Anti-Anginal Agents (Martin)

Question 1

nitroglycerin

Answer 1

nitrate

Question 2

isosorbide dinitrate

Answer 2

nitrate

Question 3

verapamil

Answer 3

CCB

Question 4

Diltiazem

Answer 4

CCB

Question 5

Nifedipine

Answer 5

DHP CCB

Question 6

Amlodipine

Answer 6

DHP CCB

Question 7

Felodipine

Answer 7

DHP CCB

Question 8

Aspirin

Answer 8

Anti-platelet

Question 9

Clopidogrel

Answer 9

Anti-platelet

ADP receptor blocker on platelets

Question 10

Dipyridamole

Answer 10

Antiplatelet

Question 11

nicardipine

Answer 11

CCB- DHP

Question 12

UFH

Answer 12

unfractionated heparin- anticoagulant

Question 13

LMWH

Answer 13

anticoagulant

Question 14

what are the 3 drug groups traditionally used in the treatment of angina

Answer 14

oraganic nitrates
ccb
b-blockers

Question 15

what is angina pectoris?

Answer 15

Angina is the primary symptom of ischemic heart disease
temporary and reversible imbalance between myocardial O2 supply and demand

increase demand - from increase HR, increase ventricular contraction, and increase ventricular wall tension
decrease supply – from decreased coronary blood flow, O2 carrying capacity of blood, or both
coronary artery disease (CAD) usually the underlying cause

Question 16

what is the sensation of angina

what patients have atypical symptoms of angina

Answer 16

Heavy pressing substernal discomfort (rarely called pain)= pressure
Often radiating to left shoulder, flexor aspect of left arm, jaw, or epigastrium
Significant minority of patients describe a different location or character
Women, elderly, and diabetes most likely to have atypical symptoms

Question 17

what is typical angina

Answer 17

(exertional angina)
Usually fixed atherosclerotic narrowing of an epicardial coronary artery on which exertion or emotional stress superimposes an increase in myocardial O2 demand

Hx = angina induced by exercise, relieved by rest and/or nitroglycerin (NTG)- acute acting vasodilator

lasts no longer than 15 min, 5 - 15 episodes/wk

ST segment depression

Question 18

what is atypical angina

Answer 18

angina at rest

Variant, vasospastic, prinzmetal’s

focal or diffuse coronary vasospasm episodically reduces coronary flow

transient ST segment elevation during angina

Question 19

what is unstable angina

Answer 19

Rupture of an atherosclerotic plaque, with consequent platelet adhesion and aggregation  coronary blood flow
Abrupt decreases in blood flow due to thrombus or embolus signals impending myocardia infarction (MI)
If symptoms not relieved by 3 NTG tablets within 15 minutes should call 911 or get to nearest ED immediately

Question 20

Typical angina therapeutic objectives?

Answer 20

decrease O2 demand - decrease HR, decrease contractility or wall tension

B-blocker + aspirin (use clopidogrel if aspirin is contraindicated)

B-blocker + aspirin + long -acting nitrate

nitrate (usually NTG sublingual) For acute attacks

ACE inhibitor in patients with diabetes or left ventricular dysfunction

Long-acting calcium channel blocker (DHPs) or long-acting nitrates for reducing symptoms when initial therapy with b blocker is contraindicated, not successful, or leads to unacceptable side effects.

Question 21

which agents decrease the O2 DEMAND of the heart…

Answer 21

b-blockers
ccb’s

organic nitrates - modify preload and afterload

Question 22

what agents increase O2 supply?

Answer 22

vasodilators (Ca entry blockers)

Question 23

therapeutics in unstable angina?

Answer 23

MONA***

1st
morphine- relieve pain and anxiety
O2
nitroglycerin- coronary vasodilator
Aspirin 

+ beta blocker OR CCB non-DHP if beta blocker is contraindicated (decrease O2 demand of the heart)

increase blood flow (aspirin) + heparin to decrease thrombus

percutaneous coronary interventions (PCI)
–> angioplasty, placement of stents, require a cath lab

Coronary bypass graft

thrombolytics (alteplase, reteplase, tenecteplase, streptokinase)

Question 24

what are organic nitrates

what is their MOA

Answer 24

prodrugs that are sources of NO

nitroglycerin is an organic nitrate

MOA
decrease preload and afterload
relax vascular smooth m.
Mainly relaxation of large veins decrease¯ venous return decrased ¯ preload decrease ¯ O2 demand (major effect)

smaller ¯ in afterload

Directly dilate coronary arteries, especially subendocardial regions compressed during systole

­ increase in oxygen supply (transient), effective in prevention of coronary vasospasm

MECHANISM
In healthy subjects, NO dilates coronary arteries
In exertional angina, direct infusion of NTG into heart does not relieve angina, but sublingual NTG does.*** (not an effect on myocardium per se and must be converted to NO)

Question 25

what is the mechanism of NTG at the molecular level

Answer 25

Nitrate (NTG) is converted to NO NO activates guanylyl cyclase to activate guanylyl cyclase active GC converts GTP to cGMP (normally phosphodiesterase inactivates cGMP) cGMP leads to dephosphorylation of myosin LC and relaxation of smooth muscle

Question 26

isosorbide dinitrate

Answer 26

long acting nitrate vasodilator sublingual Q2-3 hr, oral, sustained release tablet Q12 hr

Question 27

what are the adverse effects of nitrates?

