Nitrates

pharmacology of nitrate

1. Nitrates By : Somayyeh Nasiripour , Pharm.D , board of clinical pharmacy Assistant professor at IUMS

2. Mechanism of Action 1-Nitrates entering vascular smooth muscle cells and combining with sulfhydryl groups to form nitric oxide and eventually S- nitrosothiols The nitrosothiols stimulate forms free radical nitric oxide. In smooth muscle, nitric oxide activates guanylate cyclase which increases guanosine 3’5’ monophosphate ( cGMP ) leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload (left ventricular end-diastolic pressure); may modestly reduce afterload; dilates coronary arteries and improves collateral flow to ischemic regions 2- For use in rectal fissures, intra-anal administration results in decreased sphincter tone and intra-anal pressure

3. Side effects

4. Nitrates in all forms should be avoided

5. major problem with the use of nitrates as chronic antianginal therapy. first observed in individuals exposed to nitroglycerin during the production of explosives. These workers developed severe headache and dizziness after the initial exposure. These side effects would then diminish after several days. If, however, exposure was avoided for several days, the symptoms would return after reexposure

6. Mechanisms of tolerance Impaired nitroglycerin bioconversion to 1,2-glyceryl dinitrate by ALDH m with decreased formation of nitric oxide. This effect is nitrate-specific and is not seen with non-nitrate sources of nitric oxide such as nitroprusside Reduced bioactivity of nitric oxide .Consistent with this theory is the finding in an animal study that vascular and hemodynamic tolerance to nitrates occurred despite high levels of nitric oxide Activation of the vasoconstrictor renin-angiotensin-aldosterone and sympathetic nervous systems in response to nitrate-induced vasodilation

7. A polymorphism in this enzyme (ALDH2*2), which is present in 30 to 50 percent of Asians, virtually eliminates mtALDH activity and nitric oxide production These patients were significantly less likely to respond to nitroglycerin for relief of angina.

8. Prevention most effective being intermittent therapy with an adequate nitrate-free interval. It is thought that a nitrate-free interval permits the regeneration of reduced sulfhydryl groups There are, however, two concerns regarding intermittent therapy: ●A time-zero effect, which refers to a deterioration in exercise performance relative to placebo prior to the morning dose of nitrates. ●Rebound angina, which refers to an increase in angina during the nitrate-free interval. There may result from a supersensitivity of the vessel wall to vasoconstrictors or an increased vasomotor response to acetylcholine, suggesting the development of endothelial dysfunction Whether these effects occur to a clinically significant degree remains unclear

9. Folic acid can reverse endothelial dysfunction, possibly by restoring the bioavailability of tetrahydrobiopterin , a cofactor for nitric oxide synthase and/or arginine, its substrate . Compared to placebo, folic acid prevented the development of both endothelial dysfunction and nitrate tolerance Treatment for five to 10 days with L-arginine, the substrate for nitric oxide synthesis, can modify or prevent the development of nitrate tolerance during continuous transdermal nitroglycerin use [30]. ●Hydralazine may attenuate nitrate tolerance, perhaps by preventing superoxide generation . This relationship could contribute to the efficacy of combined nitrate-hydralazine therapy in patients with heart failure. In patients with angina pectoris, hydralazine should be given in combination with a beta blocker because of the reflex sympathetic activation. ● antioxidants may be helpful, at least from a theoretical perspective, such as vitamin E , vitamin C . In addition, carvedilol , a beta and alpha blocker that also has antioxidant activity, may prevent nitrate tolerance Other drugs have had variable or no effect. These include angiotensin converting enzyme (ACE) inhibitors

10. Sublingual nitroglycerin therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina The onset of action is within two to five minutes and the duration of action is 15 to 30 minutes. Tolerance is not a problem with sublingual nitroglycerin because of its intermittent administration, even in patients on chronic nitrate therapy Dose : one nitroglycerin dose (0.3- 0.4 mg ) sublingually every five minutes for up to three doses . One-half the dose (0.15 mg) can be used if the patient becomes hypotensive or develops symptoms such as headache or flushing with the higher doses : Do not chew, crush, or swallow sublingual tablet. Place under tongue and allow to dissolve. Alternately, may be placed in the buccal pouch.

