ch05.qxd 8/13/2001 2:00 PM Page 453 A NTIDEPRESSANTS NEFAZODONE 453 Serzone Pharmacology Nefazodone is a postsynaptic serotonin 5-HT2A antagonist and presynaptic serotonin reuptake inhibitor These two serotonergic effects make it different from SSRIs and TCAs.153–156 (See Antidepressants Comparison Chart.) Administration and Adult Dosage PO for depression 100 mg bid initially (50 mg bid in the elderly), increasing q 4–7 days to the effective dosage range of 150– 300 mg bid After initial dosage titration, once-daily bedtime administration is preferred to minimize daytime sedation.157 Dosage Forms Tab 50, 100, 150, 200, 250 mg Pharmacokinetics Nefazodone has an oral bioavailability of about 20% Singledose studies in the elderly have shown a 100% larger AUC; with multiple doses, the AUC differences decreased to 10–20% above those in younger populations It is >99% protein bound and extensively metabolized, with a dose-dependent elimination half-life of about 1–2.3 hr in young patients, modestly prolonged in the elderly, and 2–3 times longer in hepatic disease The major active metabolite, hydroxynefazodone, has a half-life of 1.2–1.6 hr in young and elderly patients, increasing to 2–4 hr with hepatic disease Renal impairment does not markedly affect nefazodone pharmacokinetics Adverse Reactions Although chemically similar to trazodone, it causes less sedation and orthostatic hypotension, and its lower ␣-adrenergic blockade makes priapism much less likely (no cases reported) Frequent adverse effects include sedation, dry mouth, nausea, and dizziness Unlike SSRIs, nefazodone’s effects on sexual function, agitation, tremor, insomnia, and weight are no different from placebo Drug Interactions Nefazodone is a potent inhibitor of the CYP3A4 isoenzyme and a weak inhibitor of the CYP2D6 isoenzyme Drug interactions of particular concern include the triazolobenzodiazepines (ie, alprazolam, triazolam, midazolam) A 1- to 2-week washout period is recommended when converting a patient to or from a MAOI and nefazodone PAROXETINE Paxil Pharmacology Paroxetine is a highly selective and potent inhibitor of serotonin reuptake (an SSRI) similar to fluoxetine.126,158–164 (See Antidepressants Comparison Chart.) Administration and Adult Dosage PO for depression 20 mg/day; a few patients require 30–50 mg/day for full efficacy PO for social anxiety disorder and panic disorder 10 mg/day initially; usual maintenance dosage is 20–60 mg/day PO for OCD 20 mg/day initially; maintenance dosage is 40 mg/day to a maximum of 60 mg/day, preferably as a single dose in the morning or evening The starting dosage for all uses in elderly patients and those with marked renal or hepatic impairment is 10 mg/day For the elderly or those with severe renal or hepatic impairment, the maximum dosage is 40 mg/day Dosage Forms Tab 10, 20, 30, 40 mg; SR Tab 12.5, 25 mg; Susp mg/mL ch05.qxd 454 8/13/2001 2:00 PM Page 454 C ENTRAL N ERVOUS S YSTEM D RUGS Pharmacokinetics Paroxetine is completely orally bioavailable; protein binding is 93–95% Unlike fluoxetine, paroxetine is metabolized to inactive metabolites and has an elimination half-life of 24 hr Adverse Reactions Paroxetine causes the typical SSRI adverse effects of nausea, sexual dysfunction, and headache but is more likely to cause sedation than insomnia and can cause more delay of orgasm or ejaculation and more impotence than other SSRIs.165 Like the other SSRIs, it is much safer in overdose than TCAs Drug Interactions Paroxetine is a potent inhibitor of CYP2D6, so most other antidepressants, antipsychotics, ␤-blockers, and type Ic antiarrhythmics can have increased serum levels and adverse effects when paroxetine is combined with these drugs Do not use