Organic nitrates and nitrites for angina

Isosorbide dinitrate

Isosorbide dinitrate (ISDN) (also known as Dilatrate) is a nitrate used pharmacologically as avasodilator, e.g. in angina pectoris but also for anal fissure, a condition which is known to involve decreased blood supply leading to poor healing. It is also used as a direct vasodilator to treat congestive heart failure.

Isosorbide dinitrate is sold under the brand names Isordil^[1] by Biovail, Cedocard, Sorbitrate and Isotrate. In UK, Argentina and Hong Kong, a trade name of it is Isoket. It is also a component ofBiDil.

Uses

It is more useful in preventing angina attacks than reversing them once they have commenced. It may be given as a tablet for the treatment of an angina attack.

Advantages

Long acting nitrates can be more useful as they are generally more effective and stable in the short term. It is more effective with African Americans.

Disadvantages

After long term use for treating chronic conditions, tolerance may develop in a patient reducing its effectiveness. The mechanisms of nitrate tolerance have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. these include:

1.    Impaired biotransformation of ISDN to its active principle NO (or a NO-related species)

2.    Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by ISDN

3.    Plasma volume expansion

4.    The oxidative stress hypothesis (proposed by Munzel et al. in 1995).

Recent evidence suggests that the latter hypothesis might represent a unifying hypothesis, and an ISDN-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, ISDN can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain as well as severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration.

­­Isosorbide mononitrate

Isosorbide mononitrate is a drug used principally in the treatment of angina pectoris^[1] and acts by dilating the blood vessels so as to reduce the blood pressure. It is sold by AstraZenecaunder the trade name Imdur, and marketed in the UK under the trade names: Monosorb,Chemydur. In India this drug is available under the brand names of Ismo, Monotrate,Solotrate, and Monit.

Uses

Isosorbide mononitrate is used for the prophylactic treatment of angina pectoris; that is, it is taken in order to prevent or at least reduce the occurrence of angina. Research on isosorbide mononitrate as a cervical ripener to reduce time at hospital to birth is supportive.

Side effects

The adverse reactions which follow have been reported in studies with isosorbide mononitrate:

Very common: Headache predominates (up to 30%) necessitating withdrawal of 2 to 3 % of patients, but the incidence reduces rapidly as treatment continues .

Common: Tiredness, sleep disturbances (6%) and gastrointestinal disturbances (6%) have been reported during clinical trials with isosorbide mononitrate modified release tablets, but at a frequency no greater than for placebo. Hypotension (4 to 5%), poor appetite (2.5%), nausea (1%).

Adverse effects associated with the clinical use of the drug are as expected with all nitrate preparations. They occur mainly in the early stages of treatment.

Hypotension (4%) with symptoms such as dizziness and nausea (1%) have been reported. These symptoms generally disappear during long-term treatment.

Other reactions that have been reported with isosorbide mononitrate modified release tablets include tachycardia, vomiting, diarrhoea, vertigo and heartburn.

Interactions

§                     Sildenafil (Viagra). Concomitant administration of isosorbide mononitrate and sildenafil (Viagra) can potentiate the vasodilatory effect of isosorbide mononitrate with the potential result of serious side effects such as syncope ormyocardial infarction. Therefore, sildenafil should not be given to patients already receiving isosorbide mononitrate therapy.

§                     Sulfhydryl containing compounds. The metabolism of organic nitrates to nitric oxide is dependent on the presence of sulfhydryl groups in the muscle. The combination of oral N-acetylcysteine and a single dose of sustained release isosorbide mononitrate 60 mg significantly prolonged the total exercise time in patients with angina pectoris and angiographically proven significant coronary artery disease, when compared with isosorbide mononitrate alone. Concomitant administration of other exogenous sources of sulfhydryl groups such asmethionine and captopril may produce a similar interaction.

§                     Phenylalkylamine calcium antagonists. The addition of a calcium channel blocker of the verapamil type, such as gallopamil 75 mg, has been shown to further improve left ventricular functional parameters when given in combination with isosorbide mononitrate in a sustained release formulation.

§                     Propranolol. The addition of isosorbide mononitrate to propranolol treatment in patients with cirrhosis and portal hypertension caused a marked fall in portal pressure, a reduction in hepatic blood flow, cardiac output and mean arterial blood pressure, but no additional change in azygos blood flow. The additional effect of isosorbide mononitrate was especially evident in patients whose portal pressure was not reduced by propranolol.

§                     Calcium antagonists (general). Marked symptomatic orthostatic hypotension has been reported when calcium antagonists and organic nitrates were used in combination. Dose adjustments of either class of agent may be necessary.

Amyl nitrite

Amyl nitrite is the chemical compound with the formula C₅H₁₁ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group. Like other alkyl nitrites, amyl nitrite is bioactive in mammals, being a vasodilator, which is the basis of its use as a prescription medicine. As an inhalant, it also has a psychoactive effect, which has led to its recreational use.

ynthesis and reactions

Alkyl nitrites are prepared by the reaction of alcohols with nitrous acid:

C₅H₁₁OH + HONO → C₅H₁₁ONO + H₂O

The reaction is called esterification. Synthesis of alkyl nitrites is, in general, straightforward and can be accomplished in home laboratories. A common procedure includes the dropwise addition of concentrated sulfuric acid to a cooled mixture of an aqueous sodium nitrite solution and an alcohol. The intermediately-formed stoichiometric mixture of nitrous and nitric oxide then converts the alcohol to the alkyl nitrite, which, due to its low density, will form an upper layer that can be easily decanted from the reaction mixture.

Isoamyl nitrite decomposes in the presence of base to give nitrite salts and the isoamyl alcohol:

C₅H₁₁ONO + NaOH → C₅H₁₁OH + NaNO₂

Amyl nitrite, like other alkyl nitrites, reacts with carbanions to give oximes.

Amyl nitrites are also useful as reagents in a modification of the Sandmeyer reaction. The reaction of the alkyl nitrite with an aromatic amine in a halogenated solvent produces a radicalaromatic species, this then abstracts a halogen atom from the solvent. For the synthesis of aryl iodides diiodomethane is used, whereas bromoform is the solvent of choice for the synthesis of aryl bromides