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1、1,PHARMACOKINETICS,DR.ABDUL LATIF MAHESARKING Dr.SAUD UNIVERSITY October 2008D,2,DRUG ABSORPTION,Is the passage of the drug through body barriers or cell membranes to reach its site of action,3,Mechanism of Drug Movements Across Cell Membrane,Passive diffusion(simple diffusion)Active transport Facil
2、itated diffusion(need carrier)Pinocytosis(endocytosis),4,Passive diffusion,Types:a)Aqueous Diffusion(filtration through the pores)=water soluble and low molecular weight.B)Lipid diffusion=lipid soluble and low molecular weight.,5,6,Characters,CommenestNon selectiveRequire no energyDepends on concent
3、ration gradientDepends on lipid/water partition coefficientDepends on PKa(of drug)and PH(of the medium.,7,PKa(is the dissociation or inization constant)is the PH at which half of the substance is ionized and half is unionized PH is the ionization of the drug weak acids=best absorbed in stomach(becau
4、se acid wont be ionized lipid soluble best absorption.Note:strong acids or bases are fully ionized(polar+water soluble)-can not cross cell membrane,given IV infusion,8,Active transport,Relatively not common Against concentration gradient Requires carrier+energy Specific e.g iodides Saturable with re
5、ceptor Depends on lipid/water coefficient Iron absorptionUptake of levodopa by brain,9,Carrier mediated,Along concentration gradient Requires carrier Doesnt need energy Selective Saturable e.g uptake of glucose.vit.B12 and intrinsic factor.,10,Endocytosis,High molecular weight drugs There is engulfm
6、ent of the substrate by the cell e.g vit A,E,D,K,11,Factors affecting Drug absorption,a)Drugs:1.Molecular weight 2.PKa 3.Lipid water partition coefficient.4.Drug formulation,12,b)Patient:1.PH of the gut 2.Rate of the gastric emptying 3.Presence of the food in the gut 4.Intestinal motility(transient
7、time)5.Surface area available for absorption 6.Drug interaction,13,c)Food:1.Reduces absorption e.g aspirin,pencillin v,tetracyclin,erythromycin 2.Increases absorption e.g propranolol,diazepam,dicoumrol,14,2.DISTRIBUTION,1.ECF(extra cellular fluid)Plasma(5%of body weight)Interstitial fluid(16%of body
8、 weight)Lymph(1%of body weight)2.ICF(intracellular fluid)35%sum of fluid contents of all cells in the body3.Transcellular fluid(2%)cerbrospinal,synovial,peritoneal,pleural,digestive secretion.,15,THE MAJOR BODY FLUID COMPARTMENTS,1.Intravascular(one compartment)in blood(not filtered through endothel
9、ium)2.Extra vascular(2 compartments)i-e blood and interstitial fluid pass endothelium but not cell membranes e.g Nitroglycerine.3.Extravascular and intracellular(multicompartment)pass endothelium and cell membranes.e.g physostigmine.,16,Factors affecting distribution,Cardiac output and blood flow.in
10、creased cardiac output increases the distributionPhysiological properties of the drugPermeablity across tissue barrierPlasma protein binding with drugTissue binding with drugPHPKaLipid solubility(fat water partition),17,Volume of distribution(vd),It is the amount of drug in the body to the concentra
11、tion of the drug in blood or plasma.vd=amount of drug in the body Cp(concentration in plasma)Increase in Cp,decreased is the volume of distribution and vice versa,18,Drugs with high volume of distribution,Higher concentration in tissue than in plasma Relatively lipid soluble Distributed intracellula
12、rly low molecular weight easy to cross barrier.not efficiently removed by the hemodialysis e.g phenyton,morphine,digoxin,tricyclic anti-depressants cross BBB or placental barrier easily,19,Drugs with low volume of distribution,confined to plasma and interstitial fluids(not tissues)Distributed in ext
13、racellular compartment mostly High MW,eg.heparin,insulin,dextran these are polar or lipid insoluble drugs e.g carbenicillin,vecuronium,gentamycin High plasma protein binding e.g warfarin Dont cross BBB or placental barrier because of lipid insolubility All skeletal muscle relaxants have low vd.,20,P
