Other Warnings/Precautions

• If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

• Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

• Use with caution in patients with respiratory disorders, glaucoma, or urinary retention

• Avoid undue exposure to sunlight

• Avoid extreme heat exposure

• Antiemetic effect may mask signs of other disorders or overdose; suppression of cough reflex may cause asphyxia

• Do not use epinephrine in event of overdose as interaction with some pressor agents may lower blood pressure

• Use only with caution if at all in Parkinson’s disease or Lewy body dementia

Do Not Use

• If patient is in a comatose state or has CNS depression

• If there is the presence of blood dyscrasias, bone marrow depression, or liver disease

• If there is a proven allergy to trifluoperazine

• If there is a known sensitivity to any phenothiazine

TRIFLUOPERAZINE: SPECIAL POPULATIONS

Renal Impairment

• Use with caution

Hepatic Impairment

• Not recommended for use

Cardiac Impairment

• Dose should be lowered

• Do not use parenteral administration unless necessary

Elderly

• Lower doses should be used and patient should be monitored closely

• Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with dementia-related psychosis

• Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

• Not recommended for use in children under age 6

• Children should be closely monitored when taking trifluoperazine

• Oral: initial 1 mg; increase gradually; maximum 15 mg/day except in older children with severe symptoms

• Intramuscular: 1 mg once or twice a day

• Generally consider second-line after atypical antipsychotics

Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

• Reports of extrapyramidal symptoms, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

• Trifluoperazine should only be used during pregnancy if clearly needed

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

• Some drug is found in mother’s breast milk

✽ Recommended either to discontinue drug or bottle feed

TRIFLUOPERAZINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Intramuscular formulation for emergency use

Potential Disadvantages

• Patients with tardive dyskinesia

• Children

• Elderly

Primary Target Symptoms

• Positive symptoms of psychosis

• Motor and autonomic hyperactivity

• Violent or aggressive behavior

Pearls

• Trifluoperazine is a higher potency phenothiazine

✽ Although not systematically studied, may cause less weight gain than other antipsychotics

• Less risk of sedation and orthostatic hypotension but greater extrapyramidal symptoms than with low potency phenothiazines

• Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

• Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic such as trifluoperazine or from switching to a conventional antipsychotic such as trifluoperazine

• However, long-term polypharmacy with a combination of a conventional antipsychotic such as trifluoperazine with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

• For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

• In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

• Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

Suggested Reading

Doongaji DR, Satoskar RS, Sheth AS, Apte JS, Desai AB, Shah BR. Centbutindole vs trifluoperazine: a double-blind controlled clinical study in acute schizophrenia. J Postgrad Med 1989;35:3–8.

Frankenburg FR. Choices in antipsychotic therapy in schizophrenia. Harv Rev Psychiatry 1999;6:241–9.

Kiloh LG, Williams SE, Grant DA, Whetton PS. A double-blind comparative trial of loxapine and trifluoperazine in acute and chronic schizophrenic patients. J Int Med Res 1976;4:441–8.

Marques LO, Lima MS, Soares BG. Trifluoperazine for schizophrenia. Cochrane Database Syst Rev 2004;(1):CD003545.

TRIHEXYPHENIDYL

TRIHEXYPHENIDYL: THERAPEUTICS

Brands

• Artane

see index for additional brand names

Generic?

Yes

Class

• Antiparkinson agent; anticholinergic

Commonly Prescribed for

(bold for FDA approved)

• Extrapyramidal disorders

• Parkinsonism

• Idiopathic generalized dystonia

• Focal dystonias

• Dopa-responsive dystonia

How the Drug Works

• Diminishes the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked

• May also inhibit the reuptake and storage of dopamine at central dopamine receptors, prolonging dopamine action

How Long Until It Works

• For extrapyramidal disorders and parkinsonism, onset of action can be within minutes or hours

If It Works

• Reduces motor side effects

• Does not lessen the ability of antipsychotics to cause tardive dyskinesia

If It Doesn’t Work

• For extrapyramidal disorders, increase to highest tolerated dose

• Consider switching to benztropine, diphenhydramine, or a benzodiazepine

• Disorders that develop after prolonged antipsychotic use may not respond to treatment

• Consider discontinuing the agent that precipitated the extrapyramidal side effects

