Elimination

Elimination

1. Definition: Irreversible loss of chemically unchanged DRUG or METABOLLITES from body

   • Renal
     • Depends on
       • Glomerular Filtration
         • GF occurs to:
           • Low molecular weight drugs
           • Ionized and Unionized drugs
           • Free drugs
           • Low volume of distribution drugs
         • Determined by:
           • Creatinine
           • Insulin
         • INFOS
           • Filtration affected by:
             • Renal blood flow
             • Health of kidney
           • Patients with impaired kidney function
             • GFR (RATE) maybe significantly lower than normal
         • Glomerular Filtration Rate (GFR): Amount of blood filtered by Glomerulus in a given time (GFR=about 125 ml/min)
       • Active Tubular secretion
         • INFOS
           • Drugs that are not transferred into the glomerular filtrate, leave the glomeruli
             • divide to form:
               • a capillary plexus surrounding the nephric lumen in the proximal convoluted tubule.
           • Nitrogenous waste product such as uric acid along with several organic acids are secreted in Proximal convoluted tubule
           • Small amounts of sodium and potassium ions are secreted in distal convoluted tubule
           • Hydrogen ion is secreted into collecting duct
         • Needs Energy
           • Secretion takes place my two energy dependant active transport systems:
             • Organic Acids/anions (DEPROTONATED form of weak acids)
               • Penicillin, Salicylates, Probenecid, Uric acid
               • PS PU
             • Organic Base/cations (PROTONATED form of weak bases)
               • Morphine, Atropine, Cathecholamine, Quinine
               • MACQ
         • requires carrier (transporter) and the process is saturable
         • Active Process
       • Active/Passive Tubular reabsorption
         • INFOS
           • It takes place along all the renal tubules (80% of the solute reabsorbed in Proximal convoluted tubules, the rest in loop of Henle, Distal convoluted tubule and Collecting duct)
           • It increases the half life of a drug.
           • Depends on ionization and lipid solubility.
             • Ionization depends on pH of urine and pKa of a drug.
             • Lipid soluble and unionized drugs are reabsorbed back.
             • Ionized drugs cannot be reabsorbed. They will be excreted
           • Changing the urine pH
             • increase the fraction of ionized drug in the lumen
               • reduces back diffusion
               • increase the clearance of an undesirable drug
         • Passive tubular reabsorption:
           • Only lipid soluble drugs undergo passive reabsorption
           • Ionized drugs are poorly reabsorbed.
         • Active tubular reabsorption:
           • It occurs with endogenous substances or nutrients
             • (e.g., glucose, electrolyte, amino acids, uric acid, vitamins etc.
     • INFOS
       • Kidney + Most drugs are excreted in Urine as UNCHANGED or POLAR metabollites
       • Driving force: Hydrostatic pressure of blood
       • Most drugs filtered through Glomerulus
     • Dose adjustment for patients with renal failure:
       • Adjusted dose = average dose X CCp/CCn
         • Creatinine clearance of the patient should be determined.
           • CCp = Creatinine Clearance of Patient
           • CCn = Creatinine Clearance of Normal
     • Application of ionization
       • Weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine.
         • Therapeutics advantage of competition:
           • Probenecid is used to block renal tubular secretion of some acidic drugs (e.g., penicillin) and thus prolong its duration of action.
             • A 50% reduction in penicillin G dose is suggested especially when the drug is given in large doses as in gonococcal infection.
               • Active secretion of anionic drugs (probenecid) suppress carrier mediated reabsorption of the endogenous metabolite, uric acid and is thus of therapeutic value as a uricosuric agent in the treatment of gout
         • Therapeutic disadvantage of competition:
           • Probenecid inhibits renal tubular secretion of nitrofurantoin, thus decreases its efficacy in urinary tract infection (UTIs)
         • Practice Question
   • Non-Renal
     • Biliary excretion (bile acid)
       • Chloromphenicol, indomethacin
     • Pulmonary excretion (exhaled air)
       • General anesthetics (Halothane)
     • Salivary excretion (saliva)
       • Caffeine, Theophylline
     • Mammary excretion (breast)
       • Tetracycline
     • Skin / Dermal excretion (sweat)
       • Benzoic acid, salicylic acid
     • Gastrointestinal excretion (feces)
       • Nicotine and quinine
     • Factors affecting renal excretion
       • Physicochemical properties of drug:
         • Physicochemical factors affecting renal excretion are – molecular size, pKa and lipid solubility
         • Compounds between 300 - 500 daltons (if water soluble) are readily excreted by the kidney
         • Urinary excretion of unchanged drug is inversely related to lipid solubility.
       • Plasma concentration of drug:
         • Drugs that are actively secreted, the rate of excretion increases with increase in plasma concentration upto a saturation level.
         • In case of actively reabsorbed drugs, excretion is negligible at low plasma concentrations.
       • Blood flow to kidney:
         • Renal perfusion increases the clearance of drugs (for both glomerular filtration and active secretion).
       • Biological factor:
         • Renal excretion is approximately 10% lower in females than males. ● The renal function of newborns is 30 to 40% less in comparison to adults. ● In old age GFR is reduced and tubular function is altered.
       • Drug interaction:
         • Any drug interaction that alters binding characteristics, renal blood flow, active secretion, urine pH and forced diuresis would alter renal clearance.
       • Disease state:
         • Renal dysfunction, uremia

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