Prescribing Chlorpromazine

Why Chlorpromazine Still Matters

Chlorpromazine is the drug that created modern psychiatry. Synthesized in 1950 and introduced clinically in 1952, it was the first agent that could reliably quiet psychosis and mania, empty the back wards of asylums, and prove that a molecule could touch the machinery of madness. For roughly a decade it was, for many patients, the psychiatric medication, used in one form or another for the majority of hospitalized psychiatric patients. Every antipsychotic since is measured, one way or another, against the standard it set.

Seventy years later almost no one starts a patient on chlorpromazine for chronic schizophrenia, and they shouldn't. The atypicals are better tolerated for maintenance, lithium and lamotrigine are better long-term mood agents, and the low-potency phenothiazine side-effect stack (sedation, orthostasis, anticholinergic load) makes it a poor daily companion for most patients over years. So why keep a guide to it on your shelf?

Because chlorpromazine still does a few things extraordinarily well, and cheaply. It is a fast, sedating tranquilizer for acute agitation. It is a legitimate low-dose, non-addictive anxiolytic in a benzodiazepine-wary era. It remains a workhorse for intractable hiccups and for nausea. And it is one of the least expensive antipsychotics on earth, a real consideration in cost-constrained settings and for uninsured patients. Knowing how to use it well, and knowing its specific hazards cold, is part of being a complete prescriber.

This guide is about using it deliberately. The thesis throughout: chlorpromazine is a low-potency, sedating, highly anticholinergic phenothiazine whose value today lies in short-term and low-dose use: acute agitation, PRN tranquilization, hiccups, nausea, where its sedation is a feature, not a bug. Its liabilities (orthostasis, anticholinergic burden, sedation, tardive dyskinesia over time, and photosensitivity) are predictable and manageable if you respect them. Use it for the right job, at the right dose, for the right duration.

Part 1: Indications: Who Is Chlorpromazine For?

FDA-Approved Uses

Chlorpromazine carries an unusually broad legacy label, reflecting an era when it was tried for nearly everything:

• Schizophrenia and other psychotic disorders
• Manic phase of bipolar disorder (acute mania)
• Severe behavioral problems in children (ages 1–12), including combative/explosive hyperexcitability and short-term hyperactivity
• Nausea and vomiting
• Preoperative apprehension (restlessness/anxiety before surgery)
• Intractable hiccups
• Acute intermittent porphyria
• Adjunct in tetanus

Where It Actually Earns Its Keep Today

Strip away the historical label, and the modern, defensible uses cluster into a short list:

Acute agitation and acute mania, the sedation advantage. This is chlorpromazine's most credible psychiatric role. When you need to bring down a floridly agitated, manic, or psychotic patient quickly, chlorpromazine's heavy sedative and behavioral-calming effect works within hours, faster than lithium, which takes days to weeks to touch mania. Head-to-head studies from the 1960s found chlorpromazine and lithium comparably effective for mania overall, with chlorpromazine winning on speed of behavioral and agitation control and lithium winning on how the patient felt (lithium "normalizes"; chlorpromazine puts a "blanket over the head").

Low-dose, non-addictive tranquilization. In a climate of appropriate caution about benzodiazepines, low-dose chlorpromazine (on the order of 25 mg once or twice daily PRN) is a legitimate non-addictive anxiolytic. At these doses tardive dyskinesia risk is low, and it competes directly with the common off-label practice of using 25 mg of quetiapine for the same purpose, at a fraction of the cost. It took over this niche from thioridazine (Mellaril) after Mellaril's QT boxed warning pushed it to the sidelines.

Intractable hiccups. Chlorpromazine is the classic pharmacologic rescue for persistent hiccups that don't respond to conservative measures, one of its oldest and most durable niches, and still FDA-labeled for it.

Nausea and vomiting. As a dopamine antagonist it is a genuine antiemetic, though modern practice usually reaches for cleaner agents (ondansetron, prochlorperazine, metoclopramide) first.

Treatment-resistant schizophrenia, what it is NOT for. Chlorpromazine is a reasonable first antipsychotic trial for schizophrenia in a resource-limited setting, but it is decisively not the drug for refractory illness. In the landmark Kane trial (1988), after failure of three prior antipsychotics, clozapine produced a 30% response rate at six weeks versus roughly 4% for chlorpromazine. Refractory schizophrenia means clozapine, not more phenothiazine.

