Vasodilator Agents

Question 1

Factors that affect cardiac supply

Answer 1

Coronary blood flow - occurs only during diastole and is dependent on aortic pressure (perfusion pressure)

Coronary vascular resistance - via autoregulation

Question 2

Factors that affect cardiac demand

Answer 2

Contractile state (Inotropy)
Heart Rate
Wall tension - increases with greater LV pressure and ventricular volume

Question 3

Nitrates - Mechanism

Answer 3

Converted to NO which activates guanylate cyclase in vascular smooth muscle cells; cGMP activates PKG, which phosphorylates SERCA, activating it and leading to decreased intracellular Ca2+ concentration

Question 4

Role of Nitrates in Angina

Answer 4

Venous dilation increases venous capacitance and leads to reduced pre-load; less pre-load means less myocardial work and MVO2 consumption

Secondary effect to dilate coronary arteries resulting in increased myocardial oxygen supply plays a greater role in variant angina

Question 5

Nitrates - Pharamcokinetics

Answer 5

Administered orally (sustained release), transdermally (24-hour efficacy), or sublingually (rapid release)

Oral ROA requires higher doses (first pass metabolism); duration of effect 4-8 hours

Sublingual ROA provides rapid onset pain relief (seconds) but effect lasts <30 mins

Question 6

Nitrates - Uses

Answer 6

Treatment of acute angina (sublingual)

Treatment of chronic, stable angina (sustained release oral, transdermal; reduces MVO2)

Variant angina - increases coronary blood supply

Question 7

Nitrates - Adverse Reactions

Answer 7

Throbbing headache
Orthostatic hypotension
Reflex tachycardia

Tachyphylaxis (tolerance) occurs with continuous exposure

Question 8

Role of Ca2+ channel blockers in Angina

Answer 8

Primary target is block of L-type Ca2+ channels in vascular smooth muscle to reduce vasoconstriction in both coronary and non-voronary vessels, increasing coronary blood flow and reducing cardiac afterload

Diltiazem and Verapamil also have secondary action in the heart to decrease rate and contractility, reducing myocardial oxygen demand

Question 9

Dihydropyridines (Nifedipine) - Mechanism

Answer 9

Ca2+ channel blocker with a greater ratio of vascular to cardiac selectivity; preferentially induces vasodilation with less reduction in cardiac contractility and heart rate

Question 10

Verapamil and Diltiazem - Mechanism

Answer 10

Ca2+ channel blockers with greater relative effect on cardiac tissue - suppresses SA/AV node impulse generation (decreased HR) and decreases contractility

Question 11

Ca2+ channel blockers - Adverse Reactions

Answer 11

Cardiac depression (bradycardia, AV block, congestive heart failure) - more likely with Verapamil and Diltiazem

Increased angina due to reflex activation of SNS (tachycardia) - more likely with short-acting dihydropyridines

Question 12

Ranolazine - Mechanism & Adverse Reactions

Answer 12

Inhibits inappropriate, late Na+ current in cardiac tissue (result of delayed inactivation); prevents reversal of NCX and thus the influx of Ca2+ - therapeutic effect is to reduce diastolic tension and MVO2

Adverse Effects: Prolonged QT interval, bradycardia, hypotension, palpitations, edema

Question 13

Use of B-Blockers in angina

Answer 13

Useful in chronic, stable angina - reduces MVO2 by decreasing chronotropy; blocks reflex tachycardia associated with use of nitrate vasodilators

Indicated in angina patients with HTN or arrhythmias

NOT vasodilators, thus no role in variant angina

Question 14

Ranolazine - Pharmacokinetics

Answer 14

Oral absorption
Hepatic elimination via CYP450 enzymes

BID

Question 15

Use of Ranolazine in Angina

Answer 15

Add-on to standard anti-anginal therapy; reduces symptoms of chronic stable angina and increases exercise capacity

Can substitute for B-blockers if they are not tolerated or are contraindicated