Basic Pharmacokinetics Class Notes

What is pharmaockinetics (PK)? • The study of handling of drugs by the body- what the body does to the drug • It is the time course of drugs (how long the drug is in the body) and their effects in the body • Pharmacokinetic processes include ADME, and these determine the concentration of a drug in the body, which then determine the effectiveness of a dosage regimen • The study of pharmacokinetics allows the processes of ADME to be quantified • Clinical pharmacokinetics is the application of PK principles to allow safe and effective drug therapy in individuals • It allows for individualised drug treatment eg by adjusting drug doses/ frequency to ensure the patient is receiving the optimal dose so that the levels of drug in their blood stay within the effective range (not too high that it causes side effects but not too low that it is ineffective) What is pharmacodynamics (PD)? • The study of the time course of the drug effect in the body- what the drug does to the body • It explains the relationship between drug concentration and therapeutic effects • PD is important in determining the change in drug effect due to changes in PK What is the link between PK and PD? • PK: concentration vs time • PD: concentration vs effect (log scale) • PK-PD: effect vs time 1 / 27 • Ideally the concentration of drug should be measured at the site of action of the drug, at the receptors. However this is inaccessible • Therefore drug concentrations are normally measured in the blood/ plasma, How should drug concentration be meaor occasionally in saliva, urine or ceresured? brospinal fluid (CSF). It is assumed that the drug concentrations in these fluids are in equilibrium with the drug concentration at the receptor (the concentration won't be exactly the same but it will be similar) What are the pharmacokinetic processes? ADME Absorption Distribution Metabolism Excretion What is absorption? • Drug action requires adequate concentration of the drug at the target tissue (receptors on the site of action) • A systemic effect occurs via entry of the drug into the systemic circulation. It requires absorption of the drug into the bloodstream (unless it is given intravenously) • A topical or local effect occurs when the medicine is applied directly to the site of action eg an emollient for dry skin, antibiotic eye drops for infection. Absorption should usually be minimal to avoid systemic side effects (however patches are applied with the aim for the drug to be absorbed from the skin into the systemic circulation) What factors affect drug absorption? • Physical properties of the drug • Formulation • Physiological factors 2 / 27 How do the physical properties of the drug affect drug absorption? • The physical state of the drug affects absorption. A drug dissolved in a liquid medium is more readily dissolved than solids as it skips the disintegration step. • The lipid and water solubility of the drug affects absorption, especially for medicines given orally. The lumen of the GI tract contains water and therefore drugs which are water soluble are absorbed faster. At the cell surface of the GI lumen, there are phospholipid cell membranes so drugs which are lipid soluble penetrate more rapidly into the cell. • The pH of the surroundings affects absorption. When the drug is in the GI tract, the GI mucosa is impermeable to ionised molecules, so the unionised form of the drug will be better absorbed. Most drugs are weak acids or weak bases. Weakly basic drugs remain unionised in the small intestine, as this is where the pH is higher, thus they are absorbed at a faster rate in the small intestine. Weakly acidic drugs are unionised in the stomach where the pH is lower so they are absorbed faster in the stomach. Most orally administered drugs are absorbed in the small intestine. • Disintegration and dissolution rate affect absorption. If the disintegration is faster, dissolution will be faster so the drug can be absorbed at a quicker rate • Particle size and surface area can affect How does formulation of the drug affect absorption. The smaller the particle size, drug absorption? the greater the surface area, the faster the dissolution and the faster the absorption. For drugs that are not intended to be absorbed into the body, the particle size is kept large 3 / 27 • Dosage form affects absorption. Tablets and capsules have the slowest absorption and emulsions and solutions have the fastest absorption. • Changes in gastric motility/ emptying affects absorption. This causes a delay in absorption of medicines taken, so there is reduced therapeutic effects • First-pass effect affects absorption for orally administered medicines. A drug given orally first enters the portal circulation into the liver where it is metabolised, so less of the drug enters the systemic circulation, therefore there is reduced therapeutic effect (a higher oral dose would have to be given) • Disease states affects absorption. CerHow do physiological factors affect drug tain diseases result in malabsorption eg absorption? cirrhosis of the liver, biliary