Drugs used for psychopharmacologic therapy include antidepressants, anxiolytics, lithium, antipsychotics, and anticonvulsants. The development of relatively safe and effective psychotherapeutic drugs has made it possible to effectively treat as ambulatory patients many individuals with depression and anxiety disorders. Antidepressants and anxiolytics are the drugs most likely to be prescribed by primary care physicians for the treatment of depression in adults. Lithium, anticonvulsants, and antipsychotic drugs are useful for treatment of bipolar disorders and psychotic disorders including schizophrenia. It is estimated that up to 10% of the population is treated for a depressive illness at some time in life, and mood disorders requiring antidepressant therapy are an increasingly frequent occurrence in the elderly population in whom side effects may be less well tolerated due to coexisting disease.
It is well accepted that anesthesia can be safely administered to patients being treated with drugs used to treat mental illness.1,2 There appears to be growing acceptance that the problem of drug interactions between psychopharmacologic drugs and drugs administered in the perioperative period is less than previously perceived and that past recommendations for discontinuation of antidepressant therapy are not justified. Nevertheless, it remains important to remain alert for potential drug interactions.3 This is particularly true in elderly patients who are at particular risk for toxicity.
Antidepressants
Considering the wide range of disorders for which antidepressant drugs are effective, the term antidepressant has become a misnomer (Table 43-1). The broad spectrum of effectiveness of antidepressants does not imply a common pathophysiology but rather reflects the diverse roles of monoamine neurotransmitters in the human nervous system.
Antidepressants are logically classified based on their chemical structures and their acute neuropharmacologic effects (Table 43-2). The precise mechanism by which antidepressants work is unknown, but they appear to act by altering noradrenergic neurotransmission and/or serotoninergic neurotransmission (see Table 43-2). This suggests that antidepressants work by increasing the amount of norepinephrine and serotonin in synapses. Nevertheless, the most important observation not explained by this hypothesis is the time course of clinical improvement. Neurobiologically, reuptake blockade or monoamine oxidase (MAO) inhibition (necessary for breakdown of free norepinephrine and serotonin) occurs promptly after initiation of antidepressant therapy, but clinical improvement typically does not occur for 2 to 4 weeks. Perhaps adaptive changes including downregulation of neurotransmitter receptors are necessary before evidence of clinical improvement appears.
Selective Serotonin Reuptake Inhibitors
The selective serotonin reuptake inhibitors (SSRIs) are the most broadly prescribed class of antidepressants and are the drugs of choice for the treatment of mild to moderate depression.4 SSRIs are the first-line pharmacotherapy for panic disorder and obsessive-compulsive syndrome. These drugs are also effective in treatment of social phobia and posttraumatic stress disorder. SSRIs that share the ability to block the reuptake of serotonin (and thus enhance serotonergic activity) include fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. Other newer SSRIs are believed to act on serotonin and norepinephrine pathways in the brain by a variety of mechanisms, including dual serotonin and norepinephrine reuptake blockade (venlafaxine) and α2-receptor blockade (mirtazapine).5 Different SSRIs have different side effect profiles, and patients who do not respond to one drug or who fail to tolerate the drug may do well on a different SSRI. Standard practice dictates trying several SSRIs before moving to another class of medication.
There is abundant evidence that serotonin receptors are involved in the etiology of anxiety. Potent inhibition of serotonin reuptake appears to be necessary for effectiveness in the treatment of obsessive-compulsive disorders. Compared with tricyclic antidepressants, SSRIs lack anticholinergic properties, do not cause postural hypotension or delayed conduction of cardiac impulses, and do not appear to have a major effect on the seizure threshold. Perhaps the most important advantage of SSRIs compared with tricyclic antidepressants is the relative safety of SSRIs when taken in overdose.6 The exception may be venlafaxine that may be similar to tricyclic antidepressants with respect to elevated overdose-associated risk associated with proconvulsant and cardiac side effects.7 Common side effects of SSRIs include insomnia, agitation, headache, nausea, and diarrhea. A prominent cause of noncompliance with SSRI therapy is drug-induced sexual dysfunction in both men and women (delayed ejaculation, anorgasmia, decreased libido).8
Abrupt discontinuation of SSRIs with short elimination half-times (paroxetine, venlafaxine) may be associated with dizziness, paresthesias, myalgias, irritability, insomnia, and visual disturbances. Tapering all SSRIs before discontinuance is recommended especially for drugs with short elimination half-times.9
In September 2004, the U.S. Food and Drug Administration recommended a “black box” warning for newer antidepressant drugs, primarily SSRIs.10 This warning is based on evidence that suicidal tendencies in children and adolescents may be increased in those age groups when they are treated with SSRIs. Nevertheless, the risk is small and many patients benefit from treatment with SSRIs emphasizing the need to individualize therapy.
Fluoxetine
Fluoxetine was the first SSRI introduced in the United States in 1988.11 The drug is commonly administered once daily in the morning to decrease the risk of insomnia. Because fluoxetine has a prolonged elimination half-time (1 to 3 days for acute administration and 4 to 6 days for chronic administration), the drug can be taken every other day. An active metabolite, norfluoxetine, has an elimination half-time of 4 to 16 days. A therapeutic effect produced by fluoxetine is usually evident in 2 to 4 weeks. Because of this drug’s prolonged elimination half-time, increases in dosage are often limited to no more often than once every 4 weeks.
Side Effects
The most common side effects of fluoxetine are nausea, anorexia, insomnia, sexual dysfunction, agitation, and neuromuscular restlessness, which may mimic akathisia. Appetite suppression associated with fluoxetine therapy may help patients achieve weight loss.12 Like tricyclic antidepressants, fluoxetine may be an effective analgesic for treatment of chronic pain as may be associated with rheumatoid arthritis.13 Fluoxetine does not cause hypotension, and changes in conduction of cardiac impulses seem infrequent. Bradycardia causing syncope has been reported in occasional elderly patients.14 Because of its long elimination half-time, fluoxetine should be discontinued for about 5 weeks before initiating treatment with an MAO inhibitor. The long elimination half-time of fluoxetine appears to prevent withdrawal symptoms induced by abrupt discontinuance of the drug. An overdose with fluoxetine alone is not associated with the risk of cardiovascular and central nervous system (CNS) toxicity.
Drug Interactions
Among the SSRIs, fluoxetine is the most potent inhibitor of certain hepatic cytochrome P-450 enzymes. As a result, this drug may increase the plasma concentrations of drugs that depend on hepatic metabolism for clearance. For example, the addition of fluoxetine to treatment with a tricyclic antidepressant drug may result in a two- to fivefold increase in the plasma concentration of the tricyclic drug. Neuroleptic drugs may inhibit the metabolism of fluoxetine or vice versa. Several cardiac antidysrhythmic drugs as well as some β-adrenergic antagonists may be metabolized by the same enzyme system that is inhibited by fluoxetine, resulting in potentiation of these drug effects. MAO inhibitors combined with fluoxetine may cause the development of a serotonin syndrome characterized by anxiety, restlessness, chills, ataxia, and insomnia.14 The combination of fluoxetine and lithium or carbamazepine may also provoke this potentially fatal syndrome.
Sertraline
Sertraline was the second SSRI introduced in the United States and has a spectrum of efficacy similar to fluoxetine. This drug has a shorter elimination half-time (25 hours) than fluoxetine and is a less potent inhibitor of hepatic microsomal enzymes. A potentially active metabolite has an elimination half-time of 60 to 70 hours.
Compared with fluoxetine, sertraline may cause more gastrointestinal symptoms (nausea, diarrhea) but may be less likely to cause insomnia and agitation. The recommended washout period before starting an MAO inhibitor is 14 days.
Paroxetine
Paroxetine was the third SSRI introduced in the United States and has an efficacy similar to that of fluoxetine. This drug has a relatively short elimination half-time (24 hours), and there are no active metabolites. Side effects resemble those of other SSRIs with the exception of a possibly increased incidence of sedation. The levels of paroxetine in breast milk are greater than levels in patients receiving fluoxetine or sertraline. Paroxetine produces less inhibition of hepatic cytoplasmic P-450 enzymes than is fluoxetine. Enhancement of the anticoagulant effect of warfarin reflects competition for common protein-binding sites. The recommended washout period before starting an MAO inhibitor is 14 days.
Citalopram/Escitalopram
Citalopram was the fourth SSRI introduced in the United States. Escitalopram is simply the S isomer of citalopram, which is the more pharmacologically active stereoisomer. Citalopram causes dose-dependent QT interval prolongation, which can place patients at risk for torsades de pointes.15,16 Escitalopram may also prolong the QT interval but possibly to a lesser degree. Citalopram should be used with caution in patients at risk for prolonged QT intervals.
Fluvoxamine
Fluvoxamine is effective in the management of obsessive-compulsive disorders. In addition, this drug probably has a spectrum of therapeutic efficacy similar to that of other SSRIs. The most common side effects associated with this drug are nausea, vomiting (possibly a greater frequency than with other SSRIs), headache, sedation, insomnia, and sexual dysfunction. Although it produces less inhibition of hepatic cytoplasmic P-450 enzymes than the other SSRIs, fluvoxamine may still cause clinically significant drug interactions.
