Pharmacokinetics for medical students 2014.

Information about Pharmacokinetics for medical students 2014.

Published on August 6, 2014

Author: drahmedabulhadia

Source: authorstream.com

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بسم الله الرحمن الرحيم: ِ ما تيسر من أول سورة إبراهيم بسم الله الرحمن الرحيم A brief review of Pharmacokinetic (PK) principles Dr. Ahmed S. Ali revised 2014: A brief review of P harmaco k inetic (PK) principles Dr. Ahmed S. Ali revised 2014 Topics : Topics ٌ Recall what is pharmacokinetics Factors affecting (ADME ) PK parameters Half life, Vd, Clearance PK after Single IV injection ; repeated IV injection, constant rate IV infusion, oral administration. Drug accumulation & steady state ( Css) Use of loading dose Estimation of maintenance dose Case: Case A woman, 56 years of age, weighing 70Kg, with a serum creatinine of 91micromol/L. Will receive 160 mg gentamicin once daily (i.v.) Will this regime be satisfactory? What is pharmacokinetics ?: What is pharmacokinetics ? PK deals with the processes to which drug is subjected within the body i.e absorption , distribution, , metabolism & excretion ( ADME ). Pk is clinically applied to avoid serious interaction, situations that optimization of dosage regimen, ( neonates, elderly , renal or liver impairment , drug –interaction. Absorption : Absorption Absorption is the movement of a drug from its site of administration ( e.g GIT ) into the blood. Lipid soluble non – ionized drugs are absorbed faster. Most of the absorption of the drug takes place in the small intestine. Acidic drugs such as asprin will be absorbed in the stomach. Some drugs are not absorbed or significant amount is subjected to inactivation by acidity, enzymes, bacterial enzymes or binding to GIT content. Some drugs are significantly metabolized in GIT wall or liver before reaching the general circulation (1 st pass effect) There are many other factors that should be considered. See the flash provided Clinical significance: Clinical significance Absorption affect bioavailability, onset , peak level , duration √Some factors affecting oral absorption or Bioavailability: √ Some factors affecting oral absorption or Bioavailability F actors related to the drug Physiochemical properties Stability. Lipid solubility Mol wt Factors related to the formulation Syrup ready for absorption > tablet Sustained release tab. slow absorption Factors related to the patient Physiological : age related change in Gastric PH, motility , gastric emptying time pathological : certain disease e.g. diarrhea , vomiting Other : interaction with food or other drugs . Factors related to the drug : Factors related to the drug 12000–15000 g/mol Theophyllin Genatmicin Heaprine Not absorbed orally Well absorbed orally Formulation: Formulation These formulations of Cyclosporine A show different bioavailability Cyclosporine A : exhibit great intra-individual variation in bioav. : Cyclosporine A : exhibit great intra-individual variation in bioav. Adapted from Johnston A et al. Transplant Proc . 2000;32:53S-56S. Hours Post-Dose 0 200 400 600 800 1000 1200 1400 0 2 4 6 8 10 12 Cyclosporine Concentration (ng/mL) C-0 C-2 AUC 0-12 AUC 0-4 Factors related to the patient : Factors related to the patient Delayed absorption of orally administered analgesic drugs Interaction with food or other drugs: Interaction with food or other drugs Complexes of ciprofloxacin with antacid Complex of tetracycline and calcium in milk or Fe , Al or Mg in antacid These complexes are poorly absorbed Tetracycline metal complex Factors related to the patient: Factors related to the patient Reduced absorption of SC injection Lipodystrophy Drug Distribution: Drug Distribution Distribution is the process by which the drug reversibly leaves the blood stream and enters the extra cellular fluids and or cells of tissues Distribution allows the drug to reach the site