Drugs in Renal Failure

Drugs in Renal Failure

1. Why the kidney matters for drug handling — physiological premise

• The kidney is the most important organ for excreting drugs and their metabolites; renal excretion of unchanged drug is a major route of elimination for 25–30% of all drugs administered to humans (G&G 14e Ch.2, p.30).
• Excretory organs (lung excluded) eliminate polar compounds far more efficiently than lipid-soluble ones; lipophilic drugs are not readily excreted until biotransformed to more polar metabolites — so loss of renal function chiefly threatens water-soluble drugs and polar (often still-active) metabolites (G&G 14e Ch.2, pp.29–30).
• Renal drug handling is the net result of three distinct processes (G&G 14e Ch.2, pp.30–31):
  • Glomerular filtration — only unbound (free) drug is filtered; the filtered load depends on the glomerular filtration rate (GFR) and the extent of plasma-protein binding.
  • Active tubular secretion — carrier-mediated, in the proximal tubule; the majority of drugs enter the tubule by secretion, not filtration. Separate carriers handle organic anions (acidic drugs — furosemide, penicillin, indomethacin) and organic cations (basic drugs — amiloride, dopamine, histamine). Transporters named: OAT1, OAT3, OCT, MDR1 (P-gp), MRP2, URAT1 (G&G 14e Ch.2, pp.30–31).
  • Passive tubular reabsorption — pH-dependent; non-ionised forms of weak acids/bases are reabsorbed across the distal tubule. Ion trapping: alkalinising the urine ionises weak acids → faster excretion (exploited in salicylate/phenobarbital poisoning); acidifying does the converse (G&G 14e Ch.2, p.31).
• Worked physiology example — penicillin: t½ ≈ 30 min, eliminated largely by tubular secretion via OAT1/OAT3; probenecid competes at these transporters to slow secretion and prolong the antibiotic level — the classic demonstration that secretion (not just filtration) governs renal clearance (G&G 14e Ch.2, p.31).
• Clinical consequence framing: any significant fall in renal function reduces CL_renal, and for drugs where renal clearance is a large fraction of systemic clearance this lowers total CL, raising steady-state concentration and prolonging half-life unless the dose is adjusted (G&G 14e Ch.2, pp.32–33).