Historical Perspective
In 2016, 395 million prescriptions for drugs used in the treatment of mental health were dispensed in the United States. A further 387 million prescriptions were dispensed for other neurologic disorders. Combining these two therapeutic classes, neuropharmacologic agents represent the most prescribed family of drugs, exceeding antihypertensives (721 million), antinociceptives (460 million), antibacterials (270 million), lipid regulators (264 million), and diabetes treatments (224 million). Antidepressants are the most frequently used drugs in adults aged 18 to 44 years and are taken by 13% of persons aged 20 years and older. Neuropharmacology also includes a heterogeneous and expanding collection of antipsychotics, mood stabilizer agents, psychostimulants, and drugs used in the treatment of epilepsy, Parkinson disease, and addiction. Considered together, drugs used to treat mental health and neurologic disorders are encountered by anesthesiologists as a matter of routine daily practice. They have diverse effects on neuronal systems, including those that are the principal targets of anesthetic agents, and many are associated with significant unwanted actions on central and peripheral signaling across broad transmitter classes. Many alter hepatic cytochrome P450 isoenzyme (CyP) activity and thus can have significant drug interactions by affecting metabolism of other agents. The potential impact of psychopharmacologic drugs on perioperative physiology is enormous. In addition to altering the central nervous system (CNS) response to sedative and hypnotic agents, they can alter autonomic responsiveness, cardiac conduction, bleeding, seizure potential, the endocrine response to stress, and multiple other physiologic variables that fall under the purview of anesthesiology. Similar considerations apply to the anticonvulsant and anti-parkinsonian therapeutic classes. Finally, drugs of abuse, with wide-ranging short- and long-term effects on the CNS, have critically important implications for the safe delivery of anesthesia in both the acutely intoxicated and addicted patient.
Because the core aspects of clinical practice in both psychiatry and neurology are distinct from those of anesthesiology, and because many psychopharmacologic agents have emerged only very recently, anesthesiologists might have an incomplete baseline awareness of the actions and adverse effects associated with these drugs and be less likely to encounter timely updates. This chapter presents a focused introduction to most of the neuropsychiatric drugs encountered in perioperative patients. An exhaustive description can be found in dedicated reference texts.
Antidepressant Drugs
Tricyclic Antidepressants
History
The iminodibenzyl derivatives were initially investigated in humans in the 1950s for their sedative and antihistaminic properties. The sedative properties of the archetypal drug imipramine proved to be of little benefit in the treatment of agitated patients, but serendipitously it was noted to relieve the symptoms of depression. Subsequently, several other tricyclic compounds were developed, and the class remained the first-line treatment for depression until the rapid expansion in use of selective serotonin reuptake inhibitors (SSRIs) in the 1990s. Early advances in the neuropsychopharmacology of depression—including the importance of the serotonin and noradrenergic pathways—owed much to the study of this class of compounds.
Basic Pharmacology
Structure-Activity
The tricyclic antidepressants are named because of their central three-ring complex with a single side chain. The class is then further divided into two subgroups on the basis of the side chain: the tertiary amines have two methyl groups at the end of the side chain, whereas the secondary amines possess a single methyl group ( Fig. 12.1 ). Although these compounds block both the serotonin transporter and the norepinephrine transporter, the relative potency for each is largely determined by the nature of the side chains. The tertiary amines have dominant effects on serotonin reuptake, whereas the secondary amines have greater potency on norepinephrine reuptake. Amoxapine is a structurally unique tricyclic antidepressant derived from the antipsychotic loxapine; it is characterized by potent inhibition of norepinephrine reuptake and dopamine receptor block by the metabolite 7-hydroxy-amoxapine. Maprotiline is unique in possessing a four-ring central structure and is referred to as a tetracyclic or heterocyclic. It possesses the secondary amine side chain and predictably has dominant effects on norepinephrine transport.
