Drug Elimination PDF

Drug Elimination Objectives Explain the drug clearance by kidney, liver & other routes Compare & contrast between first order & zero order kinetics Estimate the loading dose, maintenance dose & steady state concentration of a drug. Enumerate the methods of prolonging drug action Drug Eli...

Drug Elimination Objectives Explain the drug clearance by kidney, liver & other routes Compare & contrast between first order & zero order kinetics Estimate the loading dose, maintenance dose & steady state concentration of a drug. Enumerate the methods of prolonging drug action Drug Elimination Excretion Excretion is the passage out of systemically absorbed drug. Drugs and their metabolites are excreted in: 1. Urine/ Kidney: Most of drugs excreted thro kidney 2. Faeces: erythromycin, ampicillin 3. Exhaled air: general anaesthetics, alcohol 4. Saliva and sweat: Lithium, pot. Iodide 5. Milk: Amphetamine, chloramphenicol RENAL EXCRETION 1. Glomerular filtration 2. Tubular reabsorptior 3. Tubular secretion Net renal excretion= (glomerular filteration+ tubular secretion)-tubular reabsorption RENAL EXCRETION 1. Glomerular filtration Glomerular capillaries have large pores. Thus, glomerular filtration of a drug depends on its plasma protein binding and renal blood flow. Glomerular filtration rate (g.f.r.), normally- 120 ml/ min, declines progressively after the age of 50, and is low in renal failure. RENAL EXCRETION 2.Tubular reabsorption This is mainly by passive diffusion Depends on lipid solubility, ionization More lipid soluble drugs, unionized drugs reabsorb back Clinical significance (poisoning) Urine is alkalized in barbiturates poisoning (acidic drug) Urine is acidify in morphine poisoning (basic drugs) RENAL EXCRETION 3. Tubular secretion ▪ Mainly occurs in the proximal tubules ▪ Occurs by active transport processses. ▪ Excretion of protein bound drug KINETICS O F ELIMINATION Clearance (CL) The clearance of a drug is theoretical volume of plasma from which drug is completely removed in unit time CL =Rate of elimination/ C (plasma concentartion) First order (exponential) kinetics The rate of elimination is directly proportional to drug concentration, CL remain constant; Constant fraction of drug present in body is eliminated in unit time.  Zero order (linear) kinetics The rate of elimination remains constant irrespective of drug concentration, CL decreases with increase in concentration; Constant amount of drug is eliminated in unit time, e.g. ethyl alcohol.  Plasma half-life Plasma half-life (T1/2) of a drug is time taken for its plasma concentration to be reduced to half of its original value. 1 T1/2: 50% drug is eliminated. 2 T1/2: 75% (50 + 25) drug is eliminated. 3 T1/2: 87.5% (50+ 25 + 12. 5) drug is eliminated 4 T1/2: 93. 75% (50 + 25 + 12. 5 + 6.25) Thus, nearly complete drug elimination occurs in 4-5 half lives. Steady State Plasma Concentration (Cpss) When a drug is repeatedly given at relatively short intervals, it accumulates in body until elimination balances input & a steady state plasma concentration (Cpss) is attained dose rate Cpss = Dose rate/ CL (clearance) Steady State Achieved Drug is no longer accumulating Amount in = Amount out Loading dose This is a single or few quickly repeated doses given in beginning to attain target concentration rapidly Loading dose =(VD ) X desired plasma concentartion/Bioavailability Maintenance dose This dose is one that is to be repeated at specified intervals after attainment of target Cpss so as to maintain same by balancing elimination Dosing rate (average dose per unit time) =(CL ) X desired plasma concentartion/Bioavailability CL=clearance; PROLONGATION OF DRUG ACTION Advantages Frequency of administration is reduced more convenient Improved patient compliance Large fluctuations in plasma concentration are avoided Drug effect could be maintained overnight without disturbing sleep Methods of prolonging drug action Methods By prolonging absorption from site of administration By increasing plasma protein binding By retarding rate of metabolism By retarding renal excretion Further reading: Lippincott’s Illustrated Review of pharmacology 7 th edition Katzungs Basic and clinical pharmacology- 15th edition