Glyceryl Trinitrate

Registered South African indications:

• Angina
• Unresponsive left ventricular failure
  - Secondary to myocardial infarction
  - Various aetiologies in which afterload reduction is indicated

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other nitro compounds
• Acute circulatory failure, including shock or collapse
• Hypovolaemia
• Marked hypotension (systolic pressure below 90mmHg)
• Hypotensive shock
• Cardiogenic shock (unless an appropriate left-ventricle end diastolic pressure is ensured by intra-aortic balloon pump or by positive inotropic agents) (inj, spo)
• Acute myocardial infarction with low filling pressure
• Left heart failure with low filling pressure
• Angina pectoris caused by hypertrophic, obstructive cardiomyopathy
• Hypovolaemia caused by hypertrophic, obstructive cardiomyopathy (inj)
• Constrictive pericarditis (spo)
• Pericardial tamponade (spo)
• Aortic and mitral stenosis (spo)
• Primary pulmonary hypertension
  - Coronary patients are especially at risk in this respect (spo)
• Possible increased intracranial pressure, including cerebral haemorrhage or head trauma
• Arterial hypoxemia (inj)
• Severe anaemia
• Toxic pulmonary oedema (inj)
• Closed-angle glaucoma (tab)
• Coadministration with phosphodiesterase type 5 inhibitors (e.g. sildenafil, vardenafil, tadalafil)

Cautions 

• Pregnancy
• Breastfeeding
• Renal impairment (spo)
• Severe renal impairment (tab, inj)
• Hepatic impairment (spo)
• Severe hepatic impairment (tab, inj)
• Elderly (tab)
• Patients in whom adequate preload is important for maintaining cardiac output
• Acute circulatory shock, including hypovolemic shock or cardiogenic shock with inadequate diastolic filling pressures (tab)
• Severe mitral stenosis (tab)
• Pericardial tamponade (tab, inj)
• Constrictive pericarditis (tab, inj)
• Orthostatic dysfunction (tab)
• Cardiogenic shock (unless an appropriate left-ventricle end diastolic pressure is ensured by intra-aortic balloon pump or by positive inotropic agents) (tab)
• Cerebrovascular disease (tab, spo)
• Lung disease (tab, spo)
• Cor pulmonale (tab, spo)
• Left ventricular hypertrophy associated with aortic stenosis
• Ambulant patients with the combination of angina and moderate to severe valvular aortic stenosis
• Myocardial infarction
• Hypothyroidism
• Hypoxaemia
• Hypothermia
• Malnutrition
• Hypertrophic obstructive cardiomyopathy (inj)
• Low filling pressures arising from conditions including acute myocardial infarction and left ventricular failure with a reduction of the systolic blood pressure <90mmHg (inj)
• Aortic and mitral stenosis (inj)
• Tendency to orthostatic disturbances of circulatory regulation
• Volume depleted patients
• Diabetes mellitus(inj)
• Bolus injection (inj)
• Use of polyvinylchloride tubings (inj)
• Predisposition to postural hypotension (spo)
• Narrow-angle glaucoma (spo)
• Migraine (spo)
• Alcoholism (spo)
• Epilepsy (spo)
• Cerebral trauma (spo)
• Central nervous system disorders (spo)
• Children (spo)
• Galactose intolerance (tab)
• Lapp lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)

Forms avail. in SA and covered in this monograph: tab, inj, spo

Angina pectoris - acute attack

• Oral (tab): Initial dose: 0.5mg when angina starts; Repeat dose at 5min intervals if needed; Max: 3 doses
• Oral (spo): Initial dose: 400-800μg sprayed when angina starts; Repeat dose at 5min intervals if needed; Max: 3 doses

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If symptoms have not resolved after a total of three doses, the patient should seek prompt medical attention

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The patient should preferably rest in the sitting position upon administration because of the risk of symptomatic postural hypotension

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Tab: To be placed under the tongue (administered sublingually) and retained in the mouth until dissolved or discarded

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Spo: To be sprayed under the tongue (see additional prescribing points)

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Angina pectoris - prophylaxis

• Oral (tab): 0.5mg taken 5-10min prior to activity which is likely to precipitate angina pectoris
• Oral (spo): Initial dose: 400-800μg immediately prior to activity likely to precipitate angina pectoris

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Tab: To be placed under the tongue (administered sublingually) and retained in the mouth until dissolved or discarded

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Spo: To be sprayed under the tongue (see additional prescribing points)

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The patient should preferably rest in the sitting position upon administration because of the risk of symptomatic postural hypotension

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International manufacturer's recommendations

Angina pectoris - refractory unstable

• IV: Initial: 10-15μg/min; Titrate in increments of 5-10μg/min until required effect is obtained

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Titrate cautiously in increments of 5-10μg until either relief of angina is achieved, headache prevents further increase in dose or the mean arterial pressure falls by more than 20 mmHg

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Surgery

• IV: Initial: 25μg/min as an infusion; Titrate until desired systolic arterial pressure obtained; Usual maintenance dose: 25-200μg/min

Unresponsive congestive heart failure
- Including that secondary to acute myocardial infarction

• IV: Initial: 10-100μg/min as a continuous infusion

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The infusion should be started at the lower rate and increased cautiously until the desired clinical response is achieved

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Other haemodynamic measurements are extremely important in monitoring response, these include pulmonary capillary wedge pressure, cardiac output and precordial electrocardiogram depending on the clinical picture

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For intravenous use, glyceryl trinitrate should be administered by means of a micro-drip set infusion pump or similar device which permits maintenance of constant infusion rate