Mechanism
The antidepressant effects of the tricyclic drugs are mediated by effects on two monoaminergic systems—serotonin and norepinephrine—although it is not clear to what extent this implicates specific abnormalities of serotonin and norepinephrine signaling and pharmacology in the biochemical pathogenesis of depression ( Fig. 12.2 ). Although modulation of reuptake occurs rapidly, clinical benefit is not seen until several weeks of treatment, suggesting that downstream changes in gene expression and neuroplasticity are critically involved. The decreased uptake initially causes feedback inhibition via presynaptic 5-HT 1A autoreceptors, but this is followed by desensitization and a return to normal firing rate after 2 weeks. Postsynaptic 5-HT 1A receptors become sensitized, while antagonism of postsynaptic 5-HT 2 receptors further increases the effects of serotonin. In contrast, presynaptic α 2 -receptors do not desensitize, and the firing rate of noradrenergic neurons remains inhibited throughout treatment. The noradrenergic mechanism likely includes complex modulatory effects on the expression of postsynaptic α 1 -, α 2 -, and β-adrenergic receptors and on their second-messenger systems. Tricyclic antidepressants also have variable antagonist activity at 5-HT 6 , 5-HT 7 , N-methyl- d -aspartate (NMDA)-type glutamate, H 1 – and H 2 -histaminergic, and muscarinic acetylcholine receptors. They also have variable agonist activity at µ 1 -opioid receptors. Accumulating evidence also suggests that the antidepressant effects of the tricyclics, and other classes of antidepressants, may involve transduction by the neurotrophin brain-derived neurotrophic factor (BDNF) and the tropomysin-related kinase B (TrkB) receptor.
Metabolism
Metabolism is almost exclusively hepatic and dominantly involves either hydroxylation of the ring structure or demethylation of the side chain. The tertiary amines are demethylated to active secondary amines (e.g., imipramine to desipramine), which incurs an increase in noradrenergic activity. Many of the hydroxylated metabolites are also active. The principal CYP) isoenzymes involved are 2D6, 1A2, 3A4, and 2C19. Variability in metabolism and plasma levels can be dramatic, owing to both exogenous modulation of the CYP system and to genetic polymorphisms that occur in up to 20% of Asian and 10% of Caucasian and African black populations.
Clinical Pharmacology
Pharmacokinetics
The tricyclic antidepressants are rapidly absorbed from the small intestine and mostly attain peak plasma levels in 2 to 8 hours. They are highly protein bound (>90%) and lipophilic, with large volumes of distribution up to 60 L/kg. Bioavailability is variable, with on average about 50% to hepatic first-pass metabolism. Plasma half-life is longer than 24 hours for most drugs (the exception being amoxapine), allowing for once-a-day dosing. However, variation is significant and determined largely by genetic and phenotypic variability. The daily dose is thus not a reliable determinant of steady-state plasma levels. Further, a relationship between plasma concentration and therapeutic response, while demonstrated for some drugs, has not been established across the entire class. Monitoring of plasma levels, though often suggested, remains controversial because of the lack of validated interpretation studies. The level of recommendation for plasma monitoring is highest for amitriptyline, nortriptyline, clomipramine, and imipramine. Dosing is often started low and increased gradually based on therapeutic response, with monitoring of plasma levels reserved for patients suspected to be at the extremes of rapid and slow metabolizers.
Pharmacodynamics
Therapeutic Effects.
Tricyclic antidepressants have demonstrated efficacy in the treatment of major depression. Response rates for patients completing treatment with imipramine, the most studied drug, exceed 65%. However, substantial caution must be implied in the interpretation of efficacy studies, as the response to placebo is ~40%; a recent Cochrane review suggests that compared with placebo, the median number needed to treat was 9. They are also effective for maintenance therapy, with up to 80% of patients successfully maintained for 3 years. Relative to other classes of antidepressants, the tricyclics might have an efficacy advantage in patients with severe or endogenous depression, or in those who are hospitalized, although this is not clearly established. Low doses (75–100 mg) of tricyclics are as effective as higher doses. They have no particular advantage over other agents in the treatment of anxious, atypical, psychotic, bipolar, or late-life depression. Because of its high serotonergic activity, clomipramine is effective and is used for the treatment of obsessive-compulsive disorder. The tricyclics are also used in panic disorder. Desipramine is effective in the treatment of attention deficit/hyperactivity disorder, but its use is contraindicated in children because of reports of sudden cardiac death. Tricyclics are also widely used in the treatment of chronic and neuropathic pain syndromes (see Chapter 19 ), and are more effective than the SSRIs in this regard. A recent Cochrane review showed a number-needed-to-treat of 3.6 and a relative risk of 2.1 for at least moderate relief of neuropathic pain with tricyclic antidepressants. The effects appear independent of those on depression, and generally occur at lower doses, consistent with a distinct underlying mechanism, with antinociceptive actions mediated by effects on descending serotonin and norepinephrine spinal pathways.
Adverse Effects.
