Vasodilators & Nonadrenergic Inotropes

Question 1

**What potential side effect occurs with inamrinone, but not with milrinone?

Answer 1

Inamrinone (Inocor) can produce thrombocytopenia with long-term therapy. Milrinone (Primacor) does not produce any apparent effects on platelets.

Question 2

What are the cardiovascular actions of glucagon? What

second messenger is involved in these responses?

Answer 2

Glucagon increases myocardial contractility (has a positive inotropic effect) and heart rate. The positive inotropic and chronotropic effects of glucagon increase cardiac output. Glucagon increases intracellular levels of cyclic AMP by mechanisms independent of beta-adrenergic receptor stimulation.

Question 3

List three cardiac effects of digitalis.

Answer 3

Digitalis: (1) enhances myocardial contractility, (2) decreases heart rate, and (3) slows impulse propagation through the atrioventricular node. The decreased heart rate and slowed conduction through the atrioventricular node occur because digitalis enhances parasympathetic nervous system activity.

Question 4

What are the two principle clinical uses of digoxin?

Answer 4

Digoxin (digitalis) is used to treat congestive heart failure and to control supraventricular dysrhythmias (atrial tachycardia, atrial flutter, or atrial fibrillation).

Question 5

Digitalis produces its positive inotropic effect by what mechanism?

Answer 5

Digitalis inhibits the sodium-potassium pump. When the sodium-potassium pump is inhibited, sodium accumulates in the cell. As sodium accumulates intracellularly, a sodium-calcium exchange system (sodium out in exchange for calcium in) is accelerated. Hence, calcium accumulates in the cardiac cell. As calcium accumulates in the cardiac cell, contractility increases.

Question 6

In what phase of the cardiac cycle does digitalis work to slow heart rate?

Answer 6

Digitalis works in phase 4. Digitalis decreases automaticity and lowers heart rate. Automaticity is reflected in the slope of phase 4 depolarization. Digitalis decreases phase 4 depolarization by activating the parasympathetic nervous system.

Question 7

What are three signs of digitalis toxicity?

Answer 7

Signs of digitalis toxicity include: (1) atrial or ventricular cardiac dysrhythmias, (2) prolonged PR interval, and (3) gastrointestinal disturbances (anorexia, nausea, and vomiting).

Question 8

What three electrolyte disturbances enhance digitalis toxicity?

Answer 8

Hypokalemia, hypercalcemia and hypomagnesemia are electrolyte disturbances that increase the likelihood of digitalis toxicity.

Question 9

Why does hypokalemia enhance digitalis toxicity?

Answer 9

Hypokalemia allows increased binding of digitalis to the Na= K+ ATPase (pump) in cardiac cells, resulting in an excessive drug effect.

Question 10

Why should hyperventilation be avoided during anesthesia for the patient who is taking digitalis?

Answer 10

Hyperventilation may cause hypokalemia, and hypokalemia increases the likelihood of digitalis toxicity. Plasma potassium concentration decreases 0.5 mEq/L for each 10 mmHg decrease in PaC02.

Question 11

What are five uses of calcium entry blockers?

Answer 11

Calcium channel blockers are used to treat: (1) supraventricular tachydysrhythmias (verapamil); (2) essential hypertension; (3) coronary artery vasospasm (nifedipine and diltiazem); (4) angina pectoris, and (5) cerebral artery vasospasm (nimodipine).

Question 12

How does verapamil effect systemic vascular resistance (SVR) and heart rate?

Answer 12

Verapamil decreases both SVR (by relaxing vascular smooth muscle) and heart rate.

Question 13

Verapamil potentiates the actions of what drugs used in anesthesia?

Answer 13

Verapamil potentiates the actions of nondepolarizing and depolarizing muscle relaxants.

Question 14

Verapamil is contraindicated in what six patient groups?

Answer 14

Verapamil should not be given to patients with (1) Wolff- Parkinson White syndrome, (2) sick sinus syndrome, (3) atrioventricular block, or (4) heart failure. Verapamil should also be avoided or used cautiously in (5) patients on beta blockers, and (6) patients taking digitalis.