11. Nitroglycerin tablets are both heat and light sensitive. They should therefore be stored in a tightly capped dark bottle in the refrigerator with only a small supply being carried by the patient . Nitroglycerin tablets in an opened bottle should be discarded after 12 months If the sublingual nitroglycerin is potent, a slight tingling sensation should be felt under the tongue. Tablets that crumble easily should not be used. The sublingual mucosa should be moist for adequate dissolution and absorption of the tablet. A drink of water in patients with dry sublingual mucosa prior to ingestion of the tablet may be necessary Patient education is extremely important for the proper use of sublingual nitroglycerin.

12. Nitroglycerin spray A less popular but equally effective means of administering sublingual spray dispenses of 0.4 mg of nitroglycerin One to two sprays can be used at the start of an attack and up to three sprays can be used in a 15 minute period shelf life of two to three years

13. INTRAVENOUS NITROGLYCERIN typically initiated in patients with persistent ischemic chest pain despite three sublingual nitroglycerin tablets and other adjunctive therapies, such as supplemental oxygen and morphine sulfate . little objective information documenting the effectiveness of intravenous nitroglycerin in unstable angina

14. The goal of intravenous therapy is relief of symptoms or a mean arterial blood pressure 10 percent below baseline in normotensive patients and up to 25 to 30 percent in hypertensive patients. The blood pressure lowering should be gradual with careful attention to signs or symptoms of hypoperfusion . The systolic pressure should not fall below 90 mmHg or by more than 30 mmHg . The initial infusion rate is 5 to 10 µg/min . ●If the above goals are not met, the infusion rate is gradually increased at approximately 10 minute intervals by 5 to as much as 20 µg/min. ●In general, the dose should not exceed 400 µg/min. The infusion is indicated in the first 48 hours for persistent ischemia, heart failure, or hypertension. Intravenous, oral, or topical nitrates can be given after 48 hours for recurrent of persistent indications. At any time, the administration of nitroglycerin should not preclude therapy with beta blockers and angiotensin converting enzyme inhibitors.

15. GTN retard Angina/coronary artery disease 2.5 to 6.5 mg 3 to 4 times/day (maximum dose: 26 mg 4 times/day) Swallow whole. Do not chew, break, or crush . Take with a full glass of water.

16. Topical patch, transdermal 0.2 to 0.4 mg/hour initially and titrate to doses of 0.4 to 0.8 mg/hour. Tolerance is minimized by using patch-off period of 10 to 12 hours/day. Application site should be clean, dry and hair-free. Rotate patch sites.

17. Topical 2% ointment 1/2” upon rising and 1/2” 6 hours later ; if necessary, the dose may be doubled to 1” and subsequently doubled again to 2” if response is inadequate. Recommended maximum: 2 doses/day; include a nitrate free-interval ~10 to 12 hours/day. Application site should be clean, dry, and hair-free. Apply to chest or back with the applicator or dose-measuring paper . Spread in a thin layer over a 2.25 x 3.5 inch area. Do not rub into skin. Tape applicator into place.

18. ISDN Sustained Release Tablet: 40mg Sublingual Tablet: 5mg Tablet: 10mg Sublingual: Prophylactic use: 2.5-5 mg administered 15 minutes prior to activities which may provoke an anginal episode Treatment of acute anginal episode (use only if patient has failed sublingual nitroglycerin): 2.5-5 mg every 5-10 minutes for maximum of 3 doses in 15-30 minutes

19. Oral: Immediate release: Initial: 5-20 mg 2-3 times daily; Maintenance: 10-40 mg 2-3 times daily or 5-80 mg 2-3 times daily (Anderson, 2011) Sustained release : 40-160 mg/day has been used in clinical trials ( a nitrate free interval of at least 18 hours is recommended; however, a clinically efficacious dosage interval has not been clearly established) or 40 mg 1-2 times daily Do not administer around the clock; allow nitrate-free interval ≥14 hours (immediate release products) and >18 hours (sustained release products). Do not crush sublingual tablets or extended release formulations.

20. ISMN Sustained Release Tablet: 60mg