The most common side effects associated with tricyclic antidepressants result from their antimuscarinic and antihistaminic actions. Amitriptyline and clomipramine have the greatest antimuscarinic potency and desipramine the lowest. Dry mouth, urinary hesitancy, decreased gastric motility, and blurred vision are relatively common. Ocular crisis can be precipitated in patients with narrow-angle glaucoma. H 1 -histaminic blockade results in sedation. Confusion and delirium are dose-dependent and result from the combination of anticholinergic and antimuscarinic activity. Patients with preexisting dementia or psychotic depression are especially at risk, and the incidence is highest with amitriptyline. There is also a dose-dependent risk of seizure, although the incidence is poorly defined. It is less than 1% across the drug class if plasma level monitoring is appropriately used. A recent study of more than 150,000 patients found the incidence of seizure to be no greater than in nonusers of antidepressants. Nonetheless, use of these drugs in patients with elevated seizure risk is not advisable. The overall incidence of CNS toxicity is approximately 6%. Tricyclic antidepressants cause orthostatic hypotension, especially in patients receiving antihypertensive therapy, and also cause a persistent increase in heart rate. They inhibit sodium-potassium adenosine triphosphatase (Na + ,K + -ATPase) and act like class Ia (quinidine-like) antiarrhythmics by stabilizing excitable membranes and delaying His bundle conduction, and so must be used cautiously in patients with a prolonged QTc interval. In overdose, sudden death can occur from cardiac arrhythmia at doses of only 10 times the therapeutic dose. Largely because of this arrhythmia risk, the mortality associated with tricyclic overdose is approximately 15 times that associated with SSRI overdose a significant factor in the rapid acceptance of SSRIs as first-line therapy for treatment of depression.
Drug Interactions
The complex effect of tricyclic antidepressants on presynaptic and postsynaptic noradrenergic signaling can alter the response of patients to sympathomimetic drugs used in the perioperative period (see Chapter 25 ). During initial treatment, patients can have an exaggerated response to indirect-acting sympathomimetics such as ephedrine owing to increased presynaptic availability of norepinephrine. In contrast, adrenergic desensitization and catecholamine depletion can result in a relatively refractory response to sympathomimetics in patients treated long term; such patients might respond best to the potent direct-acting sympathomimetic norepinephrine. Tricyclic antidepressants can exaggerate rebound hypertension following discontinuation of antihypertensives, likely owing to changes in norepinephrine uptake. Tricyclic antidepressants can increase arrhythmogenicity in the presence of volatile anesthetics, although these observations are dominantly with halothane and have not been seen with newer volatile anesthetics. The anticholinergic effects of tricyclic antidepressants are expected to be additive to those of other drugs used in the perioperative period, and special caution should be used in administering centrally acting anticholinergics in those patients taking tricyclics who are at increased risk of delirium and dementia. Chronically administered barbiturates are potent inducers of CYP3A4 and can increase metabolism of tricyclic antidepressants, but significant effects are unlikely after a single anesthetic administration. Tricyclics are not known to have any effects on CYP isoenzyme induction or inhibition that are of significance to common anesthetic management.
Selective Serotonin Reuptake Inhibitors
History
The SSRIs were developed in the early 1970s when series of compounds derived from 3-phenoxy-3-phenylpropylamine—which is structurally similar to diphenhydramine—were tested for selective inhibition of serotonin (5-HT) reuptake. The most potent and selective of the compounds was identified and named fluoxetine, and was eventually approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depression in 1987 (Prozac). This was followed by sertraline (Zoloft) in 1991, paroxetine (Paxil), citalopram (Celexa) in 1998, and escitalopram (Lexapro) in 2002. Fluvoxamine (Luvox) was approved in 1993, and is distinctive because its FDA approval is restricted to the treatment of obsessive-compulsive disorder; it is, however, approved for the treatment of depression in other countries. A highly favorable safety profile compared with the tricyclic antidepressants rapidly propelled fluoxetine and later SSRIs to become the dominant antidepressant agents, although in recent years their commercial success relative to their clinical efficacy has been questioned.
