Psychotropic Drugs for Dental Practice PDF

CONTINUING EDUCATION Psychotropic Drugs: Implications for Dental Practice Daniel E. Becker, DDS Professor of Allied Health Sciences, Sinclair Community College, and Associate Director of Education, General Dental Practice Residency, Miami Valley Hospital, Dayton, Ohio Appropriate preoperative asse...

CONTINUING EDUCATION Psychotropic Drugs: Implications for Dental Practice Daniel E. Becker, DDS Professor of Allied Health Sciences, Sinclair Community College, and Associate Director of Education, General Dental Practice Residency, Miami Valley Hospital, Dayton, Ohio Appropriate preoperative assessment of dental patients should always include analysis of their medications. Psychiatric illnesses including panic/anxiety disor- der, depression, psychoses, and manic disorders are prevalent within our society. An impressive number of drug formulations are prescribed for these disorders, and they introduce concern regarding side effects and possible drug interactions with medications the dentist may deem necessary for dental care. This article will address essential pharmacology of these psychotropic medications. Key Words: Preoperative assessment; Drug interactions; Drug side effects; Drug toxicity; Psychotropic drugs. L ike the peripheral system, the performance of neu- rons within the central nervous system is predi- cated on the activity of neurotransmitters. In addition anger) and is considered a central component of this sys- tem. Other components include portions of the cortex, thalamus, and basal ganglia that function to integrate to acetylcholine and norepinephrine, however, many emotional state with motor and visceral activities. additional transmitters have been identified. Their pre- Psychiatric illnesses are believed to result in part cise functions are not fully understood, but some use- from biochemical derangements within the limbic fulness can be derived from the simple fact that neu- structures. Much of this reasoning is based on known ron-to-neuron synapses are either excitatory or inhibi- pharmacological actions of several psychotropic drug tory. Normal function of the CNS requires a delicate classes. For example, the efficacy of antipsychotic balance between these influences. It must be under- medications is attributed to inhibiting the actions of stood that a particular neurotransmitter can inhibit dopamine, and the psychoses are therefore believed neurons in one brain area while exciting those in an- to be attributable in some manner to excess dopamine other. This is because neurotransmitters bind and acti- transmission. This reasoning is hardly scientific and vate a specific class of receptor, but receptors exist as merely reflects our current futility in comprehending many subtypes. For example, there are at least 14 sub- psychiatric illnesses. types of serotonin (5-HT ) receptors distributed Psychotropic drugs are agents used to treat psychi- throughout the various brain regions. Despite being atric disorders. They include sedative-anxiolytics, anti- activated by the same neurotransmitter, one subtype psychotics, antidepressants, and the antimanic agents. may produce excitation while another produces inhibi- While these drugs all act in some manner to alter the tion. A simplified synopsis of the principal neurotrans- activity of neurotransmitters, psychiatric illness cannot mitters and their most common responses mediated is be explained entirely on biochemical defects. Indeed, presented in Table 1. one cannot overlook the importance of psychological The ‘‘limbic system’’ is a functional label for all tracts and social factors in both the pathophysiology of men- and nuclei that contribute to emotional behavior and mo- tal illness, and its response to specific pharmacothera- tivational drive. The hypothalamus is credited as the peutic agents.2 source of most vegetative functions (eg, hunger, thirst, Received February 11, 2008; accepted for publication April 1, Sedative-Anxiolytics 2008. Address correspondence to Dr Daniel Becker, Miami Valley Drugs in this particular class have the ability to calm Hospital, Dayton, Ohio 45409; [email protected]. (anxiolytic), induce drowsiness (sedative), or promote Anesth Prog 55:89^99 2008 ISSN 0003-3006/08 E 2008 by the American Dental Society of Anesthesiology SSDI 0003-3006(08) 89 90 Psychotropic Drugs Anesth Prog 55:89^99 2008 Table 1. CNS Neurotransmitters, Receptors, and Response Mediated1 Neurotransmitter Receptors Response Gamma-aminobutyric acid (GABA ) GABA Inhibitory Glutamate, aspartate NMDA Excitatory Dopamine DA Inhibitory , excitatory 5-Hydroxytryptamine (serotonin) 5-HT Excitatory. inhibitory Histamine H-1 Excitatory. inhibitory Acetylcholine Muscarinic Excitatory. inhibitory Norepinephrine Alpha, beta Excitatory. inhibitory Epinephrine Alpha, beta Excitatory. inhibitory sleep (hypnotic). These effects generally follow a clas- ditional benzodiazepines. These newer agents include sic dose-response pattern. For example, a drug mar- zolpidem ( Ambien) and Zaleplon ( Sonata), having rel- keted as an anxiolytic is formulated as a lower dosage atively fast onset and short durations, and eszopiclone than if it were to be promoted as a sedative or hypnot- ( Lunesta) having a slower onset and longer duration. ic for insomnia. Several of these agents are prescribed as skeletal muscle relaxants, but this effect is likely