Different individuals given the same drug show a wide range of response ranging from no detectable change to grossly excessive reactions of various kinds .These variations are due to age, sex , body weight , surface area ,nutrition ,alcoholic ,cigarette smoking ,pregnancy ,genetic factor ,environment and pathological condition.
Age:
The kinetics of drugs are changed with age.Neonates ,infants ,children and older people and more sensitive to the effects of drug than the adults.
The absorption of drug from the gastrointestinal tract is slower in neonates than in older children. The use of soap containing hexachlorophene causes more neurological damage in premature infants, due to its ready penetrability, than in adults. The binding of.drug with plasma proteins is decreased in both neonates and infants. The premature neonates and infants are less capable of metabolizing drugs than the adult patients. The enzymes responsible for the metabolism of drugs are poorly developed in patients of these age group. There are some drugs (phenytoin,Carbamazepin ,chlorpromazine, ethoguximide, and pheno-harbitone) which are given in higher doses to children than to adults, this is due to increased rate of metabolism of these drugs at this age group.
In neonates especially premature one chloramphenicol may cause cyanosis, abdominal distension, vomiting, and loose green colored stool (Grey baby syndrome due to the inability to metabolize the drug as a result of glucuronyl tranaferase deficiency). The deficient glucuronidation of most drugs is compensated by early development of sulfate conjugation. This can be represented by a study showing that paracetamol is predominantly excreted a; sulfate conjugate in neonates and only to a minor degree as the glucuronide whereas the proportion between these metabolites is reserved in adults.
The rate of excretion of drug in infant may be altered due to poor renal function.
The dose of many drugs should be reduced when administered by injection. Streptomycin undergoes less biotransformation in old people resulting in adverse effects with conventional dosage. When swallowed, a drug may he absorbed less completely or more slowly due to reduction in available absorptive surface, blood flow or altered gastrointestinal motility. The plasma half life of benzylpenicillin is 20 minutes in an adult of 20 years and this is increased to 40 minutes at 65 years .Chiidren are smaller individuals, weigh less, consequently need smaller doses of drug.
Dosage can be calculated from the adult doses by using age, body weight, or body surface The most reliable methods are those based on body surface :
Young's formula (on the basis of age) : (Age in years / Age in years + 12) × Adult dose
For example, a 3-year-old child having body weight of 30 pound requires to administer Drug A. The adult dose is 100 mg. So, using age of the child the dose will be 20 mg.
Children may react qualitatively different to some drugs. For example, barbiturates frequently produce excitement rather than depression. Young babies are relatively more sensitive to the respiratory depressive action of morphine than are older children or adult.
Sex:
In comparison to men, some women may show increased sensitivity to certain drugs. This is due to hormonal effect. Males have higher mixed-function oxidase activity than females because testosterone induces microsomal enzymes whereas estradiol decreases their activity. In the adult female, the amount of adipose tissue-is usually greater and there is increased chance of accumulation of drug in those tissues.
Body weight and surface area:
The amount of drug requires to produce therapeutic effect should be adjusted in proportion to the body weight or surface area. The greater the body weight or surface area, the more the drug can become diluted in the body. Female has relatively low body weight and thus smaller dose is required One should be careful about the doses of drug having low margin of safety .
Nutrition:
Malnutrition impairs the biotransformation of drug It includes the deficiency of protein, fat, vitamin A. riboflavin. and ascorbic acid. The rate of biotransformation of theophy-lline can be prolonged 2-fold as the percentage of total calories represented by carbohydrate doubled from 35 to 70 and the percentage of protein is decreased from 44 to 10 Experimentally produced scurvy In guinea pig impairs the biotransformation of several drugs- Some vegetables such as cabbage, cauliflower stimulate the intestinal biotransformation of some drugs.
Alcoholic:
Intake of alcohol alters the biotransformation of drug .Acute intake of alcohol inhibits the biotransformation whereas chronic alcohol intake increases the biotransformation. The plasma half-life of tolbutamide is 5 9 hours in case of non-alcoholic person and decreased to 2.7 hours in chronic alcoholic.
Cigarette smoking:
The biotransformation of some drugs such as theophylline, caffeine, and imipramine are several times higher in Cigarette smoker than in non-smokers. Cigarette smoking is rich source of benzo pyrene which is a potent enzyme inducer. There is a 12-fold increase in pulmonary monooxygenase activity after continuous exposure of rats to a mixture of cigarette smoke and air for 5 hours daily for 3 days.
Pregnancy:
During pregnancy, the use of all drugs except those essential to maintain pregnancy should be used with caution. , However, the absorption of drug is not decreased during pregnancy.
Genetic factor:
The population can be clearly seen to consist of a bimodal distribution of rapid and slow acetylator on the basis of their ability to biotransform isoniazid. Genetic factors contributing largely . Still research continuing.
Environment:
In urban area, the atmosphere is polluted with hydrocarbon. There is more fresh air in the rural area. This hydrocarbon has effect on drug metabolism as well as drug effects.
Disease:
Some antimicrobial agents penetrate the cerebrospinal fluid well across the normal meninges, while other antimicrobials penetrate well only when the meninges are inflammed (meningitis). For example, sulfonamides, metronidazole, chloramphenicol, isoniazide and refampicin penetrate well through the normal meninges. Other antimicrobial agents such as benzylpenicillin. ampicillin, tetracyclines, streptomycin, gcntamicin. and cephalosporm penetrate only when the meninges are inflamed.
Acute or chronic liver diseases markedly modify the. rate and extent of biotransformation of drug. There is depression of glucuronic acid conjugation. The half-life 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. imipramine, isoniazid, lignocaine, morphine, and propranolol. Similarly, renal and pulmonary diseases may modify the biotransformation of some drugs like insulin or isoprenaline. Excretion of drug is impaired in chronic renal disease.
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