14、hysiological barriers,Blood brain barrier(BBB)Placental barrier,21,Placental barrier,Drugs cross placenta by simple diffusion lipid soluble drugs readily(easily)enter the fetal blood In mother if given Morphine respiratory depression in the fetus Warfarin hemorrhage(if taken in the 1st 3months conge
15、nital malformation)Anti-thyroid drugs neonatal goiter,22,Passage of drugs in to CNS and CSF,Controlled by BBB lipid soluble drugs e.g general anesthetics,CNS depressants,antibiotics chloramphenicol and sulphadiazine.Inflammation as in meningitis(in meningitis permeability is increased e.g penicillin
16、,gentamycin.,23,Binding of Drugs,Tissue binding(some drugs posses and affinity for certain tissues and get accumulated in there like:Bone e.g tetracycline and heavy metals such as lead(which combine with collagen)2.Fat:drugs like thiopental and ether3.Salivary and thyroid glands:Iodides4.Liver:quina
17、crine(300 time more in liver)chloroquine with nucleic acid5.Hair and Skin:arsenic(combines with keratin),24,Plasma Protein Binding,Albumin:acidic drugs bind with albumin such as warfarin,phenetoin,aspirin,sulphonamides Globulin:Basic drugs such as quinidine,diazepam,25,Drugs exists in,Bound form Unb
18、ound or free form Bound drugsNot available for combination with receptorNo pharmacological actionNot available for metabolismNot available for excretionlong duration of actionmay lead to clinically important drug-drug interaction,26,Unbound Drug,Pharmacologically active Available for metabolism Avai
19、lable for excretion Has short duration of action.,27,Displacement,some drugs can compete with each other for the same site on the plasma protein and displace drugs thus increasing their concentrations to toxic level.e.g.Warfarin-strong+tolbutamide-weak hypoglycemia(warfarin is binding where tolbutam
20、ide is free+effect)Aspirin strong+warfarin-weak bleeding,28,Termination of the drug,Biotransformation Excretion Redistribution,29,Resdistribution:resdistribution of the drug from its site of action to other tissues e.g thiopental,30,METABOLISM,Drug metabol(biotransformation)It is the chemical reacti
21、ons which lead to modification of drugs Sites of metabolism-Hepatic:microsomes,mitochondria,cytoplasm-Extrahepatic:lung,blood,skin,GIT,kidney.,31,Microsomes:,Microsomal enzyme system mixed function oxidase mono-oxigenase.its components:cytochrome P450Flavinoprotein NADPHMolecular oxygen,Mg,32,Mitoch
22、ondria:mono-amine oxidase enzyme(MAO)Acetylation Cytoplasm:Alcohol dehydrogenase Blood(plasma)EstrasesAmidasesCatechol-o methyltransferases(COMT)Intestinal Mucosa and Lumen:GIT flora:Glucouronidase,Asoreductases.GIT mucosa:Monoamime oxidase(MAO),Suphatase,33,Types of Metabolic Reaction,Phase I react
23、ion(non-synthetic)Phase II reaction(synthetic),34,Phase I Reaction:,Make the drug more polar more water solulble.(oxidation reduction-hydrolysis)Oxidarion reaction:introduces functional group(OH,NH2,SH)Can be mirosomal or nonmicrosomal,35,Microsomal:,Drug+O2+NADPH+Hchanged drug+H2O+NADPH e.g.1.Aliph
24、atic hydroxylation Phenobarbitalhydroxyphenobarbital2.Aromatic hydroxylation Phenacetin 2-hydroxyphenacitin(paracetamol)3.Oxidation of amine Aniline nitrobenzene4.sulphoxidation Parathione paroxon,36,Non-microsomal:,oxidation by soluble enzyme in cytosol or mitochondria of cells e.g 1.dehydrogenases
25、 and oxidasesEthanol acetaldehyde acetic acid.Methanol formaldehyde formic acid CH3CH2OH CH3CHOCH3COOH 2.monoamide oxidase(noradrenaline)3.Hypoxanthine xanthine uric acid,37,Reduction Reactions:Microsomal or non-microsomal Microsomasl:nitrobenzene anilineNO2 NH2 Non-Microsomal:Chloral hydrate trichl
26、oroethanol Hydrolysis:Non-microsomal ONLYEster-C-O and amides-C-N Acetylcholine choline+acetate(ester)Procainamide(lidocaine)(amide),38,Characteristics of Phase I Products(Result of Drug Metabolism),1.Inactivation(abolish the activityOxidation of Phenobarbital and alcoholHydrolysis of acetylcholine2
