Nitrates, organic adverse effects

Erythrityl is readily absorbed from the GI tract. It undergoes extensive first-pass metaboHsm ia the Hver by glutathione organic nitrate reductase. Time to onset of effect is 5—10 min by subHngual adrninistration and 20—30 min when swallowed. The duration of effects for the two routes ate up to 3 and 6 h, respectively. Adverse effects are similar to those described for nitroglycerin (99). 

The acute adverse effects of the organic nitrates as well as molsidomine are directly related to their therapeutic vasodilation as they can cause orthostatic hypotension, tachycardia and throbbing headache. 

Cardiovascular Effects. Palpitations, low blood pressure, and tachycardia were described in subjects exposed to 1,3-DNB by the inhalation (Okubo and Shigeta 1982), oral (Kumar et al. 1990), and dermal (White and Hay 1901) routes of exposure. These responses are consistent with effects of organic nitrates. 1,3-DNB is an organic nitrate and shares many of the cardiovascular properties of therapeutic nitrates. Organic nitrates induce relaxation of the vascular smooth muscle which can result in peripheral vasodilation and a fall in blood pressure followed by a compensatory vasoconstriction (Abrams 1980). The general information available on organic nitrates suggests that exposure to 1,3-DNB or 1,3,5-TNB at ammunition waste sites or at work places where these chemicals are used may lead to adverse cardiovascular effects. 

The primary adverse effects associated with organic nitrates are headache, dizziness, and orthostatic hypotension.47 These effects are related to the drugs ability to dilate peripheral blood vessels and decrease peripheral resistance. Nausea may also be a problem in some patients. As indicated earlier, tolerance to the beneficial effects of nitrates can occur during continuous administration, but providing daily nitrate-free intervals should prevent this problem. 

Organic nitrates have been in use for over 135 years, and their adverse effects are therefore weU documented. The first compound of this class to be used was amyl nitrite, synthesized in 1844 by Ballard and used to treat angina pectoris by Brunton in 1869. Glyceryl trinitrate was first synthesized by Ascagne Sobrero in 1847 and was used by William Murrell to treat angina pectoris in 1879. 

The irritation of air enriched solely with NO or NO2 did not produce photo-oxidants this only occurred when hydrocarbons were also present in the polluted urban atmosphere. This leads to a build-up of tropospheric ozone, and hence to faster rates of photoinitiation through photodissociation of ozone, and then to a further build-up of ozone, and so on. Besides ozone, which is toxic at low concentrations (0.1-1 ppmv), other intermediates responsible for adverse effects include aldehydes and organic nitrates, such as peroxyacetyl nitrate (PAN). 

Formulations usually contain a combination of different anodic and cathodic inhibitors. Commonly used are ortho- and polyphosphates, phosphonates, tannins, lignins, benzoates, silicates, chromates, molybdates, nitrites, nitrates, zinc salts, aromatic azoles, carboxylic acids, amides, amines, soluble oils, and oxygen scavengers, such as hydrazine and sulfites [3, 46]. Some of these substances (e.g. silicates) are employed predominantly in synergy with other inhibitors, whereas in other cases the combination of inhibitors may have adverse effects (e.g. nitrites and organic amines or amides may form carcinogenic nitrosamines at elevated temperatures). 

An example for the early incorporation of new scientific knowledge in dermatological practice by using an extemporaneous preparation is the treatment of chronic anal fissures with diltiazem hydrochloride. The mechanism of action is based on the reduction of the pressure in the anal sphincter. In comparison to organic nitrates diltiazem hydrochloride causes less adverse effects (headache). Based on published experiences with this treatment and the need for a stable preparation, formulations for a gel and a cream were developed (Table 12.1). 

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