Peripheral Vasodilators


Preload reduction

Afterload reduction

Decreased pulmonary venous congestion

Reduction in ventricular wall stress

Decreased ventricular wall stress

Increased coronary blood flow

Increased coronary blood flow

Enhanced oxygen delivery

Improved myocardial oxygen delivery

Improved systolic contractile function

Reduction in mitral regurgitation


Vasodilators work by reducing preload, afterload, or both preload and afterload. Preload reduction results in decreased intraventricular pressures and improved myocardial oxygen delivery. Afterload reduction results in decreased work for the heart which improves hemodynamics in patients with heart failure




Table 16.2
Classification of systemic vasodilators

























Therapeutic objective

Medication

Arterial vasodilation

(Decreased afterload)

Hydralazine

Fenoldopam

Venous vasodilation

(Decreased preload)

Nitroglycerin

Mixed

(Decreased afterload and preload)

Nitroprusside

ARBs (e.g., losartan)

ACEI (e.g., enalapril)


ARB angiotensin receptor blocker, ACEI angiotensin-converting enzyme inhibitors



Nitroglycerin



Class: Antianginal Agent, Nitrate, Vasodilator


Nitroglycerin is originally discovered in 1847 by Swedish Scientist Dr. Sobrero by interacting glycerol, nitric acid, and sulfuric acid. Originally discovered as an explosive, nitroglycerin was quickly shown to relieve the chest pain associated with angina pectoris. The exact mechanism for the pain relief remained a mystery for greater than 100 years. It is now known that nitroglycerin releases nitric oxide from vascular smooth muscle cells, which initiates a cascade of events that results in venous relaxation. The investigator Ferid Murad won the Nobel Prize in 1998 for his discovery (along with Robert F. Furchgott, Louis J. Ignarro) [5].


Mechanism of Action


Nitroglycerin binds to the surface of endothelial cells and acts as substrate for formation of nitric oxide (NO). The nitric oxide then moves out of the endothelial cells and binds with its receptor on smooth muscle cell (Fig. 16.1). Once inside the smooth muscle cells, NO converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The cGMP reduces cytosolic calcium levels by two mechanisms: First, cGMP-dependent protein kinase G is activated which prevents calcium entry into the cell. Second, mitochondrial uptake of calcium is simulated. The overall effect is decreased intracellular calcium levels resulting in smooth muscle cell relaxation [5].

A310120_1_En_16_Fig6_HTML.jpg


Fig. 16.1
Mechanism of action of nitric oxide (NO) induced vasodilation. NO activates the cytosolic guanylate cyclase, to form cyclic guanosine monophosphate, which in turn activates protein kinases. These kinases block calcium entry inside the cell and enhance migration of calcium to intracellular stores resulting in vasodilation. NO nitric oxide, GC guanylyl cyclase, cGMP cyclic GMP


Indications


The primary indication of nitroglycerin is the treatment and prevention of acute chest pain associated with angina pectoris. Acute onset of chest pain can be treated with quickly dissolving sublingual tablets (0.3–0.6 mg) or oral spray (0.4–0.8 mg) administered every 5 min until pain is relieved up to three doses within 15 min [6]. Prevention of pain can be achieved with quickly acting sublingual tablets (0.3–0.6 mg) or oral spray (0.4–0.8 mg) just prior to activity, or extended release tablets (isosorbide-5-mononitrate). The IV form of nitroglycerin is indicated for persistent unstable angina that is poorly responsive to oral form, congestive heart failure with acute MI, hypertensive emergency with acute pulmonary edema, and induction of intraoperative hypotension. Start 10–20 mcg/min and titrate up by 5–10 mcg/min every 5–10 min until desired effect. The maximum dose is 500 mcg/min [7]. Not recommended in pediatrics. Pregnancy safety: Category C, not known if it is secreted in breast milk.


Drug Interactions and Contraindications


Nitroglycerin decreases the anticoagulation effect of heparin, increases the paralytic effect of pancuronium, and potentiates the vasodilatory effect of phosphodiesterase inhibitors which can result in vasodilatory shock. Patients taking ASA >500 mg may have decreased metabolism of nitroglycerin. Nitroglycerin is contraindicated in hypersensitivity to nitrates, glaucoma and hypovolemia, head trauma, constrictive pericarditis, and cardiac tamponade.


Side Effects


The most common side effect is headache, which can be persistent and severe due to dilation of cerebral blood vessels. Other side effects include postural hypotension, tachycardia, syncope, palpitation, anxiety, dizziness, vertigo, anxiety, and weakness. Most of these side effects are related to excessive vasodilation.


Clinical Pearls




I.

Nitroglycerine is the first-line treatment of acute chest pain.

 

II.

Must use nonabsorbable infusion set because of absorption of the nitroglycerine by standard PVC tubing.

 

III.

Warn patients about the most common side effects of nitroglycerine: headache, orthostatic hypotension, and dry mouth.

 

IV.

Administration of IV nitroglycerine requires continuous hemodynamic monitoring.

 

V.

Administration of nitroglycerine with other vasodilators can precipitate a shock state.

