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.