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Metabolism

1)Physicochemical propertiese of the drug:


Molecular size and shape, pKa,acidity/basicity, lipophillicity and steric and electronic characteristics of a drug influenced its metabolism.

2)Chemical Factors:
i)Induction of drug metabolising enzymes:
Phenomenon of increased drug metabolising ability of the enzymes by several drugs and chemical is called as enzymes induction and the agents which bring about such an effect are known as enzyme inducers.ex-phenobarbital like barbiturates which can increase enzyme activity up to 4 times of the phenytoin and sex hormones

ii) Inhibition of drug metabolising enzymes:


Decrease in the drug metabolising ability of an enzyme is called as enzyme inhibition. * Direct inhibition: is fast and rapid a) Competitive inhibition:ex.methacholine inhibits acetylcholine by competing with it for cholinesterease enzyme b) Non competitive inhibition:ex.isoniazid inhbits metabolism of phenytoin c) product inhibition Indirect inhibition: a) Represion:means decrease in enzyme content,ex.puromycine

Environmental Chemicals:

Several envioromental agents influenced the drug metabolising enzymes Halogenated pesticides such as DDT and polycyclic aromatic hydrocarbon contained in cigarette smoke have enzyme induction effect. Organophosphate insectiside and heavy metals such as mercury tin, nickel, cobalt, and arsenic inhibit drug metabolising ability of enzymes

Biological Factors..
1)Sex: Difference:ex.In,women benzodiazepine drugs
slowly metabolise than men. 2)Age: 1)In neonates the enzyme system not fully developed so many drugs biotransformed slowly 2)In elderly persons the liver size is reduced , The microsomal enzyme activity reduced and hepatic blood flow decreased 3)Diet:1)low protien diet decreases and high protien diet increases the drug metabolising ability. 2)fat free diet depresses cytochrome p-450 levels. 3)grapefruits inhihibits metabolism of many drugs.

Disease states
1)In,hepatic deseases ,such as hepatitis ,carcinoma ,jaundice which causes decrease in hepatic metabolism. 2)Congestive heart failure and myocardial infarction which leads to low blood flow towards the liver causes slow metabolism of drug.

Preganancy
The maternal drug metabolising ability is reduced during later stages of pregnancy. During pregnancy ,the metabolism of pethidine and promazine is reduced.

Excretion
Physicochemical propertiese of the drug
Important physicochemical factors affecting renal excretion of the drug are molecular size,pKa and lipid solubility.

Molecular weight of a drug is very critical in its urinary elimination


small molecular size can be easily filtered through the glomerulus compounds of weight below 300 dalton, if water soluble can easily excreted from the kidney Ex.chloroquine ,disopyramide,terbutaline are excreated through kidney.

Plasma conc. Of the drug


Glomerular filteration and reabsorption are directly affected by plasma drug conc. Since both are passive processes. A drug that is not bound to plasma protein and excreted by filtration only, shows a linear relationship between rate of excretion and plasma drug conc. In case of actively reabsorbed drugs, excretion is negligible at low plasma conc. Such agents are excreted in urine only when there conc . In glomeruler filtrate Exceeds active reabsorption capacity.ex.glucose.

Distribution and binding characteristics of the drug


Clearance is inversely related to apparent volume of distribution of drugs. A drug with large Vd is poorly excreted in urine.

Drug restricted to blood compartment have higher excretion rates.


Drugs that are bound to plasma proteins behave as macromolecules and thus cannot be filtered through the glomerulus. Only unbound or free drug appear in the glomerular filterate.

Blood flow to the kidneys


The renal blood flow is important in case of drugs excreted by glomerular filteration only and those that are actively secreted.

In later case, incresed perfusion increses the contact of the drug with the secretory sites and enhances their elimination.
Renal clearance in such instances is said to be perfusion rate limited.

Biological Factors
Age,sex,speciese and strain difference, difference in the genetic make up alter the excretion. Renal excretion is appriximately 10% lower in female than in male. The renal function in newborn is 30 to 40% less in comparison to adults and attain maturity between 2.5 to 5 months of age

Disease state
Renal Dysfunction
Renal dysfuction greatly impairs the elimination of drugs especially those that are primarily excreted by the kidney. Some of the causes of renal failure are hypertension, diabetes mellitus, nephroallergens (nephrotoxic serum) etc

Uraemia
Uraemia is characterised by impaired glomerular filteration and accumulation of fliud and protein metabolites also impair renal clearance of drug. In both condition half life of drugs increased . All these disease states affects the drug action in body.

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