Pharmacology: ANS - Sympathetic System & Prescription

Pharmacology: ANS - Sympathetic System

Adrenergic Agonists ("Sympathomimetics")

Receptors of the ANS: Sympathetic System - Adrenoreceptors

Adrenoreceptors

• Alpha1, Alpha2, Beta1, Beta2 - G Protein Coupled Receptors

Alpha1 (α1)

• Effects:
  • Vasoconstriction: Increases peripheral resistance and blood pressure.
  • Mydriasis: Pupil dilation.
  • Increased closure of the internal sphincter of the bladder.

Alpha2 (α2)

• Effects:
  • Inhibition of norepinephrine release (presynaptic feedback inhibition).
  • Inhibition of acetylcholine release.
  • Inhibition of insulin release.

Beta1 (β1)

• Effects:
  • Tachycardia: Increased heart rate.
  • Increased lipolysis.
  • Increased myocardial contractility.
  • Increased release of renin.

Beta2 (β2)

• Effects:
  • Vasodilation: Decreased peripheral resistance.
  • Bronchodilation.
  • Increased muscle and liver glycogenolysis.
  • Increased release of glucagon.
  • Relaxed uterine smooth muscle.

Receptor/G Protein Coupling and Physiological Effects

• A1/Gq: Increases peripheral resistance and blood pressure via vascular smooth muscle contraction.
• A2/Gi: Inhibits further norepinephrine (NE) release through feedback inhibition.
• B1/Gs: Increases heart rate, cardiac contractility, and renin release. Primarily affects the heart and kidneys.
• B2/Gs: Causes vasodilation, bronchodilation, and relaxation of uterine smooth muscle. Affects vascular smooth muscle, uterus, and lungs.
• B3/Gs: Stimulates lipolysis in adipose tissue.

Mechanism of Action (MoA) of Sympathomimetic Drugs

• Direct-Acting Sympathomimetics:
  • Directly stimulate adrenergic receptors (e.g., Epinephrine, Dobutamine).
• Indirect-Acting Sympathomimetics:
  • Increase the release of norepinephrine from nerve endings or inhibit its reuptake/degradation (e.g., Amphetamines, Cocaine).
• Mixed-Acting Sympathomimetics:
  • Act through both direct and indirect mechanisms (e.g., Ephedrine, Pseudoephedrine).

Adrenergic Agonists – Direct Acting

Epinephrine

• Interacts with both Beta and Alpha receptors.
• Low doses: Beta stimulation dominates, leading to vasodilation.
• High doses: Alpha stimulation dominates, leading to vasoconstriction.
• Therapeutic Uses: EpiPen, Local Anesthesia, Bronchospasm, Intraocular Surgery, Cardiac Arrest.
• Side Effects: Stimulation of the Sympathetic Nervous System (Sy) – generalized effect.

Norepinephrine

• At therapeutic doses, the alpha receptor is most activated, leading to increased vasoconstriction.
• Used in shock.
• Side Effects: Stimulation of the Sympathetic Nervous System (similar to Epinephrine).

Albuterol

• SABA (Short-Acting Beta Agonist).
• Therapeutic Uses: Bronchodilator in acute asthma.
• Adverse Effects: Tremor, restlessness, apprehension, and anxiety.
• Caution: Consider contraindications in patients with hypertension or increased heart rate.

Salmeterol

• LABA (Long-Acting Beta Agonist).
• Therapeutic Uses: Bronchodilator in COPD or Asthma for prolonged action.
• Caution: Not for acute asthma attacks.

Mirabegron

• Therapeutic Uses: Overactive bladder.
• Caution: Should not be used in patients with uncontrolled hypertension.

Dobutamine (Acute Heart Failure)

• Class: Selective β1-adrenergic agonist.
• Mechanism of Action: Increases cardiac contractility and cardiac output by stimulating β1 receptors in the heart.
• Indication: Acute heart failure, cardiogenic shock.
• Key Point: Enhances heart function with minimal effect on heart rate; monitor for tachycardia at high doses.

Methyldopa (Hypertension in Pregnancy)

• Class: Central-acting α2-adrenergic agonist.
• Mechanism of Action: Reduces sympathetic outflow from the CNS, lowering blood pressure.
• Indication: Hypertension in pregnancy (safe for pre-eclampsia).
• Key Point: Safe in pregnancy, but may cause sedation and orthostatic hypotension.

Oxymetazoline (Nasal Congestion)

• Class: α1-adrenergic agonist.
• Mechanism of Action: Causes vasoconstriction in nasal mucosa by stimulating α1 receptors, reducing swelling and congestion.
• Indication: Nasal congestion from colds or allergies.
• Key Point: Limit use to 3-5 days to avoid rebound congestion (rhinitis medicamentosa).