an extension of their anxiolytic properties. Distinct cen- Dental Implications for Patients Medicated tral mechanisms for anxiolysis, sedation, and skeletal With Sedative-Anxiolytics muscle relaxation have been postulated but have not been confirmed. Drug tolerance and dependence are the principal con- In addition to their useful effects, sedative-anxiolyt- cerns for the dentist when managing patients taking ics also have in common several side effects. As might sedatives chronically. Common sense dictates caution be expected, high doses of any CNS depressant can when administering sedation or general anesthesia depress respiration and cardiovascular tone. Chronic due to the potential for enhanced CNS depression. use leads to tolerance and dependence and, following However, tolerance develops following chronic use of abrupt discontinuation, a withdrawal syndrome oc- these agents, and patients may actually require greater curs. Furthermore, some patients experience paradox- doses to provide adequate sedation for dental treat- ical responses, ie, excitation rather than sedation. The ment. Further complicating matters is the fact that de- precise mechanism for this peculiar response cannot grees of tolerance or dependence can only be estimat- be explained but is known to occur with greater fre- ed based on the patient’s frequency and duration of quency among pediatric and geriatric patients. use. Although intravenous sedation allows for accura- The benzodiazepines are by far the most widely pre- cy of titrated doses, any decision regarding an oral scribed agents of this class. Virtually all of their effects dosage is empiric at best. Furthermore, if the patient can be explained by an ability to activate specific ben- has developed benzodiazepine dependence, over-se- zodiazepine receptors leading to a potentiation of dation cannot be countered using the reversal agent, gamma-aminobutyric acid (GABA )^ mediated influx flumazenil, for fear of inducing withdrawal. of chloride ions. They are unique compared with other The only drug interaction with benzodiazepines of sedatives in their ability to produce anterograde amne- concern to the dentist is the use of macrolide antibiot- sia. This is an advantage for the dentist prescribing ics, eg, erythromycin. These antibiotics compete for them for treatment anxiety but introduces concern CYP3A4 enzymes, which catalyze oxidative reactions when prescribed chronically for anxiety disorders or that inactivate most benzodiazepines and thereby ele- insomnia. This issue, added to those regarding abuse vate serum levels and prolong their half-lives. Loraze- and dependence, has diminished their medical use pam ( Ativan) is a notable exception because it is me- for chronic disorders in favor of antidepressant medi- tabolized via conjugation rather than oxidation. cations that lack these influences. In recent years, novel agents have been introduced for insomnia that are not benzodiazepine- derived, but Antidepressants nevertheless act as agonists at benzodiazepine recep- tors. Marketing strategies advertise them as nonbenzo- Major depression is one of the most common psychiat- diazepines in an effort to separate them from negative ric illnesses, afflicting more than 12% of men and impressions regarding traditional benzodiazepines. 20% of women at some point in life.3 The suicide rate However, their potential for anterograde amnesia and in such patients is roughly 30 times that of the general dependence is no different than that for the more tra- population and emphasizes the importance of effec- Anesth Prog 55:89^99 2008 Becker 91 tive treatment. Psychotherapy alone is effective in Tricyclic Antidepressants some forms of mild depression and is a useful adjunct in others, but drug therapy is clearly the treatment of Tricyclic antidepressants ( TCA ) are so named because choice for severely depressed patients.2 of their 3-ringed molecular structure. They differ in Precise neurochemical mechanisms for depression their propensities to inhibit neuronal uptake of either have not been defined. Historically, depressed patients norepinephrine or serotonin. Formerly, this was be- were thought to suffer deficiencies in central biogenic lieved to provide a basis for prescribing specific agents amines, eg, norepinephrine and serotonin. This belief for selected patients, and perhaps offered a biochemi- spawned continued development of drugs that elevate cal basis for classifying various forms of depression. the concentrations of these neurotransmitters within This belief is no longer tenable and, in fact, all agents the central nervous system. Although these drugs are and classes of antidepressants exhibit comparable effi- the foundation of treatment for depression, elevation cacy. Any basis for selecting a particular agent is large- of norepinephrine and serotonin levels per se cannot ly empiric and is correlated more with the patient’s entirely explain their effectiveness. Neurotransmitter medical status or the side effect profile of the particu- concentrations are elevated within hours of adminis- lar agent.4 tering an antidepressant, but clinical improvement is The tricyclic compounds also differ in their activity not appreciated for several weeks and may require as antagonists at cholinergic, histamine, and alpha re- several months for maximum benefit. Current specula- ceptors. All of these actions