Presentation on theme: "Absorption, distribution, metabolism and excretion"— Presentation transcript:
1 Absorption, distribution, metabolism and excretion relevant to ALL drugslarge research/development areafrequent cause of failure of treatmentfailure of compliancefailure to achieve effective levelproduce toxic effectscan enhance patient satisfaction with treatment
2 Learning objectives Know the processes involved in ADME of drugs Know how these processes may affect the action of xenobioticsAppreciate how these processes can affect the outcome of the treatment of patients with drugsAppreciate how differences in these processes between patients can affect therapyKnow how these processes have been exploited to improve therapyBe able to exemplify the above
3 Passage through lipid membranes diffusion through gaps between cells (glomerulus = 68K; capillary 30K)passage through the cell membranediffuse through pore (very small; use dependent)carrier mediated transport (specific, saturable; Fe in gut; L-DOPA at blood-brain barrier; anion/cation transport in kidney)pinocytosis (insulin in CNS; botulinum toxin in gut)diffusion through lipid of cell membrane (depends on AREA, DIFFUSION GRADIENT, DIFFUSION COEFFICIENT, LIPID SOLUBILITY)
4 Weak acids and weak bases HA <==> H+ + A B + HCl <==> BH+ + Cl-[ UI ] [ I ] [ UI ] [ I ]pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)pKa = 4.5 (a weak acid)pH = 2pH = 7.40.1 = [ I ][ I ] = 9990100 = [ UI ][ UI ] = 100= total drug =
5 Routes of administration Enteral; oral, sub-lingual (buccal), rectalParenteral; iv, im, sc, id, it, etc.Surface; of skin, of lungs? for local or systemic effect?Inhalation; local or systemic effect?Vaginal; (usually local)Eye; (usually local)
6 Factors affecting oral absorption Disintegration of dosage formDissolution of particlesChemical stability of drugStability of drug to enzymesMotility and mixing in GI tractPresence and type of foodPassage across GI tract wallBlood flow to GI tractGastric emptying time
7 Bioavailabilitythe proportion of the drug in a dosage form available to the bodyi.v injection gives 100% bioavailability.Calculated from comparison of the area under the curve (AUC) relating plasma concentration to time for iv dosage compared with other route.Says nothing about effectiveness.
8 Bioavailability Destroyed in gut Not absorbed Destroyed by gut wall by liverDosetosystemiccirculation
10 Distribution into body compartments Plasma 3.5 litres, heparin, plasma expandersExtracellular fluid 14 litres, tubocurarine, charged polar compoundsTotal body water 40 litres, ethanolTranscellular small, CSF, eye, foetus (must pass tight junctions)Plasma protein binding; Tissue sequestration
11 Alter plasma binding of drugs 1000 molecules90.099.9% bound1molecules free100100-fold increase in free pharmacologicallyactive concentration at site of action.Effective TOXIC
12 Biotransformation of drugs Mutations allowing de-toxification of natural toxic materials are advantageous and are selectedDrugs are caught up in these established de-toxification processesDrugs may converted toless toxic/effective materialsmore toxic/effective materialsmaterials with different type of effect or toxicity
13 Sites of biotransformation where ever appropriate enzymes occur; plasma, kidney, lung, gut wall andLIVERthe liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation
14 The liver bile Hepatocytes venous blood smooth portal endoplasmic reticulumbilemicrosomescontain cytochrome P450dependentmixed function oxidasessystemicarterialbloodvenous blood
15 Cytochrome P450 dependent mixed function oxidases DRUGMETABOLITE=DRUG+OO2microsomeNADP+NADPHWATERH+
17 Phase I in action N CH2 N CH3 CH3 4-OH; active; 4-OH; cardiotoxic NCH2NCH3 CH3desmethyl;active;antidepressant+Conjugates;phase II
18 PHASE 2 reactions (not all in liver) CONJUGATIONS-OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides-OH with sulphate to give sulphates-NH2, -CONH2, aminoacids, sulpha drugs with acetyl- to give acetylated derivatives-halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugatesall tend to be less lipid soluble and therefore better excreted (less well reabsorbed)
19 Other (non-microsomal) reactions Hydrolysis in plasma by esterases (suxamethonium by cholinesterase)Alcohol and aldehyde dehydrogenase in cytosolic fraction of liver (ethanol)Monoamine oxidase in mitochondria (tyramine, noradrenaline, dopamine, amines)Xanthene oxidase (6-mercaptopurine, uric acid production)enzymes for particular drugs (tyrosine hydroxylase, dopa-decarboxylase etc)
20 Inhibitors and inducers of microsomal enzymes INHIBITORS cimetidineprolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs)INDUCERS barbiturates, carbamazepine shorten action of drugs or increase effects of those biotransformed to active agentsBLOCKERS acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)
21 Factors affecting biotransformation age (reduced in aged patients & children)sex (women more sensitive to ethanol?)species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); route of biotransformation can also changerace (fast and slow isoniazid acetylators, fast = 95% Eskino; 50% Brits; 13% Finns; 13% Egyptians.clinical or physiological conditionfirst-pass (pre-systemic) metabolism
22 Excretion of drugsGlomerular filtration allows drugs <25K MW to pass into urine; reduced by plasma protein binding; only a portion of plasma is filtered.Tubular secretion active carrier process for cations and for anions; inhibited by probenicid.Passive re-absorption of lipid soluble drugs back into the body across the tubule cells.Note effect of pH to make more of weak acid drug present in ionised form in alkaline pH therefore re-absorbed less and excreted faster; vica-versa for weak bases.
23 Special aspects of excretion lactating women in milklittle excreted in faeces unless poor formulation or diarrhoeavolatile agents (general anaesthetics) via lungsthe entero-hepatic shunt glucuronic acid conjugates with MW >300 are increasingly excreted in bile; hydrolysis of say -OH conjugate by beta-glucuronidase in gut will restore active drug which will be reabsorbed and produce an additional effect.