 


Nitroprusside (SNP)



Class: Antihypertensive, Nitrate, Vasodilator


The first recorded use of sodium nitroprusside (SNP) in humans was in 1928; however, FDA approval was delayed until 1974, because of safety concern over cyanide toxicity. SNP is a rapidly acting (<30 s) powerful vasodilator, which affects both arterial and venous smooth muscle cells. In addition to its quick onset, the vasodilatory effect of SNP ceases within 1–3 min of discontinuing the infusion.


Mechanism of Action


Sodium nitroprusside is comprised of five cyanide moieties and one nitrosyl group. Once infused, it converts oxyhemoglobin (Fe++) to methemoglobin (Fe+++) and releases cyanide and NO moieties. Unlike nitroglycerin, SNP directly generates NO, which relaxes vascular smooth muscle by a similar mechanism described above. The cyanide moiety is converted to thiocyanate by thiosulfate sulfurtransferase within the liver. The conversion of cyanide to thiocyanate utilizes sulfur stores. Depletion of sulfur stores by malnutrition or in postoperative patients facilitates accumulation of cyanides and increases the risk of developing cyanide toxicity. The metabolite thiocyanate is excreted in the urine [8].


Indications


The rapid onset of action makes SNP ideal for the treatment of hypertensive crisis. The short duration of action allows SNP to be utilized for deliberate hypotension in a variety of surgical procedures, such as major spinal surgery.


Dosing Options


The only route of administration of SNP is via an intravenous infusion. The dosing for pediatrics and adults is the same. The initial infusion rate is started low at 0.3 g/kg/min and is titrated up every few minutes to a maximum does of 10 g/kg/min [9]. It is not indicated in patients with renal impairment (creatinine clearance <10 ml/min). The use of higher doses limited to a maximum duration of 10 min. Nitroprusside should not be given to pregnant women. It is not known if SNP and its metabolites are excreted in human milk [6].


Drug Interactions and Contraindications


The most common side effects are hypotension, palpitations, restlessness, retching, retrosternal discomfort, and muscle twitching which are related to rapid reduction of blood pressure and disappear once infusion is discontinued. Less commonly seen are the following: significant methemoglobinemia whose incidence increases when the maximum recommended dose of 10 g/kg/min is infused for more than 16 h and when medications such as benzocaine and lidocaine that cause methemoglobinemia are concurrently administered. The administration of >2 mcg/kg/min in patients with renal insufficiency or administration at the maximum dose for greater than 24 h can increase the risk of cyanide toxicity [9]. The signs and symptoms of cyanide toxicity (>5 mg/dl) include metabolic acidosis, nausea, mental confusion, and muscle weakness. The degree of pulmonary shunting can also increase due to SNP attenuating the normal physiologic response of pulmonary artery constriction to hypoxia.


Clinical Pearls




I.

Methemoglobinemia should be suspected in patients exhibiting low oxygen saturation (~85 %) despite adequate cardiac output and PO2. Pay attention at chocolate color blood while taking ABG sample [8].

 

II.

Cyanide toxicity is a clinical diagnosis because cyanide level assay is technically difficult to perform and metabolic acidosis is a lagging indicator. In an awake, spontaneously breathing patient, their breath will smell like almonds and the patient will suddenly become confused. Suspicion should be high when the drug’s hypotensive effect is gone despite increased infusion rates. Treatment should include stopping the infusion, mechanical ventilation with 100 % oxygen, and administering sodium thiosulfate (150 mg/kg over 15 min) or 3 % sodium nitrate (5 mg/kg over 5 min) [10].

 

III.

If blood pressure is not controlled by the maximum rate after 10 min, check acid-base balance and venous oxygen concentration for evidence of cyanide toxicity; however, these indicators are not reliable.

 

IV.

Nitroprusside administration is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because these patients are unable to clear methemoglobin [11].

 


Hydralazine



Class: Antihypertensive, Arterial Vasodilator


Hydralazine is a direct arteriolar vasodilator with almost no effect on the venous circulation. It was discovered in 1950 by Franz Gross. The increase in renal blood flow despite the fall in blood pressure has been considered a unique feature of this drug [12].


Mechanism of Action


Hydralazine reduces afterload by causing arterial vasodilation. The decrease in diastolic blood pressure is greater than the decrease in the systolic blood pressure. Some studies suggest that potassium channels are opened for prolonged period causing hyperpolarization of the smooth muscle cells. Another proposed mechanism involves the production of NO stimulating cGMP as described previously [13]. Lastly, hydralazine has been shown to interfere with the release of calcium from the endoplasmic reticulum which inhibits vasoconstriction.


Indications


Hydralazine specifically dilates arteries which minimizes orthostatic hypotension that is associated with other vasodilators. Renal flow is usually maintained or slightly increased by hydralazine making it an ideal medication to use in patients with renal disease; however, clearance is dependent on renal function. Similarly, hydralazine is a first-line medication for the treatment of preeclampsia because it slightly increases uteroplacental blood flow. The reduction of afterload by this drug is beneficial for treatment of congestive heart failure when conventional therapy fails.

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Sep 18, 2016 | Posted by in ANESTHESIA | Comments Off on Peripheral Vasodilators
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