contribute to their seda- tion is that benefit arises from sustained elevations in tive side effect but individually explain their bother- these neurotransmitters that lead to alterations in the some peripheral autonomic side effects. Anticholiner- number or sensitivity of specific receptor subtypes.2,3 gic side effects most often present as xerostomia, Additional biochemical derangements that have been urinary retention, and constipation, while alpha recep- implicated in depression include dopamine deficien- tor blockade accounts for orthostatic hypotension. An- cies and elevations in stress hormone levels such as ticholinergic activity on cardiac tissues introduces a cortisol and corticotropin.3 The sum of all these con- risk for cardiac arrhythmias that is particularly trou- siderations suggests that depression is a consequence bling following drug overdoses. Although a precise of many derangements acting alone and in concert. mechanism has not been established, tricyclic agents It is not uncommon for antidepressant medications may also produce seizure activity, especially if patients to be described using the lay term, ‘‘mood-elevator.’’ have a preexisting disorder. Unfortunately, use of such a term nurtures a miscon- Amitriptyline ( Elavil) is generally regarded as the ception that antidepressants are CNS stimulants prototype of this group of antidepressants, but today when, in fact, their most troubling side effects often in- it is more commonly used in the management of in- clude sedation and lethargy. Conventional CNS stimu- somnia and chronic pain. Neurotransmission of pain lants such as amphetamine and cocaine increase con- (nociception) is inhibited by descending neural path- centrations of these neurotransmitters and transiently ways that release norepinephrine as a neurotransmit- elevate mood but produce agitation and lack benefit ter. Tricyclic antidepressants elevate norepinephrine in improving chronic negative ideations. Unlike CNS concentrations within these synapses and are effective stimulants, and conventional sedatives, antidepres- adjuncts for pain management at dosages well below sants have no potential for recreational abuse. those required for the treatment of depression. Their sedative influences make them particularly useful at night. Monoamine Oxidase Inhibitors The monoamine oxidase inhibitors ( MAOI ) were the Selective Serotonin Reuptake Inhibitors first class of drugs used to treat depression. As their name implies, they elevate norepinephrine and sero- The selective serotonin reuptake inhibitors ( SSRI ) in- tonin levels by limiting their oxidation by the enzyme hibit the neuronal uptake of serotonin and lack most monoamine oxidase ( MAO). The major drawback of of the annoying autonomic side effects associated with this drug class is its potential for serious food and drug tricyclic antidepressants. Fluoxetine ( Prozac) was the interactions, many of which precipitate an acute hy- first of this class to be introduced. The most common pertensive crisis. Compliance with medication instruc- adverse effects of SSRIs include nausea, diarrhea, tions is critical, and the depressed patient may not be headache, jitteriness, insomnia, fatigue and sexual so inclined. Phenelzine ( Nardil) is the only member of dysfunction. Sexual dysfunction (including decreased this class in current use. libido, impaired arousal and anorgasmia) is a common 92 Psychotropic Drugs Anesth Prog 55:89^99 2008 adverse effect and affects a significant number of pa- fusion, agitation, and neuromuscular irritability. This tients treated. Abrupt discontinuation of an SSRI re- has been observed with St John’s wart, an over-the- sults in dizziness, anxiety, and dysphoria. This with- counter herbal antidepressant, and the various ‘‘trip- drawal can be minimized by gradual tapering and is tan’’ drugs used for migraine headaches, eg, sumatrip- least likely to occur with fluoxetine, which has the lon- tan ( Imitrex). gest half-life.4 The SSRI antidepressants and many of the atypical It is difficult to assess negative publicity regarding a agents are gaining widespread use for conditions other possible association between SSRI antidepressants than depression. They have virtually replaced the ben- and suicidal or homicidal ideation. Current scientific zodiazepines for chronic management of most anxiety evidence does not support these concerns and most disorders. Other uses include chronic pain, eating dis- likely reflects the extensive use of SSRIs in psychiatric orders, and as adjuncts in managing alcohol abuse. patients already predisposed to suicidal tendency. The biochemical defect in premenstrual dysphoric There is particular controversy regarding the influence syndrome ( PMS ) is related to interplay of elevated sex of antidepressants on suicidal tendency among chil- hormone and diminished serotonin. Although fluoxe- dren and adolescents, but scientific data are sparse. tine is the only SSRI that has FDA approval for this Depression is a major risk factor for suicide, which indication, all of these antidepressants are effective. ranks third as the most common cause of death Dosages must be individualized, but are generally ad- among teens. During the past decade, the increased ministered for 7^10 days preceding each menses. use of antidepressants in teens has actually paralleled It should be emphasized that no category of antide- a