Chapter 3  ·  Module 3  ·  Pharmacodynamics

Signal Transduction and Receptor Regulation

G protein second messenger pathways, desensitization, and withdrawal syndromes at a glance

G Protein Second Messenger Pathways

Gs pathway

Gs → Cyclic Adenosine Monophosphate

  • Gs activates adenylyl cyclase
  • Adenylyl cyclase makes cyclic adenosine monophosphate
  • Cyclic adenosine monophosphate activates protein kinase A
  • Phosphodiesterase terminates signal (inhibited by milrinone, theophylline)
  • Examples: beta-adrenergic agonists, glucagon, vasopressin V2

Gi pathway

Gi → Inhibits Cyclic Adenosine Monophosphate

  • Gi inhibits adenylyl cyclase
  • Reduces cyclic adenosine monophosphate and protein kinase A activity
  • Opposes Gs effects
  • Examples: opioids (mu, delta, kappa), M2 muscarinic (cardiac rate ↓), alpha-2 agonists (clonidine), dopamine D2

Gq pathway

Gq → Calcium + Protein Kinase C

  • Gq activates phospholipase C
  • Phospholipase C cleaves to inositol trisphosphate + diacylglycerol
  • Inositol trisphosphate releases calcium from endoplasmic reticulum
  • Diacylglycerol activates protein kinase C
  • Examples: alpha-1 adrenergic (vasoconstriction), M1/M3 muscarinic, angiotensin II type 1 receptor

Nitric oxide/cGMP pathway

Nitric Oxide → Cyclic Guanosine Monophosphate

  • Nitric oxide activates soluble guanylyl cyclase
  • Cyclic guanosine monophosphate activates protein kinase G
  • Smooth muscle relaxation and vasodilation
  • Organic nitrates: prodrug nitric oxide donors
  • Phosphodiesterase 5 inhibitors (sildenafil, tadalafil): prolong cyclic guanosine monophosphate
  • Nitrates + phosphodiesterase 5 inhibitors: risk of severe hypotension

Receptor Desensitization — Time Course

ProcessTime scaleMechanismClinical consequence
Desensitization Seconds to minutes G protein-coupled receptor kinase phosphorylates receptor; beta-arrestin binds; G protein uncoupling Reduced response during continuous agonist exposure; waning bronchodilation with chronic beta-agonist use
Downregulation Hours to days Receptor internalization into endosomes; degradation in lysosomes; reduced surface receptor number Loss of receptor-mediated effect; recovery requires new receptor synthesis
Tachyphylaxis Minutes to hours Rapid tolerance: receptor desensitization, substrate depletion (nitrates, ephedrine) Nitrates: 24-hour tolerance; require 8-12 hour nitrate-free interval. Ephedrine: progressive loss of pressor effect with repeated doses

Tolerance and Withdrawal — Clinically Important Syndromes

Antagonist withdrawal

Beta-Blocker Withdrawal Syndrome

  • Chronic blockade → beta-1 receptor upregulation
  • Abrupt stop: upregulated receptors + catecholamines = rebound
  • Rebound tachycardia, hypertension, angina, arrhythmia
  • Risk: acute myocardial infarction in coronary artery disease
  • Management: taper over 1–2 weeks; never stop abruptly

Agonist withdrawal

Clonidine Rebound Hypertension

  • Clonidine: central alpha-2 agonist, reduces sympathetic outflow
  • Chronic use → compensatory sympathetic adaptation
  • Abrupt stop: sympathetic surge unmasked
  • Onset 18–24 hours: severe hypertension, tachycardia, diaphoresis
  • Management: reinstate and taper; never stop abruptly

Opioid tolerance and withdrawal

Opioid Withdrawal — Adenylyl Cyclase Superactivation

  • Chronic opioids → Gi inhibits adenylyl cyclase → cell compensates by making more adenylyl cyclase
  • Withdrawal: adenylyl cyclase overexpressed and unopposed → cyclic adenosine monophosphate surge
  • Symptoms: lacrimation, rhinorrhea, piloerection, diarrhea, tachycardia, dysphoria
  • Clonidine (Gi → cyclic adenosine monophosphate ↓) partially suppresses withdrawal
  • Methadone/buprenorphine: sustained low-level mu activation prevents withdrawal

Glucocorticoid withdrawal

Adrenal Insufficiency on Withdrawal

  • Chronic supraphysiological glucocorticoids → hypothalamic-pituitary-adrenal axis suppression
  • Adrenal cortex atrophies without adrenocorticotropic hormone stimulation
  • Abrupt stop after > 3 weeks: adrenal insufficiency, hypotension, circulatory collapse
  • Management: slow taper; stress-dose coverage during illness or surgery