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

4. 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

5. Side effects
hypotension (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

6. 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

7. NITRATE
TOLERANCE

8.  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

9. 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

10. 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.

11. 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

12.  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

13. Dosage form

14. 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.

15.  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.

16. 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

17. 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

18.  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.

19. 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.

20. 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.

21. 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.

22. 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

23. 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.

24. ISMN
 Sustained Release Tablet: 60mg