Nitropress

NITROPRESS Info

__Sodium Nitroprusside Info__ __Katsung__ CYCLIC GUANOSINE MONOPHOSPHATE (CGMP) Unlike cAMP, the ubiquitous and versatile carrier of diverse messages, cGMP has established signaling roles in only a few cell types. In intestinal mucosa and vascular smooth muscle, the cGMP-based signal transduction mechanism closely parallels the cAMP-mediated signaling mechanism. Ligands detected by cell-surface receptors stimulate membrane-bound guanylyl cyclase to produce cGMP, and cGMP acts by stimulating a cGMP-dependent protein kinase. The actions of cGMP in these cells are terminated by enzymatic degradation of the cyclic nucleotide and by dephosphorylation of kinase substrates. Increased cGMP concentration causes relaxation of vascular smooth muscle by a kinase-mediated mechanism that results in dephosphorylation of myosin light chains (see Figure 12–2). In these smooth muscle cells, cGMP synthesis can be elevated by two transmembrane signaling mechanisms utilizing two different guanylyl cyclases. Atrial natriuretic peptide, a blood-borne peptide hormone, stimulates a transmembrane receptor by binding to its extracellular domain, thereby activating the guanylyl cyclase activity that resides in the receptor's intracellular domain. The other mechanism mediates responses to nitric oxide (NO; see Chapter 19), which is generated in vascular endothelial cells in response to natural vasodilator agents such as acetylcholine and histamine. After entering the target cell, nitric oxide binds to and activates a cytoplasmic guanylyl cyclase (see Figure 19–2). A number of useful vasodilating drugs, such as nitroglycerin and sodium nitroprusside used in treating cardiac ischemia and acute hypertension, act by generating or mimicking nitric oxide. Other drugs produce vasodilation by inhibiting specific phosphodiesterases, thereby interfering with the metabolic breakdown of cGMP. One such drug is sildenafil, used in treating erectile dysfunction (see Chapter 12). (pg48 CH2) SODIUM NITROPRUSSIDE Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle (Figure 12–2). In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.

Pharmacokinetics & Dosage Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into red blood cells with liberation of cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney. Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. The drug is given by intravenous infusion. Sodium nitroprusside in aqueous solution is sensitive to light and must therefore be made up fresh before each administration and covered with opaque foil. Infusion solutions should be changed after several hours. Dosage typically begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/min as necessary to control blood pressure. Higher rates of infusion, if continued for more than an hour, may result in toxicity. Because of its efficacy and rapid onset of effect, nitroprusside should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording. Toxicity Other than excessive blood pressure lowering, the most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted. In a few cases, toxicity after relatively low doses of nitroprusside suggested a defect in cyanide metabolism. Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide. Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. Both have been advocated for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion. Thiocyanate may accumulate over the course of prolonged administration, usually several days or more, particularly in patients with renal insufficiency who do not excrete thiocyanate at a normal rate. Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions, and the diagnosis is confirmed by finding serum concentrations greater than 10 mg/dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate inhibition of iodide uptake by the thyroid. Methemoglobinemia during infusion of nitroprusside has also been reported. (pg235 CH11) Nitroprusside (generic, Nitropress) Parenteral: 50 mg/vial (pg245 CH11) __Lipincott’s Illustrated Review of Pharmacology__ A. Sodium nitroprusside Nitroprusside [nye-troe-PRUSS-ide] is administered intravenously and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension (Figure 19.14). The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. [Note: Because nitroprusside also acts on the veins, it can reduce cardiac preload.] Nitroprusside is metabolized rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. [Note: Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.] Nitroprusside is light sensitive, and when in solution, it should be protected from light. (pg417)

