Drug Excretion

Drug excretion Excretion is the process whereby compounds are removed from the body to the external environment. Routes of drug excretion Removal of a drug from the body may occur via a number of routes: - Kidneys (urine) - The intestinal tract (bile and feces) - The lungs (exhaled air) - Breast milk (in nursing mother) - Sweat Excretions in the urine and feces are the most important routes of drug elimination.

Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high lipid solubility. Lipidsoluble drugs thus are not readily eliminated until they are metabolized to more polar compounds. The kidney is the most important organ for excreting drugs and their metabolites. Substances excreted in the feces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract and not reabsorbed. Conjugation, particularly with glucuronic acid, facilitates biliary excretion.

Excretion of drugs in breast milk is important not because of the amounts eliminated, but because the excreted drugs are potential sources of unwanted pharmacological effects in the nursing infant. Excretion from the lung is important mainly for the elimination of anesthetic gases or volatile materials.

Fig: Bile duct

Renal elimination of a drug The kidney: Plays significant role in regulating volume and composition of body fluids. Conserves essential substances and removes waste products. Removes H2O soluble drugs & metabolites from body. Excretion of drugs and metabolites in the urine involves three distinct processes: Glomerular filtration Proximal tubular secretion Distal tubular reabsorption

Glomerular filtration: Drugs enter the kidney through renal arteries (afferent arterioles), which divide to form a glomerular capillary plexus. Free drug (not bound to protein and RBC) flows through the capillary slits into Bowman's space as part of the glomerular filtrate. The glomerular filtration rate (GFR=125ml/min) is normally about 20% of the renal plasma flow (RPF =650ml/min). Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. Low molecular weight compounds (<60,000 dalton) filtered from blood.

Warfarin is approximately 98% bound to albumin (molecular weight approximately 68,000 dalton), the concentration in the glomerular filtrate is only 2% of that in plasma, and clearance of this drug by filtration is thus correspondingly reduced.

Proximal tubular secretion: Drug that was not transferred into the glomerular filtrate leaves the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems, one for anions (for example, deprotonated forms of weak acids) and one for cations (protonated forms of weak bases). - Most effective mechanism - Reduces plasma drug concentration nearly to zero

Active secretion of both free & protein-bound drug by transporters: Anions: indomethacine, urate, penicillin, glucuronic acid conjugates, gluycine conjugates, & sulphate conjugates (acidic compounds) Cations: morphine, choline, histamine (basic compounds)

Penicillin, about 80% penicillin remain as protein-bound form and therefore cleared only slowly by filtration, is almost completely removed by proximal tubular secretion, and its overall rate of elimination is very high. Many drugs compete for the same transport system, leading to drug interactions. For example, probenecid was developed originally to prolong the action of penicillin by retarding its tubular secretion.

Distal tubular reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases (as H2O reabsorbs). In this part the drug, if uncharged (remain lipid soluble), may diffuse out of the nephric lumen back into the systemic circulation (reabsorption- passive transport). Manipulating the pH of the urine [The pH of urine is close to neutral (7) but can normally vary between 4.5 and 8] to increase the ionized form of the drug in the lumen may be used to minimize the amount of back diffusion and hence increase the clearance of an undesirable

A patient presenting with an acidic drug (phenobarbital, aspirin) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If the drug is a weak base (amphetamines), acidification of the urine with NH4Cl leads to protonation of the drug and an increase in its clearance. This process is called "ion trapping."

Rate of excretion = Rate of filtration + Rate of secretion - Rate of reabsorption

Factors influencing renal drug excretion : Gender: Female 80% renal function of males Age: Renal function ⇓ 50% with age (25 –75 yr) Pregnancy: Renal function ⇑ 50% Disease: Renal disease, heart failure

Alteration of renal excretion of drugs :1. Competitive inhibition of tubular secretion The renal clearance of penicillin ⇓ 90% by probenecid. 2. Influence of pH • Sodium bicarbonate used to alkalinize urine; ie ⇑ pH, ⇑ ionization of weak acids (salicylate, methotrexate), ⇓ tubular reabsorption → ⇑ excretion. • Ammonium chloride used to acidify urine to ⇑ excretion of basic drugs (amphetamines).

3. Influence of urinary flow rate • ⇑ urinary flow rate dilutes drug conc. in tubule → ⇓ conc. gradient for passive reabsorption of drug → ⇑ excretion. • ⇓ urinary flow rate has the opposite effect.

Excretion of drugs by the kidney - Most drugs, unless highly bound to plasma protein, cross the glomerular filter freely. - Many drugs, especially weak acids and weak bases, are actively secreted into the renal tubule and thus more rapidly excreted. - Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule, so are not efficiently excreted in the urine. - Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa. - Several important drugs are removed predominantly by renal excretion, and are liable

Drug clearance Clearance is the ability of the body or its organs of excretion (usually the kidneys and the liver) to remove drug from blood. Clearance is expressed as a volume per unit of time (usually ml/min). Clearance is not the amount of drug removed from the body. Clearance represents the volume of blood which is completely cleared from drug in a given period of time. Total clearance is the sum of clearance by different organs like the kidneys, the liver & others.

Clearance as through the kidneys and metabolism in the liver are the major routes:

Clearance (total) = Clearance (hepatic) + clearance (renal) + Clearance (others) A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination.

BLOOD + DRUG

BLOOD + DRUG

KIDNEYS

CLEAN BLOOD 30 ml/min

LIVER

CLEAN BLOOD 50 ml/min

Drug clearance

Rate of elimination of drug Rate of elimination is the number of mg of drug eliminated from the body per time (mg/min). Rate of elimination depends on the concentration of drug in blood and clearance:

Rate of elimination (mg/min) = Plasma drug concentration (mg/ml) x Clearance (ml/min) Example: Plasma drug concentration = 10mg/ml Clearance = 8ml/min Rate of elimination = 80mg/min So, The amount of drug eliminated in one