Depression, of historical interest only. Between 1960 and 1976, roughly 17 double-blind trials tested chlorpromazine (and thioridazine) in depression, and most were positive, plausibly via downstream 5-HT2A effects resembling how some atypicals help. This is a footnote now. Do not reach for chlorpromazine as an antidepressant; dedicated agents are safer and better.

And what it does NOT treat: panic. A historically important negative: chlorpromazine does not block panic attacks. A 1962 observation that a patient on Thorazine kept having panic attacks but responded to imipramine helped Donald Klein carve panic disorder out as a distinct syndrome. Sedation is not the same as anxiolysis at the level of the panic circuit, don't expect chlorpromazine to abort panic.

Who Is a Reasonable Candidate?

• Patients needing rapid, short-term control of agitation, mania, or psychosis where sedation is desirable
• Patients needing low-dose non-addictive anxiolysis/sedation, especially where benzodiazepines are contraindicated
• Patients with intractable hiccups or refractory nausea
• Cost-constrained or uninsured patients who need an effective antipsychotic and can't afford atypicals
• Patients who cannot tolerate the metabolic burden of high-weight-gain atypicals (chlorpromazine causes relatively little weight gain, see below)

Who Is a Poor Candidate?

• Patients needing chronic maintenance who have better-tolerated options (atypicals, mood stabilizers)
• The elderly with dementia (boxed warning, see Part 6), and elderly patients generally (orthostasis/falls, 10-fold higher tardive dyskinesia risk)
• Patients with significant cardiac conduction disease or on other QT-prolonging drugs
• Patients prone to orthostatic hypotension / falls
• Patients with narrow-angle glaucoma, significant BPH/urinary retention, or severe constipation (anticholinergic load)
• Patients with hepatic impairment or prior phenothiazine-associated jaundice

Part 2: Before You Start: Workup and Candidacy

Chlorpromazine does not require the intensive lab surveillance lithium does, but a low-potency phenothiazine has its own predictable hazards worth baselining, especially if you anticipate anything beyond brief PRN use.

For brief, one-off use (a dose of chlorpromazine for acute agitation in the ED, or PRN 25 mg for anxiety in an otherwise healthy adult), you do not need the full panel. Scale the workup to the intended duration and dose.

Part 3: How to Start and Dose

Formulations

Chlorpromazine's versatility across routes is part of why it endured:

• Oral tablets (including small 25 mg "dosettes" convenient for low-dose PRN use)
• Oral concentrate/liquid (useful for fine titration and for patients who won't reliably swallow pills)
• Intramuscular injection (for acute agitation when oral isn't feasible; onset faster than oral)
• Intravenous (used in specific medical settings, e.g., hiccups, some nausea protocols; generally diluted and given slowly because of hypotension risk)

Dose Ranges by Indication

Chlorpromazine has an enormous dose range, from 25 mg PRN to, historically, well over 1,000 mg/day for severe hospitalized psychosis. Modern outpatient use lives at the low end. Approximate, mainstream ranges:

Because of chlorpromazine's variable oral bioavailability and heavy side-effect load, the guiding principle is: start low, titrate to effect and tolerability (chiefly sedation and orthostasis), and use the lowest dose that does the job for the shortest time that does the job.

Chlorpromazine as the "100 mg" Yardstick

Historically, antipsychotic potency was expressed in chlorpromazine equivalents, with 100 mg of chlorpromazine as the reference unit (e.g., roughly 2 mg of haloperidol ≈ 100 mg chlorpromazine). You rarely need this arithmetic day to day, but it's worth knowing that chlorpromazine is the historical benchmark: the "low-potency" label means you need many milligrams to achieve a given antipsychotic effect, which is exactly why the sedating, anticholinergic, and hypotensive burden per milligram of antipsychotic effect is high.

Why Sedation and Orthostasis Govern Titration

Unlike lithium, chlorpromazine has no meaningful therapeutic drug level to chase and no narrow toxic window to titrate against. What limits the dose is tolerability: sedation ("blanket over the head"), orthostatic dizziness, and anticholinergic dryness. Titrate against those, not against a number.

Part 4: Monitoring

Monitoring intensity should track duration and dose. Brief PRN use needs little; sustained antipsychotic-dose use needs a real schedule.

