Email: declan.mckernan@universityofgalway.ie
Course: PM309 Cardiovascular Drugs
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
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
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.
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.
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.
Various factors influence vascular tone, including:
Shear stress
Agonists (ACh, BK, thrombin)
Electrotonic spread via gap junctions
Endothelial-derived factors (NO, PGI)
Classes include:
Endothelin receptor antagonists (ETA, ETB)
Alpha-1 antagonists
Calcium channel blockers
Organic nitrates
Use: Target mechanisms that undermine hypertension.
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.
Key Characteristics:
Rapidly acting NO donor.
Clinical Use:
Hypertensive emergencies.
Side Effects:
Risk of cyanide toxicity, especially with prolonged therapy.
MoA:
Inhibition of cAMP/cGMP degradation.
Examples:
Sildenafil, amrinone, milrinone.
Clinical Use:
Pulmonary hypertension, erectile dysfunction.
Mechanism of Action:
Affect SA node activity, myocardial contractility, and vascular smooth muscle.
Examples:
Amlodipine, diltiazem, verapamil.
Clinical Uses:
Hypertension, angina, arrhythmias.
Mechanism of Action:
Open KATP channels, leading to hyperpolarization and relaxation.
Examples:
Minoxidil, nicorandil.
Uses:
Hypertension, hirsutism.
Mechanism of Action:
Competitive blockage of ETA and ETB receptors.
Examples:
Bosentan, ambrisentan.
Uses:
Pulmonary arterial hypertension (PAH).
Mechanism of Action:
Affect various receptor pathways influencing blood pressure and vascular resistance.
Mechanism:
Block α1 adrenergic receptors, leading to vasodilation.
Examples:
Prazosin, doxazosin.
Clinical Uses:
Hypertension, prostatic hyperplasia.
Mechanism of Action:
Decrease heart rate and contractility, reducing blood pressure.
Examples:
Propranolol, metoprolol.
Clinical Uses:
Dysrhythmias, anxiety, hypertension.
Centrally acting sympatholytics (e.g., clonidine) inhibit sympathetic outflow.
Renin-angiotensin blockers include ACE inhibitors and ARBs.
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.