Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and Pharmacodynamics Dr Ayman Antoun What is a Drug? “A chemical substance of known structure, other than a nutrient/essential dietary ingredient, which when administered to a living organism, produces a biological effect” “A chemical applied to a physiological system ------ affects its function in a specific way” Medicine Chemical preparation usually contains one or more drugs, administered with the intention of producing a therapeutic effect Pharmacology Pharmaco – pertaining to drugs ology – knowledge The study of the actions of drugs and their metabolites in the body Classically - divided into Pharmacokinetics and Pharmacodynamics Pharmacology • “The study of how drugs affect the function of living systems and how their effect can be applied to therapeutics” • What the drug does to the body – Pharmacodynamics • What the body does to the drug – Pharmacokinetics • Involves aspects of physiology and chemistry Pharmacology Pharmacokinetics and Pharmacodynamics Drug Extracellular R Intracellular Change in cell function moulder.temple.edu Pharmacokinetics Administration – delivery of drug to the body Absorption – movement of drug across membranes Distribution – description of the compartments of the body entered by the drug Metabolism – chemical alteration of the drug Elimination – transfer of the drug from inside the body to the outside Administration • Oral (including buccal and sub-lingual) • Rectal • Skin (topical) • Lungs (plus nose) • Eye, Ear • Urethra •Intramuscular •Subcutaneous •Intradermal •Intraperitoneal •Intrathecal •Intra-arterial Administration • Parenteral – Rapid – Poorly absorbed drugs/ Irritants – localised • Oral: – Convenient – First pass metabolism in liver via portal circulation Administration • Unless given intravenously drugs must cross membranes to reach systemic circulation Determined by:• Lipid solubility • Area available for absorption • Possible specific carriers • Amount that reaches the target may also be compromised by “first pass” metabolism Plasma Concentration ug cm-1 Oral vs Intravenous dosing I.V. oral Time (hours) Bioavailability (F) • Can be used to define how well a drug is absorbed and reaches its site of action • Usually determined by comparison of oral and IV absorption F= amount of drug absorbed in systemic circulatio n following oral administra tion amount of drug absorbed when the same dose is administer ed intravenou sly Measuring the drug in the plasma • Half-life (T0.5 ) – The time for the plasma drug concentration to fall to half its original value • Clearance rate of eliminatio n clearance = plasma drug concentration Removal of drug from plasma First order kinetics • Most drugs are eliminated with first order kinetics. • T0.5 is constant • A constant fraction is removed in unit time Plasma Concentration ug cm-1 Oral vs Intravenous dosing I.V. oral Time (hours) Removal of drug from plasma • The normal plot is usually transformed by plotting plasma concentration as the logarithm of plasma concentration against time (log Cp vs t) • From the graph it is possible to calculate T0.5, original concentration of drug in plasma, Vd and clearance. Co Plasma Concentration mg cm-3 Zero Order Kinetics Time Co = plasma concentration at time 0 Co Plasma Concentration mg cm-3 (ln) First Order Kinetics Time Co = plasma concentration at time 0 Absorption • Membrane permeability – Direct diffusion through lipids • Depend on lipid/water partition • Ionisation-weak acid/base where non ionised form is lipophilic-easily transferred – Carrier mediated Pharmacokinetics - Distribution • Distribution – the transfer of drugs in and out of the various tissues of the body • Maintaining an adequate concentration of drug at the site of action • Difficult to measure at the site of action, the practice is to measure the amount in blood. No effect Therapeutic window Toxic Not enough drug Little or no effect The right amount to be effective The amount of drug present is crucial Too much drug Too great an effect Pharmacokinetics Distribution • 1. 2. 3. 