Excretion of drugs

Routes of drug excretion Urine : it is the most important channel of excretion for most drugs Faeces : most of the drug present in faeces are derived from bile. Exhaled air : gases & volatile liquids ( general anaesthetics, alcohol) are eliminated by lungs, irrespective of their lipid solubility Saliva & sweat : these are of minor importance for drug excretion. (Lithium, thiocyanates)

Breast Milk : suckling infant inadvertently receives the drug Breast Milk : suckling infant inadvertently receives the drug. Most drugs enter milk by passive diffusion. More lipid soluble & less protein bound drugs cross better. Alkaline drugs are more concentrated in it since the pH of milk is lower than the plasma. ( e.g. Morphine)

Renal excretion Kidney is responsible for excretion of all water soluble substances The amount of drug &/or its metabolite present in the urine is a sum total of glomerular filtration, tubular re-absorption & tubular secretion Glomerular filtration : all non-protein bound drug ( lipid soluble or insoluble) is filtered. GFR declines progressively after 50 years of age & is low in renal failure

Tubular re-absorption : this depends on lipid solubility & ionization of the drug at the urinary pH. non-lipid soluble & highly ionized drugs are unable to be re-absorbed. Weak bases ionize more & are less reabsorbed in acidic urine Weak acids ionize more & are less reabsorbed in alkaline urine This principle is utilized for facilitating elimination of drug in poisoning. E.g. urine is alkalinized in Barbiturate & salicylate poisoning. Urine is acidified in Morphine & Amphetamine poisoning

Tubular secretion : this is the active transport of organic acid & base substances via 2 transport mechanism. Organic acid transport Organic base transport Active transport of the drug across the tubules reduces the concentration of its free form in the tubular vessels and promotes dissociation of protein bound drug, which again is secreted

Kinetics of elimination Drug elimination is the sum total of metabolic inactivation & excretion Clearance (CL) : it is the theoretical volume of plasma from which the drug is completely removed in a unit time CL is calculated as : CL = Rate of elimination Plasma concentration (C)

First order kinetics Also known as exponential kinetics the rate of elimination is directly proportional to the drug concentration Here, CL remains constant A constant fraction of the drug is eliminated in a unit time

Zero order kinetics Also known as linear kinetics The rate of elimination remains constant irrespective of drug concentration CL decreases with increase in concentration of drug A constant amount of drug is eliminated in a unit time

Plasma half life The plasma half life (t ½ ) of a drug is the time taken for its plasma concentration to be reduced to half of its original value Plasma concentration Time Distribution Elimination 10 5 t ½

1st t ½ - 50% drug is eliminated 2nd t ½ - 75% ( 50 + 25) drug is eliminated 3rd t ½ - 87.5% ( 75+ 12.5) drug is eliminated 4th t ½ - 93.75% ( 87.5 + 6.25) drug is eliminated Thus, nearly complete drug elimination occurs in 4 – 5 half lives For drugs eliminated by First order kinetics – t ½ remains constant Zero order kinetics – t ½ increases with dose because CL progressively decreases