BIOAVAILABILITY

Defined as the proportion of drug conc that reach the systemic circulation following administration. This is measured by the area under the curve AUC AUC= A / Ke A: the point or concentration where the drug reach max plasma concentrated Ke: elimination rate constant (0.7/ t½) f = AUC PO/AUC IV

Ke: the time were the concentration of the drug in plasma drop by 50% (elimination constant) IV doses have 100% bioavailability, f = 1

Factors affecting Bioavailability A- Extent of absorption: Usually any drug taken by oral administration is incompletely absorbed B- First- pass metabolism: After absorption of a drug it goes to the liver through portal circulation were it is metabolized to active or inactive compounds (can occur in the gut). Some of these compounds are excreted in bile.

Hepatic Extraction ratio (ER) It is affected by: rate of hepatic clearance of the drug and hepatic blood flow ER= CL liver/ Q CL liver: liver clearance of the drug Q: hepatic blood flow

Systemic Bioavailability (F) F= f(1-ER) f: the extent of absorption of the drug Example: A drug like morphine if taken orally almost completely absorbed f=1 hepatic ER=0.67 so F=(1-ER)=1-0.67=0.33 F= 0.33×100=33%

VOLUME OF DISTRIBUTION Vd: relates to the amount of drug in the body to the concentration of the drug in blood or plasma Vd= amount of drug in body C It is affected by protein binding. Only unbound drug (free fraction) exerts pharmacolological effects

The higher the Vd, the lower the plasma concentration and vice versa Vd is low when a high % of drug is bound to plasma proteins

Special Barriers to Distribution Placental Most drugs cross the placental barrier, but fetal blood level is usually lower than maternal Blood-Brain Permeable to lipid soluble or very small drug molecules Redistribution Lipid-soluble drugs redistribute into fat tissues prior to elimination - repeated doses cause saturation – may prolong duration of action

DRUG ELIMINATION It involves the following: 1- Drug metabolism: which include enzymatic conversion of one chemical entity to another 2- Drug excretion: includes the elimination of drugs either unchanged or metabolized It occurs through the kidney, hepato-billiary and lung.

Drug Metabolism Lipophilic compound are not excreted by the kidney and they need to become more soluble or polar to be excreted. Metabolism occurs mainly in the liver (CYP450 system) Metabolism may result in formation of active metabolites (diazepam – nordiazepam) Prodrugs lack activity until they undergo bioactivation (clorazepate – nordiazepam)

Metabolism involves two phases: Phase -1 reaction: (catabolic) it includes: oxidation, reduction, and hydrolysis reaction. It is called “the microsomal mixed function oxidase system”. Major phase 1 enzymes – localized in smooth ER of liver, GI tract, lungs, and kidneys

It includes two enzymes: NADPH cytochrome reductase CYP450 system Require O2 and NADPH Multiple CYP families vary by substrate specificity and sensitivity to inhibitors & inducing agents

CYP3A4 Major isoform with wide substrate range Inhibited by cimetidine, macrolides, azoles & ethanol (acute) Induced by carbamazepine, phenobarbital, phenytoin, rifampicin, & ethanol (chronic)

CYP2D6 Genotypic variations in hydroxylation (fast / slow) Substrates include codeine, debrisoquin & metoprolol Inhibited by haloperidol & quinidine; not inducible

Other Phase 1 metabolism Non-microsomal oxidations Monoamine oxidases metabolize NE, 5HT, and tyramine Alcohols metabolized via alcohol dehydrogenase (ADH) to aldehydes then aldehyde dehydrogenoase (inhibited by disulfram)

Phase -2 reaction: It include conjugation with other groups to make it more soluble. Groups used in conjugation: glucoronyl, sulfate, methyl, acetyl, glycyl glutathione

This phase can occur in the kidneys Acetylation is genetically determined. Fast acetylators and slow acetylators (develop SLE like syndrome when given INH, hydralazine, procainamid or INH Transferases: usually inactivate drugs, but may activate (e.g. morphine, minoxidil). May follow a phase I hydroxylation, but also occur directly Glucuronidation – inducible; reduced activity in neonate

RENAL EXCRETION There are 3 main process for Renal excretion of a drug: 1- Glumerular filtration rate: (GFR) This depends on the molecular weight of the drug and the extents of binding to plasma proteins. 2- Tubular secretion: Here drug molecules are transferred by two independent and non-selective carrier systems i.e. Transport of acidic compounds or basic compounds

They transport drug molecules against conc They transport drug molecules against conc. gradient so can reduce the plasma conc. of the drug to zero. E.g. penicillin 3- Diffusion across the renal tubules: Renal tubes can be freely permeable (the drug concentration in the plasma and in the renal tube is equal)

DRUG ELIMINATION (CLEARANCE) Defined as the volume of plasma containing the amount of substance that is removed by the kidney in unite time CL= Cu Vu Cp CL: Clearance Cu: Urine Concentration Cp: Plasma Concentration Vu: Volume of Urine

CLEARANCE Equals rate of elimination divided by plasma level Constant for 1st order elimination Total body clearance CL = CLR + CLER (extra renal) With no secretion or reabsorption renal clearance is the same as glomerular filtration rate, CLR = GFR If drug is protein bound then CLR = GFR x free fraction

There are two ways for drug elimination: 1- First Order Kinetic 2- Zero Order Kinetic

First Order Kinetic (un- saturable) Defined as the amount of drug removed is direct proportion to its concentration in plasma.

ZERO- ORDER KINETICS (SATURABLE) Here drugs are removed at a constant rate regardless the plasma concentration levels because it is an enzyme dependent process so it has limited capacity. Example: Ethanol Phenytoin Salicylates

t½ 10.9 Blood Alcohol concentration 7.6 4.3 Alcohol is eliminated at a rate of 4mmol/l regard less the plasma concentration TIME Dose Administration

t½ HALF LIFE OF A DRUG Is the time required by the body to eliminate 50% of the drug concentration t½= Vd x 0.7 CL It is important to indicate the time required to attain 50% of the steady state This helps in the setting up of a dosage regime which produces: stable plasma drug concentrations keeps the level of drug below toxic levels but above the minimum effective level

Loading Dose This is given when an effective plasma level of drug must be reached quickly. This requires a dose of the drug which is larger than is normally given. This dose is given as a one off. Maintenance dose: This is the dose given when the required plasma level of drug has been reached. It is the normal recommended dose. This is then continued at regular intervals to maintain a stable plasma level .