Nitrites and Nitrates

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Chapter: Medicinal Chemistry : Antianginals

Antianginals : Nitrites and Nitrates: Synthesis and Drug Profile- i. Amylnitrite (Vaporole) ii. Nitroglycerine iii. Erythrityl tetranitrate (Cardilate) iv. Pentaerythritol tetranitrate v. Nicorandil (Nicoram, Corflo,Zynicor) vi. Isosorbide dinitrate (Isordil, Orbitrate)


SYNTHESIS AND DRUG PROFILE

Nitrites and Nitrates

Mode of action: These types of drugs are rapidly denitrated enzymatically in the smooth cells to release the reactive free radical nitric oxide (NO), which activates cytostolic guanyl cyclase and increases the cyclic guanosine mono phosphate (cGMP) that causes dephosphorylation of myosin light chain kinase (MLCK) through cGMP dependent protein kinase. The reduction in phosphorylated MLCK interferes with myosin and fails to cause contraction. Relaxation also occurs due to reduced Ca2+ entry.

Metabolism: All organic nitrates are subjected to first-pass metabolism, not only by the action of glutathione nitrate reductase in the liver, but also in the extra hepatic tissues. Some metabolites of long-acting nitrates are active as vasodilators. An example of this is isosorbate dinitrate, which is metabolized primarily in the liver by glutathione nitrate recductase, which also participates in the metabolism of other organic nitrates, catalyzing the denitration of the parent drugs to yield two metabolites, 2and 5-isosorbate mononitrate.


i. Amylnitrite (Vaporole) 

(CH3)2 CHCH2CH2O.NO

Dose: The usual dose of amyl nitrite 0.18 or 0.3 ml.

Synthesis

(CH3)2CHCH2CH2OH  HNO2  (CH3)2 CHCH2CH2O·NO

lsopentyI aIcohoI                   AmyI nitrite


Properties and uses: It is a clear yellowish liquid with an ethereal, fruity odour, and pungent, aromatic taste. It is insoluble in water, but miscible with alcohol, chloroform, or ether. It is a mixture of isomeric amyl nitrites, but is principally isoamyl nitrite. It is mainly used to treat angina pectoris. It is also effective in the emergency management of cyanide poisoning by causing the oxidation of haemoglobin to the compound methemoglobin.

Dose: The usual dose of amyl nitrite 0.18 or 0.3 ml.


ii. Nitroglycerine


Synthesis


Properties and uses: It is a colourless, odourless liquid with a sweet taste. Glyceryl trinitrate is the trinitrate ester of glycerol. Nitroglycerine is used in angina pectoris and extensively as an explosive in dynamite. A solution of the ester, if spilled or allowed to evaporate, will leave a residue of nitroglycerine. To prevent an explosion of the residue, the ester must be decomposed by addition of alkali. Even then the material dispensed is so dilute that the risk of explosions does not exist.


iii. Erythrityl tetranitrate (Cardilate)


Synthesis


Properties and uses: Erythrityl tetranitrate is a white powder with a slight odour of nitric oxide and bitter taste. It is soluble in acetone and alcohol, but insoluble in water. It is used in the treatment of angina pectoris and to reduce blood pressure in arterial hypertonia.

Dose: 10 mg thrice/day by oral tablet.


iv. Pentaerythritol tetranitrate


Synthesis


Properties and uses: It is a white or slightly yellowish powder that is practically insoluble in water, soluble in acetone, and slightly soluble in alcohol. It is used in the treatment of angina pectoris. It relaxes the smooth muscle of smaller vessels in the coronary vascular tree.

Assay: It is assayed by adopting liquid chromatography technique.

Storage: It should be stored in well-closed airtight containers and protected from light.

Dose: 40–80 mg every 4–6 h, orally.


v. Nicorandil (Nicoram, Corflo,Zynicor)


Synthesis


Properties and uses: The cardiac unloading effect of this drug contributes to its antianginal action.

Dose: Orally for angina pectoris: Adult: 10 mg twice/day, increase if necessary. Usual dose: 10–20 mg twice/day. May use 5 mg twice/day for patients prone to headache. Maximum dose is 30 mg twice/day.


vi. Isosorbide dinitrate (Isordil, Orbitrate)


Synthesis


Properties and uses: It is a fine white crystalline powder, slightly soluble in water, well soluble in acetone, but sparingly soluble in alcohol. It is effective in the treatment of acute angina attack.

Assay: It is assayed by adopting liquid chromatography technique.

Storage: It should be stored in well-closed airtight containers and protected from light.

Dose: Sublingual: 5–10 mg every 2–3 h, Oral: 5–60 mg every 4–6 h; chewable tablet: 5–10 mg every 2–4 h.

Dosage forms: Isosorbide dinitrate tablet B.P.


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