CV Effects of the Autonomic Nervous System (ANS)

CV Effects of the Autonomic Nervous System (ANS)

Lecture Objectives

  • Describe cardiovascular (CV) effects, therapeutic uses, and side effects of prototype adrenergic blockers (antagonists)
  • Explain how agonist effects are modified when pretreated with blockers
  • Predict blood pressure and heart rate changes when given sympathomimetics alone and in combination with ANS blockers

1. Cardiovascular Effects, Therapeutic Uses, and Side Effects of Adrenergic Blockers

  • Alpha-Blockers:

    • Effects: Vasodilation, decreased blood pressure.
    • Uses: Hypertension, BPH.
    • Side Effects: Orthostatic hypotension, reflex tachycardia.

  • Beta-Blockers:

    • Effects: Decreased heart rate, reduced cardiac output.
    • Uses: Hypertension, angina, heart failure, arrhythmias.
    • Side Effects: Bradycardia, fatigue, bronchoconstriction.

2. Modification of Agonist Effects with Blockers

  • Alpha-Blockers: Prevent vasoconstriction by alpha-agonists; may cause "epinephrine reversal" (decreased BP).
  • Beta-Blockers: Reduce heart rate and contractility effects of beta-agonists; can lead to unopposed vasoconstriction by alpha-agonists.

3. Predicting Blood Pressure and Heart Rate Changes

  • Sympathomimetics Alone:

    • Epinephrine: Increases heart rate and BP.
    • Norepinephrine: Increases BP, slight decrease in heart rate (reflex).

  • Combination with Blockers:

    • Alpha-Blocker + Epinephrine: Decreased BP (epinephrine reversal), increased heart rate.
    • Beta-Blocker + Epinephrine: Decreased heart rate, minimal effect on BP; unopposed vasoconstriction.

Cardinal Rule of Pharmacology

  • Blockers are designed to block. They will inhibit underlying activation and future endogenous or exogenous stimulation.
  • There will be no effect when there is nothing to block.

Agonists and Antagonists

  • Agonists: Drugs that occupy receptors and activate them. Example: Achieving full activation.
  • Antagonists: Drugs that occupy receptors but do not activate them. They block receptor activation by agonists, resulting in no activation. Example: Achieving no activation.

Alpha and Beta Blockers

  • Alpha blockers (Xα) and Beta blockers (Xβ):
    • α1: Causes vasoconstriction
    • β1: Causes heart stimulation
    • Vasodilation: Result of alpha blockage
    • Heart suppression: Result of beta blockage

Examples of Alpha Blockers

  • Phentolamine
  • Phenoxybenzamine
  • Prazosin (α1)

Alpha Blocker Summary

  • Vasodilation and decreased blood pressure: Used in hypertensive crisis (pheochromocytoma, cocaine overdose, MAOI hypertensive crisis)
  • Smooth muscle dilation: Prazosin is used for benign prostatic hyperplasia (BPH)
  • Main side effects:
    • Reflex tachycardia
    • Orthostatic hypotension

Clinical Uses and Side Effects of Alpha Blockers

  • Pheochromocytoma: Tumor in adrenal gland producing too much NE, Epi. Use phenoxybenzamine to reduce peripheral vascular resistance (PVR) and blood pressure before adding beta-blocker until surgery.
  • Hypertensive crisis caused by MAOI+tyramine or cocaine: Use phentolamine to reverse vasoconstriction, but be cautious of reflex tachycardia.
  • Raynaud’s disease: Abnormal vasoconstriction to extremities in response to cold/stress.
  • Benign prostatic hyperplasia (BPH): Use α1-selective blockers like prazosin. Prefer once-daily α1 blockers over prazosin, which may be needed 2-4 times daily.

Reflex Tachycardia and Orthostatic Hypotension

  • Reflex Tachycardia: Increase in heart rate due to baroreflex in response to low blood pressure after vasodilation.
  • Orthostatic Hypotension: Drop in blood pressure when standing up, leading to potential dizziness or fainting.

Epinephrine Reversal

  • Before alpha blockade: Large doses of epinephrine (Epi) act on α1, α2, β1, and β2 receptors, causing vasoconstriction (dominant α1 effect) and an increase in systemic vascular resistance (SVR) and blood pressure (BP).
  • After alpha blockade: Large doses of Epi primarily act on β1 and β2 receptors due to blocked α receptors, resulting in vasodilation (β2 effect) and a decrease in SVR and BP, known as epinephrine reversal.

Beta Blockers

  • Examples:
    • Non-selective (β1 and β2): Propranolol, Timolol
    • Cardioselective (β1): Atenolol, Metoprolol

Beta Blocker Summary

  • Therapeutic Uses:
    • Treat cardiac conditions (β1 block), hypertension, and glaucoma (decrease aqueous humor production with Timolol).
  • Side Effects:
    • β2 blockade: Bronchoconstriction and hypoglycemia.
    • General side effects: Tiredness, insomnia, depression, etc.

Rationale for Beta Blocker Use in Heart Conditions

  1. Angina: Decrease O2 demand by reducing heart rate (HR) and contractility.
  2. Heart Failure: Prevent overworking; decrease mortality with specific beta-blockers like bisoprolol, carvedilol, and metoprolol.
  3. Arrhythmia: Slow down abnormal heart rhythm via SA or AV node modulation.
  4. Hypertension: This is not first-line therapy anymore, but it is useful in combination, particularly for addressing reflex tachycardia.

Pharmacological Actions of Beta Blockers

  • Decrease HR, contractility, cardiac output (CO), and AV conduction velocity.
  • It may decrease total coronary blood flow (β2 blockade) and increase airway resistance.
  • In insulin-dependent diabetics, β1 antagonists are preferred to avoid hypoglycemic issues.
  • Associated with increased plasma triglycerides (VLDL) and decreased HDL.

Clinical Uses of Beta Blockers

  • Widespread Uses: Arrhythmia, angina pectoris, hypertension, myocardial infarction.
  • Secondary Uses: Hyperthyroidism, glaucoma, migraine prophylaxis, acute dissecting aortic aneurysm, and pheochromocytoma (only after α-blockers).

Adverse Effects of Beta Blockers

  • Decreased HR and CO can be problematic in congestive heart failure or bradycardia.
  • Bronchoconstriction is a concern for patients with obstructive airway disease.
  • Hypoglycemia risk for insulin-dependent diabetics.
  • Tiredness, insomnia, depression, nightmares.
  • Gastrointestinal issues: Diarrhea, heartburn.
  • Skin issues: Rash and fever.