obstruction etc • Presence of other substances eg antacids, foods, at the same time as a medicine is being taken will affect absorption. For example, calcium-containing antacids or preparations containing iron or zinc should not be taken at the same time as tetracyclines, since tetracyclines are consequently less well absorbed. Food can reduce the absorption of some drugs so should be taken on an empty stomach. • Enteral routes (oral/ rectal) involve the drug being absorbed into the systemic circulation via the GI tract How does absorption differ with different • Parenteral routes involve all systemic routes of administration? routes other than oral/rectal eg intramuscular, intravenous, subcutaneous, inhalation, sub-lingual etc. The drug would 4 / 27 generally be absorbed more quickly than via oral administration. • Intravenous (i.v.) injections are the only route that do not require the drug to be absorbed into the circulation What is drug disposition? • The movement of a drug after it is absorbed until it is excreted • It includes the processes of distribution, metabolism and excretion What is distribution? • The movement of drugs around the body • Once absorbed, the drug molecules may spend some time in one organ, and then be carried by the blood to another organ, and so on What factors affect drug distribution? • Tissue permeability of the drug • Organ or tissue perfusion • Plasma protein binding of the drug • Patient factors eg age, pregnancy, disease, obesity etc • Some drugs are less permeable into cell membranes of tissues so the distribution of these drugs are limited • Factors that affect the drug distribution into tissues include - the molecular weight of the drug - the degree of ionisation- ionised drugs How does tissue permeability of the drug cannot readily permeate the cell memaffect drug distribution? brane so the distribution is limited - solubility- drugs which are lipophilic are better at crossing cell membranes - the partition coefficient of the drug • Physiological barriers to drug distribution are capillary and cell membranes, and the blood brain barrier 5 / 27 • An organ or tissue that is highly perfused has a richer blood supply • Lipid soluble drugs can enter highly perfused tissues eg the tissues of the lungs, kidney, liver, heart, brain etc, quite rapidly • The extent to which a drug is distributed into the tissue or organ depends on the How does organ or tissue perfusion afsite of the tissue and the partition coeffifect drug distribution? cient of the drug • Adipose tissue are less well perfused, so if a lipid soluble drug is given to those who have more adipose tissue eg those who are obese, the drug may become stored in the fat to form a reservoir for the drug. • The main protein in plasma is albumin • Some drugs are highly bound to plasma protein, which influences DME of the How does plasma protein binding of the drug drug affect drug distribution? • The bound drug is not available to exert its effect. Only the free drug can show pharmacological activity What is elimination? • The irreversible removal of the drug from the body • It includes the processes of metabolism and excretion • Elimination can be described as either zero-order or first-order What is metabolism? • The destruction of the drug by chemical alteration • This is usually in the liver What is excretion? • The removal of the chemically unaltered drug from the body in the kidneys 6 / 27 What is first-order elimination? • A constant proportion of drug in the plasma is metabolised per unit time. The amount of drug eliminated in a set amount of time is directly proportional to the amount of drug in the body/ the dose. Therefore, you can assume that if you double the dose, you will double the plasma concentration. • Most drugs at therapeutic doses are eliminated by a first order process • Accumulation of the drug does not occur above the normal therapeutic levels (at normal doses) • However if you continue to increase the amount of drug administered (overdose) then all drugs will change from showing a first-order process to a zero-order process What is zero-order elimination? • The amount of drug eliminated for each time interval is constant, regardless of the amount of drug in the body • Some drugs at high doses display zero-order elimination eg aspirin, and also alcohol • The body's ability to eliminate the drug has reached maximum capacity and accumulation above the normal therapeutic levels occurs, and this is more likely for higher doses of the drug • Any change in plasma concentration with increasing dose is less predictable especially at the high doses. Therefore it is not as simple to say doubling the dose doubles the plasma concentration. • Drugs like phenytoin have a narrow therapeutic window so there is a short range of concentrations over which the drug exerts a therapeutic effect, so even smaller changes in dose result in the 7 / 27 drug plasma levels going above the upper threshold, making it easy to reach a toxic level. Therefore care must be taken when adjusting the dose of such drugs • Hypothetical structures that are used