For Sustained Use

Thresholds to Act On

• Orthostatic drop with symptoms: reduce dose, slow titration, counsel on rising slowly and hydration.
• Emerging involuntary movements: reassess the need for the drug; reduce dose or switch to a lower-risk agent; the longer TD persists, the lower the odds of recovery.
• Jaundice, dark urine, pruritus, RUQ discomfort: check LFTs; cholestatic hepatitis warrants discontinuation.
• Fever, sore throat, or other infection with malaise: check CBC urgently to rule out agranulocytosis.
• Fever + rigidity + autonomic instability + altered mental status: think neuroleptic malignant syndrome; stop the drug and treat as an emergency (see Part 6).

Part 5: Side Effects and How to Manage Them

Chlorpromazine's side-effect profile is essentially a map of its receptor pharmacology: heavy antihistamine (sedation), anticholinergic (dry mouth, constipation, urinary retention, blurred vision, cognitive fog, but, helpfully, low EPS), and alpha-1 adrenergic blockade (orthostatic hypotension), layered over the D2 blockade that drives both efficacy and the movement/prolactin effects common to all antipsychotics.

Sedation

The signature effect. Patients describe feeling like they have "a blanket over their head."

Management:

• This is a feature in acute agitation: lean into it there.
• For sustained use, dose the bulk at night to convert sedation into a sleep aid and reduce daytime grogginess.
• Lower the dose; sedation is dose-dependent.
• If daytime function matters and sedation persists, this drug is probably the wrong long-term choice: switch to a less sedating agent.

Orthostatic Hypotension (Alpha-1 Blockade)

Common, and the leading tolerability problem in older patients: dizziness, falls, syncope.

Management:

• Rise slowly; sit on the edge of the bed before standing.
• Titrate gradually; the effect often attenuates over days to weeks.
• Maintain hydration and adequate salt.
• Lower the dose or split it.
• Avoid stacking other hypotensive agents.
• Never use epinephrine to treat drug-induced hypotension (epinephrine reversal, see Part 3).

Anticholinergic Effects (Anti-"SLUDC")

Chlorpromazine is the most inherently anticholinergic of the conventional antipsychotics. The muscarinic blockade produces dry mouth, dry/blurred eyes, urinary retention, constipation, and cognitive dulling.

The double-edged sword: this same anticholinergic activity is why chlorpromazine causes relatively little EPS. Within the striatum, dopamine and acetylcholine sit in reciprocal balance; blocking ACh offsets the effect of blocking dopamine, so low-potency anticholinergic agents like chlorpromazine rarely need the add-on benztropine (Cogentin) or trihexyphenidyl (Artane) that high-potency haloperidol demands.

Management:

• Dry mouth: sugar-free gum/lozenges, sips of water, good dental hygiene.
• Constipation: hydration, fiber, stool softeners; don't let it progress to obstruction, especially in the elderly.
• Urinary retention: caution in BPH; ask about hesitancy.
• Blurred vision / glaucoma: avoid in narrow-angle glaucoma.
• Cognitive dulling: dose-dependent; reduce dose. Be especially wary of stacking anticholinergic burden in older adults (delirium risk).

Extrapyramidal Symptoms (EPS)

Comparatively low for chlorpromazine, thanks to its intrinsic anticholinergic activity, one of its genuine advantages over high-potency typicals. But "low" is not "none," particularly at higher antipsychotic doses. Watch for:

• Acute dystonia (early; treat with IM/IV diphenhydramine or benztropine)
• Akathisia (inner restlessness; reduce dose, add propranolol; don't mistake it for worsening agitation and reflexively escalate the antipsychotic)
• Drug-induced parkinsonism (bradykinesia, rigidity, tremor; reduce dose or add anticholinergic)

Tardive Dyskinesia (TD): The Defining Long-Term Risk

Chronic D2 blockade produces receptor upregulation and supersensitivity, yielding involuntary, often irreversible movements (classically oro-facial: lip-smacking, chewing, tongue protrusion, grimacing; sometimes limbs/trunk).

The numbers to know:

• Low-potency agents carry meaningfully lower TD risk than high-potency haloperidol; older cohort data put low-potency 1-year cumulative TD incidence well below the ~25-30%/year seen with high-potency agents (exact paired figures vary by study). Chlorpromazine sits in the low-potency, lower-risk group.
• Typical antipsychotics as a class run substantially higher annual TD incidence than atypicals in younger adults.
• In the elderly, that advantage of atypicals disappears: annual TD incidence is on the order of ~5% for both classes, and older patients carry roughly 10-fold the annual TD risk of younger ones.
• Lower dose and lower potency reduce risk: which is precisely the argument for low-dose chlorpromazine over high-dose haloperidol when a typical is chosen.

