Pharmacokinetics - Drug Metabolism - Warwcik Medical School PDF

Pharmacokinetics - Drug Metabolism  Learning Outcomes 1. Outline the biochemical pathways of drug metabolism in the liver 2. Describe the effects of age on hepatic drug metabolism 3. Describe drug interactions at the level of hepatic metabolism 4. Describe the effects of g...

Pharmacokinetics - Drug Metabolism  Learning Outcomes 1. Outline the biochemical pathways of drug metabolism in the liver 2. Describe the effects of age on hepatic drug metabolism 3. Describe drug interactions at the level of hepatic metabolism 4. Describe the effects of genetic polymorphisms on drug metabolism 5. Describe the effects of liver disease on drug action 6. Identify the precautions that should be taken when prescribing in liver disease The Four Phases of Pharmacokinetics Drug Metabolism: Effect on Drug Activity Conversion of drugs to inactive compounds: – most common fate of active drugs – conversion in liver can promote excretion by kidneys Pro-drugs: inactive pro-drugs undergo metabolism to become active drugs: – altered absorption kinetics – prevent adverse effects – improved distribution Active metabolites – e.g. codeine (inactive) is converted to morphine (active) Drug Metabolism – points to note The liver is the major site of drug metabolism. Orally-administered drugs, absorbed by the GI tract, are transported via the portal system through the liver where they are metabolised to an extent before entering the systemic circulation. This is “first pass metabolism”. A drug may pass through the liver many times because of continual systemic blood circulation. Each time a drug passes through the liver, a fraction of it is metabolised. Molecules of metabolized drugs are excreted out of the body either via the kidneys or through the bile.  Biochemical Pathways of Drug Metabolism in the Liver The liver is the most important organ in which drugs are structurally altered. phase I intermediate drug metabolite phase II phase II conjugated metabolite phase III transport excretion via the kidney/ bile  Phase I Metabolism oxidation reduction hydrolysis Provide a functional group (e.g. OH or NH2) to: increase polarity of the drug provide a site for phase II reactions For many drugs, decreases pharmacological activity of drug. (N.B. for less commonly used pro- drugs, increases pharmacological activity.)  The Cytochrome P450 Enzymes A superfamily of enzymes located on the smooth endoplasmic reticulum of hepatocytes. Several hundred isoforms exist, differing in: protein amino acid sequence regulation by inhibitors and inducing agents specificity of chemical reactions catalysed Some are constitutive; some are inducible Are haem-containing proteins Require the presence of molecular oxygen (also NADPH and NADPH cytochrome P450 reductase) in order to function.  Major Cytochrome P450 Isoforms CYP3A CYP2D6 CYP2C9 CYP1A2 Approx. % of current drugs that are metabolised by the indicated isozymes Image: Raffa et al. Netter’s Illustrated Pharmacology (Elsevier) Oxidation of a drug by cytochrome P450 The process of drug oxidation involves both chemical oxidation and reduction steps. Cytochrome P450 catalyses the transfer of one oxygen atom to the substrate (drug) while the other oxygen atom is reduced to water: DH + O2 + NADPH + H+ DOH + H2O + NADP+ (drug) (oxidised drug)  Other Phase I Reactions Reductions (much less common than oxidations). Oxidations that do not involve the CYP450 system. For example: Ethanol is metabolized by alcohol dehydrogenase (cytosolic enzyme). Monoamine oxidase enzymes inactivate many biologically active amines (e.g. noradrenaline, serotonin, dopamine). Hydrolytic reactions are not restricted to the liver and occur in plasma and in many tissues. For example, aspirin (acetylsalicylic acid) is hydrolysed to salicylic acid.  Drug Metabolism in the Liver The liver is the most important organ in which drugs are structurally altered. phase I intermediate drug metabolite Biochemical pathways of drug metabolism in phase II phase II the liver conjugated metabolite phase III transport excretion via the kidney/ bile  Phase II Reactions Drug molecules that possess a suitable chemical site that was either present before phase I or is the result of a phase I reaction, are susceptible to phase II reactions. Phase II reactions involve conjugation - the attachment of a large chemical group to a functional group on the drug molecule. The resulting conjugate is almost always pharmacologically inactive and is more hydrophilic and thus more easily excreted from the body.  Conjugation Occurs mainly in the liver (other tissues such as lung and kidney can also be involved) The chemical groups most often involved in conjugate formation are glucuronyl, acetyl, methyl, sulphate and glutathione. The conjugating enzymes exist in many isoforms. Some (glucuronyl transferases) are located on the ER, close to the CYP450s. Some are located in the cytosol. Image: Waller et al. Medical Pharmacology and Ttherapeutics (Elsevier) The glucuronide conjugation reaction O- O- OH DRUG + Uridine O P O P O OH OH O O O UDP-a-glucuronide COOH glucuronyl transfer UDP-glucuronyl transferase OH OH OH + UDP Drug-b-glucuronide DRUG O O COOH  Phase III Transport phase I intermediate drug metabolite phase II phase II conjugated metabolite phase III transport excretion via the kidney/ bile Into the circulation (for renal elimination) - most common route. Into bile (for elimination in faeces/ enterohepatic circulation) – can be an excretion route for larger molecules (>500 Da). Multi-purpose membrane-bound transport carrier systems remove hydrophilic metabolites from hepatocytes.  