Drug clearance

Excretion

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• Renal Clearance: Drugs (or active metabolites) excreted by kidneys. Water-soluble (polar, ionized at physiological pH)

  • High-Yield Drugs:
    • Antibiotics: Aminoglycosides (Gentamicin), Vancomycin, most Penicillins & Cephalosporins (except Nafcillin, Ceftriaxone), Fluoroquinolones (most), TMP-SMX.
    • Cardio: Digoxin, Lisinopril (most ACEIs), Atenolol (hydrophilic beta-blockers).
    • Other: Lithium, Methotrexate (low dose), Gabapentin, Metformin, H2 blockers (Ranitidine).
  • USMLE Pearl: NSAIDs & ACEIs can affect renal clearance. Watch for nephrotoxicity.

• Hepatic Clearance (Metabolism & Biliary Excretion): Drugs metabolized by the liver (often by CYP450 enzymes) and/or excreted in bile. Lipid-soluble (non-polar)

  • High-Yield Drugs (Metabolism):
    • Warfarin, most Benzodiazepines (safer: Lorazepam, Oxazepam, Temazepam - “LOT”), Statins, Macrolides (not Azithromycin), most Antidepressants & Antipsychotics, Opioids, Acetaminophen, Isoniazid, Rifampin, Phenytoin, Propranolol.
  • High-Yield Drugs (Biliary Excretion/Enterohepatic Circulation):
    • Ceftriaxone, Nafcillin, Azithromycin, Digoxin, Oral Contraceptives, Rifampin.
  • USMLE Pearls:
    • CYP Inducers (decrease drug levels): Rifampin, Phenobarbital, Phenytoin, Carbamazepine (“CRAP GPS”).
    • CYP Inhibitors (increase drug levels): Macrolides (not Azithro), Azole antifungals, Grapefruit Juice, Cimetidine, Ritonavir (“SICKFACES.COM G”).
    • First-pass metabolism: Reduces oral bioavailability (e.g., Lidocaine, Propranolol).

• Pulmonary Clearance: For volatile substances.

  • High-Yield Drugs: Volatile anesthetics (e.g., Isoflurane), Ethanol (partially).
  • USMLE Pearl: Recovery from anesthesia depends on this.

Metabolism

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• Zero order kinetics: The rate of metabolism and/or elimination remains constant and is independent of the plasma concentration of a drug at steady state (Cp decreases linearly over time)
  • Zero-order is a capacity-limited elimination.
  • $\text{Rate of elimination}=k_0$
  • Plasma concentration over time: $C_p(t)=C_p(0)-k_{0}t$
  • Examples include ethanol, phenytoin, aspirin (at high concentrations)
    • High-Yield Drugs (“PEA”):
      • Phenytoin
      • Ethanol
      • Aspirin (at high doses/overdose)
  • USMLE Pearl: Small dose changes can lead to large changes in plasma concentration and toxicity.
• First order kinetics: The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (Cp decreases exponentially over time)
  • First-order is a flow-dependent elimination.
  • $\text{Rate of elimination}=k\cdot C_p$
  • Plasma concentration over time: $C_p(t)=C_p(0)\cdot e^{-kt}$
  • Half life: $t_{1/2}=\frac{0.693}{k}$
  • Applies to most drugs