1. Explain why diuretic drugs have roles in the treatment of several disease states
    1. alter renal excretion
    2. replace kidney products
    3. DRUGS THAT INCREASE KIDNEY NaCl/H2O EXCRETION
  2. Discuss the different modes of action of the different classes of diuretic drugs
    1. loop diuretics
      1. examples
        1. furosemide
        2. bumetanide
      2. mech of action
        1. decrease Na/K/2Cl absorption in thick ascending limb
          1. since the thick asc. LoH has a high capacity for absorbing NaCl...
          2. drugs that act on this site produce a diuresis that is much greater than other diuretics
        2. inhibits reabsorption of 15-20% of glomerular Na filtrate
      3. indications
        1. heart failure
        2. renal failure
        3. pulmonary and peripheral oedema
        4. hypertension
      4. dose
        1. 40-80mg oral daily (also IV)
      5. side effects
        1. hypokalaemia
          1. potassium supplements may be required
          2. often clinically unimportant unless there's a risk factor for arrhythmias
          3. eg digoxin treatment
        2. hyponatraemia
        3. alkalosis
          1. because of...
          2. decrease in Cl- reabsorption =>
          3. lumen = more negative =>
          4. 'pulls in' hydrogen/K+ ions into lumen
          5. also paracellular Ca and Mg reabsorption reduced
        4. fluid depletion (hypovolaemia)
        5. incontinence
        6. ototoxicity (deafness)
          1. due to a change in the electrolyte composition of endolymph
      6. Notes
        1. very rapid onset
        2. fairly short duration of action
        3. very powerful (high-ceiling)
        4. can cause serious electrolyte imbalances and dehydration
        5. very specific
          1. because of their high local conc. in the renal tubules
        6. highly plasma bound but secreted into tubule by OAT
    2. thiazide diuretics
      1. examples
        1. metolazone
        2. bendroflumethiazide
        3. hctz
        4. indapamide
      2. mech of action
        1. inhibit Na/Cl co-transport in DCT
        2. maximum natriuresis of 5% of filtered Na
        3. vasodilator
      3. indications
        1. hypertension
      4. dose
        1. 2.5mg oral daily
      5. side effects
        1. hypokalaemia
        2. hyponatraemia
        3. fluid depletion
        4. incontinence
        5. hyperuricaemia
        6. glucose intolerance
        7. hyperlipidaemia
        8. impotence
      6. notes
        1. relatively weak diuretics
        2. safe, orally active
    3. potassium sparing diuretics
      1. examples
        1. spirinolactone
        2. amiloride
      2. mech of action
        1. act at aldosterone-sensitive site in the late DCT
          1. inhibits action of aldeosterone
        2. aldosterone boosts Na/K exchange
      3. indications
        1. heart failure
        2. ascites/chronic liver failure
      4. dose
        1. 50-200mg oral daily
      5. side effects
        1. hyperkalaemia
        2. spironolactone oestrogenic effects
      6. notes
        1. weak when used alone
        2. but cause potassium retention
          1. often given with thiazides or loop diu. to prevent hypokalaemia
    4. osmotic diuretics
      1. examples
      2. mech of action
      3. indications
        1. cerebral oedema
        2. maintain diuresis during surgery
      4. dose
      5. side effects
      6. notes
        1. osmotic diuretics = compounds that are filtered but not reabsorbed
        2. excreted with an osmotic equivalent of water
  3. Discuss the adverse effects associated with diuretics such as electrolyte disturbances and dehydration
    1. loop diuretics
      1. decrease in Cl- reabsorption =>
        1. lumen = more negative =>
          1. 'pulls in' hydrogen/K+ ions into lumen
          2. also paracellular Ca and Mg reabsorption reduced
      2. salt reabsorption decreases
        1. medullary interstitium conc. decreases
          1. reduce kidney's ability to concentrate urine
          2. increased Na delivery to principal cells in collecting duct increases potassium secretion in return for Na reabsorption
  4. Explain how diuretics interact with other drugs
    1. loop diuretics
      1. small increase in effect requires large increase in dose
        1. with long-term use, distal tubule hypertrophy can reduce the efficacy of loop diuretics
          1. so thiazide can be added
          2. = 'serial nephron blockade'
      2. digoxin
        1. hypokalaemia with digoxin => toxicity
      3. lithium
        1. toxicity due to decreased renal elimination of lithium
    2. thiazide diuretics
      1. given with antidiabetic drugs
        1. causes decreased blood level of antidiabetic drugs
        2. doses of antidiabetic drugs may need to be increased
      2. digoxin
        1. hypokalaemia with digoxin => toxicity
      3. lithium
        1. toxicity due to decreased renal elimination of lithium
    3. potassium-sparing diuretics
      1. ACE inhibitors
      2. NSAIDS
      3. severe hyperkalaemia
  5. Discuss how other drugs have adverse effects on the kidneys eg NSAIDS, ACE inhibitors, gentamicin
    1. uricosuric drugs - inhibit uric acid reabsorption in the P Conv.T
      1. probenecid
        1. used to increase antibiotic concentrations in serious infections (penicillin)
      2. sulphinpyrazone
    2. drugs that induce dehydration
      1. cause low BP which injure kidneys
        1. ie pre-renal effects
      2. eg
        1. loop diuretics
        2. drugs=> diarrhoea
          1. antibiotics
          2. digoxin
          3. laxatives
          4. many others
    3. drugs that alter renal perfusion
      1. ACE inhibitors
        1. block RAAS which is defensive of renal perfusion
        2. renal function is really threatened because of ...