to describe the fate of a drug in a biological system following its administration • The body is viewed as a series of hypothetical compartments between which drugs can move • Organs and tissues in which drug disWhat are pharmacokinetic compartmentribution is similar are grouped into one tal models? compartment • There can be one, two or multi-compartmental models • Most clinically relevant drug pharmacokinetic scenarios are adequately described by one-compartment or two compartment models What are one-compartment models? • They present the body as one large, central compartment consisting of highly perfused organs eg liver, kidney, heart, lungs, brain, grouped together with blood, plasma and extracellular water • It assumes that a drug will be distributed instantaneously in the central compartment throughout the whole body and equilibrates instantaneously between tissues • The one compartmental model shows dose independent pharmacokinetics, as metabolism and excretion of the drug do not change with dose. These processes are not saturated at normal doses. • Changes in the plasma concentration quantitatively reflect changes in the tis8 / 27 sue concentration (not exactly equal, but similar) What are two-compartment models? • They present the body as two different components: the central compartment and the peripheral compartment • It assumes that a drug does not achieve instantaneous distribution/ equilibrium, between compartments. It takes some time for the drug to be distributed between compartments. • The peripheral compartment contains poorly perfused tissues into which the drug distributed more slowly eg fat, muscle, skin. Each of these may form separate compartments. • The two compartment model describes drugs which are extensively distributed into tissues eg Digoxin • When the drug is absorbed/ IV injection is administered, the drug density in the central compartment is at its highest. The distribution phase begins where the drug density in the central compartment reduces as the drug is distributed out of the central compartment and into the peripheral compartment. At one point, the distribution equilibrium is reached, where the drug concentration in the central and peripheral compartments are equal. The elimination phase then starts where the drug is eliminated from both compartments out of the body at approximately the same rate. What are different k parameters? • Ka is the absorption rate constant, which is the fraction of the drug dose absorbed per unit time. Different formulations of the same drug can have different ka values. 9 / 27 • K is the elimination rate constant, which is the fraction of the drug dose eliminated per unit time. • k1 and k2 are the distribution rate constants • A concentration of drug in plasma vs time graph for a single iv dose on a linear scale would give an exponential curve with the equation Ct = C0 e^-kt, where Ct is the concentration at time t, C0 is the How do you show first order elimination initial concentration, k is the elimination following an one-compartmental model rate constant and t is the time on a graph? • Where the concentration is on a log scale, it would give a straight line (diagonal going downwards) • A constant proportion/ fraction of the drug is eliminated per unit time, and the half-life is constant • A concentration vs time graph for a single iv dose on a linear scale would show a straight line (diagonal going downwards) How do you show zero order elimination • Where the concentration is on a log following an one-compartmental model scale, it would give a curve (going downon a graph? wards from left to right) • A constant amount of drug is eliminated per unit time- accumulation can occur above the therapeutic levels • A concentration vs time graph for a single iv dose on a linear scale would show a curvilinear graph (curved at the How do you show first order elimination top left and becomes straight towards the following a two-compartmental model on bottom right- check my goodnotes) • Where the concentration is on a log a graph? scale, it would give a biphasic graph with two connected straight lines going from top left to bottom right 10 / 27 • The graph is biphasic with two connected straight lines going from top left to bottom right • The 1st line shows the distribution phase. It begins at C0 where the drug was absorbed/ IV injection was first administered, and the drug density in the central compartment is at its highest. The line dips downwards as the drug density in the central compartment reduces as What does the concentration vs time the drug is distributed out of the cengraph for first order elimination following tral compartment and into the peripheral a two-compartmental model look like on compartment a log scale? • The point at which the 1st line ends and the 2nd line starts is the point of distribution equilibrium. The drug concentration in the central and peripheral compartments are equal. • The 2nd line shows the elimination phase. The line dips downwards (at a slower rate than the 1st line) as the drug is eliminated from both compartments out of