paroxetine within 14 days of using an MAOI REBOXETINE (Investigational—Pharmacia) Vestra Pharmacology Reboxetine is the first in a new class of selective norepinephrine reuptake inhibitors with no affinity for serotonin or dopamine reuptake sites It has negligible affinity for muscarinic, histaminic, or adrenergic receptors This noradrenergic mechanism for antidepressant efficacy is similar to TCAs such as desipramine without the potential for appreciable adverse anticholinergic, cardiovascular, and sedative effects It has efficacy for major depression equal to fluoxetine and desipramine.166,167 (See Antidepressants Comparison Chart.) Administration and Adult Dosage PO for depression 8–10 mg/day given bid, 4–6 mg/day given bid in the elderly Dosage Forms Tab mg (investigational) Pharmacokinetics Reboxetine is rapidly absorbed Metabolism occurs through three oxidative pathways: hydroxylation, dealkylation, and oxidation The CYP450 isoenzymes responsible for metabolism have not been identified, and the degree of activity of the metabolites is unknown Reboxetine has no inhibitory effect on CYP450 isoenzymes Elimination half-life is 13 hr.166 Adverse Reactions The most common adverse effects include dry mouth, constipation, increased sweating, insomnia, and urinary hesitancy, which are greater than placebo, but less frequent than imipramine These “anticholinergic-like” effects are believed to result from increased norepinephrine levels Side effects commonly associated with serotonin reuptake inhibitors such as nausea, anxiety or agitation, and daytime somnolence were no more common with reboxetine than with placebo.167 No information is available regarding reboxetine overdose in humans SERTRALINE Zoloft Pharmacology Sertraline is an SSRI similar to fluoxetine, which indirectly results in a downregulation of ␤-adrenergic receptors It has no clinically important effect on noradrenergic or histamine receptors and no effect on MAO It lacks stimulant, cardiovascular, anticholinergic, and convulsant effects Sertraline has antidepressant effects equal to TCAs and fluoxetine and might have anorectic effects and efficacy in OCD.130,168–170 (See Antidepressants Comparison Chart.) Administration and Adult Dosage PO for depression, panic disorder, OCD, and posttraumatic stress disorder 50 mg/day initially, increasing if necessary at weekly intervals to a maximum of 200 mg/day in a single dose in the morning or evening ch05.qxd 8/13/2001 2:00 PM Page 455 A NTIDEPRESSANTS 455 Dosage Forms Tab 25, 50, 100 mg; Soln 20 mg/mL Pharmacokinetics Sertraline has an oral bioavailability of 36%, and, when it is taken with food, peak serum concentrations and bioavailability increase by 30–40% Peak serum concentrations are reached in 6–8 hr Sertraline concentrations in breast milk are the lowest of the SSRIs and produce minimal serum levels in the breast-fed infant.171 Its primary metabolite is N-desmethylsertraline, which has 5–10 times less activity than sertraline as an SSRI and has no demonstrated antidepressant activity Cl is decreased by up to 40% in the elderly Steady-state half-life is 27 hr Adverse Reactions Frequent adverse effects include nausea, diarrhea, ejaculatory delay, tremor, and increased sweating It causes less agitation, anxiety, and insomnia than fluoxetine and is a less potent inhibitor of the CYP2D6 isoenzyme at a dosage of 50 mg/day Use with caution in patients with renal or hepatic impairment and not use it within 14 days of using an MAOI SIADH has been reported.172 VENLAFAXINE Effexor Pharmacology Venlafaxine is a potent reuptake inhibitor of serotonin and norepinephrine, like many TCAs, but lacks effects on muscarinic, ␣-adrenergic, or histamine receptors.173–176 (See Antidepressants Comparison Chart.) Administration and Adult Dosage PO for depression (immediate-release) 75 mg bid or tid initially, increasing q 4–7 days to an effective antidepressant dosage of 225–375 mg/day in or divided doses; (sustained-release) 75 mg once daily initially, increasing in increments of up to 75 mg/day at intervals of or more days to a maximum of 225 mg/day The sustained-release preparation does not reduce side effects but allows once-daily administration PO for generalized anxiety disorder 75–225 mg/day in 2–3 divided doses Patients with renal impairment or on hemodialysis require a 25–50% dosage reduction Dosage Forms Tab 25, 37.5, 50, 75, 100 mg; SR Cap 37.5, 75, 150 mg (Effexor XR) Pharmacokinetics Venlafaxine is well absorbed orally; food has no effect on absorption Serum concentrations in elderly patients are no different from those in younger patients Unlike SSRIs, venlafaxine has minimal protein binding (27–30%) It undergoes extensive hepatic metabolism Venlafaxine has an elimination half-life of hr, and one major active metabolite has an 11-hr half-life Venlafaxine exhibits linear pharmacokinetics over the recommended dosage range, and steady state is reached in days Adverse Reactions Frequent adverse effects include expected serotonin-related effects (eg, nausea, headache, insomnia or somnolence, and sexual dysfunction) At higher dosages (375 mg/day), venlafaxine is unique in causing a consistent but mild elevation in diastolic blood pressure (6 mm Hg) Regular blood pressure monitoring is required for all patients Drug Interactions Venlafaxine is not a potent inhibitor of the cytochrome P450 enzyme system, making it different from most of the SSRIs Avoid it in patients who have received an MAOI within the past 14 days ch05.qxd 456 ANTIDEPRESSANTS COMPARISON CHARTa THERAPEUTIC SERUM LEVELS (µG/L) Sedation 15–45 b Moderate None None 300–450 b None None None 300–600 b Low Low Low Tab 15 mg 45–90 b Moderate Low Very High Tab 10 mg 30–60 b Low Low Very High 8–10 b Very Low Low Very Low DOSAGE FORMS RELATIVE FREQUENCY OF SIDE EFFECTS Anticholinergic Orthostatic Hypotension α2-ADRENERGIC BLOCKERS Tab (conventional and rapidly dissolving) 15, 30, 45 mg 2:00 PM Mirtazapine Remeron CHLOROPROPIOPHENONES Tab 75, 100 mg SR Tab 100, 150 mg Page 456 Bupropion Wellbutrin Zyban DIBENZOXAZEPINESc Amoxapine Asendin Various Tab 25, 50, 100, 150 mg MONOAMINE OXIDASE INHIBITORS (MAOIs) Phenelzine Nardil Tranylcypromine Parnate MORPHOLINES Reboxetine Vestra 8/13/2001 USUAL DAILY ADULT DOSAGE RANGE (MG) CLASS AND DRUG (continued ) ch05.qxd ANTIDEPRESSANTS COMPARISON CHARTa (continued ) DOSAGE FORMS USUAL DAILY ADULT DOSAGE RANGE (MG) THERAPEUTIC SERUM LEVELS (µG/L) RELATIVE FREQUENCY OF SIDE EFFECTS Sedation Anticholinergic Orthostatic Hypotension SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Tab 20, 40 mg Soln mg/mL 20–60 b Very Low Very Low None Fluoxetine Prozac Cap, Tab 10, 20, 40 mg SR Cap 90 mg Soln mg/mL Tab 10 mg 10–80 b None Very Low None Fluvoxamine Luvox Tab 25, 50, 100 mg 100–300d b None None None Paroxetine Paxil Tab 10, 20, 30, 40 mg SR Tab 12.5, 25 mg Susp mg/mL 20–50 b Low Low Very Low Sertraline Zoloft Tab 25, 50, 100 mg Soln 20 mg/mL 50–200 b None None None 2:00 PM Citalopram Celexa 8/13/2001 CLASS AND DRUG Venlafaxine Effexor Effexor XR Tab 25, 37.5, 50, 75, 100 mg SR Cap 37.5, 75, 150 mg 225–375 b Very Low Very Low Very Low Tab 25, 50, 75 mg 150–225 200–300b Moderate Moderate Moderate TETRACYCLICS c 457 Maprotiline Ludiomil Various (continued ) Page 457 SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) ch05.qxd 458 ANTIDEPRESSANTS COMPARISON CHARTa (continued ) DOSAGE FORMS USUAL DAILY ADULT DOSAGE RANGE (MG) THERAPEUTIC