Pharmacokinetics and Dynamics

4PY019 Pharmacokinetics and Pharmacodynamics Pharmacokinetics and dynamics Student Study Guide Facilitators Required References Names: Required: Dr Waseem Kaialy This reading pack (W.Kaialy@wlv.ac.uk) Optional: Dr Ben Butler Rang and Dale's pharmacology (B.Butler2@wlv.ac.uk) Rang, H. P.; Dale, M. Maureen; Flower, R. J. (Rod J.); Henderson, G. (Graeme); Ritter, J. M. 2016; Eighth edition. Dr Zeeneh Elsaid (Z.Elsaid@wlv.ac.uk) Dr Ayman Antoun Reyad (a.antounreyad@wlv.ac.uk) Learning Outcomes This study pack will provide fundamental knowledge of drug action. This knowledge is required to underpin further study in pharmacological aspects of pharmacy, pharmaceutical science, and pharmacology. On completion of this topic, you should be able to: • Relate the impact of mode of delivery, physiological and biochemical mechanisms to the achievement of effective drug levels • Describe the structure and function of drug targets and role in pharmacodynamics • Relate the action of drugs on biochemical and physiological function to therapeutics and toxicology • Apply quantitative methods to the analysis of pharmacokinetic and pharmacodynamic data Page 1 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Contents Rang and Dale's pharmacology ...................................................................................... 1 Learning Outcomes .................................................................................................................... 1 What is pharmacology ................................................................................................................ 3 Pharmacokinetics ....................................................................................................................... 3 Definition ............................................................................................................................... 3 Pharmacokinetics includes: .................................................................................................... 3 Importance .............................................................................................................................. 4 Administration ............................................................................................................................ 4 Routes of administration ........................................................................................................ 4 Bioavailability (F) ...................................................................................................................... 7 Measuring the drug in the plasma .............................................................................................. 8 Half-life (T0.5 ) ........................................................................................................................ 8 Clearance ................................................................................................................................ 8 Removal of drug from plasma .................................................................................................... 8 Zero order kinetics ................................................................................................................. 8 Pseudo zero-order kinetics ..................................................................................................... 9 First order kinetics ................................................................................................................ 10 Pharmacokinetics - Distribution ............................................................................................... 12 Partition co-efficient ............................................................................................................. 14 Drugs and membranes .............................................................................................................. 14 Protein binding ......................................................................................................................... 15 Volume of distribution ............................................................................................................. 16 Pharmacokinetics – Metabolism and Elimination .................................................................... 17 Metabolism – Induction and Inhibition .................................................................................... 20 Pharmacokinetics – variations in metabolism .......................................................................... 20 Pharmacodynamics................................................................................................................... 20 Binding Assays ..................................................................................................................... 22 Dose –response curves ......................................................................................................... 24 Receptor Reserve.................................................................................................................. 25 Receptor Antagonists ........................................................................................................... 25 Schild Plots and pA2 ............................................................................................................ 