Bupropion
Bupropion, which is structurally related to amphetamine, is effective in the treatment of major depression, producing improvement in 2 to 4 weeks. In addition, bupropion is effective for smoking cessation. The mechanism of action of bupropion is obscure but may include inhibition of dopamine and norepinephrine reuptake. This drug does not inhibit MAO. Bupropion is associated with a greater incidence of seizures (about 0.4%) than other antidepressants.17Some patients experience stimulant-like effects early in therapy. Like the SSRIs, bupropion has no anticholinergic effects, does not cause postural hypotension, and lacks significant effects on conduction of cardiac impulses. Unlike the SSRIs, bupropion is not associated with significant drug interactions and is not commonly associated with sexual dysfunction. Ataxia and myoclonus have occurred rarely. Bupropion should not be administered in combination with an MAO inhibitor; elevated blood pressure and serotonin syndrome have been reported.18
Venlafaxine
Venlafaxine is perceived to have a profile of efficacy similar to that of the tricyclic antidepressants but has a more favorable side effect profile. Like the tricyclic antidepressants, this drug inhibits the reuptake of norepinephrine and serotonin and may potentiate the action of dopamine in the CNS. Unlike tricyclic antidepressants, venlafaxine does not produce anticholinergic effects or postural hypotension. Side effects include insomnia, sedation, and nausea. At high doses, a modest but persistent increase in diastolic blood pressure occurs in 5% to 7% of patients. Some studies have suggested that venlafaxine may be beneficial in patients with neuropathic pain. Venlafaxine is metabolized by cytochrome P-450 enzymes and also acts as a weak inhibitor of these enzymes. The elimination half-time is 5 hours and that of its active metabolite is 11 hours. Venlafaxine should not be used in combination with an MAO inhibitor, and the recommended washout period is 14 days.
Duloxetine
Duloxetine is a serotonin and noradrenaline reuptake inhibitor, similar to venlafaxine. Indications for its use include major depression, fibromyalgia, and diabetic neuropathy.19,20 Its side effect profile includes nausea, dry mouth, insomnia, and sexual dysfunction. It does not cause significant changes in blood pressure and is a moderate inhibitor of CYP2D6.21 Duloxetine should be avoided in patients with severe renal dysfunction and chronic liver disease. Like venlafaxine, duloxetine should not be used in combination with an MAO inhibitor. The potential for the development of serotonin syndrome is present when this drug is used in conjunction with another serotonergic drug.
Trazodone
Trazodone inhibits serotonin reuptake and may also act as a serotonin agonist via an active metabolite. Although effective in the management of depression, its greatest efficacy may be treatment of insomnia induced by SSRIs or bupropion. Common side effects of trazodone include sedation, orthostatic hypotension, nausea, and vomiting. Priapism may occur in males. This drug lacks effects on conduction of cardiac impulses but on rare occasions has been associated with cardiac dysrhythmias. The elimination half-time of this drug is brief (3 to 9 hours), and toxicity associated with an overdose is less than what accompanies an overdose of tricyclic antidepressants and MAO inhibitors. Combination therapy with an MAO inhibitor is not recommended.
Nefazodone
Nefazodone is chemically related to trazodone but with fewer α1-adrenergic blocking properties. Like trazodone, this drug inhibits reuptake of serotonin and norepinephrine. The risk of sedation and priapism may be less than in patients treated with trazodone. The principal side effects are nausea, dry mouth, and sedation. Orthostatic hypotension may occur. Nefazodone-induced inhibition of cytochrome P-450 results in elevated plasma concentrations of benzodiazepines, antihistamines, and of protease inhibitors used in the treatment of HIV infection. Combination therapy with an MAO inhibitor is not recommended.
Management of Anesthesia
Several studies have suggested that SSRIs may have antiplatelet activity and increase the risk of bleeding particularly in the setting of antiplatelet medication use.22–24 The risks of discontinuing an SSRI may take 2 to 3 weeks for full washout and reinitiation may require 2 to 4 weeks for reestablishment of clinical antidepressant effect. Furthermore, discontinuation of a patient’s SSRI may expose them to the risks of a major depressive episode. Anesthesia providers may consider holding antiplatelet medication in the perioperative setting if their patients are taking SSRIs, as there may be increased risk of bleeding in the setting of SSRI and antiplatelet medication use.
Tricyclic and Related Antidepressants
Before the availability of SSRIs, tricyclic antidepressants and related cyclic antidepressants were the most commonly used drugs to treat depression (see Table 43-2). Although tricyclic antidepressants are highly effective, they have been supplanted as first-line drugs in many clinical situations because of their unfavorable side effect profile (largely resulting from their anticholinergic, antiadrenergic, and antihistaminic properties). Tricyclic antidepressants also have a narrow therapeutic index and are potentially lethal in overdose (resulting in part from inhibition of sodium ion channels) reflecting a slowing of conduction of cardiac impulses and appearance of life-threatening cardiac dysrhythmias.
Measurement of plasma drug levels for the tricyclics imipramine, desipramine, and nortriptyline can be useful in guiding therapeutic decisions. Generally, plasma levels should not exceed 225 ng/mL when imipramine is administered. Plasma levels should not exceed 125 ng/mL when desipramine is administered, and the therapeutic range for nortriptyline is 50 to 150 ng/mL. It is preferable to taper tricyclic and tetracyclic antidepressants during a 4-week period to avoid the risk of withdrawal symptoms (chills, coryza, muscle aches). These symptoms have been attributed to supersensitivity of the cholinergic nervous system.
Chronic Pain Syndromes
The tricyclic antidepressants (especially amitriptyline and imipramine), in doses lower than those used to treat depression, may be useful in the treatment of chronic neuropathic pain and other chronic pain syndromes including fibromyalgia. Although there is no consensus on the mechanism of pain relief, current hypotheses include serotonin activity and reuptake inhibition, potentiation of CNS endogenous opioids, and antiinflammatory effects.25 Because of their structural similarities to local anesthetics and known sodium channel blockade, it is possible that tricyclic antidepressants produce antiinflammatory effects similar to local anesthetics. Because many chronic pain syndromes include an inflammatory component, it is possible that the clinical efficacy of tricyclic antidepressants in chronic pain patients is due to inhibition of an overactive inflammatory system.26 The efficacy of tricyclic antidepressants on chronic pain syndromes may be limited by a narrow therapeutic index and intolerability of side effects.
Structure–Activity Relationships
The structure of tricyclic antidepressants resembles that of local anesthetics and phenothiazines. Similar to local anesthetics, tricyclic antidepressants include a hydrophobic portion linked to an amide via a linear intermediate moiety. Tricyclic denotes the three-ring chemical structure of the central portion of the molecule. Imipramine, which is the prototype of the tricyclic antidepressants, differs from phenothiazine only in the replacement of the sulfur atom with an ethylene linkage to produce a seven-membered central ring. Desipramine is the principal metabolite of imipramine, and nortriptyline is the demethylated metabolite of amitriptyline. Maprotiline is a tetracyclic antidepressant with a clinical profile that resembles imipramine. Mirtazapine is a tetracyclic antidepressant that may enhance central norepinephrine and serotonin activity in the CNS. Maprotiline and mirtazapine should not be administered to patients being treated with MAO inhibitors.
Mechanism of Action
Tricyclic antidepressants act at several transporters and receptors, but their antidepressant effect is likely produced by blocking the reuptake (uptake) of serotonin and/or norepinephrine at presynaptic terminals, thereby increasing the availability of these neurotransmitters. These drugs can be categorized into tertiary amines, which inhibit reuptake of both serotonin and norepinephrine (amitriptyline, imipramine, clomipramine) and secondary amines, which are primarily norepinephrine reuptake inhibitors (desipramine, nortriptyline). Despite the prompt onset of this effect, the development of a therapeutic antidepressant effect is inexplicably delayed for 2 to 3 weeks. For this reason, there is doubt that antidepressant effects are totally due to an accumulation of biogenic amines in the brain. Furthermore, some drugs without effects on uptake of biogenic amines are effective antidepressants. It seems likely that potentiation of monoaminergic neurotransmission in the brain is only an early event in a complex cascade of events that eventually results in an antidepressant effect. Indeed, chronic administration of these drugs is associated with (a) decreased sensitivity of postsynaptic β1 and serotonin2 receptors and of presynaptic α2 receptors, and (b) increased sensitivity of postsynaptic α1 receptors.
Pharmacokinetics
Tricyclic antidepressants are efficiently absorbed from the gastrointestinal tract after oral administration, reflecting high lipid solubility. Peak plasma concentrations occur within 2 to 8 hours after oral administration. Therapeutic plasma concentrations (parent drug plus the pharmacologically active demethylated metabolites) are 100 to 300 ng/ mL, whereas toxicity is likely at levels greater than 500 ng/mL. Tricyclic antidepressants are strongly bound to plasma and tissue proteins, which, in combination with high lipid solubility, results in a large volume of distribution (up to 50 L/kg) for these drugs. The long elimination half-time (17 to 30 hours) and wide range of therapeutic plasma concentrations make once-daily dosing intervals effective.
Metabolism
Tricyclic antidepressants are oxidized by microsomal enzymes in the liver with subsequent conjugation with glucuronic acid. The individual variation in rate of metabolism between patients is 10- to 30-fold. Metabolism is likely to be slowed in elderly patients. The elimination of tricyclic antidepressants occurs over several days, with 1 week or longer required for excretion.
Imipramine is metabolized to the active compound desipramine. Both these active compounds are inactivated by oxidation of hydroxy metabolites and by conjugation with glucuronic acid. Nortriptyline, which is the pharmacologically active demethylated metabolite of imipramine and amitriptyline, can accumulate to levels that exceed the precursors. Doxepin also appears to be converted to an active metabolite, nordoxepin, by demethylation.