the body at approximately the same rate What is volume of distribution (Vd)? The volume of fluid in which the total amount of drug would need to be distributed to give a concentration equal to the concentration measured in the plasma It gives an idea of how much drug is in the blood compared to the rest of the body tissues 11 / 27 • It tells us where the drug is distributed in the body and if it remains more in the plasma or in the tissues, the physicochemical properties of the drug, the amount of drug in the body at a particular time (if the concentration of the drug is sampled), and it allows calculation of the loading dose of a drug • The magnitude of V depends on whether the drug is in the plasma or kept in the tissue • A small V would show that the drug is largely held in the plasma. The drug is likely to be water soluble, highly bound to plasma proteins and have a large relative What does the volume of the compart- molecular mass, making it difficult for the ment (V) in the compartment models tell drug to pass through capillaries us? • A large V would show that the drug is held in the tissue. The drug is likely to be lipid soluble, highly bound to tissue proteins and have a smaller relative molecular mass. • The lowest volume of distribution is around 3L, which is the volume of plasma • It is usually constant for a drug, but can be affected by disease • The units of the volume of the compartment is L/kg, or if you know the weight of the patient, you can find the volume of distribution of the drug in that particular patient in L by doing V x weight. The lower the V, the lower the volume of distribution V = D/C where V is the volume of compartment D is the dose C is the concentration of the drug in the compartment 12 / 27 If there is a small concentration of drug in the plasma compared to the dose, the volume of distribution is large. V is not How do you calculate the volume of the a physiological value, it is an apparent compartment? distribution so it gives you an idea of the concentration in the blood and therefore the size of the volume of distribution What factors affect V? • Liver, renal and cardiac impairment • Reduced blood perfusion to tissues • Changes in plasma protein bindinghigh plasma protein bound gives a small V • Edema which is swelling caused by too much fluid building up in the body, and ascites, which is fluid build up in the lining of the abdomen • Molecular weight- a larger molecular weight gives a small V • Lipophilicity of drug- low lipophilicity gives a small V • Old age • Pregnancy Digoxin • It has a large volume of distribution of 7L/kg • It is a relatively small molecule What is an example of a drug with a large • It has low binding to plasma proteins. volume of distribution? It mostly binds to albumin at around 20-30%. • It has a high affinity for skeletal and cardiac muscles, the intestines and kidney Gentamicin • It has a small volume of distribution of What is an example of a drug with a small 0.25L/kg • It is a smaller molecule volume of distribution? • It does not bind to plasma proteins • It is highly ionised and does not cross 13 / 27 cell membranes easily, so it is held in the blood What is a loading dose (LD)? • It is a single large dose of drug that is used to raise the plasma concentration to the target therapeutic level faster than with smaller repeat doses. This dose is then followed by standard maintenance doses. • Without maintenance doses of LD, the concentration will fall and be eliminated When is a loading dose given? • If the drug has a long elimination half life eg digoxin, amiodarone • In acute conditions where treatment is required rapidly eg status asthmaticus (severe asthma attack), status epilepticus (severe epileptic fits) • In life-threatening arrhythmias eg rapid digitalisation 1. LD = Ctarget x Vd, where Ctarget is the desired concentration and Vd is the volume of distribution How do you calculate loading dose? 2. LD= C x V/ S x F where S is the salt factor of the drug and F is the bioavailability of the drug/the fraction of the dose that enters the system in a chemically unchanged form. For intravenous injections, all of the drug gets into the system so F would be 1 or 100% 3. If the patient has already received the drug, but the concentration of the drug in the blood needs to be increased by more: Incremental LD = Ctarget - Cmeasured) xV/SxF 14 / 27 • The fraction of drug dose eliminated from the compartment/ from the body per unit time • It's units are either /min or /hour • For example, procainamide has an elimination rate constant of 0.25/hour therefore 25% of the drug dose is eliminated from the body per hour. • Equations containing K are - Ct=C0 e^-Kt - Elimination rate = K x A, where A is the total amount of drug in the body • The amount of drug eliminated decreases as plasma concentration decreases, but the fraction of the drug eliminated is constant What is the elimination rate constant K? • The elimination displayed is first-order • On a concentration time graph where concentration is in a natural log/ ln scale, the gradient would be -K • On a concentration time graph where concentration is in a log scale, the gradient would be -K/2.303 • K enables comparison of groups of drugs. A larger K means faster rate of drug elimination from the body. Drugs with rapid elimination have a shorter half life and a short duration of effect after a single dose. For multiple administrations of a drugs, drugs with a larger K would need to be given more frequently compared to drugs eliminated slowly. 