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Transcript
LO: Pharmacokinetic (Questions 1-5) 1. Understand the concept of prodrugs and relate the duration of effect of different drugs to their metabolism and the presence of biologically active metabolites Prodrugs: inactive precursors that are metabolized to active metabolites, that is, the parent compound, which is first ingested (or injected etc.), lacks activity of its own. These are sometimes designed deliberately to overcome problems of drug delivery and to maximize bioavailability of oral ingestion. Examples include azathioprine, which is metabolized to mercaptopurine (an immunosuppressant drug) and enalapril, an angiotensin-converting enzyme inhibitor is hydrolysed to its active form, enalaprilat. Aspirin is also a prodrug of salicylic acid. Drug Metabolism Before excretion of drugs through the urine (and sometimes in the faeces, sweat or breast milk), most drugs undergo metabolism in the liver (and sometimes in the lungs, plasma or gut). Metabolism of drugs is the enzymatic conversion of one chemical entity to another for the following purposes; To terminate the drug action (except in some phase 1 reactions) Allow for elimination of the drug by have polar/charged group to molecules in order to make them more water soluble in the preparation for excretion This metabolism involves 2 types of biochemical reactions; Phase 1 reactions are catabolic (eg. Oxidation, reduction or hydrolysis) and the products are often more chemically reactive and therefore can sometimes be more carcinogenic or toxic than the parent drug Phase 2 reactions are synthetic and involve conjugation, which results in the more inactive molecules Molecules can undergo just phase 1 or just phase 2, but most undergo both. Obviously, the longer that a drug molecule is in the systemic circulation in it’s’ bioavailable form, the more effective (or toxic) it is. Therefore, in the instances where there is presystemic metabolism in the liver of the gut wall, the bioavailability of the drug is greatly reduced (hence why some drugs will be administered IV instead of orally – eg. Morphine). This is known as first pass metabolism and is a problem due to; A much larger dose of the drug is needed orally than when administered via other routes There are marked individual variations in the first pass metabolism of a drug, therefore there is an element of unpredictability 2. Outline how the metabolism and/or excretion of a drug may be influenced by the physicochemical properties of the drug Metabolism If a drug is polar, it is less-readily able to cross a plasma membrane than the non-polar molecules and therefore is unable to reach the metabolizing enzymes in the liver. Therefore, intracellular metabolism is in general less important for polar drugs than for lipid soluble drugs and the former tend to be excreted unchanged in the urine. Non-polar drugs can readily access the intracellular enzymes, but are eliminated very inefficiently due to passive tubular reabsorption (hence why the 2 stage metabolism is the most normal path). Excretion In order for a drug to be excreted in the urine, it must by hydrophilic, whereas most drugs on administration is lipophilic (which enables them to cross cell membranes) Ionized drugs (which are filtered during glomerular filtration in the kidney) undergo little reabsorption and are excreted Lipophilic or non-ionised drugs that enter the kidney will be reabsorbed back into the interstitial fluid (and may undergo another circuit of the system) and are therefore not eliminated or they undergo passive tubular reabsorption back into the urine, but this process requires a lot of energy and is largely inefficient Drugs bound to plasma proteins (most commonly albumin) cannot filter, but can sometimes dissociate and then undergo tubular secretion for excretion in the urine. The effect of pH Urinary acidification accelerates excretion of weak bases and retards that of weak acids Urinary alkalinisation has the opposite effect – it reduces excretion of weak bases and increases the excretion of weak acids Increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the plasma. The opposite is also true – by decreasing the plasma pH, weakly acidic drugs will become concentrated in the CNS, increasing their neurotoxicity 3. Describe the basic mechanisms of Phase I and Phase II reactions and how they influence the excretion of drugs Sorry… may have gone a little OTT with this one. Phase 1 reactions often introduce a reactive group, such as a hydroxyl into the molecule (termed ‘functionalisation’). This point later serves as the ‘point of attack’ to which the conjugating