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Nitroprusside

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- causes smooth muscle relaxation by a direct action which is not mediated by the nervous system. Affects all smooth muscle not just vascular smooth muscle.
- effects due to nitroso (-NO) group
- arteriolar and venous dilator
- liberates nitric oxide spontaneously in solution and thus causes vasodilatation
- effect greatest in vessels where continuous endothelial production of NO is low. Low endogenous production of NO leads to up-regulation of guanylate cyclase in the vascular SM with consequent increased sensitivity to NO

Pharmacodynamics

CVS

- CO maintained or increased unless dose so high that pre-load is reduced
- HR rises usually (NB increase in HR may be early sign of toxicity)
- no effect on cardiac conducting system or myocardial contractility
- coronary artery blood flow is increased but ? myocardial oxygenation is reduced. ? coronary steal or cyanide-induced inhibition of cytochrome-oxidase or failure of autoregulation. ? myocardial oxygen demand decreased
- total peripheral resistance decreased despite compensatory rises in catecholamines and renin. However tachyphylaxis is common and this is probably due to activation of renin-angiotensin.
- CVP consistently reduced
- PAP falls but may show a rebound increase when treatment is withdrawn
- arterial BP falls but may also show rebound, probably due to raised plasma renin levels. Rebound can be attenuated by beta blockers
- tissue hypoxia may occur, due in part to precapillary dilatation without venular dilatation. This decreases the arteriolar-venular pressure gradient and thus the functional capillary density

RS

- increased alveolar dead space due to fall in PAP
- increased intra-pulmonary shunting, possibly also due to fall in PAP which results in increased proportion of blood going to alveoli with relatively poor ventilation

CNS

- decreased cerebrovascular resistance
- changes in cerebral blood flow largely mirror changes in arterial BP

Pharmacodynamics

Admin: IVI
Metab: - very short half-life (seconds)
- broken down into nitrite and 5 cyanide radicals by 3 mechanisms:

  • rapid reaction with Hb
  • slower reaction with sulphydryl groups, found widely in RBCs
  • very slow reaction with plasma

- nitrite then reacts with Hb to form metHb which in turn combines with one of the cyanide radicals to form cyanmetHb
- cyanide converted to thiocyanate by action of 2 enzymes: rhodanase (liver and kidney) and beta-mercaptopyruvate transferase (RBCs). Activity of the latter in humans is very low.. Conversion very slow
- vitamin B12 may be a rhodanase co-factor
- t1/2 of thiocyanate is about 1 week. Excreted largely unchanged

Toxicity

Thiocyanate

- may accumulate in long-term nitroprusside use because of slow elimination
- at levels > 100 mcg/ml may cause: drowsiness, lethargy, nausea and vomiting and muscle twitching progressing to convulsions and coma
- high concentrations suppress thyroid function

Cyanide

- rapidly enters RBCs and affects oxygen transport and tissue oxygenation by blocking the action of cytochrome oxidase and probably other enzymes
- warning signs: nausea, vomiting, disorientation, resistance to hypotensive action, tachycardia, metabolic (lactic) acidosis and elevation of venous oxygen tension
- toxicity increased in patients with renal or hepatic failure, nutritional deficiency, vit B12 deficiency, and following prolonged use
- ? in vivo cyanide not released from nitroprusside but instead released from aquapentacyanoferrate which is rapidly formed on exposure of nitroprusside to light and thus it is possible that higher doses of nitroprusside could safely be used. Also emphasizes the vital importance of protecting nitroprusside from light: for example, in sunlight 45% of nitroprusside may be converted to aquapentacyanoferrate within 2 hr and the resulting solution will certainly release cyanide at blood pH

Platelet function

- doses of 3 mcg/kg/min or more associated with dose-dependant decrease in platelet aggregation and increase in bleeding time

Dosage and administration

- dissolve powder in 5% dextrose immediately before use and carefully protect from light
- 0.01% solution commonly used
- recommended maximum cumulative dose: 1.5 mg/kg
- maximum rate 10 mcg/kg/min but to avoid toxicity infusion rate should not exceed 2mcg/kg/min for longer than 3 h

Indications

- hypertensive emergencies, except when there is acute myocardial ischaemia (GTN drug of choice). In acute aortic dissection should be used with concomitant beta blockade
- pre-eclampsia. Risk of fetal cyanide toxicity can be minimized by limiting dosage to < 4mcg/kg/min or the duration of infusion to 30 min.

Further reading

Chui PT, Low JM. Acute hypertension and vasodilators. In Oh TE, Intensive Care Manual, 4th ed.

Loan W.B., Drugs used for induced hypotension. In Dundee J.W., Clarke R.S.J. and McCaughey W. (eds.) Clinical Anaesthetic Pharmacology, pg386-90. Churchill Livingstone, Edinburgh, 1991

Vallance P., Endothelial regulation of vascular tone. Postgrad Med J 68: 697-701; 1992


© Charles Gomersall December 1999

 

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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