Module 2- Pharmacokinetics and Drug MetabolismAbsorption and Distribution Drug molecules move around the body either by bulk flow (in bloodstream, lymphatic) or diffusion. Most drugs fall within the molecular weight range of 200-1000 Da. Cell membranes form barriers between aqueous compartments of the body- separates intercellular and extracellular compartments. Moat drugs are given orally and must pass through the gut wall to enter the blood stream. An epithelial barrier such as the gut consists of a layer of cells tightly connected to each other that molecules must transverse at least 2 cell membranes to pass from one side to the next. There are gaps between endothelial cells that act as filter allowing small molecules through.4 main ways of crossing membranes Passive diffusion- follows concentration gradient, across membranes via pores (has to be small molecules) Passive lipid diffusion- highly relevant to drug absorption By combination with solute carrier Pinocytosis- trapping in vesicle and released once get into target cell- used for macromolecules like glucose.The absorption process is affected by many factors but is usually proportional to the lipidsolubility of a drug.Lipid Diffusion Non ionized molecules is favored because the latter are far more lipid soluble than ionized (charged molecules) molecules which are surrounded by a shell of water molecules. Most drugs are weak acids or bases. Acids include aspirin and diazepam/ Bases include amphetamine and climetidine. Ionization determines how well a molecule moves between aqueous and lipid media. Ionization ↓ lipid solubility ↑ which gives then ↑ membrane diffusion (and vice versa) Drugs are absorbed mainly from the small intestine because of the large surface area. Drugs absorbed from gastrointestinal tract enter portal circulation and some are extensively metabolised as they pass through the liver. Drugs that are sufficiently lipid soluble to be readily absorbed orally are rapidly distributed thorough the body water compartment. The number of molecules crossing the membrane per unit area in unit time is determined by the permeability coefficient P and the concretion difference across membrane.
There is a close correlation between lipid solubility and the permeability of the cell membrane to different substances. For this reason lipid solubility is one of the most important determinants of a drug in terms of pharmacokinetics – rate of absorption form gut, penetration into different tissues and extent of rate of elimination can be predicted knowing drug lipid solubility.Henderson- Hasselbach EquationRelates the ratio of protonated to unprotanated acid or base to its pKA and the pH of the medium.Many drugs are weak acids or base their sate of ionization varies with pH according to theHenderson- Hasselbach equation. Only the uncharged species (protonated form for weak acid,unprotanated for weak base) can diffuse across lipid membrane, this gives rise to pH partition. pHpartition means that weak acids tend to accumulate in compartments of relatively high pH whereasweak bases do reverse. pH affects how much of a drug is absorbed, where drug is distributed and atwhich rate drug is excreted. Strong bases of pKa of 10 or higher and acids of pKa 3 or less are notabsorbed.Routes of Administration1. Oral - 75% of drugs are given orally - Safest method - Drug is subject to first pass metabolism - Some drugs destroyed by acid or enzymes in the gut (gastrointestinal motility) - Oral route absorption affected by: gastric emptying (rate limiting, food slows gastric emptying and decreases absorption, splanchnic blood flow), pH (ionization effect, low pH inactivate some antibiotics) and formulation. - Major site of absorption is the small intestine due to its large surface area. Little drugs are absorbed in the stomach.2. Sublingual - From blood vessels at base of tongue - Lipid soluble drugs only and small surface area (potent drugs only) - Avoids first pass effects3. Intravenous - Dangerous - Direct entry into circulation and bypasses the absorption barrier - Used when rapid effect is required, for continuous administration (infusion), for large volumes, drugs that cause local tissue damage if given by other routes.4. Intrathecal - Injection into CSF usu via spinal column - Spinal anesthesia and chemotherapy - Bypasses blood brain barrier
5. Intramuscular - Drugs with low water solubility unsuitable for oral administration - Avoids first pass metabolism - Penicillin - Painful6. Other - Eyes and Nose/ Subcutaneous ( slow, even absorption, insoluble suspensions, avoids first pass metabolism)/ rectal (severe vomiting or unconscious patients)Drug Disposition Clearance - Important concept in pharmacokinetics- efficiency of drug elimination - Irreversible elimination from circulation/ one way elimination - It is the volume of blood or plasma cleared of drug in unit time. - Clearance is the sum of individual clearance values (total clearance + metabolic clearance + renal clearance + other clearances). Volume of Distribution - The volume into which the total amount of a drug in the body would have to be uniformly is distributed to provide concentration of the drug actually measured in the plasma- apparent rather than real volume. - Used to calculate loading dose - It is back calculated from concentration of drug plasma following given dose Half Life - Time taken for concentration of drug in blood to fall by half its original value – single dose - Has 2 phases half life of distribution and half life of elimination - Determined by clearance and volume distribution - Exponential curve of plasma concentration against time - Double dose increases duration by one half life Bioavailability - term used to describe portion of administered drug reaching the systemic circulation - 100 % in intravenous but drugs orally have only portion reaching systemic circulation as drugs are subject to high degree of first pass metabolism. - Absorption- extent intact drug absorbed from gut into portal circulation (fg)
- First pass clearance-extent drug removed by liver from portal circulation on way to systemic circulation - Bioavailability- fraction of dose reaching systemic circulation intact (F) - F= fg x fh - For example morphine- almost completely absorbed from gut – hepatic (liver) extraction is around 67% thus bioavailability of morphine is around 33%. - Plasma protein binding- drugs only reach receptors if it’s free and many drugs bind to plasma protein mainly albumin.Metabolism of Drugs