Vasodilators organic nitrates

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. 

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

The toxicity of IPN is evaluated by Ref 6 as follows (a) When inhaled as a vapor or adsorbed thru the skin, IPN acts as a vasodilator and produces a headache in the same manner as other organic nitrates (b) When injected subcutaneously into rats at the rate of 4cc/kg body wt, it was concluded that the max allowable concn is lOOppm and (c) When rats were exposed to different concn levels of IPN in air the following resulted ... 

In their studies of the flavoprotein inhibitor, DPI, Bennett and colleagues [91, 120] found that DPI inhibited GTN-induced accumulation of cGMP to the same extent in aortae from naive and from GTN-tolerant animals. They argued that, if inactivation of flavoproteins is a major cause of tolerance, then there should be less scope for further, DPI-induced inactivation in tolerant animals, compared with naive ones. Their conclusion, accordingly, was that, while flavoproteins may participate in biotransformation of organic nitrates and associated vasodilation, their alteration cannot be the basis for nitrate tolerance. 

Needleman, P., Blehm, D J., Rotskoff, K. S., Relationship between glutathione-dependent denitration and the vasodilator effectiveness of organic nitrates. J. Pharmacol. Exp. Then 237 (1969), p. 296-288... 

A number of organic nitrates are potent vasodilators and have been used clinically for over lOOyears, particularly for the relief of the symptoms of angina (Fig. 8.6). The most widely used is glyceryl trinitrate (GTN) but the group includes pentaerythrityl tetranitrate (PETN), isosorbide mononitrate (ISMO) andisosorbide dinitrate (ISDN). 

Because of the high pH required for this process and the poor vasodilator properties of nitrite, this process cannot explain the biological action of organic nitrates. There are two problems in the use of organic nitrates as vasodilators 1. the conditions necessary for the biotransformation that converts an organic nitrate into NO, and 2. the phenomenon of tolerance. The two may be linked. 

The mechanism by which organic nitrates relieve the pain of angina pectoris was not discovered until nitric oxide was identified as the agent which was responsible for vasodilation of arteries. It was known for many years that endothelial cells released a factor that resulted in vasodilation a factor appropriately called endothelial relaxing factor (EDRF). It was, however, some time before the factor was identified, probably because it turned out to be a gas - nitric oxide - which was totally unexpected. Nitric oxide is now known to be a very important messenger molecule involved in the regulation of many other systems. The mechanism by which it causes vasodilation is described in Chapter 13. 

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. 

Hydralazine and dihydralazine are predominantly arterial vasodilators which cause a reduction in peripheral vascular resistance but also reflex tachycardia and fluid retention. They were used in the treatment of hypertension, in combination with a -blocker and a diuretic. Long-term use of these compounds may cause a condition resembling lupus erythematodes with arthrosis, dermatitis and LE-cells in the blood. This risk is enhanced in women and in patients with a slow acetylator pattern. When combined with the venous vasodilator isosorbide (an organic nitrate) hydralazine was shown to be mildly beneficial in patients with congestive heart failure (V-HEFT I Study). Hydralazine and dihydralazine have been replaced by other therapeutics, both in hypertension treatment and in the management of heart failure. 

Sodium nitroprusside (SNP) is both a venous and an arterial vasodilator. An important part of its vasodilator action is caused by the release of nitric oxide (NO), similarly as for the organic nitrates. SNP can only be administered via the intravenous route. It is a rapidly and short acting vasodilator. It has been used in the treatment of hypertensive emergencies and in the management of myocardial ischaemia. In spite of its vasodilator action it hardly influences heart rate, in contrast to hydralazine and minoxidil. The dosage of SNP should not be higher than 3 pg/kg/min within 48 h, in order to avoid the rise of cyanide ions and thiocyanate in the blood. 

The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure. Nitrates are contraindicated, however, if intracranial pressure is elevated. 

The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a... 

The direct or central effects of organic nitrates relieve ischemia by direct action on coronary vessels, improving myocardial oxygen supply. Direct vasodilator effects are exerted mostly on large conductance, rather than small resistance coronary vessels including intercoronary collateral vessels. Coronary stenosis dilatation is potentially a major component of the beneficial response. These mecha-... 

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