Side Effects
The side effects of tricyclic antidepressants occur frequently, most commonly manifesting as (a) anticholinergic effects, (b) cardiovascular effects, and (c) CNS effects (see Table 43-2). Individual variation in the incidence and type of side effects may be related to the plasma concentrations of the tricyclic antidepressant and its active metabolites.
Anticholinergic Effects
The anticholinergic effects of tricyclic antidepressants are prominent, especially at high doses. Amitriptyline causes the highest incidence of anticholinergic effects (dry mouth, blurred vision, tachycardia, urinary retention, slowed gastric emptying, ileus), whereas desipramine produces the fewest such effects (see Table 43-2). Anticholinergic delirium may occur in elderly patients even at therapeutic doses of these drugs. Serious anticholinergic toxicity may reflect the results of polypharmacy with more than one anticholinergic drug (over-the-counter preparations to treat diarrhea or insomnia). Elderly patients have greater sensitivity to anticholinergic and other receptor effects compared with younger patients being treated with tricyclic antidepressants.
Cardiovascular Effects
Orthostatic hypotension and modest increases in heart rate are the most common cardiovascular side effects of tricyclic antidepressants, presumably reflecting drug-induced inhibition of norepinephrine reuptake into presynaptic nerve terminals. Orthostatic hypotension may be particularly hazardous in elderly patients, who are at increased risk of fractures when they fall. The risk of hypotension during general anesthesia in patients treated with tricyclic antidepressants is low but has been reported.27 Previous suggestions that tricyclic antidepressants increase the risks of cardiac dysrhythmias and sudden death have not been substantiated in the absence of drug overdose.28Furthermore, in the absence of severe preexisting cardiac dysfunction, tricyclic antidepressants lack adverse effects on left ventricular function and may even possess cardiac antidysrhythmic properties.29
Tricyclic antidepressants produce depression of conduction of cardiac impulses through the atria and ventricles, manifesting on the electrocardiogram (ECG) as prolongation of the P-R interval, widening of the QRS complex, and flattening or inversion of the T wave. Nevertheless, these changes on the ECG are probably benign and gradually disappear with continued therapy.28 Atropine is a useful treatment when tricyclic antidepressants dangerously slow atrioventricular or intraventricular conduction of cardiac impulses.
Direct cardiac depressant effects may reflect quinidine-like actions of tricyclic antidepressants on the heart. Conceivably, there could also be enhancement of depressant cardiac effects of anesthetics by tricyclic antidepressants. Quinidine-like properties of tricyclic antidepressants are thought to reflect slowing of sodium ion flux into cells, resulting in altered repolarization and conduction of cardiac impulses.
Central Nervous System Effects
Sedation associated with tricyclic antidepressant therapy may be desirable for management of depressed patients with insomnia. Amitriptyline and doxepin produce the greatest degree of sedation (see Table 43-2). Tricyclic antidepressants, especially maprotiline and clomipramine, lower the seizure threshold, raising the question of the advisability of administering these drugs to patients with seizure disorders or to those receiving drugs that may produce seizures. Children seem to be especially vulnerable to the seizure-inducing effects of tricyclic antidepressants. Treatment with tricyclic antidepressants may enhance the CNS-stimulating effects of enflurane. Weakness and fatigue are attributable to CNS effects and may resemble those seen in patients treated with phenothiazines. Extrapyramidal reactions are rare, although a fine tremor develops in about 10% of patients, especially the elderly. Because of their cardiac toxicity, tendency to cause seizures, and depressant properties on the CNS, the tricyclic antidepressants may be fatal if taken in an overdose. The combination of a tricyclic antidepressant and an MAO inhibitor may result in CNS toxicity manifesting as hyperthermia, seizures, and coma.
Drug Interactions
The anticholinergic effects and catecholamine uptake blocking properties of tricyclic antidepressants are most likely to be responsible for drug interactions. Drug interactions may be prominent with (a) sympathomimetics, (b) inhaled anesthetics, (c) anticholinergics, (d) antihypertensives, and (e) opioids. Binding of tricyclic antidepressants to plasma albumin can be decreased by competition from other drugs, including phenytoin, aspirin, and scopolamine.
Sympathomimetics
The systemic blood pressure response to the administration of sympathomimetics to patients treated with tricyclic antidepressants is complex and unpredictable. It has been suggested that indirect-acting sympathomimetics may produce exaggerated pressor responses due to an increased amount of norepinephrine available to stimulate postsynaptic adrenergic receptors. Although acute administration of tricyclic antidepressants increases sympathetic nervous system synaptic activity due to norepinephrine reuptake blockade, chronic administration of these drugs may result in decreased sympathetic nervous system transmission due to downregulation of β-adrenergic receptors.30,31 It would appear that for patients recently started on tricyclic antidepressants, exaggerated pressor responses should be anticipated whether or not direct-acting or indirect-acting sympathomimetics are administered, although pressor responses may be more pronounced with an indirect-acting drug such as ephedrine. Smaller than usual doses of direct-acting sympathomimetics that are titrated to a specific hemodynamic response are recommended. For individuals chronically treated with tricyclic antidepressants (>6 weeks), administration of either a direct-acting or indirect-acting sympathomimetic is acceptable, although a prudent approach may be to decrease the initial dose of drug to about one-third the usual dose. Conversely, conventional sympathomimetics may not be effective in restoring systemic blood pressure in patients chronically treated with tricyclic antidepressants because adrenergic receptors are either desensitized or catecholamine stores are depleted. In these patients, a potent direct-acting sympathomimetic such as norepinephrine may be the only effective management for hypotension.32
Induction of anesthesia may be associated with an increased incidence of cardiac dysrhythmias in patients treated with tricyclic antidepressants. Likewise, the dose of exogenous epinephrine necessary to produce cardiac dysrhythmias during anesthesia with a volatile anesthetic is decreased by tricyclic antidepressants.33 Theoretically, increased availability of norepinephrine in the CNS could result in increased anesthetic requirements for inhaled anesthetics.
Anticholinergics
Because the anticholinergic side effects of drugs may be additive, the use of centrally active anticholinergic drugs for preoperative medication of patients treated with tricyclic antidepressants could increase the likelihood of postoperative delirium and confusion (central anticholinergic syndrome). Glycopyrrolate would theoretically be less likely to evoke this type of drug interaction in patients being treated with tricyclic antidepressants.
Antihypertensives
Rebound hypertension after abrupt discontinuation of clonidine may be accentuated and prolonged by concomitant tricyclic antidepressant therapy.34 Conceivably, increased plasma concentrations of catecholamines can persist for longer periods in the presence of tricyclic antidepressants that prevent uptake of norepinephrine back into sympathetic nerve endings.
Opioids
In animals, tricyclic antidepressants augment the analgesic and ventilatory depressant effects of opioids. If these responses also occur in patients, doses of these drugs should be carefully titrated to avoid exaggerated or prolonged depressant effects.
Tolerance
Tolerance to anticholinergic effects (dry mouth, blurred vision, tachycardia) and orthostatic hypotension develops during chronic therapy with tricyclic antidepressants. Conversely, tolerance to desirable effects often fails to develop. Abrupt discontinuation of high doses of tricyclic antidepressants may be associated with a mild withdrawal syndrome characterized by malaise, chills, coryza, and skeletal muscle aching.
Overdose
Tricyclic antidepressant overdose is life-threatening, as the progression from an alert state to unresponsiveness may be rapid.35 Intractable myocardial depression or ventricular cardiac dysrhythmias are the most frequent terminal events.
Presenting features of tricyclic antidepressant overdose include agitation and seizures followed by coma, depression of ventilation, hypotension, hypothermia, and striking evidence of anticholinergic effects including mydriasis, flushed dry skin, urinary retention, and tachycardia. The QRS complex on the ECG may be prolonged to greater than 100 milliseconds. Indeed, the likelihood of seizures and ventricular dysrhythmias is increased when the duration of the QRS complex is greater than 100 milliseconds.36 Conversely, plasma concentrations of tricyclic antidepressants do not allow prediction of the likely occurrence of seizures or cardiac dysrhythmias.36
The comatose phase of tricyclic antidepressant overdose lasts 24 to 72 hours. Even after this phase passes, the risk of life-threatening cardiac dysrhythmias persists for up to 10 days, necessitating continued monitoring of the ECG in these patients.
Treatment of a life-threatening overdose of a tricyclic antidepressant is directed toward management of CNS and cardiac toxicity (Table 43-3).35 Coma usually resolves in 24 hours but is frequently severe enough to require invasive airway support. Extrapyramidal effects and organic brain syndrome usually require supportive care only, although judicious use of physostigmine, 0.5 to 2 mg given intravenously (IV), for treatment of anticholinergic psychosis may be indicated.
Seizures may precede cardiac arrest and should be treated aggressively with a benzodiazepine. After initial suppression of seizure activity with diazepam, it may be necessary to provide sustained effects with a longer acting drug such as phenytoin. Acidosis associated with seizure activity may abruptly increase the unbound fraction of tricyclic antidepressants in the circulation and predispose to cardiac dysrhythmias. In this regard, alkalization of the plasma (pH >7.45) either by IV administration of sodium bicarbonate or deliberate hyperventilation of the patient’s lungs can temporarily reverse drug-induced cardiotoxicity. Lidocaine and phenytoin may be used subsequently to provide sustained suppression of cardiac ventricular dysrhythmias.
