BIOL 2048/9 Pharmacokinetics Lecture 5 PDF

BIOL 2048/9 Pharmacology PHARMACOKINETICS Lecture 5 MyEngagem ent: Dr. Charles Birts Join: vevox.app ID: 189-324-369 [email protected] Learning Outcomes Explain the pharmacokinetic processes...

BIOL 2048/9 Pharmacology PHARMACOKINETICS Lecture 5 MyEngagem ent: Dr. Charles Birts Join: vevox.app ID: 189-324-369 [email protected] Learning Outcomes Explain the pharmacokinetic processes of absorption, distribution, metabolism and excretion Apply mathematical principles to the pharmacokinetic processes of absorption, distribution and elimination. What determines the shape of the concentration-time curve? Intravenous Oral ABSORPTION DISTRIBUTION Rate Extent Extent ln [ ] ln [ ] plasma plasma Rate Terminal Slope depends on Terminal slope elimination depends on elimination Time Time Rapid and extensive Rapid and extensive Slow and limited Slow and limited How can we analyse the concentration-time curve in order to understand what happens to the drug in the human body? Intravenous Oral Intercept Area under Maximum the curve - Slope 1 AUC Area under ln [ ] Slope 1 the curve - plasma ln [ ] AUC plasma Slope 2 Slope 2 Time Time AUC = the total amount of drug that has entered the general circulation SLOPE = allows rates of change to be calculated  ABSORPTION EXTENT Equations that you should learn are highlighted by red boxes Extent of absorption - bioavailability - F F - is the fraction of an oral dose which reaches the systemic circulation as the parent compound. F - is calculated as the ratio of the AUCoral to the AUCiv (F =1 for an i.v. dose) Oral Intravenous Conc. AUCoral Conc. AUCiv AUC = total amount of drug that has entered the general circulation Time Time If the concentration of the oral dose and If the concentration of the oral dose intravenous (i.v.) dose are the same use is different to the intravenous (i.v.) this equation: dose use this equation: F= AUCoral F= AUCoral x Doseiv AUCiv AUCiv Doseoral DISTRIBUTION RATE REMINDER…. V1 V2 injection Elimination V1 V2 At equilibrium Elimination V1 V2 Post-equilibrium Elimination Lecture 3 Data can be plotted on a logarithmic scale to convert curves to 3a straight line 10 Slope will be TWO B determined mainly by Slope will be COMPARTMENT MODEL Plasma concentration Plasma concentration 2 Initial steep slope 1 distributio determined by Elimination BIPHAS Distribution out of the n plasma into tissues & (can be IC The majority of drugs affected if take a finite amount of some elimination drug time to distribute to the 1 0.1 undergoes tissues after i.v Slower terminal phase tissue re- Distribution is complete distribution) Lecture 3 and predominantly elimination 0 0.01 0 4 8 12 16 0 4 8 12 16 Time in hours Time in hours 3 10 Drug has fully A distributed by this time A ONE COMPARTMENT Plasma concentration Plasma concentration MODEL 2 1 Elimination only MONOPHASIC Elimination only Based on the assumption the drug distributes to the tissues very rapidly 1 0.1 (distributes instantaneously to all body areas) 0 0.01 0 4 8 12 16 0 4 8 12 16 Time in hours Time in hours Distribution – measured after i.V. Dose One – compartment Two – compartment Instantaneous Distribution Time to distribute to tissues 1000 10000 Plasma concentration Plasma concentration 100 1000 Distribution & some Elimination slope = - k Cp 10 slope = - Predominantly Elimination 100 Cp slope = -  1 0 1 2 3 4 5 6 10 Time in hours 0 2 4 6 8 10 12 14 16 Time in hours k Dose V Dose V1 V2 Rate of distribution - a a - is the initial rate of decrease in plasma concentrations after an i.v. bolus dose Cp is the change in the [drug] in this phase is predominately the plasma distribution and some elimination is also taking place The extrapolated black hashed this phase is line represents just elimination predominately elimination. Elimination only Slope = rate of The blue line △Cp is the Elimination (-k) difference