WEEK 6: DRUG EXCRETION

• Excretion


  The process whereby drugs or metabolites are irreversibly transferred from internal to external environment through renal or non-renal route
• Classification of Excretion


  • Renal Excretion
  • Non-Renal Excretion
• Non-Renal Excretion


  • Biliary
  • Pulmonary
  • Salivary
  • Mammary
  • Skin/Dermal
  • Gastrointestinal
  • Genital
• Renal Excretion


  1. Glomerular Filtration

  2. Tubular Secretion

  3. Tubular Reabsorption

  
• Glomerular Filtration- increase drug conc. in lumen


  • Non-selective
  • Unidirectional
  • MW< 500 Dalton
  • Ionized or unionized drugs are filtered, except those that are bound to plasma proteins
  • Driving force is hydrostatic pressure of blood flowing in capillaries
  • The glomerular barrier restricts passage of plasma proteins, RBC and other large blood constituents

  
• Active Tubular Secretion- increase drug conc. in lumen


  • Mainly occurs in proximal tubule
  • Carrier mediated process which requires energy for transportation of compounds
  • Not affected by change in pH and protein binding
• Tubular Reabsorption- decrease drug conc. in lumen


  • Occurs after the glomerular filtration of drugs
  • Along the renal tubules
  • Reabsorption results in increase in the half life of the drug
  • Can be active or passive processes

  
• Active Tubular Reabsorption


  • Commonly seen with endogenous substances or nutrients that body need to conserve, e.g. electrolytes, glucose, vitamins, amino acids

  
• Passive Tubular Reabsorption


  • Commonly for many exogenous substances
  • The driving force is concentration gradient – due to reabsorption of water, sodium and inorganic ions
  • Factors: Urine pH & pKa, Lipophilicity of drug, Urine flow rate

  
• Factors Affecting Renal Excretion


  • Urine pH and pKa
  • Urine flow rate
  • Physico-chemical properties of drug
  • Distribution and binding characteristics of drug
  • Blood flow to the kidneys
  • Biological factors
  • Drug interaction
  • Disease states
• Biliary Excretion


  • Factors: MW (>500 kd), polarity (lipophilic drug), gender, disease state, drug interaction
  • Phase II reactions mainly glucuronidation & conjugation with glutathione result in metabolites with increased tendency for biliary excretion
  • The metabolites are more excreted in bile than parent drugs due to increased polarity
  • Important in conservation of : vitamin/ folic acid/ hormone
  • Enterohepatic circulation: the phenomenon of drug cycling between the intestine and the liver, results in prolongation of half life of some drugs

  
• Pulmonary Excretion


  • Gases and volatile substances are absorbed through lungs via simple diffusion
  • Factors: Pulmonary blood flow, rate of respiration, Solubility of substance
• Salivary Excretion


  • pH of saliva: 5.8 – 8.4
  • Unionized lipid soluble drugs – excreted passively
  • E.g. Caffeine, Phenytoin, Theophylline
• Mammary Excretion


  • Milk consists of lactic secretions – rich in fats and proteins
  • Excretion of drug in milk is important as it gains entry in breast feeding infants
  • Milk contains protein: Drugs excreted can bind to it
  • Amount of drug excreted in milk is less than 1% and fraction consumed by infant is too less to produce toxic effects
  • Some potent drugs like barbiturates & morphine ay induce toxicity
• Skin Excretion


  • Drugs excreted through skin via sweat follows pH partition hypothesis
  • Excretion of drugs through skin may lead to urticaria & dermatitis
  • Compound like benzoic acid, salicylic acid, alcohol & heavy metals are excreted in sweat
• Gastrointestinal Excretion


  • Excretion of drugs Through GIT usually occurs after parenteral administration
  • Water soluble and ionized form of weakly acidic and basic drugs are excreted in GIT
  • Example: nicotine and quinine are excreted in stomach
  • Drugs excreted in GIT are reabsorbed into systemic circulation & undergo recycling (enterohepatic circulation)
• Excretion pathways, transport mechanisms & drug excreted