Drug excretion

1. Drug excretion Dr. S.O. Ogundele

2. Introduction • The elimination of drugs from the body involves the processes of metabolism and excretion • Most drugs are metabolised first prior to being excreted • Some drugs, such as aminoglycoside are polar compounds and are excreted by the kidneys without being first been metabolised

3. Introduction • Definition • Drug excretion is the removal of drugs or drug metabolites from body fluids • It predominantly occurs via urine formed in the kidneys • Other routes of excretion of drugs from the body include • Bile • Saliva • Sweat • Tears • Faeces • Milk • Exhaled air

4. Basic kidney functions • The basic functions of the kidney include • Maintaining the volume and composition of body fluids • Controlling acid-base balance • Elimination of end-products of metabolism and foreign compounds (e.g., drugs)

5. Renal Extraction Ratio Renal Extraction Ratio • The fraction of a drug that is excreted when it passes through the kidneys is called the extraction ratio (ER) of the drug • A drug that is not excreted at all has an ER of 0 • A drug that is completely removed after a single passage has an ER of 1 • Extraction ratio: • Low (< 0.2):Acetazolamide, Chlorporpamide, Digoxin, Furosemide • Intermediate: Procainamide, Quaternary ammonia compounds • High: Glucuronides, Penicillins, Sulfates, Glycine conjugates

6. Renal clearance • Renal clearance • This is the hypothetical volume of plasma completely cleared of a particular substance (e.g. drug) per minute • As with the volume of distribution (Vd) of a drug, the renal clearance rarely corresponds to a physiological rate of flow that actually occurs

7. Renal clearance • Clearance (C) = UV/P • Where: • U = concentration in urine (mg/ml) • V = rate of urine flow (ml/min) • P = plasma concentration (mg/ml) • The units of clearance are ml/min • In order to make comparisons between species we may use ml/min/kg

8. Sites of renal handling of drug

9. Mechanisms drug excretion by kidney • MECHANISMS of Renal Drug Elimination • Glomerular Filtration • Renal Tubular Secretion • Reabsorption by Non-Ionic Diffusion (passive) • Active Reabsorption

10. Mechanisms drug excretion by kidney • Drugs/metabolites are transported by the capillaries to the kidney tubule • Some drugs enter the tubule by glomerular filtration at the renal corpuscle • This acts like a sieve allowing small drugs and those not bound to plasma protein to filter from the blood into the Bowman’s capsule

11. Glomerular filtration • Glomerular filtration • Affects all drugs and metabolites of appropriate molecular size • Influenced by protein binding • Elimination is by first order process • Large drugs like heparin or those bound to plasma-protein cannot be filtered and are poorly excreted by glomerular filtration • Drug Filtration Rate = GFR x fu x [Drug] • fu = free fraction

12. Glomerular filtration • Regardless of mechanism, renal drug elimination declines in parallel with decreases in GFR • Therefore, CLCr canbe used to assess impact of renal impairment on renal excretion of drugs

13. Tubular Secretion • Most drugs do not enter the kidney tubule by glomerular filtration but do so by tubule secretion • In the proximal convoluted tubule active secretion of ionized drugs into the lumen occurs • This ensures that drugs which are protein-bound are excreted • It is energy dependent

14. Tubular Secretion • Active tubular secretion can be saturated, and drugs can compete for secretion • Tubule secretion involves two carrier systems • Basic carriers which transport basic drugs (amiloride, procainamide, dopamine, histamine) • Acidic carriers for acidic drugs (frusemide, penicillin, indomethacin)

15. Tubular Secretion • When therapeutic effect needs to be prolonged, agents can be co-administered to block tubular secretion • This will lead to the slowing of excretion of the drug e.g. penicillin with probenecid

16. Tubular Reabsorption • Despite glomerular filtration and active secretion renal clearance of many drugs is still slow because they are substantially reabsorbed from the distal portion of the nephron • Reabsorption of drugs can either be passive or active

