Continuing Education Activity

Protriptyline hydrochloride is a tricyclic antidepressant used to improve mood in people with depression. It is also useful in treating anxiety. It is a more potent antidepressant and has fewer sedative and tranquilizing effects than other TCAs. FDA-approved uses include mental depression, narcolepsy, attention deficit hyperactivity disorder, and headaches. It also has other non-FDA approved indications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of protriptyline, so providers can direct patient therapy in treating conditions for which it is indicated, as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of protriptyline.
• Review the approved and off-label indications for initiating protriptyline therapy.
• Describe the adverse event profile and contraindications of protriptyline.
• Summarize interprofessional team strategies for improving care coordination and communication to advance protriptyline and improve patient outcomes.

Indications

Protriptyline hydrochloride is a tricyclic antidepressant used to improve mood in people with depression. It is also used for anxiety. Protriptyline was first patented in 1962, and it is sold under many brand names. It is an amine with the empirical formula of CHN. It is a more potent antidepressant and has fewer sedative and tranquilizing effects than other TCAs.

FDA-Approved Uses[1][2]

• Mental depression
• Narcolepsy
• Attention deficit hyperactivity disorder
• Headaches

Results of one study of 25 women who were treated with 20 mg of protriptyline each morning for 12 weeks showed 86% fewer headaches each month, with an average dropping from 28.2 to 11.7 days[3]. More than two-thirds had a 50% reduction in the number of headaches per month. The study also showed an average of 1 pound (0/45 kg) per month of weight loss.

Non-FDA-Approved Uses

• Treatment-resistant depression
• Local anesthetic
• Smoking cessation
• Cocaine dependence
• Apnea

One study reported that protriptyline could be helpful in brain-injured adults with attention and behavioral difficulties.[4][1] Research has also shown it to improve the drowsiness, apneic episodes, snoring, and cataplexy related to narcolepsy.[5]

Mechanism of Action

When it comes to mood, the two important chemicals in the brain are serotonin and norepinephrine. These often decrease in people who are depressed and are the main targets of antidepressants. Protriptyline has the fastest onset of action among other tricyclic antidepressants, and thus clinical effects can occur within the first week of use. It is a secondary tricyclic amine and structurally similar to nortriptyline. It undergoes limited first-pass hepatic metabolism and can cross the blood-brain barrier. Protriptyline has a long half-life of 80 to 200 hours when used long-term, requiring up to a month to reach a steady state. The half-life of protriptyline is approximately 74 hours (greater than three days).

• Increases norepinephrine neurotransmission by blocking norepinephrine reuptake pump.
• In the frontal cortex, dopamine neurotransmission increases secondary to the norepinephrine reuptake inhibition.[4]
• At high doses, protriptyline can increase serotonin neurotransmission.
• Protriptyline also can cause calcium-independent cell death.[6]

Administration

Unlike other tricyclic or tetracyclic antidepressants, which have doses from 75 to 300 mg/day, protriptyline dosing uses much lower doses and then increased as necessary. Unlike other tricyclic and tetracyclic drugs, which often have once a day dosing, dosage for protriptyline is divided into 3 or 4 times a day. When stopping the medication is necessary, taper to avoid the effects of withdrawal.

• Protriptyline is available in tablets of 5 or 10 mg.
• Initiate at 15 to 40 mg a day, starting with the morning dose.
• Divide dose into 3 or 4 doses, not to be taken all at one time.

The maximum dose is 60 mg a day, if necessary, beginning at a lower level and increasing gradually while looking for the patient’s response and any side effects as the dosage increase. 

Adverse Effects

Protriptyline, like all TCAs, has multiple adverse effects. Although as effective as SSRIs and SNRIs, TCAs, and MAOs are not first-line treatment due to their side effects. Among the TCAs, protriptyline is the most likely to cause tachycardia, hypotension, anxiety, and agitation, and for this reason, some European countries have discontinued protriptyline use.[7][8][2][9]

Adverse Effects (like all TCAs) 

• CNS depression
• Convulsions
• Cardiac toxicity
• Weight gain
• Coma

Most Common Adverse Effects

• Anxiety
• Agitation
• Apathy
• Anorexia
• Nausea
• Headache
• Diarrhea
• Constipation
• Urinary retention
• Dizziness
• Restlessness
• Insomnia (decrease of REM sleep)
• Nightmares
• Hypotension
• Hyponatremia
• Diaphoresis
• Itching
• Rash
• Blurred vision
• Dry mouth Impotence
• Change of libido
• Impotence
• Difficulty having an orgasm
• Suicidal thoughts and suicide attempts (black box warning) and risk, especially in that younger than 24 years old, is greater during the initial two months of starting the drug and during dosage adjustment.