28 Page 2 of 29 4PY019 Pharmacokinetics and Pharmacodynamics What is pharmacology Greek words Pharmaco – pertaining to drugs ology – knowledge of The study of the actions of drugs and their metabolites in the body. Classically pharmacology is divided into Pharmacokinetics (what the body does to the drug) and Pharmacodynamics (what the drug does to the body). Pharmacokinetics Definition Pharmaco – pertaining to drugs; Kinetics – movement The study of the time course of drugs and their metabolites in the body What the body does to the drug; or: administration, absorption, distribution, metabolism and excretion. Before a drug can affect any of the systems in the body; the drug has to enter the body and be distributed around that body so that eventually (hopefully) enough drug has reached the site of action where it has an effect, i.e., the right drug in the right amount in the right place at the right time. Pharmacokinetics includes: Administration – delivery of drug to the body Absorption – The movement of a 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 You should be aware of each stage and familiar with the terms as each refers to important aspects of ensuring that sufficient drug is present, long enough to give the required response. Page 3 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Importance Pharmacokinetics can help to describe: • Absorption from the site of administration • Delivery to the site of action • Elimination • Time to onset of effect • Duration of effect • Accumulation on repeat dosage • Drug interactions Pharmacokinetics can be a predictive science that allows us to work out the required dose of a given drug by noting each of these aspects. Administration Routes of administration • Oral (plus buccal and sub-lingual) • Rectal • Skin (topical) • Lungs (plus nose) • Eye, Ear • Urethra Injection: • Intramuscular • Subcutaneous • Intradermal • Intraperitoneal • Intrathecal • Intra-arterial Page 4 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Although some of these routes for administering may be more popular than others it is important to realise there is a range and that there is often a pharmacokinetic reason for the choice of route. Often, administration by injection (parenteral administration) avoids passing through the gastrointestinal tract. If a drug is given enterally – either by oral or rectal route then it is likely to be absorbed from the intestine and pass to the liver (an important site for metabolising drugs) so before the drug has been in the body for very long it is quite likely been metabolised to a different form which could be less effective. This is a very important effect, referred to as First Pass Metabolism. Once into the body, the drug gets distributed to different places. Whilst there may be some exceptions, the majority of drugs are transported around the body in the blood - The concentration of drug in plasma could be a good indication of drug present in the body. Unless given intravenously, drugs must cross membranes to reach the systemic circulation The transition of drugs through the membrane barriers is determined by: • Lipid solubility Page 5 of 29 4PY019 Pharmacokinetics and Pharmacodynamics • Area available for absorption • Possible specific carriers • Amount that reaches the target may also be compromised by “first pass” metabolism This follows the same rules as any other physiological transport mechanism. So the more lipid soluble the drug and the bigger the surface area available, the drug is likely to cross the membrane barrier more easily. The oral route is the most well used, it allows self-medication with a number of forms – liquid, tablet, capsule. Along with rectal administration, the drug enters the intestinal tract. Some drugs can be given just under the tongue so the drug enters into the blood vessels in that area. It is a well vascularised area. Transdermal patches are becoming a very popular way of delivering drugs e.g. nicotine patches. Lungs are a very quick route for drug administration. Think about the narrow divide between the inside of the alveolus and the blood capillary and the large surface area available for exchange. Nasal – a convenient point of entry easily accessed. Page 6 of 29 4PY019 Pharmacokinetics and Pharmacodynamics IM and SC – drug goes into areas near to blood vessels so the drug has to pass through smooth muscle and endothelial lining in order to enter the plasma. Intravenous injection is an ideal means of achieving a rapid response as drug arrives virtually immediately into the plasma. As well as the properties listed on the slide – it also demands very sterile conditions and should only be administered by trained personnel. Oral route Safer and more convenient than injection Buccal/sublingual Avoids presystemic metabolism Rectal Useful in patients who are vomiting/unconscious Transdermal Becoming more popular avoids presystemic metabolism Lungs Nasal Useful absorption of some peptides (DDAVP) Intramuscular Useful in emergencies Subcutaneous Useful for insulin, heparin administration Intrathecal Directly into the CNS, very high risk Intravenous Very useful in emergencies for most rapid and predictable reactions but too rapid an administration is potentially dangerous, not easily reversed The difference between IV and oral dosing is illustrated by the following graph of the elimination of the drug from plasma with time. IV starts high and follows an exponential decay curve as the drug will leave the plasma to go to its target organs and is eventually metabolised and eliminated. An oral dose may not give the same peak in plasma and the time to get to a peak is longer because the drug will have to pass through the GI tract, then via the hepatic portal vein to the liver where it will experience first-pass metabolism. 