Tolerance and Dependence

Repeated and frequent exposure to organic nitrates is accompanied by the development of tissue tolerance to the drug's vasodilating effects. When nitroglycerin formulations (e.g., transdermal patches, sustained-release oral dosing, or ointments) that produce sustained plasma and tissue levels are used, tolerance may occur within 24 hours. The mechanism underlying the phenomenon of nitrate tolerance is not as yet completely understood but may be related to a nitrate-induced oxidation of sulfhydryl groups via the formation of free radicals, a decrease in the sensitivity of vascular smooth muscle soluble guanylate cyclase, or activation of the renin-angiotensin system.

To help avoid nitrate tolerance, clinicians should employ the smallest effective dose and administer the compound infrequently. A daily nitrate-free period is also recommended, particularly with use of the transdermal patches or ointment. A better understanding of the pharmacokinetic profile achieved with these sustained-release formulations should result in more effective dosing regimens.

Since depletion of tissue stores of sulfhydryl groups has been proposed to play an important role in nitrate tolerance, some investigators have administered sulfhydryl-containing compounds in an attempt to reverse or prevent the development of tolerance. The most commonly used agent is ^-acetylcysteine (NAC), which is hydrolyzed in vivo to cysteine. Although some

Peripheral Neuropathy Natural Treatment Options

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