__Stoeling & Hiller__ SNP is a direct-acting, nonselective peripheral vasodilator that causes relaxation of arterial and venous vascular smooth muscle. Its onset of action is almost immediate, and its duration of action is transient, requiring continuous intravenous infusion to maintain a therapeutic effect. SNP interacts with oxyhemoglobin, dissociating immediately and forming methemoglobin while releasing cyanide and NO. NO is the active mediator responsible for the direct vasodilating effect of SNP. Metabolism of SNP begins with the transfer of an electron from the iron of oxyhemoglobin to SNP, yielding methemoglobin and an unstable SNP radical. The unstable SNP radical breaks down, resulting in the nonenzymatic release of all five cyanide ions, one of which reacts with methemoglobin to form cyanomethemoglobin. Cyanide toxicity reflects the cyanide binding of tissue cytochrome oxidase, resulting in prevention of oxidative phosphorylation. Increased cyanide concentrations may precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis. Cyanide toxicity should be suspected in any patient who is resistant to the hypotensive effects of the drug despite maximum infusion rates (>2 Â"g/kg/minute or 10 Â"g/kg/minute for longer than 10 minutes) or in a previously responsive patient. Mixed venous PO2 is increased in the presence of cyanide toxicity, thus indicating paralysis of cytochrome oxidase. Plasma lactate concentrations are increased. No evidence suggests that preexisting hepatic or renal disease increases the likelihood of cyanide toxicity. Thiocyanate toxicity is rare, because thiocyanate is 100-fold less toxic than cyanide. Clinical evidence of neurotoxicity produced by thiocyanate includes hyperreflexia, confusion, and psychosis.
 * // SODIUM NITROPRUSSIDE //**
 * // Mechanism of Action //**
 * // Metabolism //**
 * // Toxicity Cyanide Toxicity //**
 * // Treatment //**** (Table 16-4) ****// Thiocyanate Toxicity //**

Methemoglobinemia is unlikely, as it requires doses of SNP that exceed 10 mg/kg. Patients receiving high doses of SNP who present with evidence of impaired oxygenationdespite an adequate cardiac output and arterial oxygenation should have methemoglobinemia considered in the differential diagnosis. When protected from light, the in vitro breakdown of SNP to cyanide is not excessive in the first 24 hours after the solution of SNP is prepared. SNP produces direct venous and arterial vasodilation, resulting in prompt decreases in systemic blood pressure. Systemic vascular resistance is decreased, as evidenced by arterial vasodilation, whereas venous return is decreased because of vasodilation of venous capacitance vessels. Although decreased venous return would tend to decrease cardiac output, the net effect is often an increase in cardiac output due to reflex- mediated increases in peripheral sympathetic nervous system activity (tachycardia) combined with decreased impedance to left ventricular ejection. SNP-induced decreases in systemic blood pressure may result in decreases in renal function. SNP may increase the area of damage associated with a myocardial infarction (coronary steal).
 * // Methemoglobinemia //**
 * // Phototoxicity //**
 * // Dose and Administration //**** (Table 16-5) ****// Effects on Organ Systems //**
 * // Cardiovascular System //**

SNP is a direct vasodilator, leading to increased cerebral blood flow and cerebral blood volume. In patients with decreased intracranial compliance this may cause undesirable increases in intracranial pressure. Decreases in PaO2 may accompany the infusion of SNP and other peripheral vasodilators used to produce controlled hypotension (attenuation of hypoxic pulmonary vasoconstriction is the presumed mechanism). Increased intracellular concentrations of cGMP, as produced by SNP and nitroglycerin, may inhibit platelet aggregation. Infusion rates of SNP >3 Â"g/kg/minute may result in increased bleeding times. Increased bleeding time could also be the result of vasodilation secondary to a direct effect of SNP on vascular tone. The ability of SNP to rapidly and predictably decrease mean arterial pressure to desired levels makes this vasodilator a useful drug, especially during operations requiring nearly a bloodless field. Mean arterial pressures of 50 to 60 mmHg can be maintained in healthy patients without apparent complications (see Table 16-5).  SNP is more likely to be administered as a temporary initial treatment, with replacement by longer-lasting medications as soon as feasible.  SNP infusion, by virtue of decreasing left ventricular afterload, may be of benefit in the management of patients with mitral or aortic regurgitation or congestive heart failure and after acute myocardial infarction complicated by left ventricular failure. The surgical repair of thoracic aortic aneurysms, dissections, and coarctations may include SNP to attenuate the proximal hypertension associated with cross-clamping the aorta. Systemic hypertension during cardiac surgery is often treated with SNP, whereas SNP- induced vasodilation during the rewarming phase of cardiopulmonary bypass permits increased flow rates and improved heat delivery to peripheral tissues.
 * // Vasodilator Effects //**
 * // Hypoxic Pulmonary Vasoconstriction //**
 * // Platele //****// t Aggregation //**
 * // Clinical Uses Controlled Hypotension //**
 * // Hypertensive Emergencies //**
 * // Cardiac Disease //**
 * // Aortic Surgery //**
 * // Cardiac Surgery //**