Phase III Transport Uptake transporters Efflux transporters Multi-drug resistance (MDR) proteins P-glycoproteins Factors Affecting Drug Metabolism  Effects of Age on Drug Metabolism Neonates Hepatic drug-metabolizing enzyme systems are immature. N.B. renal clearance is also inefficient. Lower doses of all drugs are needed. Children Metabolic clearance can be quicker in children than in adults (because CYPs are mature and the relative liver mass and hepatic blood flow are higher). Dosages of medicines should be obtained from a paediatric dosage handbook. Prescribed dosages are judged by considering both age and body surface area.  Effects of Age on Drug Metabolism Older Adults Overall capacity for hepatic drug metabolism, particularly phase I reactions, is reduced (because the relative liver mass and hepatic blood flow are lower). Simultaneous use of several drugs is common. It is usual to start drug treatment with the smallest effective dose. Rational prescribing should seek to minimise the number of drugs used.  Drug Interactions at the Level of Hepatic Metabolism Commonly due to interaction at CYP450 enzymes. Multiple factors (including drugs, alcohol, chemicals in food, environmental contaminants) can either increase or decrease CYP450 enzyme activity. CYP450 enzyme induction results in more rapid metabolism of the drug and all other drugs metabolised by the same enzyme. CYP450 enzyme inhibition results in reduced metabolism of drugs metabolised by the same enzyme.  CYP450 Enzyme Induction Long-term administration of drugs often induces CYP450 activity by enhancing the rate of synthesis or reducing the rate of degradation of the CYP enzyme(s). CYP450 enzyme induction results in more rapid metabolism of the drug and all other drugs metabolised by the same CYP450 enzyme(s). Plasma levels and biological effects of the drugs decrease. A lack of therapeutic efficacy can result. N.B. Except for pro-drugs, whose biological effects will increase. Drug metabolism: more points to note In general, the overall purpose of drug metabolism is to make drugs less active and more hydrophilic. However: Some drugs are administered as pro-drugs and are activated by phase I metabolism, e.g. ACE inhibitors.  St. John’s Wort A “herbal remedy” commonly taken for depression. Available over-the-counter. Induces activity of many P450 enzymes including CYP3A4, CYP2C9, CYP2E1 and CYP1A2. Increases the metabolism, and therefore reduces the plasma concentration, and potentially the therapeutic efficacy, of drugs such as warfarin, antiepileptic drugs, oral contraceptives.  CYP450 Enzyme Inhibition Drugs and other substances can inhibit CYP450 activity. CYP450 enzyme inhibition results in reduced metabolism of other drugs metabolised by this CYP450 enzyme(s). Plasma levels and biological effects of the drug(s) increase. Potentially toxic drug levels and adverse effects can result. N.B. Except for pro-drugs, whose biological effects will decrease.  Omeprazole A proton pump inhibitor drug that reduces acid secretion. A broad, but relatively weak, inhibitor of many CYP450 enzymes. Reduces the metabolism of endogenous steroids and co- administered drugs such as warfarin (for anticoagulation) and phenytoin (for epilepsy). Plasma levels of these drugs will therefore be elevated and biological effects increased. Potentially toxic drug levels and adverse effects can result. For example, increased levels of warfarin can cause excess internal bleeding  How Can You Attempt to Avoid Drug Interactions? 1. Take a full medication history, including: herbal remedies Over-the-counter (OTC) medicines. 2. Remember “high risk” patients: Polypharmacy - 4 or more medications (more in Block 4) warfarin, anticonvulsants, antibiotics etc. 3. A good understanding of P450 metabolism is helpful. 4. Consult the British National Formulary, including interactions content: https://bnf.nice.org.uk/interaction/  4. Effects of Genetic Polymorphisms on Drug Metabolism Within human populations, there are major inter-individual variations in the activity of CYP450 enzymes. Mutations in a gene encoding a given CYP450 enzyme result in variations in expression, and hence activity, of the CYP450 enzyme. If the mutation is relatively common in a population (more than 1%), it is said to have a polymorphic distribution. Individuals expressing the polymorphism will metabolize drugs by that CYP450 enzyme at a different rate compared with the rest of the population: Example 1: a drug INACTIVATED by CYP metabolism Hepatic metabolism by CYP2C19 inactivates omeprazole CYP2C19 omeprazole 5-hydroxy-omeprazole Active proton Inactive pump inhibitor  Effects of CYP Phenotype on Therapeutic Efficacy Phenotype Active drug INACTIVATED by Pro-drug ACTIVATED CYP metabolism by CYP metabolism Poor metaboliser Increased efficacy Decreased efficacy (no/low CYP450 activity) Active drug may accumulate to Pro-drug may toxic levels accumulate to toxic levels May require