Question 15

Why is verapamil a poor choice when treating patients with Wolff-Parkinson-White syndrome?

Answer 15

Verapamil may increase conduction velocity in the accessory tract and increase heart rate excessively.

Question 16

Why should verapamil be avoided or used cautiously in the patient taking either a beta blocker (propranolol) or digitalis?

Answer 16

Verapamil and propranolol, or verapamil and digitalis, can produce complete heart block.

Question 17

What are the cardiovascular actions of diltiazem?

Answer 17

Diltiazem is a good coronary vasodilator but a poor peripheral vasodilator. Diltiazem also decreases heart rate.

Question 18

How does nifedipine affect systemic vascular resistance (SVR) and heart rate?

Answer 18

Nifedipine decreases systemic vascular resistance (SVR) and causes a reflex increase in heart rate.

Question 19

When would you use sublingual nifedipine?

Answer 19

Sublingual nifedipine might be used to treat intraoperative myocardial ischemia when hemodynamics are normal.

Question 20

Name four vasodilators that decrease blood pressure by direct effects on vascular smooth muscle independent of alpha or beta receptors.

Answer 20

Direct acting vasodilators are: (1) hydralazine, (2) nitroprusside, (3) nitroglycerin, and (4) diazoxide.

Question 21

Name four vasodilators that decrease blood pressure by direct effects on vascular smooth muscle independent of alpha or beta receptors.

Answer 21

Direct acting vasodilators are: (1) hydralazine, (2) nitroprusside, (3) nitroglycerin, and (4) diazoxide.

Question 22

How do the nitrovasodilators, nitroprusside and nitroglycerin, relax vascular smooth muscle? What substance is produced? What enzyme and what second messenger are involved?

Answer 22

Nitroprusside and nitroglycerin donate nitric oxide (NO). Nitric oxide (NO) activates the enzyme soluble guanylate cyclase, which increases the production of cyclic guanosine monophosphate {cGMP). Cyclic GMP, a second messenger, relaxes vascular smooth muscle, thereby promoting vasodilation and a decrease in blood pressure.

Question 23

What are four contraindications for using sodium nitroprusside?

Answer 23

Avoid nitroprusside if the patient has (1) liver disease, (2) kidney disease, (3) hypothyroidism, or (4) vitamin B-12 deficiency.

Question 24

What are acceptable nitroprusside doses? What are maximum acceptable nitroprusside infusion rates?

Answer 24

The acceptable dose range for IV nitroprusside is 0.25 - 10 mcg/kg/min. Begin IV infusion at 0.5 mcg/kg/min. Acceptable maximum infusion rates are 10 mcg/kg/min for 10 - 15 minutes or 2 mcg/kg/min for 1-3 hours or 0.5mg/kg/hr for chronic infusion.

Question 25

How is cyanide produced?

Answer 25

With high doses of nitroprusside, the ferrous iron of nitroprusside reacts with sulfhydryl groups in red blood cells and releases cyanide.

Question 26

**Sodium nitroprusside contains 5 cyanide ions (CN-) and may cause cyanide toxicity, as you know. What three reactions may cyanide ions (CN-) undergo?

Answer 26

Cyanide ions (CN-) may react in three ways: (1) binding to methemoglobin to form cyanomethemoglobin, (2) reaction with thiosulfate in the liver to produce thiocyandise, catalyzed by rhodanase, and (3) binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization by the tissues.

Question 27

**How do cyanide ions interfere with oxygen utilization at tissue cytochrome oxidase?

Answer 27

Binding of cyanide ions to tissue cytochrome oxidase uncouples oxidative phosphorylation, preventing the formation of ATP.

Question 28

**List the four hallmark signs and symptoms of cyanide toxicity.

Answer 28

Acute cyanide toxicity is characterized by (1) metabolic acidosis (base deficit), (2) cardiac arrhythmias, (3) increased venous oxygen content due to inhibition of cytochrome oxidase and consequent inability of cells to utilize oxygen, and (4) tachyphylaxis.

Question 29

What is the best indicator of cyanide toxicity?