15 / 27 What is the half life of a drug (t½)? • The time taken for the plasma drug concentration to fall by half of what it was at the beginning of the measurement period • The units are minutes or hours, or sometimes days • It is another parameter of rate of drug elimination, along with K and CL (clearance) • The half life is inversely proportional to the elimination rate constant. t½ = 0.693/K • Half life is constant over the whole time curve • You can use a graph to determine approximately how many half lives it takes for a drug to be completely eliminated from the body • In a one compartmental model assuming linear pharmacokinetics, it will take approx 4-5 half lives to reach steady state plasma drug concentration, and 4-5 half lives for the drug to be effectively eliminated from the body. • Example of drugs with a low half life are Lansoprazole and Ranitidine. • Examples of drugs with a high half life are Amiodarone and Infliximab. 16 / 27 What is steady state? • Steady state is when the amount of drug administered over a dosing interval is the same as the amount of drug being eliminated over the same period (the rate of drug going in is the same as the rate of the drug going out). • For 1st order elimination, steady state will always be reached after repeated administration at the same dosing interval. • Instead of the drug being eliminated from the body before another dose is administered, a constant supply of the drug is given to achieve a steady state • The time taken to achieve steady state varies from drug to drug. Drugs with a high K and short half life reach steady state quicker than drugs with a lower K and longer half life. Example of drugs which reach steady state quick is Aspirin and Ranitidine. Examples of which reach steady state slower are Digoxin. • A loading dose can be used in drugs with a long half-life that need to reach steady state quickly How do you calculate half life? t½ = 0.693/K t½= 0.693V / CL where K is elimination rate constant, CL is clearance and V is volume of distribution 17 / 27 What factors affect half life? • Volume of distribution. Elimination processes eg metabolism and excretion, only work on the drug when it's in the plasma. A large V shows that little of the drug is in the plasma and most of it is in the body tissues, so less of the drug is eliminated therefore the half life would be longer, whereas a small V shows most of the drug is in the plasma therefore shorter half-life. • Clearance. It is the volume of plasma emptied of drug per unit time, therefore if the drug has a high clearance, it will have a shorter half life. • Disease can decrease both V and CL. Hepatic or renal failure reduces drug clearance. Because V and CL have opposing effects on half-life, a decrease in both might still result in no change in half-life, therefore half-life is not a good indicator of changes in drug CL. What is the half-life of PPIs? • They have a short elimination half life of around 1 hour • They have a quick onset of action • They are taken around 30 mins before breakfast, so peak blood concentrations of the drug coincide with maximal gastric pump activation, to be able to inhibit gastric acid secretion • Due to the short half life, only about 70% of proton pump enzymes are inhibited. This equates to around 66% inhibition of maximal acid output (if it is being administered once daily). • However although the half life is short, the effects of PPIs last around 24 hours, as the pump inhibition is permanent • They take 2-3 days to achieve a steady state of inhibition of acid secretion 18 / 27 • Increasing the dose doesn't have much further effect once the optimal dose is reached. However, increasing frequency of administration from once to twice a day, it increases the effects to around 80% inhibition of maximal acid output. • Taking a dose of the PPI before sleeping does not add to nocturnal acid breakthrough, because, due to the short half life, most of the drug has gone by the time the nighttime acid secretion becomes significant. New PPIs with a longer plasma half life are being created to improve acid inhibition • The area under the curve is a measure of drug exposure • It gives a measure of how much and for how long a drug stays in the body • It is used extensively in the calculaWhat is the area under the curve (AUC) tion of bioavailability of different dosage in a plasma drug concentration vs time forms of a drug curve? • AUC values can be used to determine other pharmacokinetic parameters eg clearance • The efficacy of PPIs correlates well to AUC rather than peak plasma levels • The units of AUC are mg.hr/L How do you calculate area under the curve? 