Best Augmenting Combos for Partial Response or Treatment Resistance

• If ineffective, switch to another agent rather than augment

• Trihexyphenidyl itself is an augmenting agent to antipsychotics

Tests

• None for healthy individuals

TRIHEXYPHENIDYL: SIDE EFFECTS

How Drug Causes Side Effects

• Prevents the action of acetylcholine on muscarinic receptors

Notable Side Effects

• Dry mouth, blurred vision, diplopia

• Confusion, hallucinations

• Constipation, nausea, vomiting

• Dilation of colon

• Erectile dysfunction

Life-Threatening or Dangerous Side Effects

• Angle-closure glaucoma

• Heat stroke, especially in elderly patients

• Tachycardia, cardiac arrhythmias, hypotension

• Urinary retention

• Anticholinergic agents such as trihexyphenidyl can exacerbate or unmask tardive dyskinesia

Weight Gain

• Reported but not expected

Sedation

• Many experience and/or can be significant in amount

What to Do About Side Effects

• For confusion or hallucinations, discontinue use

• For sedation, lower the dose and/or take the entire dose at night

• For dry mouth, chew gum or drink water

• For urinary retention, obtain a urological evaluation; may need to discontinue use

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

TRIHEXYPHENIDYL: DOSING AND USE

Usual Dosage Range

• Extrapyramidal disorders: 5–15 mg/day

• Parkinsonism: 6–15 mg/day

Dosage Forms

• Tablet 2 mg, 5 mg

• Injection 2 mg/5 mL

How to Dose

• Extrapyramidal disorders: 5–15 mg/day; assess effect and increase dose empirically as tolerated; total daily dose varies from patient to patient

• Parkinsonism (oral): initial 1 mg/day; after 3 days can increase the dose in 2 mg increments every 3–5 days as tolerated until clinical effect is reached; total daily dose should be divided into 3 doses and given with meals

Dosing Tips

• If drug-induced extrapyramidal side effects occur soon after initiation of a neuroleptic drug, they are likely to be transient; thus, attempt to withdraw trihexyphenidyl after 1–2 weeks to determine if still needed

• To achieve more rapid relief, temporarily lower the dose of the offending agent (phenothiazine, thioxanthene, or butyrophenone) when starting trihexyphenidyl

• Taking trihexyphenidyl with meals can reduce side effects

• In Parkinson’s disease, the usual dose is 6–10 mg/day (divided into 3 doses) for idiopathic Parkinson’s disease and 12–15 mg/day (divided into 3 or 4 doses) for post-encephalitic Parkinson’s disease

Overdose

• Circulatory collapse, cardiac arrest, respiratory depression or arrest, CNS depression or stimulation, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis and hyperthermia, fever, dysphagia, decreased bowel sounds, sluggish pupils

Long-Term Use

• Safe

• Effectiveness may decrease over time (years) and side effects such as sedation and cognitive impairment may worsen

Habit Forming

• No

How to Stop

• Taper not necessary

Pharmacokinetics

• Half-life 6–10 hours; time to peak effect is 1–1.3 hours

• Metabolism is not well understood

Drug Interactions

• Use with amantadine may increase side effects

• Trihexyphenidyl and all other anticholinergic agents may increase serum levels and effects of digoxin

• Can lower concentration of haloperidol and other phenothiazines, causing worsening of schizophrenia symptoms

• Can decrease gastric motility, resulting in increased gastric deactivation of levodopa and reduction in efficacy

Other Warnings/Precautions

• Use with caution in hot weather, as trihexyphenidyl may increase susceptibility to heat stroke

• Anticholinergic agents have additive effects when used with drugs of abuse such as cannabinoids, barbiturates, opioids, and alcohol

Do Not Use

• In patients with glaucoma, particularly angle-closure glaucoma

• In patients with pyloric or duodenal obstruction, stenosing peptic ulcers, prostate hypertrophy or bladder neck obstructions, achalasia, or megacolon

• If there is a proven allergy to trihexyphenidyl

TRIHEXYPHENIDYL: SPECIAL POPULATIONS

Renal Impairment

• No known effects, but use with caution

Hepatic Impairment

• No known effects, but use with caution

Cardiac Impairment

• Use with caution in patients with known arrhythmias, especially tachycardia

Elderly

• Use with caution

• Elderly patients may be more susceptible to side effects

Children and Adolescents

• Do not use in children ages 3 and younger

• Generalized dystonias may respond to anticholinergic treatment and young patients usually tolerate the medication better than the elderly