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 amount of drug absorbed in systemic circulation following oral administration F= amount of drug absorbed when the same dose is administered intravenously Page 7 of 29 4PY019 Pharmacokinetics and Pharmacodynamics This means that less drug tends to be available following an oral dose. There are a number of ways in which bioavailability is interpreted – here we are comparing IV to oral dosing and using the comparison to give the fraction of drug available. Measuring the drug in the plasma Two important measurements give us some idea of the way how the body is dealing with the drug. Half-life (T0.5 ) The time it takes for the plasma drug concentration to fall to half its original value. Half-life is important as it gives information on the length of time that a drug will remain in the body. Clearance clearance = rate of elimination plasma drug concentration Removal of drug from plasma Gives information on the behaviour of the drug in the system Zero order kinetics • Rate of elimination is constant and independent of drug concentration. Page 8 of 29 4PY019 Pharmacokinetics and Pharmacodynamics • T0.5 depends on the amount of drug given and is longer when more drug is given • Note though that few drugs behave in this way. For zero order, the plot of plasma concentration Cp vs time is a straight line and half-life is directly related to the amount of drug given. Pseudo zero-order kinetics • At high concentration the kinetics are zero order whilst at low concentration first order. • Ethanol is removed in this way • Depends on the pathways for drug metabolism This is an interesting example of elimination by drugs that seem to show a mix of zero and first order kinetics. This is concentration dependent. Page 9 of 29 4PY019 Pharmacokinetics and Pharmacodynamics As you can see, the line is in two stages – the first part representing zero order (straight line) but the second part where first order kinetics is demonstrated (exponential decay curve). First order kinetics • Most drugs are eliminated with first order kinetics. • T0.5 is constant • Rate of removal depends on how much drug is present A constant fraction is removed in unit time • The normal plot is usually transformed by plotting plasma concentration as logarithm of plasma concentration against time (log Cp vs t) • Possible to calculate T0.5, original concentration of drug in plasma, the volume of distribution of the drug and clearance. However it is inconvenient to try to perform calculations from these sorts of plots so we transform the line by plotting time against the logarithm of plasma concentration or by plotting on semilogarithmic graph paper. Page 10 of 29 4PY019 Pharmacokinetics and Pharmacodynamics This is the appearance of a semi-logarithmic plot which is a way of presenting the data. The horizontal axis is linear whilst the vertical axis is logarithmic. It gives a straight line so that we are able to make various calculations and predictions about the way the drug is being handled by the body. Individuals don’t just take one drug just once. Often we take a drug several times a day. As the amount of drug in plasma may well influence its action we prefer to have a steady state concentration where dose in is balanced by elimination out. As you can see from this plot although there is a little bit of movement up and down of the line by timing the doses we are able to achieve a reasonable sort of steady state. Page 11 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Pharmacokinetics - Distribution • Distribution – the transfer of drugs in and out of the various tissues of the body • This relates to the therapeutic objective of maintaining an adequate concentration of drug at the site of action • As it is difficult to measure the amount at the site of action, we measure the amount in blood. The amount of drug present is crucial It is important to achieve the right amount of drug into the right place. The distribution of the drug is a vital part of ensuring this as if too little drug is present then no effect is achieved whereas too much drug, adverse reactions and possible toxicity occur. The amount of drug that is effective falls into the therapeutic window. Drugs usually reversibly distribute into various tissues of the body, this depends upon: 1. Perfusion rate of the tissue (i.e. blood flow through the tissue) 2. Physicochemical ability of the drug to cross membranes 3. Nature of the membranes 4. The extent to which the drug is bound (note only free or unbound drug is available to diffuse across membranes) It is important to emphasise that distribution is dynamic. Drugs are always “on the move” and will enter and leave compartments. Apart from the basic physicochemical influence distribution is very much affected by blood flow, obviously the greater the flow rate, the more drug will pass through Page 12 of 29 4PY019 Pharmacokinetics and Pharmacodynamics the tissue – tissues that are well vascularised (= plenty of blood vessels) such as the liver…. the kidney…. will receive more of a drug than other parts of the body. It is useful to have some sort of overview of the main pattern of distribution. This is a useful “skeleton”. Each main compartment here can obviously be sub-divided further e.g. blood into cells and plasma. Try to remember that there is reversible movement between blood, tissue and cell sites and sites where metabolism takes place. Remember that the impact of distribution is either achieving steady state (for regular dosing) or a peak plasma concentration followed by removal from the body for drugs given as a single dose or after a course of medication. Reversible transfer between blood and tissue This graph is based on the assumption that a drug is supplied until a steady state is achieved and essentially the amount of drug entering the blood (or plasma) compartment is balanced by drug leaving that compartment. We refer to this as the distribution equilibrium or, perhaps