Management:

• Prevent: use the lowest effective dose for the shortest necessary time; reassess the need at every visit; screen with the AIMS.
• Catch early: the longer TD is present before you act, the lower the chance of recovery.
• On detection: reassess the indication; reduce or discontinue if feasible; taper slowly, since abrupt withdrawal can unmask or worsen dyskinesia ("withdrawal-emergent dyskinesia," which can appear or worsen within 4–8 weeks of stopping).
• Pharmacotherapy: VMAT2 inhibitors (valbenazine, deutetrabenazine; tetrabenazine off-label) are the evidence-based treatments for established TD.

Metabolic Effects

Here chlorpromazine has a relative advantage over the worst atypicals: it causes relatively little weight gain compared with olanzapine, clozapine, risperidone, and quetiapine, and fewer lipid problems than those agents.

But don't over-read that. Among typical antipsychotics, the low-potency phenothiazines (chlorpromazine, thioridazine) are the metabolically "dirtiest": they cause more weight and lipid trouble than high-potency or mid-potency typicals like haloperidol or perphenazine. It's genuinely better than olanzapine and genuinely worse than haloperidol. Monitor per Part 4, and don't skip metabolic surveillance just because the class reputation is "weight-neutral."

Cardiovascular / QT

• Orthostasis (above) is the dominant cardiovascular effect.
• Phenothiazines can affect cardiac conduction; chlorpromazine is generally regarded as less QT-prolonging than thioridazine (which carries a QT boxed warning), but it is not QT-neutral. Be cautious with other QT-active drugs, electrolyte abnormalities, and cardiac disease; get a baseline ECG in at-risk patients.

Dermatologic: Don't Forget Photosensitivity

A classic, often-overlooked phenothiazine effect: marked photosensitivity. Patients sunburn easily and can develop exaggerated sunburn-type reactions; long-term high-dose use is associated with blue-gray skin discoloration and pigmentary changes in skin and eyes (lens/corneal deposits, retinal changes).

Management:

• Counsel every patient to use sun protection: sunscreen, hats, covering clothing.
• Consider periodic eye examination with prolonged high-dose use.

Endocrine: Hyperprolactinemia

As a D2 blocker, chlorpromazine raises prolactin, which can cause galactorrhea, gynecomastia, menstrual irregularity, and sexual dysfunction. Ask about these directly; reduce dose or switch if problematic.

Hepatic

Cholestatic jaundice is a recognized idiosyncratic phenothiazine reaction, usually early in treatment. Check LFTs if jaundice, dark urine, pruritus, or malaise appears; discontinue if confirmed.

Hematologic (Rare but Serious)

Rare agranulocytosis and other blood dyscrasias. Any fever, sore throat, or infection with malaise should prompt an urgent CBC.

Lowered Seizure Threshold

Phenothiazines lower the seizure threshold; use caution in patients with epilepsy or other risk factors.

Part 6: Toxicity, Overdose, and Boxed Warnings

Boxed Warning: Dementia-Related Psychosis

Neuroleptic Malignant Syndrome (NMS)

The feared idiosyncratic emergency of any antipsychotic:

• Tetrad: hyperthermia, "lead-pipe" rigidity, autonomic instability (labile BP, tachycardia, diaphoresis), and altered mental status.
• Labs: markedly elevated CK, leukocytosis.
• Management: stop the drug immediately; supportive care and aggressive cooling; ICU-level monitoring; dantrolene and/or bromocriptine in severe cases. This is a medical emergency.

Overdose

Chlorpromazine overdose is dominated by its receptor pharmacology writ large:

• CNS depression (sedation → coma), hypotension (alpha blockade, often profound), anticholinergic signs, cardiac conduction disturbances/arrhythmias, seizures, and hyperthermia or hypothermia.
• Management is supportive: airway/breathing/circulation, IV fluids and alpha-agonist pressors (norepinephrine/phenylephrine, not epinephrine) for hypotension, cardiac monitoring, seizure control with benzodiazepines. There is no specific antidote; dialysis does not effectively remove chlorpromazine (large volume of distribution, high protein binding).

Part 7: Drug Interactions

CNS depressants (additive sedation/respiratory depression): alcohol, benzodiazepines, opioids, other sedating agents. Anticipate and counsel.

