The Pharmacist: Introduction to Pharmacology

What is a drug? A chemical substance/agent that interacts with a biological system to produce a physiological effect, to provoke a measurable response. - Psychotropic action - alter your behaviour and perception of the world around you. What are the different physiological ef- - Antidepressant action - lifts a low mood. fects of drugs? - Lowers blood pressure - Addictive properties Chemicals in coffee and chocolate can also have a physiological effect. Administer the appropriate drug dosage for a particular concentration at the receptor (its molecular action). Once a drug has achieved its concenWhat is the purpose of pharmacology? tration at the receptor, it binds and then (different effects and responses) produces a cellular response which then produces a clinical response (usually alleviation of a disease process). These different responses are known as an integrated systems response. The study of what the drug does to the body. The actions of drugs in terms of molecWhat is pharmacodynamics? (in terms ular responses, cellular responses, sysof responses) tems and the entire organism (clinical response). The magnitude of response to the drugs is related to the dose/concentration. The movement of drugs. You look at the rates of absorption, distriWhat is pharmacokinetics? What rates bution, metabolism, and excretion. can you look at? You can predict plasma levels in relation to the dose administered. What do drugs act on? 1 / 15 Target proteins, affecting their function, these can include enzymes, carriers, and ion channels. A target molecule (often a protein macromolecule) that a drug molecule can combine with to produce a specific effect. - A drug (ligand when it binds) is specific What is a receptor and where are they to a particular receptor. It is a unique present? recognition site, and the binding of a ligand sets off a chain of events (transduces) that produces a particular effect. Receptors are present on the cell surface, cytoplasm, or in the nucleus. - Recognition of specific ligand molecule What are the 2 general functions of re- (ligand binding domain) ceptors? - Transduction of signal into response (effector domain) What are the different types of receptors? - Ion channels - G-protein coupled receptors (activate G-proteins which generate a second messenger to activate cell signalling) - Enzyme-linked receptor which alters key signalling molecules to activate cell signalling. - Intracellular receptors on the nucleus can activate transcription and translation. - If an action occurs, then the drug is called an agonist. - If it binds and does nothing, the drug is called an antagonist. It can sometimes What happens when a drug binds to a bind irreversibly. - There may be competition for the recepreceptor? (Different type of drugs) tor if both are present, but the antagonist can also bind allosterically and change the receptor, stopping the agonist from binding (non-competitive inhibition). 2 / 15 What non-receptor mechanisms are there? - Drug action can result from physical and chemical properties (antacids or osmotic fluid expanders). - Membrane perturbation (anaesthetics) - Displacement of endogenous systems (by dilution for example). What factors govern drug action (agonists)? - Affinity - Intrinsic activity What is affinity? A measure of the tightness with which a drug binds to receptors (strength of binding). There is an inverse relationship between the binding constant (KD) and affinity. What is the relationship of the bindThe smaller the KD, the higher the affining/dissociation constant (KD) with affinity. ity? The units of the KD is Molar (concentration). How is affinity measured? Using the law of mass action, which suggests that the rate of a chemical reaction is proportional to the product of the concentration of the reactants. A (agonist drug) + R (free receptor) <--> AR A Hill-Langmuir equation can then be created. PAR = [A] / KD+[A] PAR is the occupancy (the percentage of receptors that have drugs bound to them). When PAR is 50%, [A] = KD, as 50% is where the most change occurs What is PAR and how can you calculate in the graph (PAR against concentration graph). the KD from this? What is KD? The KD (dissociation constant) tells us the agonist concentration that occupies 50% of receptors. The lower the value, the higher the affinity. 3 / 15 If PAR is plotted against log [A], rather What graph is plotted more often than than just [A], you get a Hill-Langmuir sigPAR against [A] (concentration of drug)? moid curve which is plotted more often. What is intrinsic activity? A measure of the ability of an agonist (that is bound to the receptor) to generate an activating stimulus and produce a change in cellular activity (the effect you can measure). The intrinsic activity is different in different tissues (even if same receptor). All receptor binding events do not result in an equal magnitude of effector response. AJ Clark's Occupancy Theory assumes there is a direct proportionality between What does AJ's occupancy theory sug- receptor occupancy percentage and tisgest? sue response. Percentage receptors occupied (PAR) = response/maximum response You can substitute the PAR equation into the Hill-Langmuir equation. You can then plot response against log [A] (dose response curve), which produces a similar sigmoid curve. 