Answer 27

headaches (can be severe), facial flush, dizziness (Monday disease) orthostatic hypotension (alcohol worsens this) ***Can develop tolearance - effectiveness diminishes with continued use! drug holidays can alleviate the tolerance (8 hr drug free period per day)

Question 28

what are the contraindications for Nitrates

Answer 28

In acute MI - avoid if right ventricular infarction b/c higher right sided filling pressures are needed patients on erectile dysfunction drugs *** these drugs also are phosphodiesterase inhibitors which elevated cGMP, and synergistic effects with NO can lead to potentially dangerous fall in BP -Sildenafil (Viagra) Tadalafil (Cialis) Vardenafil (Levitra)

Question 29

CCB's mechanism of action.... in angina

Answer 29

normally Ca2+ activates Calmodulin --> which activates myosin light chain kinase --> leading to phosphorylation of Myosin Light chain and contraction.... all these drugs bind to L-type calcium channels at different sites and block Ca2+ entry through these channels this leads to relaxation of arteriolar smooth muscle --> decreased afterload and decreased O2 demand also these increase O2 supply due to dilation of coronaries

Question 30

CCB's mechanism on smooth muscle

Answer 30

Voltage-sensitive (L-type) Ca++ channels mediate entry of Ca++ into smooth muscle, cardiac myocytes, SA & AV nodal cells in response to electrical stimulation Ca++ triggers contraction of vascular smooth muscle CCBs block channel and produce relaxation of arterioles***, little effect on veins Mostly decrease afterload***, little effect on preload

Question 31

CCB's mechanism of action of cardiac cells

Answer 31

In myocytes, Na+ entry through “fast” channels is the primary carrier of current in the depolarization event, but Ca++ entry through slow channels is an additional component Ca++ entry may also induce Ca++ release from SR Ca++ binds to troponin- relieves inhibition of troponin on contractile apparatus – allows actin-myosin contraction CCBs block Ca++ entry, cause negative inotropic effect –but concurrent decrease in vascular resistance causes decrease BP and baroreceptor reflex (reflex tachy) which negates negative inotropic effect

Question 32

what are the MOA's of DHP CCB's and nonDHP CCB's on the SA and AV nodes ....

Answer 32

Depolarization is largely through L-type Ca++ current DHPs block channel but do not effect recovery of channel & are not “frequency (use) dependent” Verapamil & diltiazem block channel, delay recovery of channel, & are frequency dependent Therefore, verapamil & diltiazem decrease the rate of SA node depolarization + slow AV nodal conduction These properties makes them useful for treatment of supraventricular tachyarrhythmias

Question 33

what are the hemodynamic effects of CCB's I.e. effects coronary vascular resistance and coronary blood flow?

Answer 33

All ccb's decrease coronary vascular resistance and increase coronary blood flow DHP's are more potent arterolar vasodilators than the non-DHP's DHPs decrease arterial P, slight reflex increase HR & contractility, CO increase, ventricular function improved, peripheral blood flow improved, venous tone unchanged verapamil--> reflex tachy due to arterial dilation is blunted by direct negative inotropic effects

Question 34

Contraindications of CCB's

Answer 34

non-DHP's are contraindicated in a patient taking a beta blocker*** b/c of the potential for AV block non-DHP's should not be used in patients with ventricular dysfunction, SA or AV nodal conduction defects and systolic BP <90

Question 35

what are signs of toxicity of CCB's

Answer 35

Excessive vasodilation – dizziness, hypotension, headache, flushing, nausea Constipation*** (esp., verapamil), peripheral edema, coughing, wheezing, pulmonary edema “Coronary steal” worsens angina It is caused when there is narrowing of the coronary arteries and a coronary vasodilator[2] is used - "stealing" blood away from those parts of the heart. This happens as a result of the narrowed coronary arteries being always maximally dilated to compensate for the decreased upstream blood supply. Thus, dilating the resistance vessels in the coronary circulation causes blood to be shunted away from the coronary vessels supplying the ischemic zones, creating more ischemia.

Question 36

aspirin

Answer 36

blocks production of prostaglandins --> irreversibly inhibits Cyclooxygenase decreases mortality in patients with unstable angina, reducing incidence of MI and death decrease incidence of MI in chronic stable angina due to inhibition of platelet aggregation once per day 85-325 mg tablet

Question 37

Clopidogrel

Answer 37

Selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex Irreversible, long-term inhibition of platelet aggregation Useful for unstable angina, prophylaxis and treatment of TIA and completed stroke Standard practice to treat for patients undergoing stent placement

Question 38

therapeutic guidelines for acute prophylaxis and treatment of single anginal attack

Answer 38

nitroglycerin onset 1-3 min. 20-30 min duration

Question 39

therapeutic guideline for maintanence therapy of chronic stable angin

Answer 39

b-blockers, CCB's or long duration nitrates or combination

Question 40

therapeutic guidelines for vasospastic angina....

Answer 40

Ca channel blockers or nitrates