ADME Slides Sept 24 PDF

Absorption, Distribution, Metabolism, Elimination (ADME) Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Sunday, 08 September 2024 1  Learning Obj...

Absorption, Distribution, Metabolism, Elimination (ADME) Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Sunday, 08 September 2024 1  Learning Objectives Describe the routes by which medicines can be administered Identify and discuss factors affecting drug uptake Identify and discuss factors affecting drug distribution, to include areas where there are specific restrictions (e.g. the blood brain barrier, placenta) Explain phase 1 and phase 2 reactions and species differences in the metabolism of drugs Describe the major routes and factors affecting drug elimination Sunday, 08 September 2024 2  Learning Objective 1 Describe the routes by which medicines can be administered  Routes of administration Pre-read The most common routes used in veterinary medicine are oral, intravenous, intramuscular, subcutaneous, topical Factors which influence the choice of route of administration of drugs include species anatomy and physiology, disease state, mentation state, practicality and safety, desired speed of onset of drug action, local vs systemic disease, cost Sunday, 08 September 2024 4  ADME - Introduction Four physiological processes govern the time course of a drug: Absorption – Distribution – Metabolism – Excretion Taken from Riviere et al (2009) Sunday, 08 September 2024 5  Learning Objective 2 Identify and discuss factors affecting drug uptake  Drug absorption Core concept: Drug absorption is the process by which a drug moves from its site of administration to the systemic circulation. Absorption involves drugs crossing cell membranes (lipid bilayers), e.g. epithelium of the GI tract. Drugs cross these membranes by: 1. Passive diffusion through the lipid 2. Solute carrier-mediated transport 3. Diffusing through aqueous pores (Recall VMS1004 – GI Physiology) Taken from Rang & Dale (2024) Most drugs must be absorbed to reach their site of action Drugs given intravenously directly enter the blood stream Some medicines are designed to act locally (e.g. creams, inhaled drugs) Sunday, 08 September 2024 7  Chemical & physical factors affecting drug uptake Rate and extent of drug absorption depends in part on the drug’s physicochemical properties, particularly solubility in water / lipid Drug dissolution in water is affected by molecular size, degree of hydrophobicity, formulation characteristics (e.g. particle size, salt form) Drug diffusion across membranes is influenced by the concentration gradient across the membrane, molecular size and conformation, degree of ionization - most drugs are weak acids or weak bases For a weak acid For a weak base Non-polar drugs dissolve freely in lipid, ionised drugs have low lipid solubility (unable to diffuse through membranes) Sunday, 08 September 2024 8  Biological factors affecting drug uptake Vascularity and local blood flow to the absorption site Gastric content (diet), emptying and motility for oral drugs Surface area for absorption Local pH (e.g. acidic drugs will be non-ionised in low pH) Local enzymes in gut wall and liver Specific transport systems in GIT allow absorption of nutrients (and drugs) not absorbed by passive diffusion Rumen content SEM duodenal mucosa Sunday, 08 September 2024 9  By-passing absorption Individual patient variation in absorption can be avoided by using the iv route - useful for: Rapid effect e.g. calcium borogluconate for milk fever Fluid therapy for restoration of blood volume Precise dosing e.g. anaesthesia Administration of short acting drugs e.g. heparin Administration of irritant drugs e.g. chemotherapy drugs Sunday, 08 September 2024 10  Modifying absorption through formulation Drug absorption can be altered through formulation e.g. - Depot injections (e.g. vehicle, salt, particle size) - Controlled/sustained release products Sunday, 08 September 2024 11  Case study Roxy has vomited 5 times today after eating something she shouldn’t have from the kitchen bin. You decide she needs an antiemetic. Which of the following products is most suitable to treat her? maropitant metoclopramide maropitant tablets solution injection Sunday, 08 September 2024 12  Learning Objective 3 Identify and discuss factors affecting drug distribution, to include areas where there are specific restrictions (e.g. the blood brain barrier, placenta)  Drug distribution Core concept: Drug distribution is the reversible passage of drug between tissues, organs, and compartments. Drugs move around the body by bulk flow in the blood Bulk flow: Gaps between vascular endothelial cells allow drugs sized < 1000 Da to leave the blood vessel Some membranes (e.g. BBB and placenta) have tight junctions - prevent penetration of harmful substances Typical capillary Blood-brain barrier https://basicmedicalkey.com/pharmacokinetics-pharmacodynamics-and-drug-interactions/ Sunday, 08 September 2024 14  Drug distribution Drug distribution is influenced by the degree of reversible binding to proteins in the plasma (esp. albumin). Only unbound (free) drug can distribute into tissues https://basicmedicalkey.com/pharmacokinetics-pharmacodynamics-and-drug-interactions/ Sunday, 08 September 