vasodilators and the treatment of angina

Question 1

define: angina pectoris

Answer 1

angina( pain) is caused by the accumulation of metabolites in striated muscle
- angina pectoris is severe chest pain that occurs when coronary blood flow is inadequate to meet the oxygen requirements of the heart

Question 2

classic angina

Answer 2

aka angina of effort
-myocardial oxygen requirement increase but coronary blood flow does not increase proportionally due to atheromatous obstruction of coronary vessels

Question 3

variant angina

Answer 3

aka angiospastic angina

- oxygen delivery decrease as a result of reversible coronary vasospasm

Question 4

unstable angina

Answer 4

aka acute coronary syndrome

• characterized by the progression of stable angina to repeated episodes even at rest
• usually due to atherosclerotic plaque rupture
• very often a precursor of acute myocardial infarction

Question 5

goals of therapy (4)

Answer 5

1. increase the delivery of oxygen to cardiac tissue by increasing coronary blood flow
2. decrease oxygen demand by decreasing cardiac work
3. for angina of effort-> pharmacological interventions usually only decrease cardiac work thru systemic vasodilation
4. for variant angina -> pharmacological agents can be used to reverse coronary vasospasm

Question 6

Pathophys of angina : determinants of myocardial oxygen demand

Answer 6

HR, cardiac contractility, arterial pressure, ventricular volume

Question 7

pathophy of angina : determinants of coronary blood flow

Answer 7

aortic diastolic pressure , duration of diastole, coronary vascular bed resistance

Question 8

pathophy of angina : determinants of vascular tone

Answer 8

arteriolar and venous tone play a role in peripheral vascular resistance and arterial blood pressure

Question 9

ways to relax vascular smooth muscle 4

Answer 9

increase cGMP: cGMP facilitates dephosphorylation of myosin light chain, preventing myosins interaction with actin ( organic nitrates)

decreasing intracellular Ca++ by preventing Ca++ entry: reduces activity of myosin light chain kinase ( ca++ channel blockers ( verapamil, diltiazem dihydropyridines)

stabilizing or preventing depolarization of membrane potential by increasing K+ permeability: prevents activation of voltage-gated Ca++ channels ( K+ channel openers- minoxidil, hydralazine)

increase cAMP: cAMP increased the rate of inactivation of myosin light chain kinase ( not used for treatment of angina)

Question 10

Organic nitrates

Answer 10

• agents release nitric oxide at target tissues
• released NO activates guanylate cyclase -> increase of cGMP
• at therapeutic doses action is confined to smooth muscle
• dilation of large coronary arteries and arterioles leads to redistribution of blood flow from epicardial to endocardial regions providing some relief from ischemia
• MAIN EFFECT -> venodilation which reduces preload and ventricular filling -> decreases myocardial O2 demand

Question 11

administration of organic nitrates

Answer 11

high capacity hepatic organic nitrate reductase -> extensive first pass metabolism of orally introduced nitroglycerin and isosorbide dinitrate, so bioavailability is low .
isosorbide 5-mononitrate is not subject to first pass metabolism so it can be delivered orally and has a longer duration of action than isosorbide dinitrate and nitroglycerin
- sublingual and slow release buccal of NG and ID allows for therapeutic levels rapidly by bypassing the hepatic system
-inhalation of volatile nitrites ( amyl nitrite) also bypasses hepatic system
- rapid metabolism = acute treatment

Question 12

tolerance of organic nitrates

Answer 12

• repeated admin -> loss of effectiveness
• apparent after use of long-acting ,slow-release preparations or infusions of several hours of more are used
• large degree of cross-tolerance between nitrates
• thought to diminish release of NO from organic nitrates but mech is obscure
• system compensation make be involved in loss of effectiveness ( retention of salt and water)

Question 13

calcium channel blockers - MOA and channel they attack

Answer 13

reduce Ca++ influx thru ca++ channels to effect a reduction in intracellular Ca++ levels leading to relaxation
- main target - L-type Ca++ channel

Question 14

two classes of Ca++ blockers

Answer 14

dihydropyridines ( DHPs; nifedipine, amlodipine, felodipine) ( A+F are longer lasting and newer gen)
non-DHPs such as verapamil and diltiazem

all bind to different sites on Ca++ channels

Question 15

2 main actions of Ca++ blockers

Answer 15

• decrease myocardial contractile force (verapamil and diltiazem)
• decreased arterial tone and systemic vascular resistance ( all)

Question 16

major effect of DHPS

Answer 16

vasodilator only

Question 17

major effect of verapamil and diltiazem

Answer 17

vasodilators and negative inotropes and chronotropes

Question 18

when are Ca++ blockers used

Answer 18

stable angina (all) 
unstable angina ( verapamil and diltiazem)
HTN - all
supraventricular tachycardia ( verapamil and diltiazem)

Question 19

side effects of Ca++ blockers

Answer 19

hypotension
decrease cardiac contractility
bradycardia

Question 20

Cardiovascular effects of Ca Channel blockers

Answer 20

• SA node - decrease automaticity
• AV node - decrease conduction
• cardiac myocytes - decrease afterload and myocardial O2 demand
• coronary arteries - increase vasodilation and myocardial O2 supply
• peripheral veins - minimal venodilation
• peripheral arterioles - increase vasodilation , decrease afterload and myocardial O2 demand

Question 21

Beta-adrenergic blockers

Answer 21

NOT vasodilators

• decrease HR and contractility to reduce oxygen demand
• all b-blockers are equally effective as antianginals
• often used with DHP Ca++ channel blockers to off set side effects ( dont use with verapamil or diltiazem)

Question 22

Ranolazine

Answer 22

approved for pts who haven’t responded to other antianginal agents
- MOA- inhibition of late Na+ current-> decrease Na+ entry into the myocyte and increase Ca++ transport by the Na+/Ca++ exchanger, resulting in reduction of ischemia-induced Ca++ overload.

net effect would be improved diastolic function and decreased oxygen demand

don’t use in pts with QT prolongation

Question 23

goal of treatment for unstable angina

Answer 23

reduce myocardial oxygen consumption

• hospitalize/ bed rest
• b-adrenergic blockers
• antiplatelet ( aspirin, clopidogrel) and anti-coagulant ( heparin, LMWH)

Question 24

treatment of prinzmetal’s ( vasospastic angina)

Answer 24

• reversible coronary vasospasm

- responses to nitrates and calcium channel blockers