Pharmacokinetics II PDF

Pharmacokinetics II Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours 1 1 Reading List Thieme eBook Collection Pharmacology: An essential Textbook Unit 1: General Principles of Pharmacology – Introduction and Pharmacokinetics Pages 2 -...

Pharmacokinetics II Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours 1 1 Reading List Thieme eBook Collection Pharmacology: An essential Textbook Unit 1: General Principles of Pharmacology – Introduction and Pharmacokinetics Pages 2 - 15 2 2 Learning Objectives • There are main areas for discussion: 1. 2. 3. 4. Drug Distribution Drug Metabolism Drug Excretion Drug Accumulation 3 3 Drug Distribution 1. 2. 3. Define the term "drug distribution“ Explain the concept of ”redistribution of drugs” Describe how the features of two specialized barriers in the body affect drug distribution: ➢ Blood-brain barrier ➢ Placenta 4. 5. 6. Define the "volume of distribution" (Vd) of a drug. List the main drug factors affecting the Vd of a drug. Explain why the Vd can predict to a certain extent the pattern of the distribution of a drug in the body. 4 4 Drug Distribution 7. 8. 9. Describe the main features of drug-protein binding. Explain the criteria predictive of clinically relevant drug interactions at the level of protein binding. Perform relevant pharmacokinetic calculations: ▪ ▪ ▪ Calculate the Vd of a drug, given sufficient data. Calculate the Cp0 of a drug, given sufficient data. Identify the Cp0 of a drug from a graph. 5 5 LO 1,2 Drug Distribution • Distribution can be defined as the passage of drug from the systemic circulation to body tissues (e.g. from the circulation to the target receptor) • A drug may initially distribute to organs with high blood flow. Later lipophilic drugs may go into less vascular or adipose tissue (this is redistribution) – the plasma drug concentration will decrease • A quantitative measure of drug distribution is achieved by the pharmacokinetic parameter: volume of distribution (Vd) 6 6 LO 3 Drug Distribution • Physiological barriers to drug distribution: these are specialized barriers in the body which prevent drugs from being readily distributed: 1. Blood brain barrier • Drugs may cross the BBB to reach the Central Nervous System (CNS) across the cerebral capillaries (plasma to extracellular fluid) or across the choroid plexus (from plasma to cerebrospinal fluid) 2. Placenta • Barrier between maternal and fetal blood vessels 7 7 Physiological barriers to drug distribution LO 3 Blood Brain Barrier (BBB) • Delivery of drugs to the CNS is limited by the BBB primarily due to: ❖ tight junctions between the endothelial cells, unavailability of transport vesicles, and lack of transcellular pathways especially for hydrophilic drugs • Several drugs are actively transported out of the cerebrospinal fluid and back into the blood by a P-glycoprotein, present in the epithelial cells of the choroid plexus 8 8 Physiological barriers to drug distribution LO 3 Blood Brain Barrier (BBB) • Drug characteristics that are favorable for crossing the BBB are: ❖ high lipophilicity, small size and molecular weight, the drug is unionized at physiologic pH. • Transfer of drugs across the BBB is mainly by lipid diffusion • Drugs that do not cross the BBB are administered by intrathecal injection directly into the cerebrospinal fluid (if action on the CNS is required) Introduction to Neuropharmacology: Semester 2/2x 9 9 Physiological barriers to drug distribution LO 3 Placental Transfer of Drugs • Most drugs taken by mother reach the fetus – the placental barrier is generally quite permeable to drugs • Factors affecting placental transfer of drugs include: 1. 2. 3. 4. The molecular size of the drugs (drugs with MW greater than 1500 cross the placenta poorly) Physiochemical properties (lipophilic, un-ionized drugs cross readily) Degree of protein binding Placental blood flow 10 10 Physiological barriers to drug distribution LO 3 Placental Transfer of Drugs • Factors affecting placental transfer of drugs include (cont’d): 5. 6. 