Pharmacokinetics: Drug Distribution, Metabolism, And Elimination PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Drug distribution, metabolism and elimination Class Year 1 medicine Course FFP1-71 Lecturer...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Pharmacokinetics: Drug distribution, metabolism and elimination Class Year 1 medicine Course FFP1-71 Lecturer ST Safrany [email protected] 341 Date October 2023  2 Learning outcomes Describe the pharmacokinetic process of drug distribution Define the term ‘apparent volume of distribution (Vd)’ and be able to calculate it Explain the important role of the liver in drug metabolism Describe the main routes of drug elimination from the body Explain first- and zero-order drug elimination kinetics Define the term half-life (t1/2) and its clinical relevance  3 Drug distribution Process by which a drug reversibly leaves blood stream and enters the extracelluar fluid and/or cells of the tissue (intracellular fluid)  4 Drug distribution – blood flow Rapid equilibration with well perfused tissues – Lung – Kidneys – Liver – Heart – Brain ( with exception of “blood brain barrier”) – Intestines Slower entry to less perfused tissues – Peripheral organs – Skeletal muscle – Skin – Connective tissue – Fat  5 Drug distribution - capillary permeability Capillary structure − ‘blood brain barrier’ due to endothelial cell tight junctions, reduced pores, and layer of astrocytes Drug structure −hydrophobic drugs (no net charge) readily move across most membranes −hydrophilic drugs (charged) do not penetrate cell membranes  6 Drug distribution - protein binding Reversible association of drugs and plasma proteins albumin (acidic & neutral drugs) α1-acid glycoprotein (basic drugs) Protein binding lowers concentration of free drug Bound drugs are pharmacologically inactive  7 Protein binding of drugs Protein bound drug can act as a drug reservoir / depot (as [free drug] decreases due to elimination, the bound drug dissociates from protein). Free Biological Free drug ↑Cleared Effect drug ↓Cleared effect Bound ↓ Bound Protein Protein  8 Drug distribution – altered protein binding Reduced protein – Hypoalbuminaemia, e.g., low albumin in liver disease Uraemia – Excess urea in blood from kidney damage, affects the binding sites such that drugs are less extensively bound than in non-uraemic patients Age – Lower capacity in the foetus, neonates, elderly Displacement from binding sites  9 Competition example Administration of a highly protein bound drug (aspirin) to a patient already receiving maintenance therapy with a drug that binds reversibly to plasma proteins (warfarin) Warfarin (anticoagulant) ~98% protein bound A 5 mg dose, only 0.1 mg of drug is free to work If patient takes normal dose of aspirin at same time (normally occupies ~50% of protein binding sites), the aspirin displaces / competes with warfarin so that ~96% of the warfarin dose is protein-bound Now, 0.2 mg warfarin free; double the dose  10 Extent of distribution of a drug from plasma into the tissues Determines – The relationship between plasma concentration and total amount of drug in the body – The amount of a drug that has to be administered in order to produce a particular plasma concentration – this is why certain drugs require a “loading dose”, which will be higher than subsequent maintenance doses Descriptive parameter – Apparent volume of distribution (Vd)  11 Apparent volume of distribution (Vd) “Theoretical volume of fluid a drug would occupy if the total amount of drug in the body was in solution at the same concentration as in the plasma” Vd is not a real, physical volume but reflects the ratio of drug in extravascular space relative to plasma space Gives us a measure of the tendency of a drug to move out not of the plasma to some other site  12 Volume of distribution (Vd) Before drug Small Vd Medium Large Vd Large Vd administration Mostly Vd Most of But not trapped in Evenly drug evenly the plasma spread outside the distribute  Calculation of volume of 13 distribution Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma Total amount of drug in body Vd = Plasma concentration Dose = [Plasma] at time zero  Calculation of volume of 14 distribution A patient is administered an intravenous analgesic at a dose of 30 mg. A few minutes after, a blood sample is taken and the concentration of analgesic in the microgram=g= blood is 0.5 mg/ml mcg milligram=mg What is the volume of distribution of the Watch out for different analgesic? units!!! Vd = D/C = 30 mg / 0.5 mg/ml = 30,000 mg / 0.5 mg/ml = 60,000 ml = 60 litres  15 Clinical usefulness of Vd Reflects size of distribution space Large Vd - need higher dose to fill (load) Small Vd - need lower dose to load Vd used to calculate loading dose (LD) Loading dose given so therapeutic concentrations are achieved quickly LD= Vd x desired plasma concentration  16 Range of volumes of distribution Mainly located in tissue, very little in plasma Similar concentration in both plasma and tissues Localised mainly in plasma, little in  17 Learning outcomes Describe the pharmacokinetic process of drug distribution Define the term ‘apparent volume of distribution (Vd)’ and be able to calculate it Explain the important role of the liver in drug metabolism Describe the main routes of drug elimination from the body Explain first- and zero-order drug elimination kinetics Define the term half-life (t1/2) and its clinical relevance  18 Drug elimination Irreversible loss of drug from the body; occurs by two processes: 1.Metabolism (usually converts lipid soluble chemical to water soluble species) – Phase 1 (oxidation, reduction, hydrolysis) – Phase 2 (conjugation) 2.Excretion – Fluids (urine, bile, sweat, tears, milk) – Solids (faeces, hair) – Gases (expired air)  19 Routes of drug excretion Major