General Pharmacology-ABSORPTION & DISTRIBUTION.pptx

drug absorption and distribution

1. ABSORPTION and DISTRIBUTION

2. ABSORPTION BIOLOGICAL MEMBRANE –lipid bilayer –hydro carban chain in matrix–extrinsic and intrinsic protien molecules Aqueous pores Paracellular spaces /channels Adsorbed proteins-enzymatic carrier- receptor- signal transducers Lipid moleculecules lateral movement

3. PASSIVE DIFFUSION Against conc gradient Influence of PH - weak electrolytes- quick ionisation Pka negative log of acidic dissociation constant PH= Pka slightchange in ionisation produce considerable change in absorbtion Acidicdrugs readily absorbed from stomach

4. FILTRATION Against osmotic gradient Specialised transport –carrier/transporter Facilitated diffusion-solute carrier transporter- no energy is needed-electro chemical gradient Active transport- energy is needed -prim act transport-ATP Hydrolysis Secondary active transport- symport - cotransport Antiport - exchange transport

5. PINOCYTOSIS VESICAL FORMA TION - BIGGER MOLCULES AND PROTINES -NOT VERY MUCH INVOLVED

6. FACTORS MODIFING ABSORPTION Aqueaous solubility conc of the drug Area of absorption surface Vascularity of absorptive area Route of administration ORAL-Stomach- nonionised lipid soluble-acidic drugs

7. Factors affecting Wall thickness –mucosal thickening - small surface area –gastric emptying time Particle size Presence of food -TC with milk Ionisation of the drug Degradation of the drug in git-eg peniciinG Remedy –Sustained release –enteric coated tablets Efflux transporter P- gp -Inducer – eg rifampicin phenobarbitone -inhibitors – Em – verapamil -drugs absorped is digoxin cyclosporin

8. Factors affecting Presence of other drugs-luminal effect –TC with antacid Entero hepatic circulation digoxin OCP Motility of gut – anticholinergic,Metoclopromide Damage to mucosa-neomycin anti cancer drugs S.C .I.M. Lipid soluble -passes through- direct deposition near capillary

9. l Large molecule – paracellular space Very large molecule lymphatic–heat –muscular exercise-increase absorption Vasoconstrictor drugs –adrenalin with LA Absorption retarded Hyaluranidase presence enchances absn Depot preparations benzathin penicillin TOPICAL-Intact skin – hyocin GTN Nicotin

10. Abaraded skin-more drug absorbed quickly Cornea – physostigmine –permeable –neomycin not permeable Mucous membrane vaginal cream oestrogen feminisation in male partner

11. BIOAVAILABILITY DEFN measure of the fraction –F of administered drug that reaches the systemic circulation in unchanged form I.V. 100% S.c . & i.m . less due tolocal binding Oral – incmplete absorption & first pass metabolism inliver & intestine - low bioavailability

12. BIOEQUIVALENT DEFN -when the rate & extent of bioavailability is not significantly different under identical condition of two formulations it is called as bioequivalent Signification only for drugs with low safety margin eg digoxin & dose needs precise control eg oral hypoglyceamic oral anti coagulants In anti microbial also should be consiered when there is failure of therapy

13. DISTRIBUTION Factors affecting distribution are Lipid solubility Ionisation at physiological Ph Plasma \tissue protine binding Tissue specific transporters Regional blood flow Volume of distribution =dose administered\plasma concentration

14. REDISTRIBUTION High lipid soluble drugs –high blood flow organs –brain kidney heart liver first –muscle and fat tissue later -drug released slowly to the plasma eg thiopentone sodium i.v . Blood brain barrier Capillary lined by tight jned choroidal epithelium- lipoidal -no entry for nonlipid soluble drugs eg steptomycin,neomycin

15. Eflux transporters – Pgp and anion transporter extrude other drugs entering by other means Enzymatic blood brain barrier-MAO cholinesterase DEFICIT CTZ medulla periventricular sites[anterior hypothalamus] Inflammation of meninges and brain increase the Permeability Endogenous substances –accumulate by transporters

16. PLACENTAL BARRIER Lipoidal drugs easily passes through Hydrophylic drugs are restricted Placental eflux Pgp limit drugs from maternal blood Influx transporters allow entry of drug It is not so protective as BBB Eg Morphine given at delivery – resp depression in foetus

17. PLASMA PROTEIN BINDING physicochemical affinity- plasmaprotine Acidic drugs –albumin Basic drugs –alpha1acid glycoprotine CLINICAL IMPLICATIONS 1.High ppb drugs restricted to vascular compartment -small vol of distribution Temporary storage organ –no action of bound drug

18. Drug interaction-many sites of binding in albumin molecule more than one drug competes for the same site displacement interaction Eg salicylate – sulphonyl urea- methotrexate Indomethacin , phenytoin -- warfarin Sulphonamides , vit k- bilirubin – kernicterus in new born

19. 3.Longer duration of action –bound drug Does not undergo metabolism and excretion In poisoning not removed by hemodialysis Drug plasma conc calculated will be incorrect Disease states – hypoalbumineamia -reduced binding eg phenytoin , furosemide Ureamia -reduced binding – eg digoxin phenytion pethedin Pregnancy ,inflammatory disease increased binding- eg propran olol as alpha1 glycoprotein increase

20. TISSUE STORAGE Accumulate in specific organs by active transport –bound to specific tissue constituents Eg TC – bone and teeth & mitochondria Chloroquine -retina & nuclei SM –vestibular apparatus Emetine –heart & skeletal muscle

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