of action e.g. cardiac muscles, CNS, Drugs may distribute into any or all of the following compartments: Plasma Interstitial Fluid Intracellular Fluid What is One & two compartment models ??: One compartment Two compart distribution After distribution What is One & two compartment models ?? Rapid distribution Slow distribution Effect of Blood flow on drug distribution: Effect of Blood flow on drug distribution Blood flow to brain, liver, kidney is greater than skeletal muscles, Adipose tissues has lower blood flow Blood flow to the liver is important for drugs subjected to significant metabolism. Redistribution Ex Thiopental sod . Produces Rabid anesthesia but has short duration Why ? High lipid solubility & high blood flow allow high conc within CNS leads to rapid loss of consciousness after IV. Slow distribution to skeletal and adipose tissues decrease plasma level , this lead to decrease conc in CNS, and consciousness is regained ( 20-30 min) Influence of Capillary permeability on drug distribution: Influence of Capillary permeability on drug distribution .. Brain capillaries have a dense-walled structure and are surrounded by glial cells (lipid). This prevents many drug molecules from entering the surrounding tissue General body capillaries allow drug molecules to pass freely into the surrounding tissue Binding of drugs to proteins to plasma proteins: Binding of drugs to proteins to plasma proteins Many drugs bound to circulating plasma proteins such as albumin albumin : binds many acidic drugs and a few basic drugs b -globulin and an a 1 acid glycoprotein have also been found to bind certain basic drugs Free drug is the active form. Bound drug albumin Protein Binding & drug Interactions: Protein Binding & drug Interactions Plasma Tissue Drug A protein bound Drug A free Drug A free Drug B Drugs A and B both bind to the same plasma protein Some Factors influencing distribution : Some Factors influencing distribution Drug Chemical structure of drug Mol.wt , polarity, lipid solubility Binding to blood components (, RBC, plasma albumin) Age : body composition ( water, lean body & fat ) Physiological state : pregnancy. Rate of blood flow Capillary permeability Diseases Liver disease ( low plasma protein levels ) Renal impairment ( uraemia, low albumin ) Diabetes ( increase free Fatty acid ) Cystic fibrosis ( increase blood volume ) Blood flow is an important factor affecting drug distribution: Blood flow is an important factor affecting drug distribution Rabid distribution : Blood flow to brain, liver, kidney is greater than skeletal muscles, Slow distribution : Adipose tissues has lower blood flow Why Thiopental sod show . Rabid effect but short duration The reason is Drug Re-distribution ( not rabid metabolism ) The drug has High lipid solubility & The brain is highly perfused organ This allow high conc of the drug within CNS i.e rapid loss of consciousness after IV. The drug has slow distribution to skeletal and adipose tissues, this leads to decrease its plasma level , concequently decrease conc in CNS, finally consciousness is regained ( 20-30 min) Factors which can increase the fraction of unbound drug:: Factors which can increase the fraction of unbound drug : Renal impairment ( uraemia ) Low plasma albumin levels (<20-25g/L) E.g. chronic liver disease, malnutrition Late pregnancy Increased albumin production, but diluted by increased blood volume Displacement from binding site by other drugs e.g. aspirin, sodium valproate, sulphonamides, Saturability of plasma protein binding within therapeutic range e.g.. valproic acid Clinical significance of Protein Binding: Clinical significance of Protein Binding Higher free level associated with certain disease states or using other drugs . Increased availability of free drug; potential toxicity Important for drug with high plasma protein binding Renal impairment , lower albumin level , reduced