27、.conversion of active drug to another active one.Diazepam oxydiazepamCodeine,heroin MorphinePhenylbutazone oxyphenylbutazonePropranolol 4-hydroxypropranolol 3.conversion of drug to toxic metabolites:Paracetamol acetaminopen(hepatic toxicity)Halothane metabolite hepatotoxicity 4.Activation of pro-dru
28、gChloral hydrate trichloral hydrate 5.Product might undergo phase II,39,Phase II Conjugation Reaction(Synthetic reaction),Glucuronide conjugationAminoacid eg.glycine Acetylation reaction e.g CO-CH3 Sulphate conjugation SO4 Methylation reaction e.g CH3Noradrenaline adrenaline ALL is non-microsomal en
29、zyme Except glucouronidation(catalyzed by glucouronyl transferase),40,Characteristics of Phase II Products,Product=Conjugate Pharmacologically inactive More water soluble to be excreted More readily excreted in urine,41,Modulation of Liver Microsomal Enzymes,Induction Inhibition Liver Microsomal Ind
30、ucersAlcoholBarbituratesCigarette smokingPhenytoinRifampicinSpironalactoneGriseofulvin,42,Enzyme Induction results in,Increase metabolism of the inducer Tolerance:decreased pharmacological action of the drug Increase the metabolism of co-administered drug(drug interaction)Barbiturate+WarfarinPhenyto
31、in+Oral contraceptivesRifampicin+Hydrocortisone Increased metabolite-mediated tissue toxicityParacetamol and phenacetin As therapy(phenobarbitone+hyperbilirubinemia),43,Liver Microsomal Inhibitors,CimetidineErythromycinketoconazoleMetronidazoleProbenecidEnzyme inhibition may Retard the metabolism an
32、d excretion of the inhibitor and co-administered drugs Prolong the action of the inhibitor and co-administered drugs increased pharmacological activity.,44,First Pass Metabolism,A drug can be metabolized before the drug reaches the systemic circulation so the amount reaching systemic circulation is
33、less than the amount absorbed Where?Liver,gut wall,lungResult:low bioavailabilityShort duration of action How is it given e.g MorphineSalbutamol,45,4.EXCRETION,Main routes of excretionRenal excretionBiliary excretion Minor routes of excretionExhaled airSalivary secrtetionsSweat MilkTears,46,Renal ex
34、cretion:,Glomerular filtration Active tubular secretion Passive tubular reabsorption Alteration in tubular PHe.g:gentamycin,ampicillin,benzylpencillin,digoxinContraindicaited:in case of renal failurein case of elderly,47,Glomerular filtration,Only free drug(not bound to albumin)Low molecular weight
35、drug(below 20000)renal plasma flow=600ml/min GFR 20%of renal plasma flow=125 ml/min,48,Active Tubular secretion:,Characters:Selective Require energy carrier Against concentration gardient Clearance to plasma protein bound drugsTypesSystem for acidic drugsSystem for basic drugs,49,System for Acidic D
36、rugs:e.g.of acidic drugs:salicylates,sulphonamides,penicillin,glucouronide conjugate,sulphate conjugate.Blocked by:probenicid(inhibitor)carrier will carry this drug so,acidic drugs long duration of action+blocker will excertion.System for Basic Drugs:e.g catecholamines,atropine,morphine,quinine,neos
37、tigmine.,50,Passive tubular reabsorption,Non ionized form(lipid soluble)can be reabsorbed back into systemic circulation and excretion will be low Ionized drugs are poorly reabsorbed and so rapidly excereted.,51,Alteration in urine PHUrine is normally slightly acidic and favors excretion of basic dr
38、ugsAcidification of urine increased excretion of basic drugsAlkalization of urine increased excretion of acidic drugs.,52,Acidification of urine:byammonium chlorideascorbic acid Alkalization of urinebySodium bicarbonateSodium lactateSodium citrate.,53,Biliary excretionIs important for some drugs tha
39、t are metabolized in the liver e.g:digoxinBiliary excretion is useful in treating biliary infectionIt plays a role in the removal of conjugated metabolites particularly glucouronides,54,Enterohepatic CirculationBile passes into the intestine where drug if lipid soluble is reabsorbed again and cycles is repeated.Glucouronides are hydrolyzed in intestine liberating free drugs that can be reabsorbed backThis prolongs the action the druge.g.morphine,ethinyl estradiol,thyroxine,55,Drug clearance,