7. Stage of placental development (the passage seems easier during the third trimester) Placental drug metabolism (placenta is the site of metabolism of some drugs e.g., ethanol) The activity of P-glycoprotein that is present in placental vessels which can put some compounds back into maternal blood 11 11 LO 4 Volume of distribution (Vd) • Vd is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. Volume of distribution = 𝐃𝐨𝐬𝐞 𝐨𝐟 𝐝𝐫𝐮𝐠 𝐗 𝐅 𝐃𝐫𝐮𝐠 𝐜𝐨𝐧𝐜𝐞𝐧𝐭𝐫𝐚𝐭𝐢𝐨𝐧 If a patient received 7 mg of drug X IV and the blood sample has a concentration of 1 mg/L. It would mean that the Vd is 7 L. *Vd = 7x1 / 1 = 7 L 12 The volume of distribution (Vd) of a drug is independent of the dose (therefore it is constant). If a drug if given IV, the bioavailability (F) is 1. However, is the drug is given by any other route, the F must be considered such that: Volume of distribution = (Dose of the drug x F)/Drug concentration (Cpo) ** Cpo is the plasma concentration at zero time or the initial plasma concentration Consider the following example: 1000 mg of a drug is given IV and the resultant concentration is 0.01 mg/ml. What is the volume of distribution of this drug? Answer: if the drug is given IV, the F is 1. Therefore, the Vd = (1000mg x 1)/ (0.01mg/ml) = 100 000 ml (or 100 L) You can also use this formula to determine a suitable dose to administer. For example, if you know the volume of distribution of a drug and the desired plasma concentration, you can use the above formula to calculate a suitable dose for a 12 patient (don’t forget to take the bioavailability into consideration!) 12 LO 5 Volume of distribution (Vd) • The volume is distribution (Vd) does not have a true anatomic space and is therefore referred to as the apparent Vd • Factors affecting Vd: ❖ The drug molecular weight ❖ Lipid solubility ❖ Ionization in physiological pH ❖ Protein Binding ❖ Blood flow ❖ Disease states 13 13 LO 5 Factors affecting Volume of Distribution (Vd) Molecular Weight (MW) • Drugs with low MW can diffuse across biological membranes and distribute to the tissues better than high MW drugs. Lipid solubility • Lipophilic drugs distribute faster to tissues than hydrophilic drugs • Hydrophilic drugs have a low Vd and are distributed predominately into the extracellular fluid (ECF) 14 14 Factors affecting Volume of Distribution (Vd) LO 5,6 Total body water volume = 40 L, 60% body weight ECF volume = 15 L, 20% body weight Intracellular fluid volume= 25 L, 40% body weight Interstitial fluid volume = 12 L, 80% of ECF Plasma volume = 3L, 20% of ECF If the drug is unable to cross the phospholipid membrane, it will remain in the ECF. 15 If the volume of distribution of a drug is provided, the distribution pattern of a drug can be appreciated. For example, (a) if a drug has a Vd of 2-3 L, it can be assumed that the drug is confined to the plasma (b) If a drug has a Vd of 13 L, it can be assumed that the drug is distributed in the ECF but does not penetrate the cells (c) If the drug has a Vd of 40 L, it can pass most biological barriers and it is distributed in total body water (extra and intracellularly) (d) If the drug has a Vd > 50 L, the drug is likely stored within specific cells or tissues. 15 Features of drugs that predominate in each fluid compartment Fluid compartment LO 5, 6 Feature Plasma High molecular weight Bound to plasma albumin Interstitial fluid Low molecular weight Hydrophilic Intracellular fluid Low molecular weight Hydrophobic 16 16 LO 5 Factors affecting Distribution (Vd) Degree of ionization • Recall the previous discussion in the PK 1 lecture – Ionized drugs become trapped Protein Binding • The drug in the systemic circulation can bind to plasma proteins such as albumin, alpha-1-acid glycoprotein and lipoprotein Protein Concentration (g/L) Type of Drug Bound Example Albumin 3 – 4.5 Anionic, cationic Phenytoin Alpha-1-acid glycoprotein 0.4 – 1 Cationic Lidocaine Lipoprotein Variable Lipophilic Cyclosporin 17 Recall from the PK 1 lecture: drugs become trapped when present in the ionized form, depending upon the pH of the medium. This fact can be used to make the drug concentrate in specific compartments 17 LO 5,7 Factors affecting Distribution (Vd) Protein Binding • Binding of drugs to plasma proteins is reversible but only free drugs can diffuse into tissues and exert a pharmacological effect • The ratio of bound drug to free drug is constant, when the drug plasma concentration falls (due to metabolism or elimination) – bound drug proportionally dissociates from albumin. 