2024 15  Drug distribution Drug distribution occurs initially in the ‘central compartment’ (plasma and highly perfused tissues) before distribution into peripheral compartments (low/poorly perfused tissues) Distribution between different compartments depends on: 1. Physicochemical characteristics of the drug 2. Local pH 3. Blood flow 4. Transport mechanisms 5. Disease processes 6. Protein binding within compartments Taken from Rang & Dale (2024) Sunday, 08 September 2024 16  Drug distribution Core concept: Individual variation in drug response refers to differences in response between individuals to the same dose of a drug. An example of individual variation affecting drug distribution is genetic mutation of P-glycoprotein (P-gp) transporters that form efflux mechanisms (i.e. pump molecules out of cells). Mutations in the MDR-1 gene coding for P-gp contribute to: Drug resistance to some cancer therapies Sensitivity to ivermectins in Collies/herding dogs Sunday, 08 September 2024 17  Case study Ginger has a nasty wound infection. What factors might affect the distribution of systemically administered antibiotic to her wound? Sunday, 08 September 2024 18  Learning Objective 4 Explain phase 1 and phase 2 reactions and species differences in the metabolism of drugs  Drug Metabolism Core concept: Drug metabolism is the chemical transformation of a drug into one or more products within the body. Polar drugs can be eliminated unchanged via the kidney, however lipophilic drugs are not eliminated efficiently by the kidney – they first need to be metabolised to more polar products which can then be excreted Drug metabolism occurs predominantly in the liver – cytochrome P450 enzymes (CYP450) play an important role Drug metabolism involves 2 kinds of reaction CYPP450 Enzyme Phase 1 – catabolic Phase 2 – anabolic http://scottlab.info/illustration/human-cytochrome-p450-2a13/ Sunday, 08 September 2024 20  Phase I and Phase II Reactions Phase 1 reactions Catabolic – CYP450 enzymes introduce a reactive chemical group (e.g. hydroxyl group) producing a metabolite more reactive than the original drug – Usually involve oxidation, reduction or hydrolysis Phase 2 reactions Anabolic – involve conjugation producing (usually) inactive, polar Taken from Rang & Dale (2024) products readily excreted in urine – Insert glucuronyl, sulfate, methyl or acetate group Sunday, 08 September 2024 21  Phase I and Phase II Reactions Phase 1 reactions Catabolic – CYP450 enzymes introduce a reactive chemical group (e.g. hydroxyl group) producing a metabolite more reactive than the original drug – Usually involve oxidation, reduction or hydrolysis Phase 2 reactions Anabolic – involve conjugation producing (usually) inactive, polar Taken from Rang & Dale (2024) products readily excreted in urine – Insert glucuronyl, sulfate, methyl or acetate group Sunday, 08 September 2024 22  Drug metabolism Not all drugs are metabolised – some are excreted unchanged Drug metabolites may be biologically active or inert Biotransformation is a major factor accounting for differences in drug effects across species (esp. CYP450 enzymes) e.g. Cats have very low glucuronidation capacity Do not give paracetamol to cats Cats are not small dogs The owner has been reported to the RSPCA (allegedly)! Sunday, 08 September 2024 23  First-pass (pre-systemic) metabolism Some drugs are metabolised by gut and liver enzymes to such extent that the amount of drug reaching the systemic circulation is considerably less that the amount ingested Systemic plasma concentrations of drugs given orally can be significantly lower than the same drug given parenterally – consequently higher doses may be required when a drug is given orally Considerable patient variation in first-pass metabolism Sunday, 08 September 2024 24  Case study Snowy has severe atopic dermatitis. He is routinely treated with cyclosporine. Snowy has developed a fungal infection – you decide to treat with ketoconazole. Both cyclosporine and ketoconazole are metabolized by the same CYP450 liver enzyme. What will be the effect of treating Snowy with ketoconazole on plasma levels of cyclosporine? Sunday, 08 September 2024 25  Drug interactions Snowy’s case is an example of a drug interaction. Core concept: Drug Interaction is the process by which a substance alters the action and/or kinetics of a drug. Drug interactions may result in effects that are beneficial or deleterious (e.g. in Snowy’s case). Interactions between drugs and food constituents primarily change the amount of drug absorbed. Sunday, 08 September 2024 26  Learning Objective 5 Describe the major routes and factors affecting drug elimination  Drug elimination Core concept: Drug Elimination is the removal of drug from the body through metabolic and/or excretory processes. Drug elimination is the physical process that leads to the irreversible removal of a drug from the body The main route of drug elimination is via the kidneys, thus renal function has a major influence on drug plasma concentrations and duration of action Drugs are eliminated through Glomerular filtration Passive, flow-dependent diffusion Active tubular secretion (Recall VMS1007 – Renal physiology) https://www.pinterest.co.uk/pin/565905509399614119/ Sunday, 08 September 2024 