Drugs that modify ANS activity can be classified by their site of action and the mechanism of action or pathology (antihypertensives) for which they are administered.
- Cholinergic Drugs. Muscarinic agonists act at sites in the body where ACh is the neurotransmitter.
- Indirect Cholinomimetics. Anticholinesterases (neostigmine, pyridostigmine, edrophonium) inhibit activity of acetylcholinesterase, which normally destroys ACh by hydrolysis. As a result of this inhibition, ACh accumulates at muscarinic and nicotinic receptors. Simultaneous administration of an anticholinergic drug protects patients against undesired muscarinic effects (bradycardia, salivation, bronchospasm, intestinal hypermotility) without preventing the nicotinic effects of ACh (reversal of nondepolarizing muscle relaxants).
- Cholinergic Drugs. Muscarinic antagonist
refers to a specific drug action for which the term anticholinergic is often used (any drug that interferes with the action of ACh as a transmitter). Anticholinergic drugs (atropine, scopolamine, glycopyrrolate) interfere with the muscarinic actions of ACh by competitive inhibition of cholinergic postganglionic nerves.
- There are marked variations in sensitivity to anticholinergic drugs at different muscarinic sites.
- Central anticholinergic syndrome is characterized by symptoms that range from sedation to delirium, presumably reflecting inhibition of muscarinic receptors in the CNS by anticholinergics (this is unlikely with glycopyrrolate, which cannot easily cross the bloodbrain barrier). Treatment is with physostigmine. Its tertiary amine structure allows it to cross the bloodbrain barrier rapidly; other anticholinesterases are quaternary ammonium compounds that lack the lipid solubility necessary to gain prompt entrance into the CNS.
- Sympathomimetic Drugs. Catecholamines and sympathomimetic drugs continue to be the pharmacologic mainstay of cardiovascular support for the low-flow state (Table 15-3: Doses and Principal Sites of Action of Adrenergic Agonists). It is necessary to become familiar with only a few drugs to manage most clinical situations (Table 15-4: Hemodynamic Effects of Adrenergic Agonists). Low-
output syndrome is present when an individual has abnormalities of the heart, blood volume, or blood flow distribution. When low-output syndrome is present for more than 1 hour, it usually reflects all three abnormalities.
- Septic shock is the most common distributive abnormality, and volume repletion is an important initial consideration. Treatment of cardiogenic shock requires multiple autonomic interventions.
- Adverse Effects. Side effects of αagonists most often reflect excessive α- or β-receptor activity.
- Adrenergic Agonists
- Phenylephrine is considered a pure α agonist that produces greater venoconstriction than arterial constriction. As a result, venous return and blood pressure are increased (cardiac output may not increase owing to drug-induced bradycardia).
- Phenylephrine is favored in operating rooms to increase blood pressure during cardiopulmonary bypass, in patients with critical aortic stenosis or tetralogy of Fallot, and in those with hypotension during cesarean section.
- Phenylephrine is becoming the vasopressor of choice in obstetric practice. (Ephedrine crosses the placenta more easily and may worsen fetal pH and base excess.)
- Phenylephrine is administered as a single dose (50100 µg intravenously [IV]) to treat anesthetic-induced decreases in blood pressure and hypotension during cardiopulmonary bypass and as a continuous infusion to maintain perfusion pressure during cerebral and peripheral vascular procedures. Use of phenylephrine to maintain perfusion pressures during cerebral and peripheral vascular procedures must be done cautiously because it may evoke myocardial ischemia in susceptible patients.
- Norepinephrine and methoxamine produce similar dose-related hemodynamic effects characterized by greater αthan βeffects.
- Vasoconstriction increases systemic blood pressure but may also decrease tissue blood flow (especially renal blood flow) and increase myocardial oxygen requirements.
- Continuous infusion of norepinephrine (which must be through a centrally placed IV catheter) to maintain systolic blood pressure above 90 mm Hg requires invasive monitoring and attention to fluid management.
- In clinical conditions characterized by a low perfusion pressure and high flow (vasodilation) and maldistribution of flow, norepinephrine has been shown to improve renal and splanchnic blood flow by increasing perfusion pressure provided the patient has been volume resuscitated.
- Epinephrine. Whereas the αeffects of epinephrine predominate in renal and cutaneous vasculature to decrease blood flow, the βeffects increase blood flow to skeletal muscles.
- Cardiac dysrhythmias are a hazard of excess βstimulation. (Children tolerate higher subcutaneous doses than adults.)
- Epinephrine is administered to treat asthma (0.30.5 mg subcutaneously), treat cardiac arrest or life-threatening allergic reactions (0.30.5 mg IV), produce hemostasis (1:200,000 or 5 µg/mL injected subcutaneously or submucosally), prolong regional anesthesia (0.2 mg added to local anesthetic solutions for spinal block or as a 1:200,000 concentration for epidural block), or provide a bloodless arthroscopic field by large-volume infusions of dilute epinephrine-containing solutions (1:200,000).
- Intramuscular epinephrine is the preferred method of administration for treatment of anaphylaxis and moderate to serve croup.