18 A constant percentage of the drug is bound; therefore protein binding is independent of the dose. 18 LO 5 Factors affecting Distribution (Vd) Blood flow • Changes in blood flow can influence drug uptake by tissues. Distribution is therefore dependent on blood flow and the rate of delivery of drug via the blood stream to the tissues. Disease states • In heart failure, cardiac output is reduced, and this is associated with a reduced volume of distribution of some drugs • In hepatic disease there maybe a reduction in the production of albumin which will affect protein binding 19 19 LO 7,8 Protein binding interactions • Accumulation of endogenous compounds that can compete with drugs for their binding sites results in reduction of the percent drug bound and increase in the drug free fraction. This occurs hyperbilirubinemia, jaundice, renal failure, and liver diseases. • Exogenous compounds such as drugs with high protein binding affinity (e.g., warfarin, valproic acid, and nonsteroidal anti-inflammatory drugs) can compete and displace other drugs from their protein binding sites. 20 20 Learning Objectives • There are main areas for discussion: 1. 2. 3. Drug Distribution Drug Elimination ❖ Metabolism ❖ Excretion Drug Accumulation 21 21 Drug Elimination 1. 2. Define the term ‘drug elimination’ Define the term "clearance of a drug." 22 22 Clearance LO 1,2 • Drug elimination is the irreversible removal of drug from the body. ❖ The two major sites of drug elimination are the kidneys and the liver • Clearance is the volume of fluid cleared of drug from the body per unit time (e.g units ml/min) • Total clearance reflects all mechanisms of drug elimination ❖ The removal (or excretion) of drug into the urine represents renal clearance ❖ Within the liver, biotransformation of parent drug to one or more metabolites may occur, or excretion of unchanged drug into the bile, or both CLT = CLH + CLR+ CLOTHER 23 23 Drug Metabolism 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Define the term "drug biotransformation". Explain the consequences of biotransformation with respect to the pharmacological activity of the drug. List the main categories of drug biotransformation reactions. Describe the main features of oxidation reactions. Describe the main features of glucuronic acid conjugation. Give examples of drugs that can induce or inhibit drug metabolizing enzymes. Explain the consequences of drug induction or inhibition of microsomal enzymes. List the primary factors affecting drug biotransformation. Explain the concept of ‘first-pass effect’ of a drug. Describe the relationship between oral bioavailability and first pass effect of a drug. Explain the meaning of “order kinetics”. Explain the concept of pharmacokinetic models and the meaning of "onecompartment open model". 24 24 Biotransformation (Metabolism) LO 1,2 • Metabolism leads to the termination or alteration of a drug’s biologic activity • Drugs can be metabolised in three (3) ways ✓ Pharmacologically Active drug ⇒ Pharmacologically inactive metabolite (Most common scenario) ✓ Pharmacologically Active drug ⇒ Pharmacologically active metabolite with the same or different pharmacological activity ✓ Inactive drug (prodrug) ⇒ Pharmacologically active metabolite • Biotransformation reactions can be assigned to one of two major categories called phase I and phase II reactions 25 25 LO 3 Biotransformation (Metabolism) • Metabolism by phase 1 followed by phase 2 produces a metabolite that is highly water soluble and readily eliminated from the body (sometimes phase 2 reactions occur directly) • Phase 1 reactions e.g. oxidation (most common), reduction, or hydrolytic reactions) 26 . 26 LO 3,4 Oxidation Reactions • Main type of Phase 1 reaction • Most important site of metabolism is the microsomal enzyme system (occurs in the liver) • Reactions are catalyzed by microsomal enzymes (known as the mixed function oxidases (MFOs), or monooxygenases) ❖ The most important is the cytochrome P-450 family of enzymes 27 27 LO 3,5 Biotransformation (Metabolism) • Phase 2 reactions (e.g. conjugation reactions) enzymes catalyze the conjugation of the substrate (the phase 1 product) with a second molecule ❖ Glucuronidation (most common), sulfonation, acetylation, methylation, water conjugation, glutathione conjugation and glycine conjugation • Drugs that are polar may undergo conjugation directly without going through phase I. 28 If phase I metabolites are sufficiently polar, they may be readily excreted. