitus ESTROGEN AND PROGESTIN AGENTS
• Old: DES
1. Mifepristone
• New: Ethinyl Estradiol + Levonorgestrel
• Progesterone antagonist
Side Effects:
• Contraceptive; abortifacient
• Nausea and vomiting
• Mastalgia
• Breakthrough bleeding (progestin only)
• Headache
2. Aromatase Inhibitors
• Mood changes
• Risk of breast cancer (ER) • Drugs: Anastrozole, Letrozole
• Risk of thromboembolic events • Lower estrogen
o DVT/PE: Estrogen > 50 mcg/day
o Stroke: Age > 35 yrs old 3. Selective Estrogen Receptor Modulator (SERMs)
o MI: CAD risk factor
• Tamoxifen
(atherosclerosis)
o Tx for estrogen (+) breast CA
FERTILITY DRUGS o Partial agonist
• Raloxifene – mgt of osteoporosis
1. Clomiphene Citrate
ANDROGEN AGENTS

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• MOA: Inhibit 5-α-reductase DRUGS FOR COUGH

• Drugs: Finasteride, Dutasteride
• Productive = ↓ viscosity
• Clinical Use: Treatment of BPH (w/ α1
• Non-productive = dry
agonist)
MUCOREGULATORS
ANDROGEN RECEPTOR ANTAGONISTS
• MOA: Increase water layer of mucus that
• Bicalutamide, Flutamide – tx of prostate
aids expectoration
CA and BPH
• Examples:
• Cyproterone acetate – mgt of excessive
✓ Ambroxol (Mucosalvan®)
sexual drive in men
✓ Bromhexine (Bisolvan®)
TESTOSTERONE ✓ Carbocisteine (Solmux®)

Testosterone –(5-α-reductase)→ DHT MUCOLYTICS

TESTOSTERONE ANALOGUES • MOA: Inhibits disulfide linkage between

mucus molecules (lysis of mucus)
• Drugs:
• Example: N-Acetylcysteine (NAC) –
✓ Danazol
available as an effervescent tablet PO
✓ Nandrolone
• Route: Direct instillation into the tracheal
✓ Anabolic steroids
bronchial tree
• Side Effects:
o Increased CA risk (hepatocellular, EXPECTORANTS
prostate)
o Testicular atrophy • MOA: Stimulates bronchial gland to
increase water secretion
RESPIRATORY DRUGS • Example: Guaifenesin (Glyceryl glycolate)
= Robitussin®; Robitussin DM (+
DRUGS FOR COLDS Dextromethorphan)

• Common colds ANTITUSSIVES

• Allergic colds
• Cough suppressants
COMMON COLDS • Peripherally Acting – MOA: Decreases
sensitivity of peripheral cough
• Caused by Viruses: (CAR) ✓ Levodropropizine
✓ Coronavirus ✓ Butamirate citrate
✓ Adenovirus • Centrally Acting:
✓ Rhinovirus ✓ Codeine
• Mgt: α1 agonist (Phenylephrine), APAP ✓ Dextromethorphan
• Avoid antihistamines (prolonged use of ✓ Noscapine
antihistamine can cause drying effects) • Clinical Use: Useless cough / dry non-
o Topical: NMT 3 days productive / harmful cough (px with TB)
o Oral: NMT 5 days
o Risk: Rhinitis medicamentosa DRUGS FOR BRONCHOSPSATIC DISORDERS

ALLERGIC COLDS • Reliever Medications

o PRN
• Caused by allergic endogenous o Effect: Provides immediate relief
compounds of symptoms of bronchospasm
• Management: Antihistamines + nasal (Ex. asthma / COPD)
decongestants (Ex: Chlorpheniramine + • Controller Medications
Phenylephrine) o Maintenance

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o Effect: Reduce severity, duration, NOTES: Late phase allergic reaction is

and frequency of subsequent characterized by bronchospasm in early stage
episodes of bronchospasm (bronchodilation); late phase means there’s
BRONCHODILATORS inflammation

