Describe the Adrenoreceptors by subunit, distribution, effects (including non-cardiovascular effects)

 

Receptor Subunit Distribution Effect Non-cardiovascular effects
α₁ Gq → ↑ IP₃/DAG → ↑ Ca²⁺ Vascular smooth muscle, iris radial muscle, prostate/bladder neck, GI/GU sphincters Smooth muscle contraction → vasoconstriction, mydriasis, urinary retention • Mydriasis via radial muscle contraction • GI sphincter contraction • Bladder neck/prostate contraction • Piloerection • Skin vasoconstriction
α₂ Gi → ↓ adenylate cyclase → ↓ cAMP Presynaptic sympathetic nerve terminals, CNS, platelets, pancreatic β cells ↓ noradrenaline release; ↓ sympathetic outflow; ↓ insulin; platelet aggregation • Reduced insulin secretion>higher BGls • Reduced sympathetic outflow, sedation/analgesia • Reduced noradrenaline release
β₁ Gs → ↑ adenylate cyclase → ↑ cAMP Heart, juxtaglomerular cells of kidney ↑ HR, ↑ contractility, ↑ conduction; ↑ renin • Increased renin release
β₂ Gs → ↑ adenylate cyclase → ↑ cAMP Bronchial smooth muscle, skeletal-muscle vasculature, uterine smooth muscle, GI smooth muscle Smooth muscle relaxation → bronchodilation, vasodilation, uterine relaxation • Bronchodilation • Increased aqueous humour production[hence why beta blockers are used in glaucoma] • Reduced GI motility • Detrusor relaxation • Uterine relaxation • Tremor • Increased K uptake into cells>hypokalaemia • Increased glycogenesis>increased BGL • Increased lipolysis • Increased insulin secretion>lower BGLs
β₃ Gs → ↑ cAMP Adipose tissue, bladder detrusor Lipolysis; detrusor relaxation • Increased lipolysis

What is the effect of Alpha agonism and how can it be useful?

α₁ receptor → Gq → ↑ IP₃/DAG → ↑ intracellular Ca²⁺ → smooth-muscle contraction

  • Blood vessels: vasoconstriction, useful in shock (noradrenaline has stronger alpha effect than adrenaline and is often used for this reason as a vasopressor, adrenaline also useful in anaphylactic shock for this reason)
  • Nasal mucosa: reduced mucosal oedema, useful in nasal decongestion
  • Eye radial muscle: mydriasis, e.g. phenylephrine to look at retina
  • Bladder neck/prostate: urinary retention, usually this is a negative effect
  • GI/GU sphincter: contraction
  • Skin: vasoconstriction, useful for achieving haemostasis

α₂ receptor → Gi → ↓ cAMP

  • Presynaptic effect and CNS effect: reduces noradrenaline release, reduces sympathetic outflow, reduces BP/HR , causes sedation, analgesia, (clonidine and Dexmedetomidine useful for this)

Alpha and Beta agonists; their pharmacodynamics and pharmacokinetics

Drug Main receptors Main PD effect Typical clinical role Key PK
Adrenaline α₁,=β₁=β₂ >α₂ ↑ HR/contractility[chronotropy/inotropy], vasoconstriction, bronchodilation Anaphylaxis, cardiac arrest, severe shock IV/IM/SC; rapid onset, short duration; metabolised by COMT + MAO
Noradrenaline α₁>α₂>β₁ minimal β₂ ↑ SVR/MAP, some ↑ contractility; reflex bradycardia possible Vasodilatory shock/vasopressor [slightly more α₁ than adrenaline] IV infusion; very short half-life; metabolised by COMT + MAO
Isoprenaline β₁ + β₂ ↑ HR/contractility + vasodilation → ↓ SVR Severe bradycardia/chronotropic support; specialist use IV infusion; very short acting; COMT/MAO metabolism
Dobutamine Predominantly β₁, some β₂/α₁ ↑ contractility and CO[inotropy], relatively little change in SVR Low-output cardiac failure/cardiogenic shock with poor contractility IV infusion; short half-life (~2 min); rapid metabolism
Dopamine Dose-dependent D₁ → β₁ → α₁ Dose-dependent; Low dose: Vasodilation in renal/mesenteric/cerebral vessels; Mod dose: ↑ contractility + HR; High dose: Vasoconstriction→ ↑ SVR Selected shock/bradycardia situations; less commonly first-line vasopressor. Methyldopa is used in pregnancy HTN as it ↓ PVR IV infusion; very short half-life (~2 min); metabolised by MAO/COMT

What are the different effects of various beta blockers? How is this important in toxicity?

General overview of the adverse effects of beta blockers:

Cold hands: Beta blockade can lead to a rise in peripheral vascular resistance as β₂ vasodilation is blocked, leading to unopposed alpha action. Can worsen claudication in PVD.

Worsening of asthma: β₂ blockade → bronchoconstriction

Sinus bradycardia: beta blockers are contraindicated in patients with symptomatic bradycardia or sinus node dysfunction (↓ AV conduction)

Verapamil interaction: co-administration can lead to bradycardia, heart failure, severe hypotension

Hypoglycaemia: endogenous adrenaline is critical in the counter-regulatory response to hypoglycaemia, so beta blockers should be avoid in insulin-dependent diabetes with frequent hypoglycaemia. β₁-selective antagonist preferred in these patients.

Fatigue, depression

Sexual dysfunction: impaired ejaculation due to GU/GI sphincter activity.

Metabolism and lipids: beta blockade leads to a small increase in triglycerides and decrease in HDL

Acute withdrawal: sudden tachycardia can result from abruptly ceasing beta blockers. Should taper.