1. Assuming that the drug follow one-compartmental model with 1st order administration and the drug is administered intravenously AUC= C0 / K, where C0 is the initial concentration of the drug and K is the elimination rate constant. 2. AUC = Dose / CL. This equation does not depend on models 19 / 27 What is bioavailability (F)? • The fraction of the dose that reaches the systemic circulation in a chemically unaltered form • It does not have any units • Examples of drugs with a high oral bioavailability are Valproate (100%), Esomeprazole (89%) and Lansoprazole (80-90%) • Examples of drugs with a low oral bioavailability are Gentamicin (<5%, so it cannot be given orally, it is only given by injection) and Verapamil (22%) • Failure of disintegration or dissolution • Chemical, enzymatic or bacterial attack eg PPIs are weak bases so exposure to stomach acid greatly reduces its absorption, therefore PPIs have enteric coatings • Failure of absorption eg Infliximab cannot be taken orally because the drug What are reasons for drugs having inwould be destroyed by the digestive syscomplete oral bioavailability? tem so would fail to be absorbed when taken orally • First pass metabolism in gut wall or liver eg H2 receptor antagonists like Famotidine and Larotidine undergo first pass metabolism which reduces bioavailability, Nizatidine has very little first pass metabolism How do you calculate bioavailability? F = AUC oral dose / AUC IV dose 20 / 27 What is clearance? • The removal of a drug from a volume of plasma in a given unit of time • It's units are L/h or ml/min • It is a model-independent parameter • Most drugs are eliminated by a combination of hepatic clearance (metabolism) and renal clearance (excretion without metabolism) • A decrease in drug clearance means a slower rate of elimination. Dosage adjustments may be required in those who have organ dysfunction eg renal or hepatic impairment, as the drug is usually eliminated by these routes • Examples of drugs with a low clearance are Infliximab (0.18-0.25ml/min) and Gentamicin (30ml/min) • Examples of drugs with a high clearance are Ranitidine (600ml/min) and Cephalexin (300ml/min) 1. The total clearance of a drug is given by the sum of the clearances by different organs CLt = CLr + CLm + Cb + CLother where CLt is total clearance, CLr is renal clearance, CLm is metabolic clearance, Cb is clearance in the bile, CLother is other clearances How do you calculate total clearance of 2. For 1st order elimination, as plasa drug? ma concentration falls, rate of elimination also falls. At steady state, the rate of administration is equal to the rate of elimination, therefore: Clearance = rate of elimination / C, where C is the concentration of the drug 3. For 1st order elimination, drug clearance remains constant at all doses 21 / 27 Clearance = K x V, where K is the elimination rate constant and V is the volume of distribution What factors can affect clearance? • Body weight • Body surface area • Cardiac output • Drug-drug interactions • Hepatic extraction ratio • Genetics • Hepatic and renal function • Plasma protein binding What is renal clearance? • Drugs being eliminated by renal excretion ie through the kidneys • Impaired renal function can be common in the elderly, as renal function declines with age, and impaired renal function can be caused by kidney disease eg chronic kidney disease CKD • Impaired renal function results in reduced excretion of drugs eg aminoglycosides which are nephrotoxic drugs eliminated by the kidneys with a narrow therapeutic window. Therefore dosage adjustment would be needed • Using eGFR (estimated glomerular filtration rate), which assesses the severity of CKD, and is the initial assessment of change in renal function. eGFR is normalised to a body surface area of 1.73m2 • Using creatinine clearance, which is the preferred method and is more commonly How can you estimate renal function? seen in product literature to show effects of renal impairment on drug elimination. Creatinine clearance is a fairly reliable marker for kidney function, and is usually used as a basis for dosage adjustment in renal impairment in the elderly at extremes of muscle mass, and for narrow 22 / 27 therapeutic index drugs that are mainly renally excreted. Creatinine is a chemical waste product that is produced by muscle metabolism, and it is eliminated by the kidneys in the urine. The kidneys maintain the blood creatinine within a normal range. If the kidneys become impaired, the blood creatinine will rise due to poor creatinine clearance by the kidneys It is estimated using the Cockcroft and Gault equation CrCl = (F x (140 - age x weight)) / serum creatinine where F is 1.04 in females or 1.23 in males, age is in years, weight is in kg, serum creatinine is in micromol/L However this equation tends to overestimate the renal function, and it is not How do you calculate creatinine clearstandardised for body surface area ance? • A creatinine clearance of 50-20ml/min shows mild level of renal impairment • A creatinine clearance of 20-10ml/min shows moderate level of renal impairment • A