1.

Biological Variations
1.Response to drugs has individual variation
2. Response of drugs is affected by:
- Race
- Nutritional state
- Environmental factors
3. Start by low dose and increase gradually
2. Age
1.Stated dose is for adult males, aged 20-60 years old
2. Dose decreases in extremes of age { pediatrics and geriatrics}
3. Infants and children require smaller doses of drugs
3. Weight and Surface Area
1. For adults aged 20-60 years {Weight ~ 70 kg}: Dose is
calculated according to Lean body weight is used to calculate
dose
2.Increased weight due to obesity and edema should not be
taken into consideration as fat is inert tissue
3. Body surface area (BSA) is more accurate to calculate dose of
infants and children {Adult surface area =1.73}
4. Child dose = [Adult dose X Child surface area] /1.73
4. Gender
1. Females require smaller doses than males. WHY?
- - Large percent of fat ➔ Slower oxidation
- Female hormones ➔ Inhibit hepatic microsomal enzymes\
2. AVOID
- In pregnancy oxytocics & teratogenics { Abortion &
fetal anomalies}
 - In labour {Neonatal asphyxia}  Morphine &
Barbiturates
- In lactation {Excreted in milk}  Tetracyclines
 Purgatives
 Anticoagulants
5. Route of Administration
1. In a descending order of absorption
- - Affect bioavailability & amount of dose
- Intravenous >> Intramuscular >> Subcutaneous >> Rectal
>>Oral
2. Route of administration may modify mode of action of
drugs
- Magnesium sulfate {MgSO4}
 Oral {Empty stomach}➔ Saline purgative (15 g) &
Cholagogue (5 g)
 Intravenous➔ CNS depressant; Antiarrhythmic;
smooth muscle relaxation and skeletal muscle relaxant
 Rectal {Retention enema}➔ Dehydrating agent in
brain edema
6. Time of Administration
1. Relation to meals
Give irritant drugs given after meals e.g. NSAIDs
Some drugs are given 30 minutes before meals e.g. Proton pump
inhibitors
- Absorption occurs rapidly

2. Relation to daytime & bedtime

- Give CNS stimulants in the morning e.g. Amphetamines &
Ephedrine
- Give CNS depressants at bedtime e.g. Sedative-hypnotics
7. Psychological Factors
1. Placebo
- Inert preparation, useful for therapeutic effect in psychotherapy
and for evaluation of new drugs
2. Placebo effect
- Some patients improve by psychological “suggestion”
rather than pharmacological effect of drugs
8. Pathological State
1. Some drugs act ONLY in presence of disease
 Aspirin acts as antipyretic, ONLY in fever
2. Liver And/or kidney disease may affect the dose of some
drugs
9. Supersensitivity = Drug Intolerance
. What is meant by supersensitivity?
- Exaggerated normal pharmacological response to the usual
dose
- Use Lower doses in these conditions e.g. thyrotoxicosis
10. Tolerance
- Use higher dose
- Change to another drug
11. Drug Interactions
1. Pharmaceutical
2. Pharmacokinetic
- Absorption - Distribution
- Metabolism - Excretion
3. Pharmacodynamic
- At specific receptor sites - At neurons
- On same physiological system
- Involve change in blood volume & electrolyte balance
- Involve combined toxicity
4. How to minimize incidence of drug interactions?
 - Modify dose - Change to another drug

Drug Interactions
i. Altered pharmacological responses due to multiple drugs
acting concurrently

