Long acting nitrates
Nitrates act to reduce myocardial workload and consequently reduce oxygen demand through vasodilation.
Long acting nitrates are used to protect against angina symptoms. Nitrates used long-term have been shown to both reduce the frequency and severity of angina attacks. They are available as tablets, transdermal patches and also injections.
Nitrates are administered as either isosorbide mononitrate or dinitrate. Isosorbide dinitrate is metabolised to the mononitrate form which delays its onset of action in comparison to the mononitrate. The dinitrate has a duration of action of approximately 5 hours which necessitates three times a day administration. This dosage regime adversely affects patient adherence and has resulted in the drug being rarely used.
Isosorbide mononitrate has a quick onset of action reaching peak plasma concentration within 30-60 minutes. It is available in sustained release formulations which allow once daily administration facilitating patient adherence.
Isosorbide mononitrate is generally preferred over isosorbide dinitrate.1
Tolerance
A limiting factor in the use of long acting nitrates for the prevention of angina symptoms is the development of tolerance. Many patients prescribed long acting or transdermal nitrates rapidly develop tolerance and consequently a reduction in therapeutic effect.
Tolerance can be prevented by reducing blood nitrate concentrations to low levels for 4 to 12 hours each day - a nitrate-free period. Practically this requires adjustments to the dosing schedule, for example for twice daily administration it would be appropriate to administer the second dose after 8 hours rather than 12 hours e.g. first dose at 8am and the second at 4pm. In the case of transdermal preparations the patch can be removed for 8-12 hours each day, usually overnight allowing blood nitrate levels to fall.
Long acting mononitrate formulations incorporate a nitrate free period releasing the drug over a 15 hour period. It is important to ensure that long acting isosorbide mononitrate formulations are only administered once daily to avoid the development of tolerance.
Side effects
A common side effect associated with nitrate therapy is headache caused by cerebral vasodilation. Patients should be advised of this effect before starting nitrate therapy and encouraged to persevere with treatment. Tolerance to the effect develops rapidly with regular dosing, usually within 3-7 days. Simple paracetamol based analgesics can be used to control the headache during this period.
Other side effects commonly associated with nitrate therapy include dizziness, postural hypotension and facial flushing. Patients can be advised that these symptoms generally subside as they develop a tolerance to the nitrate.
Interaction with PDE-5 inhibitors
Erectile dysfunction is a recognised complication of cardiovascular disease. An additional complication concerning the use of nitrates for the prevention of angina is the potential for interaction with phosphodiesterase type 5 inhibitors such as sildenafil, vardenafil or tadalafil.
Concomitant use of nitrates and a PDE- 5 inhibitor leads to a profound drop in blood pressure which may precipitate a myocardial infarction. Consequently these drugs should not be used within 24 hours of a nitrate dose, 48 hours in the case of tadalafil because of its longer half-life.7
Patients prescribed both drugs should be advised that if they experience symptoms of angina during sexual activity after taking a phosphodiesterase type 5 drug they should cease sexual activity and rest for 5-10 minutes. If the pain does not ease they should dial 999 for an ambulance, advising them of the medication that has been taken. GTN should not be used to relieve the angina symptoms.