50% response tells you the potency of the drug How do you plot a response against log (how much of a particular dose will elicit [A] graph and what does it tell you? a response). This will also give an effective dose (known as ED50). The maximal effect is when you reach saturation. What can you compare using the response vs log conc graph? Potencies of different drugs (the more potent drug requires less to produce the same response). 4 / 15 - Spare receptors (we can get a maximum response without occupying all the receptors). - Threshold (we have to occupy a lot of What are the exceptions to the direct receptors before we see any response) proportion between drug conc/receptor Receptor numbers and the threshold can occupancy and response? vary in different cells. You can get very different responses using the same concentration of drug in different tissues, as agonist functional potency varies. - Affinity - Intrinsic activity - Potency - Dose response What four factors can determine the strength/concentration of the drug? - Competitive - binds to the same receptor site as the agonist, this can be irreversibly. - Non-competitive - binds to the alWhat are the different types of antago- losteric site (different site on the recepnists? tor), changing the binding site for the agonist. - Functional antagonist - binds to a different receptor/tissue, to stop the response via a separate mechanism. We cannot use a response against log dose [A] to calculate potency because antagonists do not produce a response. Antagonist potency can be measured by using a dose response curve of an agHow can you calculate the potency of an onist with different concentrations of anantagonist? What is the dose ratio? tagonist. Dose ratio is the ratio by which the agonist concentration has to be increased (at the 50% response rate) to restore a certain level of response. 5 / 15 Measured using a Schild plot, achieved by plotting antagonist concentration (x axis) versus log of the dose ratio (y axis). This gives a value known as pA2 which How do you measure the affinity of the tells us how strongly the antagonist binds to the receptors (affinity) and thus how antagonist? effective the drug might be. Measure of antagonist potency (concentration) by 50% inhibition of agonist response. What is the pA2? It is also the concentration of antagonist that requires a 2-fold increase in the concentration of agonist for the same initial response. What is specificity? A drug's selectivity for one receptor What is the definition of affinity? The ability of a ligand to bind to a receptor (and how tightly it binds). What is efficacy of a drug? The ability of a drug - once bound - to initiate events that lead to a response. What is potency? the relative amount of drug needed to produce an effect. - Full agonist - Some agonists can act as partial agonists at some receptors, because there What are the different types of agonists? is different intrinsic activity of receptors in different tissues. Not all receptor binding events will result in an equal magnitude of effector response. 6 / 15 - An inverse agonist reduces the effect below baseline, this is because some receptors have low levels of activity in the absence of ligands. - Drug A can affect the action of Drug B (if it acts on the same physiological system) to alter the action of B without affecting its concentration. This can be predictable, What are the two types of drug interac- as you can measure pharmacodynamtions? ics. - Drug A can affect the action of Drug B if it alters the concentration of B (this is less predictable, as it is difficult to look at pharmacokinetics). - Beta blockers (adrenergic antagonists) reduce the action of salbutamol (which is a beta 2 agonist). - Many diuretics lower plasma potassium ions, which increases digoxin action due What are some examples of pharmaco- to reduced competition at potassium site dynamic interactions? on Na/K pump. Both diuretics and digoxin are used in heart failure. - H1 histamine antagonists can react with alcohol which enhances drowsiness. - Mono-amine oxidase inhibitors and camembert What is the interaction between mono-amine oxidase inhibitors and camembert? MAO normally breaks down neurotransmitter amines (control mood and blood pressure for example). MAO inhibitors increase the amount of noradrenaline in nerve terminals (exerts antidepressant action). However, the agonist tyramine (also acting on noradrenaline receptors) is found in fermented cheese and beers. Tyramine is normally broken down by MAO in gut wall, but MAO inhibitors mean tyramine is not broken down and it is taken up systemically. This 7 / 15 means it can get into nerve terminals, cause noradrenaline to leak out. This can cause acute hypertension and severe headache, which is life threatening. Pharmacokinetics is broken down into 4 phases: absorption, distribution, metabolism and excretion. Pharmacokinetics What is involved in pharmacokinetics? looks at the rates of these 4 processes. And why is it so important in drug devel- This is the major reason why new chemopment? ical entities fail in drug development, because the drug does not reach its site of action in sufficient concentration to have a beneficial effect. oral, intravenous, intramuscular, subcuWhat are the different routes of administaneous, buccal, rectal, transdermal, intration? halation. What is the first pass effect? First pass effect is associated with orally administered drugs. Drugs absorbed from GI tract enter mesenteric capillary network. The