between the red line Cp (Distribution and Elimination) and the extrapolated black =α hashed line (Elimination) Distribution & elimination – Elimination = distribution The gradient of △Cp is the rate of distribution = ⍺ a - is the rate of distribution. It is the gradient of the blue line (△Cp). - a characteristic for the drug, which depends on rate of uptake by tissues  DISTRIBUTION EXTENT Equations that you should learn are highlighted by red boxes Apparent volume of distribution – V or vd V Compound Explanation (litres/kg) Bumetanide 0.1 99% plasma bound Gentamicin 0.3 Low lipid solubility Aciclovir 0.7 Low lipid solubility Propranolol 4.3 Lipid soluble Cannabinol 8.9 Lipid soluble Amiodarone 66 Very lipid soluble Chloroquine 115 Very lipid soluble Apparent volume of distribution – V or vd V - is the dose divided by the plasma concentration of the drug (C 0) after it has been distributed For a one – compartment model: ONE - Assumes the drug distributes COMPARTMENT instantaneously to all tissues At time 0 hrs full distribution has already 1000 taken place Drug distributed Use C0 this represents the plasma C0 instantaneously concentration after the drug has fully Plasma concentration Fully distributed slopeat = -time 0 hrs 100 k 2.303 distributed and can be calculated from the intercept of the extrapolated 10 line (hashed line) 1 0 1 2 3 4 5 6 V = dose/C0 Time in hours Apparent volume of distribution – V or vd V - is the dose divided by the plasma concentration of the drug (C 0) after it has been distributed For a two – compartment model: TWO - At t = 0 very little or no distribution COMPARTMENT will have occurred 10000 Using the actual plasma concentration at t = 0 would not be representative of plasma intercept concentration after tissue distribution Plasma concentration 1000 Use plasma concentration if distribution Cp was instantaneous, this can be calculated from the y-intercept of the extrapolated 100 (black hashed line) Cp 10 V = dose/y-intercept 0 2 4 6 8 10 12 14 16 Time in hours Apparent volume of distribution – V or vd V - is dependent upon the physicochemical properties of the drug V - is an indication of the extent of tissue uptake of the drug, a large/extensive distribution gives a large V V - is independent of dose V - is the volume of plasma in which the dose appears to have been dissolved V - is a non-physiological “dilution factor” V - is the parameter which allows you to calculate the dose necessary to give a particular plasma concentration (therapeutic window - Lecture 2) V - it can be presented as L or L/kg - based on the weight of the individual e.g. if the weight of an individual is 70kg and V is 70L it will be presented as 1L/kg  ELIMINATION RATE First-order reaction kinetics The rate of change in concentration is proportional to the concentration Equations that you should learn are highlighted by red boxes Rate of elimination – k (min-1) 10 Plasma concentration k is the terminal rate of decrease in plasma 1 Elimination concentrations after either an oral or i.v. dose 0.1 k is a characteristic for the drug 0.01 0 4 8 12 16 Time in hours k is directly proportional to the clearance (CL) and inversely proportional to the apparent volume of distribution (V) k = CL V The rate of elimination is inversely proportional to the half-life (t½) Plasma clearance - CL Key facts: CL - is the volume of plasma cleared of drug per minute (or per hour) e.g. ml/min or L/h CL - depends on how good the body is at eliminating that drug (this will be determined by the organs involved in elimination of the drug) CL - is a specific value for each drug Plasma clearance - CL CL - is the parameter that best reflects the relationship between the blood and the organs of elimination CL - Plasma clearance of a drug will be very similar to the blood flow for the organ via which it is eliminated. e.g: - approaches liver blood flow for very rapidly metabolized