General pharmacology

In this chapter, we will discuss:

1. Pharmacokinetics: ‫كيف يتعامل الجسم مع الدواء‬
• Absorption
• Distribution
• Metabolism
• Excretion
2. Pharmacodynamics: ‫ما يفعله الدواء بالجسم‬
• Mechanism of drug actions
• Actions and adverse effects related to the drug.
3. Pharmacotherapeutics: ‫دواعي استخدام الدواء‬
• Treatment
• Prevention
• Diagnosis

Pharmacokinetics

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First step to understand the pharmacokinetics is to know how drugs could pass across cell
membrane which occurs by the following mechanisms:

1. Simple (passive) diffusion

• Occurs along concentration gradient …. No need for energy
• Drugs are lipid soluble (easily pass the cellular membrane) … No need for
carrier
• Ex … Most drug absorption and renal reabsorption
2. Facilitated transport
• Occurs along concentration gradient … No need for energy
• Drugs are lipid insoluble …. Need specific carrier
• Ex … Glucose absorption via glucose transporters
3. Active transport
• Occurs against concentration gradient …. Need energy
• Need specific carrier
• Ex … Penicillin secretion via renal tubules
4. Pinocytosis
• Cellular engulfment
• Ex …. Vit B12 + intrinsic factor , Iron + transferrin

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 Absorption
Transfer of a drug from its site of administration to systemic circulation.

Factors affecting absorption:

A. Factors related to the drug:
1. Water and lipid solubility
• Drugs must be water and lipid soluble
• The more the lipid solubility …. Better absorption
2. Degree of ionization
• Non-ionized drugs are lipid soluble, while ionized drugs are water soluble
• Depends on PH of the media and PKa of the drug
• Quaternary ammonium compound (+) ….. poor absorption
• Tertiary ammonium compounds …. ( ) …. Better absorption
3. PH of the media & PKa of the drug
• Stomach media is acidic while intestinal media is alkaline
• Most drugs are either weak acids or bases
• Drugs are better absorbed in the same media (acidic drugs are absorbed better
in acidic media while basic drugs are absorbed in alkaline media) ….. see
diagram for illustration
• Drugs are easily excreted in opposite media where drugs are ionized and water
soluble (acidic drugs are excreted in alkaline media while basic drugs are
excreted in acidic media)
• One important clinical application is how to delay the absorption of drugs &
fasten their excretion in case of toxicity???????

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4. Valency …. Ferrous iron is better absorbed than ferric iron
5. Nature …. Inorganic drugs (small molecules) are better absorbed than organic drugs
(large molecules)
6. Pharmaceutical preparation:
• Dosage form ….. solution better absorption than suspension
• Size of particles and rate of dissolution (paracetamol has a rapid dissolution
rate)

B. Factors related to the patient:

1. Route of administration … IM> S.C> Oral> Skin
2. Absorbing surface
• Surface area
• Vascularity
• Health state
3. Systemic circulation
• In case of shock, subcutaneous route is not preferred due to vasoconstriction

4. GIT related factors

a. Presence of food
• food containing calcium or iron decreases the absorption of tetracycline
• Grape fruit juice … increases absorption of drugs by inhibiting P. glycoprotein
b. Presence of other drugs … adrenaline added to local anesthesia to decrease its
absorption??
c. PH of the gut …. See before
d. Specific factor … Intrinsic factor for Vit B12 absorption
e. Motility of the GIT and rate of dissolution
• Rapid GIT motility (prokinetic drugs) will increase the absorption of rapidly
dissolved drugs like paracetamol while decreasing the absorption of slowly
dissolved drugs like digoxin
f. First pass effect ….. ‫هام جداااااااااا‬
• Metabolism of drug before reaching systemic circulation
• See diagram for examples
• It decreases the percent of the unchanged drug that reach systemic circulation
(bioavailability)
• To avoid either use other routes (if completely destroyed by first pass effect)
or increase the dose (if partially destroyed by first pass effect)

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We could summarize all factors in the following diagram.