17. Passive reabsorption • Passive reabsorption process is affected by the following factors • Concentration • About 99% of the water filtered through the glomerulus is reabsorbed in the kidney tubule • This results in a considerable concentrating effect which will lead to passive reabsorption • This is reduced by increasing the urine flow

18. Passive reabsorption • PH • Excretion of weak acids is increased significantly by alkalinizing the urine (sodium bicarbonate) • Excretion of weak bases is increased by acidifying the urine (ammonium chloride) • Lipid solubility • Highly lipid-soluble drugs are rapidly reabsorbed from the kidney tubule • Protein binding • Many protein-bound drugs are actively secreted into the proximal tubule, there is reabsorption of drugs that are largely protein-bound in plasma

19. Passive reabsorption • Passive reabsorption affects mainly weak acids and weak bases • E.g. • Weak Acids: Phenobarbital • Weak Bases: Quinidine • Important only if excretion of freedrug is the major elimination pathway • Ion trapping reduces reabsorption • Amphetamine (weak base, pKa9.2) is trapped in acidic urine, t1/2 7-34 hr • Ephedrine (weak base, pKa9.6) is trapped in acidic urine • Phenobarbital (a weak acid, pKa7.4) and salicylic acid(weak acid, pKa 3.0), are trapped in an alkaline urine

20. Active reabsorption • Affects ion mainly and a few drugs that are or resemble endogenous substances • E.g. • Halides: Fluoride, Bromide • Alkaline Metals: Lithium • Glucose • Salicylic acid(uric acid)

21. Effect of age on renal function • Infants • Glomerular filtration and tubular secretion are decreased in the newborn • Body water is increased in the newborn • Elderly • Glomerular filtration and tubular secretion are decreased in the elderly. • Glomerular filtration decreases 30 %from age 25 to age 65 and 48 %by age 90. • Tubular secretion decreases 38%from age 25 to age 65 and 62%by age 90

22. Effect of disease on renal function • Plasma protein binding decrease will increase the fraction of free drug and therefore the fraction available for filtration for some antibiotics • Renal blood flow decrease will decrease glomerular filtration (digoxin) and tubular secretion • Accumulation of drugs such as digoxin which are primarily eliminated by the kidney

23. Effect Of Drugs On Renal Function • Osmotic diuretics (mannitol) increase urine flow and reduce drug reabsorption • Nephrotoxic drugs (gentamicin) and heavy metals (Hg) reduce renal function • NH4Cl and NaHCO3 ion trap basic and acidic drugs, respectively, in the renal tubule • Probenecid reduces the secretion of penicillin and other anions

24. Restrictive Vs. Nonrestrictive Elimination • Restrictive • Clearance depends on protein binding • Kidney: Drug Filtration Rate = fU*GFR • Liver: CL = fU*Clint • Nonrestrictive • Clearance independent of Protein Binding • Kidney: CL = Q (renal blood flow)

25. Excretion from other route • Excretion in the Bile • This is the second most important route by which drugs and their metabolites are excreted • Large polar molecules (MW > 300) are often excreted in bile since they are not reabsorbed in the intestine • These drugs cannot diffuse across membranes and are therefore actively transported into bile

26. Enterohepatic Circulation • Drugs and drug conjugates entering the gut in bile may be reabsorbed and subsequently excreted in urine or returned to the bile • This occurs particularly with small, less polar drugs • Glucuronide conjugates of drugs may also be cleaved by enzymes in the intestinal microflora (e.g., beta-glucuronidase) to liberate the parent lipid-soluble drug, which is then reabsorbed

27. Excretion from other route • Saliva and Gut • Secretions from the saliva and gut play a small part in excretion • Bile is the major source of drugs excreted in the feces • Alveolar • This route is of major importance in the excretion of volatile anesthetics • The large surface area and rich blood supply ensure that equlibration between blood and alveolar air is extremely rapid • Milk • Excretion in milk is of particular concern in dairy animals

28. Conclusion!