NitratesBy : Somayyeh Nasiripour, Pharm.D, board of clinical pharmacy Assistant professor at IUMS

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

Dilatation of large coronary arteries and arterioles (>100 millimicrons in diameter), which may lead to increased perfusion of ischemic zones.

●Dilatation of the venous system with decreased preload. This effect is useful in patients with pulmonary congestion.

●Systemic arterial dilatation, which decreases afterload, also occurs but to a lesser degree. These changes lower wall stress and oxygen consumption

●Reduction of infarct size in experimental animal studies

●Termination of an episode of variant angina.

●Enhanced collateral blood flow.

Antiplatelet and antithrombotic properties

Side effectshypotension (especially in patients with ventricular

ischemia or hypovolemia)

•headache

•Tachycardia

Prolonged infusion of high dose nitroglycerin may lead to the development both of methemoglobinemia

(which can be treated with intravenous methylene blue

heparin resistance

Nitrates in all forms should be avoided• Systolic blood pressure less than 90 mmHg or ≥30 mmHg below baseline. Nitrates may induce symptomatic hypotension and can lead to hemodynamic decompensation in the setting of cardiac ischemia.

• Marked bradycardia (heart rate less than 50 beats per minute) or tachycardia (heart rate greater than 100 beats per minute). In this setting nitrates may cause hemodynamic decompensation.

• Known or suspected right ventricular infarction. Nitrates should be avoided because of the increased risk of inducing hypotension

• Patients who have taken a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (or perhaps as long as 48 hours with tadalafil

• Hypertrophic cardiomyopathy. Nitrates can induce or increase outflow tract obstruction, even in those not known to have a resting gradient.

• Severe aortic stenosis. A sudden decrease in blood pressure can lead to cardiovascular collapse

NITRATE TOLERANCE

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

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

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.

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

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

Dosage form

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.

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.

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

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

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.

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.

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.

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.

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

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.

ISMN Sustained Release Tablet: 60mg