β2 Agonists, Methylxanthines, Anti-muscarinics • Drugs:

Short Acting β Agonists (SABA) ✓ Theophylline – PO controller
✓ Aminophylline – IV reliever
• Drugs: • Clinical Uses:
✓ Albuterol ✓ Alt in bronchial asthma
✓ Salbutamol ✓ Respiratory stimulant in COPD
✓ Pirbuterol • Side Effects:
✓ Terbutaline – also a tocolytic o Central: Overstimulation of CNS,
✓ Metaproterenol anxiety, confusion, agitation,
• Route: Inhalational, MDI, nebulization, PO, seizure
SQ o CV: Palpitation, tachycardia,
• Clinical Use: Reliever meds tachyarrhythmia
✓ 1st line for bronchial asthma o Diuresis – methylxanthine is an
✓ 2nd line for COPD aquaretic diuretic
• S/E: Tachycardia, tremors, muscle
weakness, palpitations, hypokalemia Anti-muscarinics

Long Acting β Agonists (LABA) • Quaternary ammonium compounds

• SAMA – reliever
• Drugs: ✓ Ipratropium
✓ Formoterol o 1st line reliever for
✓ Salmeterol COPD
✓ Bambuterol o Add-on in BA, not
✓ Indacaterol responding well with
• Route: MDI SABAs
• Clinical Uses: • Tiotropium – long acting muscarinic
✓ 1st line controller for COPD antagonist
✓ In bronchial asthma, combined
with corticosteroids (never given MAST CELL STABILIZERS
alone) • Mechanism of Action:
✓ If given alone in bronchial ✓ Induces hyperpolarization of the
asthma, increases risk of mast cell membrane. Therefore,
hospitalization and morbidity prevents degradation of
✓ In COPD, can be given as a single histamine from mast cell (inhibits
agent histamine degranulation)
✓ Not to be given to children ✓ Increases Cl- influx and K+ efflux
Methylxanthines • Drugs: (Cromores)
✓ Nedocromil
• Mechanism of Action: ✓ Cromolyn Na
✓ Inhibits PDE = increasing cAMP • S/E: Bronchial irritation (bronchospasm) –
✓ Inhibits adenosine even at low Mgt: SABA
doses, can have anti-
inflammatory effects; given to ANTI-INFLAMMATORY
inhibit late phase allergic reaction
Anti-leukotriene / Leukotriene Modifiers

• Lipoxygenase Inhibitor

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o MOA: Decreases the formation of o Hypertension

leukotriene o Hyperglycemia
o Drug: Zileuton
SYSTEMIC PARENTERAL CORTICOSTEROIDS
• LTD-4 Antagonist
o Drugs: • Drugs:
✓ Montelukast ✓ Hydrocortisone (IV) – synthetic
✓ Zafirlukast counterpart of cortisol
o Clinical Use: First line controller ✓ Methylprednisolone
of BA especially in children • Clinical Uses:
o S/E: Unmasking of Churg-Strauss ✓ Px with severe asthma
Syndrome (historical), increased exacerbation
suicidal tendency, psychotic ✓ DOC for prevention of status
reaction (recent) asthmaticus
Glucocorticoids • Side Effects:
o Hypertension
• MOA: Inhibits cytokine release from the o Hyperglycemia
macrophage o Increased risk of infection
• Clinical Use: Late phase allergic reaction
• Triggers status asthmaticus: Anti-IgE
o ECP: Eosinophilic cationic protein • MOA: Antibody against IgE
o MBP: Major basic protein • Drug: Omalizumab
INHALED CORTICOSTEROIDS • Clinical Use: Poorly controlled BA with
increased serum IgE
• Drugs:
✓ Budesonide ANTI-CANCER DRUGS
✓ Fluticasone
✓ Triamcinolone Cancer – uncontrolled growth of abnormal cells in a
• Clinical Use: Controller; combined for BA; part of the body
controller for COPD PHASES OF CELL CYCLE
• Side Effects:
o Systemic: Minimal if dose < 1000- • G0 / Resting Phase – cell is not committed
1200 mcg/day to division
o Local: Oral thrush, hoarseness of • G1 Phase – RNA and proteins are
the voice – remedy: gargle after synthesized; cells grow larger; preparatory
each dose for synthesis
• S Phase – DNA synthesis and replication
occurs
SYSTEMIC ORAL CORTICOSTEROIDS • G2 Phase – DNA synthesis ceases; RNA and
other enzymes (ex. Topoisomerase I and II)
• Drugs: are produced to prepare for cell
✓ Prednisone duplication; preparatory for mitosis
✓ Prednisolone • M Phase / Mitosis – cell divides into 2
✓ Methylprednisolone daughter cells; PMAT
• Clinical Use:
✓ BA: Combined controller in px
with severe exacerbation
✓ COPD: May have the same
benefit as BA
• Side Effects:
o Increased risk of infection