Basic Pharmacology
Structure-Activity
There is considerable diversity in the chemical structure-activity relations among the SSRIs ( Fig. 12.3 ). Fluoxetine exists as a racemate, with both the (S)- and (R) -enantiomers pharmacologically active. Citalopram was initially introduced as a racemate, with the more potent (S)- enantiomer (escitalopram) subsequently isolated. All SSRIs possess relatively high affinity for serotonin uptake sites, low affinity for norepinephrine uptake sites, and very low affinity for neurotransmitter receptors, although there is considerable variability. Fluoxetine is the least selective of the class, with citalopram and escitalopram the most selective. Sertraline is unique as a more potent inhibitor of dopamine uptake than any of the SSRIs or tricyclic antidepressants. Activity at H 1 -histaminergic, α 1 -adrenergic, and muscarinic receptors is minimal and unlikely to be of clinical significance, which is responsible for the absence of many of the side effects associated with tricyclic antidepressants.
Mechanism
The mechanisms for the therapeutic effects of the SSRIs are not clearly established, but were initially believed to derive from blockade of 5-HT reuptake into serotonergic neurons, prolonging the duration of exposure to 5-HT at postsynaptic binding sites (see Fig. 12.2 ). In contrast to direct 5-HT receptor agonists, the action of SSRIs depends on presynaptic 5-HT release, and they are ineffective if release of 5-HT is compromised. Because therapeutic effects are not fully realized within 2 to 8 weeks, it is unlikely that reuptake inhibition, which occurs far sooner, is mechanistically sufficient. Several downstream effects have been mechanistically postulated. Initially, inhibitory autoreceptors in the soma (5-HT 1A ) and terminals (5-HT 1B ) are stimulated, and neuronal firing rates decrease. Normalization of firing rates occurs with downregulation of these autoreceptors and decreased production of 5-HT 1B messenger ribonucleic acid (mRNA), and coincides temporally with the onset of therapeutic efficacy. In the same temporal window there is increased production of neuroprotective proteins, including BDNF ( Fig. 12.4 ). SSRIs also possess significant antiinflammatory properties, which may target proinflammatory signaling associated with the onset of depression.
Metabolism
SSRIs are oxidatively metabolized in the liver. Several CYP isoenzymes are involved, including 2D6, 2C9, 2C19, 1A2, and 3A4, with significant differences among the drugs in relative importance. While all SSRIs except fluvoxamine have pharmacologically active major metabolites, only that of fluoxetine (norfluoxetine) is likely of therapeutic significance.
Clinical Pharmacology
Pharmacokinetics
The SSRIs are well absorbed from the small intestine and most attain peak plasma levels in 2 to 8 hours. Protein binding is high (>80%), except with escitalopram, with volumes of distribution mostly in the range of 10 to 20 L/kg, somewhat less than seen with the tricyclic antidepressants. Plasma half-life is mostly around 20 to 30 hours, with fluoxetine somewhat longer (24–72 hours) and fluvoxamine shorter (15 hours). Norfluoxetine, the active metabolite of fluoxetine, has a half-life of 1 to 3 days. Once-a-day dosing is commonly used for all drugs except fluvoxamine, for which twice-daily dosing is preferred. There are known age and sex effects on plasma concentrations: sertraline concentrations are approximately 40% lower in young males than in older males or females, while fluvoxamine concentrations are 40% to 50% lower in males across all ages. Because no clear relationship between therapeutic efficacy and steady-state plasma concentrations has been established and because the therapeutic index is wide, plasma level monitoring is not used.
Pharmacodynamics
Therapeutic Effects.
SSRIs are efficacious in the initial treatment of major depression. There is little evidence to support that SSRIs as a class are more efficacious than other classes of antidepressants, including the tricyclic antidepressants, although one 2009 meta-analysis suggests that sertraline and escitalopram could have therapeutic advantages over other drugs, including other SSRIs. There is little evidence to support efficacy in children and adolescents, with a 2016 meta-analysis identifying that only drug in the class with possible benefit over placebo is fluoxetine. Although frequently prescribed for less severe depression, recent meta-analyses—some including trial data submitted to the FDA—question whether SSRIs have any significant therapeutic benefit. The onset of clinical improvement takes 2 to 3 weeks and might not be maximal for up to 8 weeks, suggesting that downstream effects, rather than 5-HT reuptake inhibition per se, are responsible.
SSRIs are also prescribed and are probably efficacious in several other psychiatric disorders believed to involve abnormalities of 5-HT systems. Meta-analysis has demonstrated SSRIs, and especially sertraline, to be effective in the initial treatment of obsessive-compulsive disorder, although it is unclear how serotonergic selectivity confers therapeutic benefit. SSRIs are also used for the prevention of panic attacks in panic disorder, and, because of postulated involvement of 5-HT in feeding behaviors, have been used in bulimia nervosa, anorexia nervosa, and obesity. They reduce symptoms of premenstrual dysphoric disorder and posttraumatic stress disorder, and are effective in the treatment of premature ejaculation.
