Pharmacokinetic

1. Pharmacokinetic Dr. Hayder B Sahib

2. Ш-Metabolism:- • Is a general term for chemical transformation that occur within the body and its process change drugs in 2 major ways:- • a-Reducing lipid solubility. • Making drug molecule more water soluble to be eliminated in urine. • b-Altering biological activity by • 1-Conversion of active to inactive drug: this applies to most drug. • 2-Conversion of active to another active drug: (effect of prolonging drug action) e.g. amitriptyline to nortriptyline and codeine to morphine. • 3-Conversion of inactive to active drug i.e. prodruge.g levodopa to dopamine and terfenadine to fexofenadine.

3. *The metabolic processes:- • Liver is the most important metabolizing organ , although kidney, gut mucosa, lung and skin also contributes. Metabolic processes include 2 phases: • -Phase 1: • - Metabolism brings about a change in the drug molecule by oxidation, reduction or hydrolysis. The new metabolite may retain biological activity but have different pharmacokinetic properties e.g. a shorter half life.. • - Oxidation is the most important single group of reaction in particular mixed function (microsomal) oxidases. The most important enzyme is cytochrome P450 • - Cytochrome P450 enzymes are grouped into families denoted by the letters CYP fallowed by numerals. • -6 isoenzymes are the most important for the majority of cytochrome P450 catalyzed reactions : CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1 and CYP1A2.

4. -CYP3A4 is the most important and it is responsible for about 60% of drugs oxidation reaction in human. • -*Examples of phase 1 reactions:- • -Oxidation P450 dependent(hydroxylation)-phenytoin, amphetamine • -Oxidation P450 dependent(deamination)-diazepam • -Reduction- chloromphenicol, naloxone • -Hydrolyses(esters)-aspirin • -Hydrolyses(amides)-lidocaine

5. Phase 2:- • -A synthetic reaction that involve addition(conjugation) of subgroups to –OH, -NH2, and –SH functions on drug molecules. • -The subgroups that added include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. • -Most of these groups are relatively polar and make the product less lipid soluble. • *Examples of phase 2 reactions: • -Glucuronation: digoxin , morphine • -Acetylation: dapsone, isoniazid • -Glutathione conjugation: ethacrynic acid. • -Sulfation: methyldopa. • -Methylation: histamine.

6. Co administration of certain agents may alter the metabolism of many drugs. Mechanisms include the fallowing:- • 1-Enzyme induction: • -Induction usually from increase synthesis of cytochrome P450-dependent drug-oxidizing enzymes in the liver. • - The most common strong inducers of drug metabolism are carbamazepin, phenobarbital, phenytoin, and rifampin. • *Clinical significance of enzyme induction:- • 1-Drug interaction may result e.g. failure of oral contraceptive • 2-Disease may result e.g. antiepilepsy drugs increase the breakdown of vitamin D which cause vitamin D deficiency

7. 3-Tolerance to drug therapy may result e.g. tolerance to antiepileptic drugs. • 4-Variability in response to drugs increased e.g. failure to achieve the expected response to warfarin in heavy smokers. • 5-Drug toxicity may be more likely. e.g hepatotoxicity due to paracetamol in patient taking rifampicin(enzyme inducer)

8. 2-Enzyme inhibition: • -The most important drug inhibitors clinically are amiodarone, cimetidine, furanocoumarins present in grapefruit juice, ketoconazole, and ritonavir. • -Inhibition is more selective than enzyme induction. • -Also important drug interaction may occur due to enzyme inhibition.

9. 3-Inhibitors of intestinal P-glycoprotein: • -P-glycoprotein (P-gp) is an important modulator of intestinal drug transport (expel drugs from intestinal mucosa into the lumen). • -Inhibition of (P-gp) (similar to enzyme inhibition) will lead to increase bioavailability of certain drugs. • -P-gp inhibitors include verapamil, grapefruit . • -Important drugs that are usually expelled by P-gp include digoxin, cyclosporine, and saquinavir. • IV-Elimination: • Drugs are eliminated from the body after being partly or wholly converted to water-soluble metabolites, or, in some cases without being metabolized .

10. *Renal elimination: • 1-Glomerular filtration: • Substances of mol. wt. less than 10000(which include almost all drugs) pass easily through the pores of glomerular membrane. • 2-Renal tubular excretion: • - Cells of proximal renal tubule actively transfer strongly charged molecules from the plasma to tubular fluid. • -There are 2 such systems • One for acids e.g. penicillin, probenecid, frusemide • And one for bases e.g. amiloride, amphetamine

11. 3-Renal tubular reabsorption: • -Since the tubular epithelium has the properties of a lipid membrane, the extent to which the drug diffuse back into blood will depend on its lipid solubility . • -If the fluid become more alkaline, an acidic drug ionized, become less lipid-soluble and its reabsorption diminishes, but basic drug become unionized (more lipid-soluble) and its reabsorption increases. • -Manipulation of urine pH is e.g. by given sod. Bicarbonate to alkalinize the urine is useful in aspirin overdose

12. *Fecal elimination: • -Less important rout of elimination than renal elimination. • - Proportion of orally administered drug may be eliminated through this route. • -Locally administered drug e.g. neomycin and back diffusion from blood into gut lumen also eliminated through this route. • -The effectiveness of activated charcoal by mouth for drug over dose depend partly on its absorption of such diffused drug , which then eliminated in the faeces. • *Pulmonary elimination. • -The lungs are the main route of elimination of volatile anaesthetics. • -A part from above, they play a unimportant role in drug elimination.

13. *Prolongation of drug action: • 1-Delay absorption: • a-Oral administration e.g. sustained release preparation. • b-Parenteral administration • -Aqueous suspension e.g. procaine penicillin, benzathin pen. • -Implants or pellets e.g. progestin implants • -S.C injection of drug along with vasoconstrictor e.g. adrenaline with local anaesthetic.

14. 2-Delay metabolism: • E.g co administration of carbidopa with levodopa(carbidopa inhibit peripheral decarboxylation of levodopa) • 3- Plasma protein binding e.g. long acting sulphonamide. • 4-Delay excretion e.g.probencid compete with penicillin and ampicillin at tubular secretion. • 5-Modification of molecular structure of drug e.g. benzodiazepines.