Drug safety and effectiveness

A. Factors modifying the dosage and action of drugs :
Individuals differ both in the degree and the character of the response that a drug may elicit and
therefore the optimum dose of a drug which produces the desired therapeutic effect varies from
person to person. The important factors which influence the effect of a drug are:

Drug intolerance: It is a quantitative deviation from the anticipated response to a given dose
of a drug. Thus drug intolerance is inability of the individual to tolerate a drug. It is also
called as hypersusceptibility.

2. Sex difference: Special care should be exercised when drugs are administrated during
   menstruation, pregnancy and lactation.
   a) Menstruation: Drugs producing pelvic congestion should be avoided during menstruation
   e.g. drastic purgatives.
   b) Pregnancy: During pregnancy, the use of all drugs except those essential to maintain
   pregnancy should be used with caution. Drugs which may stimulate the uterine smooth
   muscle, are contraindicated during pregnancy. Further, many drugs administered to
   mother are capable of crossing the placenta and affecting the foetus. Most of drugs can
   produce teratogenicity when they are used in pregnancy. Teratogenicity means
   congenital malformation i) Drugs known to produce teratogenicity e.g thalidomide,
   cyclophosphamide, methotexate, tetracyclines, phenytoin, carbamazepine and
   progestogens. ii) drugs may be teratogenic e.g Warfarin, lithium, quinine, primaquine,
   trimethoprim, rifampicin, anaesthetic agents.
   c) Breast feeding: Nearly all agents received by mother are likely to be found in her milk
   and could theoretically harm the infant. Most of the lipid soluble drugs get into breast
   milk. Therefore the drugs, which are excreted in the milk and harm the infant health
   should be, avoided by breast-feeding mothers e.g. sulphonamides, tetracyclines,
   nalidixic acid, isoniazid, diazepam, lithium, Indomethacin, aspirin, etc.
3. Body Weight: The average dose is mentioned either in terms of mg per kg body weight or as
   the total single dose for an adult weighing between 50-100kg. However, dose expressed in
   this fashion may not apply in cases of excessively obese individuals or those suffering from
   edema, or dehydration nutritional factors can sometimes alter drug metabolizing capacity
   and this should be kept in mind in malnourished patients.
4. Age: The pharmacokinetics of maany drugs changes with age. Thus gastric emptying is
5. prolonged and the gastric pH fluctuates in neonates and infant, further the liver capacity to
6. metabolize drugs is low, renal function is less developed and the proportion of body water is
7. higher in the newborn and the neonates. Hence children may not react to all drugs in the
8. same fashion as young adults. With a few exceptions, drugs are more active and more toxic
9. in the new born than the adults.

The paediatric doses are expressed in terms of body weight (mg/kg per dose or day) or in terms
of body surface area (mg/m2
per day). The body surface area can be calculated from the height
and weight of the child.
Like children, old people also present problems in dosage adjustment and this may vary widely
with different people. The metabolism of drugs may diminish in the elderly and the renal function
declines with age. Elderly are sensitive to the drugs like hypnotics, tranquilizers,
phenylbutazone, diazepam, pethidine, etc.
i) Dose adjustment on the basis of age (young’s formula)
Age in years____ x adult dose
Age in years + 12
ii) Dose adjustment on the basis of body weight (Clark s formula) (1 Kg=2.2 pounds)
Weight of child in pound x Adult dose
150
e.g. A 3 year old child having body weight of 30 pound requires to administer drug X.
The adult dose is 100mg. So
a) Using age of the child the dose will be
3 x 10 = 3 x100 = 20mg
3+12 15
b) Using body weight of the child it will be
30 x 100 = 1 x 100 = 20mg
150 5

