Zhong Lecture

ROCKY VISTA UNIVERSITY

Instructor Information

  • Dr. Qing Zhong, MD, PhD

  • Email: gzhong@rvu.edu

  • Location: Ivins, C224

Course Objectives

  • Describe physiological responses in cardiovascular (CV) and respiratory systems when sympathetic nervous system activates.

    • Correlate responses to specific tissues and receptor subtypes.

  • Describe the baroreceptor reflex in detail.

    • Include neurotransmitters, receptors, and cardiac and vascular responses.

  • Analyze cardiovascular responses to autonomic drugs.

    • Differentiate direct effects on autonomic receptors from indirect reflex mechanisms.

  • Differentiate direct and indirect adrenergic agonists.

  • Distinguish between selective and nonselective adrenergic agonists and antagonists for α1, α2, β1, and β2 receptors.

  • List mechanisms, applications, and side effects of cardiovascular drugs:

    • Nitroglycerin, Amlodipine, Verapamil, Digoxin.

  • Apply knowledge to clinical scenarios and case studies.

Drugs Overview

Sympathomimetics (Adrenergic Agonists)

  • List of Drugs:

    • Phenylephrine

    • Dobutamine

    • Albuterol

    • Isoproterenol

    • Norepinephrine

    • Epinephrine

    • Dopamine

    • Amphetamine

Other Cardiovascular System Drugs

  • Drugs Affecting cGMP:

    • Nitroglycerin

    • L-calcium channel blockers:

    • Amlodipine

    • Verapamil

    • Digoxin

Sympatholytics (Adrenergic Antagonists/Blockers)

  • List of Drugs:

    • Propranolol

    • Metoprolol

    • Carvedilol

    • Phentolamine (α1, α2)

    • Prazosin (α1)

Special Cases

  • Clonidine (α2 agonist): classified under sympatholytics because it decreases blood pressure.

  • Note: Red font drugs will be covered in assessments; blue font indicates important concepts.

Adrenergic Agonists

Direct vs. Indirect Agonists

  • Direct adrenergic agonists:

    • Activate adrenergic receptors directly.

    • Examples: Alpha receptor agonists, Beta receptor agonists.

  • Indirect adrenergic agonists:

    • Increase norepinephrine levels in the synaptic cleft without directly activating adrenergic receptors.

    • Examples: Amphetamine, Cocaine, Tyramine, and Ephedrine.

  • Also termed sympathomimetics as they emulate endogenous sympathetic nervous system actions.

Baroreceptor Reflex

Function and Mechanism

  • Baroreceptors: Sense vessel stretch; increased stretch causes increased depolarization.

  • Increased Blood Pressure (BP):

    • Baroreceptors increase afferent nerve activity.

    • CNS medulla reduces sympathetic output and enhances parasympathetic output.

    • Effects:

    • Decreased sympathetic activity.

    • Reduced norepinephrine release -> Less β1 activity.

    • Increased M2 activity -> Heart rate reduced.

    • Alterations in renal renin release.

  • Decreased BP: Opposite responses to increased BP occur. Heart rate increases and renin release is augmented.

Adrenergic Receptors and Drugs

Alpha and Beta Receptors

  • α1: Sphincter contraction, mydriasis.

  • α2: Inhibit norepinephrine release (Centrally and peripherally).

  • β1: Increases heart rate and contraction force.

  • β2: Bronchodilation and vasodilation.

Catecholamines

  • Norepinephrine:

    • Structure: HO-(side chain)-NH2

    • Effects: Increases BP, heart rate.

  • Epinephrine: Similar structure to norepinephrine with additional hydroxyl groups.

    • Acts on both alpha and beta receptors.

  • Isoproterenol: Selective beta agonist.

    • Primarily acts on β1 and β2 receptors.

  • Dopamine: A precursor; effects depend on dose.

Clinical Applications

Phenylephrine

  • Mechanism: Selective α1 agonist leading to increased BP.

  • Uses: Nasal decongestant, pupil dilation.

  • Side Effects: Delayed reflex bradycardia.

Dobutamine

  • Mechanism: Selective β1 agonist used to improve heart function.

  • Used For: Acute heart failure management.

Selective β2 Agonists

  • Albuterol:

    • Primary use in asthma treatment.

    • Side Effects: Tremor, tachycardia.

  • Terbutaline: Used for premature labor.

Norepinephrine and Epinephrine Dosing

Norepinephrine

  • Actions: Increases TPR, BP due to α1 activation.

  • Cardiovascular effects: Reflex bradycardia possible due to BP increase.

Epinephrine

  • Low Dose: β > α receptor affinity.

    • Decreases TPR, slight decreases in diastolic pressure.

  • Medium Dose: α = β, SBP increases, DBP decreases, minimal change in mean BP.

  • High Dose: α > β, leads to significant increases in systemic BP due to vasoconstriction.

Dopamine

  • Dose-dependent actions:

    • Low dose (1-3 μg/kg/min): stimulate D1 receptors, enhancing blood flow.

    • Moderate dose (3-7.5 μg/kg/min): stimulate β1 receptors, increasing cardiac output.

    • High dose (>10 μg/kg/min): stimulates α1 receptors, inducing significant vascular resistance.

    • Use: Cardiac or septic shock.

Drugs Affecting cGMP

Nitroglycerin

  • Mechanism: Donates nitric oxide, increasing cGMP levels leading to vasodilation.

  • Uses: Primarily in treating angina.

  • Side Effects: Reflex tachycardia.

L-type Calcium Channel Blockers

Dihydropyridine

  • Example: Amlodipine

    • Mechanism: Causes vasodilation in arterioles.

    • Uses: Hypertension treatment.

    • Side Effects: Ankle edema, constipation.

Non-dihydropyridine

  • Example: Verapamil

    • Mechanism: Decreases heart contractility and rate.

    • Uses: Treats tachyarrhythmias.

    • Side Effects: Risk of heart failure, AV block.

Digoxin

Mechanisms of Action

  1. Inotropic effect:

    • Inhibits Na+/K+-ATPase -> Increased cytosolic calcium leading to enhanced contractility.

  2. Para-sympathomimetic effect:

    • Reduces A-V conduction due to enhanced parasympathetic tone triggered by elevated calcium.

Clinical Use

  • Treats atrial fibrillation and heart failure.

  • Side Effects: GI upset, arrhythmia, CNS disturbances (e.g., visual changes).

  • Risk: Digoxin toxicity, especially in patients with renal dysfunction.

Summary of Important Concepts

  • Blood Pressure Equation:
    BP = CO imes TPR = SV imes HR imes TPR

  • Key Terms:

    • CO = Cardiac Output

    • TPR = Total Peripheral Resistance

    • SV = Stroke Volume

  • Baroreflex Mechanism: Important in modulating heart rate based on BP changes.

Practice Questions

  • Q1: Activation of which receptors by norepinephrine at therapeutic doses?

    • A. M3

    • B. β1

    • C. β1, β2

    • D. α1, α2, β1

    • E. α1, α2, β1, β2

  • Q2: Which drug is a selective beta-2 agonist?

  • Q3: Identify the selective beta-1 blocker.

  • Q4: Which drug reduces heart contraction?

References

  • Katzung BG, Basic & Clinical Pharmacology, 16th Edition, 2023. McGraw-Hill Education.

  • David C, Harris SR. Kaplan USMLE Pharmacology lecture note.

  • UWorld Step 1 Q bank.