nitrates & nitrites

Organic nitrates and nitrites:

Inorganic nitrates are ineffective

Classification:

1. Short-acting nitrates:

• Amyl nitrite (inhalation)
• Nitroglycerine (SL)
• Isosorbide dinitrate (SL)
• i.v. nitroglycerin

2. Long-acting nitrates:

• Isosorbide dinitrate or
• mononitrate (Oral)

3. Transdermal patches

Pharmacokinetics:

Absorption: nitrates are rapidly absorbed from buccal membrane, GIT, and bronchioles.

Metabolism: in the liver:

• If given oral → extensive first-pass hepatic metabolism (oral bioavailability <10%).
• If given sublingual → no first-pass metabolism → high bioavailability.

Excretion: via the kidney.

Mechanism of action:

acts by causing systemic venodilation by causing liberation of the free radical nitric oxide (NO) which is identical to the endothelial derived relaxing factor (EDRF) → ↑ cGMP → ↓ Ca2+ influx into the vascular sm ms → VD (more on the veins).

Pharmacological effects:

CVS:

• Blood vessels: VD of the venous (and to lesser extent to the arterial) side leading to ↓ preload . So, Reducing myocardial wall tension and oxygen requirements

  Dilating the epicardial coronary vessels leading to increased coronary blood flow

  • Increasing blood flow in collateral vessels
  • VD of the arteries in the face and neck leading to flushing.
  • VD of meningeal arteries leading to throbbing headache.  

• Heart: Reflex tachycardia (in high dose) 2ry to ↓ BP.

• BP: High doses cause ↓ in both systolic and diastolic BP.

Smooth ms:

• relaxation of bronchial, GIT, uterine, and biliary sm ms.   Respiration:
• reflex tachypnea (↑ resp rate) due to hypotension.   Blood:
• Methemoglobinemia in high doses due to oxidation of Hb into met-Hb.

Therapeutic uses:

1-Angina pectoris:

• Nitrates are used for treatment of all types of angina both for relieving the acute attack and for prophylaxis.

These effects will lead to: A-Reduction of myocardial O2 demand through:

• Venodilatation → ↓ venous return (preload) .
• Arteriolodilatation → ↓ peripheral resistance (afterload).   B-Enhancement of myocardial perfusion through:
• Coronary VD.
• Redistribution of blood from large epicordial vessels to ischemic subendo-cardial vessels.

2-Myocardial infarction: to ↓ the area of myocardial damage.   3-Acute heart failure: to ↓ preload and afterload.   4-Treatment of cyanide poisoning: cyanide has high affinity for metHb more than normal Hb.   5-Biliary colic.   6-Management of constriction ring during labor.

Side effects:

1. Hypotension and reflex tachycardia: may aggravate angina.

2. Throbbing headache: with nitroglycerin, due to VD of meningeal arteries.

3. Flushing of the face.

4. Tolerance to its effect: with long acting preparation due to:

   • Depletion of sulfhydryl (-SH) containing enzymes necessary for liberation of NO from nitrates → ↓ formation of NO → ↓ VD effect.
   • Reflex sympathetic activation (due to hypotension), this will cause VC.
   • Prevention of tolerance: make a daily nitrate-free interval (8-10–12 h) to give chance for the SH- containing enzymes to regenerate.
   • During this period, give another anti-anginal drug (e.g. beta-blocker or CCBs).

5. Methemoglobinemia in high doses (rare).

6. Never to be combined with other drugs causing vasodilation (Viagra®) or hypotension - would result in irreversible hypotension

Precautions during nitrate therapy:

• Tablet should be held under tongue until dissolved. Avoid eating, drinking, or smoking until tablet is dissolved.
• Advise patient to sit down.
• Relief should occur in 1 to 3 minutes
• Use the smallest effective dose to avoid hypotension and reflex tachycardia.
• The patient should consult his doctor if anginal pain does not improve after taking 3 SL tablets of NG during 15 min (may be MI). May be repeated every 5 minutes for 3 doses.
• Nitroglycerine tablets should not be put in direct sunlight or with cotton .
• The expiry date (60 days) should be checked (active tablets have burning taste).
• Sudden withdrawal may cause acute MI.

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Sustained Released Tablet

Administer dose 1 hour before or 2 hours after meal with a full glass of water for faster absorption.

Nitroglycerine Patch

• Place the patch on a hairless area of chest or upper arm each day.
• Move patch to a different place on your body each day to prevent skin irritation.
• Remove the patch for 8 to 12 hours each night and put on a fresh patch each day.
• Patches – takes 40 minutes to an hour to start working
• Place the patch on a hairless area of chest or upper arm each day.
• Move patch to a different place on your body each day to prevent skin irritation.
• Remove the patch for 8 to 12 hours each night and put on a fresh patch each day.
• Patches –  takes 40 minutes to an hour to start working

Nitroglycerine Ointment

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Acute Coronary Syndrome

• The resulting vasodilation of veins and peripheral and coronary arteries may reduce excessive cardiac preload and afterload.

• Route: Intravenous nitroglycerin is preferred

• Indications: The first 24 to 48 hours of acute MI and heart failure , large anterior MI, persistent ischemia , or hypertension.