Rare, More Serious Adverse Effects

• Hepatic failure
• Increased intraocular pressure
• Induction of mania
• Paralytic ileus
• Extrapyramidal symptoms
• QTc prolongation, arrhythmia, tachycardia, myocardial infarction
• Stroke, seizures, coma
• Sudden death

Contraindications

Tricyclic antidepressants have many side effects, some of which are life-threatening. Among the tricyclic antidepressants, protriptyline is the most potent and most likely to cause hypotension, agitation, and cardiac effects. For this reason, protriptyline has multiple contraindications, including people with the following [7][9][8][9]:

• Heart problems such as prolonged QTC interval, uncompensated heart failure, arrhythmias, heart block, palpitations, hypotension, hypertension, and recent myocardial infarction.
• Use of drugs that inhibit TCA metabolism, inhibit CYP450 2D6, or prolong QTc interval. (Look for hypokalemia before starting protriptyline.)
• Use of tramadol (increase the risk of seizures with TCAs), and people with a seizure disorder require careful monitoring.
• Use of anticholinergic drugs (risk of hyperthermia and paralytic ileus).
• Use of SSRIs, SNRIs, and MAOIs to prevent serotonin syndrome, hypertensive crisis or hypotensive crisis, hyper-pyretic, and convulsions, a washout period of at least 14 days must take effect before starting one of these drugs.
• Weight gain concerns and/or metabolic syndrome.
• Psychosis due to TCAs aggravating psychotic symptoms
• Possible pregnancy or women who are breastfeeding (due to potential adverse effects to the fetus such as fetal malformations, lethargy, and withdrawal symptoms. protriptyline is classified in pregnancy category C)
• Age younger than 12 due to the increased risk of suicidal thoughts/suicidal attempts in children
• History of hypersensitivity to protriptyline
• Hyperthyroidism, urinary retention, and angle-closure glaucoma merit closer monitoring.
• Renal or hepatic impairment may need to lower dose and may need to monitor closely.
• Consumption of alcohol should also be avoided due to the additive CNS effects.

Monitoring

Protriptyline’s initial dose is 15 mg per day divided into 3 or 4 doses per day, with a max dose of 60 mg per day. However, taking more than recommended or taking the daily dose at one time can have significant consequences which can manifest in cardiac arrhythmias or EKG changes, especially QRS-widening hypotension, confusion, visual hallucinations, delusions, ataxia, tremors, syndrome of inappropriate ADH, tinnitus, hyperactive reflexes, muscle rigidity stupor, convulsions, coma, and even death.[2][7]

ECG is a recommendation and close monitoring for patients over the age of 50, especially in those taking more than 20 mg per day, due to sensitivity to anticholinergic, cardiovascular, hypotensive, and sedative effects.

Like other antidepressants, protriptyline increases suicidal ideation and attempts in children, adolescents, and young adults. It is not recommended in patients under the age of 12 or intended for those under the age of 6.

Toxicity

Tricyclic antidepressants, like all antidepressants, are used in a group of patients that are already at increased risk of attempted suicide. Thus, overdose with such drugs is something that needs to have a plan at hand. Furthermore, TCAs are often used in drug-resistant depression, which makes them even more of a risk than the first-line SSRIs and SNRIs. Thus protriptyline is a very potent TCA and a dangerous drug for overdose.

Treatment of protriptyline toxicity includes gastrointestinal decontamination with gastric lavage and activated charcoal l and treating the symptoms that arise due to the overdose as necessary; for example, norepinephrine and IV fluids for hypotension, IV sodium bicarbonate for prolonged QRS duration, and benzodiazepines for anxiety, agitation, or seizures.

Enhancing Healthcare Team Outcomes

Protriptyline is an older tricyclic antidepressant which has little use today. Healthcare workers, including the pharmacist and prescribing nurse, should be familiar with newer antidepressants, which are much safer. Patients already on protriptyline should be gradually weaned off and started on the newer antidepressants if there are no contraindications.