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the compound to form a highly polar conjugate. Such conjugation reactions are the hallmarks of phase II metabolism. A great variety of drugs undergo these sequential biotransformation reactions, although in some instances, the parent drug may already possess a functional group that may form a conjugate directly. 28 LO 3,5 Glucuronidation • Most common Phase 2 reaction • Compounds are conjugated with glucuronic acid • Occurs mainly in the liver and catalyzed by a microsomal enzyme: UDPglucuronosyltransferase 29 29 LO 1,2,3 Biotransformation (Metabolism) Katzung, B. G. (2017). Basic and Clinical Pharmacology 14th Edition. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781259641169/ 30 30 LO 1, 2, 3 Biotransformation (Metabolism) Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 31 31 The Cytochrome P 450 Enzymes LO 7 • The P450 system is important for the metabolism of many endogenous compounds and for the biotransformation of exogenous substances. • CYP is a superfamily of heme-containing isozymes located in most cells, but primarily in the liver and GI tract. • There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90 percent of drugs. • CYP450-dependent enzymes are an important target pharmacokinetic induction and inhibition drug interactions for 32 32 LO 7 CYP P450 inducers and inhibitors • Induction ❖ results in accelerated substrate metabolism and usually in a decrease in the pharmacologic action. ❖ in the case of drugs metabolically transformed to reactive metabolites, enzyme induction may exacerbate metabolite-mediated toxicity ❖ Some drugs can induce their own metabolism ❖ What happens with prodrugs? • Inhibition ❖ significant increases in plasma drug concentration and resultant adverse effects or drug toxicity 33 A prodrug needs to be metabolized into a pharmacologically active drug. If the metabolism of a prodrug is induced – the drug will be rapidly converted into the active drug. If the metabolism of a prodrug is inhibited, the drug will not be converted into the active drug (or the conversion will occur very slowly). Example: Clopidogrel is an antiplatelet drug, it is a prodrug. The CYP2C19 isozyme is mainly responsible for the bioactivation of clopidogrel. Concurrent use of clopidogrel and drugs that inhibit CYP2C19 could inhibit conversion of clopidogrel to its active form. A proton pump inhibitor, omeprazole, is one of the inhibitors of CYP2C19. Before this interaction was widely known, proton pump inhibitors (e.g. omeprazole) were prescribed with clopidogrel to prevent gastrointestinal bleeding. The FDA-approved labeling now recommends avoiding concurrent use of the PPIs (e.g. omeprazole) with clopidogrel. Reason being, concurrent use of clopidogrel and a proton pump inhibitor (PPI) may result in decreased levels of the clopidogrel active metabolite, and ultimately its antiplatelet activity. 33 LO 6 Examples of some CYP P450 inducers and inhibitors • “Barbie’s race car goes phast” for inducers ❖ barbiturates, rifampin, carbamazepine, griseofulvin, phenytoin • “Clearly, Cool Ken's Vehicle Is Equally Quick” for inhibitors ❖ Clarithromycin, cimetidine, ketoconazole, valproic acid, isoniazid, erythromycin, quinidine 34 34 LO 6 Inducer example: Carbamazepine • Carbamazepine is an inducer of several potential pathways of drug elimination, including CYPs 1A2, 2C9, and 3A4, as well as the active transporter P-glycoprotein. • Carbamazepine is primarily metabolized by CYP3A4 • Carbamazepine also induces its own metabolism (it is an auto-inducer) 35 Any drug that undergoes metabolism via CYP1A2, CYP2C9, or CYP3A4 or is a substrate for the P-glycoprotein transporter, is likely to be affected by carbamazepine administration 35 Pharmacogenetics and Drug Metabolism • A specific gene encodes each CYP450 enzyme - P450 enzymes therefore exhibit considerable genetic variability among individuals and racial groups • Some persons may be classified as ‘poor metabolizers’ or even ‘ultra rapid’ metabolizers • For example: some persons are poor metabolizers of CYP2D6, which