Question

explain in detail about

1. Variation in drug responsiveness

Answer 1

The reasons for inter individual variating in drug response can be classified under these headings

1)Pharmacokinetic variations due to diseases

2)Pharmacokinetic variations due to drug interactions that cause either increased or decreased delivery at the site of action

3)Age

1)Diseases causing pharmacokinetic variations

-Impaired renal clearance:- Drugs which are excreted through kidneys cause toxicity if not dose adjusted in those with renal impairment. Dose adjustments should be done based on the GFR estimated using age and weight.Dose should be either reduced or dose interval should be lengthened.Eg:- Meperidine is not excreted through kidney ,but its metabolite normeperidine is excreted through kidneys.So ,if we use meperidine in the usual dosage for a renal impaired patient,CNS toxicity occurs in the form of agitation,convulsions etc.

-Impaired hepatic clearance:- There are no ways for adjusting the dosage of a drug with hepatic clearance,because no hepatic function parameters can tell the dosage of drug to be used to avoid toxicity. Hence for a patient with liver disease, while giving a drug with extensive first pass metabolism, toxicity can be prevented by plasma concentration measurement and looking for clinical response.

-Circulatory insufficiently due to cardiac failure or shock:- In those with circulatory insufficiency, the neuroendocrine adjustments causes a fall in the hepatic and renal blood flow. In these cases , the drug clearance will be affected. Reduction in drug dosages is needed, because even small dosages can help to reach the therapeutic plasma levels

-Altered plasma protein binding of the drug:- Hypoalbuminemia in patients with renal or hepatic disease cause reduced plasma protein binding of the drug.It is the free drug which can pass out through the capillaries for excretion.In those with reduced plasma protein binding ,the free drug levels will be more, and more clearance occurs.This should be considered important especially while administration of drug which is more than 90% plasma protein bound .In these drugs even a small change in the plasma protein binding can produce large changes in free drug levels.Estimation of free drug levels as well as shorter dosing intervals is needed.

2)Pharmacokinetic variations due to drug interactions

-This can cause decreased drug delivery to the site of action in some cases.Eg:- aluminium ions in antacids and ferrous ions in iron supplements cause chelation with tetracycline antibiotics and inhibit the oral absorption of tetracycline. Some drugs which induces the cytyochrome enzymes CYP3A4 (anticonvulsants,rifampicin)increase the metabolism of drugs which are the substrates of this enzyme (cyclosporine,tacrolimus,warfarin, prednisolone).

In some cases ,this drug interactions can cause increased drug delivery to the site of action.This can be seen with drugs that inhibit the cytochrome enzymes (fluconazole,ketoconazole).These drugs cause decreased metabolism of the drugs which are substrates of these enzymes(cyclosporine,tacrolimus etc) Hence their clearance is affected and plasma concentrations increase during maintainence therapy sometimes leading adverse toxic effects.Another mechanism by which increased drug delivery occurs is due to inhibition has drug transporters.P glycoprotein is a drug transporter seen in luminal side of gastrointestinal epithelium.This transporter is responsible for eliminating certain drugs such as digoxin.So drugs that inhibit this transporter such as verapamil,diltiazem etc causes increased plasma concentrations of digoxin and toxicity.

3)Age

- Neonates and children:- Renal and liver function will not be matured in neonates.Also the drug metabolising enzymes will not be fully functional.Also the pharmacodynamics of certain drugs in children are not the same as that in adult. Eg:- antihistamine that cause sedation in adult may cause excitation in children

-Elderly:- Decrease in the lean body mass,decrease in water content, increased proportion of body fat, decline in renal and hepatyic function etc affect the action of drugs in elderly.eg:- drugs that depress central nervous system has increased effects at any plasma concentrations in elderly. Hence drugs should be administered with caution in them.