absorbed drug is carried to the liver via portal vein where it undergoes extensive hepatic metabolism. Metabolites - not the parent drug - then enter systemic circulation. This can lower the drug concentration so the dosage must be adjusted for the oral route. What can affect the first pass? The effects of first pass depends on whether the metabolite is active. If it not active, the effects of the oral drug would be diminished (as only the metabolites are left) so a much higher concentration of drug will be needed for the oral route. If the metabolites are active, then the drug will have a much greater effect when swallowed. this is limited to potent, lipophilic drugs that cross the skin. This can include glyc8 / 15 eryl trinitrate (sticking plasters/ointment), What drugs can be administrated trans- hyoscine (sticking plaster for motion sickdermally? ness), and nicotine (sticking plaster for smoking cessation). there is a large surface area for rapid absorption and onset of effect. Drugs What drugs can be administrated by in- can include gaseous and volatile anaeshalation? thetics (halothane - which is hepatotoxic - and isoflurane) and bronchodilators (salbutamol). What is bioavailability? the fraction of a drug dose (quantity) that reaches the blood stream in an active form. What is bioavailability affected by? - First pass effect - Metabolism by bacteria in the gut wall - Hepatic disease - Drug formulation (sustained release for example) What is absorption? Absorption is the transfer of drug from site of administration to the bloodstream. Most drugs are absorbed by passive diffusion but there are other mechanisms. What are the mechanisms of absorption? - Filtration between cells (paracellular) and through pores and channels (transcellular) - Active transport against a concentration gradient using energy (such as levodopa, paraquat and amino acids). - Facilitated diffusion (for sodium and glucose). What is distribution? And what are the different compartments? Distribution is the movement of the drug. The drug will distribute into various body fluid compartments, such as the plasma water (in the blood stream) or if its lipophilic, into the lipid component. Drug molecules exist in either bound (to albumin protein for example) or free form in 9 / 15 each compartment. Only free drugs can move between compartments. Compartments include bloodstream (plasma water), interstitial water, intracellular water, extracellular water, or fat. What is the volume of distribution? Volume of distribution (Vd) is the apparent fluid volume in which a drug is distributed to provide the same concentration as it currently is in the blood plasma. The volume can give us an indicator of where a drug is distributed. If a drug is highly distributed or bound to tissues outside the blood, the Vd will be large because the free concentration in the blood will be small. If the tissue distribution is low, the Vd will approximate the blood volume (around 8l). Vd is often corrected by body weight with units L per kg. Some lipophilic drugs bind to tissue constituents where the amount in tissue is high, and therefore, the plasma concentration low. This means the calculated Vd What is the Vd like for lipophilic drugs? will be a lot higher than the total body water. This means the drug is not in the bloodstream or plasma, it is somewhere else. - Regional blood flow - a well-supplied blood flow means that drugs can be distributed quickly. - Lipid solubility - if a drug is highly lipophilic, it can cross membranes quickWhat factors can affect the rate and exer. tent of distribution? - Plasma protein binding which can be affected by competition between drugs. Drugs can be bound to proteins or in their free forms - the free form is the active part of the drug. 10 / 15 - Warfarin has 3% free form with 97% bound to plasma proteins. If an additional 3% of warfarin is displaced from its protein binding sites by a second drug, the amount of free warfarin available for diffusion to its site of action is now 6% What are two examples of drugs that can - this is equivalent to doubling the active show the issue associated with plasma dose which can lead to toxicity (bleeding protein binding? and haemorrhage). - Phenobarbital has 50% free, if 3% of this is displaced, free phenobarbital in the plasma increases to 53% which is inconsequential. The drugs which have over 90% plasma protein binding are likely to have a significant impact. Why is metabolism needed? - Polar, water-soluble drugs can be excreted unchanged. - Lipophilic drugs must be metabolised to more polar products. If a drug is highly protein bound, it reduces glomerular filtration. Lipophilic drugs are also reabsorbed from tubular fluid, and they have a high volume of distribution which increases elimination half-life. Why is metabolism important to study regarding the action of drugs? some drugs are inactive until metabolised (pro-drugs). When drugs are metabolised by the liver, metabolites may be inactive (pro-drugs), active (which can be toxic), or accumulate (if they cannot be made polar). genetic differences, sex, age (elderly paWhat can metabolism be affected by? tients may have a lower metabolism), and nutritional status. Phase 1 (change the molecule) What are the two metabolism phases? Phase 2 (add something to help elimination) 11 / 15 What is involved in the first phase of metabolism? - Functionalisation - Introduce groups that undergo phase 2 