metabolizes many beta blockers, antidepressants, and opioids • Standard drug doses may cause adverse effects related to elevated drug serum levels if a person is a poor metabolizer (the opposite will occur for rapid metabolizers) LO 7 36 Acetylation is a Phase 2 reaction (metabolism). It is catalyzed by N-acetyltransferase, an enzyme which is under genetic control. About one-half of people of Caucasian origin are slow acetylators, since they have a deficiency of the enzyme, inherited as an autosomal recessive trait 36 LO 8 Factors affecting drug metabolism • Genetics ❖ Genetic polymorphisms in both phase I and phase II drug metabolizing enzymes exist that result in altered efficacy of drug therapy or adverse drug reactions • Diet & Environment ❖ Cigarette smokers & workers exposed to pesticides – there is induction of drug metabolizing enzymes more rapidly than with non-smokers & the general population ❖ Grapefruit juice inhibits the CYP3A4 metabolism of co-administered drugs 37 Let’s look quick at a case with a patient who is a smoker and how smoking affects her medication (available at: https://www.pharmaceuticaljournal.com/download?ac=1067077) Adapted case: Kate Jones is a 50-year-old teacher. She has been using salbutamol and fluticasone/salmeterol inhalers and taking oral modified-release theophylline (400mg twice a day) to manage her emphysema, a form of chronic obstructive pulmonary disease (COPD), for several years. She has been a heavy smoker for most of her life and has recently decided to quit. She asks your advice about whether she can start nicotine replacement therapy (NRT) while taking theophylline. Answer: Smokers taking theophylline generally tend to require higher doses than non-smokers as tobacco smoke contains polycyclic hydrocarbons, which induce CYP1A2. Smoking cessation will therefore result in an increase in serum theophylline concentrations, and possibly toxicity, if the dose is not reduced. If Kate Jones wishes to quit smoking, she will need to be monitored for changes in her serum theophylline concentrations; a dose reduction of up to a third might be needed after just one week. Kate Jones should be advised to discuss her desire to stop 37 smoking, and the effects this will have on her theophylline treatment, with her GP before setting a date to quit smoking. Because it is the polycyclic hydrocarbons in tobacco smoke — not the nicotine — that increase theophylline clearance, Nicotine replacement therapy (NRT) will not affect Mrs Jones’s theophylline concentrations and it can be prescribed or sold to her 37 LO 8 Factors affecting drug metabolism • Age ❖ Infants have immature livers that reduce the rate of metabolism, elderly patients experience a decline in liver size, blood flow, and enzyme production that also slows metabolism • Drug-Drug Interactions (see discussion on induction and inhibition) • Diseases ❖ Hepatic, cardiac, endocrine and pulmonary diseases can impair drug metabolism 38 Examples: Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. Heart disease may limit blood flow to the area, affecting drugs whose metabolism is dependent on blood flow. 38 First Pass Effect LO 9,10 • When a drug is absorbed from the GI tract, it enters the portal circulation, which takes it to the liver, before entering the systemic circulation. From there, the drug is delivered to all tissues. • The first pass effect occurs if the drug is rapidly metabolized in the liver or gut wall during this initial passage. • Some routes of administration which avoid the first-pass effect: sublingual, transdermal, parenteral. • A drug that has a high first pass effect will have a low bioavailability (low first pass effect will lead to a high F) 39 Nitroglycerin is an example of a drug that has a significant first pass effect. Some studies have shown that oral doses of nitroglycerin were less than 1% bioavailable. As a result, nitroglycerin is formulated for patients as a sublingual preparation (administered under the tongue). Other routes which bypass first pass metabolism (IV) are also used for nitroglycerin administration. 