SERUM LEVELS (µG/L) RELATIVE FREQUENCY OF SIDE EFFECTS Sedation Anticholinergic Orthostatic Hypotension TRIAZOLOPYRIDINES Tab 50, 100, 150, 300 mg 50–100 (hypnotic) 200–400 (antidepressant) b High Very Low High Nefazodone Serzone Tab 50, 100, 150, 200, 250 mg 300–600 b Moderate Very low Moderate Amitriptyline Elavil Various Tab 10, 25, 50, 75, 100, 150 mg Inj 10 mg/mL 150–300 75–175e High High High Clomipramine Anafranil Various Cap 25, 50, 75 mg 100–250d 100–150f b High High High Desipramine Norpramin Various Tab 10, 25, 50, 75, 100, 150 mg 150–300 100–160 Low Low Moderate Doxepin Adapin Sinequan Various Cap 10, 25, 50, 75, 100, 150 mg Soln 10 mg/mL 150–300 110–250e High Moderate High 2:00 PM Trazodone Desyrel Various 8/13/2001 CLASS AND DRUG Page 458 TRICYCLICS (TCAs)d (continued ) ch05.qxd ANTIDEPRESSANTS COMPARISON CHARTa (continued ) DOSAGE FORMS USUAL DAILY ADULT DOSAGE RANGE (MG) THERAPEUTIC SERUM LEVELS (MG/L) RELATIVE FREQUENCY OF SIDE EFFECTS Sedation Anticholinergic Orthostatic Hypotension 150–300 >200e Moderate Moderate High Nortriptyline Aventyl Pamelor Various Cap 10, 25, 50, 75 mg Soln mg/mL 100–200 50–150 Moderate Moderate Low Protriptyline Vivactil Various Tab 5, 10 mg 30–60 70–260b Very Low Moderate Moderate Trimipramine Surmontil Cap 25, 50, 100 mg 150–300 b Moderate Moderate High 459 a Antidepressants with serotonergic activity (SSRIs, nefazodone, venlafaxine, and mirtazapine) have established efficacy for many indications other than depression Some have received approval from the Food and Drug Administration for generalized anxiety disorder, bulimia nervosa, obsessive-compulsive disorder, social phobia, panic disorder, posttraumatic stress disorder, and premenstrual dysphoric disorder Effective doses for major depression for most patients are in the low to moderate ranges listed, which is also true for generalized anxiety disorder, social phobia, panic disorder, and premenstrual dysphoric disorder The middle to high end of the listed dosage ranges is usually necessary for efficacy when treating bulimia nervosa, obsessivecompulsive disorder, and posttraumatic stress disorder.180 b Not well established c Amoxapine, maprotiline, and the tricyclic antidepressants are categorized together as heterocyclic antidepressants because their therapeutic and side effect profiles are similar d For obsessive-compulsive disorder e Includes active metabolites f Major depression From references 106, 112, 122, 126, 127, 140, 141, 145, 146, 148, 153, 159, 160, 175, and 177–179 Page 459 Tab 10, 25, 50 mg Cap (as pamoate) 75, 100, 125, 150 mg 2:00 PM Imipramine Tofranil Janimine Various 8/13/2001 CLASS AND DRUG ch05.qxd 460 8/13/2001 2:00 PM Page 460 C ENTRAL N ERVOUS S YSTEM D RUGS Antipsychotic Drugs Class Instructions Antipsychotics This drug can cause drowsiness Until the extent of this effect is known, use caution when driving, operating machinery, or performing other tasks requiring mental alertness Avoid excessive concurrent use of alcohol or other drugs that cause drowsiness Missed Doses If you miss a dose, take it as soon as you remember If it is almost time for your next dose, skip it and resume your normal schedule Do not double doses ANTIPSYCHOTIC DRUGS Pharmacology Antipsychotic efficacy is most likely related to blockade of postsynaptic dopaminergic receptors in the mesolimbic and prefrontal cortexes of the brain, although other neurotransmitter systems also are involved.181 Administration and Adult Dosage (See Antipsychotic Drugs Comparison Chart for oral dosage ranges.) Initiate therapy with divided doses until therapeutic dosage is found; then, for most patients, once-daily hs administration is preferred For maintenance, decrease acute