Indirect and Mixed-Acting Sympathomimetics

• Indirect-acting SM: Cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine (e.g., Amphetamine, Tyramine, Cocaine).
• Mixed-action SM: Not only enhance release of stored norepinephrine from nerve endings but also directly stimulate both adrenergic receptors (e.g., Ephedrine, Pseudoephedrine).

Adrenergic Antagonists ("Sympatholytics")

General Information

• Similar effects to parasympathomimetics.
• Used in hypertension and tachycardia (beta blockers - covered in the cardio module).
• Side Effects: Parasympathetic dominance, bradycardia, fatigue, hypotension, orthostatic hypotension.

Alpha-Adrenergic Antagonists

Phenoxybenzamine

• Nonselective, noncompetitive blocker of α1- and α2-adrenergic receptors.
• Cardiovascular Effects: Prevents vasoconstriction of peripheral blood vessels caused by endogenous catecholamines.
• Epinephrine Reversal: All a-adrenergic blockers reverse the a agonist actions of epinephrine.
  • The vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β2 receptors is not blocked, leading to a decrease in systemic blood pressure.
• Therapeutic Uses: Hypertension associated with pheochromocytoma.
• Adverse Effects: Postural hypotension +/- reflex tachycardia, nasal stuffiness.

Prazosin (Benign Prostatic Hyperplasia with Hypertension)

• Class: Selective α1-blocker.
• Mechanism of Action: Blocks α1 receptors in blood vessels and prostate, causing vasodilation and smooth muscle relaxation.
• Indication: Benign prostatic hyperplasia (BPH) with hypertension.
• Key Point: Treats both BPH and hypertension; monitor for orthostatic hypotension, especially after the first dose.

Tamsulosin (Benign Prostatic Hyperplasia without Hypertension)

• Class: Selective α1A-blocker.
• Mechanism of Action: Selectively blocks α1A receptors in the prostate and bladder neck, improving urinary flow.
• Indication: Benign prostatic hyperplasia (BPH) in patients without hypertension.
• Key Point: Minimal effects on blood pressure, making it suitable for BPH patients who do not require blood pressure management.

Beta-Adrenergic Antagonists

• Antagonize competitively the effects of catecholamines at β adrenoceptors.
• Selectivity: None of the clinically available β-receptor antagonists are absolutely specific for β1 receptors; selectivity is dose-related and diminishes at higher drug concentrations.
• Uses: Systemic and portal hypertension, angina, cardiac arrhythmias, myocardial infarction, heart failure, hyperthyroidism, glaucoma, prophylaxis of migraine headaches.

Propranolol

• Cardiovascular Effects:
  • Decreases cardiac output (negative inotropic and chronotropic effects) leading to bradycardia.
  • Decreases cardiac output, workload, and oxygen consumption, beneficial for the treatment of angina.
• Bronchoconstriction: Blocking β2 receptors in the lungs leads to contraction of the bronchiolar smooth muscle, potentially exacerbating COPD or asthma.
• Caution: Should never be stopped abruptly due to the risk of precipitating cardiac arrhythmias.
• CNS Effects: Dizziness, lethargy, fatigue, weakness, visual disturbances (due to inhibition of the Sympathetic system).

Propranolol (Tachycardia due to Hyperthyroidism)

• Class: Non-selective β-blocker.
• Mechanism of Action: Blocks β1 and β2 receptors, reducing heart rate and myocardial oxygen demand; also inhibits T4 to T3 conversion.
• Indication: Tachycardia and symptoms of hyperthyroidism (e.g., palpitations, anxiety).
• Key Point: First-line for adrenergic symptoms in hyperthyroidism; provides both cardiovascular and thyroid-related benefits.

Metoprolol/Bisoprolol (Chronic Heart Failure)

• Class: Selective β1-blocker.
• Mechanism of Action: Blocks β1 receptors in the heart, reducing heart rate, contractility, and sympathetic stimulation.
• Indication: Chronic heart failure with reduced ejection fraction.
• Key Point: Essential in reducing mortality in heart failure; titrate slowly to avoid worsening symptoms in severe cases.

Beta-Adrenergic Antagonist (Glaucoma Treatment)

• More potent than propanolol.
• Used for chronic treatment of glaucoma via local application.
• Effect: Decreases aqueous humor production by the ciliary body, leading to decreased Intraocular pressure (IOP).
• Advantage: Does not affect the ability to change pupil size or adapt to near vision, unlike cholinergic drugs (e.g., pilocarpine).
• Note: Pilocarpine remains the choice for acute glaucoma attacks.
• MoA: Reduces aqueous humor production

Nerve Pathways and Drug Treatment for Glaucoma

• Cholinergic agonists and AChE inhibitors enhance aqueous outflow.
• β-Adrenergic antagonists and α-adrenergic agonists decrease aqueous inflow.

Receptor Location and Effect of Antagonism