Adverse Effects.
The SSRIs have a highly favorable side effect profile compared with other classes of antidepressants. The most common side effects include sexual dysfunction, weight changes, dizziness, and insomnia. Although the effects of SSRIs on suicidality in adults are unclear, they increase suicidality in patients younger than 24 and carry an FDA black box warning for use in this age group. SSRIs have effects on cardiac Na + , K + , and Ca 2+ channels and can theoretically cause QTc prolongation, but there is no observable increase in the risk of dysrhythmia. SSRIs decrease platelet 5-HT content and inhibit platelet aggregation, and can increase bleeding, especially when combined with other anticoagulants. One retrospective study of orthopedic patients demonstrated a significantly increased risk of transfusion in patients taking serotonergic antidepressants, but not with those taking nonserotonergic agents, while another demonstrated a significant, though not clinically important, increase in bleeding in patients undergoing hip arthroplasty. However, there is insufficient consensus to support perioperative changes in SSRI therapy on the basis of bleeding risk. SSRIs have effects on bone metabolism and are associated with increased risk of fracture. Overdose with a single SSRI is very rarely fatal and is usually associated with minimal sequelae. Citalopram is the most likely to cause QTc prolongation, but even with extremely high doses, arrhythmias are exceedingly rare.
Serotonin syndrome is a potentially fatal adverse reaction to serotonergic drugs resulting in mental status changes, autonomic hyperactivity, and neuromuscular hyperactivity. Initially this can be very difficult to distinguish from malignant hyperthermia. Although theoretically possible, induction of serotonin syndrome by a single SSRI is rare, and they are usually only implicated in combination with other drugs. Several drugs used in the perioperative period—notably cocaine, ondansetron, and fentanyl—have the potential to directly or indirectly augment serotonergic activity, and this should be considered when assessing patients exhibiting hypermetabolic activity.
Drug Interactions
Significant drug interactions are less likely with SSRIs than with earlier classes of antidepressants. Perhaps the most likely source of interaction results from SSRI-induced inhibition of specific CYP isoenzymes, notably 2D6 and 2C19. However, this effect is of little relevance to the vast majority of drugs handled by anesthesiologists. Anesthesiologists should be aware of the potential for SSRIs to potentiate the QTc prolongation and antiplatelet effect of other drugs used in the perioperative period, and the serotonergic effect of methylene blue.
Monoamine Oxidase Inhibitors
The antidepressant actions of monoamine oxidase inhibitors (MAOIs) were identified in the 1950s. One member of this class—iproniazid—historically represents one of the earliest attempts to treat depression pharmacologically. MAOIs continue to have clinical utility in the treatment of resistant depression, and can be particularly effective in treating atypical depression. However, because of their severe and dangerous food and drug interactions, the classic MAOIs remain a treatment of last resort and are encountered relatively rarely. However, it is critical for anesthesiologists to recognize and be aware of these drugs, in that the potential for adverse interactions with agents used in the perioperative period exceeds that of any other psychopharmacologic class.
Basic Pharmacology
Monoamine oxidase (MAO) exists as two isoenzymes, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, epinephrine, norepinephrine, and melatonin, whereas MAO-B preferentially deaminates phenylethylamine, phenylethanolamine, tyramine, and benzylamine. Dopamine and tryptamine are deaminated by both isoenzymes. In the CNS, MAO-A is concentrated in dopaminergic and noradrenergic neurons, whereas MAO-B is concentrated in serotonergic neurons. Both are also found in glial cells. Outside the CNS, MAO-A is found in the gastrointestinal tract, liver, and placenta, and MAO-B in platelets. The reason for the apparent discrepancy between the dominant substrates and localization is unknown.
MAOIs act by inhibiting MAO, thereby increasing the availability of monoaminergic transmitters (see Fig. 12.2 ). All MAOIs currently available in the United States bind irreversibly, inhibiting enzyme activity for up to 2 weeks. Changes in α 1 -, α 2 -, 5-HT 1 , and 5-HT 2 receptors emerge after several weeks. Phenelzine is a hydrazine derivative and nonselective, while tranylcypromine is nonselective and chemically related to amphetamine. Selegiline is selective for MAO-B at lower doses but becomes nonselective at higher doses; metabolites of selegiline include L-amphetamine and L-methamphetamine. In 2006, selegiline became available as a transdermal patch. This system avoids inhibition of intestinal and hepatic MAO-A, thereby reducing food-drug interactions and obviating the need for dietary restriction.
