Isosorbide mononitrate acts as a prodrug for its active metabolite, nitric oxide (NO). NO activates soluble guanylate cyclase, increasing intracellular cGMP levels. This leads to vasodilation, predominantly of veins, which reduces cardiac preload. Its primary mechanism involves directly affecting smooth muscle cells in blood vessels, causing relaxation and vasodilation.

In vitro studies demonstrate that isosorbide mononitrate induces relaxation of isolated blood vessels, such as rat mesenteric arteries, by releasing NO. It also reduces platelet aggregation in vitro. The compound is used in cell-based assays to study NO-mediated signaling pathways and its effects on smooth muscle cell physiology.

In vivo, isosorbide mononitrate reduces the workload of the heart by producing venous and arterial dilatation. It lowers intramural pressure by reducing end-diastolic pressure and volume. In a rat model of hypertension, it reduces blood pressure and plasma levels of thromboxane A2 (TXA2), and also reduces platelet aggregation. Extended-release tablets significantly increase exercise capacity in angina patients.

Enzyme/receptor binding assays for isosorbide mononitrate typically focus on its role as a nitric oxide (NO) donor. These assays often measure the activation of soluble guanylate cyclase (sGC) in cell-free systems. The production of cGMP from GTP is quantified as a direct readout of NO bioactivity, which is stimulated by the compound's metabolites.

Cell-based in vitro experiments commonly involve culturing vascular smooth muscle cells and treating them with isosorbide mononitrate to measure increases in intracellular cGMP. Other assays include platelet aggregation studies where platelet-rich plasma is pre-incubated with the compound before induction of aggregation to evaluate its anti-aggregatory effects, which are mediated by the NO/cGMP pathway.

Animal models for studying isosorbide mononitrate include rat models of hypertension induced by cyclosporin A, where the compound is administered prior to the insult to assess its protective effects on blood pressure and platelet aggregation. Pharmacodynamic studies in dogs and other species are also used to evaluate its hemodynamic effects, such as reductions in preload and afterload.

Absorption, Distribution and Excretion
Following oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. The pharmacokinetics of isosorbide mononitrate are dose-linear, with an absolute bioavailability approaching 100%. Peak plasma concentration (Cmax) is reached within 30 to 60 minutes after administration. In a human radiolabeled drug study, approximately 93% of the total dose was excreted in the urine within 48 hours. Following an oral 20 mg dose, only 2% of isosorbide mononitrate is excreted unchanged in the urine within 24 hours. Of the excreted dose, nearly half is excreted in the urine as denitrated forms (isosorbide and sorbitol): approximately 30% is excreted as isosorbide and approximately 17% as 2-glucuronide of isosorbide mononitrate. These metabolites are not vasoactive or pharmacologically active. Renal excretion is complete after 5 days, and fecal excretion accounts for only 1% of drug clearance.
Volume of distribution is approximately 0.6 L/kg, roughly equal to the total water volume of the human body.
Systemic clearance is 115-120 mL/min.
Metabolisms/Metabolites
Isosorbide mononitrate does not undergo first-pass metabolism in the human liver. Detectable metabolites include isosorbide, sorbitol, and isosorbide mononitrate 2-glucuronide, none of which have pharmacological activity.
Biological half-life
The elimination half-life of isosorbide mononitrate is approximately 5 hours. The elimination half-lives of its metabolites, isosorbide and isosorbide mononitrate 2-glucuronide, are 8 hours and 6 hours, respectively.
Isosorbide mononitrate is administered orally and has a longer duration of action than nitroglycerin due to its slower onset of absorption and metabolism. It has high oral bioavailability as it is not subject to significant first-pass metabolism, unlike isosorbide dinitrate. It is eliminated primarily via renal excretion as metabolites.

Protein Binding
Isosorbide mononitrate binds to plasma proteins at a rate of approximately 5%.
The toxicological profile of isosorbide mononitrate is similar to other organic nitrates. Common adverse effects include headache, which is a result of vasodilation, and hypotension. Tolerance can develop with continuous use. It is contraindicated in patients taking phosphodiesterase-5 inhibitors due to the risk of severe hypotension. Overdose can cause methemoglobinemia.