Bioavailability (f):
• Percent of the drug that reach systemic circulation unchanged
• Inversely proportional to the first pass effect
• 100% after intravenous injection while variable for other routes
• To determine oral bioavailability for any drug … AUC for oral drug/ AUC for IV (see
diagram)
• Factors affecting bioavailability = Factors affecting absorption

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 Distribution
• Passage of drugs from systemic circulation to organ and tissues
• Drugs are distributed into one body compartment or two compartments or
multicompartment (see diagram)

• Some drugs have specific sites for distribution (calcium and tetracycline are
distributed mainly into bone and teeth, while iodine is mainly up taken thyroid gland)

Volume of distribution
• Apparently, the volume of body fluids at which drug is distributed
• Calculated via: Vd (L)= Amount (mg)/ C (mg/ml)
What is the significance of knowing this number (Vd)???
1. Rough estimation of drug distribution
➢ If Vd of a drug is 3L ….. Means this drug is distributed mainly in the
vascular compartment.
➢ If Vd= 45 L …. Means this drug is distributed in all body compartments
2. In case of toxicity, dialysis is only feasible for drugs with small Volume of
distribution (Aspirin)
3. Calculation of loading dose (large therapeutic dose given in emergency to rapidly
reach therapeutic drug level) via this equation:
Amount (loading dose) = Vd * C (desired drug conc)

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Factors affecting distribution:
1. Drug properties …. Molecular weight, lipid solubility
2. Binding to plasma proteins:
➢ Drugs in plasma are either in the free form (active form) or in the bound form
(reservoir)
➢ In case of hypoalbuminemia, free form of drugs will increase which may
increase drug toxicity
➢ Acidic drugs compete for the acidic binding site on plasma protein …. Aspirin
displaces warfarin from the binding sites …. Increasing free form of warfarin
…. Increasing the toxicity (hemorrhage)
➢ Drugs with high plasma protein binding affinity have longer duration (as
bound form acts as a reservoir)
3. Passage across specific barriers:
a. Blood brain barrier (BBB)

b. Placental barrier:
Lipid soluble drugs could pass the placenta to the fetus and cause
teratogenicity (during pregnancy) ….. tetracycline
or problems during labor ….. morphine causes neonatal asphyxia

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 Metabolism
Goal????
To transform lipid soluble drugs into water soluble forms which are easily excreted (see
diagram)

Site???
• Liver is the main site
• Other sites include:
➢ Lung …. Nicotine and prostaglandin
➢ Skin& kidney …. Vitamin D

What are the chemical reactions???

A. Phase one reactions(non-synthetic):
• Oxidation, reduction hydrolysis
• Either by microsomal enzymes (cytochrome P450 enzymes) or non-
microsomal

Microsomal enzymes Non-microsomal enzymes

Smooth endoplasmic reticulum in liver Cytoplasm, mitochondria …. all organs
Inducible Not inducible

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 • Results could be:

B. Phase 2 reactions (synthetic):

• Conjugation with endogenous compounds by the activity of transferases
• Ex…. Glucuronic acid conjugation, Acetic acid, methyl group, SH group,
• Usually leads to inactivation of drugs but may lead to more active metabolite
like morphine-6-glucuronide.

Most drugs pass through phase 1 then phase 2 reactions, Isoniazid (antibacterial drug)
undergoes phase 2 reactions then phase 1.