Clinical Pharmacology
MAOIs are used to treat a variety of psychiatric conditions but have received greatest acceptance for atypical depression, which is characterized by early age of onset, dysthymia, alcohol abuse, and sociopathy. They are more effective than the tricyclic antidepressants in treating this disorder. MAOIs are also therapeutic in typical major depression, panic disorder, bulimia nervosa, atypical facial pain, and treatment-resistant depression. The transdermal patch form of selegiline is approved for use in major depression, although its efficacy relative to other drugs is not well studied.
Adverse Effects, Dietary Interactions, and Drug Interactions
Common adverse effects of MAOIs include dizziness, headache, dry mouth, nausea, weight gain, peripheral edema, urinary hesitancy, and myoclonic movements. Orthostatic hypotension is common in older patients and can necessitate mineralocorticoid treatment. MAOIs can augment the response to insulin and other hypoglycemic agents increasing the risk of hypoglycemia. Phenelzine has anticholinergic action.
Dietary Interactions
Orally ingested MAOIs inhibit the catabolism of dietary amines. The consumption of foods containing tyramine can lead to severe hypertensive crisis within an hour of eating. Decreased first-pass breakdown of tyramine leads to elevated systemic levels. Tyramine is transported via vesicular monoamine transporter (VMAT) into synaptic vessels, where it displaces norepinephrine, and the release of norepinephrine precipitates the hypertensive crisis. Patients using oral MAOIs must adhere to dietary restrictions to avoid precipitation of a crisis. Key foods that must be avoided include cheese, sausage meats, red wine, overripe fruits, fermented products, and some yeasts. Transdermal selegiline does not require dietary restrictions.
Drug Interactions
Irreversible inhibition of MAO by MAOIs leads to several potentially dangerous drug interactions when therapy is combined with sympathomimetic agents. In the outpatient setting, significant caution is required when crossing over to or from other psychopharmacologic agents that alter monoaminergic activity, such as SSRIs, tricyclic antidepressants, or stimulants. Several over-the-counter medications contain indirect-acting sympathomimetics and are able to precipitate a hypertensive crisis. In the perioperative setting, several drugs have the potential for dangerous interactions. The most notable of these is meperidine, which can precipitate a type I excitatory response with hypertension, clonus, agitation, and hyperthermia, or a type II depressive response with hypotension, hypoventilation, and coma. This effect is believed to result from meperidine’s serotonin reuptake inhibition properties. Members of the phenylpiperidine opioids, which include tramadol, fentanyl, alfentanil, sufentanil, and remifentanil, are also serotonin reuptake inhibitors and have been associated with perioperative serotonergic toxicity, as has methadone. Morphine does not appear to precipitate serotonergic crisis and is perhaps the drug of choice when opioids must be used in patients taking MAOIs. Indirect sympathomimetics, such as ephedrine, can precipitate an exaggerated pressor response owing to increased release of norepinephrine and so should be avoided. Direct-acting drugs such as phenylephrine are preferable, although the response can be exaggerated owing to receptor hypersensitivity. Ketamine should similarly be avoided, although its safe use has been described.
Atypical Antidepressants
Several drugs currently used in the treatment of depression and related disorders have structures and mechanisms that cannot be placed in any of the broad classes described and are commonly referred to as atypical, second-generation antidepressants. The most important of these are summarized in Table 12.1 . Like the tricyclic antidepressants and SSRIs, the therapeutic mechanism of these agents is poorly understood. All drugs share effects on signaling or transmitter availability in at least one monoaminergic (serotonergic, noradrenergic, or dopaminergic) pathway.
Anxiolytic Drugs
Benzodiazepines
History
The first benzodiazepine, chlordiazepoxide (Librium), was introduced in 1960. This was followed in 1963 by diazepam (Valium), the archetypal compound from which many derivatives were synthesized. The benzodiazepines were rapidly embraced as treatments for anxiety because they were considerably safer than the barbiturate alternatives and were extensively prescribed until the 1980s. In the past 25 years, benzodiazepine use has declined, partly because of awareness and concerns regarding addiction, withdrawal, and recreational abuse, and also because of the evolution of the SSRIs as a safe and effective first-line therapy for anxiety and panic disorder. Nonetheless, alprazolam (Xanax), a triazolobenzodiazepine introduced in 1981 for the treatment of panic disorder, remains the single most prescribed psychiatric medication, with 48 million prescriptions in 2016.
