3.6 Tolerance & Desensitization
Tolerance is the decreased response to a drug with repeated exposure. Understanding mechanisms helps manage chronic therapy and addiction.
Types of Tolerance
Pharmacokinetic Tolerance
Increased drug metabolism (enzyme induction). Less drug reaches target. Example: Barbiturates.
Pharmacodynamic Tolerance
Receptor or signaling changes. Downregulation, desensitization. Example: Opioids, benzodiazepines.
Tachyphylaxis
Rapid tolerance (minutes-hours). Depletion of mediators. Example: Indirect sympathomimetics.
Receptor Desensitization Mechanisms
Phosphorylation
GRKs phosphorylate receptor. ฮฒ-arrestin binding. Seconds to minutes.
Internalization
Receptor endocytosis. Removed from surface. Minutes to hours.
Downregulation
Decreased receptor synthesis/increased degradation. Hours to days.
Uncoupling
Receptor-G protein dissociation. Signal transduction impaired.
Clinical Implications
Opioid Tolerance
Requires dose escalation for analgesia. Tolerance to euphoria, sedation develops. Less to constipation, miosis.
Nitrate Tolerance
Rapid tolerance to antianginal effect. Managed with drug-free intervals.
ฮฒ-Agonist Tolerance
Asthma: regular use reduces bronchodilator response. Add ICS, use as-needed.