Pharmacokinetics PDF

Pharmacokineti cs There are 4 main ways by which molecules cross the cell membrane: 1) by diffusion directly through lipids 2) by diffusion through aqueous pores formed by special aquaprotiens that traverse the lipids 3) by combination...

Pharmacokineti cs There are 4 main ways by which molecules cross the cell membrane: 1) by diffusion directly through lipids 2) by diffusion through aqueous pores formed by special aquaprotiens that traverse the lipids 3) by combination with transmembrane carrier protein that binds a molecule on one side of the membrane then changes  Ionization constant or PKa PKa: (ionization constant), is PH at which 50% of the drug is ionized. Facts: Ionized drugs are poorly absorbed Unionized forms are more lipid soluble and rapidly absorbed. Acidic groups becomes less ionized in an acidic environment. Basic groups become less ionized in a basic (alkaline) environment. Acids are ionized in basic media & Bases are ionized in acidic media  DRUG DISPOSION DIVIDED INTO: – Absorption – Distribution – Metabolism – Excretion  Bioavailability Defined as the proportion of drug concentration that reach the systemic circulation following administration. IV doses have 100% bioavailability  Factors affecting Bioavailability A- Extent of absorption: Usually any drug taken by oral administration is incompletely absorbed Factors affecting GI absorption 1- Altered gastric motility e.g. diarrhea 2- Splanchnic blood flow (it decreases in shock) 3- Particle size and formulation 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.  Volume of distribution Vd: ratio of the amount of drug in the body to the concentration of the drug in blood or plasma Vd= amount of drug in body C Factors controlling distribution of drugs: 1. Blood flow 2. Molecular size 3. PKa 4. Plasma and tissue protein binding: Only unbound drug (free fraction) exerts pharmacological effects The higher the Vd, the lower the plasma concentration and vice versa  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  Drug elimination It involves the following: A.Drug metabolism: – Which include enzymatic conversion of one chemical entity to another – It occurs mainly in the liver B. Drug excretion: – Includes the elimination of drugs either unchanged or metabolized  A. 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 – Metabolism involves two phases: Phase -1 reaction: (catabolic) it includes: oxidation, reduction, and hydrolysis reaction. It is called “the microsomal mixed function oxidase system”. Localized in smooth ER of liver, GI tract, lungs, and kidneys  It includes two enzymes: 1) NADPH cytochrome reductase 2) 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) Other Phase 1 metabolism Non-microsomal oxidations Monoamine oxidases metabolize NE, 5HT, and tyramine Alcohols metabolized via alcohol dehydrogenase (ADH) to aldehydes then aldehyde dehydrogenase (inhibited by disulfram) to acetone Phase -2 reaction (Conjugation): It include conjugation with other groups to make it more soluble. Groups used in conjugation:  Glucoronyl,  Sulfate,  Methyl,  Acetyl,  Glycine  Glutathione May follow a phase I but also occur directly  Acetylation is genetically determined. Fast acetylators and slow acetylators. Glucuronidation: inducible; reduced activity in neonate  B. Renal excretion There are 3 main process for Renal excretion of a drug: 1- Glomerular 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. 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)  Renal Clearance Defined as the volume of plasma containing the amount of substance that is removed by the kidney in unite time CL = Rate of elimination Plasma concentration (Cp) Total body clearance CL = CLR + CLER (extra renal)  Ionization increases renal clearance of drugs Both ionized and non-ionized forms of a drug are filtered Only free unbound drug is filtered Only non-ionized forms undergo secretion and active or passive reabsorption Ionized forms of drugs are trapped in the filtrate There are two ways for drug elimination: 1. First Order Kinetic (un- saturable): Defined as the amount of drug removed is direct proportion to its concentration in plasma. 2. Zero Order Kinetic (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  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 Clinical significance of half life: This helps to: – Reach stable plasma drug concentrations – keeps the level of drug below toxic levels but above the minimum effective level – Determination of the time needed to reach the plasma steady state (occur after 5 t1/2).  Steady-state plasma concentration The steady level of drug in plasma achieved when the rate of administration equals the rate of elimination. The steady state is reached after 5 t1/2. If we changed the dose, the new steady state is reached after 5 t1/2.  Dose 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. Good luck