The Kidney and Drug Elimination

Identify the role of kidneys in the excretion and regulation of the blood pH
1. Production of hormones
  1. rennin to control blood pressure
2. Filtering blood, to form urine
  1. Regulation of plasma osmolarity and volume
3. Maintain water, ionic and pH balance in body fluids
4. Elimination of nitrogen containing metabolic waste
  1. Urea= amino acid break down
  2. Uric acid = nucleic acid break down
5. Indirectly regulate composition of extra cellular fluid too
Identify processes contributing to the renal excretion and implement this on elimination of drugs
1. ELIMINATION
  1. ADME
  2. irreversible removal of the drug form the body
  3. = metabolism + excretion
    1. kindeys contribute to excretion
      1. parent drugs are often lipophillic so they remain in the body for longer, one mechanism to remove drugs involves converting these into polar, hydrophilic metabolites so they are easier to eliminate
      2. unchanged drugs eliminated via renal excretion, dominant route
    2. some metabolising in kidenys too
    3. dependant on physicochemical properties of drug
2. Glomelular filtration = non selective, passive
  1. Samll sugars, water, urea, uric acid, K Na Cl- ions
    1. No cells or large proteins
  2. Drugs unbound to plasm proteins
3. Tubular Secretion
  1. Selective transport from peritubular fluid to lumen of renal tubules
    1. Occurs in poximal and distal tublues via different tansportet proteins OAT, OCT
      1. SATURABLE PROCESS, once the conc of drug is increased, transporter proteins become saturated- limit rate of excretion
      2. acidic and basic drugs excreted this way
4. Tubular Reabsoprtion
  1. From renal tubules membrane back in to plasma either passive or use of trnasporters
  2. lipophillic unionised drugs, nutrients absorbed too - often with WA or WB depending urine pH
  3. Descending loop of Henle not permeable to NA+ Ascending loop of Henle – active reabsorption of Na+, not permeable to H20
Identify main transporters involved in renal elimination
1. OAT1, 2, 3
  1. Organic anion transporter transport small anionic drugs
    1. OAT1
      1. transmembrane
        mainly on basolateral membrane of proximal tubular cells
2. OCT2
  1. Organic cation transporter, move hydrophilic small cations
    1. Potential DDI via inhibition of OCT eg penicillin and preobenicin
Structure
1. highly perfused, receives around 20% of cardiac output
2. Cortex
  1. Medula
    1. Pyramids
      1. Nephrons
        Bowman's capsule
        Glomerulas = cluster of capillaries
        Filters the blood, remaining blood leaves via efferent ateriole
        Secretion of drugs- proximal tube Reabsorption - distal tube
        180L blood filtered per day
        Diabetes mellitus
        glucose in urine, increase in osmotic pressure in renal tubule, less water reabsorbed and more urination
3. GFR = glomerular filtration rate
  1. Creatine or inulin used- do not bind to plasma proteins
  2. 120-110 ml/min
Dose adjustment
1. Fraction of drug excreted unchanged (via kidneys) is > 50% For drugs with narrow therapeutic index - e.g., digoxin Impaired metabolism

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The Kidney and Drug Elimination

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