significant decline in suicide rate.5 This represents pressant or specific agent has proven more effective an ‘‘association,’’ but does not prove cause-effect. Nev- than others for managing depressive illness.6 Howev- ertheless, it appears the overall benefit of antidepres- er, an unsatisfactory response to one agent does not sant therapy in this age group may outweigh any po- preclude therapeutic success with another. This is fre- tential for negative outcome. Clinical studies are un- quently the case following failure with the agent ini- derway to better define these issues. Meanwhile, tially selected. Selected antidepressants are summa- antidepressant therapy in this age group must be rized in Table 2. closely monitored. SSRI antidepressants are known to produce agitation and manic behavior as side effects, and these could contribute to suicidal tendency. Dental Implications for Patients Medicated With Antidepressants Atypical Antidepressants When prescribing or administering sedatives, use cau- tion for patients taking antidepressants that have sig- Newer ‘‘atypical’’ antidepressants are structurally unre- nificant sedative properties. Otherwise, the principal lated to the other classes, and their varied pharmaco- dental considerations for patients taking antidepres- logical actions preclude a more precise classification. sant medications are their potential drug interactions. For example, venlafaxine ( Effexor) and duloxetine The most important of these are summarized in Ta- (Cymbalta) inhibit reuptake of both norepinephrine ble 3, but a few of these will receive more detailed ex- and serotonin. Many texts refer to these as serotonin- planation. norepinephrine reuptake inhibitors. Although this ac- The most storied interaction of relevance to dentists tion resembles the tricyclic antidepressants, they have was the putative interaction between epinephrine and a different molecular structure and do not produce the the monoamine oxidase inhibitors. It was believed that autonomic side effects typical of the TCAs. Aggressive inhibition of MAO could potentiate the activity of epi- marketing by the manufacturer has persuaded some to nephrine by delaying its oxidation. While this is a valid believe these serotonin-norepinephrine reuptake in- consideration for many sympathomimetic drugs, it is hibitors have the greatest efficacy, but analysis of clin- not the case for epinephrine or levonordefrin ( NeoCo- ical studies is not convincing. befrin), which are catecholamines in structure and rely most heavily on methylation by catechol-O-methyl- Clinical Considerations transferase for their termination, not monoamine oxi- dase. Antidepressants that elevate serotonin levels are a Epinephrine and levonordefrin are not without concern if taken along with other medications that en- some concern, however. Cardiac tissues may be excit- hance serotonin levels. This can lead to a so-called se- ed by antidepressants that elevate norepinephrine lev- rotonin syndrome characterized by hyperpyrexia, con- els, and this could become accentuated with concur- Anesth Prog 55:89^99 2008 Becker 93 Table 2. Selected Antidepressants and Relevant Data 7 * Amine Elevated Side Effects Drug NE 5 -HT Anticholinergic Sedation Hypotension Tricyclic agents Amitriptyline ( Elavil) + ++ +++ +++ ++ Desipramine ( Norpramin) +++ 0 + + + Nortriptyline ( Aventyl) ++ + + ++ + Mirtazapine ( Remeron) +++ +++ ++ +++ ++ SSRIs Fluoxetine ( Prozac) 0 +++ 0,+ 0,+ 0,+ Paroxetine ( Paxil) 0 +++ ++ 0,+ 0 Sertraline ( Zoloft) 0 +++ 0,+ 0,+ 0 Fluvoxamine ( Luvox) 0,+ +++ 0,+ 0,+ 0 Citalopram (Celexa) 0,+ +++ 0,+ 0,+ 0,+ Escitalopram ( Lexapro) 0,+ +++ 0,+ 0,+ 0,+ Atypical agents Trazodone ( Desyrel) 0 + + ++ + Venlafaxine ( Effexor) +++ +++ 0 0 0 Duloxetine (Cymbalta) +++ +++ 0 0 0 Bupropion ( Wellbutrin) 0,+ 0,+ ++ ++ + Nefazodone ( Serzone) 0,+ +++ 0,+ ++ + MAO inhibitors Phenelzine ( Nardil) ++ ++ 0 + ++ * 0 indicates none; +++, greatest; NE, norepinephrine; and 5-HT, serotonin. rent administration of any sympathomimetic drug. cause they also produce anticholinergic actions on This concern is for most classes of antidepressants, the heart. Epinephrine and levonordefrin are not con- other than the selective serotonin reuptake inhibitors. traindicated in these patients, but they should be used Tricyclic antidepressants present greatest concern be- cautiously. For example, heart rate and blood pressure Table 3. Antidepressant Interactions 7 * Prescribed Drug Object of Interaction Explanation of Interaction/Recommendation NSAIDs SSRIs Enhanced risk for gastrointestinal (GI ) bleeding. SSRI may deplete platelet serotonin required for aggregation. Short-term use (2^4 days) is acceptable but avoid in the elderly or those with history of GI ulcer or bleeding. Codeine and derivatives SSRIs and These antidepressants inhibit conversion of prodrug to active morphine bupropion derivative; analgesic effect reduced. If opioid is required for severe pain, consider morphine. Benzodiazepines SSRIs SSRIs inhibit oxidation of benzodiazepines leading to elevated levels. Also confirmed for zolpidem ( Ambien). May be wise to use benzodiazepines that are not oxidized; lorazepam or temazepam. Tramadol and meperidine SSRIs Combination may precipitate an acute serotonin syndrome.Well- documented for tramadol and suspected for meperidine. Avoid this combination. Meperidine MAOIs Mechanism of interaction