Drugs and the kidney

1. Drugs and the kidney

2. What does the kidney do to drugs? • What do drugs do to the kidney (in a therapeutic sense)

3. Normal kidney function • Excretion of wastes, drugs, drug metabolites and such as • Urea • Uric acid • Creatinine • Regulation of NaCl and electrolyte content (aldosterone, natriuretic peptides) • Regulation of water balance (anti-diuretic hormone)

4. Normal handling of drugs • Mechanisms • Glomerular filtration • Active tubular secretion • Passive diffusion across tubular epithelium

5. Which means that…. • Most drugs (unless protein bound) cross the glomerulus • Some drugs are actively secreted into the tubule (pH-dependant) (eg penicillin – blocked by probenecid) • Lipid soluble drugs are passively reabsorbed (not excreted in the urine) • Some important drugs are predominantly excreted by the kidney – a problem in the elderly or patients with kidney disease….

6. clearance CLr = CuVu Cp Volume of plasma containing amount of substance removed by the kidney in unit time Cu – concentration in the urine Vu rate of flow of volume of urine Cp plasma concentration

7. So what does this mean? • extended half-life

8. Potential for increased toxicity • Drugs with a narrow therapeutic index will require a reduction is dose to prevent toxicity.

9. In effect • keep the usual dose but prolong the dosing intervals (eg gentamicin) • decrease the maintenance dose without changing dosing intervals (eg digoxin) • Monitor blood levels of drug

10. Does it matter? • Applies to • Gentamicin • Methotrexate • Atenolol • Digoxin • Benzylpenicillin • Lithium

11. Managing patients Dealing with oedema: Options? • Decrease fluid intake • Increase salt/water excretion • Others?

12. diuretics • Increase the excretion of Na+ and therefore water from the body at the kidneys • decrease reabsorption of Na+ and Cl- from the filtrate • increases the excretion of water due to the hypertonicity of the filtrate

13. Overview (Rang 5th Edition) thiazides amiloride Loop diuretics

14. Summary • Sites of effect • Ascending loop of Henle – inhibit Na+ absorption(Loop diuretics) • Distal tubule - inhibit Na+ and Cl-(thiazides) • Collecting tubules and ducts - blocks Na+ - K+ exchange (amiloride, spironolactone & triamterene – so called ‘potassium sparing’)

15. Osmotic Diuretics Pharmacologically inert substances which are filtered into the glomerulus (eg mannitol) and incompletely reabsorbed or not reabsorbed by the nephron • Prevent the reabsorption of water and Na due to osmotic pressure • Indications • Cerebral swelling

16. Loop Diuretics • Indications: • Generally fluid overload states: Pulmonary oedema Adjunctive management in cardiac failure • Electrolyte disturbances where decreased calcium or potassium is desirable

17. Loop diuretics • effects: • Vigorous diuretic effects • reduces accumulation of oedema – can cause hypovolaemia, hyponatremia. • decreases potassium and magnesium reabsorption, hypokalaemia. • Decreases calcium reabsorption → hypercalcinuria, hypocalcaemia. • Ototoxicity - dose-related hearing loss that is usually reversible. Most common in patients who have diminished renal function and high doses.

18. thiazides Effects: • Diuresis – much less marked than with loop diuretics • Increase potassium excretion • Decreased excretion of uric acid • Increased chloride excretion →hypochloraemic alkalosis Indications: • Hypertension • Less commonly oedema, fluid retention

19. Potassium sparing diuretics Effects • Limited diuretic efficacy • Mildly uricosuric Indications • Combination with thiazides to prevent hypokalemia • Spironolactone in heart failure, liver disease

20. references • Rang Dale Ritter and Moore (5th Edition) • Australian Medicines Handbook