dosage by 25% q months, with a target maintenance dosage being 50–67% of the acute treatment dosage.182 Recent concern has focused on the need to establish a minimum effective dosage for antipsychotic drugs, and treatment regimens at the low end of the dosage range are preferred Oral dosages of high-potency antipsychotics (eg, fluphenazine, haloperidol) in the range of 5–20 mg/day are better tolerated and equal in efficacy to dosages >20 mg/day.183 Most patients can be given a maintenance dosage of 50% the acute dosage by the end of yr, although 10–15% of chronically ill patients require a maintenance dosage >15 mg/day of haloperidol or its equivalent.184,185 For manic episodes, no additional benefit is achieved with dosages >10 mg/day of haloperidol.186 Mesoridazine and thioridazine are indicated only in patients who fail with other drugs because of inefficacy or intolerable side effects Special Populations Pediatric Dosage As with adults, dosage is determined primarily by titration to individual response No precise dosage range exists, but in general the initial dosage is lower and increased more gradually in children Geriatric Dosage Initial dosage is 20–25% of the dosage used in younger adults Typical starting dosages in the elderly are haloperidol 0.5–2 mg/day Dosage adjustments also must be done more slowly than in younger adults.187 Other Conditions Dosages in the lower range are sufficient for most elderly patients, and the rate of dosage titration is slower Dosage Forms (See Antipsychotic Drugs Comparison Chart.) Patient Instructions (See Antipsychotics Class Instructions.) These drugs usually take several weeks for clinical response and up to weeks for full therapeutic response Pharmacokinetics Onset and Duration Onset of antipsychotic activity is variable, with noticeable response requiring days to weeks Serum Levels Correlation of serum levels with clinical response is not consistently established The best evidence exists for haloperidol, with serum concen- ch05.qxd 8/13/2001 2:00 PM Page 461 A NTIPSYCHOTIC D RUGS 461 trations of 5–15 ␮g/L (13–40 nmol/L) correlating well with therapeutic effects in adult psychotic patients, and an increasing risk of adverse effects and decreased efficacy when steady-state concentrations exceed 15 ␮g/L.188,189 Fate Haloperidol is well absorbed; peak serum levels are achieved 2–6 hr after liquid or tablets and within 30 after IM Oral bioavailability of haloperidol is 60–70% Haloperidol is extensively metabolized, with one active hydroxy metabolite Chlorpromazine and other phenothiazines are well absorbed but undergo extensive and variable presystemic metabolism in the gut wall and liver; more than 20 chlorpromazine metabolites with different activities have been identified in human plasma SR formulations result in a greater first-pass effect t¹⁄₂ Serum half-lives have no clinical correlation with biologic half-lives for antipsychotic drugs Chlorpromazine serum half-life is 30 hr, thioridazine 4–10 hr, thiothixene 34 hr, and haloperidol 12–24 hr Of more clinical importance is that steady-state CNS levels and tissue saturation allow once-daily administration of all antipsychotic drugs.141 Adverse Reactions (See Antipsychotic Drugs Comparison Chart for relative frequency of common adverse reactions.) Frequently, sedation, extrapyramidal effects (eg, parkinsonism, dystonic reactions, akathisia), tardive dyskinesia, anticholinergic effects (eg, dry mouth, blurred vision, constipation, urinary retention), photosensitivity, and postural hypotension occur Occasionally, weight gain, amenorrhea, galactorrhea, ejaculatory disturbance, neuroleptic malignant syndrome, agranulocytosis, skin rash, cholestatic jaundice, and skin