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ALKYL SULFONATES: BUSOLFAN

• Side Effects:
o Gynecomastia
o Skin pigmentation
o Pulmonary fibrosis
• Clinical Use: Mgt of chronic myeloid
leukemia (CMI)

ETHYLENEIMINES: THIOTEPA

• Largely replaced by cyclophosphamide

NON-CELL CYCLE
CELL CYCLE SPECIFIC AGENTS
SPECIFIC AGENTS TRIAZINES: DACARBAZINE
S Phase
Antimetabolites • Target is O6 of guanine
Folate Antagonists
Purine and pyrimidine analogs • Used in the mgt of metastatic melanoma
Alkylating Agents
Antibiotics PLATINUM COMPOUNDS
G2 Phase: Bleomycin
Nitrosoureas
M Phase • Cisplatin
Vinca Alkaloids o Side Effects:
Taxanes
▪ Persistent N&V
▪ Ototoxicity
ALKYLATING AGENTS ▪ Nephrotoxicity – mgt:
Amifostine or mannitol
• MOA: N7 guanine alkylation with forced hydration
• Largest group • Carboplatin – mild vomiting
• Makes the H bonds of DNA covalent, • Oxaliplatin – S/E: Cold-induced peripheral
rendering the DNA incapable of replicating neuritis – Mgt: Duloxetine
• Cross linking (to inhibit DNA replication)
• Mispairing of bases (defective) ANTIBIOTICS
• Depurination (removal of purine group =
Anthracyclines, Bleomycin, Plicamycin, Mitomycin
cleavage) of DNA strand
ANTHRACYCLINES
NITROGEN MUSTARDS
• MOA: Cleaves the DNA, breaking the
• Cyclophosphamide
strand, rendering the DNA once again
o Phosphoramide mustard
incapable of replication (no DNA synthesis)
o Acrolein (aka Propenal) – toxic;
• Drugs:
causes hemorrhagic cystitis
✓ Doxorubicin
o Rescue: MESNA
✓ Daunorubicin
o Mnemonic: Alam mo, MESNA
✓ Idarubicin
kita. Acrolein (Ako rin).
✓ Epirubicin
• Mechlorethamine
✓ Mitoxantrone
o 1st alkylating agent
• S/E: Cardiotoxic – delay CHF
o Most reactive alkylating agent
• Rescue: Dexrazoxane – prevents free
• Chlorambucil
radical formation
o 1st line drug in chronic
lymphocytic leukemia (CLL) BLEOMYCIN
o Usually combined with Imatinib
• Others: Ifosfamide, Melphalan • MOA: DNA breakage via oxidative
mechanism (free radicals = breakage)
• S/E: Pulmonary fibrosis, alopecia,
hyperpigmentation

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PLICAMYCIN PYRIMIDINE ANALOGS

• S/E: CA-related hypercalcemia • Fluorouracil (5-FU)

o MOA: Blocks thymidylate
NITROSOUREAS
synthetase
o Clinical Use:
▪ Topical: Basal cell
carcinoma
▪ Colorectal cancer
• Cytarabine

