Adverse Effects
After long term use for chronic conditions, tolerance may develop in a patient, reducing its effectiveness. Nitrate tolerance was first described soon after the introduction of GTN in cardiovascular therapy as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher dosages of the drug in order to achieve the same effects. The mechanisms of nitrate tolerance have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. These include:
- Impaired biotransformation of GTN to its active principle - NO (or a NO-related species)
- Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II, which counteract the vasodilation induced by GTN
- Plasma volume expansion
- The oxidative stress hypothesis (proposed by Munzel et al. in 1995).
Recent evidence suggests that the latter hypothesis might represent a unifying hypothesis, and a GTN-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above. Furthermore, studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis (Nakamura et al.). These include endothelial and autonomic dysfunction (Gori et al.). In the short run, glyceryl trinitrate can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain, severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration. The painful nature of these adverse effects has a marked negative impact on patient compliance.
GTN must not be used together with vasodilators that combat erectile dysfunction, such as Viagra, Cialis, or Levitra. The combination of the two can lead to severe hypotension, circulatory collapse and death.
Read more about this topic: Glyceryl Trinitrate (pharmacology)
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