Nitrates

Question 1

Indications

Answer 1

1. Short-acting nitrates (glyceryl trinitrate) are used in the treatment of acute angina and chest pain associated with acute coronary syndrome.
2. Long-acting nitrates (e.g. isosorbide mononitrate) are used for prophylaxis of angina where a β-blocker and/or a calcium channel blocker are insufficient or not tolerated.
3. Intravenous nitrates are used in the treatment of pulmonary oedema, usually in combination with furosemide and oxygen.

Question 2

Mechanisms of action

Answer 2

Nitrates are converted to nitric oxide (NO). NO increases cyclic guanosine monophosphate (cGMP) synthesis and reduces intracellular Ca2+ in vascular smooth muscle cells, causing them to relax. This results in venous and, to a lesser extent, arterial vasodilatation. Relaxation of the venous capacitance vessels reduces cardiac preload and left ventricular filling. These effects reduce cardiac work and myocardial oxygen demand, relieving angina and cardiac failure. Nitrates can relieve coronary vasospasm and dilate collateral vessels, improving coronary perfusion. They also relax the systemic arteries, reducing peripheral resistance and afterload. However, most of the anti-anginal effects are mediated by reduction of preload.

Question 3

Adverse effects

Answer 3

As vasodilators, nitrates commonly cause flushing, headaches, light-headedness and hypotension. Sustained use of nitrates can lead to tolerance, with reduced symptom relief despite continued use. This can be minimised by careful timing of doses to avoid significant nitrate exposure overnight, when it tends not to be needed.

Question 4

Warnings

Answer 4

Nitrates are contraindicated in patients with severe aortic stenosis, in whom they may cause cardiovascular collapse. This is because the heart is unable to increase cardiac output sufficiently through the narrowed valve area to maintain pressure in the now dilated vasculature. Nitrates should also be avoided in patients with haemodynamic instability, particularly hypotension.

Question 5

Interactions

Answer 5

Nitrates must not be used with phosphodiesterase inhibitors (e.g. sildenafil) because these enhance and prolong the hypotensive effect of nitrates. Nitrates should also be used with caution in patients taking antihypertensive medication, in whom they may precipitate hypotension.

Question 6

Prescribing

Answer 6

In patients with stable angina, glyceryl trinitrate (GTN) is prescribed to be taken sublingually as tablets or spray for immediate relief of chest pain. GTN has a plasma half-life of <5 minutes, so has a very quick onset and offset of action. In patients with acute coronary syndrome or heart failure, GTN is prescribed as a continuous intravenous infusion.

Isosorbide mononitrate (ISMN) has a plasma half-life of 4–5 hours and is prescribed two to three times daily as immediate-release tablets for the prevention of recurrent angina. ISMN is also available as modified-release tablets or transdermal patches, which are prescribed once daily. When prescribing modified-release preparations, prescribe by the brand name, since there are important differences between preparations.

Question 7

Administration

Answer 7

IV GTN is usually administered as a solution containing GTN 50 mg in 50 mL (1 mg/mL). You should give nursing staff clear instructions on the starting dose, normally expressed as an infusion rate, e.g. 1 mL/hr. You should provide instructions on how to increase the dose to relieve symptoms (e.g. ‘Increase GTN infusion rate by 0.5 mL/hr every 15–30 minutes until chest pain relieved’) while avoiding hypotension (e.g. ‘Keep systolic blood pressure >90 mmHg’).

Question 8

Communication

Answer 8

Explain that you are prescribing a nitrate to relieve chest pain and/or breathlessness. Advise your patient that they may develop a headache when starting nitrates, but that this is normally short-lived. As nitrates are probably more effective at preventing than terminating angina, patients should be advised to use sublingual GTN before tasks that normally bring on their angina. Due to the risks of postural hypotension, it is a good idea to advise them to sit down and rest before and for 5 minutes after taking sublingual GTN.

Question 9

Monitoring

Answer 9

The best indicators of efficacy are the patient’s symptoms (e.g. chest pain, breathlessness). When administering nitrates by IV infusion, blood pressure should be monitored frequently, and the infusion rate adjusted to ensure the systolic blood pressure does not drop below 90 mmHg.