1 PHARMACOKINETICS DR.ABDUL LATIF MAHESAR KING Dr.SAUD UNIVERSITY October 2008D
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PHARMACOKINETICSDR.ABDUL LATIF MAHESARKING Dr.SAUD UNIVERSITY October 2008D
DRUG ABSORPTIONIs the passage of the drug through body barriers or cell membranes to reach its site of action
Mechanism of Drug Movements Across Cell Membrane
Passive diffusion ( simple diffusion )
Facilitated diffusion ( need carrier )
Passive diffusionTypes: a) Aqueous Diffusion ( filtration through the pores) => water soluble and low molecular weight.
B) Lipid diffusion => lipid soluble and low molecular weight.
CharactersCommenestNon selectiveRequire no energyDepends on concentration gradientDepends on lipid/water partition coefficientDepends on PKa (of drug) and PH ( of the medium.
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( because 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
Active transport Relatively not common Against concentration gradient Requires carrier + energy Specific e.g iodides Saturable with receptor Depends on lipid/water coefficient Iron absorptionUptake of levodopa by brain
Carrier mediated Along concentration gradient Requires carrier Doesnt need energy Selective Saturable e.g uptake of glucose .vit.B12 and intrinsic factor.
Endocytosis High molecular weight drugs
There is engulfment of the substrate by the cell e.g vit A,E, D ,K
Factors affecting Drug absorption a) Drugs: 1. Molecular weight 2. PKa 3. Lipid water partition coefficient. 4. Drug formulation
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 time) 5. Surface area available for absorption 6. Drug interaction
c) Food: 1. Reduces absorption e.g aspirin,pencillin v, tetracyclin, erythromycin 2. Increases absorption e.g propranolol, diazepam, dicoumrol
2. DISTRIBUTION1. ECF (extra cellular fluid)Plasma (5% of body weight)Interstitial fluid (16% of body weight)Lymph (1% of body weight)
2. ICF (intracellular fluid)35% sum of fluid contents of all cells in the body
3. Transcellular fluid (2%) cerbrospinal , synovial, peritoneal,pleural, digestive secretion.
THE MAJOR BODY FLUID COMPARTMENTS 1.Intravascular(one compartment)in blood (not filtered through endothelium)
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.
Factors affecting distributionCardiac output and blood flow. increased cardiac output increases the distributionPhysiological properties of the drugPermeablity across tissue barrierPlasma protein binding with drugTissue binding with drugPHPKaLipid solubility (fat water partition)
Volume of distribution(vd)It is the amount of drug in the body to the concentration 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
Drugs with high volume of distribution Higher concentration in tissue than in plasma
Relatively lipid soluble
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
Drugs with low volume of distribution confined to plasma and interstitial fluids(not tissues)
Distributed in extracellular 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.
Physiological barriers Blood brain barrier (BBB) Placental barrier
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 congenital malformation) Anti-thyroid drugs neonatal goiter
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 ,gentamycin.
Binding of DrugsTissue 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 ether
3.Salivary and thyroid glands: Iodides
4.Liver: quinacrine ( 300 time more in liver) chloroquine with nucleic acid
5.Hair and Skin: arsenic( combines with keratin)
Plasma Protein Binding Albumin:acidic drugs bind with albumin such as warfarin,phenetoin, aspirin ,sulphonamides
Globulin : Basic drugs such as quinidine ,diazepam
Drugs exists in Bound form Unbound 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
Unbound Drug Pharmacologically active Available for metabolism Available for excretion Has short duration of action.
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 tolbutamide is free +effect)
Aspirin strong + warfarin-weak bleeding
Termination of the drug Biotransformation Excretion Redistribution
Resdistribution: resdistribution of the drug from its site of action to other tissues e.g thiopental
METABOLISM Drug metabol(biotransformation) It is the chemical reactions which lead to modification of drugs Sites of metabolism -Hepatic: microsomes ,mitochondria, cytoplasm - Extrahepatic: lung ,blood ,skin , GIT, kidney.
Microsomes: Microsomal enzyme system mixed function oxidase mono-oxigenase. its components:cytochrome P450Flavinoprotein NADPHMolecular oxygen, Mg
Mitochondria: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
Types of Metabolic ReactionPhase I reaction (non-synthetic)Phase II reaction (synthetic)
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
Microsomal: Drug + O2 +NADPH+Hchanged drug +H2O +NADPH e.g.1. Aliphatic hydroxylation Phenobarbitalhydroxyphenobarbital2. Aromatic hydroxylation Phenacetin 2-hydroxyphenacitin (paracetamol)3. Oxidation of amine Aniline nitrobenzene4. sulphoxidation Parathione paroxon
Non-microsomal: oxidation by soluble enzyme in cytosol or mitochondria of cells e.g 1. dehydrogenases and oxidasesEthanol acetaldehyde acetic acid.Methanol formaldehyde formic acid CH3CH2OH CH3CHOCH3COOH 2. monoamide oxidase(noradrenaline) 3. Hypoxanthine xanthine uric acid
Reduction Reactions: Microsomal or non-microsomal Microsomasl:nitrobenzene anilineNO2 NH2 Non-Microsomal:Chloral hydrate trichloroethanol
Hydrolysis:Non-microsomal ONLYEster-C-O and amides-C-N Acetylcholine choline +acetate(ester) Procainamide (lidocaine) (amide)
Characteristics of Phase I Products (Result of Drug Metabolism)1. Inactivation (abolish the activityOxidation of Phenobarbital and alcoholHydrolysis of acetylcholine2. 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-drugChloral hydrate trichloral hydrate 5. Product might undergo phase II
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 enzyme Except glucouronidation (catalyzed by glucouronyl transferase )
Characteristics of Phase II Produ