Answer 29

Base deficit may be the best indicator of cyanide toxicity.
The metabolic acidosis accompanying cyanide toxicity “allows the observant practitioner to detect this cellular toxicity.” Arterial blood gases permit determination of the base deficit and hence may most accurately assess cyanide toxicity.

Question 30

How do you know when tachyphylaxis to nitroprusside has occurred?

Answer 30

When a patient is resistant to the hypotensive effects of nitroprusside despite increasing the infusion rate up to 8 micrograms/kg/min, one should suspect cyanide toxicity.

Question 31

What are four proposed mechanisms for tachyphylaxis

associated with the use of sodium nitroprusside?

Answer 31

Tachyphylaxis to sodium nitroprusside may occur because:
(a) the sympathetic nervous system is activated; (b) the renin-angiotensin system is activated-, (c) the release of vasopressin (antidiuretic hormone) is increased (recall that vasopressin is a potent vasoconstrictor); (d) cyanide released during metabolism of nitroprusside causes contraction of vascular smooth muscle which increases systemic vascular resistance (SVR).

Question 32

During a deliberate hypotensive technique, you have maintained mean arterial pressure (MAP) at 55 mmHg with
a sodium nitroprusside infusion. The MAP begins increasing and continues to increase despite increases in the dose of nitroprusside. What is happening? What is your first response?

Answer 32

Tachyphylaxis is developing. Your first action in response to evidence of cyanide toxicity is to discontinue the sodium nitroprusside.

Question 33

Tachyphylaxis develops during sodium nitroprusside infusion. After you have turned off the sodium nitroprusside, how should cyanide toxicity be treated? Explain how this treatment works.

Answer 33

Give sodium thiosulfate (150 mg/kg IV) over 15 minutes. Thiosulfate converts cyanide to thiocyanate.

Question 34

The patient shows evidence of cyanide toxicity. You have discontinued using sodium nitroprusside and have given thiosulfate. The patient’s status remains unstable and metabolic acidosis continues. What is your next step? Why?

Answer 34

If cyanide toxicity is severe after thiosulfate administration, with deteriorating hemodynamics and metabolic acidosis, the treatment is slow administration of sodium nitrate (5 mg/kg IV) or amyl nitrate (0.3 ml) by inhalation or direct injection into the anesthesia circuit to convert hemoglobin to methemoglobin. Methemoglobin converts cyanide to cyanmethemoglobin.

Question 35

**The patient administered sodium nitroprusside
continuously (by drip) presents with the following arterial blood gases (ABGs): pH = 7.21, PaCO2 = 32 mm Hg, PaO2 = 104 mm Hg, base excess = -10 mEq/L. What is your next action? Explain the arterial blood gases.

Answer 35

Turn off the nitroprusside drip. These ABGs suggest cyanide toxicity. The base excess of -10 mEq/L (base deficit of 10 mEq/L) demonstrates that the acidosis is metabolic. The low PaC02 of 32 mm Hg demonstrates partial respiratory compensation of the metabolic acidosis.

Question 36

When the nitroprusside infusion is started, you observe that Pa02 decreases. Why did this happen?

Answer 36

The infusion of nitroprusside or other direct acting vasodilators (nitroglycerin, hydralazine) is presumed to inhibit hypoxic pulmonary vasoconstriction (HPV). Shunt increases when HPV is inhibited, and the single consequence of an increased ventilation:perfusion mismatch (shunt in this case) is a decrease in Pa02.

Question 37

On what segments of the vascular tree does nitroprusside work to decrease blood pressure?

Answer 37

Nitroprusside decreases both preload (venodilation) and systemic vascular resistance (arterial dilation). Both actions lower arterial blood pressure.

Question 38

Where in the vascular tree is nitroglycerin’s prominent site of action? Can nitroglycerin produce cyanide toxicity?

Answer 38

Nitroglycerin acts primarily on venules, which decreases venous return secondary lo venodilation. Nitroglycerin cannot produce cyanide toxicity.

Question 39

The therapeutic benefit of nitroglycerin in the treatment of myocardial ischemia is attributable to what action? Explain.