Factors affecting metabolism:

A. Personal variations:
1. Age:
• Extreme ages have low metabolic activity than adult persons
• Premature baby can’t conjugate chloramphenicol (antibacterial) …. Gray
baby syndrome
2. Gender:
• Androgen stimulates the metabolic enzyme activity while estrogen inhibits
3. Genetic variations:
• People with deficient pseudo cholinesterase enzyme couldn’t eliminate
succinylcholine ….. accumulation ….. skeletal muscle paralysis (apnea)

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B. Pathological conditions:
• Liver diseases affect the metabolism of drugs …. Why???
C. Nutritional state:
• In starvation, conjugation (phase 2 reaction) may be inhibited
D. Drugs:
• Drugs may induce or inhibit hepatic microsomal enzymes (inducible)

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 Excretion
Removal of the drug and from the body mainly via the kidney.
Certain drugs retain their effect even after their excretion from the body … Ex Aspirin
(irreversible inhibition)
Routes of excretion:
1. Renal:

• Renal excretion = Filtration + Active secretion – Reabsorption

• In case of toxicity, changing urinary pH plays an important role to enhance
drug excretion
➢ Acidification of urine by Vit C …. Will enhance the excretion of
basic drugs (Ephedrine) as it makes the drug ionized = water
soluble = no reabsorption
➢ Alkalinization of urine by bicarbonate …. Will enhance the
excretion of acidic drugs (Aspirin) as it makes the drug ionized =
water soluble = no reabsorption
• Drugs that depends mainly on renal excretion (without metabolism)
….used cautiously in renal impairment

2. Lungs: Site for excretion of gases and volatile liquids (general anesthesia)

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3. GIT:

4. Skin:
• Rifampicin (antimicrobial) is excreted in sweat changing its color into
orange-red color (also excreted in kidney and saliva)

5. Milk:
• Most drugs are detected in breast milk especially fat-soluble drugs (milk
contains excess fat) and weak basic drugs (where they are ionized and ion
trapped)
• Drugs could affect suckling baby …. Purgatives causes diarrhea for baby

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 Fundamental principles of kinetics
• To maintain a therapeutic effect of most drugs, we must reach steady concentration of
the drug on plasma which could be obtained by giving the drug at a rate equal to the
rate of elimination (rate of administration = rate of elimination)
• Elimination of drugs may be by zero order kinetics or first order kinetics

A. Zero order kinetics:

• Constant amount of the drug is eliminated per unit time
• Concentration- time curve is linear

• No constant half-live (time needed to reduce plasma drug conc to its half)
• No steady concentration is reached with repeated drug doses

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 • Modest changes in dose could lead to drug toxicity
• Ex … (PEA)
➢ P … Phenytoin
➢ E … Ethanol
➢ A … Aspirin

B. First order kinetics:

• Constant fraction of the drug is eliminated per unit time

• Concentration time curve is exponential

• Have a constant plasma half-live

• On repeated dosing, steady plasma concentration is reached after 4-5 plasma

half-lives

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• Modest change in the dose … is safe
• Ex … Most drugs

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 Plasma half-live (t1/2)
Time required to reduce plasma concentration of the drug to half the initial concentration

Value of plasms half-live:

1. Determine dose interval and route of administration:
• For most drugs, dose interval equals t1/2
• Drugs with short t1/2, given IV infusion or sustained release forms

2. Determine time needed to reach steady state concentration: usually after 4-5 t1/2

N.B: Some drugs have a biological t1/2 longer than their plasma t1/2 due to their irreversible
mechanism of action….. Ex, Aspirin antiplatelet effect remains for 7 days.

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 Pharmacodynamics
Mechanisms of drugs’ action:
1. Physical:

• Drugs acting by osmosis like mannitol or MgSo4

• Drugs acting by adsorption like charcoal and kaolin

2. Chemical:
• Neutralization …. Protamine sulfate (basic drug) is the antidote for Heparin
(acidic)
• Chelation …. Deferoxamine + iron

3. Interfere with metabolic pathway

4. Interfere with cell division

• Chemotherapy for cancer

5. Inhibition of enzymes
• Aspirin causes irreversible inhibition of COX enzyme
• Theophylline causes reversible inhibition of PDE enzyme

6. Action ion channels

• Local anesthetics and anti-arrhythmic drugs blocking sodium channels

7. Action on membrane carrier

• Drugs blocking sodium reabsorption in renal tubules via blocking Na/Cl
symport

8. Action on receptors
• Most common mechanism of action
• Receptors are macromolecules that interact (Bind) with specific ligand (drug,
hormone, neurotransmitter) to stimulate or block cellular responses
(Signaling)
• The force of drug binding to the receptor will affect the drug action (reversible
or irreversible).