unclear, but seizures and coma have been reported with this combination. Avoid this combination. Epinephrine and MAOIs Direct-acting adrenergic drugs such as epinephrine or levonordefrin have no levonordefrin interaction with MAO inhibitors because they are metabolized by catechol- O-methyltransferase, not MAO. However, mixed or indirect-acting agents, eg, ephedrine and most decongestants may result in major hypertensive episodes because they are either metabolized by MAO or stimulate release of enhanced neuronal stores of norepinephrine due to MAO inhibition. TCAs These antidepressants have anticholinergic action and potentiate sympathomimetic influences of norepinephrine. Both of these influences could potentiate the sympathetic effects of epinephrine or levonordefrin. Local anesthetics containing vasopressors can be used, but caution must be exercised; recheck vital signs following each cartridge or two. * NSAIDs indicates nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; MAOI, monoamine oxidase inhibitors; and TCAs, tricyclic antidepressants. 94 Psychotropic Drugs Anesth Prog 55:89^99 2008 should be reassessed following each 20^40 mg dose of efficacy of the 3 dozen compounds available is attrib- epinephrine administered (1^2 cartridges containing a uted to their ability to act as antagonists at dopamine 1 : 100,000 concentration). receptors within the limbic regions. Dopamine and its The SSRI antidepressants inhibit several families of receptors perform many functions throughout the hepatic enzymes (CYP-450), which may delay the bio- brain, and at least 5 dopamine receptors have been transformation and clearance of numerous other identified, labeled as D1 thru D5. Antagonism of D2 drugs. Of particular importance for dentistry is the receptors within the limbic regions is credited as the CYP2D6 family of enzymes, which is responsible for antipsychotic mechanism for these drugs, but most demethylating codeine, hydrocodone, and oxycodone agents lack specificity for this particular dopamine re- to their active metabolites; morphine, hydromor- ceptor and produce troubling side effects by virtue of phone, and oxymorphone, respectively. The SSRI an- their antagonizing D2 and other dopamine receptor tidepressants vary in their intensity for inhibiting these subtypes in additional brain regions. enzymes, with fluoxetine ( Prozac) and paroxetine Useful and several adverse effects of antipsychotic ( Paxil) having the greatest influence. Patients medicat- agents are attributed to blockade of dopamine recep- ed with these antidepressants may not experience ad- tors within specific brain regions. In addition to limbic equate pain relief from codeine or its derivatives.7,8 sites, where their antipsychotic influence is produced, these agents produce useful antiemetic effects by blocking dopamine transmission in the chemoreceptor Antipsychotic Drugs trigger zone. Within the hypothalamus, dopamine nor- mally acts to inhibit prolactin release. By blocking this The psychoses include schizophrenia and other delu- influence, antipsychotic agents may produce galactor- sional impairments in which patients have difficulty in rhea. comprehending reality. These disorders are managed The most troubling side effect of antipsychotic drugs using antipsychotic drugs. Although less descriptive, is attributed to blockade of dopaminergic transmission these agents may also be referred to as ‘‘neuroleptics,’’ within the basal ganglia. This results in so-called extra- a term less offensive to the patient. Despite our poor pyramidal syndromes that include akathisia, Parkinso- understanding of their precise mechanisms and their nian symptoms, and tardive dyskinesia. In some cases, myriad side effects, it cannot be disputed that antipsy- the physician may prescribe the concurrent use of chotic drugs are effective. Extensive clinical studies centrally acting anticholinergics such as benztropine have found that the relapse rate is much greater for (Cogentin) to obtund these effects. This is designed to patients who discontinue antipsychotic medication, offset excitatory pathways that release acetylcholine as compared with those who continue therapy. their neurotransmitter, a strategy also used in the man- It is significant that antipsychotic drugs are not dis- agement of Parkinson disease. These extrapyramidal ease specific; they can be used for conditions other influences are the most feared side effects of antipsy- than schizophrenia and other psychoses. These in- chotic drugs and deserve further analysis. clude acute agitation and delirium associated with Alz- Akathisia is a subjective feeling of restlessness lead- heimer dementia, fever, septicemia, amphetamine in- ing to a compelling need to move. Patients feel that toxication, or mechanical ventilation. They are fre- they must get up and walk or continuously move quently used in combination with lithium and anti- about, and this behavior may be mistaken for agita- convulsants during acute phases of mania, and with tion. Their distinction is critical, since agitation is treat- antidepressants for complex cases of depression. Most ed with an increase in dosage of the antipsychotic agents are excellent antiemetics and can be used to drug and will worsen akathisia. It is not uncommon manage nausea and vomiting. Finally, their sedative for this syndrome to be undiagnosed and may inter- effects