in more practical terms, a steady state. Page 13 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Partition co-efficient • Uptake of a drug is defined by its partition co-efficient (Kp) concentration in tissue Kp = drug drug concentration in blood • The bigger the value of Kp the longer it takes to achieve distribution equilibrium The extent to which a drug enters a compartment (of any sort) depends on its partition co-efficient (Kp) according to this equation. Drugs and membranes • Membranes separating tissues from blood are lipid in nature 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 is 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 An important physiological concept, because drugs are weak organic acids or bases, the degree of ionisation of the molecule will vary according to the environment of the drug. This will influence the lipid solubility of the drug and hence its ability to cross biological membranes. D = unionised drug which readily crosses the membrane Page 14 of 29 4PY019 Pharmacokinetics and Pharmacodynamics If the drug is (more) unionised then as it is lipid-soluble it crosses the membrane. This is useful for moving around the body and to different sites and compartments. However, one way in which we eliminate drugs is in the urine – for which purpose drugs need to be able to dissolve in water – so if a drug becomes (more) ionised – it will be less lipid soluble and more water soluble. and so pH (the degree of acidity or alkalinity) is important • 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 and therefore not readily transported • Acidic drugs in a high pH (basic or alkaline environment) are far less lipid soluble and therefore not readily transported It is important that you know the impact of what happens to basic drugs in acidic and basic environments and basic drugs in acidic and basic environments. Protein binding • High molecular weight proteins, such as plasma proteins, cannot cross membranes so any drug bound to them will not be available for distribution. • 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 • Binding can be reversible or irreversible This is an important point because it influences how much drug can get to its site of action. • Drug-protein binding is of low specificity and does NOT result in any pharmacological effect but serves to lower the concentration of free drug in solution. This lowers the concentration of Page 15 of 29 4PY019 Pharmacokinetics and Pharmacodynamics drug available to act at the receptor Distribution – result of two processes • R1 delivery of drug to tissue depends on perfusion rate • R2 passage of drug across membrane depends on physicochemical properties and nature of membrane • Overall rate of distribution determined by R1 and R2 Once you have dealt with pH effects and binding, the movement of free drug still depends on its ability to cross membranes and to be transported in the blood which reinforces how well the tissue is perfused with blood. The better the vasculature, i.e. the more blood vessels flowing through, the more readily drugs will get to the tissue. Volume of distribution Very invasive to measure levels in most tissue so use accessible sources – blood and urine. In pharmacokinetics we relate the amount in the body to the amount in the blood. volume of distribution a very important pharmacokinetic parameter. Volume of Distribution (Vd) = amount of drug in body concentration of drug in blood As it is less traumatic to sample urine and blood, these are used to get a measure of drug levels in the body - an indirect measure useful in giving some information about distribution. Volumes that drugs distribute in Page 16 of 29 4PY019 • Pharmacokinetics and Pharmacodynamics Vd is not a real volume but a proportionality constant that relates drug concentration to an amount. This depends on body compartments. • Compartment • Vd (l) • Drug • ECF (exc. plasma) 13 l • 4.9 • Theophylline • Plasma 3 l • 7 • Atenolol • Total 42 l • 700 • nortryptyline Volume of distribution is “apparent” and so no always “real”. As you can see from the Table nortryptyline as a huge apparent volume of distribution. 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. So volume of distribution tells us how the drug has been distributed in terms of large compartments i.e. confined to plasma or body water or accumulated in fat. Pharmacokinetics – Metabolism and Elimination • Once a drug has been absorbed, distributed, encountered its site of action it has to be removed from the body. • Although not the only means of removal, the majority of drugs are excreted via the renal system. • Most drugs will possess a degree of lipophilic properties, otherwise absorption and distribution would not have taken place. • In order to enter the renal system drug would have to become less lipid soluble and more water Page 17 of 29 4PY019 Pharmacokinetics and Pharmacodynamics soluble. • Achieved by a process of metabolism that takes place (generally) in the liver. The key issue is that eventually, once a drug has achieved its effect (and actually even before) the body has mechanisms that will modify the drug and eliminate it from the body. Although a number of routes are possible, the main route of elimination is via the renal system so the drug needs to become sufficiently water soluble to pass out of the body in the urine. • Drug metabolism can be defined as an enzyme mediated conversion of a lipophilic compound into a more water soluble one. • Involves (usually) 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 • Phase I reactions include Oxidation, Reduction, Hydrolysis • Reactions which uncover functional groups The important aspect of Phase I is that it starts the process