Basic Pharmacology
Structure-Activity
The core structure of the benzodiazepines is the fusion of benzene and diazepine ring systems. All therapeutically active drugs are substituted 1,4-benzodiazepines, with many containing a 5-phenyl-1 H -benzo[ e ][1,4]diazepin-2(3 H )-one substructure ( Fig. 12.5 ).
Mechanism
Benzodiazepines act by binding at the interface of the α and γ subunits of the GABA A receptor. This binding site is distinct from that of endogenous agonist GABA (which binds between the α and β subunits), and also from other GABAergic drugs, such as barbiturates ( Fig. 12.6 ). Benzodiazepines allosterically modulate the receptor such that it has greater affinity for GABA. This increases the opening time of the associated chloride channel, which leads to hyperpolarization or stabilization of the resting membrane potential near the chloride equilibrium potential. Because binding requires a specific histidine residue in the α subunit, benzodiazepines act only at receptors containing α 1 , α 2 , α 3 , or α 5 subunits, and have no action on receptors containing α 4 or α 6 subunits. Benzodiazepines are heterogeneous in their affinities for various GABA A receptor subtypes, which underlies the differences in their pharmacologic effects. For example, anxiolysis is associated with greater relative affinity for the α 2 subunit.
Metabolism
Most benzodiazepines are highly protein bound and undergo microsomal oxidation in the liver via CYP enzymes, especially CYP 3A4. Their metabolism is therefore altered by the presence of drugs that either inhibit or induce CYP activity, as well as by age and disease. Several benzodiazepines have active metabolites, including a number with half-lives considerably longer than the parent compound; the half-life of the partial agonist N-desmethyldiazepam, the principal metabolite of diazepam, can exceed 100 hours. Three benzodiazepines—oxazepam, lorazepam, and temazepam—are metabolized by glucuronidation and have no significantly active metabolites; these are therefore preferred in older adults and in patients with hepatic disease.
Clinical Pharmacology
Pharmacokinetics
Benzodiazepines vary substantially in their absorption and rate of elimination ( Table 12.2 ). Although differences in affinities for specific GABA A receptor subtypes lead to greater or lesser propensity to alter a particular cognitive function, heterogeneity in pharmacokinetic properties largely determines the clinical application of individual drugs. Duration of action is principally a function of α phase (distribution-redistribution) dynamics rather than rate of elimination in most applications.
| Class | Drug | Common Trade Name | Onset (min) | Duration (hr) | Vd (L/kg) | Protein Binding (%) | t{ 1/2 } (hr) |
|---|---|---|---|---|---|---|---|
| Desmethyldiazepam | Diazepam | Valium | 30 | 2–3 | 0.8–1.0 | 98 | 20–50 |
| Chlordiazepoxide | Librium | 60–120 | ≤24 | 3.3 | 90–98 | 6.6–25 | |
| Desalkylflurazepam | Flurazepam | Dalmane | 15–20 | 7–8 | 3.4 | 97 | 74–90 |
| Clonazepam | Klonopin | 20–60 | ≤12 | 1.5–4.4 | 85 | 19–50 | |
| Triazolobenzodiazepine | Triazolam | Halcion | 15–20 | 6–7 | 0.8–1.8 | 89 | 1.5–5.5 |
| Alprazolam | Xanax | 60 | 3.5–7 | 0.9–1.2 | 80 | 11.2 | |
| Thienodiazepine | Nitrazepam | Mogadon | 20–50 | 6–10 | 2.4 | 87 | 30 |
| Flunitrazepam | Rohypnol | 15–30 | 7–8 | 4.6 | 78 | 22 | |
| Oxazolobenzodiazepine | Oxazepam | Serax | 45–90 | 6–12 | 1.0–1.3 | 86–99 | 2.8–5.7 |
| Lorazepam | Ativan | 5–20 | 6–8 | 1.3 | 85 | 12.9 | |
| Temazepam | Restoril | 20–40 | 6–8 | 1.4 | 96 | 9.5–12.4 |
Pharmacodynamics
Therapeutic Effects.