can be used to potentiate sedatives and opioids fere with the patient’s medication compliance. It during anesthesia and pain management. should be noted that this extrapyramidal effect is pro- Most of the first-generation antipsychotic drugs are duced by promethazine ( Phenergan) and prochlorper- derivatives of the phenothiazine molecular structure, azine (Compazine), which are antipsychotic deriva- although haloperidol ( Haldol) is a notable exception tives used commonly for nausea and vomiting. Parkin- derived from a butyrophenone. For this reason, it is son disease is a well- defined neurologic disorder not uncommon for antipsychotics to be referred to as associated with dopamine deficiency within the basal phenothiazine compounds. Chlorpromazine ( Thora- ganglia. It should not be surprising that dopamine zine) was the first drug used specifically in the man- blockade by antipsychotic drugs can produce a syn- agement of psychoses and retains its status as the pro- drome of side effects indistinguishable from this dis- totype of the antipsychotics. The actual antipsychotic ease and is described as Parkinsonism. Clinically, Anesth Prog 55:89^99 2008 Becker 95 Table 4. Selected Antipsychotics and Relevant Data 7 * Side Effects Drug Daily Dosage (mg) Extrapyramidal Sedation Autonomic Fluphenazine ( Prolixin) 2^20 +++ + + Haloperidol ( Haldol) 2^20 +++ + + Thiothixene ( Navane) 5^30 +++ + + Trifluoperazine ( Stelazine) 5^20 +++ ++ + Perphenazine ( Trilafon) 8^32 ++ ++ + Chlorpromazine ( Thorazine) 200^800 ++ +++ +++ Thioridazine ( Mellaril) 150^600 + +++ +++ Atypical agents Clozapine (Clozaril) 300^900 0,+ +++ +++ Risperidone ( Risperdal) 4^16 + + + Olanzapine ( Zyprexa) 5^20 0,+ 0,+ 0,+ * Autonomic side effects include hypotension, constipation, and xerostomia. there is a generalized slowing of movement (bradyki- orthostatic hypotension. With the exception of those nesia) with masked facial expression and a reduction attributed to dopamine blockade, side effects of the in arm movements. The syndrome characteristically antipsychotics resemble those of the tricyclic antide- evolves gradually over days to weeks of drug use. The pressants. most noticeable signs are rigidity and tremor at rest, Although acutely psychotic patients may improve especially involving the upper extremity, and perioral within a day or two of therapy, chronic conditions gener- tremors along with ‘‘pill-rolling’’ movements may be ally require 2 to 3 weeks of treatment to notice any bene- seen. Some of these parkinsonian side effects may be fit. Maximum improvement may require several months mistaken for depression, since the flat facial expres- of therapy.9 With the exception of clozapine (discussed sion and retarded movements may resemble signs of below), no single agent can be regarded as having superi- depression. or efficacy overall or for any specific symptom. Individual Tardive dyskinesia is associated with chronic use of patients may appear to do better with one agent than an- antipsychotic drugs and occurs in as many as 15 to other, but this can be determined only by trial and error. In 25% of psychotic patients. It is characterized by ste- cases of noncompliance or with failure of oral treatment, reotyped, repetitive, tic-like movements of the face, the patient can be treated with injections of long-acting, eyelids (blinks or spasm), mouth (grimaces), tongue, depot preparations (generally every 2 weeks). These are extremities, or trunk. Like other extrapyramidal syn- particularly useful for delusional paranoid patients who dromes, these movements disappear during sleep and frequently believe that ‘‘medicines are poison.’’ Exempla- are dependent on the patient’s level of arousal or emo- ry antipsychotic agents are summarized in Table 4. Dos- tional distress. The most perplexing aspect of this syn- ages for antipsychotic agents can be quite variable and drome is that it may persist indefinitely after discontin- must be titrated to the individual patient. Notice from the uation of the precipitating medication, but fortunately, Table that the more potent conventional agents, ie, those in most cases, symptoms disappear or at least gradual- requiring ,50 mg/day, produce the greatest incidence ly decline over a period of months. Most antiparkin- of extrapyramidal effects, while those having less potency sonism drugs provide little relief, and Cogentin actual- are more likely to produce sedation and autonomic side ly worsens the condition. There is simply no adequate effects. Potency per se is hardly the explanation for these treatment available. differences; less potent agents appear to provide their The gamut of side effects produced by antipsychot- own anticholinergic influences that counter extrapyrami- ics can be explained by their ability to act as antago- dal effects. Nevertheless, it is a useful clinical caveat for nists at various receptors. In addition to dopamine re- predicting the side effect profile of a particular antipsy- ceptors described above, antipsychotic agents also chotic agent. block histaminic, cholinergic, and alpha receptors. In recent years, researchers have formulated several Within the central nervous system, these actions con- novel antipsychotic agents that preferentially block do- tribute to the sedative effects of these agents because paminergic receptor subtypes found within the limbic histamine, acetylcholine, and