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Types of ligands:
1. Agonist
• Drug has affinity to receptor (ability to bind) and efficacy (produce
pharmacological action)
• Ex … Adrenaline on Beta receptors or Acetylcholine on Muscarinic receptors

2. Antagonist
• Drug has affinity to receptor without efficacy
• Called antagonist or blocker
• Either competitive or non-competitive
• Ex … Beta blockers on Beta receptors

3. Partial agonist
• Drug has affinity to receptors with incomplete efficacy (weak response)
• Ex … succinylcholine on nicotinic receptors

4. Inverse agonist
• Some receptors have constitutive activity in absence of ligand
• Ex … Benzodiazepine receptors
• Inverse agonist makes these receptors inactive
• Ex … Beta carboline on Benzodiazepine receptors

Theories for the relation between dose and response

1. Occupation theory:
• The effect of a drug is proportional to the fraction of receptors occupied
• Maximal effect is reached when all receptors are occupied

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 • One drawback, some receptors remain free (unoccupied) despite of the
maximal response reached (spare receptors)

2. Rate theory:
• The effect of a drug is proportional to the rate of association and dissociation
between the drug and its receptor
• Maximal response is reached with higher rates of Association/dissociation

Dose-response curves
Agonist curves:

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 • Graded dose-response curve correlates the percent of response of a drug to its
concentration or dose (log)
• Many parameters could be obtained from this curve:
➢ Efficacy (Emax): maximal effect reached by the drug
➢ ED50: the dose that produce 50% of the maximal response
➢ Potency: how much dose needed to reach specific response (the lower the
dose, the higher the potency) … could be assessed from ED50 (the lower
ED50, the more potent the drug)
➢ Compare drugs regarding efficacy and potency (see diagram)

Agonist curves in presence of an antagonist

1. Competitive antagonist

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 • Antagonist competes with agonist to bind to the active site of the receptor
• The duration of action of the antagonist directly proportional to its
concentration
• Increasing dose of an antagonist shifts dose-response curve to the right:
➢ Same efficacy (Emax)
➢ EC50 is increased (lower the potency of the agonist)
• Ex …. Atropine is a competitive antagonist on Muscarinic receptors

2. Non-competitive antagonist

• The antagonist either binds irreversibly to the active site or binds to an

allosteric site (no competition)
• The duration of action of the antagonist directly proportional to rate of
receptor turnover and the metabolism of the antagonist
• Increasing dose of the antagonist shift dose-response curve downward:
➢ Efficacy (Emax) is decreased
➢ Same potency (EC50)
• Ex …. Phenoxybenzamine is a non-competitive blocker of Alpha
adrenergic receptors

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Inverse agonist and partial agonist curves

N.B. chronic use of drugs could affect number and sensitivity of receptors:

• Chronic use of the agonist could decrease number& sensitivity of receptors

(downregulation)
• Chronic use of the antagonist could increase the number& sensitivity of
receptors (upregulation)

Cellular signaling or transduction

• Binding of a ligand (drug) to specific receptor leads to conformational changes to the
receptor and intracellular molecules.
• The most important function for transduction (signaling) is amplification of the
response …
• Ex …. Binding of one adrenaline molecule to Beta 2- adrenergic receptor activates
100 G-proteins …. Activates 10000 adenyl cyclase enzymes … activates 100000
glycogen phosphorylase enzymes … stimulates glycogenolysis …. Release 10000000
molecules of glucose
• According to the signaling pathway, receptors are classified into many types

