Drugs for myocardial ischemia

Question 1

Describe the mechanisms of action of the organic nitrates.

Answer 1

- Organic nitrates are prodrugs that
must undergo denitrification by
mitochondrial aldehyde reductase
to yield nitric oxide
- NO activates soluble GC, increasing
cGMP  cGK-1 activation:
o ↑ mitochondrial Ca2+ uptake
o ↓ Ca2+ influx
o Phosphorylates MLCK
-> Vasorelaxation****

Question 2

Describe the phenomenon of nitrate tolerance and how to avoid it.

Answer 2

• When given acutely, nitrates have potent hemodynamic and therapeutic effects. However, these effects were lost rapidly during sustained therapy, almost completely when significant plasma concentrations are present throughout the 24-hr period. Tolerance develops early, and cannot be overcome with higher doses
• Practically, nitrate effects could be maintained using dosing regimens that allow for a nitrate-free or low-nitrate concentration for several hours each day. This has established the standard of nitrate therapy today.

Question 3

Describe the salient pharmacokinetic properties of ISMN.

Answer 3

Does not undergo first-pass hepatic metabolism – completely bioavailable

• Metabolites: isosorbide-2-mononitrate & isosorbide-5-mononitrate: T1/2 ∼ 2 – 4 hrs
• Available in sustained, phasic release form –> QD dosing –> avoid tolerance

Question 4

Describe the salient pharmacokinetic properties of GTN

Answer 4

undergoes hepatic and intravascular metabolism with a T1/2 ∼ 1 – 4 minutes

• Biologically active dinitrate metabolites T1/2 ∼ 40 minutes
• Very effective when given by sublingual (SL) or transdermal (TD) route (bypass first pass metabolism)
• No evidence for efficacy when given orally

Question 5

Describe the salient pharmacokinetic properties of ISDN

Answer 5

• Rapidly metabolized, T1/2 ∼ 40 minutes
• Metabolites: isosorbide-2-mononitrate & isosorbide-5-mononitrate: T1/2 ∼ 2 – 4 hrs
• Available in phasic, sustained release form –> QD dosing –> avoid tolerance
• Given PO or SL

Question 6

List the therapeutic uses of the organic nitrates.

Answer 6

1. Acute attacks of angina
2. Unstable angina and acute myocardial infarction (MI)
3. Congestive Heart Failure

Question 7

List the common side effects of the organic nitrates.

Answer 7

• Headaches: common, most pronounced early after initiation of therapy
• Hypotension: more common with a rapid onset of action nitrates, such as sublingual GTN or short-acting isosorbide dinitrates, less with transdermal
• sit or lie down at first dose during administration;
• ISDN dose should be up-titrated over several days
• Erythema or local edema at the site of transdermal application.
• Methemoglobinemia: rare.

Question 8

Angina Pectoris

Answer 8

Angina Pectoris is chest pain due to inadequate blood flow and, therefore, inadequate O2 delivery to the heart muscle
- Anginal pain is usually due to release of bradykinin and adenosine onto nociceptive afferents

Question 9

Agents or methods increasing O2 supply

Answer 9

Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply.

1. Vasodilators (esp. Ca 2+ entry blockers)
2. Statins
3. Anti thrombotics
   * all works by increasing coronary and regional myocardial blood flow

Question 10

Agents that decrease O2 demand

Answer 10

1. Beta adrenergic antagonists-dec HR and contractility?
2. some Ca 2+ entry blockers*
3. Organic Nitrates-pre load n after load?

Question 11

Agent that both decreases demand and increases supply

Answer 11

Vasodilators (esp CA 2+ entry blockers*

Question 12

ORGANIC NITRATES

Answer 12

Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)

Question 13

effects nitrates

Answer 13

Effects vary widely in different vascular beds

• Potent vasodilation in veins  ↓ ventricular volume and preload
• Dilate conduit arteries
• No effect on peripheral vascular resistance.
• Dilate epicardial coronary arteries
• Little or no effect on the coronary resistance vessels  avoid coronary steal
• In patients with CAD, nitrates can dilate coronary stenoses and collateral vessels  improve coronary blood flow

Question 14

Acute attacks angina thera use of nitrates

Answer 14

• Sublingual nitrates are classic therapy for the treatment of acute attacks of angina
• SL nitrates can be prescribed as a prophylactic therapy, taken before activity that would generally lead to angina
• Long-acting nitrates are effective in angina, ↑ exercise duration, ↓ anginal frequency
• Due to nitrate tolerance, dosing must allow for a low or nitrate-free period during the day
• ISMN in a phasic-release formulation that provides effective plasma concentrations during the day but low concentrations during the night is effective in the therapy of exertional angina

Question 15

Unstable angina and acute myocardial infarction (MI) thera effects nitrates

Answer 15

• Sublingual GTN is often used, but intravenous (IV) and transdermal formulations also have a role.
• Mechanism of action likely includes dilation and prevention of constriction of epicardial coronary constriction and potential antiplatelet effects

Question 16

congestive HF tera effects nitrates

Answer 16

Acute HF: organic nitrates (SL/IV) dramatically lower filling pressure without adverse effects on systemic BP. In acute HF and active ischemia, organic nitrates can be the therapy of choice.

• Chronic heart failure.
• ISDN and hydralazine combination: good in African-Americans with CHF, especially CHF that results from systolic dysfunction.

Question 17

Niggers with CHF of systolic origin

Answer 17

ISDN and hydralazine combination