Answer 39

The bulk of the evidence suggests that a reduction in myocardial work and thus reduced myocardial oxygen consumption is the primary effect of nitroglycerin in chronic stable angina. Nitroglycerin is a venodilator. Venodilation decreases preload, decreases stroke volume, and decreases cardiac output, which lowers blood pressure. The decreases in preload and stroke volume cause a decrease in myocardial work and oxygen consumption.

Question 40

Name three rapid-onset IV antihypertensive medications for use in an asthmatic patient.

Answer 40

Hydralazine, nitroprusside, nitroglycerin. These agents dilate the vasculature and also dilate bronchioles.

Question 41

What two types of drugs would you avoid in treating intraoperative hypertension in the asthmatic?

Answer 41

Avoid antihypertensive agents such as trimethaphan that release histamine, because histamine can cause bronchospasm. Non-selective beta-blockers such as propranolol should also be avoided because beta-2 receptor blockade can cause bronchoconstriction. Even esmolol, a cardioselective beta-1 antagonist, can cause problems because at higher doses it inhibits beta-2 receptors in bronchial smooth muscle.

Question 42

Where in the vascular tree does diazoxide work? How is diazoxide used? What is the disadvantage of diazoxide?

Answer 42

Diazoxide (Hyperstat) dilates arterial vessels more than venous vessels, thus decreasing afterload with little or no effect on preload. Diazoxide (1 -5 mg IV bolus) is used to treat hypertensive emergencies. It is not possible to titrate blood pressure to a given level with diazoxide, a disadvantage compared with nitroprusside, for example.

Question 43

How does hydralazine lower blood pressure? Are the actions of hydralazine greater on arterioles or veins?

Answer 43

Hydralazine, like nitroglycerin and nitroprusside, generates nitric oxide (NO) at the vascular wall. The second messenger, cyclic GMP, is produced and vasodilation results. Hydralazine works primarily on arterioles.

Question 44

How does hydralazine affect arterial blood pressure, arterial and venous smooth muscle tone, heart rate, stroke volume and cardiac output?

Answer 44

Hydralazine decreases blood pressure. It often decreases diastolic pressure more than systolic pressure. Hydralazine has a direct relaxant effect on vascular smooth muscle. It preferentially dilates arterioles over veins. Heart rate increases, reflecting a reflex baroreceptor-mediated increase in sympathetic nervous system activity owing to the decreases in blood pressure. Stroke volume and cardiac output also increase.

Question 45

What syndrome occurs in 10-20% of patients treated

chronically with hydralazine? Are these patients fast or slow acetylators?

Answer 45

A lupus erythematosus-like syndrome occurs, predominantly in patients who are slow acetylators.

Question 46

Which three of the following four antihypertensive agents may cause angina: hydralazine, nitroglycerin, sodium nitroprusside, trimethaphan (Arfonad)?

Answer 46

Hydralazine, nitroglycerin, and nitroprusside may cause angina. Angina is not cited in the textbooks as an adverse reaction to trimethaphan (Arfonad).

Question 47

Explain how hydralazine may promote angina.

Answer 47

Hydralazine, an arterial vasodilator, causes a reflex (baroreceptor reflex) increase in heart rate and contractility in response to the lowering of blood pressure. These compensatory responses (increased heart rate and contractility) are detrimental to the patient with coronary artery disease; angina can occur.

Question 48

Explain how nitroglycerin may promote angina.

Answer 48

Nitroglycerin may promote angina or increased angina if diastolic blood pressure falls excessively, resulting in a decrease in coronary perfusion and simultaneously an increase in myocardial oxygen consumption due to a baroreceptor-mediated increase in heart rate and myocardial contractility.

Question 49

Explain how sodium nitroprusside may cause angina.

Answer 49

Coronary steal may occur with sodium nitroprusside. Clinical evidence of coronary steal is the appearance of ischemic changes on the electrocardiogram. Decreases in diastolic blood pressure and coronary blood flow produced by sodium nitroprusside may also contribute to myocardial ischemia.