GENERAL

PHARMACOLOGY
For dental students
by
Dr/ Dina Anwar
Dr/ Asmaa farag
• Pharmacology is the scientific
study of the effects of drugs and
chemicals on living organisms

• A drug can be broadly defined

as any chemical substance,
natural or synthetic, which affects
a biological system.
Pharmacokinetics [ADME]

❑The goal of drug therapy is to prevent, cure, or control

various disease states.

❑To achieve this goal, adequate drug doses must be

delivered to the target tissues so that therapeutic
(nontoxic) levels are obtained.

❑Pharmacokinetics study the movement of a drug over

time through the body.
Pharmacokinetics [ADME]
❑First, drug absorption from the site of administration
(Absorption) permits entry of the therapeutic agent
(either directly or indirectly) into plasma.

❑Second, the drug may then reversibly leave the

bloodstream and distribute into the interstitial and
intracellular fluids (Distribution).

❑Third, the drug may be metabolized by the liver, kidney, or

other tissues (Metabolism).
❑Finally, the drug and its metabolites are removed from the
body in urine, bile, or feces (Elimination).
Pharmacokinetics [ADME]
drug
Absorption

Tissue Plasma
storage Bound drug Sites of
action
Receptors
Free drug
Distribution to Tissues

Drug Metabolism Drug Excretion

(Liver, Blood,… etc) (renal, Biliary, Exhalation,… etc)
Pharmacokinetics [ADME]
• I. Absorption
• Absorption is the transfer of a drug from its site of
administration to the systemic circulation. The rate and
efficiency of absorption depend on the route of
administration.

• For IV delivery, absorption is complete; that is, the total

dose of drug reaches the systemic circulation. Drug
delivery by other routes may result in only partial
absorption.
Pharmacokinetics [ADME]
❑To traverse cellular barriers (e.g. gastrointestinal mucosa,
renal tubule, blood-brain barrier, placenta), drugs have to
cross lipid membranes.
(a) by passive diffusion for lipid-soluble molecules:
through the lipid layer driven by concentration gradient
(b) by filtration (passive) for water-soluble- molecules:
through the aqueous pores along concentration gradient
(c) by facilitated diffusion (carrier-mediated transfer) for
large molecules: through specialized transmembrane
carrier proteins that facilitate their passage along
concentration gradient
(d) by active transport: if energy is needed for transport
against concentration gradient
Factors affecting drug absorption
I- Factors related to the drug:
1. Solubility: Drugs MUST be Water soluble as well as Lipid
soluble. The more the lipid solubility (the higher the lipid/water
partition coefficient) the faster the rate of absorption.
2. Ionization: Unionized drugs are more lipid soluble than the
ionized and so more absorbed.
3. Valency: Ferrous salts (Fe++) are better absorbed than ferric
salts (Fe+++)
4. Nature: Inorganic better absorbed than organic,
5. Drug formulation:
- Aqueous solutions are easily absorbed than solids or
suspensions.
- Rate of disintegration e.g. Paracetamol has a rapid rate of
disintegration  rapid absorption.
Factors affecting drug absorption
II- Factors related to the patient:
• Route of administration: IV and inhalation > IM > SC >
intact skin (slow).
• Surface area and vascularity of the absorbing surface:
absorption  with increase in both.
• State of health of absorbing surface: e.g. gastritis  l
absorption.
• State of general circulation: shock  absorption of
drugs. So give drugs IV.
• Specific factors: Intrinsic factor of the stomach is
essential for Vit. B12 absorption.
Factors affecting oral absorption
•
Related
1-water and lipid solubility
• 2-ionization
• 3- valency
• 4-Nature
to the • 5-Pharmacological prepartion

drug
•
Related •
•
1- Surface area.
2- State of absorping surface
3- Motility of the gut
to the •
•
4- PH within the gut
5- specific factors
•
patient •
6-Gut contents
7- First pass effect
1- Surface area of absorbing surface
2- State of absorbing surface

Gastritis
Malabsorption syndrome
3- Gut motility and rate of dissolution

➢Prokinetic:
Metoclopromide +
(Paracetamol)
Or + (Digoxin)
➢Atropine +
(Paracetamol)
Or + (Digoxin)
ine
4- PH within the gut

• Weak acidic • Weak basic

drugs drugs
e.g. Aspirin e.g Amphetamine
6- Gut contents
• -Food (bad or good)
• Drugs:
Tetracycline and calcium
7-First pass Effect
7-First pass Effect
❑First pass effect means metabolism of drug in gut wall or liver
before reaching systemic circulation (in case of oral route).
A- Gut first pass effect:
• Gastric acidity destroys benzyl penicillin.
• Digestive enzymes destroys insulin
• Mucosal enzymes destroy chlorpromazine.
B-Hepatic first pass effect:
• Drugs extensively metabolized: e.g. Nitroglycerine –
Lidocaine.
How to overcome
Hepatic First Pass Metabolism?
- Increase the oral dose of the drug
- Use other routes (NOT ORAL)”.
•
Bioavailability
• The percentage of drug that reaches systemic circulation
unchanged and becomes available for biological effect
following administration by any route.
Factors affecting oral bioavailability:
1- First pass hepatic metabolism:
2- Solubility
3- Chemical stability:
4- Nature of drug formulation:
- Particle size - Salt form
- Crystal polymorphism - Excipients
Pharmacokinetics [ADME]
II- Distribution
• The reversible transfer of a drug between blood stream, interstitium
and/or cells.
• Drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and/or the
cells of the tissues.
Pharmacokinetics [ADME]
II-Distribution
• Patterns of distribution