Antihypertensives (additive hypotension): stacking chlorpromazine's alpha blockade on other BP-lowering drugs magnifies orthostasis.

Epinephrine ("epinephrine reversal"): as above, do not use epinephrine to treat chlorpromazine-induced hypotension; the result can be paradoxically lower pressure.

Other anticholinergics (additive load): antihistamines, TCAs, oxybutynin, and, importantly, the anticholinergics used for EPS. Watch for constipation, urinary retention, and (especially in the elderly) delirium.

QT-prolonging drugs: additive conduction risk with other QT-active agents; correct electrolytes; consider ECG.

Other dopamine-active drugs: chlorpromazine antagonizes the effect of dopaminergic agents (e.g., levodopa) and vice versa.

Smoking (CYP1A2 induction): tobacco smoke induces CYP1A2, lowering chlorpromazine levels.

Lowers seizure threshold: additive risk with other proconvulsant drugs; may reduce anticonvulsant efficacy.

A Laboratory Gotcha

Chlorpromazine can produce a false-positive amphetamine result on urine drug immunoassays. If a patient on chlorpromazine screens positive for amphetamines and the result matters clinically or legally, confirm with a specific method (GC-MS). It can also cause false-positive pregnancy tests and interfere with certain urine bilirubin/PKU assays.

Part 8: Special Populations

Pregnancy

The conventional typical antipsychotics (haloperidol, fluphenazine, and chlorpromazine) are generally considered relatively safe in pregnancy, informed partly by decades of historical use of chlorpromazine for hyperemesis gravidarum, and they do not appear clearly associated with major birth defects.

Caveats:

• Neonatal effects: third-trimester exposure can produce neonatal extrapyramidal signs and withdrawal (agitation, feeding difficulty, abnormal tone), which can persist for a period after birth. The FDA carries a class caution about neonatal EPS/withdrawal with third-trimester antipsychotic exposure.
• Use the lowest effective dose.
• Weigh against untreated illness: relapse of psychosis or severe mania in pregnancy carries its own substantial risks.

Lactation

Generally avoid breastfeeding on chlorpromazine. The concern is infant drowsiness/sedation, driven by the drug's long half-life and accumulation in the nursing infant. The developmental data are mixed and worrying: while one older study found no deficits at 16-month and 5-year follow-up, another series of three infants exposed (chlorpromazine plus haloperidol) via breast milk showed developmental delay at 12–18 months. If the mother needs chlorpromazine for stability, bottle-feed.

Elderly

Use with particular caution:

• Boxed warning applies (dementia-related psychosis; increased mortality).
• Orthostasis and falls: the alpha-blockade effect is more dangerous in older patients.
• Anticholinergic burden: cognitive impairment and delirium risk; adds to the total anticholinergic load of polypharmacy.
• Tardive dyskinesia risk ~10-fold higher than in younger patients, and the atypicals' TD advantage disappears in this age group.
• Start low, go slow, monitor closely, including more frequent AIMS and orthostatic checks.

Renal and Hepatic Impairment

• Hepatic: chlorpromazine is extensively hepatically metabolized, and cholestatic jaundice is a known reaction, so use cautiously and at reduced doses in hepatic impairment; avoid in significant liver disease or with a history of phenothiazine jaundice.
• Renal: dose adjustment is less critical than for renally cleared drugs, but use general caution and monitor.

Pediatric

Chlorpromazine is FDA-approved down to age 1 for severe behavioral problems and for nausea/vomiting, reflecting its historical role before modern pediatric psychopharmacology. In contemporary practice its pediatric psychiatric use is very limited and specialist-directed. Children may be especially susceptible to acute dystonias and to withdrawal-emergent dyskinesias.

Part 9: Discontinuation

Chlorpromazine does not produce the dramatic rebound-relapse syndrome that abrupt lithium withdrawal does, but stopping still deserves care:

• Taper, don't stop abruptly. Abrupt discontinuation of a long-standing antipsychotic can produce a cholinergic rebound / withdrawal syndrome (nausea, vomiting, diaphoresis, insomnia, restlessness), a rebound of the very anticholinergic and dopaminergic systems the drug was suppressing, and can unmask or worsen tardive dyskinesia ("withdrawal-emergent dyskinesia") within 4–8 weeks.
• For brief PRN or short-course use, tapering is generally unnecessary, since these are situational doses.
• For sustained use, taper gradually and watch for both psychiatric relapse and emergent movement problems. If withdrawal-emergent dyskinesia appears, resist the urge to reinstate a full dose reflexively; manage the taper deliberately, because the movements often resolve over weeks (particularly in younger patients) though they can persist in adults.

