The Background, Chemistry, Pharmacology, Side Effects and Therapeutic Effects of Fluoxetine (Essay Sample)

 
 
 
 
 
 
The background, chemistry, pharmacology, side effects and therapeutic effects of fluoxetine
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Background
Fluoxetine also widely known as Prozac is an antidepressant under the class of selective serotonin inhibitors (SSRI). Fluoxetine is commonly used in the treatment of obsessive-compulsive disorder, major depression, bulimia nervosa, premenstrual dysphoric disorder and panic disorder ¹.
The work that led to the discovery of fluoxetine commenced in 1970 at Eli Lily and Company as a collaboration between Robert Rathbun and Bryan Molloy. During that time, it was known that antihistamine diphenhydramine exhibited some antidepressant-like properties². 3- Phenoxy-3-phenylpropylamine, a compound with structural similarity to diphenhydramine was used as the starting point, and Molloy developed dozens of its derivatives. In the hope of finding a derivative that only inhibits the reuptake of serotonin, David T. Wong, an Eli Lilly scientist proposed to retest the derivatives for the in vitro selective reuptake of serotonin, dopamine and norepinephrine ². This test carried out in May 1972 by Jong-Sir Hong showed the compound later called fluoxetine, to be the most potent and selective in the inhibition of the reuptake of serotonin. Wong went ahead to publish the first article concerning fluoxetine in 1974. A year later Eli Lily and company officially named it as fluoxetine with a trade name of Prozac.
Chemistry
Fluoxetine is chemically described as 3-phenoxy-3-phenylpropanolamine with a molecular formula of C17H19ClF3NO. Fluoxetine has a characteristic of selectivity and high affinity to the human serotonin reuptake transporter (SERT). When it comes to its Structure-Activity-Relationship (SAR) fluoxetine’s specificity for SERT primarily depends on its position and the phenoxy ring substituent.
Below is a picture of the chemical structure of fluoxetine⁹.
 
 
Fluoxetine has a molecular weight of 345.78707 g/mol, a melting point of 179 to 182 °C (354 to 360 °F), a boiling point of 395 °C (743 °F), and a solubility in water of 14 mg/mL (20 °C)³. Fluoxetine is a white to off-white crystalline solid with a maximum water solubility of 14 mg/mL. Fluoxetine is stable but incompatible with strong oxidizing agents. 
To synthesize the fluoxetine molecule, a three-step is used. The intermediates include 3-(methylamino)-1-phenyl- that is synthesized through an SN2 reaction between methylamine and 3-chloropropiophenone, 1-propanone, and α-[2-(methylamino) ethyl] benzyl alcohol that is synthesized by the reduction of the second intermediate ⁴. The first intermediate is subjected to sodium hydride and 4-chlorobenzotrifluoride to produce the desired fluoxetine molecule.
Seventy-one randomized control trials (RCTs) with 24,868 people have been conducted to compare fluoxetine with other antidepressants in the treatment of depression ⁵. After integrating all the results obtained from the trials, it was found that fluoxetine was similarly effective but more tolerable than older generation (tricyclic) antidepressants ⁵. Upon comparing fluoxetine with other new generation antidepressants, significant differences in tolerability and efficacy were found between fluoxetine and other antidepressants, fluoxetine was better tolerated than reboxetine but less effective than mirtazapine and sertraline. Such differences may have a clinical impact in day-to-day practice.
Pharmacology
The influence of serotonin on the neurosteroids is highly linked to an increase in allopregnanolone, which is a GABAA receptor and a positive allosteric modulator. A decrease in circulating brain allopregnanolone has been linked to both anxiety disorders and depression². Improvement in depressive symptoms in medicated people is associated with a fluoxetine-induced rise in allopregnanolone levels.
The bioavailability of fluoxetine is high (72%) and with a peak plasma concentration achieved in 6-8 hours ⁶. Fluoxetine is normally bound to plasma proteins, mostly α1-glycoprotein and albumin. Fluoxetine is metabolized in the liver by the cytochrome P450 system which involves isoenzymes such as CYP2D6. The role of the isoenzyme CYP2D6 in the metabolism of fluoxetine is of clinical significance as there is profound genetic variability in the functioning of this enzyme among individuals. This enzyme is responsible for the conversion of fluoxetine into its active metabolite norfluoxetine.
The slow elimination of fluoxetine and norfluoxetine from the body sets it apart from other antidepressants. Over time, there is inhibition of metabolism, changing fluoxetine’s half-life from 1 to 3 days, after one dose to 4 to 6 days after long-term use ⁶. Also, the brain concentration of fluoxetine and its metabolites keeps on increasing throughout the first four weeks of treatment. This means that the full benefits are not realized until a month from its initiation.
Side Effects / Adverse Effects / Toxicology
Side effects that have been observed in fluoxetine-treated persons during clinical trials are twice as common compared to those who have received the placebo pill including yawning, vasodilation, tremor, sweating, somnolence, sinusitis, rash, pharyngitis, nervousness, nausea, decreased libido, insomnia, impotence, dyspepsia, dry mouth, anxiety, anorexia, abnormal ejaculation and abnormal dreams. Of all the SSRIs fluoxetine is considered the most stimulating (most prone to causing agitation and insomnia).
One of the adverse effects of fluoxetine is sexual dysfunction which may include anorgasmia, erectile dysfunction and lack of vaginal lubrication. This is one of the most commonly encountered adverse effects when the treatment involves fluoxetine and other SSRIs ⁷. Early clinical trials suggested a low rate of sexual dysfunction but recent studies have suggested that the incidence is as high as 70%. Some have reported the persistence of symptoms of sexual dysfunction even after discontinuing SSRIs.
The other adverse effects that have been associated with fluoxetine is increased risk of suicide in people younger than twenty-five years. According to statistical analyses of two independent groups of FDA experts, there was a two-fold increase in suicidal behavior and ideation in adolescents and children and 1.5-fold increase in the 18–24 age group¹. Suicidality was decreased for those above 24 years and insignificant to those at 65 and older.
Upon an overdose of fluoxetine different adverse effects have been observed depending on the body system. As for the nervous system, anxiety, dizziness, tremor, fatigue, insomnia, and nervousness have been observed⁸. As for the gastrointestinal system dry mouth, vasodilation, diarrhea, nausea, and anorexia have been observed. Other effects include decreased libido, sweating, rash, and abnormal ejaculation.
Therapeutic Applications
Fluoxetine is clinically used in the treatmen...