Pharmacokinetics Academic Notes

Pharmocokinetics Relationship between the dose and the unbound drug conc at the site of action and time course of drug conc in the body LADMER Liberation Absorption Distribution Metabolism Elimination Response Type of liberation Topical Injection Oral Inhalation Rectal Vaginal Advantaged of Topical - Local site of action - Limited side effects, usually to site of application - Known duration of action - Better physical tolerance compared with injections Disadvantges of Topical - Limited choice of drugs- related to molecular size and lipid solubility - Duration of action is limited - Troublesome to use: I large areas are to be covered, drops require manual dexterity to use corrrectly - Shelf-life may be limited Type of injections - IV - IM - Intrathecally (spinal) - Intra-articularly (joint) - Sub-cutaneously (below skin) - Intra-dermally (skin) - IV is rapid acting, usually within mins , slower for SC then IM - 100% Bioavailability 1/5 Advantaged of Injections - Useful if systemic effects required urgently- except IA - Duration of action usually well known - Useful if PX id unconscious Disadvantages of Injections - Expensive - Invasive: risk of infection, painful - Unpleasant for PX: affect compliance - Normally short duration of action, may require multiple doses - Side effects may be more pronounced Advantaged of Tablets - Usually cheap - Convenient - Better compliance - Easier to take Disadvantaged of Tablets - Bioavailability variable on range of factors - Duration of action may be unknown/variable - Slow unset , usually at least 10-20 mins and undergoes first-pass effect (sublingual/buccal avoid this) Advantages of Rectal/Vaginal - Useful for local effects - Cheap - Can by-pass first pass metabolism Disadvantages of Rectal/Vaginal -Limited chocie - PX Compliance Advantages of Inhalation - Local site of action - Rapid acting - Limited site effects - Convenient Disadvantages of Inhalation - Expensive - Difficult to use- poor PX compliance - Formulation can be difficult - Duration of action can be limited - may need required dosages 2/5 - Not suitable if urgent systemic effect required What is metabolism Mechanism for chemically modifying a drug without actually removing it from the body What organ is primarily responsible for metabolising/transforming drugs Liver What organs prevent potential harm from drugs and compounds Small intestine and Skin All blood passes through.. Liver Metabolism is typically a... Enzymatic reaction that takes place within the cells What are the first organs encountered after oral administration GI and Liver (repsonsible for a significant amount of metabolism/ first pass) Wishing a cell, what is responsible for drug metabolism ER (phase 1 reactions) Factors altering metabolism - Age - Diet (grapefruit jucie) - Co-administration of drugs - Disease - Stereoselectivity - Timing - Environmental Otogeny Age - Metabolism between neonates, children, adults varied - Foetuses/newborns = slow metabolisers - Rapidly increases within firs year of life - Care to be taken w dosage for <12 Rifampicin, induce P450 such that meInduction (drug-drug interactions affect- tabolism of other drugs increases- may ing metabolism) necessitate dose increase to compensate 3/5 Autoinduction Occur where the drug actively induces its own metabolism EG- Carbamazepine necessitating large increases in dose at initiation of therapy Inhibition Drugs can bind to the P450 site and inhibit the effect of cytochrome w/out being metabolised. This inhibits metabolism of other drugs such that metabolism is reduced Diseases affecting metabolism Hepatic disease Renal Disease Will need dose adjustments to compensate for changes in metabolism to ensure adequate efficacy without toxicity Stereoselectivity - Many drugs administered as racemates - Production of mono isomeric drugs: usually to reduce or minimise unwanted side effects without effecting efficacy/activity - Metabolism can effect one isomer more than its racemate (Warfarin) Timing Changes in blood low and blood pressure occur throughout they and this may in turn have an impact First Pass Effect - Responsible for poor bioavailability due to removal of drug - Drugs metabolised by CYP3A4 most susceptible ( grapefruit can inhibit resulting in toxic rises in serum plasma levels) - Glyceryl trinitrate almost 100% metabolised by F.P.M therefore orally inactive, need to give in alternate routes - Metabolism can be saturated - If large dose given, amount of drug metabolised will remain unchanged resulting in plasma levels rising 4/5 Rate Limited Metabolism - Clearance becomes dependant upon dose. (small doses will have half-lives in order of 12hours <1hour/ large doses order of 2-3 weeks) - Referred tp a Zero Order/ Non-linear / Rate Limited kinetics 5/5