Part 10: Chlorpromazine vs the Alternatives

vs. High-potency typicals (haloperidol, fluphenazine). Chlorpromazine trades places with them. It causes far less EPS and akathisia (its anticholinergic activity is protective) and lower TD risk, and it doesn't require add-on Cogentin/Artane. In exchange it is more sedating, more orthostatic, more anticholinergic, and more metabolically active. Choose chlorpromazine when sedation is wanted and movement side effects are the concern; choose high-potency agents when you want minimal sedation/metabolic effect and can accept (and manage) EPS.

vs. Mid-potency typicals (perphenazine/Trilafon). Perphenazine emerged from the CATIE trial as the "darling of the typicals," as effective as atypicals with minimal weight gain and low metabolic burden, and less sedating. For chronic schizophrenia where a typical is chosen, perphenazine is often the more balanced pick. Chlorpromazine's edge is specifically its sedation for acute/agitated presentations.

vs. Thioridazine (Mellaril). Chlorpromazine has effectively replaced thioridazine for low-dose non-addictive tranquilization, because thioridazine now carries a QT boxed warning (requiring baseline ECG, potassium monitoring, and reserved-line status). Chlorpromazine has no such QT boxed warning and is the safer low-potency choice for this niche.

vs. Atypical antipsychotics. Atypicals win for chronic maintenance: lower TD risk in younger adults, less anticholinergic burden, and faster/cleaner options for acute mania. Chlorpromazine's counter-advantages are relatively little weight gain (vs. olanzapine/clozapine/risperidone/quetiapine), fewer lipid problems than those agents, much lower cost, and a 70-year track record. For the specific job of cheap PRN sedation or acute agitation, it competes well; for years-long maintenance, it usually loses.

vs. Clozapine (in refractory schizophrenia). No contest: clozapine is vastly superior in treatment resistance (≈30% vs. ≈4% response after three prior failures). Chlorpromazine is a reasonable first antipsychotic trial, never the answer for refractory illness.

vs. Lithium (in mania). Comparable overall efficacy in acute mania, but different strengths: chlorpromazine is faster at controlling agitation and insomnia (works in hours to days via sedation), while lithium is the superior long-term agent, non-sedating, "normalizing," neuroprotective, and uniquely anti-suicide. The modern play: chlorpromazine (or an atypical) to seize acute control, lithium/valproate/lamotrigine for maintenance.

So where does it fit today? Chlorpromazine has been broadly displaced by atypicals and mood stabilizers for chronic care, and that displacement is appropriate. It remains genuinely useful for acute agitation, low-dose non-addictive tranquilization, intractable hiccups, refractory nausea, and cost-constrained settings. Judicious, targeted use of typicals is a legitimate part of practice, chlorpromazine included, when matched to the right job.

Mechanism: The Short Version

Chlorpromazine is a low-potency phenothiazine whose clinical profile is fully explained by a broad, "dirty" receptor blockade:

• D2 dopamine blockade is the antipsychotic (and antiemetic, and prolactin-elevating) mechanism. Like other typicals, chlorpromazine binds D2 strongly and for a relatively long duration, which underlies both efficacy and the tardive dyskinesia risk that comes from chronic D2 blockade → receptor upregulation and supersensitivity.
• Muscarinic (anticholinergic) blockade: chlorpromazine is the most anticholinergic conventional antipsychotic. This produces the anti-"SLUDC" side effects and, via the striatal dopamine-acetylcholine balance, protects against EPS (why it needs no add-on anticholinergic).
• Histamine (H1) blockade drives its heavy sedation and contributes to weight gain, fittingly, since chlorpromazine began life as an antihistamine.
• Alpha-1 adrenergic blockade produces the orthostatic hypotension (and the epinephrine-reversal phenomenon).
• 5-HT2A activity is invoked to explain its historical antidepressant signal.

Its half-life is long (contributing to accumulation and to the breastfeeding concern), it is extensively hepatically metabolized (with many active metabolites), it is highly protein-bound with a large volume of distribution (which is why dialysis doesn't help in overdose), and its main metabolizing pathway is inducible by smoking (CYP1A2).

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