1- One compartment model (intravascular):

• Drugs having too large MW to move out through

endothelial slit junctions of the capillaries, are trapped
intravascularly and are distributed in a volume of plasma
of 4 L which is equal to 6% of a 70 kg body weight
individual. e.g. High MW heparin or drugs highly bound to
plasma proteins as warfarin.
•
Pharmacokinetics [ADME]
II-Distribution
❑Patterns of distribution

2-Two compartments model (extracellular):

These compartments are intravascular and interstitial
fluid. (H2O soluble) with low MW are distributed in a
volume of 14 L= 20% of body weight. e.g. quaternary
ammonium compounds (neostigmine), Mannitol, NaCl
Pharmacokinetics [ADME]
II-Distribution
❑Patterns of distribution

3- Multi compartment model (Extra and intracellular):

Drugs are distributed to total body fluids (42 L / 70 Kg).
They should be (lipid sol) and have low MW. They are
distributed to a volume of 42 L = 60% of body weight.

4. Other sites: Some drugs have special affinity for certain

tissue:-
• Tetracycline and calcium in bone and teeth.
Factors affecting distribution of drugs:
1- Physicochemical properties of the drugs:
Molecular weight (MW) – degree of ionization – lipid
solubility.
2- Binding to plasma proteins:
Drugs are carried in blood in 2 forms:
• Free form: Pharmacologically active – diffusible – metabolized –
excreted.
• Bound form: inactive, non-diffusible, not metabolized and not
excreted (act as reservoir).
• .
Factors affecting distribution of drugs:
• The amount of drug bound to plasma protein will
change according to:
a- Affinity for binding sites: Competition between drugs
for binding sites as a drug may displace another one from
its binding site e.g.
• Salicylates can displace warfarin  hemorrhage.
b- Hypo albuminemia: e.g. in liver cirrhosis  free drug
 therapeutic dose changes to toxic dose e.g. Phenytoin.
Factors affecting distribution of drugs:
3- Rate of blood flow: tissues with more blood supply receive
more amount of drug.
4- Passage across barriers (Capillry Permeability):
a- Passage to central nervous system across blood
brain barrier (BBB)
- Non-ionized, lipid-soluble drugs can pass BBB e.g.
physostigmine can stimulate CNS
- Inflammation as in meningitis  permeability of BBB
so allows better passage of drugs e.g. penicillin can pass
the BBB in sufficient amount only if there is inflammation.
Factors affecting distribution of drugs:
b- Passage to fetus across placental barrier:
• The placental barrier acts like a cell membrane. So, non-ionizable,
lipid soluble drugs pass from mother to fetus more easily and may
induce teratogenic or toxic effect during pregnancy (eg.
malformation by tetracyclines) or during labor (neonatal asphyxia
by morphine)
c- Passage of drugs through breast milk:
▪ Most drugs administered to lactating women are detectable in breast
milk.
▪ pH of milk is more acidic (7.0) than that of plasma (7.4)
So, basic drugs ionize and accumulate in milk (ion
trapping)
▪ Milk contains more fat than plasma which favors retention of lipid
soluble drugs.
Apparent Volume Of Distribution (Vd):
❑Hypothetical volume at which the drug should be
distributed (diluted) to attain the estimated plasma
concentration of the drug.

•
Apparent Volume Of Distribution (Vd):

a- Useful to estimate the amount of drug in the body (A) =

(Vd) X (C).
b- Determines the loading dose of a drug = Vd X Desired
plasma concentration.
c- Can guide management of overdose toxicity as regards
using hemodialysis.

Drugs highly bound to plasma proteins  Small Vd = Plasma volume

✓ Drugs highly bound to Tissue proteins  High Vd > Total body fluids e.g.
Digoxin
Pharmacokinetics
III- Excretion
• Irreversible removal of the drug from the
body.
• Removal of a drug from the body may occur
via a number of routes, the most important
being through the kidney into the urine. Other
routes include the GIT, skin glands, lung.

