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Pronunciation:

(mez oh RID a zeen)

U.S. Brand Names:

Serentil® [DSC]

Synonyms:

Mesoridazine Besylate

Generic Available:

Canadian Brand Names:

Serentil®

Use:

Management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from these drugs

Use - Unlabeled/Investigational:

Psychosis

Pregnancy Risk Factor:

Lactation:

Enters breast milk/contraindicated (AAP rates "of concern")

Contraindications:

Hypersensitivity to mesoridazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression and coma; prolonged QT interval (>450 msec), including prolongation due to congenital causes; history of arrhythmias; concurrent use of medications which prolong QTc (including type Ia and type III antiarrhythmics, cyclic antidepressants, some fluoroquinolones, cisapride)

Warnings/Precautions:

Has been shown to prolong QTc interval in a dose-dependent manner (associated with an increased risk of torsade de pointes). Patients should have a baseline ECG prior to initiation, and should not receive mesoridazine if baseline QTc >450 msec. Mesoridazine should be discontinued in patients with a QTc interval >500 msec. Potassium levels must be evaluated and normalized prior to and throughout treatment.

May cause hypotension, particularly with I.M. administration. Highly sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; bone marrow suppression; predisposition to seizures; subcortical brain damage; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).

Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention). Therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other antipsychotics, mesoridazine has a high potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low relative to other neuroleptics). May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy (particularly at doses >1 g/day).

Adverse Reactions:

Frequency not defined.

Cardiovascular: Hypotension, orthostatic hypotension, tachycardia, QT prolongation (dose dependent, up to 100% of patients at higher dosages), syncope, edema

Central nervous system: Pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia, dizziness, drowsiness, restlessness, ataxia, slurred speech, neuroleptic malignant syndrome (NMS), impairment of temperature regulation, lowering of seizure threshold

Dermatologic: Increased sensitivity to sun, rash, itching, angioneurotic edema, dermatitis, discoloration of skin (blue-gray)

Endocrine & metabolic: Changes in menstrual cycle, libido (changes in), gynecomastia, lactation, galactorrhea

Gastrointestinal: Constipation, xerostomia, weight gain, nausea, vomiting, stomach pain

Genitourinary: Difficulty in urination, ejaculatory disturbances, impotence, enuresis, incontinence, priapism, urinary retention

Hematologic: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Weakness, tremor, rigidity

Ocular: Pigmentary retinopathy, photophobia, blurred vision, cornea and lens changes

Respiratory: Nasal congestion

Miscellaneous: Diaphoresis (decreased), lupus-like syndrome

Overdosage/Toxicology:

Symptoms of overdose include deep sleep, coma, extrapyramidal symptoms, abnormal involuntary muscle movements, and hypotension. Monitor for cardiac arrhythmias and avoid use of drugs which prolong QT interval. Treatment is symptomatic and supportive.

Drug Interactions:

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

Epinephrine: Chlorpromazine (and possibly other low potency antipsychotics) may diminish the pressor effects of epinephrine

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by chlorpromazine

Levodopa: Chlorpromazine may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Chlorpromazine may produce neurotoxicity with lithium; this is a rare effect

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin and gatifloxacin). Concurrent use is contraindicated.

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Valproic acid: Serum levels may be increased by phenothiazines

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability:

Protect all dosage forms from light; clear or slightly yellow solutions may be used; should be dispensed in amber or opaque vials/bottles. Solutions may be diluted or mixed with fruit juices or other liquids but must be administered immediately after mixing; do not prepare bulk dilutions or store bulk dilutions.

Mechanism of Action:

Mesoridazine is a piperidine phenothiazine antipsychotic which blocks postsynaptic CNS dopamine2 receptors in the mesolimbic and mesocortical areas

Pharmacodynamics/Kinetics:

Duration: 4-6 hours

Absorption: Tablet: Erratic; Liquid: More dependable

Protein binding: 91% to 99%

Half-life elimination: 24-48 hours

Time to peak, serum: 2-4 hours; Steady-state serum: 4-7 days

Excretion: Urine

Dosage:

Concentrate may be diluted just prior to administration with distilled water, acidified tap water, orange or grape juice; do not prepare and store bulk dilutions

Adults: Schizophrenia/psychoses:

Oral: 25-50 mg 3 times/day; maximum: 100-400 mg/day

I.M.: Initial: 25 mg, repeat in 30-60 minutes as needed; optimal dosage range: 25-200 mg/day

Elderly: Behavioral symptoms associated with dementia:

Oral: Initial: 10 mg 1-2 times/day; if <10 mg/day is desired, consider administering 10 mg every other day (qod). Increase dose at 4- to 7-day intervals by 10-25 mg/day; increase dose intervals (bid, tid, etc) as necessary to control response or side effects. Maximum daily dose: 250 mg. Gradual increases (titration) may prevent some side effects or decrease their severity.

I.M.: Initial: 25 mg; repeat doses in 30-60 minutes if necessary. Dose range: 25-200 mg/day. Elderly usually require less than maximal daily dose.

Hemodialysis: Not dialyzable (0% to 5%)

Administration:

When administering I.M. or I.V., watch for hypotension. Dilute oral concentrate just prior to administration with distilled water, acidified tap water, orange or grape juice. Do not prepare and store bulk dilutions. Do not mix oral solutions of mesoridazine and lithium, these oral liquids are incompatible when mixed. Note: Avoid skin contact with oral medication; may cause contact dermatitis.

Monitoring Parameters:

Vital signs, orthostatic blood pressures; lipid profile, fasting blood glucose/Hgb A1c, baseline (and periodic) serum potassium; BMI; mental status, abnormal involuntary movement scale (AIMS); tremors, gait changes, abnormal movement in trunk, neck, buccal area or extremities; monitor target behaviors for which the agent is given; monitor hepatic function (especially if fever with flu-like symptoms); baseline ECG, do not initiate if QTc >450 msec (discontinue in any patient with a QTc >500 msec)

Patient Education:

Use exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; do not discontinue without consulting prescriber. Dilute oral concentration with water, orange or grape juice. Do not take within 2 hours of any antacid. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid skin contact with medication; may cause contact dermatitis (wash immediately with warm, soapy water). You may experience excess drowsiness, restlessness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, nausea, vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); urinary retention (void before taking medication); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); decreased perspiration (avoid strenuous exercise in hot environments); or changes in menstrual cycle, libido, ejaculation (will resolve when medication is discontinued). Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, severe dizziness; unresolved urinary retention or changes in urinary pattern; menstrual pattern, change in libido, swelling or pain in breasts (male or female); vision changes; skin rash or yellowing of skin; respiratory difficulty; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Nursing Implications:

Monitor orthostatic blood pressures 3-5 days after initiation of therapy or a dose increase; tremors, gait changes, abnormal movement in trunk, neck, buccal area or extremities; monitor target behaviors for which the agent is administered; monitor hepatic function (especially if fever with flu-like symptoms)

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

[DSC] = Discontinued product

Injection, solution, as besylate [DSC]: 25 mg/mL (1 mL)

Liquid, oral, as besylate [DSC]: 25 mg/mL (118 mL) [contains alcohol 0.61%]

Tablet, as besylate [DSC]: 10 mg, 25 mg, 50 mg, 100 mg

International Brand Names:

Lidanil® (TR); Serentil® (CA)

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

Marrs-Simon PA, Zell-Kanter M, Kendzierski DL, et al, "Cardiotoxic Manifestations of Mesoridazine Overdose,"Ann Emerg Med, 1988, 17(10):1074-8.

Peabody CA, Warner MD, Whiteford HA, et al, "Neuroleptics and the Elderly,"J Am Geriatr Soc, 1987, 35(3):233-8.

Risse SC and Barnes R, "Pharmacologic Treatment of Agitation Associated With Dementia,"J Am Geriatr Soc, 1986, 34(5):368-76.

Saltz BL, Woerner MG, Kane JM, et al, "Prospective Study of Tardive Dyskinesia Incidence in the Elderly,"JAMA, 1991, 266(17):2402-6.

Samet J and Surawicz B, "Cardiac Function in Patients Treated With Phenothiazines Comparison With Quinidine,"J Clin Pharmacol, 1974, 14(11-12):588-96.

Seifert RD, "Therapeutic Drug Monitoring: Psychotropic Drugs,"J Pharm Pract, 1984, 6:403-16.

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