Adrenergic Antagonists

Overview

• Focus on alpha blockers and beta blockers.
• Understand adrenergic neurons, norepinephrine synthesis, release, recycling, and the receptors it acts upon.

Basics of Adrenergic Neurons

• *Norepinephrine Production:
  • Starts from amino acid tyrosine.
  • Tyrosine taken into nerve terminals via co-transporter (tyrosine-sodium co-transporter).
  • Converted to L-DOPA, then dopamine, finally to norepinephrine inside vesicles.
• *Release Mechanism:
  • Action potential → voltage-gated calcium channels → calcium influx → vesicle fusion → norepinephrine release into synaptic cleft.
• *Receptors and Intracellular Mechanisms:
  • Alpha-1 receptors: GQ protein → increase IP3 and DAG → increase calcium → muscle contraction.
  • Alpha-2 receptors: Gi protein → decrease cyclic AMP → increase potassium efflux → inhibit secretion.
  • Beta receptors: Gs protein → increase cyclic AMP → varied responses including contraction, conduction, and secretion.
• *Termination of Action:
  • Metabolized by catechol-O-methyltransferase.
  • Reuptake by norepinephrine transporter or metabolized by monoamine oxidase.

Physiological Effects of Receptors

• *Alpha-1 receptors:
  • Vasoconstriction → increased systemic vascular resistance → increased blood pressure.
  • Internal urethral sphincter contraction → inhibited urination.
  • Pupil dilation.
• *Alpha-2 receptors:
  • Presynaptic inhibition of norepinephrine release.
  • Decreases insulin secretion from pancreas.
• *Beta-1 receptors:
  • Increase heart rate, contractility.
  • Increase renin secretion from kidneys.
• *Beta-2 receptors:
  • Vasodilation in skeletal muscle, bronchodilation.
  • Gluconeogenesis and glycogenolysis in liver.
  • Insulin inhibition from pancreas.
• *Beta-3 receptors:
  • Smooth muscle relaxation.
  • Lipolysis in adipose tissue.

Alpha Blockers

• *Types of Drugs:
  • Selective Alpha-1: Tamsulosin, Prazosin, Terazosin, Doxazosin.
  • Alpha-1 and Alpha-2: Phentolamine, Phenoxybenzamine.
• *Indications:
  • Hypertension (not first-line).
  • Urinary incontinence due to BPH.
  • Prazosin for PTSD-related nightmares.
• *Adverse Effects:
  • Orthostasis, reflex tachycardia, intraoperative floppy iris syndrome.

Beta Blockers

• *Cardioselective (Beta-1):

  • Atenolol, Acebutolol, Bisoprolol, Esmolol, Metoprolol.
  • Indications:
    • Supraventricular tachyarrhythmias.
    • Angina and CAD: decrease O2 demand.
    • Hypertrophic cardiomyopathy: decrease contractility and heart rate.
    • Heart failure and post-MI: reduces cardiac remodeling, decreases mortality.
  • Adverse Effects:
    • Bradycardia, cardiogenic shock, avoid in decompensated heart failure.

• *Non-selective (Beta-1 and Beta-2):

  • Nadalol, Timolol, Propranolol.
  • Indications:
    • Glaucoma (Timolol).
    • Thyrotoxicosis (Propranolol).
    • Portal hypertension (Propranolol).
    • Migraine prophylaxis (Propranolol).
    • Essential tremor (Propranolol).
  • Adverse Effects: Bronchospasm, hyperkalemia, hypoglycemia.

• *Mixed (Beta-1, Beta-2, and Alpha):

  • Labetalol, Carvedilol.
  • Indications:
    • Hypertension (Labetalol).
    • Hypertensive emergencies (Labetalol).
    • Heart failure (Carvedilol).
    • Portal hypertension (Carvedilol).
  • Adverse Effects:
    • Combining beta and alpha blockade effects.
    • Watch for orthostasis.

Beta Blocker Overdose

• *Consequences:
  • Severe bradycardia to AV block.
  • Cardiogenic shock.
  • Bronchospasm (especially in non-selective beta blockers).
  • Hypoglycemia, hyperkalemia.
• *Management:
  • Drug of choice: Glucagon.

Case Studies

1. Orthostasis in new antihypertensive: Likely prazosin (alpha-1 blocker).
2. Amphetamine overdose treatment: Likely labetalol (beta and alpha blocker).
3. Asthma exacerbation with beta blocker: Switch to metoprolol (beta-1 selective).
4. Overflow incontinence: Switch to Tamsulosin (less orthostasis).
5. Anaphylactic shock reduced response to epinephrine: likely due to propranolol (non-selective beta blocker).
6. Alpha-adrenergic blockers: Used in BPH treatment.
7. Beta blockers: Should not be stopped abruptly.
8. Glaucoma treatment: Timolol.
9. Worst orthostatic effect when combined with prazosin: Labetalol.

Summary

• Alpha blockers: Treat BPH and hypertension, watch out for orthostasis.
• Beta blockers: Cardioselective for tachyarrhythmias and heart disease, non-selective for glaucoma, thyrotoxicosis, and migraines.
• Mixed blockers: Effective in hypertension, heart failure, and portal hypertension. Manage overdose with glucagon.