of making the drug more water soluble. One example of a Phase I reaction. Oxidative deamination of amphetamine • Not every reaction necessarily decreases drug activity. Sometimes metabolism results in a more active form than the originally administered compound. • This is termed a prodrug, defined as any compound that is metabolised in the body to yield a pharmacologically active compound but is itself devoid of such activity, e.g: enalapril • It is also possible that metabolism may produce a toxic metabolite Although most of the time we tend to think of metabolism as a way of changing drugs and reducing Page 18 of 29 4PY019 Pharmacokinetics and Pharmacodynamics their pharmacological activity, it is possible for the opposite to occur and for activity to be increased. Enalapril –an ACE inhibitor used to treat high blood pressure is an example – the more active form is the metabolite enalaprit. • Phase II reactions are conjugations whereby the drug is coupled to a second, fairly large water soluble molecule (e.g. a sugar or an amino acid) • Reactions also include addition by: Glucuronidation, Methylation, Sulphation, Acetylation, Glutathione • Phase II is largely responsible for the increase in water solubility Phase II reactions are termed conjugations where a large water soluble molecule is simply joined on to the Phase I metabolite to make it even more water soluble. An example of a Phase II conjugation Sulphate conjugation of paracetamol • To achieve these reactions, there are enzyme systems in place, the key system is the cytochrome P450 family located in the endoplasmic reticulum of the liver. • Cytochrome P450 is a large “superfamily” of related but distinct enzymes. • There is a great deal of variation with: Species difference, strain difference, disease, gender, Environmental factors, diet, genetic determination of enzyme activity and age The system operates by particular enzymes that metabolise the drug molecules. The enzymes are part of the cytochrome P450 family which are absolutely key to the process of drug metabolism. Page 19 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Located in the smooth endoplasmic reticulum of the liver. Metabolism – Induction and Inhibition • Induction – some factors will induce drug metabolising enzymes, this will increase the amount of enzyme present which means that the drug is metabolised more quickly and its half life will be less (e.g. barbiturates). • Inhibition - some factors will inhibit drug metabolism, less active enzyme is available so the drug is metabolised more slowly and the half-life of the drug will increase. In simple terms, if more enzyme is present the drug is broken down more quickly. If less enzyme is present the drug will be broken down much more slowly. Pharmacokinetics – variations in metabolism • Genetic – “fast” and “slow” acetylators and oxidisers. • Extensive metabolisers of mephenytoin - poor metabolisers (3.5 % of Caucasians, 23% Japanese population). • Effect in poor metabolisers is sedation and ataxia after doses of the drug that are well tolerated by extensive metabolisers. As individuals or even as different populations we don’t all metabolise drugs at the same rate. Some people or populations can metabolise quite quickly whereas others don’t have the same capacity. The inability to break down a particular drug quickly enough can have quite serious consequences. One way around the problem might be to give smaller doses. Pharmacodynamics Drug-Receptor Interaction There are three main words that can be used to describe the properties of a drug: 1. Affinity: how well a drug binds to a receptor? Electrostatic forces initially attract a drug to a Page 20 of 29 4PY019 Pharmacokinetics and Pharmacodynamics receptor. If the shape of the drug corresponds to the receptor’s binding site, it will be held there temporarily by weak bonds. The number of bonds and how well the drug fits the binding site determines the affinity of the drug for this receptor. The greater the number of bonds and the more perfect the fit, the stronger the ‘affinity’. Those drugs that only form weak attractions have a low affinity. 2. Efficacy the ‘strength’ of an agonist at eliciting a response. So, three different molecules having very similar chemical structures can behave very differently: • one might be a very potent agonist, meaning that only a small amount elicits an effect (so possesses affinity and efficacy). • one might be a weak agonist, so requiring large amounts to elicit an effect (but still possesses affinity and efficacy). • the other an antagonist and so blocks the receptor (possesses affinity but NO efficacy). 3. Specificity how selective a ligand is. A ligand that exhibits a high degree of specificity will only bind to certain receptors. Specificity is somewhat dependent on the doses used. Salbutamol is a b2adrenoceptor agonist used for treating asthma. At low doses, it binds to airway b2-adrenoceptors. At higher doses, it will begin to also activate cardiac b1- adrenoceptors. However, salbutamol is never going to bind to muscarinic receptors, so we can think of it as having specificity for badrenoceptors. Being able to accurately describe how a ligand binds to a receptor enables the pharmaceutical industry and the medical profession to compare the relative merits of different drugs. In order to increase the accuracy of describing drugs, a whole area of pharmacology has developed that uses experiments such as bioassays and binding assays to quantitatively explain the characteristics of drugs. Such pharmacological tests are very common and the results of which can often be seen reported in pharmacological research journals. Page 21 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Binding