creatinine clearance of less than 10ml/min shows severe level of renal impairment How can you adjust dose in someone with renal impairment for drugs which are mostly eliminated through the kidneys? • Give the standard dose at extended intervals • Give a reduced dose at the usual intervals • Adjusting loading dose is generally unnecessary as accumulation doesn't usually occur after a single dose • If half life is increased, then the time taken to reach steady state will also in23 / 27 crease, for drugs which are renally eliminated in those who have renal impairment. Therefore a losing dose may be necessary for a drug that doesn't normally need one eg antibiotics for severe infections What is hepatic clearance? • Drugs being eliminated by hepatic excretion ie through the liver • This is affected by the first pass effect • The multifactorial nature of hepatic clearance (unpredictable influence, as causes of hepatic impairment eg liver disease can have many effects) makes finding direct relationships between hepatic impairment and changes in PK more challenging. This means it is more difficult to adjust the dose for drugs which are mainly metabolised by the liver. ClH = QH x EH where QH is the liver blood flow carrying How do you calculate hepatic clearance? the drug and EH is the hepatic extraction ratio • The fraction of the drug removed from the blood during one pass through the liver • The drug is extracted out quite significantly when it is absorbed into the hepatic portal vein and enters the liver, therefore the blood coming out of the liver has a reduced drug concentration What is the hepatic extraction ratio (EH)? • EH is determined by - hepatic blood flow - plasma protein binding of the drug - intrinsic clearance of the drug by the liver • Drugs with a high EH have low oral bioavailability, a short half life and it undergoes the first pass effect 24 / 27 • Drugs with a low EH have good oral bioavailability, have other routes of metabolism excluding the liver, and potentially have a prolonged half life • Examples of drugs with high EH (>0.7) are Propranolol (>0.9), Lidocaine and Morphine • Examples of drugs with moderate EH (0.3-0.7) are Aspirin and Quinidine • Examples of drugs with low EH (<0.3) are Warfarin, Phenytoin, Diazepam and Erythromycin EH = (Cin- Cout) / Cin where Cin is the How do you calculate hepatic extraction concentration of the drug going into the ratio? liver and Cout is the concentration of the drug coming out of the liver What is the first pass effect? • When most of an orally administered drug is removed by one pass through the liver. A significant amount of drug is metabolised before reaching the systemic circulation, so the amount of drug reaching the systemic circulation is considerably less than the dose given. • Drugs with high hepatic extraction ratios eg propranolol (EH = >0.9) are usually given as a higher dose due to the first pass effect • Liver function tests (LFTs) • ALT and AST levels (aminotransferases) How can you assess liver impairment? • Alkaline phosphatase (ALP) • Gamma GT (GGT), bilirubin, albumin • Clotting studies • Indicators of liver disease 25 / 27 What are infusions? • A form of drug administration • A constant iv infusion is where the drug is put in a solution in sterile saline, and it is pumped into the body at a constant rate using an infusion pump via a flexible plastic catheter inserted into a vein • On a concentration vs time graph, the curve steadily rises from the origin, as accumulation of the drug occurs, and then starts to plateau at steady state when the rate of elimination of the drug equals the rate of infusion. • Once infusion stops, the plateau of the curve will sharply decrease. Rinf = CL x Css, where CL is clearance How do you calculate rate of infusion? and Css is the steady state concentration Rinf = K x V x Css Ct= Css x (1- e^-Kt) At steady state, (1-e^-Kt) is approx equal to 1. The amount of drug in= amount of How do you calculate the concentration drug removed at time t (Ct)? Ct after stopping the infusion is calculated by Ct= Css e^-Kt What are multiple iv injections? • Where many iv injections are given to encourage accumulation of the drug to steady state levels, so that the previous dose is not eliminated before the next dose is given • On a concentration vs time graph, the line basically zigzags upwards. Average Css= dose/ (CL x Ä) where Äis the dosage interval eg if a dose is given twice daily, Äwould be 12 hours On a graph, the average plasma concen26 / 27 tration at steady state is the midpoint between the peak and trough of the zigzag How do you calculate the average plas- line at steady state. The peak would be ma concentration at steady state? Css max, right after the injection is given and the trough would be Css min, right before the next dose of injection is given How would you increase the Css with multiple oral dosing? • Give the same dose but more frequently, so reduce the dosing interval • Increase the dose but keep the dosing interval the same • Make sure to keep the time taken to reach Css the same (around 4-5 half lives) 27 / 27