Elimination of drugs

1. Elimination of drugs Electives block 2.3 (2018-19) Introduction to pharmacology - kinetics Prof Asghar Mehdi Ph.D Sulaiman Alrajhi College

2. Objectives • Clearance of drugs. • Elimination of drugs - sites • Review of renal physiology. • Nature of drugs & factors affecting elimination. • Drug half life • Steady state concentration & Maintenance dose. Sulaiman Alrajhi College

3. Excretion of Drugs • Excretion is the removal of waste substances from body fluids and predominantly occurs via kidneys. • The process by which drugs or metabolites are irreversibly transferred from internal to external environment through renal or non renal route. • Most drugs are excreted in urine either as unchanged drugs or drug metabolites Sulaiman Alrajhi College

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5. Physiology • The two kidneys constitute less than 1% of the total body weight, but receive about 25% of the cardiac output. • Afferent arterioles from the renal artery supply blood to the glomerulus at arterial pressure. • About 20% of this is converted to glomerular ultra filtrate. • Further reabsorption & secretion takes place at various points along the nephron. Sulaiman Alrajhi College

6. Physiology • The final product (urine) is only about 1% of the volume of the original glomerular filtrate. • Most drugs are metabolized first prior to being excreted. However, some drugs, such as aminoglycoside antibiotics are polar compounds and are excreted by the kidneys without being metabolized first. Sulaiman Alrajhi College

7. Renal Excretion of drugs • The most important organ for drug excretion is the kidney. The principle processes that determine urinary excretion of drugs are: • Glomerular filtration. • Active tubular secretion. • Passive or active tubular re-absorption. Sulaiman Alrajhi College

8. Because of ↑ glomerular filtration Sulaiman Alrajhi College

9. GLOMERULAR FILTRATION Glomerular filtration occurs to: • Low molecular weight drugs • Free form of the drugs (not bound to plasma proteins). • Water soluble drugs , Aminoglycosides. • Drugs with low volume of distribution (Vd) Warfarin, a drug is 98% bound to albumin, concentration in filtrate is only 2% of that in plasma, and clearance by filtration is correspondingly reduced. Sulaiman Alrajhi College

10. Tubular secretion • Penicillin, although about 80% protein bound and therefore cleared only slowly by filtration, is almost completely removed by proximal tubular secretion, and is therefore rapidly eliminated Sulaiman Alrajhi College

11. Tubular secretion Drug molecules are transferred to the tubular lumen by two independent and relatively non-selective carrier systems The OAT carrier can transport drug molecules against an electrochemical gradient, and can therefore reduce the plasma concentration nearly to zero. OCT facilitates transport down electrochemical gradient Many drugs compete for the same transport system, leading to drug interactions. Like, probenecid was developed originally to prolong action of penicillin by retarding its tubular secretion. Sulaiman Alrajhi College

12. DIFFUSION ACROSS THE RENAL TUBULE The degree of ionization of many drugs—weak acids or weak bases—is pH dependent. Ion-trapping effect means that a basic drug is more rapidly excreted in an acid urine which favors the charged form and thus inhibits reabsorption. Conversely, acidic drugs are most rapidly excreted if the urine is alkaline if the tubule is freely permeable to drug molecules, some 99% of the filtered drug will be reabsorbed passively down the resulting concentration gradient Sulaiman Alrajhi College

13. Group of drugs that are not affected by metabolism. • Only renal elimination determines their duration of action Sulaiman Alrajhi College

14. Polar drug= water soluble Non polar drug = lipid soluble Sulaiman Alrajhi College

15. Elimination - clearance • Clearance: Volume of plasma that is cleared of drug per unit time. • Elimination rate: is mass/amount of drug that is cleared from the body. • Clearance is related with elimination by a constant proportion factor. • If the clearance is low then less drug lost in urine and more in body. • If the clearance is high then more drug in urine and less in body. • Inverse relationship – decreased GFR – increased plasma concentration. • Units are in L/hr or L/hr/kg Sulaiman Alrajhi College

16. ClearanceVolume of plasma that is cleared of drug per unit timeVolume per unit time = ml/min • Clearance = Elimination rateVOLUME Plasma drug conc • Rate of drug elimination = Cl X Concamount of drug MASS • Cl = 40 mg/hr in urine = 2 ml/hr 20 mg/ ml (remaining) Clearance is related with elimination by a constant proportionate factor • Cl = 120 mg/hr in urine = 6 ml/hr 20 mg/ ml (remaining) Sulaiman Alrajhi College

17. To calculate Dose & Frequency of drugs Two vital things of drugs which determine their behavior Volume of distribution Clearance Inverse relationship • Low Vd– high conc in plasma, distributed in blood large charged molecules, Hydrophilic & high clearance. • High Vd– Low conc in plasma, Hydrophobic, lipophilic, bound to proteins & fat tissues Inverse relationship • Low = Less drug is lost in urine, more in the body. • High = More drug is lost in urine, less in the body. Sulaiman Alrajhi College

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24. Drug Half-Life Sulaiman Alrajhi College