PLANT DERIVED PRODUCTS

• Highly lipophilic = can cross BBB Vinca Alkaloids, Taxanes, Epipodophyllotoxins,

• Used in the mgt of brain tumors Camptothecin Analogs
• Drugs:
VINCA ALKALOIDS
✓ Carmustine – causes
myelosuppression • Source: Periwinkle Plant (Vinca rosea or
✓ Lomustine Catharantus roseus)
✓ Semustine • MOA: Block tubular polymerization
✓ Streptozocin – used in the mgt of • Drugs:
pancreatic CA or insulinoma ✓ Vincristine (VX)
✓ Vinblastine (VBL)
ANTIMETABOLITES
✓ Vinorelbine (VRB) – less toxic
Folate Antagonists, Purine and Pyrimidine Analogs • Side Effects:
o Peripheral neuritis – Vit B6 will
FOLATE ANTAGONISTS
not work
• Methotrexate o VX – constipation
o MOA: Blocks DHF reductase o VBL – bone marrow suppression
o S/E: N&V, diarrhea, stomatitis TAXANES
o Rescue: Leucovorin / Folinic Acid
• Pemetrexed & Pralatrexate • Source: Pacific Yew Tree (Taxus brevifolia)
o Same MOA as Methotrexate • MOA: Promote tubular polymerization
o Rescue: Vit B9 and B12 • Paclitaxel – for metastatic breast CA
supplementation o S/E: Hypersensitivity rxn
o Mgt: Pre-treated with
PURINE ANALOGS
Dexamethasone and
• Mercaptopurine Diphenhydramine
o Azathioprine – 6-mercaptopurine • Docetaxel
o DI: Allopurinol – inhibits xanthine
EPIPODOPHYLLOTOXINS
oxidase
6-MP –(XO)→ Thiouric Acid • Source: American Mandrake (Mayapple)
↑ 6-MP = bone marrow • MOA: Inhibit Topoisomerase II
suppression • Drugs: Etoposide, Teniposide
Mgt: Decrease dose of • Clinical Use: Used in combination with
azathioprine Cisplatin in the mgt of testicular CA
• Thioguanine
• Fludarabine CAMPTOTHECIN ANALOGS
• Cladribine • Source: Camptotheca Tree
• Pentostatin • Natural (Camptothecin)
• Synthetics:

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o Irinotecan • Erlotinib, Gefitinib – block epidermal GF

▪ Used in the tx of receptor Tyrosine kinase (lung CA cells)
colorectal CA • Surefenib, Sunitinib – block endothelial GF
▪ S/E: Diarrhea receptors; used for renal cancer
o Topotecan
TOXICITIES
ENZYMES

L-Asparaginase, Pagaspargase

L-ASPARAGINASE (Elspar®)

• Source: E. coli
• MOA: Catalyzes asparagine to:
o Aspartic Acid
o Ammonia
• S/E: Hypersensitivity
• NOTE: Asparagine is needed by cancer
cells

PAGASPARGASE

• Prolonged T50 – less likely to cause allergic

reactions

HORMONES

• Tamoxifen – tx of breast cancer

• Finasteride – BPH
• Flutamide – prostate CA
• Buserelin, Leuprolide – GnRH analog; tx of
endometriosis
• Octreotide – Somatostatin analog; GH
antagonist; tx for carcinoid tumor

MONOCLONAL ANTIBODIES

• Trastuzumab
o Humanized
o HER-2 blocker
o Used in breast CA
• Rituximab
o Chimeric
o 1st anti-cancer mab
o Combined with Chlorambucil for
CLL
• Bevacizumab
o Humanized
o Combined with 5-FU

TYROSINE KINASE INHIBITORS

• Imatinib, Dasatinib – block BCR-ABL

Tyrosine kinase (breakpoint cluster region
Abelson)

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