E2

Uses

Escitalopram is used for Depressive illness, Generalized anxiety disorder, Obsessive-compulsive disorder, Social anxiety disorder

Etizolam is a thienodiazepine derivative used to treat anxiety and insomnia.

Indicated for the treatment of generalized anxiety disorder with depression, panic disorder and insomnia.

E2 is also used to associated treatment for these conditions: Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD)Anxiety, Insomnia

How E2 works

Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT_1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action.

Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects.

Etizolam is selectively a full agonist at GABA-A receptors to increase GABAergic transmission and enhance GABA-induced Cl- currents . It is reported to bind to the benzodiazepine binding site which is located across the interface between the alpha and gamma subunits. Benzodiazapines are reported to only bind to receptors that contain gamma 2 and alpha 1/2/3/5 subunits . Alpha-1-containing receptors mediate the sedative effects of etizolam whereas alpha-2 and alpha-3 subunit-containing receptors mediate the anxiolytic effect . Etizolam shows high potency and affinity towards GABA-A receptor with alpha 1 beta 2 gamma 2S subunit combination . By binding to the regulatory site of the receptor, etizolam potentiates GABA transmission by facilitating the opening of GABA-induced chloride channels . Etizolam is a specific antagonist at PAFR. It inhibits PAF-induced platelet aggregation by inhibiting PAF binding to the receptors located on the surface of platelets with an IC50 of 22nM .

Dosage

E2 dosage

Adults: The initial dose of Escitalopram Oxalate is 10 mg once daily. (A fixed dose trial of Escitalopram Oxalate demonstrated the effectiveness of both 10 mg and 20 mg of Escitalopram Oxalate, but failed to demonstrate a greater benefit of 20 mg over 10 mg.)

If the dose is increased to 20 mg, this should occur after a minimum of one week.

Panic disorder: Adult over 18 years, initially 5 mg once daily increased to 10 mg daily after 7 days; max. 20 mg daily; elderly initially half adult dose, lower maintenance dose may be sufficient;

Social anxiety disorder: Adult over 18 years, initially 10 mg once daily adjusted after 2-4 weeks; usual dose 5-20 mg daily.

Elderly: A single oral dose of 10 mg/day is the recommended dose for most elderly patients. Administered in excess recommended dose has not been yet established.

Side Effects

Escitalopram is well tolerated by most people. The most commonly reported side-effects of Escitalopram are nausea, insomnia, problems with ejaculation, drowsiness, increased sweating and fatigue. Most of the side-effects experienced by patients taking Escitalopram are mild and go away with continued treatment and usually do not cause patients to stop taking Escitalopram.

Toxicity

Symptoms of overdose may include CNS effects (dizziness, convulsions, coma, somnolence), gastrointestinal distress (nausea, vomiting), and/or cardiac abnormalities (hypotension, tachycardia, ECG changes). There is no specific antidote for escitalopram overdose. Management of overdose should focus on monitoring for cardiac abnormalities and changes to vital signs as well as treatment with supportive measures as indicated. As escitalopram is highly distributed into tissue following oral administration, forced diuresis, dialysis, and other methods of extracting drug from plasma are unlikely to be beneficial.

Major adverse effects include drowsiness, sedation, muscle weakness and incoordination, fainting, headache, confusion, depression, slurred speech, visual disturbances and changes in libido and tremor . Flumazenil is a competitive antagonist of GABA-A receptors and can be also used to reverse the effect of etizolam overdosage. Etizolam demonstrates no effects on fertility, development and teratogenicity . LD50 values of etizolam when delivered orally, intraperitoneally, and subcutaneously are 3509mg/kg, 825mg/kg, and >5000mg/kg in rats, respectively, and 3070mg/kg, 783mg/kg and 5000mg/kg in mice, respectively .

Precaution

During marketing of escitalopram and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with escitalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Interaction

Escitalopram should not be started until 2 weeks after stopping an MAOI. Conversely, an MAOI should not be started until at least a week after escitalopram or related antidepressant has been stopped.

Volume of Distribution

Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg.

Apparent distribution volume was 0.9 ± 0.2 L/kg following a single oral doing of 0.5mg etizolam .

Elimination Route

Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T_max occurs after about 4-5 hours. C_max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C_max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C_max and 24h AUC, comparatively.

Etizolam is well absorbed from the intestines with a biological bioavailability of 93% following oral administration. After a single oral dosing of 0.5mg etizolam, it takes approximately 0.9 hours to reach the peak plasma concentration of 8.3 ng/mL .

Half Life

The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state.

The average elimination half life of etizolam following a single oral dose of 0.5mg is 3.4 hours but may be increased up to 17 hours depending on the rate of metabolism . The main metabolite α-hydroxyetizolam displays a longer elimination half life of 8.2 hours .

Clearance

The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance.

Elimination Route

After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose.

In a rat study, the amounts of etizolam excreted was 30% in urine was 70% in feces, while the values in a mouse study were 40% in urine and 60% in feces .

Pregnancy & Breastfeeding use

Pregnancy: The safety of escitalopram during pregnancy and lactation has not been established. Therefore, escitalopram should not be used during pregnancy unless, in the opinion of the physician, the expected benefits to the patient outweigh the possible hazards to the fetus.

Nursing Mothers: Escitalopram is excreted in human milk. Escitalopram should not be given to nursing mothers unless, in the opinion of the physician, the expected benefits to the patient outweigh the possible hazards to the child

Contraindication

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. Concomitant use in patients taking pimozide is contraindicated. Esita is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients.

Special Warning

Pediatric Use: Safety and effectiveness in children below the age of 18 years have not been established.

Geriatric patients: Escitalopram pharmocokinetics in subjects age 65 and over were compared to younger subjects in a single and multi-dose study. No overall differences in safety or effectiveness between this group and the younger subjects was observed, but greater sensitivity of some elderly individuals ca

Storage Condition

Store in a cool and dry place below 30º C. Protect from light.

Innovators Monograph

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