Hypotension may be the result of direct tricyclic antidepressant–induced vasodilation, α-adrenergic blockade, or myocardial depression. Patients remaining hypotensive despite intravascular fluid replacement and alkalinization of the plasma may require systemic blood pressure support with sympathomimetics, inotropes, or both.
Gastric lavage may be useful in the early treatment, but this is most safely performed with a cuffed tracheal tube already in place. Activated charcoal significantly absorbs drugs throughout the gastrointestinal tract (“intestinal dialysis”). Conversely, avid protein binding of tricyclic antidepressants negates any therapeutic value of hemodialysis or drug-induced diuresis.
Monoamine Oxidase Inhibitors
MAO inhibitors constitute a heterogenous group of drugs, which block the enzyme that metabolizes biogenic amines, increasing the availability of these neurotransmitters in the CNS and peripheral autonomic nervous system. MAO inhibitors are used less commonly because their administration is complicated by side effects (hypotension), lethality in overdose, and lack of simplicity in dosing. Patients treated with MAO inhibitors must follow a specific tyramine-free diet because of the potential for pharmacodynamic interactions with tyramine that can result in systemic hypertension (Table 43-4). However, many patients with major depression who do not respond to cyclic antidepressants improve with MAO inhibitors. MAO inhibitors are also effective in the treatment of panic disorder. The dosage of MAO inhibitors is the same in the elderly as in younger adults because elderly persons often have higher levels of MAO and because the metabolism of these drugs does not seem to be affected by age.
The only MAO inhibitors approved in the United States for the treatment of depression or panic disorder are phenelzine, tranylcypromine, and isocarboxazid. Selegiline, which is a MAO-B selective inhibitor (formerly termed deprenyl), has been shown to be effective in the treatment of early Parkinson’s disease. These drugs are administered orally, being readily absorbed from the gastrointestinal tract.
Monoamine Oxidase Enzyme System
MAO is a flavin-containing enzyme found principally on outer mitochondrial membranes. The enzyme functions via oxidative deamination to inactivate several monoamines including dopamine, serotonin (5-hydroxytryptamine), norepinephrine, and epinephrine. MAO is divided into two subtypes (MAO-A and MAO-B) based on different substrate specificities (Fig. 43-1).2,3 MAO-A preferentially deaminates serotonin, norepinephrine, and epinephrine, whereas MAO-B preferentially deaminates phenylethylamine. Platelets contain exclusively MAO-A and the placenta exclusively MAO-B. About 60% of human brain MAO activity is of the A subtype.
Mechanism of Action
MAO inhibitors act by forming a stable, irreversible complex with MAO enzyme, especially with cerebral neuronal MAO.37 As a result, the amount of neurotransmitter (norepinephrine) available for release from CNS neurons increases. These effects, however, are not limited to the brain, and the concentration of norepinephrine also increases in the sympathetic nervous system. Because MAO inhibitors cause irreversible enzyme inhibition, their effects are prolonged, as the synthesis of new enzyme is a slow process.
Due to its location in the outer mitochondrial membrane, MAO in neurons is only capable of deaminating substrates that are free within the cytoplasm and are unable to gain access to substrates once they are bound in the storage vesicles. As a result, cytoplasmic concentrations of monoamines are maintained at a low level.
Side Effects
The most common serious side effect of MAO inhibitors is orthostatic hypotension, which may be especially prominent in elderly patients. Orthostatic hypotension may reflect accumulation of the false neurotransmitter octopamine in the cytoplasm of postganglionic sympathetic nerve endings. Release of this less potent vasoconstrictor in response to neural impulses is the most likely explanation for orthostatic hypotension as well as the antihypertensive effect that has been associated with chronic MAO inhibitor therapy.
Phenelzine has anticholinergic-like side effects and may produce sedation in some patients. Tranylcypromine has no anticholinergic side effects but has mild stimulant effects, which may cause insomnia. Impotence and anorgasmy are side effects of MAO inhibitors. Some patients complain of paresthesias, which may respond to pyridoxine therapy. Weight gain is a common side effect of treatment with MAO inhibitors. Hepatitis is a rare complication of MAO inhibitor therapy. Effects of MAO inhibitors on the electroencephalogram (EEG) are minimal and not seizure-like, which contrasts with tricyclic antidepressants. Also in contrast with tricyclic antidepressants is the failure of MAO inhibitors to produce cardiac dysrhythmias.33
Dietary Restrictions
MAO enzyme present in the liver, gastrointestinal tract, kidneys, and lungs seems to perform a protective function in deactivating circulating monoamines. In particular, this enzyme appears to form the initial defense against monoamines absorbed from foods, such as tyramine and β-phenylethanolamine, which would otherwise produce an indirect sympathomimetic response and precipitous hypertension. MAO-A is found in the gastrointestinal tract and liver, where it acts to metabolize bioactive amines such as tyramine. The MAO inhibitors used in the United States as antidepressants inhibit MAO-A and MAO-B nonselectively. Selegiline, when used to treat Parkinson’s disease, selectively inhibits MAO-B and patients do not need to follow a tyramine-free diet. At high doses (30 mg per day), however, even selegiline becomes a nonselective MAO inhibitor, making dietary precautions necessary (see Table 43-4).
Because patients treated with MAO inhibitors cannot metabolize dietary tyramine and other monoamines, these compounds can enter the systemic circulation and be taken up by sympathetic nervous system nerve endings. This uptake can elicit massive release of endogenous catecholamines and result in a hyperadrenergic crisis characterized by hypertension, hyperpyrexia, and cerebral vascular accident. Therefore, patients taking MAO inhibitors should be instructed to report promptly the onset of serious headache, nausea, vomiting, or chest pain. The precipitous hypertension resembles that which occurs with the release of catecholamines from a pheochromocytoma. Treatment of hypertension is with a peripheral vasodilator such as nitroprusside. Cardiac dysrhythmias that persist after control of systemic blood pressure are treated with lidocaine or a β-adrenergic antagonist.
Drug Interactions
In addition to interacting with foods, MAO inhibitors can interact adversely with opioids, sympathomimetic drugs, tricyclic antidepressants, and SSRIs. These interactions can result in hypertension, CNS excitation, delirium, seizures, and death. In animals, anesthetic requirements for volatile anesthetics are increased, presumably reflecting accumulation of norepinephrine in the CNS.
Opioids and Monoamine Oxidase Inhibitors
Administration of meperidine to a patient treated with MAO inhibitors may result in an excitatory (type I) response (agitation, headache, skeletal muscle rigidity, hyperpyrexia) or a depressive (type II) response characterized by hypotension, depression of ventilation, and coma.38 Enhanced serotonin activity in the brain is presumed to be responsible for excitatory reactions evoked by meperidine. Meperidine is capable of inhibiting neuronal serotonin uptake. Slowed breakdown of meperidine due to N-demethylase inhibition by MAO inhibitors is the presumed explanation for hypotension and depression of ventilation. About 20% of MAO inhibitor–treated patients have experienced excitatory reactions in response to meperidine. There is evidence that meperidine toxicity is increased only when both MAO-A and MAO-B are inhibited.3 Derivatives of meperidine (fentanyl, sufentanil, alfentanil) have been associated with adverse reactions in patients treated with MAO inhibitors, although the incidence seems to be less than with meperidine.39 Morphine does not inhibit uptake of serotonin, but its opioid effects may be potentiated in the presence of MAO inhibitors.
Sympathomimetics and Monoamine Oxidase Inhibitors
There is no experimental evidence to support the recommendation that all sympathomimetic drugs be avoided in patients treated with MAO inhibitors. The most consistent observation has been an occasional patient who experienced an exaggerated systemic blood pressure response after the administration of an indirect-acting vasopressor such as ephedrine. The hypertensive response is presumed to reflect an exaggerated release of norepinephrine from neuronal nerve endings. If needed, the use of a direct-acting sympathomimetic (phenylephrine) is preferable to an indirect-acting drug, keeping in mind that receptor hypersensitivity may enhance the systemic blood pressure response to these drugs as well. Regardless of the drug selected, the recommendation is to decrease the dose to about one-third of normal, with additional titration of doses based on cardiovascular responses.3
Overdose
Overdose with an MAO inhibitor is reflected by signs of excessive sympathetic nervous system activity (tachycardia, hyperthermia, mydriasis), seizures, and coma. Treatment is supportive in addition to gastric lavage. Dantrolene has been suggested as a treatment for skeletal muscle rigidity and associated symptoms of hypermetabolism after an overdose with MAO inhibitors.40
Management of Anesthesia
In the past, it was a common recommendation to discontinue MAO inhibitors 2 to 3 weeks before elective surgery based on the concern that life-threatening cardiovascular and CNS instability could occur during anesthesia and surgery when these drugs were present. This policy of drug withdrawal seems to be based more on anecdotes and isolated responses than on controlled scientific studies. Furthermore, discontinuation of effective therapy potentially places patients at risk from their psychiatric disturbances. There is growing appreciation that anesthesia can be safely administered in most patients being chronically treated with MAO inhibitors.3 When anesthesia is administered to patients treated with MAO inhibitors, it remains prudent to consider certain drug interactions and to avoid certain drugs, if possible.3,37
Selection of Drugs Used during Anesthesia
The anesthetic technique selected should minimize the possibility of sympathetic nervous system stimulation or drug-induced hypotension. Regional anesthesia as in parturients is acceptable, recognizing the disadvantage of these techniques should hypotension require administration of a sympathomimetic.38 If regional anesthesia is performed, a cautious approach is not to add epinephrine to the local anesthetic solution, although problems have not been reported with a 1:200,000 dilution. An advantage of regional anesthesia is postoperative analgesia such that the need for opioids is negated or minimized. Etomidate and thiopental have been administered to MAO inhibitor–treated patients undergoing electroconvulsive therapy without adverse effects. Responses to nondepolarizing neuromuscular blocking drugs are not altered by MAO inhibitors.