❑ Renal excretion: Occurs through 3

different processes:
1- Glomerular filtration
2- Active secretion
3- Passive reabsorption
Pharmacokinetics
III- Excretion
❑Changes of pH of the urine affect excretion of drugs:
• Alkalization of urine by bicarbonate  excretion of acid drugs e.g.
Aspirin.
• Acidification of urine by NH4Cl  excretion of base drugs as
Ephedrine.
• This process is called "ion trapping“
•

❑Other routes of excretion:

1- GIT:
-Salivary glands:
- Stomach:
- Feces:
- 2- Skin glands:
- Sweat:.
3- Lung:
Pharmacokinetics
IV- Metabolism
❑Conversion of highly lipid-soluble drugs into less lipid-
soluble metabolites to be easily excreted

❑The aim of drug metabolism is to change lipid soluble

drugs to water soluble metabolites to be easily excreted

❑The metabolizing enzymes can be divided into two

general sets of reactions called phase I and phase II
Phases of biotransformation :
Phase I (Non synthetic) reactions :
Converts a drug to (water soluble) metabolites which are:

Easily excreted or Liable (Ready) to be conjugated in phase II reaction

• Oxidation
• Reduction
• Hydrolysis
Results of Phase-I Metabolism:
Inactive
prodrug Active

Active More Active

The
Active commonest
Inactive
fate

Active Toxic
Results of Phase-I Metabolism:
• Conversion of active compound into inactive:
Acetylcholine→ choline + acetic acid.
• Conversion of active compound into another active:
Phenacetin → acetaminophen.

• Conversion of inactive compound (prodrug) into

active:
Imipramine → desipramine.
• Conversion of drug into toxic metabolite:
Methanol → formaldehyde (toxic to retina).
B- Phase II (Synthetic) or(conjugation):
❑It is the addition of endogenous polar substance to a drug
directly or to its metabolites of phase I to form water soluble
inactive metabolites e.g.
❑
➢ Glucuronidation:
➢ Acetylation:

➢ Methylation:

Result; usually Inactivation

Most of drugs pass
through:

phase I phase II
 Reverse order

Isoniazid

phase I phase II
Hydrolyzed Acetylated
isonicotinic acid
Sites of biotransformation
1- Microsomal Enzymes : Smooth Endoplasmic Reticulum

•
• Oxidation and Glucuronide
reduction by conjugation
CYP450 enzymes.
• Usually act on Only.
lipophilic Affected
substrates By
•Inducible Drugs
& age
2- Non Microsomal : (in all organs)
Present in liver, kidney, plasma, skin and GIT…etc
(cytoplasm and mitochondria)
• Oxidation. • Conjugations
Activity is stable except
• Reduction. throughout life. glucuronic acid.
• Hydrolysis.

• Act on lipophilic
&hydrophillic substrates
• Not Inducible
 Enzymes responsible for drug metabolism:
Hepatic Microsomal Non-Microsomal enzymes
enzymes
• In liver: hepatic microsomal • In different tissues: non-microsomal
enzymes are present in enzymes present in cytoplasm
endoplasmic reticulum. mitochondria of liver-kidney -lung -
GIT – plasma.
• Cytochrome P450 is important
for metabolism
• Responsible for most • Responsible for oxidation,
oxidation, reduction, reduction, hydrolysis and
hydrolysis of phase I and only conjugation other than glucuronide.
glucuronide conjugation of
Phase II.

• Lipid soluble drugs. • Water soluble drugs.

• Affected by some factors ● Not induced by drugs. Not affected
by starvation,liver disease but affected
by age, sex.
Factors affecting Drug metabolism:
• 1- Drugs

❑ Some drugs act on hepatic microsomal

enzyme affecting drug metabolism. They
are:

• A- Hepatic microsomal enzyme

inducers

• B- Hepatic microsomal enzyme

inhibitors
Activators (enzyme induction) Inhibitors (enzyme inhibitors)

- Increase their own rate of - Inhibit their own rate of degradation.

degradation(Auto-induction) →
Tolerance. - Inhibit degradation of other drugs.
- Increase degradation of other drugs.

- Increase the dose Reduce the dose

e.g. Phenytoin, Carbamazepine, e.g. A-specific: Grapefruit juice, Sodium

Rifampicin valproate, Erythromycin & Omeprazole.
B-Non-specific (General):
a- Hepato-toxic drugs.
b- Drugs Hepatic blood flow: Propranolol
& Cimetidine.
- Effect: They increase Metabolism of Effect: They decrease metabolism of other
other drugs e.g. Oral anti-coagulants, drugs (e.g. Theophylline→ its plasma level
Oral hypoglycemics →Toxicity)
& Oral contraceptives→ decrease their
duration of action.
Factors affecting Drug metabolism:
2- Age: Lowering of drug metabolism occurs in extremities
of age. So drug doses should be reduced.

3- Sex: Androgens stimulate drug metabolism while

estrogen and progesterone inhibit drug metabolism.

4- Pathological conditions: In liver diseases, drug

metabolism is reduced leading to increased Susceptibility to
drug toxicity [Link] of diazepam is prolonged and it may
cause coma when given in therapeutic dose
 Factors affecting Drug metabolism:
5- Starvation: Enzyme activity is decreased
with inhibition of conjugation process
e.g. depletion of glycine with inhibition of
glycine conjugation.
6- Genetic factors: Genetic determined
polymorphism is responsible for variation in
drug toxicities.