5. Disease state: Some antimicrobial agents penetrate the cerebrospinal fluid well across the
   normal meninges while other antimicrobials penetrate well only when the meninges are
   inflammed (meningitis) e.g. sulphonamides, metronidazole, chloramphenicol, isoniazid and
   rifampicin penetrate well through the normal meninges and other antimicrobial agents like
   benzyl penicillin, ampicillin, tettetracycline, streptomycin, gentamicin and cephalosporin
6. penetrate only when the meninges are inflammed.
7. Acute or chronic liver diseases markedly modify the rate and extent of biotransformation of
8. drugs. The t1/2 of chlordiazepoxide and diazepam in patients with liver cirrhosis is greatly
9. increased with corresponding prolongation of their effects.
10. Cardiac disease by limiting blood flow to the liver may impair disposition of those drugs whose
11. biotransformation is flow limited e.g. imipramine, isoniazid, lignocaine, morphine and
12. propranolol.
13. Similarly renal and pulmonary diseases may modify the biotransformation of drugs like insulin or
14. isoprenaline. Excretion of drug is impaired in chronic renal disease.
15. Pharmacogenetics: The science pharmacogenetics is concerned with the geneticallymediated variations in drug responses. Some examples of genetically mediated variations
    are:
    Acetylation and hydroxylation of drugs: The rate of acetylation of INH, dapsone, hydralazine
    procainamide and some sulfonamides is controlled by an autosomal recessive gene and the
    dosage of these drugs depends up on the acetylator status of individuals.
    7) Drug interactions:
    It is usual for patients to receive a number of drugs at the same time.
    It is a phenomenon which occurs when the effects of one drug are modified by the prior or
    concurrent administration of another drug(s). A drug interaction may result in beneficial or
    harmful effects and may be classified into:
    a) Pharmaceutical drug interactions:
    Serious loss of potency can occur from incompatibility between an infusion fluid and a drug that
    is added to it.
    For example diazepam if added to infusion fluid there will be a precipitate formation → loss of
    therapeutic effect.
    b) Pharmacokinetic drug interactions:
    1) Interaction during absorption: Drugs may interact in the gastrointestinal tract resulting in
16. either decreased or increased absorption.
17. e.g. Tetracycline + Calcium → Decreased absorption of tetracycline.
18. 2) Interaction during distribution: A drug which is extensively bound to plasma protein can be
19. displaced from its binding sites by another drug or displacement from other tissue binding
20. sites.
21. e.g. (i) Sulfonamide can be displaced by salicylates from plasma proteins and it leads to
22. sulfonamide toxicity.
23. (ii) Quinidine displaces digoxin from binding sites in tissues and plasma and leads to
24. digoxin toxicity

) Interactions during biotransformation: This can be explained by two mechanisms:
(i) Enzyme induction.
(ii) Enzyme inhibition.
(i) Enzyme induction: By this the biotransformation of drugs is accelerated and is a cause of
therapeutic failure. If the drug A is metabolized by the microsomal enzymes, then concurrent
administration with a microsomal inducer (drug B) will result in enhanced metabolism of drug
A.
e.g. Warfarin (anticoagulant) + Barbiturate (enzyme inducer) → decreased anticoagulation.
Enzyme inducers: Rifampicine, phenytoin, sulfonamides, etc.
(ii) Enzyme inhibition: By this the biotransformation of drugs is delayed and is a cause of
increased intensity, duration of action and some times toxicity.
e.g. Warfarin + Metronidazole (enzyme inhibitor) → Haemorrhage.
Enzyme inhibitors: Disulfiram, isoniazid, allopurinol, cimetidine, etc.
e) Interactions during excretion: Some drugs interacts with others at the site of excretion i.e.
in kidneys.
e.g. Penicillin (antibiotic) + Probenecid (antigout drug) → Increases the duration of action of
penicillin (Both drugs excreted throug

C. Pharmacodynamic interactions:
(i) Drug Synergism: When the therapeutic effect of two drugs are greater than the effect of
individual drugs, it is said to be drug synergism.It is of two types.
(a) Additive effect: When the total pharmacological action of two or more drugs administered
together is equivalent to the summation of their individual pharmacological actions is called
additive effect.
i.e A + B = AB
e.g. Combination of ephedrine and aminophyllin in the treatment of bronchial asthma.
(b) Potentiation effect: When the net effect of two drugs used together is greater than the sum of
individual effects, the drugs are said to have potentiation effect.
i.e AB > A + B
e.g. Trimethoprim+sulfamethoxazole

) Drug Antagonism: The phenomenon of opposing actions of two drugs on the same
physiological system is called drug antagonism.
a) Chemical antagonism: In this the biological activity of a drug can be reduced or
abolished by a chemical reaction with another agent.
e.g. Antagonism between acids and alkalis.
b) Competitive or reversible antagonism: In this the agonist and antagonist compete for the
same receptors and the extent to which the antagonist opposes the pharmacological
action of the agonist. Competitive antagonism can be overcome by increasing the
concentration of the agonist at the receptor site.
e.g. Acetylcholine and atropine antagonism at muscarinic receptors.
c) Non competitive antagonism: In this type of the antagonism an antagonist inactivates the
receptor (R) so that the effective complex with the agonist cannot be formed, irrespective
of the agonist cocentration.