39 LO 11 Drug Metabolism: Order of reaction Zero order First order • The rate of drug metabolism is NOT proportional to drug concentration – it is constant ➢ An increase in plasma drug concentration does NOT increase the rate of drug metabolism • The rate of drug metabolism is proportional to drug concentration ➢ An increase in plasma drug concentration increases the rate of metabolism • Occurs with only a few drugs • Occurs with most drugs 40 The few drugs that follow zero order (rather than first order kinetics) include ethanol, phenytoin, salicylic acid, theophylline, warfarin, heparin and some barbiturates. Ethanol is the best example. No matter the quantity of the drug in the body, ethanol is metabolized by the liver at the rate of ≈10 g/hour. 40 LO 11 Rate of metabolism versus drug concentration plot For zero order reactions the rate of metabolism is constant whereas for first order reactions, the rate is proportional to the drug concentration Plasma drug concentration versus time plot With zero order reactions there is linear decline of the concentration with time but with first order reactions there is exponential decline of the concentration 41 41 LO 11 First order or Zero order? Time (hr) Drug Concentration (mg/L) Rate (mg/L)/hr Zero order • Rate is constant 0 10 1 8 2= ( 2 6 2 3 4 2 10−8 ) 1 Time (hr) Drug Concentration (mg/L) Rate (mg/L)/hr 0 10 1 5 5=( 2 2.5 2.5 3 1.25 1.25 10−5 ) 1 First order • Rate is NOT constant • Rate is proportional to the drug concentration 42 42 First order or zero order? Brick Exchange • Brick (scholarrx.com) 43 43 LO 11 First order kinetics If a plot of log concentration is done versus time for drugs which follow first order kinetics – a straight line is obtained First order elimination: a constant fraction of drug is eliminated whereas with zero order elimination a constant amount of drug is eliminated 44 From the previous slide, if a plot of concentration versus time is done for a drug which follows first order kinetics a straight-line graph is not obtained. A straight line will only be produced if you log the concentrations obtained and plot these concentrations versus time. For example, on your scientific calculator, there is a ‘log’ button. If you log for example a concentration of 40 mg/ml – the answer is 1.6 (it is this value that would be plotted- alternatively if logarithmic graph paper is available, the value of 40 mg/ml may be plotted directly). This is FYI and you will not be required to plot any graphs – there is a need however to appreciate the shape of the graphs for a drug which follows first order versus zero order kinetics. 44 Drug Excretion 1. 2. 3. 4. List the main excretion routes of drugs. Describe the main features of glomerular filtration, tubular reabsorption and tubular secretion of a drug. Explain the how a patient’s renal function can be monitored Calculate the total, the hepatic and the renal clearance of a drug, given sufficient data. 45 45 LO 1 Drug Excretion • Routes of drug excretion: ❖ Renal: most important ❖ Intestinal: biliary excretion, fecal elimination ❖ Pulmonary: for gases or volatile drugs ❖ Others: breast milk, saliva, sweat, tears, nasopharyngeal secretions • Renal excretion occurs by: ❖ Glomerular Filtration ❖ Tubular Secretion ❖ Tubular Reabsorption 46 46 LO 1 47 47 LO 2 Glomerular Filtration • Passive Process: driven by hydrostatic pressure within the glomerular capillaries • Occurs for molecules with a MW <500 • Protein binding decreases filtration • Glomerular integrity and total number of functioning nephrons will affect filtration 48 48 Active Tubular Secretion LO 2 • An active process: Carrier mediated requiring energy and occurs in the proximal tubule • Capacity limited and may become saturated • Maintains physiological pH by secreting substances into tubular fluid: K+ , H+ , NH4 + , Cr, Urea, some hormones, drugs • Drugs with a higher affinity for the transport system can inhibit the secretion of other drugs with a lower affinity. Two active secretion systems: ❖ Weak acids (organic anion transporter, OAT) ❖ Weak bases (organic cation transporter, OCT) 49 49 LO 2 Tubular Reabsorption • Can be active or passive process which occurs in the distal tubule • Occurs passively for lipid soluble and un-ionized drugs • Tubular cell membranes act as a barrier to reabsorption • Reabsorption depends on: molecular weight, lipid solubility, ionization (recall how changing the pH affects reabsorption – ion trapping discussion PK1) • May also depend on urine flow rate 50 50 LO 3 Monitoring Renal Function • Glomerular Filtration Rate (GFR) provides an excellent measure of the filtering capacity of the kidneys • The total kidney GFR is equal to the sum of the filtration rates in each of the functioning nephrons • Normal values: approx. 