4. Drugs usually reversibly distribute into various tissues of the body, this depends upon Perfusion rate of the tissue (i.e. blood flow) Physicochemical ability of the drug to cross membranes Nature of the membranes Extent to which the drug is bound (note only free or unbound drug is available to diffuse across membranes) Reversible transfer between blood and tissue Drug Eventually achieves a steady state Or DISTRIBUTION EQUILIBRIUM Time Drugs and membranes • Membranes separating tissues from blood are lipid so lipid soluble molecules cross these membranes most readily. Ionised or polar molecules do not cross so readily Membranes allow small polar molecules to pass but muscle will allow larger polar molecules (gentamicin poorly absorbed orally but very well intramuscularly) • • – – e.g. thiopentone very lipid soluble easily penetrates the blood brain barrier as well as any other membrane e.g. benzylpenicillin is very polar, so wouldn’t cross the barrier so readily pH • Basic drugs in a high pH (alkaline or basic environment) are lipid soluble and therefore readily transported • Acidic drugs in a low pH (acidic environment) are lipid soluble and therefore readily transported • Basic drugs in a low pH (acidic environment) are far less lipid soluble ---- not readily transported • Acidic drugs in a high pH (basic or alkaline environment) are far less lipid soluble --- not readily transported Protein binding • • • • High molecular weight proteins, such as plasma proteins, cannot cross membranes so any drug bound not be available for distribution. Binding can be reversible or irreversible Only unbound drug is free to distribute into tissues Changes in plasma protein binding may affect rate of distribution for highly bound drugs but only when passage across membranes is the slowest step in the overall process of distribution Protein binding • • Drug-protein binding is of low specificity and does NOT result in any pharmacological effect but serves simply to lower the concentration of free drug in solution - lowers the concentration of drug available to act at the receptor Large amounts of drug may be present in the body bound to proteins such as albumin Volume of distribution Very invasive to measure levels in most tissue – blood and urine In pharmacokinetics - the amount in the blood Volume of distribution a very important pharmacokinetic parameter. Volume of Distributi on (Vd) = amount of drug in body concentration of drug in blood Significance of volume of distribution • Lipid insoluble drugs are mainly confined to plasma and interstitial fluids – – Lipid soluble drugs reach all compartments and may accumulate in fat For drugs that accumulate outside the plasma compartment by being in fat or bound to tissues Vd may exceed body volume Metabolism and Elimination • Once a drug has been absorbed, distributed, encountered its site of action it has to be removed from the body • The majority of drugs pass out of the body via the renal system. • Most drugs will possess a degree of lipophilic properties • In order to enter the renal system drug would have to become less lipid soluble - more water soluble. – achieved by metabolism generally in the liver. Metabolism and Elimination • Drug metabolism can be defined as an enzyme mediated conversion of a lipophilic compound into a more water soluble one. • Involves two phases Phase I and Phase II • Phase I metabolism tends to make drugs more water soluble but its main purpose is to prepare the drug molecule for Phase II • include – Oxidation – Reduction – Hydrolysis • Reactions which uncover functional groups Pharmacokinetics Metabolism and Elimination • Phase II reactions are conjugations/addition by: – Glucuronidation – Methylation – Sulphation – Acetylation – Glutathione • Phase II is largely responsible for the increase in water solubility Metabolism and Elimination • cytochrome P450 family located in the endoplasmic reticulum of the liver. – a large “superfamily” of related but distinct enzymes. • There is a great deal of variation with: – – – – – – – Species difference Disease Gender Environmental factors Diet Genetic determination of enzyme activity Age Metabolism Induction and Inhibition • Induction – some factors will induce drug metabolising enzymes • Inhibition - some factors will inhibit drug metabolism -- so the drug is metabolised more slowly and the half-life of the drug will increase Metabolism Induction and Inhibition Isoenzymes of the hepatic cytochrome P450 system interact with a wide range of drugs. Induction of cytochrome P450 isoenzymes by one drug can increase the rate of metabolism of another --- lower plasma concentrations and a reduced effect. On withdrawal of the inducing drug, plasma concentrations could increase leading to toxicity. When one drug inhibits cytochrome P450 --- decrease the metabolism of another ---- higher plasma concentrations and increased