> [!Key Points] > - avoid in intracerebral haemorrhage; can ↑ ICP see also: [[ACS]], [[Pulmonary oedema|APO]], A nitr**i**te is a negatively charged ion that has 1 nitrogen atom and 2 oxygen atoms (NO2-) A nitr**a**te is a negatively charged ion that has 1 nitrogen atom and 3 oxygen atoms (NO3-) # Indications 1. relief of [[#For ACS|ischaemic pain]] 2. [[#For APO|Acute pulmonary oedema]] 3. hypertensive emergencies # Mechanism of action Glyceryl trinitrate provides an exogenous source of **nitric oxide** which mediates vasodilator effects. In smooth muscle cells the **nitrate group** is cleaved to **inorganic nitrite** and then to **nitric oxide**. Nitric oxide then activates cyclic guanosine monophosphate, which leads to smooth muscle relaxation # Pharm ## dynamics Glyceryl trinitrate relaxes vascular smooth muscle, producing dilation of both arterial and venous beds. **Venous** effects predominate over arterial effects. Physiological effects include: - **Venodilation**, resulting in: - Decreased venous return to the heart  - Reduced left ventricular end-diastolic pressure (i.e. **reduced pre-load**).  - **Arteriolar dilation**: - Arteriolar relaxation results in reduced systemic vascular resistance, (i.e. reduced afterload) - There is also direct coronary artery vasodilation, increasing coronary artery blood flow. - **Reduced myocardial oxygen demand**:  - Reduced preload and reduced afterload both result in a decrease in myocardial workload and hence oxygen requirements. ## kinetics **S/L:** - Initial effects sublingually occur in **30 seconds to 2 minutes**. - Maximum effects are seen within **5-10 minutes** - Duration of effect is around **15-30 minutes.** **transdermal:** - drug reaches heart and periphery before being metabolised in liver **IV**: - A therapeutic effect is apparent within **1-2 minutes of intravenous administration** - the duration of action following a single intravenous dose of glyceryl trinitrate is about **3 to 5 minutes**. ADME: Distribution - high Vd, 3L/kg metabolism: - In smooth muscle cells the nitrate group is cleaved to inorganic nitrite and then to nitric oxide (which is thought to be responsible for glyceryl trinitrate's vasodilator effect). - In the liver GTN undergoes _rapid_ hydrolysis by glutathione organic nitrate reductase to dinitrates and mononitrates. > Glyceryl trinitrate → dinitrates → mononitrates → glycerol and carbon dioxide. # contraindications / precautions - Hypotension - The elderly are particularly sensitive to the hypotensive effects of GTN. - Hypovolemia - Hypertrophic obstructive cardiomyopathy - Cardiac tamponade - Aortic or mitral stenosis  - Avoid in ICH ; can ↑ ICP - Cor pulmonale - Known hypersensitivity to glyceryl trinitrate or a known idiosyncratic reaction to organic nitrates - Patients taking Phosphodiesterase - type 5 inhibitors for erectile dysfunction (e.g. sildenafil (or “Viagra”), tadalafil and vardenafil). These agents potentiate the vasodilatory effects of glyceryl trinitrate and may result in severe hypotension. Remove nitrate patches before defibrillation or cardioversion. - Plastic containers: - Glyceryl trinitrate is readily absorbed into many plastics, including the polyvinyl chloride (PVC) tubing comprising most IV sets in general use. - Glyceryl Trinitrate IV solutions should therefore only be stored in **glass** parenteral solution bottles. - Infusions should not be prepared until just before being needed for use. Pregnancy: B2 - From the limited information available, glyceryl trinitrate use in pregnancy has not been associated with an increased risk of fetal malformations # Side effects - Hypotension: Including orthostatic hypotension. - Tachycardia - Headache - Flushing - Tolerance (i.e **tachyphylaxis**): - This may occur with prolonged and continuous dosing. - [[Methemoglobinemia|Methaemoglobinaemia]] - With excessive dosing or deliberate overdose. - Impaired oxygenation at high doses: - Occasionally, high dose GTN may lead to some impairment of arterial oxygenation due to increased pulmonary shunting (to non-ventilated regions of lung). # Evidence ## Nitrites for ischemia - [Cochrane 2009: Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event.](bookends://sonnysoftware.com/ref/DL/51116) - For 1000 patients treated with nitrates, 4 to 8 deaths were prevented during the first 2 days of this acute event. - The ACE-inhibitors class also decrease mortality when continued for 10 days (3 to 5 deaths prevented per 1000). - No other class of drug showed a reduction in mortality. > GTN is not a *treatment* and does NOT improve prognosis (see ISIS-4 and GISSI-3 studies), but can help improve symptoms. My personal practice is to use it for ischaemic chest pain with extreme prejudice in ED due to: > 1. Hypotension in any patient > 2. Risk of [[STEMI ECG patterns#right ventricular|RV infarct]] in patients with equivocal inferior STEMI > 3. Often language barrier may preclude clarity about whether they are taking a contraindicated medication such as phosphodiasterase 5 inhibitor (eg viagra/sildenafil). ## nitrites for APO - [Australian prescriber 2017: Managing acute pulmonary oedema](bookends://sonnysoftware.com/ref/DL/57102) - no clear benifit of nitrates over lasix # Dosing ## sublingual Glyceryl trinitrate **spray** 400 micrograms sublingually - Repeat every 5 minutes if pain persists, up to a maximum of 1200 micrograms, (i.e. 3 sprays). OR Glyceryl trinitrate **tablet** 300 (i.e. half a tablet) - 600 micrograms sublingually - Repeat every 5 minutes if pain persists, up to a maximum of 1800 micrograms (i.e. 3 tablets). ## Transdermal patch dose rates Glyceryl trinitrate **5 - 15 mg/ 24 hours** transdermally, **once daily** applied for a **maximum of 14 hours** in a 24 hour period. Removing patches overnight is to prevent nitrate tolerance from developing. Patches are applied to the chest or upper arm. | Patch | release rate | approx mcg/min | | :------------------------- | :---------------------- | :------------- | | nitro 25 (or nitro dur 5) | 5mg/24 h<br>(0.21mg/h) | 3.5mcg/min | | nitro 50 (or nitro dur 10) | 10mg/24h<br>(0.42mg/h) | 7mcg/min | | nitro dur 15 | 15mg/24h<br>(0.625mg/h) | 10.4mcg/min | ## IV - Commence infusions at a rate of **5 microgram/minute**.  > **The maximum upper limit is generally taken as 200 mcg/min.** ### For ACS - 10 micrograms/minute IV infusion, increasing by 10 micrograms/minute every 3 minutes until pain is controlled, providing systolic blood pressure is 90 mm Hg or more. ### For APO - 10 micrograms/minute IV infusion, increasing by **doubling the infusion rate every 5 minutes according to clinical response** and maintaining systolic blood pressure at more than 90 mm Hg # IV preparation - Add **30 mg** glyceryl trinitrate to **500mL 5%** **Dextrose.** - This gives a final concentration of **60 microgram/mL.** |dose mcg/min| rate mL/H| |---|---| |5|5| |10|10| |15|15| |...|...| |60|60|