ii. Can be desired = beneficial OR undesired = harmful

Beneficial DI
i. Combining drugs with different mechanisms
ii. One drug corrects adverse effects of another drug
iii. Treatment of: cancer; heart failure
Harmful DI
i.Predictable increased or decreased effect of one or both drugs
ii. Unpredictable toxicity
Types of drug interactions
I.Pharmaceutical II. Pharmacokinetic III.
Pharmacodynamic
II] Pharmacokinetic
1} Absorption
2} Distribution
3} Metabolism
4} Excretion
III] Pharmacodynamic
1} At Receptor Sites
2} At Neurons
3} At Same Physiological System
4} Involving Changes in Blood Volume & Electrolyte Balance
5} Involving Combined Toxicity Pharmaceutical Drug
Interactions
II] Pharmacokinetic
II.a) Affecting GIT absorption
i.Drugs affecting gut motility
Motility changes ( by metoclopramide &  by atropine) affect
absorption of other drugs
ii.Affecting gut pH
Drugs which decrease gastric acidity (antacids) affect absorption
of other drugs
iii.Drug binding or chelation
Tetracyclines chelate metals as Ca, Mg, Al & Fe ➔  their
absorption
Liquid paraffin ➔ Decreases absorption of fat-soluble
vitamins and lipid-soluble drugs
Phenytoin ➔ Interferes with absorption of folic acid
II. Affecting distribution
i.At plasma protein binding sites
Drugs with high affinity binding as aspirin & sulfa can
displace other drugs bound to plasma proteins as warfarin 
Increase free concentration & toxicity
ii.Directly in plasma
Protamine & heparin
III.Affecting metabolism
i.Enzyme induction
 Hepatic microsomal enzymes (HMEIs) inducers
➔ Increase metabolism & Decrease activity of the inducer &
co-administered drugs
 Phenobarbital, Phenytoin, carbamazepine & testosterone
ii.Enzyme inhibition
 Hepatic microsomal enzymes (HMEs) inhibitors
➔ Decrease metabolism & Increase activity of their own &
co-administered drugs
Estrogens, chloramphenicol, sodium valproate
IV.Affecting renal excretion
i.Competition for active renal tubular secretion
Probenecid ➔ Decreases active tubular secretion of weak acids
as penicillins; aspirin & indomethacin
ii.Changes in urinary Ph
- Acidification of urine by Ammonium chloride oral OR
Vitamin C > Increases excretion of basic drugs as
amphetamine & ephedrine
- Alkalinization of urine by sodium bicarbonate > Increases
excretion of acidic drugs as aspirin & phenobarbitone
III] Pharmacodynamic
i.At specific receptor sites [Pharmacological antagonism = 2
drugs acting on 1 receptor]
Types of pharmacological antagonism
1.Competitive antagonism
 Antagonist displaced by excess agonist
Acetylcholine & Atropine at muscarinic (M) receptors
2.Non-competitive antagonism
Antagonist NOT displaced by excess agonist
2a. Reversible 2b. Irreversible
ii.On same physiological system
• Aminoglycosides; procaine & quinidine ➔ Potentiate
neuromuscular blockers
 • Adrenaline ➔ Antagonizes bronchoconstriction of
histamine
iii.Involving changes in blood volume and/or electrolyte
imbalance
 Steroids & NSAIDs > Produce slat and water retention ➔
Decrease antihypertensive effects
• Thiazide diuretics > Produce hypokalemia➔ Increase
digitalis toxicity
iv.Combined toxicity
 Combined use of 2 or more drugs with toxic effects on the
same organ ➔ Increases organ damage
> Use of 2 nephrotoxic drugs as aminoglycosides &
frusemide

Adverse Drug Reactions

Are harmful effects of a drug at doses used in therapy, which calls

for:
Decrease dosage, Stop drug &/or immediate treatment.
I) TYPE A (Augmented or predictable undesirable adverse
effects):
Predictable undesirable effects related to the normal
pharmacological actions of the drug:
1- Side Effect:
a- Unavoidable undesirable normal action produced by
therapeutic dose of the drug.
b- Example: Dry mouth induced by atropine when used as
antispasmodic.
2- Secondary Effect:
a- Bad effect consequent to normal therapeutic action of the
drug.
b- Example: Oral broad-spectrum antibiotics →  Intestinal
flora →  Vit B & Vit K synthesis and superinfection.
3- Over-dose:
Exaggerated normal action due to high blood level of the drug
either:
a- Single large dose: Insulin L.D. → Hypoglycemia
b- Accumulation of repeated doses: Digitalis (Long t ½)
4- Supersensitivity (Intolerance):
a- Exaggerated normal action in response to small therapeutic
dose of the drug.
b- Example: Hyperthyroidism → Supersensitivity to
sympathomimetics.
c- Decrease the dose of the drug.
II) Type B (Bizarre or unpredictable adverse effects):
1- Allergy (Hypersensitivity):
a- Unpredictable abnormal response to drugs due to
antigen/antibody reaction.
b- NOT all patients
c- - NOT all drugs
d- - NOT first exposure
e- - NOT dose dependent
f- - NOT reuse drug again
g- Cross allergy between related drugs e.g. Penicillins &
Cephalosporins.