Serotonin Syndrome
Serotonin syndrome occurs when there is an excess of serotonin agonism in the central and peripheral nervous systems. The clinical findings can vary widely from mild tremor to altered mental status, clonus, and hyperthermia.41SSRIs, tricyclic antidepressants, and MAO inhibitors, particularly in combination, have all been associated with serotonin syndrome. The differential diagnosis includes malignant hyperthermia, neuroleptic malignant syndrome, and anticholinergic poisoning (Table 43-5). Management of serotonin syndrome includes hemodynamic and respiratory supportive care, discontinuation of offending serotonergic agents, control of agitation with sedatives, control of hyperthermia, and administration of 5-HT2A antagonists.
Anxiolytics
Benzodiazepines
Benzodiazepines (see Chapter 5) are used clinically as anxiolytics, sedatives, anticonvulsants, and muscle relaxants. They appear to produce all these effects by facilitating the actions of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the nervous system.
The effectiveness of benzodiazepines, combined with the high frequency of anxiety and insomnia in the adult population, has led to these drugs being widely prescribed. Few patients who receive benzodiazepines for valid indications abuse them or become addicted. Benzodiazepines have less of a tendency to produce tolerance, less potential for abuse, and a large margin of safety if taken as an overdose in isolation. A history of alcohol abuse or substance abuse is a relative contraindication to use of benzodiazepines for treatment of anxiety.
When benzodiazepines are used to treat situational anxiety or generalized anxiety disorder, low doses (diazepam, 2 to 5 mg three times daily) are typically selected to minimize sedation. Sedation associated with administration of benzodiazepines to treat anxiety usually subsides within 2 weeks. For short-term treatment of situational anxiety or long-term treatment of generalized anxiety disorders, a total daily dose of greater than 30 mg of diazepam or its equivalent is almost never needed. For the treatment of panic disorder, the high-potency, short-acting benzodiazepine alprazolam has the longest record of efficacy, although the long-acting benzodiazepine clonazepam is gaining increasing acceptance. Use of benzodiazepines for anxiety and panic disorders is frequently being replaced with SSRIs. Problems with benzodiazepine rebound and withdrawal symptoms can be minimized if low-potency, long-acting drugs are used for the treatment of generalized anxiety disorders. Elderly patients manifest greater sedation and greater impairment of psychomotor performance than younger persons receiving the same dose.
Buspirone
Buspirone is a nonbenzodiazepine that is effective in the treatment of generalized anxiety disorders (onset of anxiolytic effects over several days) but not panic disorder. This drug is a partial agonist at serotonin receptors, resulting in decreased serotonin turnover and anxiolytic effects. Buspirone has no direct effects on GABA receptors and thus no pharmacologic cross-reactivity with benzodiazepines, barbiturates, or alcohol. Buspirone lacks sedative, anticonvulsant, and skeletal muscle–relaxing effects characteristic of benzodiazepines. Absorption from the gastrointestinal tract is 100%, but extensive hepatic first-pass metabolism decreases bioavailability to 4%. The elimination half-time is 2 to 11 hours. Buspirone does not produce dependence and does not appear to be highly toxic if taken in overdose. The principal disadvantage seems to be a slow onset of effect (1 to 2 weeks), which may be interpreted as ineffectiveness by patients experiencing acute anxiety.
Lithium
Lithium, anticonvulsants, and antipsychotics are considered drugs of choice for the treatment of bipolar disorders. Because of the multiple drug interactions with lithium and severe toxicity, alternative drugs are being used frequently in its place in the treatment of bipolar disorder. Lithium has many neurobiologic effects, but it is not known which components are necessary for its efficacy in the treatment of bipolar disorders.42 One possible mechanism is the ability of lithium to inhibit a second messenger system that transduces signals from many neurotransmitter receptors, which ultimately lead to release of calcium ions from intracellular storage sites. With repeated firing, a neuron that has been exposed to lithium would become relatively depleted of second messengers and signal transmission would be dampened, especially in hyperactive neurons. Full therapeutic effects of lithium may take several weeks. The goal for treatment of acute mania is to maintain plasma lithium concentrations between 1.0 and 1.2 mEq/L. Plasma lithium concentrations should be measured 10 to 12 hours after the last oral dose, and levels should not be drawn sooner than 4 to 5 days after the latest change in dosage.
Pharmacokinetics
Lithium is distributed throughout the total body water and is excreted almost entirely by the kidneys. Lithium, like sodium, is filtered by the glomerulus and reabsorbed by the proximal, but not distal, renal tubules. Thus, its renal excretion is not enhanced by thiazide diuretics, which act selectively on the distal renal tubules. In fact, because proximal reabsorption of lithium and sodium is competitive, depletion of sodium as produced by dehydration, decreased sodium intake, and thiazide and loop diuretics may increase reabsorption of lithium by proximal renal tubules, resulting in as much as a 50% increase in the plasma concentration of lithium. Potassium-sparing diuretics (triamterene, spironolactone) do not facilitate reabsorption of lithium and, in fact, may increase excretion. Nonsteroidal antiinflammatory drugs, by altering renal blood flow, may produce marked increases in the plasma concentration of lithium and should be used with care.
Safe and effective use of lithium can be monitored only by measuring plasma concentrations. The therapeutic range for acute mania is 1.0 to 1.2 mEq/L, with oral doses averaging 900 to 1,800 mg per day. Plasma lithium concentrations should be measured about 12 hours after the last oral dose. Because the elimination half-time is about 24 hours and the time to reach steady state is four or five elimination half-times, plasma concentrations should be measured no sooner than 5 days after a change in dosage, unless toxicity is suspected. In elderly patients and in patients with renal disease, the elimination half-time for lithium is prolonged; the time to equilibration can be delayed to 7 days or longer. If toxicity is suspected, lithium should be withheld and the plasma concentration determined immediately, taking into account the time that has elapsed since the last dose.
Side Effects
The most common serious side effects of lithium occur at the kidneys, manifesting as polydipsia and polyuria. An estimated 20% of treated patients excrete greater than 3 L of urine daily, reflecting an impaired renal concentrating ability due to the inhibitory effect of lithium on intracellular adenosine monophosphate formation in the renal tubules. The potassium-sparing diuretic amiloride is effective in decreasing urine volume without affecting the plasma concentrations of either lithium or potassium. It is recommended that renal function be evaluated by measuring blood urea nitrogen or plasma creatinine every 6 months.
Changes on the ECG characterized by T wave flattening or inversion occur in some patients being treated with lithium, but there seem to be no related clinical effects. These changes are reversible within 2 weeks when lithium is discontinued. Clinically significant lithium-induced cardiac conduction disturbances are rare, although sinoatrial node dysfunction and sinoatrial node block have been described. Patients with preexisting sinoatrial node dysfunction (sick sinus syndrome) should probably be treated with lithium only if they have an artificial cardiac pacemaker in place.
Hypothyroidism develops in about 5% of patients treated with lithium and is more common in women than men. For this reason, it is recommended that thyroid-stimulating hormone levels be measured every 6 months. If necessary, levothyroxine therapy may be initiated without discontinuing lithium.
Clinically important dermatologic toxicities of lithium include acne and exacerbations of psoriasis or a new onset of psoriasis. Patients may complain of memory disturbance and cognitive slowing. Hand tremor occurs in 25% to 50% of treated patients and diminishes with time and in response to a decrease in the dose of lithium or treatment with a β-adrenergic antagonist. Rarely, lithium may cause extrapyramidal effects.
The association of sedation with lithium therapy suggests that anesthetic requirements for injected and inhaled drugs could be decreased. High plasma concentrations of lithium may delay recovery from the CNS depressant effects of barbiturates.43 Responses to depolarizing and nondepolarizing neuromuscular blocking drugs may be prolonged in the presence of lithium.44
Drug Interactions (Table 43-6)
Toxicity
Diuretic therapy, sodium restriction, and sodium wasting increase reabsorption of lithium and thus increase plasma lithium concentrations. Patients being treated with lithium should avoid nonsteroidal antiinflammatory drugs and diuretics.
Many symptoms and signs of toxicity are closely correlated with the plasma lithium concentration (Table 43-7).42 Mild lithium toxicity is reflected by sedation, nausea, skeletal muscle weakness, and changes on the ECG characterized by widening of the QRS complex. Atrioventricular heart block, hypotension, cardiac dysrhythmias, and seizures may occur when plasma concentrations of lithium are greater than 2 mEq/L. It is not uncommon for elderly patients who excrete lithium slowly to become confused, even in the presence of therapeutic plasma concentrations of this ion. Significant lithium toxicity is a medical emergency that may require aggressive treatment, including hemodialysis. If renal function is adequate, excretion of lithium ions can be modestly accelerated by osmotic diuresis and IV administration of sodium bicarbonate.