system in phase 2 can attach the glucuronide The P450 Monooxygenase System Cytochrome P450 enzymes are heame proteins, comprising a large family of related but distinct enzymes. These enzymes differ in amino acid sequence, sensitivity to inhibitors and inducing agents and specificity of reactions. Some members have overlapping substrate specificities, with some enzymes acting on the same substrate but at different rates Drug oxidation by the monooxygenase P450 system requires the following; o Drug o P450 enzyme o Molecular oxygen o NADPH o Flavoprotein The mechanism is somewhat complex, but the result is the addition of one atom of oxygen to the drug to form the hydroxyl group (product ‘DOH’) Bottom line: Cytochrome P450 enzymes have unique redox properties that are fundamental to their diverse functions. Important to note that there are large variations in the expression and regulation of P450 enzymes between species and environmental factors are also important – eg. Grapefruit juice inhibits drug metabolism Other Phase 1 Reactions Not all drug oxidation reactions involve the P450 system. Examples include; o Ethanol is metabolized by soluble cytoplasmic enzyme, alcohol dehydrogenase, in addition to CYP2E1 (part of the P450 system) o 6-mercaptopurine is oxidized by xanthine oxidase o Monoamine oxidase inactivates many biologically active amines (eg. Noradrenaline) Reductive reactions also take place (although are apparently less important). Eg. Warfarin is inactivated by conversion of ketone to a hydroxyl group Hydrolytic reactions (eg. In aspirin) do not involve hepatic enzymes, but do occur in plasma and many tissues. Phase 2 deals with drugs that have a suitable ‘handle’ (ie. A hydroxyl, thiol or amino group), either in the parent or as a result of a phase 1 reaction and conjugates them in order to prepare for excretion. The groups that are added most often involve glucuronyl, sulfate, methyl, acetyl and glycyl. Glucuronide formation involves the formation of a high-energy phosphate compound, uridine diphosphate (UDP) glucaronic acid, from which glucuronic acid is transferred to an electron-rich atom (N, O or S) on the substrate, forming an amide, ester or thiol bond Acetylation and methylation reactions occur with acetyl-CoA and S-adenosyl methionine respectively, acting as the donor compounds Many of the conjugation reactions occur in the liver, but other tissues (such as the lung or kidney) are also involved The resulting conjugate is almost always pharmacologically inactive and less lipid-soluble than its precursor and is excreted in bile or urine. 4. Outline the mechanisms involved in renal and biliary elimination of drugs Renal Excretion 3 fundamental processes account for renal drug excretion; Glomerular filtration o Most drugs can cross the glomerular capillary barrier freely (except those bound to albumin and heparin) o Up to 20% of renal plasma flow is filtered through the glomerulus Active tubular secretion o Approximately 80% of the delivered drug pass onto the peritubular capillaries of the proximal tubule and transferred to the tubular lumen by two independent and relatively non-selective carrier systems (one transports acidic drugs, whilst the other handles organic bases) o These carriers can carry molecules against an electrochemical gradient and can therefore reduced plasma concentration to almost 0 o This is the most effective renal drug elimination system as can actively transport protein bound molecules Passive diffusion across tubular epithelium o If the tubule is freely permeable to drug molecules, roughly 99% of the filtered drug will by reabsorbed passively, therefore this is where lipid-soluble drugs will go back into circulation, whereas the polar hydrophilic drugs will continue in the tubule to excretion Biliary Elimination Please refer to question 5 below. 5. Describe how enterohepatic recirculation prolongs the duration of action of drugs Various hydrophilic drug conjugates are concentrates in bile and delivered to the intestine, where glucuronide is usually hydrolysed, releasing the active drug once more, which then can be reabsorbed and the cycle repeated – this is termed enterohepatic circulation – the effect of this is to create a ‘reservoir’ of recirculating drug that can amount to 20% of total drug in the body and this prolongs the drug’s action. This is important for morphine, aspirin, chloramphenicole (an antibiotic) and digoxin (inotrophic agent). In the event that gut bacteria hydrolyses the drug, resulting in deacetylation (such as Rifampicin), the drug will not be reabsorbed and will not undergo enterohepatic recirculation. It is then passed out in the faeces.