or eye pigmentation occur Rarely, seizures, thermoregulatory impairment, and slowed AV conduction occur Mesoridazine and thioridazine can prolong QTc interval, leading to torsades de pointes and sudden death Low-potency drugs are more likely to cause sedation, anticholinergic effects, and orthostatic hypotension, whereas highpotency drugs cause more extrapyramidal effects Tardive dyskinesia is a longterm adverse effect, untreatable, and sometimes irreversible Tardive dyskinesia occurs at a 4% yearly incidence for at least the first 5–6 yr of treatment Neuroleptic malignant syndrome (ie, fever, extrapyramidal rigidity, autonomic instability, alterations in consciousness) occurs more frequently with high-potency antipsychotics, with a prevalence of 1.4% and a fatality rate of 4%.183,190,191 Contraindications Coma; circulatory collapse or severe hypotension; bone marrow depression; history of blood dyscrasia (Mesoridazine and thioridazine) concurrent use with drugs that prolong QTc interval; baseline QTc >450 msec Precautions Use cautiously in patients with myasthenia gravis, Parkinson’s disease, seizure disorders, or hepatic disease Drug Interactions Barbiturates can enhance phenothiazine metabolism; carbamazepine can enhance haloperidol metabolism Phenothiazines can decrease efficacy of guanethidine or guanadrel or have additive hypotensive effects with hypotensive drugs Phenothiazines can inhibit the antiparkinson activity of levodopa Haloperidol can increase the CNS toxicity of lithium Combined use of haloperidol and methyldopa can result in dementia Parameters to Monitor (Mesoridazine and thioridazine) obtain baseline and periodic ECGs and serum potassium ch05.qxd 462 8/13/2001 2:00 PM Page 462 C ENTRAL N ERVOUS S YSTEM D RUGS Notes (See also Prochlorperazine Salts in the Antiemetics section for antiemetic uses.) CLOZAPINE Clozaril Pharmacology Clozapine is an atypical antipsychotic drug that is chemically similar to loxapine and has unique pharmacologic effects and indications, as well as very serious adverse effects Whereas typical antipsychotic drugs exert their effects primarily with a blockade of dopamine-D2 receptors, clozapine affects several dopamine and serotonin receptors Its high serotonin-5HT2 to dopamine-D2 ratio is the likely explanation for its unique efficacy Compared with traditional antipsychotic drugs, clozapine is more effective for negative symptoms of schizophrenia, is more effective in treatment-resistant patients, and rarely causes extrapyramidal effects.192–195 Adult Dosage PO 100–200 mg tid is effective for most patients, but some might require up to 900 mg/day A therapeutic trial of 12–24 weeks is required for the full therapeutic effect to become apparent Dosage Forms Tab 25, 100 mg Pharmacokinetics Clozapine is nearly completely absorbed after oral administration, with about 30% oral bioavailability because of extensive first-pass metabolism Clozapine is 95% bound to plasma proteins; with multiple doses, its elimination half-life is 12 hr.196 Adverse Reactions Frequent adverse effects include sedation, orthostatic hypotension, anticholinergic effects, fever, and excessive salivation Seizures are dose related, with a frequency up to 5% in the therapeutic dosage range and a 1-yr cumulative incidence of 10% Agranulocytosis is the major adverse effect of concern, occurring in 0.8% of patients after yr.197 Most cases of agranulocytosis occur within the first months of therapy Substantial weight gain has been reported in most patients receiving clozapine.198 (See Antipsychotic Drugs Comparison Chart.) Paramaters to Monitor Patients must have a baseline WBC count and differential before initiating therapy, mandatory weekly WBC monitoring