Anticonvulsants in Treatment of Bipolar Disorder
The anticonvulsants carbamazepine and valproic acid are used commonly in the treatment of bipolar disorder and valproic acid is used for migraine off label. Side effects of valproic acid that occur between 1% and 10% include headache, somnolence, dizziness, insomnia, nervousness, pain, alopecia, nausea, vomiting, diarrhea, abdominal pain, dyspepsia, anorexia, thrombocytopenia (dose related), tremor, weakness, diplopia, amblyopia/blurred vision, infection, and flulike syndrome. Despite this wide array of common side effects, valproic acid is often better tolerated than lithium, which has life-threatening side effects. Side effects of carbamazepine, although rare, include leukopenia, aplastic anemia, and hepatitis. It is recommended that liver function tests and complete blood counts be followed in patients being treated with carbamazepine.
Antipsychotic (Neuroleptic) Drugs
The antipsychotic drugs are a chemically diverse group of compounds (phenothiazines, thioxanthenes, butyrophenones) that are useful in the treatment of schizophrenia, mania, depression with psychotic features, and certain organic psychoses (Table 43-8). Schizophrenic patients who have not responded to standard antipsychotics may respond to clozapine. In addition, antipsychotic drugs are used to treat Tourette’s syndrome and certain movement disorders. Some of these drugs may also be used as antiemetics at low doses.
Phenothiazines and thioxanthenes have a high therapeutic index and relatively flat dose-response curve, accounting for the remarkable safety of these drugs over a wide dose range. Even large overdoses are unlikely to cause life-threatening depression of ventilation. These drugs do not produce physical dependence, although abrupt discontinuation may be accompanied by skeletal muscle discomfort.
Structure–Activity Relationships
Phenothiazines have a three-ring structure in which two benzene rings are linked by a sulfur and a nitrogen atom. If the nitrogen atom at position 10 is replaced by a carbon atom with a double bond to the side chain, the compound becomes a thioxanthene. Phenothiazines and thioxanthenes used to treat psychiatric disease have three carbon atoms interposed between position 10 of the central ring and the first amino nitrogen atom of the side chain at this position. In addition, the amine is always tertiary. This structure contrasts with that of phenothiazines with significant antihistamine activity (promethazine) or phenothiazines with significant anticholinergic activity (ethopropazine, diethazine), which have only two carbon atoms separating the amino group from position 10 of the central ring. Loss of a methyl group or other substituents on the tertiary amino group, as can occur during metabolism, results in a loss of pharmacologic activity.
Mechanism of Action
The mechanism of action of antipsychotic drugs is thought to be due to blockade of dopamine receptors (especially dopamine2 receptors) in the basal ganglia and limbic portions of the forebrain.45,46 All antipsychotic drugs achieve maximum clinical efficacy over a period of weeks, emphasizing the importance of distinguishing the acute receptor antagonist effects of antipsychotic drugs from their chronic effects. Interference with the neurotransmitter functions of dopamine by these drugs is suggested by extrapyramidal side effects. Blockade of dopamine receptors in the chemoreceptor trigger zone of the medulla is responsible for the antiemetic effect of these drugs.
Pharmacokinetics
Phenothiazines and thioxanthenes often display erratic and unpredictable patterns of absorption after oral administration. These drugs are highly lipid soluble and accumulate in well-perfused tissues such as the brain. Passage across the placenta and accumulation of drug in the fetus is possible. Avid binding to protein in plasma and tissues limits the effectiveness of hemodialysis in removing these drugs.
Metabolism
Metabolism of phenothiazines and thioxanthenes is principally by oxidation in the liver followed by conjugation. Most oxidative metabolites are pharmacologically inactive, with a notable exception being 7-hydroxychlorpromazine. Metabolites appear primarily in urine and to a lesser extent in bile. Typical elimination half-times of these drugs are 10 to 20 hours, permitting once-daily dosing intervals. The elimination half-time may be prolonged in the fetus and in the elderly, who have decreased capacity to metabolize these drugs.
Side Effects
With the exception of clozapine, the chronic use of phenothiazines and thioxanthenes may be complicated by serious side effects, most likely reflecting drug-induced blockade of dopamine receptors, especially in the forebrain.45Despite the common occurrence of side effects, these drugs have a large margin of safety and overdoses are rarely fatal.
Extrapyramidal Effects
Tardive dyskinesia may occur in 20% of patients who receive antipsychotic drugs for greater than 1 year. Only clozapine has not been implicated as a cause of this potentially permanent side effect. Elderly patients and women of all ages seem to be more susceptible to the development of tardive dyskinesia. Manifestations of tardive dyskinesia include abnormal involuntary movements, which may affect the tongue, facial and neck muscles, upper and lower extremities, truncal musculature, and, occasionally, skeletal muscle groups involved in breathing and swallowing. Tardive dyskinesia only rarely remits, and there is no treatment. Compensatory increases in the function of dopamine activity in the basal ganglia may be responsible for the development of tardive dyskinesia.
Acute dystonic reactions occur in approximately 2% of treated patients and are most likely to occur within the first 72 hours of therapy. Dystonic reactions are most common in young men and in patients taking high-potency antipsychotics. Acute skeletal muscle rigidity and cramping may develop, usually in the musculature of the neck, tongue, face, and back. Opisthotonos and oculogyric crises may occur. The sudden onset of respiratory distress in a patient on neuroleptics may reflect laryngeal dyskinesia (laryngospasm).47 Acute dystonia responds dramatically to diphenhydramine, 25 to 50 mg IV. Extrapyramidal side effects including tremor, masked facies, and skeletal muscle rigidity may occur, especially in elderly patients. Patients with antipsychotic-induced akathisia often appear restless (inability to tolerate inactivity), which may be confused with the underlying psychotic disorder.
Cardiovascular Effects
IV administration of chlorpromazine causes a decrease in systemic blood pressure resulting from (a) depression of vasomotor reflexes mediated by the hypothalamus or brainstem, (b) peripheral α-adrenergic blockade, (c) direct relaxant effects on vascular smooth muscle, and (d) direct cardiac depression. Risperidone is an antipsychotic drug that has been associated with exaggerated systemic hypotension during a spinal anesthetic, perhaps reflecting risperidone-induced α blockade.48 α-Adrenergic blockade produced by chlorpromazine is sufficient to blunt or prevent the pressor effects of epinephrine. Miosis that occurs predictably may also be due to α-adrenergic blockade. A cardiac antidysrhythmic effect of chlorpromazine may reflect the potent local anesthetic activity of this drug. These drugs usually do not cause cardiac dysrhythmias. Rarely, antipsychotic drugs prolong the QTc interval on the ECG and therefore predispose to the development of ventricular tachycardia.49 Thioridazine and pimozide are potent calcium channel blockers, which may contribute to their cardiac toxicity, including prolongation of the QTc interval on the ECG.
Oral administration of these drugs is associated with less pronounced systemic blood pressure–lowering effects. Indeed, tolerance to the hypotensive effect develops so that after several weeks of therapy, the blood pressure returns toward normal. Nevertheless, some element of orthostatic hypotension may persist for the duration of therapy.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome occurs in 0.5% to 1.0% of all patients treated with antipsychotic drugs. Risk factors for the development of this syndrome may include dehydration and intercurrent illness. The syndrome typically develops over 24 to 72 hours in young men and is characterized by (a) hyperthermia; (b) generalized hypertonicity of skeletal muscles; (c) instability of the autonomic nervous system manifesting as alterations in systemic blood pressure, tachycardia, and cardiac dysrhythmias; and (d) fluctuating levels of consciousness.50 Autonomic nervous system dysfunction may precede the onset of other symptoms. Increased skeletal muscle tone may so decrease chest wall expansion that it becomes necessary to provide mechanical support of ventilation. Skeletal muscle rigidity may be severe enough to cause myonecrosis leading to increased creatine phosphokinase levels, myoglobinuria, and renal failure. Liver transaminase enzymes are likely to be increased. Mortality is 20% to 30%, with common causes of death being ventilatory failure, cardiac failure and/or dysrhythmias, renal failure, and thromboembolism.
The cause of neuroleptic malignant syndrome is not known and, as a result, treatment is empirical and includes supportive measures and the administration of the direct-acting muscle relaxant dantrolene and the dopamine agonists bromocriptine or amantadine.51 The reported efficacy of dopamine agonists in the treatment of skeletal muscle rigidity as well as the prevention of the onset of the syndrome with abrupt withdrawal of levodopa therapy suggests a role of dopamine receptor blockade in the development of this syndrome.52
Malignant hyperthermia associated with anesthesia as well as the central anticholinergic syndrome may mimic the neuroleptic malignant syndrome.50 A distinguishing feature is the ability of nondepolarizing muscle relaxants to produce flaccid paralysis in patients experiencing the neuroleptic malignant syndrome but not in those experiencing malignant hyperthermia (see Table 43-2).53
Endocrine Effects
Prolactin levels are increased as a result of blockade of dopamine receptors and loss of the normal inhibition of prolactin secretion. Galactorrhea and gynecomastia may accompany excess prolactin secretion. Amenorrhea is a possible but rare complication of therapy. Decreased secretion of corticosteroids may be due to diminished corticotropin release from the anterior pituitary. Chlorpromazine may impair glucose tolerance and the release of insulin in some patients. Hypothalamic effects may manifest as weight gain and occasionally abnormalities of thermoregulation.
Sedation
Sedation produced by antipsychotic drugs appears to be due to antagonism of α1-adrenergic, muscarinic, and histamine (H1) receptors. With chronic therapy, tolerance develops to the sedative effects produced by these drugs.