* Types of Allergy:
A) Type I (Immediate, Anaphylactic or IgE mediated):
 a- Manifestations: fever, rash, urticaria, photosensitivity,
conjunctivitis, rhinitis, angio-edema, bronchial asthma,
G.I.T. disturbances & even anaphylactic shock.
b- Avoided by: history taking, intradermal test & NEVER reuse
the drug again.
c- Treated by: Antihistaminics, S.C. Epinephrine,
Corticosteroids & desensitization.
2- Idiosyncrasy (Pharmacogenetics):
1- Unpredictable abnormal response due to genetic
abnormality.
2- Occurs on first exposure.
3- Examples:
a- Hemolytic anemia in patients with Favism (Glucose-6-
Phosphate-Dehydrogenase enzyme deficiency) induced
by: aspirin & sulfonamides.
b- Slow & Rapid Acetylators of Isoniazid:
o Slow Acetylators → Accumulation of Isoniazid
antagonize Vit B6 → Peripheral neuritis
o Rapid Acetylators → Accumulation of Acetyl-
Isoniazid → Hepatotoxic.
o  intra-ocular pressure. induced by Cortisol eye drops.

III) Type C (Chronic effects): Effects of prolonged use of a

drug:
1-Tolerance
Decreased or failed response to drugs
Either increase the dose or stop the drug for some time
Types of tolerance
 (A) Congenital tolerance
Inborn tolerance due to various factors and may be individual
(biological) variations within any population
(B) Acquired Tolerance:
1- Decreased or failed response to drugs, after their repeated
(long) use e.g. Morphine & nitrates.
* Characteristics of Acquired Tolerance:
1- Reversal, stop of the drug for sometime → Regain normal
sensitivity.
2- Varies from one drug to another: No tolerance to digitalis or
cocaine
3- Does not affect all actions to the same extent: Long use of
morphine → Rapid tolerance to analgesia &  R.C. BUT NO
tolerance to miosis or constipation.
4- It may affect therapeutic dose rather than the toxic dose → 
Therapeutic index.
5- Drug dependence (Habituation & Addiction) may follow
tolerance.

2- Drug Dependence:
a- Habituation:
- Psychic dependence.
- Sudden stop of the drug → Psychic craving for the drug
(and may be emotional distress).
- Example: Xanthine beverages (Coffee & tea).
b- Addiction:
- Psychic and Physical dependence.
- Sudden stop of the drug → Withdrawal (Abstinence)
syndrome →
- Usually the reverse of what the addicting agent does.
 - Example: Amphetamine, Morphine, Ethanol.

3- Iatrogenic Disease:
a- Drug-induced disease.
b- Examples:
- prolonged use of Chlorpromazine → Iatrogenic
Parkinsonism.
- Prolonged use of Cortisol → Iatrogenic Cushing’s
disease.

IV) Type D (Delayed effects):

Delayed effects appearing after long use of the drug:
1- Teratogenicity (Dysmorphogenesis):
a- Drug-induced fetal malformations.
b- Examples:
- Phenytoin → Hare lip and cleft palate.
- Aspirin → Cardiac septal defects
2- Mutagenicity & Carcinogenicity:
Tobacco smoking → Bronchogenic carcinoma.

V) Type E (End of Use Effect):

These are effects of sudden stopping of drug use (Drug
Withdrawal), include:
1- Abstinence syndromes of addicting drugs as morphine,
cocaine, barbiturate.
2- Acute Addisonian crisis of chronic steroid therapy.
3- Worsening of existing disease: Sudden Stopping β-
blockers → Myocardial infarction, and Clonidine →
Hypertension.