130ml/min per 1.73m2 in young men and 120ml/min per 1.73m2 in young women 51 51 Learning Objectives • There are three main areas for discussion: 1. 2. 3. Drug Distribution Drug Elimination Drug Accumulation 52 52 Drug Accumulation 1. 2. 3. 4. 5. 6. 7. 8. 9. Define the term "half-life of a drug" Calculate the half-life of a drug from a graph. Explain the relationship between the half-life of a drug and the duration of drug action. Describe the accumulation of the drug given by IV infusion Define the steady state plasma concentration (Css) of a drug Describe the accumulation of a drug given repeatedly at a constant dose. Calculate the Css of a drug, given sufficient data. Define the loading dose and the maintenance dose of a drug. Calculate the loading dose and the maintenance dose of a drug, given sufficient data. 53 53 Half-life LO 3,5 • Half-life (t ½) is the time it takes for the serum concentration of a drug to decrease by half. • Half life determines the time to steady state during the continuous dosing of a drug (it also determines the dosing interval) ❖ Steady state is the point at which the amount of drug administered over a dosing interval equals the amount being eliminated over the same period • It takes about 3 – 5 t ½ to reach steady state (for a drug administered on a continuous basis) – for first order reactions 54 The half life of a drug allows the clinician to predict essentially how much of the drug will remain in the body after it is administered. For example, if a drug is given and no subsequent doses are administered, the serum concentration of the drug may be predicted as follows: After 1 half life, 50% of the drug remains in the body “ 2 half lives 25% of the drug remains in the body “ 3 half lives 12.5% of the drug remains in the body “ 4 half lives 6.25% of the drug remains in the body “ 5 half lives 3.125% of the drug remains in the body Etc 54 Half-life • If a drug is given continuously, it should be noted that the time to reach steady state plasma concentration is independent of the dose or the dosing interval and is dependent on the half-life. Such that: – – – – – – – 50 % of the steady state is reached after 1 half-life 75 % “ “ “ “ “ “ “ 2 half-lives 87.5% “ “ “ “ “ “ “ 3 half-lives 93.75 % “ “ “ “ “ “ “ 4 half-lives 96.9 % “ “ “ “ “ “ “ 5 half-lives 98.45 % “ “ “ “ “ “ “ 6 half-lives Etc 55 55 LO 1,6 A., B. L. Applied Clinical Pharmacokinetics. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9780071476287/ 56 With reference to the graph on the slide (and the information on the previous slide) generally by 5 half-lives – approximately 95% of steady state is achieved and for clinical purposes dosing adjustments for drugs are made at this time. 56 A B LO 1,5 The time a drug takes to reach steady state can not be increased or decreased. However, the steady state concentration can be increased by using one of two methods. Method A : Increase the drug dose but maintain the same dosing interval – results in wider fluctuations between the peak and trough concentrations Method B: Maintain the dose but decrease the dosing interval – results in smaller fluctuations between the peak and trough 57 concentrations 57 LO 1,4 Drug Accumulation • Drug accumulation occurs if another dose of a drug is given before the previous dose is completely eliminated ❖ Drug accumulation therefore occurs with repetitive (or multiple doses) ❖ If the dosing interval is shorter than the half life of the drug, there will be a larger residual amount of drug in the body (i.e. more drug accumulation) • If a drug has a very short half-life (which is less than the dosing interval), then accumulation will NOT occur because the plasma concentration resulting from each dose will be the same as the dose alone 58 Drug accumulation occurs with repetitive doses of a drug. Drugs may be given intravenously in the following ways ❖IV bolus multiple dose: a single dose is given at repeated intervals (e.g. 100 mg IV every 8 hours) ❖Multiple Intermittent infusions: a dose is given over a short time at repeated intervals (e.g. 100 mg infused over 30 minutes every 8 hours) 58 ❖Continuous infusions: a drug is given over an extended time (e.g. 100 mg infused over 8 hours) Many drugs are better tolerated when infused slowly over time compared to IV bolus dosing. 