reactions - Oxidation reactions, but also reduction and hydrolysis reactions. - Increase in polarity and water solubility - Conjugation reactions (adding glucuronic acid, sulphate, amino acids, gluWhat is involved in phase 2 of metabotathione for example). lism? This increases polarity and generally increases rate of excretion. One of the most important superfamily of enzymes in drug metabolism. They are classified as a superfamily by amino acid homology. To be a family, the genes must have at least 40% sequence homology. The three major drug What are cytochrome P-450s? How are metabolising P-450 families are CYP1, they classified? CYP2 and CYP3. There are subfamilies which are denoted by a letter, which must have greater than 55% identity. Individual gene products are identified by a final number. There are 50 P-450 genes but not all are drug-metabolising enzymes. What are other phase 1 oxidases? - Monoamine oxidase (MAO) - terminate endogenous neurotransmitters (noradrenaline, dopamine and serotonin), chemically similar to tyramine (cheese), ephedrine (for cold cures). - Xanthine oxidase which metabolises 6-mercaptopurine. - Alcohol dehydrogenase which oxidises ethanol, methanol, ethylene glycol (antifreeze) and 2,2,2-trichloroethanol (active metabolite of chloral hydrate). 12 / 15 What is enzyme induction? When chemicals signal to the liver to produce more of a drug metabolising enzyme. If cytochrome P-450 is induced, drug metabolism will increase and the concentration of drug in the plasma will decrease to low therapeutic levels. What is enzyme inhibition? When chemicals inhibit P-450s. This stops the drug from being metabolised and leaving the body which can cause toxic effects. What are the routes of excretion? Kidney, lung (if the waste is volatile like anaesthetics), liver (bile), faeces, breast milk, tears, saliva, sweat, hair and skin. What drugs should be avoided in breast-feeding mothers? Penicillin which can cause hypersensitivity in babies, aspirin and oral contraceptives should be avoided as this can be toxic. What are the three processes in renal excretion? glomerular filtration, passive tubular reabsorption, active tubular secretion Only free/unbound molecules are filtered but most is reabsorbed. Drug filtration occurs if the molecular weight is less than 60,000 Daltons and if it is free, and not What happens in glomerular filtration? bound. If the clearance of the kidneys is 90-140ml per minute (greater than the average 125ml), then the drug is leaving the body mainly by filtration. Examples of drugs include digoxin, procainamide, gentamicin and the endogeWhat drugs can be excreted in glomerunous metabolite creatinine. The creatilar filtration? nine clearance rate gives you an estimate of glomerular filtration rate. Only lipid soluble molecules are reabsorbed. It depends on lipid solubility and acidity, acid pH of the tubular fluid reduces reabsorption of weak bases, 13 / 15 whereas alkaline pH reduces reabsorption of weak acids. If the clearance of What happens in passive tubular reabthe kidneys is less than the glomerular sorption? filtration rate, then a lot of the drug is being reabsorbed. free or bound drug molecules are available to leave. There are separate organic anion and cation transport mechanisms that are energy dependent and What happens in active tubular secre- saturable. This is independent of plasma tion? protein binding because as we actively remove the drug, the drug re-equilibrates between the free and the bound form which means more can be actively removed. Examples of these drugs includes salicylate, penicillin, diuretics (anion transport), dopamine, serotonin, morphine, pethidine and atropine (cation transport). Some drugs can inhibit active tubular seWhat drugs are excreted in active tubular cretion, and some can compete for active secretion? transport mechanisms, thus decreasing the clearance of one of them. If the renal clearance is much greater than the GFR, active secretion is significant, it is being removed faster than passive filtration. What is clearance? volume of plasma cleared per unit time (ml/min) and describes the quantitative aspects of the excretory process. It measures the removal of drug from the blood and is a measure of the function of clearing organs (like the liver which uses enzymes to metabolise drugs and kidneys which excrete drugs and pulmonary clearance). The sum of all clearance equals the total body clearance, and it may be corrected for body weight (ml/min/kg) 14 / 15 What is clearance affected by? - Liver disease - Kidney disease - Blood pressure - Active secretion (saturable so can cause variations) - Plasma protein binding (can keep the drug in the bloodstream for longer) - Reabsorption - Urine volume (low water intake means more water is reabsorbed and the drug can stay in the body for longer) a measure of elimination and is how most drugs leave the body. The elimination half-life is the time taken for plasma conWhat is first-order (exponential) eliminacentration to fall to half of the initial contion? What is the elimination half-life? centration. Clearance is the rate (volume per minute) whilst half-life is in terms of time. What is zero-order elimination? Zero-order elimination is also another way some drugs can leave the body, such as alcohol, phenytoin, and aspirin. The metabolism and excretion are saturated. An example is renal tubular secretion and secretion into bile. 15 / 15