drugs (1500 ml/min) - approaches renal blood flow for drugs secreted by the renal tubule (650 ml/min) - approaches glomerular filtration rate for drugs eliminated by filtration (120-130 ml/min) CL - for many drugs equals the sum of metabolic clearance and renal clearance CLplasma = CLmetabolic + CLrenal Plasma clearance - CL CL - can be calculated from plasma concentration data CL = Dose x F Units of the AUC = conc. x time AUC e.g. mg.ml-1.h i.v. Oral Plasma Conc. AUCoral AUCiv Conc. Time Time Metabolic clearance - CLM Drugs that affect the activity of the liver can change the Metabolic Clearance. Inducers will increase the CL M NORMAL LIVER Liver blood 80% flow = 1500ml/min OF DRUG 20% OF DRUG EXTRACTED CLM = 0.2 x 1500 = 300ml/min INDUCED LIVER Liver blood 60% flow = 1500ml/min OF DRUG 40% OF DRUG EXTRACTED CLM = 0.4 x 1500 = 600ml/min Half-life After one half life the concentration will be half of the original concentration Ct = concentration after 1 half-life ln Ct = ln C0 - kt -k = rate constant t = time C0 = initial concentration Therefore, if C0 is 1 then Ct will be 0.5 ln 0.5 = ln 1 – kt1/2 t1/2 = 0.693 - 0.693 = 0 – kt1/2 k Half-life Short half-life = Rapid elimination Is independent of concentration t1/2 = 0.693 Is a specific value for each drug k Is altered by changes in liver and/or kidney function (inducers/inhibitors/disease)  CHRONIC ADMINISTRATION Equations that you should learn are highlighted by red boxes Chronic administration Continuous intravenous infusion (NOT A BOLUS) Maintain a constant/stable concentration at site of action Persistent therapeutic effect Plasma (and tissue) concentrations increase until the rate of elimination is equal to the rate of input (or dosage) when a “steady state” (Css) is reached. Css is the steady state concentration when: Rate in = rate out Css 1000 Css steady-state Plasma concentration 4-5 5 x half-life Css = rate of infusion 100 clearance slope = - k or -  Infusion duration 10 0 2 4 6 8 10 12 14 16 18 Time in half-lives It takes 5 times the elimination half-life to reach Css Multiple dosing Maintain a constant concentration in the blood, by repeated oral dosing Average plasma concentration at steady state (Css) Css = Dose x F dose interval x CL Css plasma conc. The Css for a drug can be changed by 1. Changing the DOSE of drug 2. Changing the DOSE INTERVAL time Multiple dosing – Oral administration For the same drug consider keeping the dose the same and changing the dose interval Time to steady-state SAME DRUG 10mg per 4 hours PLASMA CONC. 10 mg per 8 hours A shorter interval produces a higher Css TIME ( in hours) Chronic administration - loading dose For drugs with long half-lives, the delay in the time to steady-state concentrations may be unacceptable (Remember: time to reach Css is 5 times the half life) The delay can be avoided by giving a large first dose (loading dose) which has the effect of “topping-up” the apparent volume of distribution Loading dose = Css x V (for i.v) OR Css x V/F (for oral) DESIRED PLASMA CONC. PLASMA Loading dose Maintenance doses CONC. TIME  Equations that you should learn are highlighted by red boxes: Area Under the Curve (AUC) = DOSE x F/CL Absorption: Bioavailability (F) F= AUCoral F= AUCoral x Doseiv AUCiv AUCiv Doseoral Distribution: Volume of Distribution (V) V = dose/C0 V = dose/y-intercept V= Dose x F Plasma concentration (after distribution) Elimination: Clearance (CL), Elimination Rate (k), Half life (t1/2) CL = Dose or CL = Dose x F k = CL t1/2 = 0.693 AUCi.v. AUCoral V k Chronic Administration: Concentration at Steady State (Css) Css = rate of infusion Css = Dose x F clearance dose interval x CL  Dry Practical PHARMACOKINETICS Go to vevox.app Enter the session ID: 162-056- 224 Or scan the QR code December 3 rd 10 am Building 67 Room 1037 Worksheet available on Blackboard from my lectures folder – Please try and look at it BEFORE coming to the