Side effects of intravenous glyceryl trinitrate

Until recently, glyceryl trinitrate (mtroglycerin) was available only In oral and sublingual dosage forms. The rapid metabohsm, variable absorption and unpredictable fluctuations in blood pressure that accompanied administration of these dosage forms stimulated the development of alternative preparations. Cutaneous forms of glyceryl tnnitrate have been introduced in an attempt to proVide more constant and prolonged release of the drug. Intravenous glyceryl trinitrate has now become available and provides a rapid, steady therapeutic blood concentration of nitrates during continuous Infusion.

In open trials the drug has been used successfully in the treatment of unstable angina, lett ventricular failure accompanying acute myocardial infarction a~d in the control of hypertension associated with cardiac surgery. Favourable haemodynamic re~ponses have been achieved in very short term studies In

congestive heart failure. and preliminary stu~ies suggest that the administration of glyceryl tnnltrate early after acute myocardial infarction may limit ischaemic damage. Nevertheless, the use of the drug in acute myocardial infarction remains controversial.

Intravenously administered glyceryl trinitrate is generally well tolerated. Most of the common adverse effects can generally be controlled by dosage adjustments and appropriate haemodynamic monitoring.

Hypotension: This is the most common side effect from IV glyceryl trinitrate, and has been reported to occur In approximately 18% of patients. Volume depletion and/or adbnormalities of cardiac function have all been implicated as predisposing factors. The hypotension IS potentially hazardous because of the resultant decreased perfusion to vital organs. A postural component may not be overly sigmficant because most patients receiving IV glyceryl !rinltrate are confined to bed. Should hypotenSion occur, it has been recommended that the rate of infusion be decreased or completely stopped, and if necessary. the patient be placed in a Trendelenburg position and IV fluids be given. Haemodynamic monitoring can also help lessen the problem of hypotenSion associated with IV glyceryl trinitrate. However, despite haemodynamic monitoring, hypotension has been reported to occur in many chnical trials ..

Headache: Approximately 2% of patients receiving the drug complain of headache which is mild and tranSient, may be dose-related and last several hours after the end of the infusion. Headaches have also occurred, though rarely. With intra-cardiac use of the drug In the majority of cases, the condition has not been so severe as to require reduction of the glyceryl trinitrate infusion rate. A few patients have required supplementary analgesics for pain relief.

Adverse cardiac effects. Sinus bradycardia associated with hypotension has been reported to occur in 4% of patients treated with IV glyceryl trinitrate. In 3 patients with congestive heart failure, acute myocardial infarction or angina pectoriS. infusions of IV glyceryl trinitrate of 176. 26.6 and 565

01!i7_7271184/022S-0009/0$OHIOIO ' ADIS Press

mg/min were associated with decreases in heart rate from 60 to 54, 99 to 47 and 130 to 45 beats/min, respectively. The sinus bradycardia may be vagally mediated and responds to IV atropine. Bradycardia has been reported in other studies and may also involve a partial failure of sympathetic activity with relative hypovalaemia induced by peripheral venodilation.

Tachycardia has been reported to occur in less than 1% of patients and may represent a reflex response to the arteriolar dilating effects of the drug. The Increase in heart rate, which has ranged from 10-20 beats/min, has occurred at dosages ranging from 50·170 ~g/min. Tachycardia has also been reported in patients receiving J1-blockers up until 24 hours before an infUSion of glyceryl trinitrate, while others have reported no increases in heart rate in such patients. Besides a residual ~-blocker effect, other factors that may prevent the occurrence of tachycardia include the dysfunction of autonomically mediated heart rate control in patients with heart disease, and the negative inotropic effects of medications patients receive during surgery.

Propylene glycol diluent toxicity: Many animal studies have indicated that IV propylene glycol, through vagal stimulation, may produce cardiac and respiratory disturbances such as cardiac arrest, hypertension, arrhythmias. bradycardia and prolongation of the effective refractory period. The concentration of propylene glycol in the commercially available IV glyceryl trinitrate preparations vary from 0 to 4.3% to 30% However, It has been calculated that the concentrations of propylene glycol in different dilutions of the commercial IV glyceryl trinitrate preparations that would conceivably be used in patients would range from 0.3 to 40% or 1/10th the amount used In the animal studies. Since glyceryl trinltrate is usually given by IV infusion and not by rapid bolus Injection, it would appear that the risk of complications from the propylene glycol diluent is small when the drug ;s used ;n this manner. However, intracardiac use of the drug which contains diluents of alcohol or propylene glycol may be potentially hazardous.

Miscellaneous adverse effects: Methaemoglobinaemia from IV glyceryl trinitrate has been reported In 1 patient but it is suggested that the high dosage (30 J.tg/kg/min for 6 days) used in this patient may have contributed to its occurrence. When used in standard doses, however, IV glyceryl trinitrate will not normally induce methaemoglobinaemia in clinically significant amounts in patients with normal erythrocyte and haemoglobin functions. Other adverse effects that have been noted in less than 1 % of patients receiving the drug are nausea. vomiting. apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness and abdominal pain. Sorkin. EM et al.: Drugs 21· 45 (Jan 1984)

Reactions 25 Feb 1984 9