          1. hypovolaemia
          2. renal artery stenosis
          3. In the kidneys, ang II constricts glomerular arterioles, having a greater effect on the efferent arterioles than afferent. Constriction of afferent arterioles increases the arteriolar resistance, raising systemic arterial BP and decreasing blood flow. However, kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular BP up. hence why efferent arteriole is more constricted
          4. Angiotensin II causes vasoconstriction in the efferent (outgoing) arterioles in the glomerulus, which increases perfusion pressure and GFR. This is the same (normal) response to maintain GFR with dehydration (where low volume is the cause of reduced perfusion). With stenosed renal arteries, afferent flow cannot be increased, angiotensin II can actually become the only mechanism by which the kidney can increase filtration, and with severe stenosis, efferent arteriole constriction is crucial for maintaining some degree of filtration. ACE inhibitors would prevent conversion of Ang. I (which is inactive) to Ang. II, and therefore make everything worse by removing the kidney's only remaining regulatory mechanism as well as cutting the perfusion pressure and eliminating what little renal function remains. With tubular cells that are already less effective due to damage from chronic ischemia, the resulting decrease in GFR would effectively accelerate kidney failure .
        3. eg Enalapril
          1. indications
          2. hypertension
          3. heart failure
          4. dose
          5. 2.5-40mg daily
          6. side effects
          7. cough
          8. renal impairment
          9. hyperkalaemia
          10. angioedema
      2. NSAIDS eg ibuprofen
        1. block COX
        2. this means prostaglandin synthesis is inhibited
          1. prostaglandin = vasodilate vessels (renal vessels as well)
          2. so when its synthesis is inhibited then vasoconstrction => not enough perfusion!
        3. therefore hyperalgesia is inhibited
        4. COX -1 is constitutive throughout body to control renal blood flow, platelet activity and gastroprotection
        5. dose
          1. 200-400mg every 4-6 hours as needed
        6. side effects
          1. gastrotoxicity
          2. renal impairment
          3. Na/H20 retention
    4. drugs directly toxic to kidney
      1. gentamicin (aminoglycoside antibiotic)
        1. mech of action
          1. against gram -ve organisms
          2. bactericidal, decreases protein synthesis
        2. indications
          1. gram -ve infections
          2. staphylococcal infections
        3. dose
          1. 60mg tds IV
          2. tds = ter die sumendus = three times daily
        4. side effects
          1. renal impairment (tubular/reversible)
          2. ototoxicity
      2. Others
        1. cephalosporins
        2. vancomycin
        3. allopurinol
        4. lithium
  6. Explain the role of the kidney as a key site of drug clearance from the body
    1. drugs eliminated from the kidney
      1. digoxin
        1. cardiac glycoside acting on Na/K ATPase
        2. broken down to digitoxin in body
        3. for atrial fibrillation/heart failure
          1. decreases conduction through AV node
          2. increases force of contraction
        4. low therapeutic index
          1. toxicity promoted by hypokalaemia
          2. excreted renally
          3. dose
          4. 62.5-250 micrograms/day
          5. side effects
          6. anorexia
          7. nausea
          8. vomiting
          9. visual disturbances
          10. AV block
          11. arrhythmias
      2. antibiotics
        1. gentamicin
        2. amoxycillin
        3. cephalosporins
        4. ciprofloxacin
      3. beta-blockers
        1. atenolol
        2. for hypertension
      4. some analgesics
        1. codeine, morphine metabolites
      5. some antidepressants
        1. paroxetine
      6. many others
  7. Discuss the main hazards of giving drugs to patients with renal failure
    1. impaired renal function
      1. GFR falls
      2. Plasma clearance decreases
        1. urea, creatinine
        2. phosphate, potassium
        3. drugs
    2. increase half-life and therefore increase toxicity