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G-protein coupled receptors

• Made of 7 transmembrane domains

• G-protein binds to the 3rd cytoplasmic domain
• G-protein is formed of 3 subunits (G, Gβ & G)
• There are different types of G:
➢ Gs: Linked to activation of adenyl cyclase …. Increases c-AMP (Ex … β-
adrenergic receptors)
➢ Gi: Linked to inhibition of adenyl cyclase …. Decreases c-AMP (Ex … 2
adrenergic receptors
➢ Gq: Linked to activation of phospholipase C enzyme (PLC) … increases IP3
(increases Ca release), and DAG (activates PKC) … Ex … 1 adrenergic
receptors

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Ion channel receptors

• A protein pore in the cell membrane

• Opens in response to binding to a ligand (drug)
• Has a rapid response
• Ex … Nicotinic receptors in skeletal muscle and GABA receptors in CNS

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Tyrosine-kinase linked receptors

• Insulin receptors are the classic example

• Binding of insulin to the receptor leads to aggregation of the 2 subunits which in turn
activate the tyrosine kinase (phosphorylated)
• Activated tyrosine kinase leads to phosphorylation of relay proteins (IRS: insulin
receptor substrates)
• IRS cause phosphorylation of other components like glycogen synthase (glycogen
deposition in liver), and hormone sensitive lipase (inhibits lipolysis)

Intracellular receptors

• Drugs acting on intracellular receptors should be lipophilic

• Ex … steroid hormones, Vit D, T4
• Ligand binding to the receptor will form a complex that enters the nucleus where it
binds to specific DNA segment affecting transcription (forming new proteins)

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 Pharmacotherapeutics
Adverse drug reactions:
Type A (Augmented)
Predictable undesirable effects related to the pharmacological actions of the drug which
include:
1. Side effects: (At therapeutic doses)

• Primary pharmacological action … Dry mouth induced by antimuscarinic or

antihistaminic
• Secondary pharmacological action … Fungal infection after a course of
antibiotics (secondary infection)

2. Overdose: (At doses slightly higher than therapeutic dose)

• Insulin large dose … Hypoglycemia

3. Toxic effect: (At very high doses)

• Paracetamol … Hepatotoxicity

4. Drug intolerance: (At doses lower than therapeutic dose)

• Captopril … Dry cough

Type B (Bizarre or unpredictable)

1. Allergy (Hypersensitivity)
• Immune mediated reactions
• Cross allergy may occur in chemically related drugs (Sulfonylurea&
Sulfonamides)
• Type 1(Immediate hypersensitivity, IgE mediated) leads to:
➢ Local reactions … Urticaria, angioedema, bronchospasm
➢ Systemic reactions … Anaphylactic shock
• Type 2 (Cytotoxic)
➢ IgM, IgG directed at drug-hapten coated cell … cell lysis
➢ Ex … Hemolytic anemia and thrombocytopenia
• Type 3 (Immune complex hypersensitivity)
➢ Vasculitis induced by immune complex (antigen-antibody)
➢ Ex … Glomerulonephritis
• Type 4 (Delayed, cell-mediated hypersensitivity)
➢ Contact dermatitis after topical application of drugs
2. Idiosyncrasy (pharmacogenetics):
• Abnormal unpredictable response due to genetic defect

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 • Ex … succinylcholine apnea in patients who have a deficiency in
pseudocholine esterase enzyme
• Ex … Hemolysis in patients with G6PD deficiency after aspirin intake

Type C (Chronic effects)

Tolerance:
• Decreased response to the drug that needs higher doses than the usual
therapeutic dose
• May be congenital or acquired
• Congenital tolerance:
➢ may explain the interpersonal variations in response to the same drug
➢ Ex … Warfarin resistance
• Acquired tolerance
Characterized by:
➢ Reduced responsiveness of the drug on repeated administration
➢ Higher doses are required to produce the same response
➢ Reversible … stop the drug for some time …. Regain normal
sensitivity
➢ Not all drugs … some drugs are well known to cause tolerance like
Nitroglycerine and β2- agonists, other drugs don’t produce tolerance
like digoxin
➢ Not all actions of the same drug … tolerance to analgesic effect of
morphine without tolerance to miosis or constipation
Explained by:
1. Kinetic tolerance (due to decrease drug level that reach receptors)
➢ Diminished absorption … Alcohol
➢ Increased elimination (metabolism) … barbiturates (HME
inducers)
2. Dynamic tolerance (without decrease in drug level)
➢ Downregulation … β2 receptors after long use of β2 agonists
➢ Upregulation … β1 receptors after long use of β1 blockers
➢ Activation of counter regulatory mechanism … salt and water
retention (elevate Bp) in response to some antihypertensives
➢ Antibody formation … Insulin