norepinephrine act here regions, specifically D2 receptors, or act as partial ag- as excitatory neurotransmitters. Peripherally, they pro- onists. This reduces the likelihood of their producing vide a series of bothersome autonomic effects includ- extrapyramidal or other side effects mediated at dopa- ing xerostomia, constipation, urinary retention, and minergic receptors in other brain regions. Many of 96 Psychotropic Drugs Anesth Prog 55:89^99 2008 these so-called second-generation or ‘‘atypical’’ agents Table 5. Drugs Having Anticholinergic and Antidopaminer- also block specific serotonin receptor subtypes, but the gic Actions 7 significance of this action is unknown. Clozapine was Relative Antagonist Activity the first of these agents to receive FDA approval and is generally agreed to be the most effective drug to date. Drug Cholinergic Histaminic Dopamine Its advantage is offset by its tendency to produce Scopolamine +++ 0 0 agranulocytosis in 1 to 2% of patients treated, which Diphenhydramine ++ ++ 0 requires that patients have WBC counts weekly for a Hydroxyzine ++ ++ 0 month or two and then biweekly throughout therapy. Promethazine ++ ++ + Prochlorperazine + + ++ Risperidone ( Risperdal) and olanzapine ( Zyprexa) do Droperidol 0,+ 0,+ +++ not produce agranulocytosis and are associated with a lower incidence of sedation and autonomic side ef- fects. Both of these drugs are very expensive (5^10 hyperactive behaviors, including agitation, excessive times the cost for first-generation agents), and their talkativeness, and elation, fleeting attention, increased routine use is frequently criticized. The use of these psychomotor activity and perhaps, delusion and frank agents is generally reserved for severe cases, or those psychosis. Often patients fluctuate between periods of refractory to the more traditional agents.9,10 depression and mania, in which case their affective disorder is described as bipolar rather than unipolar. The dated term for this disorder is ‘‘manic depression.’’ Dental Implications for Patients Medicated With Potent sedatives and antipsychotic drugs may be used Antipsychotic Drugs as adjuncts for the management of mania, especially acute episodes, but lithium is still regarded as the stan- There are no well-established drug interactions associ- dard for chronic treatment.10 Unlike other drugs, hav- ated with antipsychotic medications and drugs con- ing complex molecular structures, lithium is merely a ventionally used in dental practice. However, some monovalent cation, [Li +]. Its mechanism of action is consideration may be given to the use of vasopressors unknown, but it is thought to somehow stabilize neu- in local anesthetic solutions and the use of antihista- mines and antiemetics used in sedation regimens. ronal membranes, thereby reducing their rate of dis- Most antipsychotic agents have modest alpha-block- charge and neurotransmitter turnover. Lithium is ef- ing actions that may counter any increase in systemic fective for the prevention and for treatment of manic vascular resistance following systemic absorption of episodes, and also for prevention of depressive mood vasopressors contained in local anesthetic formula- swings in the patient with bipolar disorder.8 tions. Yagiela et al11 demonstrated that chlorpromazine The typical daily dose for lithium is 300 mg three or ameliorated the pressor responses to levonordefrin four times a day and results in a therapeutic serum and norepinephrine. Because epinephrine normally level of 0.4^1.2 mEq/L. Provided serum concentra- lowers systemic vascular resistance due to its beta-2 tions are sustained at this level, lithium is relatively mediated vasodilation, any influence of this vasopres- free of side effects. Higher concentrations result in tox- sor in reducing arterial constriction was observed only icity that is directly related to the serum concentration with high- dose epinephrine, such as that employed and may require hemodialysis in life-threatening cas- during the management of cardiac arrest. es. These are summarized in Table 6. To avoid toxicity, It may also be wise to avoid the use of drugs having patients must be compliant with their dosage schedule significant anticholinergic or antidopaminergic action that could enhance the potential for side effects attrib- utable to these mechanisms. Added anticholinergic in- Table 6. Correlation of Lithium Serum Levels and Toxicity fluences may precipitate delirium,12 and dopamine Concentration blockade may increase risk for extrapyramidal symp- (mEq /L) Resultant Effects toms. Antihistamines and antiemetics have these 0.4^1.2 Therapeutic antimanic activity properties and are frequently used in sedation and an- 1^2 Diarrhea, nausea, vomiting, drowsiness, esthesia regimens. These are summarized in Table 5. muscular weakness, lack of coordination 2^3 Giddiness, ataxia, blurred vision, tinnitus, vertigo, confusion, Slurred speech, blackouts, Antimanic Agents muscle twitching, urinary and fecal incontinence, agitation, manic-like behavior Mania is an affective disorder essentially opposite that.3 Seizures, cardiac arrhythmias, hypotension spasticity, stupor, coma of depression. Manic patients demonstrate a variety of Anesth Prog 55:89^99 2008 Becker 97 Table 7. Anticonvulsants Commonly Used for Nonseizure They depress excitability of neurons by hindering in- Disorders flux of sodium or calcium ions, or