Nortriptyline with Ethynodiol Interaction Details
Brand Names Associated with Nortriptyline
- Aventyl®
- Nortriptyline
- Pamelor®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 03, 2023
Interaction Effect
Attenuation of antidepressant effectiveness; tricyclic antidepressant toxicity (drowsiness, hypotension, akathisia)
Interaction Summary
In isolated cases, the pharmacologic effects of tricyclic antidepressants may be increased or decreased by estrogens, with paradoxical loss of antidepressant effect yet tricyclic antidepressant toxicity being manifested simultaneously . The effects of the interaction appear to be estrogen dose-related and may be of clinical importance primarily in patients previously stabilized on tricyclic antidepressant therapy who are being started on estrogen therapy .
Severity
Moderate
Onset
Delayed
Evidence
Theoretical
How To Manage Interaction
If signs or symptoms of altered tricyclic response are noted, dose adjustment downward of either the estrogen or tricyclic antidepressant component may be successful in restoring effectiveness or resolving toxicity. However, drug withdrawal may be required.
Mechanism Of Interaction
Possible estrogen-enhanced hepatic metabolism of the tricyclic antidepressant or estrogen inhibition of hepatic microsomal enzymes
Literature Reports
A) A study evaluated the qualitative effects of concomitant administration of estrogen and tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomly assigned to 4 treatment groups. Ten patients received placebo, 10 received imipramine (150 milligrams/day) and placebo, 5 patients received imipramine (150 milligrams/day) and ethinyl estradiol (50 micrograms/day), while 5 patients received imipramine (150 milligrams/day) and ethinyl estradiol (25 micrograms/day). The 10 patients who received placebo did not improve over the 6 weeks of the study. The 10 patients taking estrogen and imipramine demonstrated a significantly greater improvement in symptoms than did the 10 patients taking imipramine alone. However, after 2 weeks, the 5 patients who received imipramine and high-dose estrogen had not improved as much as the patients receiving imipramine and low-dose estrogen. The only side effect reported was drowsiness, which only affected the patients taking imipramine. Following the discontinuation of ethinyl estradiol, a time period of 2 weeks was required for the high-dose estrogen group to do as well as the low-dose group. This effect was attributed to the presence of residual estrogen in the high-dose group. In another group, 5 women received imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as 10 patients receiving only imipramine. Also, the patients on the combination had severe side effects including lethargy, coarse tremor and systolic hypotension .
B) A case report demonstrated an interaction in a 32-year-old female taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. The patient developed lethargy, tremors, and signs of depersonalization. After 2 years of therapy, the patient increased her estrogen dose to 5 milligrams and then 7.5 milligrams daily. The patient became nauseated, had constant headaches, and low normal blood pressure. All lab work was normal. Upon discontinuing the estrogen, the side-effects abated . Some investigators have proposed that the side effects resulted from enhanced tricyclic antidepressant effects secondary to estrogen inhibition of hepatic microsomal enzymes .
C) A study evaluated women who received clomipramine and oral contraceptives or clomipramine alone. At the beginning of the study, there were 30 women taking the combination, but 12 subsequently dropped out. The 18 patients on the combination were matched with 18 patients taking clomipramine alone. No significant difference was noted in the patients' responses to clomipramine. It was proposed that there was no significant difference in side effects between the groups; however, the groups were matched after patients had dropped out of the study. Had the patients been matched prior to the study, different conclusions may have been drawn .
D) A study evaluated the effects of oral contraceptives on clomipramine in 42 women between the ages of 18 and 40 years. Twenty-three women took clomipramine 25 milligrams at bedtime while 19 took clomipramine 25 milligrams at bedtime with oral contraceptives. Over the 4-week study, 3 patients in the control group (2 due to side effects) and 5 in the experimental group (2 due to side effects) dropped out. Venous blood samples were drawn at weekly intervals for measurement of serum clomipramine concentrations. No difference in serum concentrations was noted between the groups. However, this result may be partially due to the low dose of clomipramine given .
E) Three patients developed akathisia while receiving conjugated estrogens and tricyclic antidepressants concurrently. A 24-year-old patient receiving clomipramine 120 milligrams/day for anorexia nervosa and conjugated estrogens 1.25 milligrams/day for amenorrhea developed restless legs and a constant desire to move continuously. Estrogen was discontinued and benztropine 2 milligrams was administered, resulting in marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient on conjugated estrogens 1.25 milligrams/day who was prescribed amitriptyline 50 milligrams/day for depression. Within hours of amitriptyline, the patient was confused, restless, and possessed an inner desire to move continuously. Symptoms disappeared after discontinuing amitriptyline. Positive rechallenge at one week with doxepin 100 milligrams, with resolution following discontinuation of doxepin. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia developed within a few hours after taking the first dose of amitriptyline and resolved within 48 hours following discontinuation of the antidepressant .
F) The absolute bioavailability of imipramine increased in women who received low-dose oral contraceptives (50 micrograms or less of ethinyl estradiol) from 27% to 44% (p less than 0.05) as evident by an increase in the AUC .
G) Estrogens may inhibit the oxidation of tricyclic antidepressants (TCAs) by affecting hepatic microsomal enzymes . Many TCAs are metabolized via oxidation and conjugation pathways. Inhibition of the oxidation of TCAs could result in accumulation and toxicity due to decreased clearance. Estrogens are suspected of possessing other effects on the central nervous system resulting in an antidepressant effect .
Nortriptyline Overview
-
Nortriptyline is used to treat depression. Nortriptyline is in a group of medications called tricyclic antidepressants. It works by increasing the amounts of certain natural substances in the brain that are needed to maintain mental balance.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
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Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
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