Assays Binding of drugs to receptors can be measured using 3H, 14C or 125I labelled ligands that bind with high affinity and specificity. Samples of tissue are incubated with increasing concentrations of radiolabelled ligand, allowing equilibrium to be reached. The bound radioligand is then separated from the unbound (filtration, centrifugation etc.), before being dissolved in scintillation fluid and measured for radioactive content. In such experiments ‘non-specific’ binding will also occur, whereby the drug is taken up by non-saturable sites (proteins, lipids etc.). This can be measured by repeating the test in the presence of a saturating concentration of a non-radioactive ligand. Inhibiting specific binding of the radioligand, allow non-specific binding to be estimated. Subtracting the non-specific binding component from the total amount binding gives the specific binding: Further analysis of binding data was developed by G. Scatchard (1949) and involves plotting a graph of [bound drug]/[free drug] against [bound drug]. Binding Assays Page 22 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Scatchard Analysis So: • by plotting [bound drug] on the x-axis, • and plotting [bound drug]/[free drug] on the y-axis, it is possible to establish: • the total number of receptors (Bmax) (x-axis intercept), • and KD (dissociation constant) from the slope of the graph, \ estimating the affinity of the ligand for the receptor. Where AR = [occupied receptors], Ro = [total receptor concentration], A = ligand concentration Page 23 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Dose –response curves log [Dose]-Response Curves Plotting drug responses this way gives a sigmoidal curve useful as ~70% is a straight line and it is easier to see the maximum. The estimated maximum response of a drug Emax. Dividing Emax by half and then using the doseresponse curve allows us to establish the effective concentration required to produce 50% of the response (EC50). EC50 values are useful as they allow us to compare potencies of different drugs. Log-dose-response curves for different agonists acting on the same tissue. 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. Page 24 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Receptor Reserve Receptor Antagonists Antagonists are molecules that reduce the actions of agonists, the agonists being endogenous or drug Page 25 of 29 4PY019 Pharmacokinetics and Pharmacodynamics molecules. These form a ligand/receptor complex, but they do not evoke an active cellular response. Since antagonists block receptors they are commonly referred to as blockers. Many clinically useful drugs are antagonists, e.g. b-blockers, histamine blockers (antihistamines). Therefore antagonist can be thought of as producing a passive response. Antagonism can be produced by several different mechanisms: • competitive • irreversible competitive • non-competitive • pharmacokinetic • chemical • physiological (functional) Competitive Antagonism Competitive antagonists bind selectively to receptors, but do not elicit activation; instead they ‘block’ receptors so interfering with agonist-receptor interactions. Therefore competitive antagonists have affinity for receptors, but NOT efficacy. There is usually similarity in the chemical structures of agonists and their competitive antagonists. Competitive antagonists bind reversibly with receptors. When a competitive antagonist is present in a biological system, it will ‘compete’ with agonists for the occupancy of the receptor So, in the presence of a competitive antagonist, receptor occupancy by agonist molecules will be reduced. Since the agonist and antagonist molecules are in competition with each other, increasing the concentration of the agonist will increase the probability of agonist molecules occupying Page 26 of 29 4PY019 Pharmacokinetics and Pharmacodynamics receptors and therefore evoking a response. Therefore competitive antagonism can be referred to as ‘surmountable’. If the concentration of antagonist molecules is increased, then higher and higher concentrations of agonist are going to be required in order 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. There would not be no change in the slope of the curves, nor the maximum. Page 27 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Schild Plots and pA2 Schild Plots and pA2 Schild plots (Schild HO. pA2, a new scale for the measurement of drug antagonism. Brit. J. Pharmacol. 1947, 2:189-206) were developed to identify reversible, competitive antagonism and to obtain an estimate of the affinity for antagonists for their receptors. pA2 value for an antagonist is -log [antagonist] required to produce a two fold shift in the agonist dose-response curve. pA2 is an index of antagonist potency. The larger pA2, the more potent the antagonist. By performing an experiment, such as organ bath bioassay, it is possible to collect the necessary data to construct a Schild plot. A dose-response curve is constructed for the selected agonist, e.g. acetylcholine. Then further curves are constructed for the agonist in the presence of increasing concentrations of the antagonist, e.g. atropine. EC50 values are then obtained from all the dose-response curves. Dose ratios to be calculated for each antagonist concentration. From this example, four different EC50 values obtained to calculate dose ratios. Page 28 of 29 4PY019 Pharmacokinetics and Pharmacodynamics Dose Ratio = EC50 [antagonist] EC50 [no antagonist] Then, pA2 plots are drawn from calculating log(dose ratio-1) v. log[antagonist] pA2 is taken from the -log of the line’s intercept with the x-axis. pA2 is an empirical measure and does not have any units. Page 29 of 29