Special types:
1. Cross tolerance … tolerance to related drugs like tolerance occurs among
different members of opioids
2. Tachyphylaxis
➢ Acute acquired tolerance
➢ Can’t get the same response by increasing the dose
➢ Ephedrine tolerance due to depletion of NE stores in nerve endings

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Dependence
1. Psychic (Habituation):
• Substance produce pleasure, sense of well-being, or enhance cognitive
functions
• Ex … Tea, Coffee
2. Physical:
• Body adapted to the presence of the drug
• Acute withdrawal could produce withdrawal symptoms (the reverse of drug’s
action)
• Ex … Morphine produce analgesia, constipation, miosis, and hypotension …
withdrawal symptoms would be pain, diarrhea, dilated pupil, and hypertension

3. Addiction:
• Psychic and physical dependence +
• Impaired control over drug’s use
• Increasing priority of drug’s use over aspects of life

Iatrogenic disease
• Drug induced disease that closely mimics a natural disease
• Ex … prolonged use of cortisol … Cushing syndrome

Type D (Delayed effects)

1. Teratogenicity
• Drug-induced fetal malformations
• If drugs given early in pregnancy (1st trimester) during organogenesis
• EX … Thalidomide causes phocomelia, I131 causes fetal goiter, Tetracycline
causes dental enamel hypoplasia

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 2. Mutagenicity
• Drug-induced gene abnormalities
• Ex … metronidazole (Flagyl)

3. Carcinogenicity
• Drug-induced neoplasm
• Ex … IM iron administration

Type E (End of use effects)

Occurs after cessation of therapy:
• Addison’s crisis with corticosteroid therapy
• Withdrawal syndrome with morphine
• Ischemic heart disease after sudden withdrawal of β1 blockers
• Hypertension after clonidine withdrawal

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Drug interactions
Level of interactions:
1. Pharmaceutical
• Occurs outside the body before drug administration
• Ex … chemical or physical reactions among drugs mixed with IV fluids

2. Pharmacokinetic

a. Absorption:
• Affecting gut motility
• Affecting gut pH
• Drug binding (adsorption, chelation)

b. Distribution:
• Acidic drugs compete for acidic binding site on plasma proteins (aspirin
displaces warfarin from plasma proteins … increasing toxicity)

c. Metabolism:
• HME inducers could decrease the effect of co-administered drugs
• HME inhibitors could increase the effect or even toxicity of co-
administered drugs (especially drugs with narrow therapeutic index)

d. Excretion:
• Changing urinary pH could affect drug excretion
• Acidic drugs compete for acidic carrier in PCT (Diuretics compete with
uric acid … hyperuricemia)

3. Pharmacodynamic

a. On specific receptor: competitive and non-competitive antagonism

b. On same physiological system: Caffeine antagonizes the CNS depressant action of
barbiturates
c. Combined toxicity: loop diuretics+ aminoglycosides … more ototoxicity

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Results of interactions:

Dosage of drugs
1. Loading dose:
• Initial large dose to build up therapeutic drug level
• Ld= Vd* C (desired concentration/Css)
2. Maintenance dose:
• Repeated doses at regular intervals to maintain therapeutic drug level

3. Minimal effective dose:

• Lowest dose to produce therapeutic response

4. Maximal tolerated dose

• Largest dose without toxic effect

5. Therapeutic index (TI):

• LD50/ ED50
• Measure of drugs’ safety
• Higher the index, safer the drug

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