Antiemetic Effects
The antiemetic effects of antipsychotic drugs reflect their interaction with dopaminergic receptors in the chemoreceptor trigger zone of the medulla. These drugs seem most effective in preventing opioid-induced nausea and vomiting. Perphenazine, 5 mg IV, has been shown to be as effective as ondansetron, 4 mg IV, and droperidol, 1.25 mg IV, for prevention of postoperative vomiting after gynecologic surgery.54 Unlike these other antiemetics, perphenazine was not associated with side effects such as sedation or hypotension, making this phenothiazine derivative useful as an inexpensive prophylactic antiemetic. Perphenazine, 70 µg/kg IV, decreases the incidence of vomiting in children during the first 24 hours after tonsillectomy.55 The CNS dopaminergic activity of phenothiazines, which results in their antiemetic effects, may also produce extrapyramidal symptoms. These symptoms, which are easily treated with benztropine, appear to be rare.
Obstructive Jaundice
Obstructive jaundice that is considered to be an allergic reaction occurs rarely 2 to 4 weeks after administration of phenothiazines or thioxanthenes. Indeed, there is prompt recurrence of jaundice if the offending drug, usually chlorpromazine, is again administered. If jaundice is not observed in the first month of therapy, it is unlikely to occur at a later date.
Hypothermia
An effect of chlorpromazine on the hypothalamus is most likely responsible for the poikilothermic effect of this drug. In the past, this effect was used to facilitate the production of surgical hypothermia.
Seizure Threshold
Many antipsychotic drugs decrease the seizure threshold and produce a pattern on the EEG similar to that associated with seizure disorders. Chlorpromazine causes slowing of the EEG pattern, with some increase in burst activity and spiking. Sensory evoked potentials are often decreased in amplitude, and there is an increase in latency.
Skeletal Muscle Relaxation
Chlorpromazine causes skeletal muscle relaxation in some types of spastic conditions, presumably by actions on the CNS because the drug is devoid of actions at the neuromuscular junction.
Drug Interactions
The ventilatory depressant effects of opioids are likely to be exaggerated by antipsychotic drugs. Likewise, the miotic and sedative effects of opioids are increased, and the analgesic actions are likely to be potentiated. These drugs may interfere with the actions of exogenously administered dopamine, and the effects of alcohol are enhanced.
Clozapine
Clozapine is the only antipsychotic that does not seem to cause tardive dyskinesia or extrapyramidal side effects.45 Among the most common side effects are sedation, nausea and vomiting, and orthostatic hypotension. Excessive salivation, especially during sleep, is a common but paradoxical and poorly explained effect of this strongly anticholinergic drug. Another presumed manifestation of a parasympatholytic effect is sustained mild sinus tachycardia. Caution is advised in the use of such an anticholinergic drug in patients at risk for glaucoma, ileus, or urinary retention. Low-grade fever sometimes occurs early in the use of clozapine. Clozapine has been combined safely with lithium and antidepressant drugs, but there may be a risk of excessive sedation if this drug is combined with a benzodiazepine.
Agranulocytosis is a particularly serious side effect of clozapine, occurring in less than 1% of patients.45 For this reason, weekly monitoring of the white blood cell count is recommended in treated patients.
The incidence of seizures is 2% to 4% in those treated with high doses of clozapine. Some clinicians prescribe an anticonvulsant when high doses of clozapine (>500 mg per day) are administered or in patients with a history of epilepsy. Valproic acid may be selected as the anticonvulsant, as this drug does not alter the metabolism of clozapine.
Butyrophenones
Butyrophenones, such as droperidol and haloperidol, structurally resemble and evoke pharmacologic effects similar to those of phenothiazines and thioxanthenes. Butyrophenones can decrease anxiety that accompanies psychoses. Conversely, butyrophenones are less effective against anxiety such as that present in the preoperative period.
Droperidol is the butyrophenone most often administered in the preoperative period. Haloperidol has a longer duration of action than droperidol and lacks significant α-adrenergic antagonist effects such that decreases in systemic blood pressure are unlikely. The principal use of haloperidol is as a long-acting antipsychotic drug and for treatment of agitation and delirium in the intensive care unit.
Ziprasidone is an atypical antipsychotic drug that may be a useful alternative to haloperidol for the treatment of delirium.56 Like haloperidol, ziprasidone is associated with antidopaminergic side effects (extrapyramidal effects, tardive dyskinesia) and can cause prolongation of the QTc interval on the ECG (not recommended in patients with QTc >500 milliseconds, recent myocardial infarction, uncompensated congestive heart failure).
Pharmacokinetics
In patients anesthetized with nitrous oxide-fentanyl, the elimination half-time of droperidol is 104 minutes, clearance is 14.1 mL/kg per minute, and the volume of distribution is 2.04 L/kg.57 The total body clearance of droperidol is similar to hepatic blood flow (perfusion dependent), emphasizing the importance of hepatic metabolism rather than hepatic enzyme activity (capacity dependent) in elimination of this drug. In this regard, potential accumulation of droperidol is more likely to occur when the hepatic blood flow is decreased rather than with an alteration in hepatic enzyme activity. The short elimination half-time is not consistent with the prolonged CNS effects of droperidol, which may reflect slow dissociation of the drug from receptors or retention of droperidol in the brain. Droperidol is metabolized in the liver, with maximal excretion of metabolites occurring during the first 24 hours.
Side Effects
The side effects of butyrophenones resemble those described for phenothiazines and thioxanthenes.
Central Nervous System
The outwardly calming effect of droperidol may mask an overwhelming fear of surgery. This dysphoric response detracts from the use of droperidol in the preoperative period, especially as preoperative medication.58 Akathisia (most often a feeling of restlessness in the legs) may accompany administration of droperidol as preoperative medication.59 As a dopamine antagonist, droperidol evokes extrapyramidal reactions in about 1% of patients.60,61 For this reason, droperidol should not be administered to patients who are concurrently being treated for Parkinson’s disease. Acute laryngeal dystonia (laryngospasm) is a rare extrapyramidal reaction to the butyrophenones.47Diphenhydramine administered IV is an effective treatment for droperidol-induced extrapyramidal reactions.
Droperidol is a cerebral vasoconstrictor that causes a decrease in cerebral blood flow, but cerebral metabolic rate for oxygen is not greatly altered. Failure to decrease the metabolic rate despite decreased cerebral blood flow could be undesirable in patients with cerebral vascular disease. The reticular activating system is not depressed, and α rhythm persists on the EEG. Droperidol does not produce amnesia nor does it have an anticonvulsant action.
Cardiovascular Effects
Droperidol can decrease systemic blood pressure as a result of actions in the CNS and by peripheral α-adrenergic blockade.62 The decrease in blood pressure is usually minimal, although occasionally a patient may experience marked hypotension. Systemic and pulmonary vascular resistance is only modestly and transiently decreased. Myocardial contractility is not altered by droperidol.
Hypertension has been reported after administration of droperidol to patients with pheochromocytoma.63,64 This systemic blood pressure response reflects droperidol-induced release of catecholamines from the adrenal medulla as well as inhibition of catecholamine uptake into chromaffin granules (Fig. 43-2).65
Droperidol is a cardiac antidysrhythmic and protects against epinephrine-induced dysrhythmias.63 The mechanism for the cardiac antidysrhythmic effect has not been established but may reflect blockade of α-adrenergic receptors in the myocardium, stabilization of excitable membranes of cardiac cells by local anesthetic effects of droperidol, and decreases in systemic blood pressure, which decrease the likelihood of pressure-dependent cardiac dysrhythmias. Large doses of droperidol, 0.2 to 0.6 mg/kg IV, decrease conduction of cardiac impulses along accessory pathways responsible for tachydysrhythmias that occur in patients with Wolff-Parkinson-White syndrome (Fig. 43-3).66
Prolonged QTc Interval
Prolonged QTc syndrome is a malfunction of cardiac ion channels resulting in impaired ventricular repolarization that can lead to a characteristic polymorphic ventricular tachycardia known as torsades de pointes.67 The single most common cause of the withdrawal or restriction of the use of drugs that are already in clinical use is the prolongation of the QTc interval on the ECG associated with torsades de pointes (polymorphic ventricular tachycardia).68,69 This prolongation most often results from delayed ventricular repolarization, a process that is mediated by the efflux of intracellular potassium. The channels responsible for the current are susceptible to blockade by many drugs, producing a suitable environment for the development of torsades de pointes, which may lead to sudden death. Nondrug factors associated with prolongation of the QTc interval include female gender, advanced age, electrolyte disturbances (hypokalemia, hypomagnesemia), congestive heart failure, bradycardia, myocardial ischemia, and congenital long Q-T syndromes.
Several classes of noncardiac drugs (droperidol, thiopental, propofol, isoflurane, sevoflurane, succinylcholine, neostigmine, atropine, glycopyrrolate, metoclopramide, macrolide and quinolone antibiotics, SSRIs, 5HT3 receptor antagonists) produce dose-dependent prolongation of the QTc interval on the ECG in some patients.68 Although these drugs can provoke torsades de pointes in susceptible patients, the risk of this response in patients with no other risk factors is minimal. Nevertheless, even in low-risk patients, drug interactions can lead to life-threatening torsades de pointes. These drug interactions are characterized by (a) additive or synergistic effects when two drugs capable of prolonging the QTc are administered (haloperidol and amitriptyline) or (b) the simultaneous administration of a drug that interferes with the metabolism of a second drug capable of prolonging the QTc interval (resulting increased plasma concentration of the second drug increases the risk of torsades de pointes). Drugs capable of inhibiting P-450 enzyme and thus delaying the metabolism of second drugs capable of prolonging the QTc interval include calcium channel blockers, antifungal drugs, SSRIs, macrolide and quinolone antibiotics, antiretroviral drugs, and amiodarone.