β-blocker type Examples Important pharmacology Toxicity implications
β₁-selective Metoprolol, atenolol, bisoprolol, esmolol, nebivolol Preferentially block β₁ at therapeutic doses Mainly bradycardia, AV block, hypotension. At high doses, selectivity is lost → β₂ effects can occur
Non-selective β₁ + β₂ Propranolol, sotalol, nadolol, timolol Block both β₁ and β₂ Cardiovascular toxicity plus bronchospasm, hypoglycaemia/impaired glucose recovery. Some have additional important properties
β-blocker + α₁ blockade Labetalol, carvedilol β₁ + β₂ + α₁ blockade More vasodilation → hypotension can be prominent
β-blocker with membrane-stabilising activity (MSA) Propranolol (important), high-dose some others Blocks fast Na⁺ channels at high concentrations QRS widening, ventricular dysrhythmias, seizures; particularly important in propranolol overdose
β-blocker with K⁺-channel blockade Sotalol β-blockade + class III antiarrhythmic effect QT prolongation → torsades de pointes
Short-acting β₁-selective Esmolol Very short half-life; rapidly metabolised by esterases Toxicity generally shorter-lived once stopped

Special cases to remember

Propranolol is highly lipid soluble and crosses the blood-brain barrier. In overdose you see:

  • Beta blockade: bradycardia and hypotension
  • CNS toxicity: seizures, coma
  • Na+ channel blockage: QRS widening

Sotalol has beta blocking AND class III anti-arrthymic effects. In overdose you see:

  • Beta blockage
  • K+ channel blockage: QT prolongation, torsades

 

Beta blockers; their pharmacodynamics and pharmacokinetics

 

Most beta blockers are well absorbed orally and peak concentrations are 1-3hrs after ingestion. Most have half lives in the range of 3-10 hours (except esmolol).

Drug Receptor action Pharmacodynamics Pharmacokinetics Clinical points
Propranolol Non-selective β₁ + β₂ antagonist ↓ HR, ↓ contractility, ↓ AV conduction, ↓ renin; β₂ blockade → bronchoconstriction Oral, IV; lipid soluble; extensive first pass hepatic metabolism, low bioavailability, t½ ~3–6 h CNS effects + Na⁺ channel blockade in overdose Used in thyroid storm, infantile hemangiomas
Metoprolol β₁-selective antagonist ↓ HR, ↓ contractility, ↓ AV conduction, ↓ renin Oral, IV; extensive hepatic metabolism (CYP2D6); t½ ~3–7 h Cardio-selective, but selectivity lost at high doses. Better for asthma/copd
Atenolol β₁-selective antagonist ↓ HR, ↓ contractility, ↓ AV conduction, ↓ renin Oral, IV; hydrophilic(doesn’t cross BBB); predominantly renal excretion; t½ ~6–7 h Less CNS penetration; accumulation in renal impairment
Labetalol β₁ + β₂ + α₁ antagonist β blockade + α₁ vasodilation → ↓ HR/contractility + ↓ SVR Oral, IV; hepatic metabolism; t½ ~5–8 h Produces vasodilation without marked reflex tachycardia, used in pregnancy-associated HTN and hypertensive emergency
Esmolol β₁-selective antagonist Rapid ↓ HR, contractility and AV conduction IV only; rapidly hydrolysed by RBC esterases; t½ ~9 min Ultra-short acting; easily titrated
Nebivolol The most β₁-selective antagonist ↓ HR, ↓ contractility, ↓ AV conduction, ↓ renin +Vasodilation (Promotes endothelial NO production) Oral; extensive hepatic metabolism, including CYP2D6; relatively long effective duration; t½ ~10–30 h depending on metabolism β₁ blockade + NO-mediated vasodilation
Timolol β₁ = β₂ antagonist Reduces aqueous humour production>reduces intraocular pressure Topical; t½ ~4-5 h; lacks membrane stabilising properties Treats glaucoma, topical timolol can cause adverse effects in heart and airways i.e. heart block if co-administered with verapamil

Alpha blockers; their pharmacodynamics and pharmacokinetics

Alpha blockers can cause (negative effects);

  • Orthostatic hypotension (and tachycardia) because they block sympathetic-mediated vasoconstriction. When BP depends on increased sympathetic activity i.e. when standing up, this effect is most pronounced..
  • Nasal congestion
  • Inhibition of ejaculation(since alpha agonism normally contracts vas deferens/seminal vesicles/bladder neck)
Drug Receptor action Pharmacodynamics Pharmacokinetics Clinical points
Phentolamine Reversible α₁ + α₂ antagonist Vasodilation → ↓ SVR/BP; reflex tachycardia [blocking α₂ removes presynaptic inhibition of noradrenaline] IV/IM; short acting; hepatic metabolism Acute α-blockade, e.g. catecholamine excess
Phenoxybenzamine Irreversible α₁ + α₂ antagonist Persistent vasodilation; ↓ SVR; reflex tachycardia Oral; covalent/irreversible receptor blockade; effect lasts days Used to treat Phaeochromocytoma; long acting. Enters CNS so can cause sedation/nausea/fatigue
Prazosin Selective α₁ antagonist, reversible Vasodilation → ↓ SVR/BP; relaxes bladder/prostate smooth muscle Oral; hepatic metabolism; t½ ~2–3 h; effect longer than plasma t½ First-dose of prazosin can cause postural hypotension +/- syncope. Can help w/ urinary retention in BPH.
Tamsulosin Competitive α₁ antagonist Subtype selection i.e. α₁A + α₁D>α₁B relaxes bladder/prostate smooth muscle Oral; t½ ~9-15h; hepatic metabolism Inhibits prostate smooth muscle contraction, less effect on standing BP, higher risk of floppy iris syndrome and sometimes stopped before cataract surgery