ANTI-DEPRESSANTS DRUGS INTERACTIONS

A- Tricyclic Antidepressant (TCAs)  Bicarbonate to correct acidosis.

 Typical TCAs (Ist Generation)  Physostigmine to treat atropine likes effects
I. Tertiary amines include imipramine, amitriptyline
II. 2ry amines include desimpiramine, nortriptyline
They inhibit NE and 5HT reuptake B-Monoamine Oxidase inhibitors (MAOIs)
◊ MAO-A exist in neurons
 Atypical Antidepressants (2nd Generation) ◊ MAO-B exist in liver, GIT and in neurons (low concn.)
I- Bupropion
II- Nefazodone and Trazodone MAOI involve
III- Mitrarzapine 1- Non selective MAOIS
-Phenlizine, Pargyline, Tranylcypramine
* PHARMACOKINETICS OF TCAs -They are liver microsomal enzyme inhibitor
-Well absorbed from gastrointestinal tract -They have long half-life with residual effect lasts for 2 weeks.
-They are widely distributed all over the body (highly lipophilic)
-Highly bound to plasma proteins 2- Selective MAOIS
-They have relatively longer half-life so they have residual effect (1-2 weeks) ♦ MAOAI
-They are metabolized in microsomal enzymes by hydroxylation and N-demethylation - Meclobemide
-Their metabolites excreted by the kidney -It is a shortly acting drug with residual time of 2 days
- The demethylated metabolites of both Amitriptyline and imipramine are active (have
antidepressant activity) ♦ MAOBI
- Seligline and Rasagiline
 Adverse effects of TCAs: - It inhibits MAOB in liver, GIT and neurons
 Delayed onset of action - It is mainly used as anti-parkinsonian agent not as anti-depressants.
 CNS: Delirium, confusion, seizures.
 Atropine like action: Dry mouth, blurred vision, constipation, urine retention, * Absorption, distribution and fate
glaucoma, paralytic ileus  MAO inhibitors are well absorbed on oral administration
 α-Blocking effect: Orthostatic hypotension,  Antidepressant effects require 2-4 weeks of treatment. Enzyme regeneration, when
 Cardiovascular system: Orthostatic hypotension, reflex tachycardia, arrhythmias, irreversibly inactivated by non-selective MAOI, occurs several weeks after
depression of myocardium, termination of non-selective MAOI .
 Allergic obstructive jaundice  Thus, when switching off non selective MAOI, a minimum of 2 weeks delay must be
 Agranulocytosis allowed.-
 MAO inhibitors are metabolized by acetylation (genetic determined) leading to
 Acute toxicity of TCAs: inactive compounds excreted rapidly in the urine.
-Generally occur as a result of overdose and accidental poisoning.  Non selective MAOI is liver microsomal enzyme inhibitor
 Manifestations include:
1. Atropine like action * Adverse effects:
2. Respiratory depression, acidosis, arrhythmias, shock, seizures, coma death. -Delayed onset (2-3 weeks) except selective MAOAI meclobemide
-CNS: excitation, hallucination, hyper-hydrosis & seizures
Treatment of acute toxicity -Delay of ejaculation so it is abused in Egypt?
 Gastric lavage with activated charcoal -Hepatotoxicity.
 Lidocaine and phenytoin for arrhythmia -Some has atropine like action
 Benzodiazepines for seizure. -Weight gain
C- Selective Serotonin Reuptake Inhibitors General Drug interactions of TCAs
 ANTI-DEPRESSANTS DRUGS INTERACTIONS

Fluoxetine, Fluvoxamine, Paroxetine and Sertraline - Phenytoin, aspirin, phenothiazine compete with TCAs for plasma protein binding sites
-Elevation in the serum TCAs level can occur following inhibition of hepatic TCAs
 They have long half-life metabolism by:
 They have residual effect of 2-5 weeks
 Fluoxetine is metabolised into nor-fluoxetine (active metabolite) that has long half * Antipsychotic
life & residual effect of 5 weeks. * MAOI
 They are enzyme inhibitor except Sertraline * Fluoxetine
* Oral contraceptives
These drugs have advantages compared with TCAs & MAOIs:
* Lack of anti-cholinergic and cardiovascular side effect. - TCAs can prevent the action of antihypertensive agents as Guanidine and
* Low acute toxicity (low risk of overdose) Clonidine.
* No food reactions
* Adverse effects: - Potentiate other anti-cholinergic drugs e.g anti-Parkinsonian and other drug with anti-
-Loss of libido cholinergic activity.
-Delayed ejaculation
-Anorgasmia -They potentiate direct sympathomimetic as adrenalin, Noradrenaline by Inhibition of
-N, V, diarrhea their uptake.
-Anxiety, restlessness, insomnia and seizures

D- St John's wort (Hypericum perforatum) Safamood®

- Extracts of Hypericum Perforatum (hypercin or pseudohypercin).