Droperidol is capable of prolonging the QTc interval on the ECG.70–73 Although the QTc prolongation effect peaks 2 to 3 minutes following IV administration of droperidol, the effects may persist for several hours. Cases of QTc prolongation and/or torsades de pointes have occurred in patients receiving droperidol at (1.25 to 2.5 mg) as well as doses (0.625 to 1.25 mg) below those approved by the U.S. Food and Drug Administration.71 Some of these responses occurred in patients without known risk factors and some have been fatal. Nevertheless, there were many confounding factors in these cases that make it impossible to establish the precise cause of the adverse cardiac events.71 Of note, since droperidol was approved in 1970, there has not been a single case report where droperidol in doses used for the management of postoperative nausea and vomiting has been associated with cardiac dysrhythmias or cardiac arrest.74,75 Although even small doses of droperidol (<1.25 mg IV) may cause prolongation of the QTc interval, this prolongation is considered clinically insignificant.76,77
Based on these reports, a “black box warning” has been added to the package insert for droperidol. This warning includes the requirement that all patients should undergo a 12-lead ECG prior to the administration of droperidol to determine if a prolonged QTc interval is present (>440 milliseconds for males and >450 milliseconds for females). When treatment with droperidol is selected, ECG monitoring should be performed before administration of droperidol and continued for 2 to 3 hours. Furthermore, droperidol should be administered with caution to patients who may be at risk for development of prolonged QTc syndrome (congestive heart failure, bradycardia, hypokalemia, elderly, concomitant administration of other drugs known to prolong the QTc interval). Sudden death during treatment with haloperidol has been attributed to drug-induced prolongation of the QTc interval on the ECG.49
When considering the effects of drugs on the QTc interval, it is important to recognize that it is difficult to measure this interval with precision.75 There is inherent imprecision in identifying the end of the T wave and variation in the onset of the QRS complex on some ECG leads providing different QT values, depending on the leads selected for the measurement. Even paper speed and sensitivity can influence QT measurements. Automatic QTc measurement techniques have been found to be less accurate in cardiac patients than in healthy controls. Indeed, calculation of the QTc interval is ambiguous, as there are numerous different formulae and each produces different results.
Ventilation
Resting ventilation and the ventilatory response to carbon dioxide are not altered by droperidol.78 Furthermore, droperidol administered IV augments the ventilatory response evoked by arterial hypoxemia, presumably by blocking the action of the inhibitory neurotransmitter dopamine at the carotid body (Fig. 43-4).59 For this reason, droperidol may be an acceptable preoperative medication in patients with chronic obstructive airway disease who depend on carotid body drive to prevent hypoventilation.
Clinical Uses
Clinical uses of droperidol are limited to its use as an antiemetic.
Neuroleptanalgesia
Droperidol combined with fentanyl is administered for the production of neuroleptanalgesia. A commercially available 50:1 combination of droperidol with fentanyl was known as Innovar. This fixed combination of drugs is not associated with enhanced depression of ventilation as compared with either drug alone.79 Droperidol does not enhance analgesia produced by fentanyl but rather prolongs its duration of action. Orthostatic hypotension and dysphoria are more likely to occur after the administration of Innovar compared with fentanyl alone.
Neuroleptanalgesia is characterized by trance-like (cataleptic) immobility in an outwardly tranquil patient who is dissociated and indifferent to the external surroundings. Analgesia is intense, allowing performance of a variety of diagnostic and minor surgical procedures such as bronchoscopy and cystoscopy. The disadvantages of neuroleptanalgesia are prolonged CNS depression and failure to depress sympathetic nervous system responses predictably to painful stimulation.
The mechanism by which droperidol produces anesthesia is not known but likely involves inhibition of synaptic transmission by ligand-gated ion channels. GABA and neuronal nicotinic acetylcholine receptors (nAChRs) are important in the mechanism of action of injected and inhaled anesthetics. There is evidence that droperidol inhibits activation of GABA and nAChRs receptors within a concentration range, which might result in anxiety, dysphoria, and restlessness that limit the clinical usefulness of high-dose droperidol anesthesia.80
Antiemetic
Droperidol is a powerful antiemetic agent as a result of inhibition of dopamine2 receptors in the chemoreceptor trigger zone of the medulla. Despite the black box warning, there is a question whether small antiemetic doses (≤1.25 mg) introduce the risk of prolonged QTc interval on the ECG.71 Over nearly three decades, droperidol, 0.625 to 1.25 mg IV, has become widely accepted as a safe, cost-effective first-line therapy for the management of postoperative nausea and vomiting.81,82 The use of droperidol, 1.25 mg IV is associated with greater effectiveness, lower cost, and similar patient satisfaction compared with 0.625 mg droperidol IV or ondansetron 4 mg IV.83 Droperidol (1.25 mg) was as effective as dexamethasone (4 mg) and ondansetron (4 mg) in decreasing the incidence of postoperative nausea and vomiting by about 26% when administered as preoperative prophylaxis.84 Labyrinthine-induced vomiting (motion sickness) is not influenced by droperidol.
Cannabis
Cannabis is an alkaloid mixture of more than 400 compounds derived from the Cannabis sativa plant. Cannabis has been used for thousands of years and is presently the most commonly used illicit drug in the world. The most abundant cannabinoids are δ-9-tetrahydrocannabinol (D9THC), cannabidiol, and cannabinol.85 D9THC is the main psychotropically active cannabinoid. Two principal endogenous cannabis receptors (CB1 and CB2) have been identified. CB1 receptors are present in the CNS (especially spinal cord) and CB2 receptors are located peripherally and linked with cells in the immune system. Both receptors are members of the G protein family and like opioid receptors exert their actions by modulating second messenger activity (adenylate cyclase activity) and calcium ion function. Endogenous cannabinoid agonists (anandamide, 2-arachidonylglycerol) have been identified and produce effects similar to D9THC.
Pharmacokinetics
Cannabinoids undergo substantial hepatic first-pass metabolism following oral administration such that only 10% to 20% of the ingested dose reaches the systemic circulation. This metabolism produces large amounts of active metabolite, 11-hydroxy-d-9-tetrahydrocannabinol, which is as active as the parent compound (D9THC) and has a prolonged half-time. The peak clinical effect after oral administration occurs after 1 to 2 hours and duration of action is 4 to 6 hours. In contrast, inhalation administration results in onset of action within seconds.
Toxicity
Euphoria and feeling of relaxation occurs at plasma cannabinoid concentrations of about 3 ng/mL and this can be produced by 2 to 3 mg of D9THC. Acute intoxication may cause perceptual alterations, distortion of time, intensification of normal sensory experiences, decreased reaction times, poor motor skills, increased appetite, impairment of skilled activities, tachycardia, and hypotension. The greatest concern is the creation of long-term toxicity, development of physical dependence associated with withdrawal symptom during a period of abstinence after frequent use.86 Cannabis is often mixed with tobacco to make it burn more efficiently. Materials that are present in cannabis smoke are carcinogenic. Chronic inhalation of cannabis smoke is associated with an increased incidence of chronic obstructive lung disease and carcinoma of the lung and larynx. Persistent use of cannabis may be associated with decreased reproductive potential and reduced production of testosterone.
Clinical Uses
D9THC is increasingly used for the long-term treatment of nausea, vomiting, cachexia, and management of chronic pain including migraine.87 The role of the endogenous cannabinoid system is not fully understood but evidence suggests it is involved with analgesia, cognition, appetite, vomiting, bronchodilation, inflammation, and immune control.85 Cannabinoids are highly lipid soluble and the presence of CB1 receptors in the spinal cord suggests potential analgesic efficacy if placed in the epidural or intrathecal space. Although use of cannabis for analgesia introduces the potential for psychic and physical dependence, there is considerably less risk of life-threatening side effects compared to those associated with opioids. Pure D9THC may be effective in the treatment of chemotherapy-induced nausea and vomiting and is a recognized appetite stimulant in patients with terminal disease. Relief of skeletal muscle spasms in patients with multiple sclerosis has been described. The use of D9THC may be associated with an increased risk of myocardial infarction and thromboangiitis obliterans, perhaps reflecting D9THC-induced platelet activation.87
Two receptors for endogenous and exogenous cannabinoids have been described, CB1 and CB2. CB1 receptors are principally expressed on neurons and their activation has been associated with antinociception. CB2 receptors are principally expressed on glia and immune cells and their activation is associated with antiinflammatory activity and reduction in chronic and neuropathic pain. Subtype-specific agonists are under investigation for pain therapy in order to overcome the problem of a narrow therapeutic window seen with nonsubtype selective cannabinoid drugs between pain relief and psychogenic effects.88
PSYCHOSTIMULANTS
Methylphenidate is a psychostimulant used for the treatment of attention deficit hyperactivity disorder and narcolepsy. Similar to amphetamines, it blocks the reuptake of norepinephrine and dopamine. The data is limited as to the effect these psychostimulants may have on the anesthetized patient when used at clinical doses, but it is commonly thought that the risk of intraoperative hemodynamic instability and arrhythmias may be increased. A small case study showed that patients who take chronic prescription amphetamines are hemodynamically stable during anesthesia.89 It is unclear what the effects anesthesia may have when methylphenidate is being abused, but anesthesia providers should be aware of its abuse potential.
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