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:
1. 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.
- Menstruation: Drugs producing pelvic congestion should be avoided during menstruation e.g. drastic purgatives.
- 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.
- 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 many drugs changes with age. Thus gastric emptying is
prolonged and the gastric pH fluctuates in neonates and infant, further the liver capacity to metabolize drugs is low, renal function is less developed and the proportion of body water is higher in the newborn and the neonates. Hence children may not react to all drugs in the same fashion as young adults. With a few exceptions, drugs are more active and more toxic 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.
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, tetracycline, streptomycin, gentamicin and cephalosporin penetrate only when the meninges are inflammed.
Acute or chronic liver diseases markedly modify the rate and extent of biotransformation of drugs. The t1/2 of chlordiazepoxide and diazepam in patients with liver cirrhosis is greatly increased with corresponding prolongation of their effects. Cardiac disease by limiting blood flow to the liver may impair disposition of those drugs whose biotransformation is flow limited e.g. mipramine, isoniazid, lignocaine, morphine and propranolol.
Similarly renal and pulmonary diseases may modify the biotransformation of drugs like insulin or isoprenaline. Excretion of drug is impaired in chronic renal disease.
6. 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.
Leave a Reply