binding Significance of altered plasma protein binding of drugs: Significance of altered plasma protein binding of drugs 1000 molecules % bound molecules free 99 95 50 10 5-fold increase in free pharmacologically active concentration at site of action . Effective ?? TOXIC Highly Protein Bound Drugs: Highly Protein Bound Drugs > 95% bound Thyroxin Warfarin Diazepam Fursimide Heparin Imipramine Amitriptylline > 90% - 95% Glibenclamide Phenytoin Propranolol Sodium Valproate Changes in plasma protein binding are significant for drugs which are greater than 90% bound to plasma proteins Apparent Volume of distribution (Vd): Apparent V olume of d istribution (Vd) It is a mathematica l factor relating the amount of drug in the body and the concentration of drug in the measured compartment, usually plasma It is not a physiological volume . It won't be lower than blood or plasma volume but it can be much larger than body volume for some drugs . Lecture 2: Lecture 2 Drug - METABOLISM: Drug - METABOLISM Drugs may converted to usually less toxic/effective metabolites sometimes more toxic/effective metabolites Individual variation in drug metabolism may be genetically determined May induced or inhibited by other drugs; foods or environmental factors Several routes of metabolism liver is the main site … Factors affecting drug metabolism: Factors affecting drug metabolism Genetic factors e.g. acetylation status Liver or certain cardiac or endocrine disease Other drugs hepatic enzyme inducers hepatic enzyme inhibitors Age Impaired hepatic enzyme activity Elderly Children < 6 months (especially premature babies) Enzyme Inhibiting Drugs: Enzyme Inhibiting Drugs For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions. Important CYP inhibitors are erythromycin, ketoconazole, and ritonavir Cimetidine blocks the metabolism of theophylline, clozapine, and warfarin Enzyme Inducing Drugs: Enzyme Inducing Drugs Certain drugs, e.g phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes,, with potential decrease or loss of pharmacologic effect . example, rifampin , an antituberculosis drug significantly decreases the plasma concentrations of human immunodeficiency virus (HIV) protease inhibitors , diminishing their ability to suppress HIV virion maturation. Paracetamol Metabolism: Paracetamol Metabolism Phase II Phase I Factors affecting biotransformation: Factors affecting biotransformation race ( genetic polymorphism ) (CYP2C9; warfarin (bleeding) phenytoin (ataxia). fast and slow isoniazid acetylators, age (reduced in aged patients & children ) clinical or physiological condition other drug administration food (charcoal grill induce CYP1A) (grapefruit juice inhibit CYP3A) PowerPoint Presentation: No. of patients Plasma conc. in 267 patients after 9.8 mg/kg ionized orally Genetic polymorphism Regularly updated information on human P450-polymorphisms is available at http://www.imm.ki.se/CYPalleles/. EXCRETION: EXCRETION The removal of intact drug molecule from the body Generally urine is the main route, It is important for drugs that mainly eliminated by renal route Renal elimination is greatly affected by age & gender. Some drugs are nephrotoxic and reduce elimination of other drugs Some drugs are excreted in bile , Enterohepatic circulation: Enterohepatic circulation Ion trapping & effect of PH: Ion trapping & effect of PH Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose . Sodium bicarbonate may be given to make the urine alkaline Urine Rest of body pH 8.0 pH 7.4 Non-ionised Non-ionised Ionised Ionised Barbiturate moves into urine - eliminated from body. Creatinine clearance ***: Creatinine clearance *** Creatinine is a waste product formed continuously by muscle. Filtered by kidneys Creatinine clearance Almost no active secretion approximately equals Almost no re-absorption filtration rate (G.F.R.) Creatinine clearance used as an estimate of G.F.R. IMPORTANCE