Sympathomimetic drugs and Sympatholytic drugs

Sympathomimetic drugs

• Mechanism of Action (MOA)
  • Direct-acting: Bind directly to adrenergic receptors (α or β).
  • Indirect-acting: Increase synaptic concentration of endogenous catecholamines by inhibiting reuptake or promoting release.
  • Mixed-acting: Both direct and indirect actions.

Direct-Acting Agonists

• Phenylephrine, Midodrine, Oxymetazoline
  • Receptor: α1 > α2
  • Mechanism: ↑ IP3/DAG → ↑ intracellular Ca2+ → smooth muscle contraction.
  • Effect: Potent vasoconstriction (↑ SVR), ↑ BP (systolic & diastolic), mydriasis. Can cause reflex bradycardia.
  • Use:
    • Phenylephrine: Hypotension/shock (vasopressor), nasal decongestant, mydriatic agent.
    • Midodrine: Orthostatic hypotension.
    • Oxymetazoline: Topical nasal decongestant.
• Clonidine, Guanfacine, Methyldopa
  • Receptor: α2 (central-acting)
  • Mechanism: ↓ cAMP in brainstem → ↓ central sympathetic outflow.
  • Effect: ↓ SVR, ↓ HR, ↓ BP.
  • Use:
    • Clonidine: HTN urgency, ADHD, Tourette syndrome, opioid withdrawal.
    • Guanfacine: HTN, ADHD.
    • Methyldopa: HTN in pregnancy. (SE: Direct Coombs ⊕ hemolytic anemia).
• Dobutamine
  • Receptor: β1 > β2, α1
  • Mechanism: ↑ cAMP → ↑ Ca2+ influx in cardiac myocytes.
  • Effect: Primarily ↑ inotropy (contractility) with some ↑ chronotropy (HR). Net effect is ↑ CO with minimal change or ↓ in SVR.
  • Use: Acute decompensated heart failure, cardiogenic shock.
• Albuterol, Salmeterol, Terbutaline
  • Receptor: β2 > β1
  • Mechanism: ↑ cAMP → smooth muscle relaxation.
  • Effect: Bronchodilation, uterine relaxation (tocolysis).
  • Use:
    • Albuterol: Short-acting (SABA) for acute asthma/COPD exacerbation.
    • Salmeterol: Long-acting (LABA) for asthma/COPD maintenance.
    • Terbutaline: Tocolysis (delays premature labor), asthma.
• Isoproterenol
  • Receptor: β1 = β2 (non-selective)
  • Mechanism: ↑ cAMP.
  • Effect: Potent ↑ HR and contractility (β1) and significant vasodilation (β2) → ↓↓ SVR and diastolic BP. ↑ systolic BP. Widened pulse pressure.
  • Use: Bradycardia, AV block (rarely used).
• Fenoldopam
  • Receptor: D1
  • Mechanism: ↑ cAMP → potent vasodilation of renal, mesenteric, and coronary arteries.
  • Effect: ↓ BP, ↑ renal perfusion (promotes natriuresis).
  • Use: HTN emergency, especially in pts with renal insufficiency.

Indirect-Acting Agonists

• Cocaine, Atomoxetine, TCAs
  • Mechanism: Inhibit Norepinephrine Transporter (NET) → block reuptake of NE.
  • Use:
    • Cocaine: Local anesthetic (blocks Na+ channels), vasoconstrictor. High abuse potential.
    • Atomoxetine: Non-stimulant for ADHD.
    • TCAs: Antidepressants (off-target effect).
• Amphetamine, Methylphenidate, Tyramine
  • Mechanism: Promote release of stored catecholamines from vesicles (vesicular monoamine transporter, VMAT, displacement).
  • Use:
    • Amphetamine/Methylphenidate: ADHD, narcolepsy.
    • Tyramine: Found in aged foods (cheese, wine). Pts on MAO inhibitors are at risk for hypertensive crisis if they ingest tyramine.

Mixed-Acting Agonists

• Norepinephrine (NE)
  • Receptor: α1 > α2 > β1
  • Effect: Potent vasoconstriction (α1) → ↑↑ SVR, ↑ systolic & diastolic BP. Modest ↑ CO via β1 stimulation, but reflex bradycardia often blunts the HR increase.
  • Use: Septic shock (first-line vasopressor).
• Epinephrine (Epi)
  • Receptor: Dose-dependent.
    • Low dose: β > α (β1: ↑ HR, CO; β2: vasodilation → ↓ SVR).
    • High dose: α > β (potent vasoconstriction → ↑ SVR, ↑ BP).
  • Use: Anaphylaxis (first-line), cardiac arrest, adjunct to local anesthesia.
• Dopamine
  • Receptor: Dose-dependent.
    • Low dose: D1 → renal vasodilation.
    • Medium dose: β1 → ↑ inotropy, ↑ CO.
    • High dose: α1 → vasoconstriction, ↑ SVR.
  • Use: Bradycardia, shock (cardiogenic, septic) with hypotension.
• Ephedrine / Pseudoephedrine
  • Mechanism: Directly stimulate α and β receptors AND promote release of stored NE.
  • Use: Nasal decongestant (pseudoephedrine), hypotension (ephedrine). Tachyphylaxis can occur.

