CLINICAL PHARMACOLOGY
Mechanism of Action
Nitroglycerin forms free radical nitric oxide (NO), which activates guanylate cyclase, resulting in an increase of guanosine 3',5'-monophosphate (cyclic GMP) in smooth muscle and other tissues. This eventually leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.
Pharmacodynamics
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of the postcapillary vessels, including large veins, promotes peripheral pooling of blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). Nitroglycerin also produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial pressure (after load), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the relief of exertional angina is unclear.
Therapeutic doses of nitroglycerin may reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or increased heart rate decreases diastolic filling time.
Elevated central venous and pulmonary capillary wedge pressures, and pulmonary and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work index) is decreased and a more favorable supply-demand ratio can be achieved. Patients with elevated left ventricular filling pressure and increased systemic vascular resistance in association with a depressed cardiac index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced following nitroglycerin administration.
Pharmacokinetics
Nitroglycerin is rapidly absorbed following lingual spray administration. In a pharmacokinetic study when a single 1200 mcg dose (three activations of a 400 mcg dose) of NitroMist was administered to healthy volunteers (n=12), all subjects had detectable trinitroglycerin plasma levels (mean Cmax 0.8 ng/mL ± 0.7 ng/mL and tmax of 8 minutes, range 4 minutes to 15 minutes) beginning at 2 minutes post-dose and higher levels of the 1,2- (mean Cmax 3.7 ng/mL ± 1 ng/mL and tmax 34 minutes ± 21 minutes, range 15 minutes to 90 minutes) and 1,3-dinitroglycerin metabolites (mean Cmax 1 ng/mL ± 0.3 ng/mL and mean tmax 41 minutes ± 20 minutes, range 20 minutes to 90 minutes).
The volume of distribution of nitroglycerin following intravenous administration is 3.3 L/kg.
A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to nitroglycerin, 2 major metabolites, 1,2- and 1,3-dinitroglycerin are found in plasma. The mean elimination half-life of both 1,2- and 1,3-dinitroglycerin is about 40 minutes. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess some pharmacological activity, whereas the glycerol mononitrate metabolites of nitroglycerin are essentially inactive. Higher plasma concentrations of the dinitro metabolites, with their nearly 8-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect.
In the above referenced pharmacokinetic study the average initial half-lives (T1/2α) of nitroglycerin, and its 1,2- and 1,3-dinitroglycerin metabolites were estimated to be 3 minutes, 10 minutes, and 11 minutes, respectively. The half-life of disappearance of the nitroglycerin (T1/2β) (5 minutes) was significantly less than the half-life of appearance (T1/2α) of the 1,2- and 1,3-dinitroglycerin metabolites suggesting the possibility of an additional compartment into which the nitroglycerin disappears from plasma prior to being metabolized into the dinitroglycerin metabolites. A second indication of this other compartment is that the appearance of nitroglycerin metabolites in plasma was delayed in some subjects, with zero plasma levels seen for 4 minutes to 6 minutes after dosing. In some subjects, nitroglycerin metabolites appeared only after nitroglycerin Cmax had been observed.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal carcinogenicity studies with sublingually administered or lingual spray nitroglycerin have not been performed.
Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At the highest dose, the incidences of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.
Nitroglycerin was found to have reverse mutation activity in the Salmonella typhimurium strain TA1535 (Ames assay). A similar mutation in S. typhimurium strain was also reported for other NO donors. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with oral doses of up to about 363 mg/kg/day or in ex vitro cytogenic tests in rat and dog tissues. In vitro cytogenetic assay using Chinese hamster ovary cells showed no chromosomal aberrations.
In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 408 mg/kg/day (males) to 452 mg/kg/day (females) for 5 months (females) or 6 months (males) prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The highest dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.
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