OF CREATININE CLERANCE: The clearances of many renally excreted drugs are closely linked to GFR. e.g.. The clearance of gentamicin approximately equals GFR and therefore also approximates to creatinine clearance. When calculating a dosage regime we can assume that gentamicin clearance will equal creatinine clearance IMPORTANCE OF CREATININE CLERANCE Estimating creatinine clearance: Estimating creatinine clearance Cockcroft & Gault equation Men: CrCl = 1.23 x (140 – Age) x Wt SrCr Women: CrCl = 1.04 x (140 – Age) x Wt x SrCr CrCl = Creatinine clearance (ml/min) Age (Years) Wt = Weight (kg) SrCr = Serum creatinine ( micromol/L l) cardiac disease, and PK: cardiac disease, and PK cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Desipramine Imipramine Isoniazid Labetalol Lidocaine Meperidine Morphine Pentazocin Propranolol Verapamil liver disease & PK: liver disease & PK For example, the half-lives of chlordiazepoxide and diazepam in patients with liver cirrhosis or acute viral hepatitis are greatly increased, with a corresponding prolongation of their effects. Consequently, these drugs may cause coma in patients with liver disease when given in ordinary doses. : Diet and environmental factors also contribute to individual variations in drug metabolism. Charcoal-broiled foods and cruciferous vegetables are known to induce CYP1A enzymes, Grapefruit juice is known to inhibit the CYP3A metabolism of co administered drug substrates. Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction Industrial workers exposed to some pesticides metabolize certain drugs morerapidly than nonexposed individuals. Diet & Environmental Factors Tutorial & practical : Tutorial & practical PK estimations, related to different routes of Administrations Only IV Some important PK parameters: Some important PK parameters Volume of distribution V = DOSE / Co Plasma clearance Cl = Kel .V plasma half-life (t 1/2 ) directly from graph or t 1/2 = 0.693 / Kel Bioavailability (AUC)x / (AUC)iv IV (intravenous) bolus injection, : IV (intravenous ) bolus injection, A drug was given by iv bolus injection, blood samples were collected at various times and plasma concentrations of the drug were measured. A steady decrease in concentration was observed. ( as the drug is eliminated ) … Linear Plot of Concentration versus Time with Tangents shown . Half-life : Half-life Another important property of first order kinetics is the half-life of elimination( t 1/2 .) The half-life is the time taken for the plasma concentration to fall to half its original value . Thus if Cp = concentration at the start and Cp/2 is the concentration one half-life later then Integrated 1st order elimination equation : Integrated 1 st order elimination equation CP t = CP 0 e –Kel.t ( exponential equation ) ln Cp t = ln Cp o - kel * t ( linear equation ) √ Estimation of Volume of distribution: Estimation of Volume of distribution Volume of distribution V = DOSE / Co You provide a 300 mg of a drug to a patient , weight 60 kg ( Iv infusion -30 min ), the drug has half-life of 6 hr. The serum level , 30 min post dose was 10 ug/ml (10 mg/L ) What is the relation between total amount in the body (D)& serum level immediately after injection (Co) ?? Total amount in the body = Dose = 300 mg (Co) approx ( peak , after 30 min) = 10 mg/L 300 mg (D) = Constant (Vd) x 10 mg/L .