58 LO 4 If a single dose of a drug is given the drug concentration will gradually fall to 0 (when the drug is completely eliminated). If multiple doses are given, there will be accumulation of the drug (as the drug will not be completely eliminated from the body) After repetitive doses, steady state will be achieved (3 – 5 t1/2) https://www.memorangapp.com/flashcards/38710/L93+-+Practical+Pharmacokinetics/ 59 59 Loading Dose • LO 8 A loading dose may be given when the infusion is initiated so that the patient receives the required therapeutic concentration from onset. 60 60 LO 8 Loading Dose Clinical Application • Digoxin is used in cardiac failure; its half-life is about 40 hours. It would be too long to wait 160 hours in order to achieve the plasma concentration needed to manage a serious cardiac failure. 61 61 Basic Pharmacokinetic Equations **Equations are not provided in exams and should be memorized** • Loading Dose (LD) = (Css x Vd)/F • Maintenance dose = • Dosing rate = CL x Css • T½= • CLH = Q x ER (where Q is hepatic blood flow and ER is fraction of drug extracted by the liver) • CLR= 𝐶𝑠𝑠 𝑥 𝐶𝐿 𝑥 𝜏 𝐹 0.7 𝑥 𝑉𝑑 𝐶𝐿 𝑈𝑟𝑖𝑛𝑒 𝑓𝑙𝑜𝑤 𝑟𝑎𝑡𝑒 𝑥 𝑢𝑟𝑖𝑛𝑒 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑝𝑙𝑎𝑠𝑚𝑎 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 62 𝜏 = infusion time Note that in this section, learning objectives 2, 7 and 9 are calculations which will be addressed in the practice questions and the workshop 62 Basic Pharmacokinetic Equations • Vd = (Dose x F)/ (Cpo) • F = AUC other/ AUC IV N.B There are many other PK equations which are more complex……. 63 Add F equation 63 Learning Objectives • 1. 2. 3. The learning objectives are posted in a separate document on Canvas. There are three main areas for discussion: Drug Distribution Drug Elimination Drug Accumulation 64 64 A 24-year-old woman presents to the clinic with increased urinary frequency and urgency and burning on urination. The physician initiates treatment with the appropriate antibiotic, which has a bioavailability of 40% and a volume of distribution of 10 L. The patient’s creatinine clearance is 88 mL/min. Which of the following is the loading dose required to obtain a desired plasma concentration of 20 mg/L? A. B. C. D. E. 400 mg 50 mg 500 mg 80 mg 800 mg 65 65 A 65-year-old woman presents to the emergency department with a productive cough, intermittent chills, and fevers for the past 2 days and is subsequently diagnosed with pneumonia. A 50-mg bolus dose of an antibiotic is administered as a constant intravenous infusion, yielding a desired plasma concentration of 5.0 mg/L. If the half-life of this antibiotic is 100 minutes, which of the following is the clearance of this drug? A. 0.0007 L/min B. 0.007 L/min C. 0.01 L/min D. 0.07 L/min E. 0.10 L/min 66 66 The target concentration was 100 mg/ml for a new drug which was given orally twice daily. The drug’s bioavailability is 50%. The drug clearance is 2ml/h. Calculate a suitable maintenance dose. 67 67 • The plasma concentration obtained 1 hour after dosing a drug is 25 mg/L. Calculate the most likely dose given if the drug has a half life of 1 hour and a volume of distribution of 3 L. 68 68 Application Question 1 A 50-year-old man with epilepsy takes phenytoin which is approximately 90% protein bound. He receives a new prescription for valproic acid which is approximately 95% protein bound and a drug interaction occurs. Explain the nature of this drug interaction? 69 69 Application Question 2 Questions: 1. From the graph above, determine the half-life of the drug. 2. How would the half-life change if the metabolism of the drug is increased? (or decreased) 70 70 Application Question 3 • A 25-year-old woman takes an Ethinyl estradiol-containing contraceptive daily for birth control. The contraceptive is metabolized by CYP 3A4. She is recently diagnosed with epilepsy and receives treatment with Carbamazepine. • What would be the implication of treating the woman’s epilepsy with Carbamazepine? 71 71