- Ephedrine produces cardiovascular effects that resemble those produced by epinephrine; however, its potency is greatly decreased, although its duration of action is about 10 times longer than that of epinephrine. Venoconstriction is greater than arterial constriction; thus, venous return and cardiac output are improved. A βeffect increases heart rate and further facilitates cardiac output. The αand βeffects of ephedrine result in a modest and predictable increase in blood pressure.
- Tachycardia and cardiac dysrhythmias are possible but less likely to occur than after administration of epinephrine.
- Ephedrine is the most commonly used vasopressor (510 mg IV) to treat decreases in blood pressure produced by anesthesia (especially regional blocks).
- Ephedrine is now the second line of treatment for hypotension in obstetrics because it crosses the placenta and decreases the fetal pH.
- Isoproterenol is a nonspecific β-agonist that lacks α-agonist effects. Whereas cardiac output is increased by virtue of increases in heart rate as well as increased myocardial contractility, decreases in systemic vascular resistance contribute to decreased afterload.
- Myocardial ischemia may be evoked in vulnerable patients (increased myocardial oxygen requirements caused by tachycardia and increased myocardial contractility paralleled by decreased coronary oxygen delivery because of decreased diastolic blood pressure). Increases in cardiac output may be diverted to nonvital tissues such as skeletal muscles.
- Isoproterenol is most often administered as a continuous IV infusion for the treatment of congestive heart failure associated with bradycardia, asthma, or pulmonary hypertension. This catecholamine acts as a chemical cardiac pacemaker in the presence of complete heart block.
- Dobutamine is a synthetic catecholamine derived from isoproterenol that acts directly on β
1 receptors and does not cause norepinephrine release or stimulation of dopamine receptors. Weak α
1-agonist effects of dobutamine may be unmasked by β-blockade. Dobutamine produces a positive inotropic effect with minimal effects on heart rate and systemic vascular resistance (an advantage over isoproterenol).
- Increases in automaticity of the SA node and increases in conduction of cardiac impulses through the AV node and ventricles may occur, emphasizing the need for caution in administering this drug to patients with atrial fibrillation or other tachydysrhythmias. Dobutamine may increase heart rate more than epinephrine for a given increase in cardiac output.
- Dobutamine is most often administered (230 µg/kg/min IV) for its inotropic effects in patients with poor myocardial contractility, such as after cardiopulmonary bypass.
- At lower doses a decrease in systemic vascular resistance without a significant increase in chronotropism makes dobutamine the mainstay of inotropic therapy for septic shock in patients with myocardial dysfunction.
- Dopamine is an agonist at dopaminergic (0.52.0 µg/kg/min IV), β(210 µg/kg/min IV), and α(>10 µg/kg/min IV) receptors. Infusion rates above 10 µg/kg/min IV may produce sufficient vasoconstriction to offset desirable dopaminergic (increases renal blood flow) and β(increased cardiac output) receptor stimulation. The concept of renal dose dopamine (0.52.0 µg/kg/min IV) is considered outdated. Despite the apparent doseresponse dependency of dopamine, a wide variability of individual responses has been observed.
- Tachycardia and cardiac dysrhythmias occur infrequently. Extravasation of dopamine can produce gangrene. Pulmonary artery pressure may be increased, detracting from the use of dopamine in patients with right-sided heart failure. Insulin secretion is inhibited, explaining the common occurrence of hyperglycemia during infusion of dopamine.
- Dopamine is most often administered as a continuous IV infusion (210 µg/kg/min) for its inotropic and diuretic effects in patients with poor myocardial contractility, such as after cardiopulmonary bypass.
- Combination therapy is most often with dopamine and dobutamine in an attempt to maximize positive inotropic effect with less vasoconstriction.
- Fenoldopam is a selective dopamine1 agonist with no αor βactivity compared with dopamine.
- Clonidine is a centrally acting selective partial α
2 agonist. It is an antihypertensive drug by virtue of its ability to decrease central sympathetic outflow.
- Sedation, bradycardia, and dry mouth from sympatholytics are common. Abrupt discontinuation of clonidine, as before surgery, may result in rebound hypertension, especially if the daily dose is above 1.2 mg. This hypertension may be confused with a response to emergence from anesthesia, but it is typically delayed for about 18 hours. Transdermal administration of clonidine is an alternative to the oral route because an IV preparation is not available. Life-threatening hypertension after withdrawal may be treated with nitroprusside.
- In addition to its antihypertensive effect, clonidine administered preoperatively (5 µg/kg orally) attenuates SNS reflex responses, such as those associated with direct laryngoscopy or surgical stimulation, and greatly decreases anesthetic requirements (≥40%) for volatile drugs or opioids. When placed in the subarachnoid or epidural space, this drug produces analgesia that may be accompanied by sedation and bradycardia but not depression of ventilation.
- Dexmedetomidine is a more selective α
2 agonist than clonidine. A stereoselective ability to interact with receptors resulting in decreased anesthetic requirements is evidence for an anesthetic receptor.
- This drug produces excellent sedation (no depression of ventilation but upper airway obstruction may occur), produces analgesia, reduces blood pressure and heart rate (promotes hemodynamic stability), and greatly decreases plasma catecholamines.
- Dexmedetomidine is a valid alternative to other options for awake craniotomies because of its minimal respiratory effects and lack of impairment upon electroneurophysiologic monitoring.
- The loading infusion of 1 µg/kg is administered over 10 minutes in a monitored setting.