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Metabolism1)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 drugsand 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 rapida) 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
b Altered h siolo :due to nutritional deficienc enz me inhibition
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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
Environmental Chemicals:
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Biological Factors..
1)Sex:Difference:ex.In,women benzodiazepine drugsslowly metabolise than men.
2)Age: 1)In neonates the enzyme system not fullydeveloped 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 dietincreases the drug metabolising ability.
2)fat free diet depresses cytochrome p-450 levels.3)grapefruits inhihibits metabolism of many drugs.
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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.
PreganancyThe maternal drug metabolising ability is reduced during later stages of pregnancy.
During pregnancy ,the metabolism of pethidine and promazine is reduced.
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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.
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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.
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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.
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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.
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Biological Factors
Age,sex,speciese and strain difference, difference in the genetic make up alter theexcretion.
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
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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.
Disease state
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Thank you.
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