routes of elimination – Renal – Biliary/Gastrointestinal – Pulmonary Significant for other reasons – Mammary – Salivary, Skin & Hair 1. Renal excretion Three renal processes accounting for renal drug excretion: – Glomerular filtration – Active tubular secretion – Reabsorption  21 Urinary excretion low molecular weight polar substances Glomerular filtration – Molecules less than 20 kDa filtered (enter filtrate) – Protein bound drugs not filtered (plasma albumin 68 kDa) Tubular secretion – Active carrier-mediated elimination – Secretory mechanisms for both acidic and basic compounds – Can transport against electrochemical gradient and when drug is protein bound Reabsorption – Passive diffusion back across tubular epithelium – Lipid soluble drugs (high tubular permeability), excreted slowly  22 2. Biliary excretion Hepatocyte uptake of lipid-soluble drugs, metabolise and excrete into bile – But get re-absorbed along with the bulk of the water in small intestine – Not excreted efficiently Only works effectively if MW high enough (>500 Da) – Most drugs’ MW too low for efficient biliary excretion Conjugation to glucuronide / sulphate (+200 Da) often increases MW sufficiently for biliary excretion Bile is significant route of excretion for: – Glucuronide conjugates (e.g., morphine) – Limited number of ionised drugs with very  23 Entero-hepatic circulation Drug conjugates hydrolysed mainly by bacteria in lower intestine Conjugates Active drug in bile released once Free more; free drug drug reabsorbed and cycle repeated Free Conjugates Creates a reservoir of recirculating drug, prolongs http://sepia.unil.ch/pharmacology/index.php drug action ?id=57  24 3. Pulmonary excretion Excretion via the lungs and breath Significant route of excretion for some volatile molecules – e.g., anaesthetics, ethanol 4. Excretion through the skin - sweat Drugs secreted into sweat by passive diffusion – This depends on the plasma / sweat partition – (sweat pH 4.0 – 6.8)  25 5. Mammary – (milk) Concentration in milk generally reflects free concentration in blood Clinical relevance for the effect of a drug on a breast-feeding baby, e.g., – Tetracyclines: Incorporated into teeth which become weakened and ‘mottled’ – Chloramphenicol: Bone marrow toxicity and ‘grey baby’ syndrome, (baby cannot metabolise the drug effectively)  26 Learning outcomes Describe the pharmacokinetic process of drug distribution Define the term ‘apparent volume of distribution (Vd)’ and be able to calculate it Explain the important role of the liver in drug metabolism Describe the main routes of drug elimination from the body Explain first- and zero-order drug elimination kinetics Define the term half-life (t1/2) and its clinical relevance  27 Rates of reaction (elimination) Most drugs First Order Kinetics Log Rate of elimination proportional Plasma Plasma to amount of drug Conc Conc e.g., glomerular filtration Time Time Non-saturating kinetics “Elimination of a constant fraction per time unit of the drug quantity present in the organism. Elimination is proportional to [drug].” [Drug] (µg/ml) 80 – 40 – 20 – 10 – 5  28 Rates of reaction (elimination) Zero Order Kinetics Elimination occurs at a fixed maximum Plasma rate, (independent of drug Conc concentration) e.g., protein mediated reactions (metabolism of ethanol*) Time Saturation kinetics “Elimination of a constant quantity per time unit of the drug quantity present in the organism”. [Drug] (mmol/L) 40 – 36 – 32 – 28 – 24 *rate of oxidation by the enzyme alcohol dehydrogenase reaches a maximum at low ethanol concentrations because of limited availability +  29 First-order kinetics may be summarised by the plasma half-life (t1/2) Drug a Plasma t1/2 Linear = time for plasma Drug b Drug b’ (smaller dose) concentration to fall by 50% Is independent of dose Characteristic for that Logarithmic particular 1st order process and that Single-compartment particular drug model following iv drug administration at time 0  30 Plasma half-life (t1/2) Plasma t1/2 determined by: Activity of metabolising enzymes or excretion mechanisms – clearance Distribution of drug between blood into tissues – high Vd (drug mainly located in tissue) results in prolonged t1/2 Time % drug in plasma % eliminated General rules: 0 hour 100% 0% 1 t1/2 50% 50% 4 half-lives after 2 t1/2 25% 75% stopping drug 3 t1/2 12.5% ~88% plasma conc. will 4 t1/2 6.25% ~94% have fallen by 5 t1/2 ~3% ~97% ~94%; 5-6 half-lives, drug  31 Steady-state With infusion & first-order elimination, at a certain point in therapy, the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted When this equilibrium occurs (rate in = rate out), steady-state is reached Aim to maintain steady-state conc. of drug within therapeutic range  32 Plasma half-life (T1/2) also determines time to steady state e.g., Heparin t1/2 = 1 hour Time % of steady state General rule: achieved 3-5 half-lives after 0 hour 0% starting dosing 1 hour 50% (constant iv infusion, 2 hour 75% regular oral delivery of 3 hour 87% drug), plasma 4 hour 94% concentration will be at steady-state  33 Plasma half-life (T1/2) also determines time to steady state  34 Learning outcomes Describe the pharmacokinetic process of drug distribution Define the term ‘apparent volume of distribution (Vd)’ and be able to calculate it Explain the important role of the liver in drug metabolism Describe the main routes of drug elimination from the body Explain first- and zero-order drug elimination kinetics Define the term half-life (t1/2) and its clinical relevance  35 Further reading Textbook: – Pharmacology, Authors: Rang, Dale, Ritter, Moore – Section 1, General Principles, Chapter 8 – Ch 8: Drug Elimination and Pharmacokinetics Useful site: Merck Manual – http://www.merck.com/mmpe/sec20/ch3 03/ch303f.html – http://sepia.unil.ch/pharmacology/index. php?id=94