NITRATES

Adverse effects

Nitrate tolerance

One major drawback with nitrates is that repeated administration can cause tolerance to develop relatively quickly. The mechanism by which tolerance develops is uncertain, however one mechanism may involve the depletion of sulfhydryl (-SH) groups which are required for the synthesis of NO from organic nitrates.
Tolerance rarely develops with short-acting nitrates such as S/L GTN, but occurs with sustained use of IV and oral nitrates.
To prevent nitrate tolerance, it is recommended that patients who take long-term nitrates, such as oral ISMN, should have a 4-12 hour 'nitrate-free' period between doses as this may allow -SH stores to replenish.

Postural hypotension

Systemically, nitrates lower blood pressure.
This is can be accentuated in elderly patients who have a reduced baroceptor response to a decline in their arterial blood pressure when they stand up.
For this reason, caution should be taken in prescribing nitrates to patients with a pre-existing risk of syncope and/or falls.

Headache

Why do patients get headache with nitrates?

Vasodilatation of the cerebral blood vessels can cause a rise in intracranial pressure due to expansion of the vessels within the confined space of the cranium.

It is often throbbing in nature, due to the pulsation of the dilated meningeal arteries.

Cerebral vasodilatation can cause a throbbing headache

Interaction with sildenafil

Nitrates work by upregulating cyclic-GMP in vascular smooth muscle cells.
Sildenafil works by inhibiting phosphodiesterase - an enzyme which prevents the degradation of cyclic-GMP.
The combined effect of nitrates and sildenafil can causes over-production of cGMP and so the 2 drugs when given concurrently can synergistically lead to excessive vasodilatation, which accentuates side-effects such as hypotension and headache.

Flushing

Vasodilatation of capillaries means that patients can look and feel flushed when taking nitrates.

Reflex tachycardia

How can nitrates cause reflex tachycardia?

When a person stands up from a sitting/lying position the baroreceptors in the carotid sinus and the aortic arch detect a drop in blood pressure and quickly send signals to the medulla oblongata to increase sympathetic drive (and inhibit parasympathetic drive) in to order to cause systemic vasoconstriction and tachycardia which act to increase blood pressure.

Nitrates lower blood pressure, therefore they stimulate the baroreceptor reflex leading to a reflex tachycardia.

NOTE: Many patients with HF are also on diuretics, which can lead to severe hypotension.

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