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Excretion of drugs and kinetics of elimination

The document discusses the excretion of drugs through various organs, focusing on the mechanisms and kinetics involved in renal and biliary excretion. It explains concepts such as glomerular filtration, tubular reabsorption, and secretion, outlining how different drugs are processed based on their characteristics, such as solubility and ionization. Additionally, it covers the principles of drug clearance, elimination kinetics, and the impact of plasma half-life on dosage regimens.

Health & Medicine◦
Excretion of Drugs and Kinetics of elimination Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
Goal • Different organs of drug excretion and mechanism • Renal excretion of drugs • Concepts of drug clearance and plasma half life • Concept of the platue principle
Organs of Excretion • Excretion is a transport procedure which the prototype drug (or parent drug) or other metabolic products are excreted through excretion organ or secretion organ • Hydrophilic compounds can be easily excreted. • Routes of drug excretion – Kidney – Biliary excretion (Faeces) – Exhaled air – Sweat and saliva – Milk
Faeces (Hepatic Excretion) • Unabsorbed and derived from bile • Drugs can be excreted in bile, especially when they are conjugated with – glucuronic acid  Organic acids - OATP and MRP2  Organic Bases – OCT  Lipophilic drugs – P-gp  Larger molecules are eliminated (MW>300) • Drug is absorbed  glucuronidated or sulfatated in the liver and secreted through the bile  glucuronic acid/sulfate is cleaved off by bacteria in GI tract  drug is reabsorbed (steroid hormones, rifampicin, amoxycillin, contraceptives) - ENTEROHEPATIC CIRCULATION • Anthraquinone, heavy metals – directly excreted in colon
Renal Excretion  All water soluble substances  Amount of Drug in urine is Net Renal Excretion = (GF + Tubular secretion) – Tubular reabsorption • Glomerular Filtration • Tubular Reabsorption • Tubular Secretion
Glomerular Filtration • Net Renal excretion: (GF + tubular secretion) – tubular reabsorption • Glomerular capillaries have pores larger than usual • All nonprotein bound drugs (lipid soluble or insoluble) presented to the glomerulus are filtered • Glomerular filtration of drugs depends on their plasma protein binding and renal blood flow - Protein bound drugs are not filtered ! • Normal GFR – 120 ml/min • Renal failure and aged persons – declines progressively
Tubular Re-absorption • Physiologically 99% of Glomerular Filtrates are reabsorbed • Back diffusion of Drugs (99%) – lipid soluble drugs • Depends on pH of urine, ionization etc. • Lipid insoluble ionized drugs excreted as it is – aminoglycoside (amikacin, gentamicin, tobramycin) • Changes in urinary pH can change the excretion pattern of drugs – Weak bases ionize more and are less reabsorbed in acidic urine. – Weak acids ionized more and are less reabsorbed in alkaline urine • Utilized clinically in salicylate and barbiturate poisoning – alkanized urine • Acidified urine – atropine and morphine etc. • Effects of changes in urine pH is best observed with Drugs having pKa of 5 – 8
Tubular Secretion • Active transfer of organic acids and bases: Proximal tubule – OAT – organic acid transport: penicillin, probenecid, uric acid salicylates, methotrexate – OCT – organic base transport: quinine, thiazides, furosemide, amiloride – Also P-gp and MRP2 • Renal clearance >120 ml/min – tubular secretion • Advantage: Reduces the free concentration of drugs – further, more drug dissociation from plasma binding – again more secretion (protein binding is facilitator for excretion for some drugs) • Bidirectional transport – Blood Vs tubular fluid • Exogenous (drugs) Vs Endogenous (uric acid) • Utilized clinically – penicillin Vs probenecid and probenecid Vs uric acid • Salicylate Vs uricosuric action of probenecid in gout (gets block) • Quinidine decreases renal and biliary clearance of digoxin by inhibiting efflux carrier P-gp
Renal Excretion – must remember! • Acidic urine • alkaline drugs eliminated • acid drugs reabsorbed • Alkaline urine - acid drugs eliminated - alkaline drugs absorbed
Kinetics of Elimination • Provide basis for devising dosage regime and modify them • Pharmacokinetics - F, V and CL • AUC p.o. F = ------------ x 100% AUC i.v. 10 mcg/ml Drug in >10 mcg/ml Plasma 500mcg/min (RoE) 10 mcg/ml (C) = 50 ml/min CL = 500 mcg/min Organ of Drug Elimination (Kidney, liver etc.)
Clearance • Clearance: The clearance (CL) of a drug is the theoretical volume of plasma from which drug is completely removed in unit time CL = Rate of elimination (RoE)/C Example = If a drug has 20 mcg/ml and RoE is 100 mcg/min CL = 100/20 = 5 ml /min
Kinetics of Elimination • First Order Kinetics (exponential): Rate of elimination is directly proportional to drug concentration, CL remaining constant – Constant fraction of drug is eliminated per unit time • Zero Order kinetics (linear): The rate of elimination remains constant irrespective of drug concentration – CL decreases with increase in concentration – Alcohol, theophyline, tolbutmide etc.
Plasma half-life • Defined as time taken for its plasma concentration to be reduced to half of its original value – 2 phases rapid declining and slow declining t1/2 = In2/k In2 = natural logarithm of 2 (0.693) k = elimination rate constant = CL / V t1/2 = 0.693 x V / CL CL = RoE/C V = dose IV/C
Kinetics of Elimination Zero Order 1st Order conc. Time
Plasma half-life 1 half-life …………. 50% 2 half-lives………… 25% 3 half-lives …….…..12.5% 4 half-lives ………… 6.25% 5 half-lives ………… 3.125% • 1st order kinetics – t1/2 does not change (V and CL remains unchanged • 0 order kinetics – t1/2 increases (CL decreases as dose is increased) 50 + 25 + 12.5 + 6.25 = 93.75 93.75 + 3.125 + 1.56 = 98% after 5 HL
Repeated Dosing • At steady state, elimination = input Cpss = dose rate/CL Dose Rate = target Cpss x CL In oral administration Dose rate = target Cpss x CL F Dose Rate AveCpss
Excretion - The Platue Principle Repeated dosing: • When constant dose of a drug is repeated before the expiry of 4 half-life – peak concentration is achieved after certain interval • Balances between dose administered and dose interval
Target Level Strategy • Drugs whose feect are not quantifiable, low safety margin drugs (anticonvulsants, antidepressants, Lithium, Theophylline etc. – aimed at achieving certain concentration within therapeutic range • Drugs with short half-life (2-3 Hrs) – drugs are administered at conventional intervals (6-12 Hrs) – fluctuations – target levels only intermittently – however therapeutically acceptable for many drugs • Long acting drugs: Prolonged half-life – accumulate and toxicity – Have to wait for 4 half-life for steadty state – Single dose or repeated dose in quick succession – to attain target conc. Quickly • Loading dose = target Cp X V/F – Maintenance dose: dose to be repeated at specific intervals – Dose Rate = target Cpss x CL F
Summary – Must Know • Drug Clearance • Orders of kinetics • Plasma half-life • The Platue principle
Excretion of drugs and kinetics of elimination
Excretion of drugs and kinetics of elimination