Nitrates / NO Donor

Question 1

Mechanism of Action

Answer 1

1. Preferentially dilates large vessels ( veins, arteries) over smaller ones (arterioles)
2. Venous dilation: dilation of veins –> decreases pressure of venous return –> reduces end-diastolic volume –> decrease in preload –> decrease in myocardial oxygen demand
3. Arterial dilation: dilation of arteries –> decrease systemic resistance –> decrease afterload
4. Adverse effects: flushing, headache, fainting

Question 2

Coronary Steal Phenonmenon

Answer 2

Process whereby healthy tissue receives more oxygen blood supply than ischaemic tissue due to the occlusion of collateral vessels not allowing for compensation to ischemic arteries; blood is essentially not shared between adjacent coronary arteries and this exacerbated the ischaemic plaque

Nitrates dilate the collateral coronary vessels which provide compensation by allowing blood to be shared between healthy area and ischemic area

Question 3

Tolerance Mechanism

Answer 3

Continuous/Frequent exposure of organic nitrates may lead to tolerance

1. Diminished ability to convert nitrate to NO
2. Depletion of sulfhydryl compounds, glutathione and cysteine causing decreased release of NO
3. Altered or decreased action of guanylyl cyclase.
4. Endothelial vascular changes as a result of opposing vasoconstrictor response
5. Oxidative stress due to NO reacting with O2- to form peroxynitrite
6. Plasma volume expansion as a compensatory reflex due to sympathetic activation

Question 4

Glyceryl Trinitrate / Isosorbide Mononitrate
MOA

Answer 4

Gives rise to nitric oxide (NO) in the cell which activates protein kinase G (PKG) and reduces
contraction

Question 5

Glyceryl Trinitrate / Isosorbide Mononitrate
Abs/Distb/Elim

Answer 5

Glyceryl trinitrate:
sublingual spray, acts immediately (effects last ~30 mins)
transdermal patch (effects last 24h)

Isosorbide mononitrate:
given orally;
half-life 4h; slow-release

Question 6

Glyceryl Trinitrate / Isosorbide Mononitrate
Clinical use

Answer 6

Angina
Chronic heart failure

Question 7

Glyceryl Trinitrate / Isosorbide Mononitrate
Adverse effects

Answer 7

Headache
Hypotension
Tolerance
Methemoglobinemia