Vasodilators in Angina

Question 1

Angina pathophys

Answer 1

xx

Question 2

Major types of angina + characteristics

Answer 2

1. stable = narrowed lumen by plaque. inappropriate vasoconstrict 2. unstable = plaque rupture, thrombus form, unopposed vasoconstrict 2. variant = no plaque, intense vasospasm

Question 3

Stable angina: major precipitating cause

Answer 3

-fixed stenotic endothelialized atheromatous plaque -imbalance occurs when O2 demand increases and supply (coronary blood flow) is unable to increase in response

Question 4

Variant angina: major precipitating cause

Answer 4

-coronary vasospasm with or without atheromatous plaque -imbalance occurs as oxygen supply decreases due to reversible coronary vasospasm (associated with atheromas) -commonly occurs at rest

Question 5

Unstable angina: major precipitating cause

Answer 5

-ruptured atheromatous plague with subocclusive thrombus -myocardial infarction from occlusive thrombus -angina at rest, signaled by change in frequency, character, duration, and precipitating factors in patients with stable angina

Question 6

Summary of anti-anginal drug efficacy (table)

Answer 6

Question 7

Nitrates: MOA

Answer 7

-Nitrates –> nitric oxide (NO) @ plasma membrane of vascular smooth muscle cells -NO activates guanylate cyclase –> GTP to cGMP –> relaxation of smooth muscle -vasodilation –> decreased venous return & systemic vascular resistance –> decreased wall tension –> decreases myocardial O2 requirement (primary effect) -also improves perfusion of ischemic myocardium (secondary effect).

Question 8

Nitrates: Pharmacokinetics

Answer 8

-Low oral bioavailabilty; administered orally (sustained-release), sublingually, transdermally, parenterally. -Best route=sublingual -Half-lives of 2-8 min (rapid denitration in liver).  Sublingual administration. Rapid pain relief (45 sec-5 min) lasting < 30 min. May repeat x 3 every 5 min; if no relief seek assistance (strongly indicative of impending MI).

Question 9

Nitrates: Adverse rxns

Answer 9

-Throbbing headache (30-60%), -orthostatic hypotension -reflex tachycardia -facial flushing -tachyphylaxis (tolerance) can occur with continuous exposure –>nitrate free interval of 6-14 hours each day is recommended.

Question 10

Ca2+ channel blockers: MOA

Answer 10

-block of L-type Ca++ channels in cardiac and smooth muscle (vascular smooth muscle is most sensitive, arterioles > veins). -Prevents calcium entry into cell leading to smooth muscle relaxation and vasodilation -Agents differ in selectivity for vascular vs heart calcium channels.

Question 11

Ca2+ channel blockers: Major drugs

Answer 11

-Verapamil -Diltiazem -Nifedipine

Question 12

Ca2+ channel blockers: various drug selectivities

Answer 12

• Dihydropyridines (nifedipine) have a greater ratio of vascular (relaxation) to cardiac (contractility, SA node impulse generation, AV nodal conduction) effects
• Verapamil and diltiazem, each at a distinct site, have prominent effects at cardiac nodal tissue (phase 0 at SA and AV node) and on cardiac muscle (phase 2)

Question 13

Ranolazine: MOA

Answer 13

-no effect on HR or BP -failure of late Na+ current to inactivate in heart disease –> intracellular Na+ overload –> reversal of the Na+-Ca++ exchanger –> intracellular Ca++ overload  Ca++ overload can result in both mechanical dysfunction (increased diastolic tension) and further imbalance between O2 demand and supply  Ranolazine inhibits this late Na+ current

Question 14

Beta-blockers: MOA

Answer 14

Useful in stable angina due to hemodynamic effects that result in decreased heart rate, blood pressure, and contractility with a subsequent decrease in O2 requirements (during rest and exercise)  Can block the reflex tachycardia associated with use of nitrate vasodilators in chronic stable angina  NOT vasodilators, thus no role in variant (vasospastic angina)

Question 15

Beta-blockers: Site of Action

Answer 15

Target is block of beta-1 adrenergic receptors in the heart, reducing rate and contractility, leading to a reduction in myocardial oxygen demand

Question 16

Nitrates: Site of Action

Answer 16

Primary target is relaxation of venous capacitance vessels leading to a reduction in preload and a reduction in myocardial oxygen demand. The action to dilate coronary artery vessels, resulting in an increase in myocardial oxygen supply, plays a greater role in variant angina.

Question 17

Ca2+ channel blockers: Site of Action

Answer 17

Primary target is block of L-type calcium channels to reduce vasoconstriction in both coronary and noncoronary vessels, increasing coronary blood flow and reducing cardiac afterload (all classes). Diltiazem and verapamil also have secondary action in the heart to decrease rate and contractility, reducing myocardial oxygen demand.

Question 18

General effects of vasodilators on O2 demand of myocardium

Answer 18

ALL drug groups decrease O2 requirement (demand) by decreasing peripheral vascular resistance and / or decreasing cardiac output. Nitrates and Ca++-channel blockers can reverse arterial spasm which would tend to increase blood flow / O2 supply.

Question 19

Summary of effects of drug therapy on: HR, myocardial contractility, LV systolic pressure, LV volume

Answer 19

Question 20

Ca2+ channel blockers: Adverse rxns

Answer 20

-Cardiac depression (cardiac arrest, bradycardia, AV block, congestive heart failure); more likely with verapamil or diltiazem. -Minor toxicities: Flushing / edema / dizziness, nausea, constipation, gingival hyperplasia

Question 21

Nitrates: major uses

Answer 21

-Treatment of acute angina (sublingual tablet, translingual spray). -Prophylaxis for chronic angina (long-acting oral, topical, transdermal). -Control of blood pressure in perioperative hypertension.

Question 22

Ca2+ channel blockers: major uses

Answer 22

-angina results in a long-lasting decrease in peripheral vascular resistance reducing heart O2 requirement and coronary arterial tone (aiding in spasm-induced angina) -Other uses include: -arrhythmias (cardiac tissue), -hypertension (vascular tissue), -subarachnoid hemorrhage (cerebral vasculature) -inhibit premature labor

Question 23

Beta-blockers: major uses

Answer 23

-indicated in angina patients with concomitant hypertension or arrhythmias that are responsive to β-blockers.

Question 24

Ranolazine: major uses

Answer 24

-Add-on to standard anti-anginal therapy - reduces symptoms of chronic stable angina and increases exercise capacity -Can substitute for beta-blockers if they are not tolerated or contraindicated