25. Natural log 2 which is equal to 0.7. This is the extraction ratio of an organ. 0.2 Sulaiman Alrajhi College

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34. Kinetics of Metabolism: First Order Kinetics Zero Order Kinetics • The rate of drug metabolism is directly proportional to the concentration of the drug. • A constant fraction of drug is metabolized per unit of time. • The rate of drug metabolism is constant and independent of the drug dose. • A constant amount of drug is metabolized per unit of time. Sulaiman Alrajhi College

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36. Factors affecting renal excretion of drug Sulaiman Alrajhi College • Physiochemical properties of drugs • Molecular weight • Lipid solubility • Volume of distribution • Binding character • Degree of ionization • Blood flow to the kidney - CCF • Urine pH • Biological factor - Age • Disease states

37. Factors affecting renal excretion Sulaiman Alrajhi College Drug MW: larger MW drugs are difficult to be excreted than smaller MW especially by glomerular filtration. Drug lipid solubility: urinary excretion is inversely related to lipophilicity, increased lipid solubility increase volume of distribution of drug and decrease renal excretion. Volume of distribution: clearance is inversely related to volume of distribution of drugs (Vd). A drug with large Vd is poorly excreted in urine. Drugs restricted to blood (low Vd) have higher excretion rates.

38. Factors affecting renal excretion Sulaiman Alrajhi College Renal blood flow:increased perfusion leads to increased excretion; important for drugs excreted by glomerular filtration. Binding characteristics of the drugs: Drugs that are bound to plasma proteins behave as macromolecules and cannot be filtered through glomerulus. Only unbound or free drug appear in glomerular filtrate. Protein bound drug has long half lives. Biological factor:age can affect renal clearance. Renal clearance is reduced in neonates and elderly. Disease states impairs the elimination of drugs e.G. Hypertension, diabetes, pyelonephritis

39. URINE pH • Urine pH is a great influence on whether a drug is excreted quickly or slowly and in some clinical situations is manipulated to control the excretion of certain drugs from the body. • Urine is normally slightly acidic and favors excretion of basic drugs. • Most drugs are either weak acids or weak bases. In alkaline urine, acidic drugs are more readily ionized. In acidic urine, alkaline drugs are more readily ionized. Ionized substances (also referred to as polar) are more soluble in water so dissolve in the body fluids more readily for excretion. Sulaiman Alrajhi College

40. Urinary pH trapping • It is used to enhance renal clearance of drugs during toxicity. • Urine acidification: by ammonium chloride (NH4Cl) increases excretion of basic drugs (amphetamine). • Urine alkalization: by sodium bicarbonate NaHCO3 increases excretion of acidic drugs (aspirin). Sulaiman Alrajhi College

41. Ion trapping Consider a barbiturate (weak acidic drug) overdose. Urine Blood pH 5.3 pH 7.4 Non-ionised weak acid drug + Ionized Urine Most of acidic drug will be reabsorbed back into body. Sulaiman Alrajhi College

42. Ion trapping In presence of sodium bicarbonate, urine is alkaline and more excretion of acidic drug into urine Urine Blood pH 8.0 pH 7.4 Less Non-ionised weak acid drug + More Ionized Urine Most of acidic drug will be eliminated into urine. Sulaiman Alrajhi College

43. Effect of Lipid solubility and pH ionised drug is less lipid soluble Glomerular blood flow; filtrate 99% of GF is re-absorbed; concentration of drug rises in tubule If lipid soluble drug moves down concentration gradient back into blood Sulaiman Alrajhi College Re-absorption

44. Drug renal clearance: • If renal clearance is impaired, this may increase T ½ of drugs and toxic levels of drugs may remain in the body. Renal clearance is especially important for some drugs which are: • Mainly excreted by the kidney • Have narrow therapeutic index (eg. Lithium, digoxin, warfarin). Sulaiman Alrajhi College

45. So what should we do in renal impairment? Diseases that can decrease renal clearance • Reduced renal blood flow • Congestive heart failure. • Hemorrhage • Cardiogenic shock • Decreased renal excretion : • renal disease (eg. Glomerulonephritis). This may increase half-life (t ½ ) of drugs • Dose reduction of drugs is required (when creatinine clearance is below 60 ml/min). • Keep the usual dose but prolong the dosing intervals (eg. Gentamicin) • Decrease the dose without changing dosing intervals (eg Digoxin) • Monitor blood levels of drugs (therapeutic drug monitoring). Sulaiman Alrajhi College

46. Dose reduction in renal impairment Antibiotics: • Penicillins, cephalosporins • Aminoglycosides (gentamycin) • Sulfonamides • Non steroidal anti-inflammatory drugs (NSAID’s) • Lithium • Digoxin • Immunosuppressants (cyclosporine) • Anticancer drugs (cisplatin - cyclophosphamide) When dose reduction is not required in renal impairment ? Drugs like Ceftriaxone, minocycline that are excreted into feces (biliary excretion) doesn’t need dose adjustment in renal impairment. Sulaiman Alrajhi College

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50. Thank youReferences • Basic & clinical Pharmacology Katzung 12th edition • Lippincott’s Pharmacology 6th edition. • Rang & Dale 8th edition • Clinical pharmacology 11th edition peter Bennett • Principles of pharmacology: the pathophysiologic basis of drug therapy, By Golan 2nd edition Sulaiman Alrajhi College