for the first months, and then q weeks throughout treatment and for weeks after discontinuation HALOPERIDOL DECANOATE Haldol Decanoate, Various Pharmacology Haloperidol decanoate (HD) is the preferred long-acting depot antipsychotic drug Depot antipsychotics are indicated only for patients who demonstrate good response but are consistently drug-noncompliant with resultant frequent psychotic relapses Depot antipsychotics provide fewer relapses and hospitalizations, stable serum drug levels, and side effects equal to oral antipsychotic drugs HD can be given q weeks; fluphenazine decanoate (FD) is similar in efficacy and adverse effects, but it must be administered q weeks Do not use HD or FD to treat acute psychotic symptoms; rather, use the drug only after a patient has been stabilized on an oral antipsychotic drug.199–203 ch06.qxd 8/13/2001 2:10 PM Page 555 A NTIEMETICS 555 and vomiting It might not be as effective as smoking Cannabis, which is easier to titrate.85 (See Antiemetic Drugs Comparison Chart.) GRANISETRON Kytril Pharmacology Granisetron is a selective antagonist at the 5-HT3 receptor used for the prevention of nausea and vomiting associated with cancer chemotherapy Its use in cancer chemotherapy is similar to that of ondansetron, and its efficacy and side effects are comparable to those of ondansetron.72,86 (See Antiemetic Drugs Comparison Chart.) Adult Dosage IV for cancer chemotherapy-induced nausea and vomiting 10 ␮g/kg administered in 20–50 mL NS or D5W over min, 30 before the start of chemotherapy PO for cancer chemotherapy-induced nausea and vomiting mg up to hr before chemotherapy and additional mg doses at 12-hr intervals thereafter while receiving chemotherapy Pediatric Dosage IV (>2 yr) same as adult dosage, but this dosage might not be adequate for children.86 Dosage Forms Inj mg/mL; Tab mg Pharmacokinetics Oral absorption is approximately 60% Vd is 30 ± 1.5 L/kg; Cl is 0.060 ± 0.54 L/hr/kg Elimination is mostly by hepatic metabolism, with 16 ± 14% appearing in the urine as unchanged drug The half-life is 5.3 ± 3.5 hr (can be longer in cancer patients than in normals) The metabolism of granisetron might be changed by inducers or inhibitors of the cytochrome P450 system, but dosage adjustment is not recommended Adverse Reactions (See Ondansetron) ONDANSETRON HYDROCHLORIDE Zofran Pharmacology Ondansetron is a selective antagonist at the 5-HT3 receptor used for the prevention of nausea and vomiting associated with cancer chemotherapy, especially cisplatin, and for postoperative nausea and vomiting It also is useful for radiotherapy-induced nausea and vomiting Ondansetron is thought to block these receptors at both peripheral sites in the GI tract and within the area postrema in the CNS.87 It is not a dopamine receptor antagonist, so it has no extrapyramidal side effects (See Notes.) Administration and Adult Dosage IV for chemotherapy-induced nausea or vomiting 0.15 mg/kg for doses (30 before chemotherapy and then and hr after) or 0.45 mg/kg, to a maximum of 32 mg as a single dose or mg IV as a single dose for cisplatin doses 2 yr) 2.5 mg IM (>9 kg or >2 yr) 0.13 mg/kg X Promethazine Phenergan Various Syrup 1.25, mg/mL Tab 12.5, 25, 50 mg Supp 12.5, 25, 50 mg Inj 25, 50 mg/mL PO, PR 25 mg IM, IV 12.5–25 mg PO, PR, IM (>2 yr) 0.25–0.5 mg/kg X 2:10 PM CANNABINOIDS 8/13/2001 INITIAL DOSEa,b PHENOTHIAZINES Page 560 X (continued ) ch06.qxd ANTIEMETIC DRUGS COMPARISON CHART (continued ) DRUG DOSAGE FORMS Adult INDICATIONS Pediatric Nausea and Vomiting Tab 10 mg Inj mg/mL PO, IM 10 mg — X Triflupromazine Vesprin Inj 10, 20 mg/mL IM 5–15 mg IM (elderly) 2.5 mg IV mg IM (>2.5 yr) 0.2–0.25 mg/kg Vertigo X 2:10 PM Thiethylperazine Torecan Motion