(Co) Constant (Vd)= 300 mg / 10 mg/L = 30 L or 30 L/ 60 kg = 0.5 L/kg this constant is known as apparent volume of distribution . Uses of Volume of Distribution: Uses of Volume of Distribution Volume of distribution can help you calculate the dos e needed to achieve a certain peak plasma concentration Loading Dose (LD) = (Vd) x (C P ) Example: Gentamicin theophylline PowerPoint Presentation: Reference books say the V d of theophylline is 0.5 L per kg of body weight. What is the IV loading dose to give a serum theophylline concentration of 10 mg/L in a 62 kg man? LD = C p V d LD = (10 mg/L) x (0.5 L/kg ) = 5 mg /kg Total dose = 5 x62 =310 mg theophylline we usually use mcg/mL (or ug/mL), which is the same thing as mg/L Multiple dosing: Multiple dosing On multiple dosing plasma concentration will rise and fall with each dose and will increase until administration = elimination ie. steady state is reached . At each dose the level will oscillate through a range The objective is to remain within the therapeutic window , with acceptable variation at each dose and with a regimen which promotes compliance . Concentration at Css: C ss,max = “Peak” C ss (Average) C ss,min = “Trough” Concentrations at Steady State Concentration at Css Single i.v. bolus dose into one compartment: Single i.v. bolus dose into one compartment Dose = 400 mg V = 100 Litres K = 0.3 h -1 Initial conc (C 0 ) = 4 mg/L D V K i.v. bolus assuming a one compartment model : i.v. bolus assuming a one compartment model 0 2 4 6 8 10 4 3 2 1 0 C 0 C t t C t = C 0 .e -Kt Time (h) Conc (mg/L) Half-life and K: Half-life and K 0 2 4 6 8 10 4 3 2 1 0 Conc (mg/L) Time (h) C 0 = 4 mg/L t ½ = 2.3 h Low K / Long t ½ t ½ = 5.4 h High K / Short t ½ Less efficiently eliminated More Efficiently eliminated Linear regression: Linear regression C 0 0 2 4 6 8 10 8 6 4 2 0 C t = C 0 .e -Kt Time (h) Conc (mg/L) C t Time (h) 0 2 4 6 Ln Conc (mg/L) 2.0 1.0 0.0 LnC t = LnC 0 - Kt C 0 C t slope = -K Non-linear kinetic of DPH: Dose (mg/day) Plasma Concentration (mg/L) Relationship between Phenytoin Daily Dose and Plasma Concentration In 5 Patients Non-linear kinetic of DPH Example 3: Example 3 D = 10 mg V = 50 L K = 0.05 h-1 What is the expected drug conc. after 12 hours? C 0 = D/V = 10mg/50L = 0.2mg/L = 200  g/L C t = C 0 .e -Kt = 200  g/L . e -0.05h-1 x 12h = 200  g/L . e -0.6 = 200  g/L . 0.55 = 110  g/L alternative formula : LnC t = LnC o -Kt Example 4 : Example 4 Time (h) Conc (mg/L) 1 17.0 4 10.0 8 5.3 500 mg of drug given i.v.... Calculate: V, K , Cl & Level after 12 hr 2 14.0 6 7.4 10 3.8 Using calculator: Using calculator mode : Linear regression Clear Stat memory Ex Casio Fx 115MS Shift Mode Sc1 Mode all , Select 1 Mode Mode Select REG Lin Log Exp select 1 Enter data as X , Lny then dt ( M+) Shift [ 2] press A = intercept B = slope r = coefficient Ln Concen. vs time, 1st order elimination: Time (h) 0 2 4 6 8 10 12 100 50 30 10 5 3 1 ‘Theoretical C 0 ’ = 19.5 mg/L Ln Conc (mg/L) t ½ = 4.4 h Ln Concen. vs time, 1st order elimination : Key Point how to use EXCEL to Solve PK problems Make a table of 4 columns A ,B,C& _D input of data in two columns A : Time B: Concern Write again the time in column C In the upper cell of column D insert = Then insert/ function / Ln / select the Cell containing ( 1 st conc ) e.g A2 Repeat or Copy the function down [ Highlight the cells down &CTRL D- Draw graph use scatter type Highlight the graph add trotline Select Linear , option Show equation & R Y = value a + value b X Y = Ln C & Value a = LnCo , Value b = slope = -K Answer 4 , PK parameters : Answer 4 , PK parameters V = D / C 0 = 500mg / 19.5mg/L = 25.6 Litres K = 0.693 / t ½ = 0.693 / 4.4h = 0.158 h -1 Cl = K.V = 0.158 h -1 x 25.6 L = 4.04 L/h IV-infusion (graph): I.V. Infusion C ss Rinf > Elim Rinf >> Elim Rinf = Elim IV-infusion (graph) Predicting Css: Predicting C ss C ss = R inf Clearance This equation is general i.e. it is not restricted to one compartment models. Calculating infusion rate: Calculating infusion rat e We want to achieve a C ss of 15 mg/L. Clearance = 3 Litre/h C ss = R inf / Cl R inf = C ss x Cl = 15 mg/L x 3 Litre/h = 45 mg/h PowerPoint Presentation: Calculating loading dose: Calculating loading dose Concentration achieved = Loading dose Vol Dis C = LD V LD = C x V Target conc = 15 mg/L Vol dis = 50 Litres LD = 15 mg/L x 50 L = 750 mg (LD is given i.v., so no need to consider F)

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