- Effective in the short-term management of mild or moderate depression.

- It inhibits reuptake pump for serotonin to a great extent and NE to a less extent.

- Hypericum may induce the metabolism of other drugs which may lead toxicity on
discontinuation.

TCAs - CLONIDINE INTERACTION TCAS - FLUOXETINE INTERACTION TCAS - DIRECTLY ACTING SYMPATHOMIMETIC
 ANTI-DEPRESSANTS DRUGS INTERACTIONS
* Clonidine (catapress®) is antihypertensive drug * This is a one of most commonly used combination  Outcome
* It is α-2 agonist so it must be re-uptaken by amine Hypertension and arrhythmia.
pump to exert its action  Outcome:
* Increase anti-depressant effect due to increase level of
 Mechanism:
 Outcome and Mechanism(s): NE & 5HT.
*TCAS inhibit termination mechanism or reuptake of
-TCAs reduce & minimize the antihypertensive effect of catecholamine → increase availability of NE at adrenergic
clonidine. * Augmentation of anti-cholinergic side effects → (dry
neurons
mouth, blurred vision, constipation, urine retention,
-TCAs competitively inhibit amine reuptake pump thus heat stroke, glaucoma, paralytic ileus plus orthostatic
*In addition DAS are α or ß agonist or both → exaggerated
they decrease uptake of clonidine resulting in reduction hypotension, reflex tachycardia and agranulocytosis
sympathetic activity.
of clonidine anti-hypertensive effect.
- No serotonin syndrome!!!! Since excess 5HT in synaptic
cleft will metabolised by MAOA  Management:
 Management: - It should be avoided.
-This interaction should be avoided
-Dose adjustment (augment dose of clonidine)  The mechanisms involved include:
- Phentolamine
- Use another anti-hypertensive pharmacological class. -PD mechanism (additive antidepressant activity)
- Labetalol
-PK (Fluoxetine is an enzyme inhibitor) → increases both
- Nifidipine for HTN & arrhythmia.
 NOTES: efficacy and adverse reactions of TCAS
 Notes
-Guanithidine, Reserpine (Brinerdin®) &α-Methyldopa  Management :  Such DI is common for patients stabilised on TCAS &
(aldomet®) undergo the same interaction with TCAs. -Monitoring serum level of TCAS or monitor their anti- undergo teeth management under local anaesthesia
cholinergic SE containing V.C agent as Mepacaine-L ® or Carbol®
-These three drugs mentioned above should not used for -Dose adjustment (Reduce dose of TCAS) but attention to (Mepacaine HCL+ Levonorfine)
depressed patients? residual effect.

-As one of their SE is depression -Use sertraline instead of fluoxetine? Sertraline is not
i.e. dual or bilinear pharmacodynamic antagonism enzyme inhibitor.

TCAS- L-DOPA TCAS – CLOZAPINE TCAS – PHENOTHIAZINES

 Outcome * Clozapine is atypical antipsychotic.  Phenothiazine have antipsychotic, anti-cholinergic, ant-
-Reduction of L-DOPA plasma level with subsequent * It is a selective D4 receptor blocker so it has a emetic & antihistaminic effect and also having extra-
 ANTI-DEPRESSANTS DRUGS INTERACTIONS
decrease of its effect. neglected extrapyramidal side-effect in contrast to pyramidal side effect in
phenothiazine and traditional antipsychotics. contrast to clozapine.
 Mechanism:
** TCAS reduce GIT motility (anti-cholinergic effect) so, -On the other hand, Clozapine has a strong anti-  Outcome :
they decrease GER. cholinergic activity. - Increase plasma level of both drugs with subsequent
extra-pyramidal side effects.
** L- DOPA mainly metabolized in gastric & intestinal  Outcome :
mucosa mainly by dopa decarboxylase and to less extent -Increase plasma level of both drugs with subsequent  mechanism:
by MAO & COMT. additive anti-cholinergic effect (weakness, confusion, Phenothiazines compete with TCAS for the same
disorientation, constipation. metabolic pathway, so they inhibit metabolism of each
** So, by decreasing GER & decrease GIT motility L-DOPA other → increase plasma level of both drugs resulting
will be exposed to its metabolizing enzymes for long - dry skin, heat stroke during hot climate due to reduced Extra-pyramidal side effects of phenothiazine.
period leading to increase its metabolism & decrease its sweating; dry skin; effect of anti-psychotic on
therapeutic effect, hypothalamic control of temperature)  Management:
-Reduce dose or reduce frequency of administration if
 Management:  mechanism: there is a fixed dose combination (fluphenazine +
1- Carbi-dopa (decarboxylase inhibitor) should be given • Clozapine competes with TCAS for the same metabolic nortryptyline or motival™).
with L-DOPA. pathway.
 Monitor extra-pyramidal effects.
Notes  Management:
-Bioavailability of L-dopa is 1%, SO, concurrent use of -Reduce doses of both drugs.  Dopaminergic agonist as Bromocriptine.
anti-chlonergic drugs will significantly affect L- DOPA.
-Starts with small doses & go ahead slowly with close
-This interaction is common with all drugs having anti- monitoring of SE  Anticholinergic as benzatropine.
cholnergic effect
 Replace phenothiazine by atypical antipsychotic as
Clozapine but attention to anti-cholinergic effect

