3.5 Drug excretion and elimination

Drug excretion is the final step in pharmacokinetics, removing drugs and their metabolites from the body. It's crucial for determining a drug's duration of action, dosing regimen, and potential for toxicity. Understanding excretion helps predict drug effects and guide safe, effective use.

Excretion mainly occurs through urine, feces, and breath. The kidneys play a key role, filtering drugs from blood. Liver metabolism and bile secretion are also important. Factors like age, organ function, and drug interactions can affect how quickly drugs leave the body.

Drug excretion and pharmacokinetics

Defining drug excretion and its pharmacokinetic role

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• Drug excretion removes drugs and their metabolites from the body through urine, feces, and exhalation
• Represents final phase of pharmacokinetics after absorption, distribution, and metabolism (ADME)
• Rate and extent of drug excretion impact drug's duration of action and therapeutic effect
• Determines drug's half-life and dosing regimen for maintaining therapeutic levels
• Predicts potential drug-drug interactions
• Guides dosage adjustments for patients with impaired excretory function
• Influences drug accumulation and toxicity risks

Clinical significance of drug excretion

• Affects drug efficacy by altering plasma concentrations over time
• Impacts dosing frequency required to maintain therapeutic effects
• Determines duration of drug action in the body
• Influences potential for adverse effects or toxicity with repeated dosing
• Guides therapeutic drug monitoring and dose individualization
• Affects drug-drug interactions involving shared elimination pathways
• Informs risk assessment for drugs in special populations (renal/hepatic impairment)

Routes of drug excretion

Major excretion pathways

• Renal excretion eliminates most drugs and metabolites through urine
  • Involves glomerular filtration, tubular secretion, and tubular reabsorption
  • Affected by renal blood flow, glomerular filtration rate, and tubular function
• Hepatobiliary excretion removes drugs through liver metabolism and biliary secretion
  • Metabolized drugs excreted into bile and eliminated via feces
  • Important for drugs with high molecular weight or conjugated metabolites
• Pulmonary excretion eliminates volatile drugs and gases through exhalation
  • Significant for anesthetic agents (nitrous oxide, halothane)
  • Rate depends on drug's vapor pressure and blood-gas partition coefficient

Minor and specialized excretion routes

• Sweat glands excrete some drugs (amphetamines, anticonvulsants)
• Salivary excretion occurs for certain medications (lithium, metronidazole)
• Breast milk excretion impacts drug use during lactation
• Enterohepatic recirculation reabsorbs some drugs excreted in bile
  • Prolongs drug effects (morphine, estrogens)
  • Can lead to drug accumulation with repeated dosing

Clearance and its implications

Understanding clearance concepts

• Clearance measures volume of blood/plasma cleared of drug per unit time
  • Typically expressed in mL/min or L/hr
• Total body clearance sums all organ clearances
  • Renal and hepatic clearance contribute most for many drugs
• Determines drug elimination rate
• Calculates dosing regimens to maintain steady-state concentrations
• Estimates drug half-life and time to reach steady state
• Relates clearance to bioavailability for first-pass metabolism drugs

Clinical applications of clearance

• Guides initial dose selection and maintenance dose adjustments
• Predicts drug accumulation risk in organ dysfunction
• Assesses impact of drug interactions on elimination
• Explains variability in drug response between individuals
• Informs therapeutic drug monitoring strategies
• Aids in designing dosing regimens for drugs with narrow therapeutic indices
• Supports development of extended-release formulations

Factors influencing drug excretion

Physiological and pathological factors

• Renal function affects drug clearance
  • Reduced function leads to drug accumulation (aminoglycosides, digoxin)
• Hepatic function impacts drug metabolism and biliary excretion
  • Liver disease alters elimination of drugs like warfarin or benzodiazepines
• Age-related changes reduce drug clearance in elderly patients
  • Increased risk of adverse effects with reduced renal/hepatic function
• Genetic polymorphisms cause variations in drug elimination rates
  • CYP2D6 variants affect codeine metabolism and efficacy

Drug-related and environmental influences

• Drug-drug interactions alter excretion rates
  • Enzyme inhibition (ketoconazole inhibiting CYP3A4)
  • Enzyme induction (rifampicin inducing CYP enzymes)
  • Competition for elimination pathways (probenecid and penicillin)
• Physicochemical properties of drugs affect elimination
  • Molecular size influences glomerular filtration
  • Lipophilicity impacts renal tubular reabsorption
  • Protein binding affects drug availability for excretion
• Environmental factors modify excretion rates
  • Diet influences drug metabolism (grapefruit juice inhibiting CYP3A4)
  • Hydration status affects renal drug elimination
  • Urinary pH alters excretion of weak acids/bases (amitriptyline, aspirin)