• Usual dose is 0.05 mg/kg once or twice daily

Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

Breast Feeding

• Unknown if trihexyphenidyl is secreted in human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed unless the potential benefit to the mother justifies the potential risk to the child

• Infants of women who choose to breast feed while on trihexyphenidyl should be monitored for possible adverse effects

TRIHEXYPHENIDYL: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Extrapyramidal disorders related to antipsychotic use

• Generalized dystonias (well tolerated in younger age groups)

Potential Disadvantages

• Patients with long-standing extrapyramidal disorders may not respond to treatment

• Multiple dose-dependent side effects may limit use

Primary Target Symptoms

• Tremor, akinesia, rigidity, drooling, dystonia

Pearls

• Often abused in correctional settings for its euphoric and sedative/hypnotic action, especially at high doses

• Although any anticholinergic agent is potentially abusable, especially in a correctional setting, trihexyphenidyl may be more abusable than others, presumably due to its dopamine-enhancing actions

• Useful adjunct in younger Parkinson’s patients with tremor

• Useful in the treatment of post-encephalitic Parkinson’s disease and for extrapyramidal reactions, other than tardive dyskinesias

• Post-encephalitic Parkinson’s patients usually tolerate higher doses better than idiopathic Parkinson’s patients

• Generalized dystonias are more likely to benefit from anticholinergic therapy than focal dystonias; trihexyphenidyl is used more commonly than benztropine

• Sedation limits use, especially in older patients

• Patients with mental impairment do poorly

• Dystonias related to cerebral palsy, head injuries, and stroke may improve with trihexyphenidyl, especially in younger, cognitively normal patients

• Schizophrenia patients may abuse trihexyphenidyl and other anticholinergic medications to relieve negative symptoms, for a stimulant effect or to improve symptoms of drug-induced parkinsonism

• Can cause cognitive side effects with chronic use, so periodic trials of discontinuation may be useful to justify continuous use, especially in institutional settings as adjunct to antipsychotics

Suggested Reading

Brocks DR. Anticholinergic drugs used in Parkinson’s disease: an overlooked class of drugs from a pharmacokinetic perspective. J Pharm Pharm Sci 1999;2(2):39–46.

Colosimo C, Gori MC, Inghilleri M. Postencephalitic tremor and delayed-onset parkinsonism. Parkinsonism Relat Disord 1999;5(3):123–4.

Costa J, Espírito-Santo C, Borges A, Ferreira JJ, Coelho M, Sampaio C. Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst Rev 2005;(1):CD004312.

Sanger TD, Bastian A, Brunstrom J, et al. Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy. J Child Neurol 2007;22(5):530–7.

Zemishlany Z, Aizenberg D, Weiner Z, Weizman A. Trihexyphenidyl (Artane) abuse in schizophrenic patients. Int Clin Psychopharmacol 1996;11(3):199–202.

TRIIODOTHYRONINE

TRIIODOTHYRONINE: THERAPEUTICS

Brands

• Cytomel

see index for additional brand names

Generic?

Yes

Class

• Synthetic hormone; antidepressant adjunct

Commonly Prescribed for

(bold for FDA approved)

• Replacement or supplemental therapy in patients with hypothyroidism (except transient hypothyroidism during the recovery phase of subacute thyroiditis)

• Pituitary thyroid-stimulating hormone (TSH) suppressant in the treatment or prevention of various types of euthyroid goiters

• Major depressive disorder (adjunct)

How the Drug Works

• Hypothetically boosts monoamine actions in the CNS

• May work synergistically with traditional antidepressants

How Long Until It Works (for depression)

• Can work within days, but therapeutic effects may be delayed for up to 8 weeks

If It Works (for depression)

• The goal of treatment is complete remission of current symptoms as well as prevention of future relapses

• Treatment most often reduces or even eliminates symptoms, but not a cure since symptoms can recur after medicine stopped

• Continue treatment until all symptoms are gone (remission) or significantly reduced

• Once symptoms gone, continue treating for 1 year for the first episode of depression

• For second and subsequent episodes of depression, treatment may need to be indefinite