Uses

Sodium nitroprusside is usually administered as a 0.005–0.02% (50–200 μg/ml) intravenous infusion, the dose of 0.5–6 μg.kg⁻¹.min⁻¹ being titrated to effect.

Mechanism of Action

Sodium nitroprusside vasodilates arteries and veins by the production of nitric oxide (NO). This activates the enzyme guanylate cyclase leading to increased levels of intracellular cyclic guanosine monophosphate (cGMP). Although Ca²⁺ influx into vascular smooth muscle is inhibited, its uptake into smooth endoplasmic reticulum is enhanced so that cytoplasmic levels fall, resulting in vasodilation.

Effects

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  Cardiovascular – arterial vasodilation reduces the systemic vascular resistance and leads to a drop in blood pressure. Venous vasodilation increases the venous capacitance and reduces preload. Cardiac output is maintained by a reflex tachycardia. However, for those patients with heart failure the reduction in pre- and afterload will increase cardiac output with no increase in heart rate. The ventricular wall tension and myocardial oxygen consumption are reduced. It has no direct effects on contractility. Some patients develop tachyphylaxis, the exact mechanism of which is unclear.

  
  
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  Respiratory – SNP may inhibit pulmonary hypoxic vasoconstriction and lead to increased shunt. Supplemental oxygen may help.

  
  
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  Central nervous system – intracranial pressure is increased due to cerebral vasodilation and increased cerebral blood flow. However, cerebral autoregulation is maintained well below the normal limits during SNP infusion.

Kinetics

Sodium nitroprusside is not absorbed following oral administration. It has a short half-life and its duration of action is less than 10 minutes. However, the half-life of thiocyanate (SCN) is 2 days.

Metabolism

The metabolism of SNP is complicated (see Figure 16.1). Initially within the red blood cell it reacts with oxyhaemoglobin to form NO, five CN⁻ ions and methaemoglobin. The methaemoglobin may then combine with CN⁻ to form cyanomethaemoglobin, which is thought to be non-toxic.

Figure 16.1 Metabolism of sodium nitroprusside (SNP). CN^–, cyanide; SCN, thiocyanate.

The remaining CN⁻ is then able to escape from the red blood cell where it is converted in the liver and kidney by the mitochondrial enzyme rhodanase with the addition of a sulfhydryl group to form thiocyanate (SCN). Red blood cells contain the enzyme thiocyanate oxidase, which can convert SCN back to CN⁻, but most SCN is excreted in the urine. SCN has an elimination half-life of 2 days but this may increase to 7 days in the presence of renal impairment. Alternatively CN⁻ combines with hydroxycobalamin (vitamin B₁₂) to form cyanocobalamin, which forms a non-toxic store of CN⁻ and can be excreted in the urine.

Toxicity

The major risk of toxicity comes from CN⁻, although SCN is also toxic. Free CN⁻ can bind cytochrome oxidase and impair aerobic metabolism. In doing so a metabolic acidosis develops and the mixed venous oxygen saturation increases as tissues become unable to utilise oxygen. The management of CN⁻ toxicity involves halting the SNP infusion and optimising oxygen delivery to tissues. Three treatments are useful:

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  Dicobalt edetate, which chelates CN⁻ ions.

  
  
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  Sodium thiosulfate, which provides additional sulfhydryl groups to facilitate the conversion of CN⁻ to SCN. This is sometimes used as prophylaxis.

  
  
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  Nitrites – either sodium nitrite or amyl nitrite will convert oxyhaemoglobin to methaemoglobin, which has a higher affinity for CN⁻ than cytochrome oxidase. While vitamin B₁₂ is required to complex CN⁻ to cyanocobalamin, it is of little value in the acute setting. It is, however, sometimes used as prophylaxis.

Presentation

Glyceryl trinitrate is prepared in the following formulations: an aerosol spray delivering 400 μg per metered dose and tablets containing 300–600 μg, both used sublingually, as required. Modified-release tablets containing 1–5 mg for buccal administration are placed between the upper lip and gum and are used at a maximum dose of 5 mg tds while the 2.6–10 mg modified-release tablets are to be swallowed and used at a maximum dose of 12.8 mg tds. The transdermal patch preparation releases 5–15 mg/24 hours, and should be resited at a different location on the chest. The clear colourless solution for injection contains 1–5 mg.ml⁻¹ and should be diluted to a 0.01% (100 μg/ml) solution before administration by an infusion pump and is used at 10–200 μg.min⁻¹. GTN is absorbed by polyvinyl chloride; therefore, special polyethylene administration sets are preferred. GTN will explode if heated so transdermal preparations should be removed before DC cardioversion.

Uses

Glyceryl trinitrate is used in the treatment and prophylaxis of angina, in left ventricular failure associated with myocardial infarction and following cardiac surgery. It has also been used in the control of intra-operative blood pressure and for oesophageal spasm.

Mechanism of Action

Glyceryl trinitrate vasodilates veins by the production of nitric oxide. This activates the enzyme guanylate cyclase leading to increased levels of intracellular cyclic GMP. Although Ca²⁺ influx into vascular smooth muscle is inhibited, its uptake into smooth endoplasmic reticulum is enhanced so that cytoplasmic levels fall resulting in vasodilation (see Figure 16.2).

Figure 16.2 Metabolism of glyceryl trinitrate (GTN).

Effects

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  Cardiovascular – in contrast to SNP and despite a similar mechanism of action, GTN produces vasodilation predominantly in the capacitance vessels, that is, veins, although arteries are dilated to some extent. Consequently, it produces a reduction in preload, venous return, ventricular end-diastolic pressure and wall tension. This in turn leads to a reduction in oxygen demand and increased coronary blood flow to subendocardial regions and is the underlying reason for its use in cardiac failure and ischaemic heart disease. The reduction in preload may lead to a reduction in cardiac output although patients with cardiac failure may see a rise in cardiac output. Postural hypotension may occur. At higher doses systemic vascular resistance falls and augments the fall in blood pressure which, while reducing myocardial work, will reduce coronary artery perfusion pressure and time (secondary to tachycardia). Coronary artery flow may be increased directly by coronary vasodilation. Tolerance develops within 48 hours and may be due to depletion of sulfhydryl groups within vascular smooth muscle. A daily drug-free period of a few hours prevents tolerance. It has been suggested that infusion of acetylcysteine (providing sulfhydryl groups) may prevent tolerance.

  
  
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  Central nervous system – an increase in intracranial pressure and headache resulting from cerebral vasodilation may occur but is often only problematic at the start of treatment.

  
  
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  Gut – GTN relaxes the GI sphincters including the sphincter of Oddi.

  
  
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  Haematological – rarely methaemoglobinaemia is precipitated.

Kinetics

Glyceryl trinitrate is rapidly absorbed from sublingual mucosa and the GI tract although the latter is subject to extensive first-pass hepatic metabolism resulting in an oral bioavailability of less than 5%. Sublingual effects are seen within 3 minutes and last for 30–60 minutes. Hepatic nitrate reductase is responsible for the metabolism of GTN to glycerol dinitrate and nitrite (NO²⁻) in a process that requires tissue thiols (R-SH). Nitrite is then converted to NO, which confers its mechanism of action (see above). Under certain conditions nitrite may convert oxyhaemoglobin to methaemoglobin by oxidation of the ferrous ion (Fe²⁺) to the ferric ion (Fe³⁺).