TCAS- MAOIS MAOIS- FLUOXETINE INTERACTION MAOIS- INDIRECTLY ACTING SYMPATHOMIMETICS

 Outcome: * This anti-depressant combination is highly serious→ Indirectly acting sympathomimetic: Amphetamine,
** HTN, Arrhythmia & Serotonin syndrome serotonin syndrome tyramine.
** Anti-cholinergic side effects.
 ANTI-DEPRESSANTS DRUGS INTERACTIONS
 Outcome  Outcome:
 mechanism: - Increase plasma levels of both anti-depressant drugs → - Hypertension crisis (fatal).
A- PD INTERACTION: Increase efficacy and toxicity of both drugs (serotonin
 TCAS reduce reuptake of catecholamines. syndrome)  mechanism:
 Indirectly acting sympathomimetic could increase
 MAOIS inhibit metabolic degradation of
 mechanism: release of endogenous catechol amines.
catecholamines & serotonin.
* Both drugs are liver microsomal enzyme inhibitors,
thus they inhibit metabolism of each other with  MAOI inhibit MAO enzyme, so inhibit metabolism of
subsequent increase of their plasma levels → Increase NE→ increase level of Catechol amines that acts on α1&
B- PK INTERACTION
activity & toxicity. ß1 receptors leading sever hypertension, arrhythmia→
 MAOIS inhibit TCAS’ metabolism → Antichlonergic
hypertension crisis which may be fatal due to cerebral
side effects.
* Fluoxetine is a SSRI→ Inhibit reuptake of 5H. haemorrhage
 Management: * MAOI inhibit MAO enzyme, accumulation of 5HT in
 It is a fatal interaction so, it should be avoided.  Management:
neurones with subsequent release to synaptic cleft (5HT
 Clonazepam as Tranquilizer and for management of pool) → Serotonin syndrome which can be manifested -Such interaction should be avoided.
myoclonus by central & peripheral signs.
 Nifidipine for arrhythmia and hypertension -α- blocker Phentolamine (Rigitine).
 Labetalol and Phentolamine for hypertension.
A- Peripheral signs: -α and ß blocker Labetalol.
** Notes -Hypertension, arrhythmia & diarrhoea
-The PK mechanism is more pronounced than PD -Calcium channel blocker Nifidipine, Verapamil or
mechanism. B- Central signs: Deltiazime.
- (agitation, restlessness, tremors, confusion, shivering &
-If necessary to use such combination, start with small myoclonus).
doses and go slowly over month with close monitoring of
adverse effects.  Management:
- Such interaction should be avoided.
-Also use oral route of administration not parenteral
route - If necessary sequential use is recommended but take
-Sequential use but attention to residual effect care to residual effect.

-BZ for serotonin syndrome central effects as it is

tranquilizer & it reduces muscle tone.

- Calcium channel blocker Nifidipine for peripheral

effect of serotonin syndrome (hypertension &
arrhythmia).

FLUOXETINE – CYPROHEPTADINE FLUOVOXAMINE – BZ MAOIs- TYRAMINE RICHE FOOD INTERACTION

 Outcome :  Outcome : Cheese reaction
 Decrease anti-depressant effect of fluoxetine. * Disorientation, sedation & other SE of BZ.  TYRAMINE CONTAINING FOOD:
-Aged cheese
 ANTI-DEPRESSANTS DRUGS INTERACTIONS
 mechanism:  mechanism: - Yeast
* It is PD antagonism * It is PK interaction - Yoghurt
-Fluoxetine is a SSRI * Fluvoxamine is a SSRI & also it is an enzyme inhibitor - White chocolates
-Cyproheptadine is 5HT antagonist (anti-serotonin) , so * So, it inhibit the metabolism of BZ with subsequent - Tropical fruits
it will antagonize fluoxetine effect. Development of BZ adverse effects. ** Tyramine is indirectly acting sympathomimetic

 Management:  Management:
- It should be avoided. -Use short acting BZ as Oxazepam, Lorazepam
-Use sertraline instead of fluvoxamine.

 NOTES
- This DI depends on the type of BZ involved.

-Long acting BZ (Diazepam, Alprazolam) interacts

significantly with fluvoxamine Since they are
metabolised by CYP 450 system.

- On the other hand short acting BZ (Oxazepam,

Lorazepam) show no interaction with fluvoxamine?
Since they are metabolised by glucronidation and then
eliminated via kidney.

- The same interaction is valid with fluoxetine,

paroxetine