effect with a risk of toxicity. Metabolism Induction and Inhibition Knowledge of which isoenzymes involved --- predict whether pharmacokinetic interactions will occur. e.g: Carbamazepine is a potent inducer of CYP3A4 ketoconazole is potent inhibitor of CYP3A4 midazolam is a substrate of CYP3A4. ▪ Carbamazepine and other drugs that are potent inducers of CYP3A4, reduce midazolam concentrations. ▪ Ketoconazole and other drugs that are potent inhibitors of CYP3A4 increase midazolam concentrations Phase II reactions enzymes, UDP-glucuronyltransferases might be induced by rifampicin --- decreased metabolism of mycophenolate to active form, mycophenolic acid. Elimination Exit routes • • • • • Renal Faecal Respiratory Skin (in sweat) Mother’s milk Excretion • Kidney – Filtration in glomerulus • Small molecules filtered; bound molecules not filtered – Reabsorption from tubules Bioassay Dose-Response Curves It is extremely useful to know how strong the biological response is to a drug. Could be assessed by observing the contraction or relaxation of smooth muscle in an organ bath. tissue response The tissue responses to varying concentrations of a drug can then be recorded/plotted -a dose-response curve. 0 [agonist] log [Dose]-Response Curves Plotting drug responses - a sigmoidal curve that is useful as ~70% is a straight line and it is easier to determine the maximum. response (% max) 100 The estimated maximum response of a drug is Emax. 50 EC50 0 -7 -6 -5 Dividing Emax by half and then using the dose-response curve allows us to establish the effective concentration required to produce 50% of the response (EC50). log concentration (mol/L) EC50 values are useful to compare potencies of different drugs. Log-dose-response curves for different agonists acting on the same tissue. 100 full agonist ‘a’ response (% max) full agonist ‘b’ full agonist ‘c’ partial agonist 50 0 -8 EC50 values -6 -4 -7 log concentration (mol/L) -3 As drugs become less potent, their dose response curves shift to the right and their EC50 values increase. Partial agonists cannot elicit the same maximum response as full agonists, even at high concentrations. This is a further illustration of pharmacological efficacy. Competitive Antagonism antagonist molecules agonist molecules Extracellular membrane receptor Intracellular receptor firing So, in the presence of a competitive antagonist, receptor occupancy by agonist molecules will be reduced. Since the agonist and antagonist molecules are competing, increasing the concentration of the agonist will increase the probability of agonist molecules occupying receptors and therefore evoking a response. Therefore competitive antagonism can be referred to as ‘surmountable’. ‘Surmountable’ Antagonism antagonist molecule high agonist concentration Extracellular membrane Under these conditions the chances of antagonist molecules occupying receptors are reduced. receptor Intracellular receptor firing If the concentration of antagonist molecules is increased, then higher and higher concentrations of agonist are going to be required to evoke a response. Therefore, a graph of agonist-dose response curves in the presence of different antagonist concentrations, would show a parallel shift to the right with increasing antagonist concentration. No change in the slope of the curves or the maximum. Agonist-Dose Response Curves in the Presence of Antagonist 100 response (% max) agonist alone agonist and low concentration of antagonist 50 0 agonist and high concentration of antagonist -8 -6 -5 -7 log agonist concentration -4 Parallel shift to the right with increasing antagonist concentration Terminology • Plasma Half-life (t½): Time taken for the plasma concentration of a drug to fall by half. • Bioavailability: fraction of a drug that has reached the circulation. • Therapeutic Index: – A measure of the margin of safety for a drug – Ratio of LD50(dose that is lethal in 50% of population) and ED50 (dose that is effective in 50%). The higher the therapeutic Index, the safer the drug. – Drugs with low therapeutic index include Lithium, Theophylline, Warfarin. Pharmacokinetic formulas •The concentration at T0 (µgcm-3) Plasma conc. at time zero (C0) •The drug’s plasma elimination half-life (h) t0.5, time taken for the concentration to drop by half •The elimination rate constant (h-1) •The volume of distribution (L) •The plasma clearance (Lh-1) kel = 0.693 t0.5 Clp = kel x Vd DOSE = C0 x Vd Clp = F x DOSE AUCoral F = AUC oral AUC i.v.