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Sympatholytic drugs

Centrally Acting Sympatholytics (α2-Agonists)

• Mechanism: Act on presynaptic α2-adrenergic receptors in the CNS (medulla) to ↓ sympathetic outflow from the brain.
• Drugs
  • Clonidine
  • α-Methyldopa

Adrenergic Neuron-Blocking Agents

• Mechanism: Interfere with the synthesis, storage, or release of norepinephrine (NE) from presynaptic terminals.
• Drugs
  • Reserpine
    • Mechanism: Irreversibly blocks the vesicular monoamine transporter (VMAT), preventing dopamine from entering vesicles to be converted to NE. This depletes catecholamine stores (NE, dopamine, serotonin).
    • Uses: Rarely used for HTN due to side effects.
    • Side Effects: Severe depression (suicidality risk), sedation, parkinsonism.
  • Guanethidine
    • Mechanism: Displaces NE from storage vesicles and inhibits NE release.
    • Uses: Obsolete; severe HTN.

Adrenergic Antagonists (Blockers)

Alpha (α) Adrenergic Blockers

• Non-selective α-blockers (α1 and α2)
  • Mechanism: Block both receptor subtypes. α1 block causes vasodilation; α2 block increases NE release (blunting the BP lowering effect).
  • Drugs:
    • Phenoxybenzamine: Irreversible antagonist. Used for preoperative management of pheochromocytoma.
      • High doses of norepinephrine can overcome the α-adrenergic inhibition of reversible and competitive Phentolamine
    • Phentolamine: Reversible antagonist. Used for pheochromocytoma diagnosis/management and to treat hypertensive crisis from MAOI + tyramine ingestion.
  • Side Effects: Orthostatic hypotension, reflex tachycardia.
• Selective α1-blockers
  • Mechanism: Block α1 receptors on vascular smooth muscle (↓ TPR, ↓ BP) and in the bladder neck/prostate (↓ urinary resistance).
  • Drugs:
    • Prazosin, Terazosin, Doxazosin: Used for HTN and BPH.
    • Tamsulosin: α1A/1D selective; specific for prostate, minimal effect on BP. Used for BPH only.
  • Side Effects: First-dose orthostatic hypotension (esp. with “-zosins”), dizziness, headache.
• Selective α2-blockers
  • Mechanism: Block presynaptic α2 autoreceptors, leading to ↑ sympathetic outflow and NE release.
  • Drugs:
    • Mirtazapine: Atypical antidepressant. Also blocks serotonin and histamine receptors.
    • Yohimbine: Used in the past for erectile dysfunction.

Beta (β) Adrenergic Blockers (-olol)

• General Mechanism: Block β receptors to ↓ HR, ↓ contractility, ↓ cardiac output, and ↓ renin release (via β1 block on JGA cells).
• General Uses: HTN, Angina pectoris, MI (↓ O2 demand), CHF (specific agents), Arrhythmias (Class II antiarrhythmic), Glaucoma (↓ aqueous humor production), Hyperthyroidism (symptom control), Migraine prophylaxis, Performance anxiety.
• General Side Effects: Bradycardia, AV block, impotence, fatigue, dyslipidemia (metoprolol), masking of hypoglycemia symptoms (except sweating).
• Non-selective (β1 + β2)
  • Drugs: Propranolol, Nadolol, Timolol, Pindolol.
  • Cautions: Contraindicated in asthma/COPD due to β2 blockade causing bronchoconstriction.
• Cardioselective (β1 > β2)
  • Mnemonic: A BEAM (Acebutolol, Betaxolol, Esmolol, Atenolol, Metoprolol).
  • Notes: Safer for pts with COPD/asthma. Esmolol is very short-acting, used IV for acute arrhythmias.
• Mixed α1 and β-blockers
  • Mechanism: Combine β-blockade with α1-blockade (vasodilation), leading to a greater reduction in BP without significant reflex tachycardia.
  • Drugs:
    • Carvedilol: Used extensively in chronic CHF.
    • Labetalol: Used in hypertensive emergencies and hypertension in pregnancy.
• Partial β-Agonists (Intrinsic Sympathomimetic Activity - ISA)
  • Drugs: Pindolol, Acebutolol.
  • Notes: Weaker antagonists. Avoid post-MI as they do not reduce mortality. Not first-line agents.