) Physiological antagonism: When the physiological effect of a drug is antagonized by
another drug by acting on two different types of receptors
e.g. Acetyl choline causes constriction where as adrenaline causes dilatation of pupil.
Importance of drug antagonism
(i) Correcting adverse effects of drugs
(ii) Treating drug poisoning.
e.g. Morphine with naloxone, organophosphate compounds with atropine.
(iii) Predicting drug combinations which would reduce drug efficacy.
8) Repeated administration and drug cumulation:
If a drug is excreted slowly, its administration may build up a sufficiently high concentration in
the body to produce toxicity. e.g. digitalis, emetine.
To avoid cumulation. a) One must know if a drug is eliminated slowly or rapidly, b) Stop the drug
administration at the appearance of the first warning symptoms c) Carefully select the form in
which the drug is to be administered.

Drug tolerance:
When an unusually large dose of a drug is required to elicit an effect ordinarily produced by the
normal therapeutic dose of the drug, the phenomenon is termed as drug tolerance.
Tachyphylaxis: Rapid development of tolerance on repeated administration is called
tachyphylaxis
e.g. Ephedrine, amphetamine and nitroglycerine which produce tachyphylaxis on repeated
administration.
10) Emotional factors.
eg. Placebo response.
Placebo: It is a Latin word meaning” I shall please” and it is a tablet looking exactly like the
active treatment but containing no active component. It refers originally to substances merely to
please the patient when no specific treatment was available.
B. Adverse drug reactions:
The drugs that produce useful therapeutic effect may also produce unwanted or toxic effects. It
has been estimated that about 0.5% of patients who die in hospitals do so as a result of their
treatment rather than the condition for which they were treated. Serious systemic drug toxicity
may result from overdoses. If is always an exaggeration of its pharmacological actions and
some times it is predictable.

e.g. Hypotension following antihypertensive drugs. Hypoglycaemia following insulin.
An adverse drug reaction is defined as any response to a drug that is noxious and unintended
and that occurs at doses used in man for prophylaxis, diagnosis or therapy (WHO).
The adverse effects are 1)Side effects 2)untoward effects 3)allergic reactions 4)idiosyncratic
reactions and 5)teratogenic effects.
1) Side effects: Side effects are infact pharmacological effects produced with therapeutic dose
of the drug.
e.g: Dryness of mouth with atropine which is troublesome in peptic ulcer patients and useful
when used as a preanaesthetic medication.

2) Untoward effects: Untoward effects develop with therapeutic dose of a drug. They are
undesirable and if very severe, may necessitate the cessation of treatment.
e.g: Diarrhoea with ampicillin and potassium loss with diuretics.
3) Allergic reactions: Most of the drugs and sera used in therapeutics are capable of causing
allergic or hypersensitive reactions. These reactions may be mild or very severe like
anaphylaxis. When an individual has been sensitized to an antigen (allergen) further contact
with that antigen can some times lead to tissue damaging reactions. These allergic reactions
are 4 types.

• Type-I reactions or anaphylactic reactions (Immediate hypersensitive reaction).
• Type-II reactions or cytotoxic reactions.
• Type-III reactions or immune complex mediated reactions.
• Type-IV reactions or cell mediated reactions (Delayed hypersensitive reactions).
  4) Idiosyncratic reactions: The term idiosyncrasy means one’s peculiar response to drugs.
  With the increasing knowledge of pharmacogenetics, many idiosyncratic reactions have
  been found to be genetically determined.
  e.g: Drugs like primaquine, sulfonamides and dapsone may cause haemolysis in patients with
  glucose -6 phosphate dehydrogenase defeciency.
  5) Teratogenic effect: Some drugs given in the first three months of pregnancy may cause
  congenital abnormalities and are said to be teratogenic. The best known example is
  thalidomide which results in early easily recognizable abnormalities such as absent or
  grossly abnormal limbs.
  Other drugs with teratogenic potential are androgens, steroids, anti convulsants, anti neoplastic
• drugs, cortisone, lithium, pencillamine, tricyclic antidepressants and warfarin