Organic Nitrates - Cardiovascular Poisons

ORGANIC NITRATES

Examples

Nitroglycerine, amyl nitrite, isosorbide dinitrate, isosorbide-5-mononitrate, erythrityl tetranitrate, pentaerythritol tetrani-trate.

Physical Appearance

Organic nitrates are polyol esters of nitric acid.* Amyl nitrite is a highly volatile liquid, while low molecular mass nitrates such as nitroglycerine** are moderately volatile, oily liquids, and high molecular mass nitrate esters such as erythrityl tetranitrate are solids.

All organic nitrates are capable of denitration (i.e. they release nitric oxide), and are collectively termed nitrovaso-dilators.

Uses

Treatment of

·              Angina pectoris (and some cases of myocardial infarction).

·              Prinzmetal’s angina.

·              Congestive heart failure.

Toxicokinetics

■■   Glyceryl trinitrate can be administered orally, sublin-gually, transdermally (ointment or patch), or as IV infu-sion. Erythrityl tetranitrate is usually administered only sublingually, while pentaerythritol tetranitrate is given orally. Isosorbide-5-mononitrate is also given orally, while isosorbide dinitrate can be administered orally and sublin-gually.

■■   Metabolism is effected by the hepatic enzyme glutathione-organic nitrate reductase which converts the lipid soluble nitrate esters into more water soluble denitrated metabolites and inorganic nitrite.

■■   Peak plasma concentrations of glyceryl trinitrate and isosorbide dinitrate (sublingually) are achieved in 4 minutes and 6 minutes respectively. Plasma half-life is 1 to 3 minutes for the former and 45 minutes for the latter. Isosorbide-5-mononitrate (which is actually a metabolite of isosorbide dinitrate) has a half-life of 2 to 5 hours.

■■   Sublingual organic nitrates as well as those which are administered orally or transdermally, exhibit the unfor-tunate phenomenon of tolerance which attenuates their pharmacologic effects on repeated administration.

Mode of Action

·              Organic nitrates exhibit the following actions:

·              Relaxation of smooth muscle (especially of blood vessels).

·              Reduction of pre-load (due to reduced venous return).

·              Relief of coronary vasospasm.

·              Reduction of after-load (due to dilatation of arterioles).

Adverse Effects

■■   Nitrite-induced peripheral vasodilatation may occur after nitrates have been converted to nitrites in vivo. Headache is common. Vertigo and weakness may occur due to postural hypotension, and can be severe in concomitant alcohol ingestion.

■■   Other effects include tachycardia, decreased periph-eral vascular resistance, and cardiovascular collapse. Bradycardia occurs less often.

■■   Drug rash can occur especially in the case of pentaerythritol tetranitrate.

Drug Interactions

·              Combined use with calcium channel blockers, antihyperten-sives, phenothiazines, and tricyclics can cause severe orthos-tatic hypotension.

·              Patients on organic nitrate therapy must not consume alcohol (vide supra).

Toxic (Clinical) Features

·      Nausea and vomiting are the first signs to be noted following ingestion.

·      Methaemoglobinaemia is induced in overdose which can be life-threatening. Once nitrates have been converted to nitrites, cyanosis and dyspnoea may develop due to methaemoglobin formation. Suspect methaemoglobinaemia in all cyanotic patients, who do not improve with supplemental oxygen.

·      There is also headache, vertigo, flushing and hypotension.

·      Arrhythmias including atrial fibrillation, frequent ventric-ular premature beats, and bigeminy may occur with severe poisoning.

Diagnosis

·      Cooking test: Clotted blood sample is placed in a boilingwater bath. After “cooking” and cooling, the sample turns salmon pink. Normal blood sample will be chocolate brown.

·      Commercial urine reagent strips for detection of urinary tract infections will turn intensely pink in organic nitrate poisoning.

Treatment

·      Ensure airway. Administer 100% oxygen. Assisted ventila-tion may be required.

·      Determine methaemoglobin concentration and measure arterial blood gases in all cyanotic patients or patients with dyspnoea or other signs of respiratory distress. Normal methaemoglobin level is less than 3%. A G-6-PD assay is indicated in patients who develop methaemoglobinaemia and/or haemolysis. Blood with methaemoglobinaemia that has been exposed to oxygen has a characteristic chocolate brown colour. Initial bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby. If there is greater than 15% methae-moglobinaemia, the affected blood will have a chocolate brown colour in comparison with the control blood.

·      Obtain an ECG and institute continuous cardiac monitoring if the patient has ischaemic symptoms or significant meth-aemoglobin concentration.

·      Treat hypotension with Trendelenburg position, IV fluids, pressors (dopamine).

·      Decontamination : activated charcoal, stomach wash, etc.,in oral ingestions.

·      Nitrate salts are irritating to mucous membranes; dilution with milk or water is appropriate following ingestion. Treatment should focus on hypotension and methaemoglobinaemia. Give supportive care, appropriate airway management, and administration of 100% oxygen. Cardiac and haemodynamic parameters should be monitored continuously.

·      Antidote: Methylene blue is the antidote of choice in severepoisoning (methaemoglobin level more than 30%).

o     Dose*: 1 to 2 mg/kg (25 to 50 mg/m2) of 1% solution (10 mg/ml), IV, over 5 minutes. This can be repeated once after 1 hour if symptoms do not subside.

o     Adverse effects: dyspnoea, chest pain, anxiety, tremor, dysuria, increased frequency of micturition, bluish skin discolouration. Overdose can cause haemolysis.

o     Patients with G6PD deficiency are especially suscep-tible.

o     Failure of methylene blue therapy suggests one of the following: inadequate dose of methylene blue,zinadequate decontamination, NADPH dependant methaemoglobin reductase deficiency, haemoglobin M, sulfhaemoglobinaemia, or G6PD deficiency.

·      Blood transfusion may have to be considered in the event of severe anaemia produced by haemolysis. Hyperbaric oxygen (HBO) may be used as a supportive measure while preparations for exchange transfusion are being made. HBO therapy can provide sufficient oxygen to maintain life as dissolved oxygen in blood, and obviates temporarily the need for functional haemoglobin.

Forensic Issues

■■   Adverse reactions to organic nitrates are not uncommon. Toxicity is usually the result of therapeutic errors in dosage. Occasionally accidental poisoning occurs (especially in children).

■■   It is important to remember that nitrates not used in cardiovascular therapeutics can cause poisoning in other situations. For example, ammonium nitrate is widely used in disposable cold packs, and cases have been recorded of deliberate self-ingestion resulting in gastritis, hypoten-sion, and methaemoglobinaemia. Anion gap was reduced in some patients.

■■Sodium nitrate is said to be a frequent cause of nitrate poisoning in China, where 1 to 2 grams are often ingested at each meal.

Lipoprotein Lowering Drugs

·              HMG CoA Reductase Inhibitors: atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.

·              Bile Acid-binding Resins: cholestyramine, colestipol hydrochloride.

·              Nicotinic Acid (Niacin).

·              Probucol.

·              Fibric Acid Derivatives: clofibrate, gemfibrozil, bezafibrate.