Isosorbide mononitrate is a crystalline solid, highly flammable, and can cause poisoning if ingested. It is a nitrate and glucol derivative with nitric oxide donor and vasodilator properties. Isosorbide mononitrate is an organic nitrate drug with vasodilatory effects, used as an antianginal agent. Its mechanism of action is to reduce cardiac preload by relaxing the smooth muscle of arteries and veins (primarily acting on veins). Isosorbide mononitrate is the active metabolite of isosorbide dinitrate. Like other organic nitrates, isosorbide mononitrate is a prodrug of its active metabolite, nitric oxide, which mediates its therapeutic effects. Due to its slow absorption and metabolism, isosorbide mononitrate has a longer duration of action than nitroglycerin. Isosorbide mononitrate was first approved by the U.S. Food and Drug Administration (FDA) in 1991 for the prevention and treatment of angina pectoris caused by coronary artery disease; however, oral isosorbide mononitrate does not have a rapid onset of action and cannot relieve acute angina attacks. This drug is available in oral tablet form, with the generic and brand names ISMO and Monoket, respectively. A sustained-release formulation is also available with the generic and brand name Imdur. Isosorbide mononitrate is a nitrate vasodilator. Its physiological action is achieved through vasodilation. Isosorbide mononitrate is the mononitrate form of isosorbide, an organic nitrate with vasodilatory activity. Isosorbide mononitrate relaxes vascular smooth muscle by generating the free radical nitric oxide (NO), which is identical to endothelial relaxing factor (EDRF). Nitric oxide (NO) activates guanylate cyclase, thereby increasing the synthesis of cGMP in smooth muscle, leading to dephosphorylation of light chain myosin, and causing dilation of peripheral arteries and veins. In addition, isosorbide mononitrate can dilate coronary arteries, thereby increasing blood circulation to ischemic areas. (NCI05)
See also: Isosorbide (containing the active ingredient).
Indications
Isosorbide mononitrate is indicated for the prevention and treatment of angina pectoris caused by coronary artery disease. Oral isosorbide mononitrate has an insufficient onset of action to terminate an acute angina attack.
FDA Label
Mechanism of Action
Isosorbide mononitrate is a prodrug of nitric oxide (NO), a potent vasodilator released during drug metabolism. Nitric oxide (NO) activates soluble guanylate cyclase in vascular endothelial cells, thereby increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinases G and I, which in turn activate downstream intracellular signaling cascades. Downstream signaling cascades lead to a decrease in intracellular calcium ion concentration. The mechanisms include inhibition of IP₃-mediated signaling pathways, phosphorylation of potassium channels activated by large calcium leading to hyperpolarization and reduced calcium ion influx, and increased calcium ion efflux via the Ca²⁺-ATP pump. The decreased intracellular calcium ion concentration results in myosin light chain dephosphorylation, thereby relaxing smooth muscle cells.

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Pharmacodynamics
Isosorbide mononitrate is an antianginal drug and vasodilator that prevents and treats angina by relaxing vascular smooth muscle. The pharmacological action of isosorbide mononitrate is mediated by its active metabolite, nitric oxide, which is released during the metabolism of isosorbide mononitrate. Nitric oxide acts on arteries and veins, but primarily on veins: by dilating veins and reducing central venous pressure, nitric oxide causes venous blood pooling, reducing venous return and thus decreasing cardiac preload. In healthy subjects, reduced stroke volume while standing and venous congestion can lead to orthostatic hypotension and dizziness. At therapeutic doses of isosorbide mononitrate, nitric oxide has a greater effect on larger muscular arteries than on smaller resistance arteries. Arterial dilation leads to a decrease in systemic vascular resistance and systolic blood pressure (aortic pressure), thereby reducing cardiac afterload. Its direct vasodilatory effect on the coronary arteries can counteract coronary artery spasm in variant angina or angina. High doses of nitric oxide dilate resistance arteries and arterioles, reducing arterial blood pressure through coronary artery dilation, thereby increasing coronary blood flow. Nitric oxide reduces cardiac preload and afterload, thereby reducing myocardial oxygen consumption; the reduced myocardial oxygen consumption, combined with increased coronary blood flow, leads to increased coronary sinus oxygen content, thereby relieving ischemia. The ultimate effects of isosorbide mononitrate include reducing myocardial oxygen consumption, redistributing coronary blood flow to ischemic areas through collateral circulation, and relieving coronary artery spasm. Nitric oxide can also accelerate myocardial relaxation, an effect not limited to vascular smooth muscle. Organic nitrates can also relax other types of smooth muscle, including esophageal and biliary smooth muscle. The antianginal activity of isosorbide mononitrate is observed approximately 1 hour after administration and peaks 1–4 hours after administration. With an asymmetric dosing regimen, the duration of antianginal effect is at least 12 hours.
Isosorbide mononitrate is an FDA-approved drug for the prophylaxis of angina pectoris. It is available in immediate and extended-release oral formulations under brand names such as ISMO, Monoket, and Imdur. Its role as the active metabolite of isosorbide dinitrate makes it a key compound in nitrate therapy. It is not indicated for the acute relief of anginal episodes due to its slow onset.

C6H9NO6

191.139

191.042

16051-77-7

Isosorbide;652-67-5

27661

White to off-white solid powder

1.6±0.1 g/cm3

364.5±42.0 °C at 760 mmHg

88-93 °C

174.2±27.9 °C

0.0±1.8 mmHg at 25°C

1.543

-0.51

1

6

1

13

216

4

O1C([H])([H])[C@]([H])([C@]2([H])[C@@]1([H])[C@]([H])(C([H])([H])O2)O[H])O[N+](=O)[O-]

YWXYYJSYQOXTPL-SLPGGIOYSA-N

InChI=1S/C6H9NO6/c8-3-1-11-6-4(13-7(9)10)2-12-5(3)6/h3-6,8H,1-2H2/t3-,4+,5+,6+/m0/s1

[(3S,3aR,6R,6aS)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate

BM 22-145; AHR-4698; AHR 4698

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~523.18 mM)
H2O : ~50 mg/mL (~261.59 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 33.33 mg/mL (174.37 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)