PROTRIPTYLINE HYDROCHLORIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROTRIPTYLINE HYDROCHLORIDE (PROTRIPTYLINE HYDROCHLORIDE).

How it works

Tricyclic antidepressant; inhibits reuptake of norepinephrine and serotonin at presynaptic neuronal membrane, increasing their concentrations in the synaptic cleft. May also downregulate beta-adrenergic and serotonin receptors.

What the body does with it

Metabolism	Hepatic; primarily via CYP2D6, with minor contributions from CYP1A2, CYP2C19, and CYP3A4. Metabolites: naphthalene ring hydroxylation, glucuronidation.
Excretion	Primarily renal (50-70% as metabolites, <5% unchanged); biliary/fecal elimination accounts for ~10-20%.
Half-life	Terminal elimination half-life: 54-92 hours (mean ~74 hours); due to long half-life, steady-state is reached in 11-18 days.
Protein binding	92% bound primarily to alpha1-acid glycoprotein and albumin.
Volume of Distribution	Vd: 15-20 L/kg; indicates extensive tissue distribution (e.g., brain, lungs, liver).
Bioavailability	Oral: ~75% due to first-pass metabolism.
Onset of Action	Oral: anticholinergic effects within 1-2 hours; antidepressant effect begins after 1-2 weeks.
Duration of Action	Oral: single dose effects may persist 24-48 hours; antidepressant effects require continued dosing for weeks.

Classification & Brands

Dosing & administration

15 mg orally 3 to 4 times daily, not to exceed 60 mg per day.

Dosage form	TABLET
Renal impairment	GFR 30-89 mL/min: no adjustment required. GFR <30 mL/min: use with caution, reduce dose by 50%. Hemodialysis: supplemental dose not required. Peritoneal dialysis: insufficient data.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated.
Pediatric use	Adolescents (12-18 years): 5 mg orally 3 times daily; maximum 20 mg per day. Children <12 years: not recommended (safety and efficacy not established).
Geriatric use	Initiate at 5 mg orally 3 times daily; increase slowly. Maximum 20 mg per day. Monitor for orthostatic hypotension, cardiac arrhythmias, and anticholinergic effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROTRIPTYLINE HYDROCHLORIDE (PROTRIPTYLINE HYDROCHLORIDE).

Breastfeeding	Drug is excreted into breast milk; M/P ratio not established; consider risk of infant exposure; avoid breastfeeding due to potential CNS effects and limited safety data.
Teratogenic Risk	First trimester: Limited data; animal studies show developmental toxicity at high doses; clinical data insufficient to rule out risk. Second and third trimesters: Risk of neonatal withdrawal (irritability, respiratory distress) if used near term; no structural abnormalities clearly associated.

Warnings & precautions

■ FDA Black Box Warning

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Not approved for use in pediatric patients.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to tricyclic antidepressants, recent myocardial infarction, concurrent use with MAOIs (within 14 days), narrow-angle glaucoma, prostatic hypertrophy with urinary retention, severe hepatic impairment.

Clinical Precautions

Precautions

Activation of mania/hypomania, exacerbation of schizophrenia, cardiovascular toxicity (arrhythmias, QT prolongation, orthostatic hypotension), anticholinergic effects (urinary retention, constipation, blurred vision), seizures, serotonin syndrome, hypoglycemia, antagonism of guanethidine and clonidine.

Clinical Tips & Counseling

Drug interactions

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PROTRIPTYLINE HYDROCHLORIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROTRIPTYLINE HYDROCHLORIDE (PROTRIPTYLINE HYDROCHLORIDE).

How it works

What the body does with it

Metabolism	Hepatic; primarily via CYP2D6, with minor contributions from CYP1A2, CYP2C19, and CYP3A4. Metabolites: naphthalene ring hydroxylation, glucuronidation.
Excretion	Primarily renal (50-70% as metabolites, <5% unchanged); biliary/fecal elimination accounts for ~10-20%.
Half-life	Terminal elimination half-life: 54-92 hours (mean ~74 hours); due to long half-life, steady-state is reached in 11-18 days.
Protein binding	92% bound primarily to alpha1-acid glycoprotein and albumin.
Volume of Distribution	Vd: 15-20 L/kg; indicates extensive tissue distribution (e.g., brain, lungs, liver).
Bioavailability	Oral: ~75% due to first-pass metabolism.
Onset of Action	Oral: anticholinergic effects within 1-2 hours; antidepressant effect begins after 1-2 weeks.
Duration of Action	Oral: single dose effects may persist 24-48 hours; antidepressant effects require continued dosing for weeks.

Classification & Brands

Dosing & administration

15 mg orally 3 to 4 times daily, not to exceed 60 mg per day.

Dosage form	TABLET
Renal impairment	GFR 30-89 mL/min: no adjustment required. GFR <30 mL/min: use with caution, reduce dose by 50%. Hemodialysis: supplemental dose not required. Peritoneal dialysis: insufficient data.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated.
Pediatric use	Adolescents (12-18 years): 5 mg orally 3 times daily; maximum 20 mg per day. Children <12 years: not recommended (safety and efficacy not established).
Geriatric use	Initiate at 5 mg orally 3 times daily; increase slowly. Maximum 20 mg per day. Monitor for orthostatic hypotension, cardiac arrhythmias, and anticholinergic effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROTRIPTYLINE HYDROCHLORIDE (PROTRIPTYLINE HYDROCHLORIDE).

Breastfeeding	Drug is excreted into breast milk; M/P ratio not established; consider risk of infant exposure; avoid breastfeeding due to potential CNS effects and limited safety data.
Teratogenic Risk	First trimester: Limited data; animal studies show developmental toxicity at high doses; clinical data insufficient to rule out risk. Second and third trimesters: Risk of neonatal withdrawal (irritability, respiratory distress) if used near term; no structural abnormalities clearly associated.

Warnings & precautions

■ FDA Black Box Warning

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Not approved for use in pediatric patients.