Nitrates

Angina is a common symptom of coronary artery disease and the first effective treatment was using nitrates, described in 1867.¹ Nitrates are still very important for symptom relief in angina and useful in the treatment of acute left ventricular failure. The high and rising number of nitrate prescriptions reflects a rising prevalence of coronary heart disease, as around 1.1 million people in the UK have angina.^2,3

Nitrates act through the vascular smooth muscle nitrous oxide/cGMP pathway¹ causing vasodilatation. They are potent coronary artery vasodilators but their main benefit is the reduction of venous return and thus left ventricular work and myocardial oxygen demand.⁴

• Acute angina - sublingual glyceryl trinitrate (GTN) tablets or spray provide very rapid symptomatic relief of anginal pain, starting within minutes but lasting for only 20-30 minutes.⁵ Isosorbide dinitrate (ISDN) is also effective sublingually. Subsequent intravenous infusion of GTN or ISDN can be very effective in severe chest pain caused by more severe ischaemia or myocardial infarction (but does not improve mortality).⁶
• Angina prophylaxis- both isosorbide mononitrate (ISMN) and dinitrate are available for the prevention (prophylaxis) of angina. ISMN is the main active metabolite of ISDN; long acting preparations of both are available allowing 12 hourly dosing for ISDN and once daily for ISMN. Transdermal GTN patches are also available but nitrate tolerance may be more of a problem.
• Left ventricular failure
• Other uses - topical ointment in anal fissure.^7,8

It has been tried for other conditions such as dysmenorrhoea but efficacy is unproven.⁹

There is a paucity of comparative trials but:

• A systematic review of trials in the prethrombolytic era found that nitrates reduced mortality in patients with acute myocardial infarction compared with placebo. However subsequent RCTs of nitrates with thrombolysis have shown no significant difference in mortality between nitrates and placebo.¹⁰
• There is consensus that nitrates treat symptoms effectively in angina and that headache as a side effect is common¹⁰
• Isosorbide dinitrate in combination with hydralazine in heart failure improves symptoms and prognosis for people unable to tolerate an ACE inhibitor or angiotensin-II receptor antagonist.^11,12,13

• This is a common problem on long acting preparations and produces reduced therapeutic effect. Techniques to prevent it employ the same principle of breaking up dosing to allow blood levels to fall for several hours, usually overnight (asymmetric dosing regime).
• To avoid tolerance to the effects of long acting nitrates:
  • Long acting immediate release nitrates should be doses asymmetrically i.e. at 8am and 3 pm or 9am and 2pm.
  • Long acting modified release preparations should be prescribed as a single dose, even in two tablets each days are required i.e. isosorbide mononitrate 60mg modified release, 2 om not 1 bd.
  • With patches a patch free interval is used. Using nitrates continuously renders them ineffective.

Immediate relief of symptoms

Sublingual glyceryl trinitrate (GTN) is one of the fastest acting drugs but lasts only 20-30 minutes.

• Patients should be advised to get urgent medical help if pain persists after 3 doses over 15 minutes
• A starting dose of 300 micrograms is suggested when first used
• Relief of pain does not confirm angina as placebo response and response to some oesophageal conditions also occurs
• May be used as prophylaxis before certain activities
• May be spat out once effective if side effects
• Tablets have limited shelf life of 2 months

• There are usually 200 doses of 400 micrograms each dose
• It is sprayed under the tongue and the mouth then closed

For longer duration of action

Modified release GTN 2mg-3mg buccal tablets and 2.6mg tablets or 1-2 inches of ointment.
It is important to be aware of nitrate tolerance when prescribing any nitrate preparations with a long duration of action.

For stable angina and angina attacks more than twice weekly-prophylaxis

See angina record (linked at start of article) and further reading for more detail.
Long-acting nitrate:

• Isosorbide mononitrate (ISMN) best, but usually with another drug as dual therapy i.e.:
  • Mild to moderate angina and no left ventricular dysfunction if maximum tolerated monotherapy with beta-blocker inadequate, add:
    • First long acting dihydropyridine (e.g. modified-release nifedipine) or diltiazem (caution: bradycardia)
    • Then, if unsatisfactory, second/third ISMN or potassium-channel activator
  • Mild to moderate angina, no left ventricular dysfunction and beta blocker contraindicated/not tolerated:
    • If taking calcium-channel blocker or verapamil add ISMN or potassium-channel activator
    • If taking nitrate add calcium channel blocker or potassium-channel activator
  • Angina WITH left ventricular dysfunction-first line is monotherapy with ISMN
• Continue regular aspirin(or clopidogrel) and GTN as required
• Use asymmetric dosing twice a day e.g. 8am and 3pm to avoid tolerance
• Isosorbide dinitrate not recommended-more frequent dosage schedules
• ISMN cheapest but:
  • Use modified-release ISMN if asymmetric dosing poorly tolerated - expensive
  • Consider ISMN patches if asymmetric dosing poorly tolerated - more expensive - but use high dose and have patch free interval as continuous use does not work-tolerance develops

For unstable angina and suspected myocardial infarction

• GTN, aspirin 300mg, analgesia and admit to hospital informing of treatments given
• If necessary intravenous nitrates can be given in hospital but other therapies can be employed

Acute left ventricular failure

(see heart failure management)

• Hydralazine and isosorbide dinitrate intravenously and in combination have been shown to improve symptoms and prognosis and should be considered after ACE inhibitors and angiotensin-II receptor antagonists if these are not tolerated.^11,12,13

Treating anal fissure with GTN ointment

• This may obviate the need for surgery
• 0.3% ointment applied twice daily for 6 weeks gave good results but can cause side effects (see below)¹⁴

• Throbbing headache - reduces after a few days - eases as dose increases
• Flushing-reduces after a few days - eases as dose increases
• Dizziness
• Postural hypotension or tachycardia - reduce dosage

Interestingly, a recent study reported significantly more headaches in patients with normal coronary arteries or minimal coronary artery disease than in patients with more severe coronary artery disease.¹⁵

Caution in:

• Severe hepatic or renal impairment, hypothyroidism, malnutrition, hypothermia, head trauma, recent myocardial infarction

Contraindicated in:

• Closed angle glaucoma
• Hypotension/hypovolaemia
• Hypertrophic obstructive cardiomyopathy
• Aortic stenosis
• Mitral stenosis
• Constrictive pericarditis
• Cardiac tamponade
• Severe anaemia

This is done according to severity and the overall management plan and investigations for the angina.
Stepping up and down of treatment may be required. Remember that driving may need to be restricted until it is clear that unimpaired driving is possible. Avoidance of tolerance is an important factor to be borne in mind.