28  Drug elimination Other drug elimination routes include: Biliary excretion Exhaled air (e.g. volatile anaesthetics) Milk (consider milk withhold time) Sweat, tears, saliva Drug metabolites excreted in bile can be reabsorbed from the intestine (enterohepatic circulation) Enterohepatic circulation Sunday, 08 September 2024 29  Drug elimination Species differences in urinary pH influence the rate of renal excretion of ionisable drugs Birds and reptiles have a renal portal system. Consequently, large amounts of drug can be eliminated directly by the kidneys (akin to first-pass metabolism) High reabsorption of water from avian excreta may increase their susceptibility to toxicoses caused by agents that normally leave via the urine Sunday, 08 September 2024 30  Case study Tiddles is an inpatient and has vomited several times today. You decide to treat her with maropitant. Tiddles has chronic kidney disease but no other underlying medical conditions. Do you need to adjust the normal dose of maropitant for her? Check the SPC for Emeprid 10 mg/ml solution for injection for dogs and cats (using the VMD Product Information Database). Sunday, 08 September 2024 31  Key Points LO – Describe the routes by which drugs can be administered Drugs can be administered via a variety of routes. The most common routes used in veterinary medicine are oral, intravenous, intramuscular, subcutaneous, topical Factors which influence the choice of route of administration of drugs include species anatomy and physiology, disease state, mentation state, practicality and safety, desired speed of onset of drug action, local vs systemic disease, cost Sunday, 08 September 2024 32  Key Points LO – Identify and discuss factors affecting drug uptake Core concept: Absorption is the process by which a drug moves from its site of administration to the systemic circulation. Most drugs need to be absorbed from their site of administration into plasma and cross cell membranes to reach their site of action Drug physical and chemical factors affecting uptake include formulation factors, drug lipid solubility, ionization and concentration gradient across the membrane. Other factors include molecular size and conformation. Biological factors affecting uptake include vascularity and local blood flow; surface area for absorption; local pH; gastric content, emptying and GI motility; transport mechanisms in epithelium; local enzymes gut wall and liver Sunday, 08 September 2024 33  Key Points LO – Identify and discuss factors affecting drug distribution, to include areas where there are specific restrictions (e.g. the blood brain barrier, placenta) Core concept: Drug distribution is the reversible passage of drug between tissues, organs, and compartments. Drugs move around the body by bulk flow (e.g. blood) and between compartments primarily by diffusion Most drugs will pass through gaps in vascular endothelium. Tissues with tight junctions (e.g. BBB, placenta) prevent penetration of many drugs Many drugs are bound to protein (albumin) in plasma. Only unbound drug is free to move between body compartments Sunday, 08 September 2024 34  Key Points Drug distribution between compartments depends on permeability across tissue barriers, binding within compartments, pH partition, lipid:water partition Cell membranes possess specialised transport mechanisms to move molecules against the concentration gradient (e.g. ABC + SLC transporters) Mutations in the MDR1 gene have important clinical implications for drug resistance (e.g. cancer therapy) or sensitivity (e.g. Collie/herding breeds) Sunday, 08 September 2024 35  Key Points LO – Explain phase 1 and phase 2 reactions and species differences in the metabolism of drugs Core concept: Drug metabolism is the chemical transformation of a drug into one or more products within the body. Polar drugs can be eliminated unchanged via the kidney; Lipophilic drugs are metabolised to more polar compounds Phase 1 reactions are catabolic, forming reactive products through oxidation, reduction or hydrolysis. Cytochrome P450 liver enzymes play a key role. Phase 2 reactions are anabolic and involve conjugation, leading to polar metabolites that are readily excreted in urine Sunday, 08 September 2024 36  Key Points Drugs may induce or inhibit the CYP450 enzymes that metabolise them Biotransformation is a major factor accounting for differences in drug effects across species Pre-systemic metabolism by gut and liver enzymes reduces bioavailability of orally administered drugs (first-pass metabolism) Sunday, 08 September 2024 37  Key Points LO – Describe the major routes and factors affecting drug elimination Core concept: Drug Elimination is the removal of drug from the body through metabolic and/or excretory processes. Most drugs and their metabolites are eliminated via the kidney, through glomerular filtration, active secretion and passive diffusion. Renal function has a major influence on elimination Other drug elimination routes include biliary excretion, exhaled air (e.g. volatile anaesthetics), milk, sweat, tears, saliva Drugs competing for the same elimination process can interact Drugs and metabolites excreted through bile can be reabsorbed from the GIT – enterohepatic recycling Sunday, 08 September 2024 38