6. Pharmacology of Hypertension 2

Pharmacology of Hypertension II

Dr. Declan McKernan

  • Email: declan.mckernan@universityofgalway.ie

  • Course: PM309 Cardiovascular Drugs

Learning Outcomes

  • Understand the role of systemic vascular resistance/tone in blood pressure regulation.

  • Identify cell types and proteins involved in smooth muscle contraction and relaxation.

  • Compare and contrast antihypertensive drugs with respect to:

    • Mechanisms of action

    • Pharmacokinetics

    • Potential side effects

Antihypertensive Therapy

  • Baroreceptor discharge influence on cardiovascular dynamics.

  • Major drug classes and their roles include:

    • Moxonidine

    • Clonidine

    • Methyldopa

    • Alpha-blockers

    • Calcium channel blockers

    • Beta-blockers

  • Actions on:

    • Blood volume

    • Sodium excretion

    • Cardiac output

    • Vascular resistance

Vascular Resistance

  • Influences on ventricular wall stress:

    • Systemic arteriolar and venous tone.

  • Formula for mean arterial pressure (MAP):

    • MAP = Systemic Vascular Resistance (SVR) x Cardiac Output (CO)

  • Key Terms:

    • Afterload: Resistance faced by ventricle during systole.

    • Preload: Stretch on ventricular fibers before contraction.

Vascular Smooth Muscle

  • Contraction regulated by intracellular calcium levels [Ca2+]i.

  • Mechanisms increasing [Ca2+]i:

    • Voltage-gated calcium channels (VGCCs)

    • Release from sarcoplasmic reticulum

  • Vasoconstriction process:

    • Activation of calmodulin (CaM) leading to MLCK activation stabilizing actin-myosin interaction.

  • Vasodilation process:

    • MLC dephosphorylation via MLCP stimulated by cGMP pathways.

Smooth Muscle Contraction & Relaxation

  • Contraction:

    • Involves Ca2+ influx via VGCCs and activation of MLCK.

    • Formation of actin-myosin cross-bridges.

  • Relaxation:

    • Inhibitory mechanisms through cGMP signaling and MLCP activation.

Regulators of Vascular Tone

  • Various factors influence vascular tone, including:

    • Shear stress

    • Agonists (ACh, BK, thrombin)

    • Electrotonic spread via gap junctions

    • Endothelial-derived factors (NO, PGI)

Vasodilator Drugs

  • Classes include:

    • Endothelin receptor antagonists (ETA, ETB)

    • Alpha-1 antagonists

    • Calcium channel blockers

    • Organic nitrates

  • Use: Target mechanisms that undermine hypertension.

Organic Nitrates

  • Mechanism of Action (MoA):

    • NO donors activating GC, promoting vasorelaxation.

  • Clinical Uses:

    • Angina pectoris, heart failure.

  • Pharmacokinetics (PK):

    • Rapid metabolism; short half-life.

  • Side Effects:

    • Venous pooling, postural hypotension, headache.

Sodium Nitroprusside

  • Key Characteristics:

    • Rapidly acting NO donor.

  • Clinical Use:

    • Hypertensive emergencies.

  • Side Effects:

    • Risk of cyanide toxicity, especially with prolonged therapy.

PDE Inhibitors

  • MoA:

    • Inhibition of cAMP/cGMP degradation.

  • Examples:

    • Sildenafil, amrinone, milrinone.

  • Clinical Use:

    • Pulmonary hypertension, erectile dysfunction.

Calcium Channel Blockers (CCBs)

  • Mechanism of Action:

    • Affect SA node activity, myocardial contractility, and vascular smooth muscle.

  • Examples:

    • Amlodipine, diltiazem, verapamil.

  • Clinical Uses:

    • Hypertension, angina, arrhythmias.

Potassium Channel Openers

  • Mechanism of Action:

    • Open KATP channels, leading to hyperpolarization and relaxation.

  • Examples:

    • Minoxidil, nicorandil.

  • Uses:

    • Hypertension, hirsutism.

Endothelin Receptor Antagonists

  • Mechanism of Action:

    • Competitive blockage of ETA and ETB receptors.

  • Examples:

    • Bosentan, ambrisentan.

  • Uses:

    • Pulmonary arterial hypertension (PAH).

Adrenergic Agents

  • Mechanism of Action:

    • Affect various receptor pathways influencing blood pressure and vascular resistance.

Alpha Antagonists

  • Mechanism:

    • Block α1 adrenergic receptors, leading to vasodilation.

  • Examples:

    • Prazosin, doxazosin.

  • Clinical Uses:

    • Hypertension, prostatic hyperplasia.

Beta Blockers

  • Mechanism of Action:

    • Decrease heart rate and contractility, reducing blood pressure.

  • Examples:

    • Propranolol, metoprolol.

  • Clinical Uses:

    • Dysrhythmias, anxiety, hypertension.

Other Agents

  • Centrally acting sympatholytics (e.g., clonidine) inhibit sympathetic outflow.

  • Renin-angiotensin blockers include ACE inhibitors and ARBs.

Summary

  • Vascular tone and systemic vascular resistance are crucial in managing hypertension.

  • Targeted drug classes include:

    • Organic nitrates

    • PDE inhibitors

    • Calcium channel blockers

    • Endothelin antagonists

    • Potassium channel openers

    • Alpha and beta blockers.

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