decrease in dose May require alternative drug Extensive metaboliser Therapeutic efficacy Therapeutic efficacy (normal CYP450 activity) Rapid Metaboliser Decreased efficacy Increased efficacy (high CYP450 activity) Active drug rapidly inactivated Rapid onset of effect May require increase in dose May require decrease in to offset inactivation dose to prevent excessive accumulation of active metabolite Example 2: a drug ACTIVATED by CYP metabolism Hepatic metabolism by CYP2D6 converts codeine into morphine – activating opioid analgesia CYP2D6 Codeine Morphine Inactive opioid Active opioid  Effects of CYP Phenotype on Therapeutic Efficacy Phenotype Active drug INACTIVATED by Pro-drug ACTIVATED CYP metabolism by CYP metabolism Poor metaboliser Increased efficacy Decreased efficacy (no/low CYP450 activity) Active drug may accumulate to Pro-drug may toxic levels accumulate to toxic levels May require decrease in dose May require alternative drug Extensive metaboliser Therapeutic efficacy Therapeutic efficacy (normal CYP450 activity) Rapid Metaboliser Decreased efficacy Increased efficacy (high CYP450 activity) Active drug rapidly inactivated Rapid onset of effect May require increase in dose May require decrease in to offset inactivation dose to prevent excessive accumulation of active metabolite Neither poor metabolisers (PM) nor ultra-rapid metabolisers (URM) respond well to codeine: Phenotype Metabolic defect Impact Poor metaboliser Cannot convert No pain relief (PM) codeine to Exaggerated side-effects morphine of codeine, especially if dose is increased in futile attempt to relieve pain Ultra-rapid Ultra-rapid Toxic levels of morphine metaboliser conversion of Opioid toxicity (URM) codeine to morphine Side effects of Codeine (more in Block 3…!) include: Nausea and vomiting Light-headedness Dizziness Sweating Constipation Neither poor metabolisers (PM) nor ultra-rapid metabolisers (URM) respond well to codeine: Phenotype Metabolic defect Impact Poor metaboliser Cannot convert No pain relief (PM) codeine to Exaggerated side-effects morphine of codeine, especially if dose is increased in futile attempt to relieve pain Ultra-rapid Ultra-rapid Toxic levels of morphine metaboliser conversion of Opioid toxicity (URM) codeine to morphine Opioid Toxicity (more in Block 3) Includes: Respiratory depression Skeletal muscle flaccidity Cold and clammy skin Bradycardia Hypotension Constipation Effects of Liver Disease on Drug Action The liver is the most important organ in which drugs are structurally altered. In cirrhosis: Impaired liver function: decreased drug-metabolising capacity. hypoproteinaemia. Porto-systemic shunting directs drugs away from the liver. Impact on drug action: Increased bioavailability resulting from impaired first-pass metabolism. Decreased plasma protein binding of drugs.  Bioavailability and Sites & Routes of Drug Administration DEFINITION – BIOAVAILABILITY “The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action.” Drug Metabolism – points to note The liver is the major site of drug metabolism. Orally-administered drugs, absorbed by the GI tract, are transported via the portal system through the liver where they are metabolised to an extent before entering the systemic circulation. This is “first pass metabolism”. A drug may pass through the liver many times because of continual systemic blood circulation. Each time a drug passes through the liver, a fraction of it is metabolised. Molecules of metabolized drugs are excreted out of the body either via the kidneys or through the bile.  First Pass Metabolism After absorption, orally-administered drugs enter the portal system Hepatic portal vein Drugs can be rapidly metabolised by enzymes in the liver. Thus levels reaching systemic circulation can be greatly reduced i.e. has a major effect on bioavailability  Increased bioavailability resulting from decreased first-pass metabolism First-pass metabolism of drugs is decreased in liver disease because: Drug metabolising capacity is reduced where hepatocytes are either sick or, if functioning normally, are reduced in number. Hepatocytes that metabolise drugs are by-passed when portal-to- systemic shunts develop in cirrhosis. Plasma levels and biological effects of the drug will be increased. Potentially toxic drug levels and adverse effects can result. Initial doses of drugs that are inactivated by first-pass metabolism should be smaller than usual. N.B first-pass activation of pro-drugs such as many ACE inhibitors will be decreased.  Decreased protein binding Liver disease may cause hypoproteinaemia, leading to reduced drug-binding capacity. This allows more unbound and pharmacologically active drug to circulate. Doses of drugs that are highly protein-bound in plasma should be smaller than usual.  Prescribing in Liver Disease Prescribing in liver disease should be carried out with care. Drugs that are extensively metabolised by the liver should be given in smaller doses. Patients with existing liver disease are more likely to be susceptible to potentially hepatotoxic drugs (e.g. the antibiotic erythromycin).  Resources Medical Pharmacology and Therapeutics 6th Edition. Waller & Sampson. Chapter 2 (Available via ClinicalKey Student) Rang & Dale’s Pharmacology 9th Edition. Chapters 10-12 (Available via ClinicalKey Student)