Benzodiazepines have a wide spectrum of uses in psychopharmacology owing to their sedative, hypnotic, amnesic, anxiolytic, anticonvulsant, and muscle-relaxant properties. They are efficacious in the short-term treatment of panic disorder, but have largely been replaced by SSRIs as the first-line pharmacotherapy and are generally not regarded as appropriate for long-term monotherapy or combination therapy. Similarly, they are effective in the initial management of generalized anxiety disorder, but do not modify the course when used long term. Benzodiazepines remain a common therapy for short-term treatment of insomnia, although their use has declined with greater awareness of dependence and cognitive side effects in older adults. The time to onset and duration of sleep are prolonged, but there is a characteristic reduction in rapid-eye movement (REM) sleep, increase in non-REM sleep, and reduction in delta electroencephalographic activity. They are also used as second-line treatment in the nonacute management of seizure disorders and as first-line treatment in alcohol withdrawal syndrome. Benzodiazepines are also used for their muscle relaxant properties. Despite clear evidence that long-term benzodiazepine use is rarely helpful and can be harmful, long-term use remains common.
Adverse Effects.
Benzodiazepines can cause prolonged sedation, impaired cognition, and psychomotor performance, and unwanted amnesia. In older patients, they can precipitate delirium states and increase the risk of accidents and falls. Drugs with long-acting metabolites pose the greatest risk. However, the most significant risks associated with benzodiazepine use occur owing to dependence and withdrawal effects. Abrupt withdrawal can precipitate delirium, anxiety, panic, seizures, insomnia, and muscle spasm.
Drug Interactions
Although widely believed, it is not clear that patients on chronic benzodiazepine therapy have significant cross-tolerance to nonbenzodiazepine GABAergic anesthetic agents, or that the risk of intraoperative recall is elevated with long-term use. Acutely, benzodiazepines augment the CNS depressant effects of sedative-hypnotic anesthetic drugs and opioids, such that dosage reduction is appropriate. Although many benzodiazepines are metabolized by CYP 3A4, they are generally not strong inducers or inhibitors, and effects on the metabolism of other drugs used in the perioperative period are generally not significant.
Antipsychotic Drugs
First-Generation (Typical) Antipsychotics
The introduction of chlorpromazine (Thorazine) in 1952 arguably represents the most significant single development in psychopharmacology. Before that, treatment for psychosis was largely supportive and ineffective, with only electroconvulsive therapy and psychosurgery standing as controversial therapeutic options. The ability to treat psychosis effectively with drugs heralded massive deinstitutionalization as patients were discharged from psychiatric long-term care facilities and integrated into the community.
Pharmacology
The first-generation, or typical, antipsychotics include drugs from several classes: phenothiazines, butyrophenones, thioxanthenes, dihydroindolones, dibenzepines, diphenylbutylpiperidines, benzamides, and iminodibenzyls ( Table 12.3 ). The butyrophenone class includes haloperidol (Haldol) and droperidol, two of the only psychopharmacologic agents commonly administered by anesthesiologists, although the latter is usually used for its antiemetic rather than its antipsychotic actions (see Chapter 34 ).
The principal mechanism for treatment of schizophrenia and other psychoses is blockade of D 2 dopamine receptors in the mesolimbic dopamine system. Dopamine receptors are G-protein–coupled receptors that exist in multiple subtypes ( Table 12.4 ). They can be grouped as D 1 -like (activate adenylyl cyclase) or D 2 -like (inhibit adenylyl cyclase) based on their signaling mechanisms. However, first-generation antipsychotic (FGAs) are not selective and have variable effects on D 1 , D 3 , and D 4 receptors; M 1 muscarinic cholinergic receptors; H 1 -histamine receptors; α 1 – and α 2 -adrenergic receptors; and both 5-HT 1 and 5-HT 2 serotonergic receptors. The effects on these other receptors appear to have little influence on the therapeutic efficacy, but they are of considerable importance to the side effect profile of individual drugs. Most FGAs are highly protein bound and lipophilic, and have large volumes of distribution (10–40 L/kg) with very significant variation in steady-state plasma concentrations. Oral preparations undergo extensive hepatic first-pass metabolism through hydroxylation, demethylation, and glucuronidation via CYP enzymes, and metabolites are dominantly eliminated in urine and bile. Elimination half-lives vary from 18 to 40 hours, allowing for once-a-day dosing. In the United States, depot preparations of haloperidol and fluphenazine are available as the decanoate ester suspended in sesame oil. After intramuscular injection, the esterified drug is slowly excreted from the oil and hydrolyzed, permitting dosing at intervals of 2 to 4 weeks.
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