Sickness 8/13/2001 INITIAL DOSEa,b Page 561 SEROTONIN 5-HT3 ANTAGONISTS Dolasetron Anzemet Tab 50, 100 mg Inj 20 mg/mL PO 100 mg IV 1.8 mg/kg PO 1.8 mg/kg IV 1.8 mg/kg X Granisetron Kytril Tab mg Inj mg/mL PO mg IV 10 µg/kg IV (>2 yr) 10 µg/kg X Ondansetron Zofran Tab 4, 8, 24 mg Tab (rapidly dissolving) 4, mg Soln 6.8 mg/mL Inj 0.64, mg/mL PO or 16 mg IV 0.15–0.45 mg/kg (max 32 mg) PO (>4 yr) mg IV (>2 yr) 0.15 mg/kg X Elxr 0.1 mg/mL Soln 0.1, mg/mL Tab 0.25, 0.5, 0.75, 1, 1.5, , 4.6 mg Inj 4, 10, 20, 24 mg/mL PO, IV 10–20 mg PO, IV 10 mg/m2 e MISCELLANEOUS 561 Dexamethasone Decadron Various (continued) ch06.qxd ANTIEMETIC DRUGS COMPARISON CHART (continued ) 562 DRUG DOSAGE FORMS Adult INDICATIONS Pediatric Nausea and Vomiting IM, IV 0.625–1.25 mg IV 0.015–0.075 mg/kg f Lorazepam (C-IV) d Ativan Various Tab 0.5, 1, mg Soln mg/mL Inj 2, mg/mL PO 1–2 mg PO 0.05 mg/kg e Methylprednisolone Solu-Medrol Various Inj 40, 125, 500 mg IV up to 100 mg IV 2–4 mg/kg e Metoclopramide Reglan Inj mg/mL IV 1–2 mg/kg IV 1–2 mg/kg X Scopolamine Scopace Transderm Scop Transdermal Patch 1.5 mg (delivers mg over days) Tab 0.4 mg disk behind ear over days PO 0.4 mg Trimethobenzamide Tigan Various Cap 100, 250 mg Supp 100, 200 mg Inj 100 mg/mL PO 250 mg PR 200 mg IM 200 mg a — — PO (14–40 kg) 100–200 mg PR (6 yr) 5–10 mg or 0.3 mg/kg once daily; PR (≤6 yr) safety and efficacy not established; (6–12 yr) mg; (>12 yr) 10 mg Geriatric Dosage Same as adult dosage Dosage Forms EC Tab mg; Enema (adult) 10 mg; Supp 10 mg Patient Instructions Swallow tablets whole (not chewed or crushed) and not take within hour of antacids or dairy products Do not use oral products in children years of age or less Pharmacokinetics Onset and Duration Onset PO 6–12 hr; PR 15 min–1 hr.101,102 Fate Absorption is less than 5% by oral or rectal route, with subsequent conversion to the glucuronide salt and excretion in urine and bile Rapidly converted in the gut by intestinal and bacterial enzymes to its active, but nonabsorbed, desacetyl metabolite.103 Adverse Reactions Abdominal cramps occur frequently; with long-term use, metabolic acidosis or alkalosis, hypocalcemia, tetany, loss of enteric protein, and malabsorption occur occasionally; suppositories can cause proctitis and rectal inflammation and are not recommended for long-term use Drug Interactions Antacids or milk can dissolve the enteric coating of oral bisacodyl tablets, causing drug release in the stomach and gastric irritation Contraindications Acute surgical abdomen; nausea, vomiting, or other symptoms of appendicitis; fecal impaction; intestinal or biliary tract obstruction; abdominal pain of unknown origin Notes Useful for preoperative or preradiographic bowel preparation Bisacodyl has been used in combination with polyethylene glycol (PEG) electrolyte lavage solution to decrease the amount of solution required.100,101,104 (See PEG Electrolyte Lavage Solution.) DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE Lomotil, Various Pharmacology Diphenoxylate is a synthetic meperidine congener without analgesic activity that slows GI motility Because high doses of diphenoxylate (40– 60 mg) cause systemic opioid activity, atropine is added in subtherapeutic amounts to decrease abuse potential Administration and Adult Dosage PO for diarrhea tablets or 10 mL qid initially and then, if control is achieved (usually within 48 hr), decrease to a maintenance dosage as low as tablets or 10 mL daily prn If chronic diarrhea is not ch06.qxd 564 8/13/2001 2:10 PM Page 564 G ASTROINTESTINAL D RUGS controlled in 10 days at the full dosage, then symptoms are unlikely to be controlled by further administration Special Populations Pediatric Dosage Use liquid only (