potentiating the ac- Carbamazepine ( Tegretol) Gabapentin ( Neurontin) tions of inhibitory neurotransmitters such as GABA. Clonazepam ( Klonopin) Pregabalin ( Lyrica) Regardless of their precise mechanisms, they suppress Clorazepate ( Tranxene) Lamotrigine ( Lamictal) the spontaneous firing of actual seizure foci and/or Topiramate ( Topamax) Valproic acid ( Depakene) the spread of impulses from these foci to neighboring neuron pathways.7,13 The stabilizing influence of these and have their serum concentrations monitored peri- drugs on neuronal membranes has proven useful in odically. managing several conditions in addition to seizure dis- orders. These include bipolar affective disorders (man- ic depression), anxiety disorders, and pain syndromes Anticonvulsants having neuropathic components such as trigeminal neuralgia. Although lithium is regarded as the conventional agent The various anticonvulsants differ in their efficacy for managing manic disorders, several anticonvulsant for managing different categories of seizures. The agents have been shown to be equally effective and agents commonly used also for nonseizure disorders safer for patients who are questionably compliant. such as pain and bipolar disorders are listed in Table 7. Seizures are clinical manifestations of synchronous discharges from cortical neurons and may be caused by drug toxicity, or a variety of injuries and diseases. Dental Implications for Patients Medicated With If a cause cannot be ascertained, the seizure is regard- Lithium and Anticonvulsants ed as primary or idiopathic. Seizures reflect the gener- al function of the brain region involved and include al- All anticonvulsants have sedative properties, but patients tered consciousness (absence seizures), involuntary develop tolerance to this influence within a few weeks of movements (convulsive seizures), and behavioral au- use. Nevertheless, this property should be considered tomatisms. Seizures are designated as ‘‘epileptic’’ only when administering sedatives. Patients chronically med- if they have a chronic pattern of recurrence. Indeed, it icated with clonazepam or clorazepate invariably develop is common for patients to experience a single seizure, tolerance and dependence to benzodiazepines. This is never experiencing another; in many cases it is found problematic when choosing dosages for oral sedation, to be secondary to a syncopal episode. but careful intravenous titration of benzodiazepines is Despite the fact that many seizures are neither con- generally without problem. The use of flumazenil for re- vulsive nor epileptic, antiseizure medications are versal should be avoided. Drug interactions to be consid- called anticonvulsants or antiepileptics by convention. ered are summarized in Table 8. Table 8. Anticonvulsant and Antimanic Drug Interactions* Prescribed Drug Object of Interaction Explanation of Interaction Acetaminophen Carbamazepine ( Tegretol) Increased metabolism of acetaminophen, decreasing its analgesic Phenytoin ( Dilantin) effect but increasing accumulation of metabolite that is hepatotoxic. Generally not significant at normal doses. Lamotrigine ( Lamictal) Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects. Not a concern during short-term use (2^5 days). NSAIDs Lithium ( Lithobid) Lithium excretion is reduced and toxic blood levels may develop over 5^10 days of NSAID therapy. Limit NSAID use to 2 or 3 days. Metronidazole Lithium ( Lithobid) Case reports of lithium toxicity associated with concurrent use of metronidazole. Choose alternative antibiotic. Propoxyphene Carbamazepine ( Tegretol) Increased serum levels of carbamazepine leading to toxicity. Hydrocodone Gabapentin ( Neurontin) Increased gabapentin and decreased hydrocodone levels. Morphine Gabapentin ( Neurontin) Increased gabapentin levels. Macrolides, eg, Carbamazepine ( Tegretol) Increased serum levels of carbamazepine and valproic acid leading to erythromycin Valproic acid ( Depakote) severe toxicity. Hospitalization has been required. Benzodiazepines Valproic acid ( Depakote) Valproate displaces benzodiazepines from their plasma albumin binding sites and inhibits their metabolism.This may increase the intensity and duration of CNS depression. * NSAIDs indicates nonsteroidal anti-inflammatory drugs; CNS, central nervous system. 98 Psychotropic Drugs Anesth Prog 55:89^99 2008 REFERENCES 6. Abramowicz M ( Ed.). Which SSRI? 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Which of the following drugs must be avoided in pa- ment of pain.To be useful, however, the antidepres- tients medically managed with monoamine oxidase sant must have an action that includes inhibiting the inhibitors ? reuptake of which neurotransmitter ? A. Epinephrine A. Norepinephrine B. Meperidine B. Serotonin C. Erythromycin C. Dopamine D. A and B D. Gamma-aminobutyric acid ( GABA ) E. A, B, and C 2. Tricyclic anti depressant an d antipsychotic drugs 4. Which of the following psychotropic drug classes have significant anticholinergic actions.To avoid po- can limit the efficacy of codeine derivatives ? tentiating this action and producing an‘‘anticholiner- gic syndrome,’’ it is wise to avoid which of the follow- A. Tricyclic antidepressants ing drug classes when sedating these patients ? B. Selective serotonin reuptake inhibitors A. Benzodiazepines C. Antipsychotics B. Opioids D. Antimanics C. Antihistamines D. Barbiturates