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South African manufacturer's recommendations

Unresponsive left ventricular failure
- Secondary to myocardial infarction
- Various aetiologies in which afterload reduction is indicated

• IV: Initial: 10-50μg/min by slow infusion

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Dose should be adjusted to meet the individual needs of the patient and the responses of the monitored haemodynamic parameters

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Close attention to pulse and blood pressure is necessary during the administration of infusions

Not established for use in children 

Pregnancy

• Caution
• Animal studies did not indicate harmful effects with respect to pregnancy, embryofoetal development, parturition or postnatal development. However, the relevance of these animal findings to man is unknown. The administration of glyceryl trinitrate during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus

Breastfeeding

• Caution; not recommended
• It is unknown if glyceryl trinitrate or its metabolites are excreted in human milk. A risk to the breastfeeding child cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from glyceryl trinitrate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• Animal studies did not indicate harmful effects with respect to fertility. However, the relevance of these animal findings in humans is unknown

Renal Impairment

• Mild to moderate: No dose adjustment recommended (tab, inj)
• Severe: Caution; no dose adjustment recommended (tab, inj)
• Caution; no information available (spo)

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended (tab, inj)
• Severe: Caution; no dose adjustment recommended (tab, inj)
• Caution; no information available (spo)

Elderly

• No dose adjustment recommended (inj, spo)
• Caution; no dose adjustment recommended (tab)
  Hypotension and syncope can be a particular problem with use of nitrates in the elderly. Patients should be advised to sit down whenever possible when taking sublingual glyceryl trinitrate

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Restlessness
• Throbbing headache
• Dizziness
• Drowsiness
• Syncope
• Asthenia
• Cerebral ischaemia

Cardiovascular Disorders

• Tachycardia
• Enhanced angina pectoris symptoms
• Bradycardia
• Cyanosis
• Orthostatic hypotension
• Hypotension
• Facial flushing
• Circulatory collapse
• Hypoxaemia
• Palpitations

Respiratory Disorders 

• Impairment of respiration

Gastrointestinal Disorders 

• Nausea and vomiting
• Localised burning sensation
• Tongue blisters
• Heartburn
• Halitosis

Skin and Subcutaneous Tissue Disorders 

• Exfoliative dermatitis
• Rash
• Diaphoresis

Immune, Blood and Lymphatic System Disorders

• Methaemoglobinaemia
• Hypersensitivity
  - Allergic skin reactions

Sensory Disorders

• Increased ocular pressure
• Taste disturbance (metallic taste)
• Vertigo

Others

• Drug tolerance
• Weakness

• Phosphodiesterase type 5 inhibitors
• Sildenafil
• Vardenafil
• Tadalafil
• Hypotensive agents
• Anti-hypertensives
• Vasodilators
• Beta-blockers
• Calcium channel blockers
• Neuroleptics
• Tricyclic antidepressants
• Sapropterin
• N-acetylcysteine
• Long-acting nitrate preparations
• Organic nitrates
• Isorsorbide dinitrate
• Isorsorbide-5-mononitrate
• Heparin
• Anticholinergics (tab)
• Antimuscarinics (tab)
• Ergot alkaloids
• Dihydroergotamine
• Morphine-like analgesics

Other interactions

• Alcohol

• Blood pressure
• Heart rate

None routine. Some cases may require

• Pulmonary capillary wedge pressure
• Cardiac output
• Precordial electrocardiogram
• Coagulation parameters

Methods of administration (spo)

• There is no need to shake the canister before dosing
• The canister should be held vertically with the spray head uppermost
• The pump may need to be primed when first used or if the product has not been used for a period of time. The priming actuation should be released into the air
• The spray orifice should then be placed close to the mouth and the dose should be sprayed under the tongue. The mouth should be closed immediately after each dose. The spray should not be inhaled
• Patients should be instructed to familiarise themselves with the position of the spray orifice so that administration at night can be easily achieved

Special precautions for handling (inj)

• Glyceryl nitrate need not be diluted before use but can be diluted with Dextrose Injection BP, Sodium Chloride and Dextrose Injection BP, 0.9% Sodium Chloride Injection BP or other protein-free infusion solution, if required
• The solution, whether or not diluted, should be infused slowly and not given by bolus injection
• Systems made of polyvinyl chloride may absorb up to 50% of the glyceryl trinitrate from the solution, thus reducing the efficacy of the infusion
• If the recommended type of system is unavailable, a 1:10 dilution should be used and the infusion rate modified according to the haemodynamic response of the patient

Glyceryl trinitrate, a vasodilator, exerts its effects through binding to the so-called nitrate receptors located on the membrane of smooth muscle cells and inducing nitrous oxide production and intracellular cGMP accumulation. By preventing calcium-ions from entering the cell, the accumulation of cGMP results in the relaxation of smooth muscle elements.

The predominant effect is an increase in venous capacitance resulting in marked diminution of both the left ventricular filling pressure and volume (preload). There is also a reduction in afterload due to moderate dilation of the arteriolar resistance vessels. These haemodynamic changes lower the myocardial oxygen demand. By direct action and through the reduction of myocardial wall tension glyceryl trinitrate also lowers the resistance to flow in the coronary collateral channels and allows re-distribution of blood flow to ischaemic areas of the myocardium.

Tablet sublingual 0.5mg

• Angised (GSK)  originator

Injection (per ml) 1mg

• Nitrocine (GSK) originator

Spray (per spray) 0.4mg

• Nitrolingual spray (Merck) originator