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Psychopharmacy: Fluoxetine

A. Definition Fluoxetine is an antidepressant drug from the selective serotonin reuptake inhibitor (SSRI) class which is mainly used for depression. Besides fordepression, fluoxetine and other SSRI groups are also indicated for obsessive-compulsive disorder (OCD), panic disorder, premenstrual dysphoric disorder, and bulimia. 1 Since its discovery in 1988, fluoxetine has become the most widely prescribed antidepressant drug due to its ease of use ( once a day), the risk of overdose is minimal, relatively tolerable, inexpensive, and a broad spectrum of indications. SSRI class drugs work by inhibiting the serotonin reuptake process through inhibition of the serotonin transporter (SERT). Since the pathogenesis of depression is thought to result from decreased levels of serotonin in the synaptic cleft, it is inhibition of SERT that is responsible for the antidepressant effect of fluoxetine. Compared to tricyclic antidepressants such asamitriptyline, SSRIs have a milder side effect profile so they have better drug adherence than the tricyclic group. Although no studies have shown fluoxetine to have better efficacy than tricyclic antidepressants, fluoxetine has better tolerability, low overdose lethality, is safe in patients with cardiovascular disorders, and relatively lower weight gain. Studies show that approximately 50% of depressed patients receiving fluoxetine for 8 weeks begin to show a response to therapy at week 2, and more than 75% begin to show response at week 4. It was also reported that there was no response at week 4. -6 represents a 73% - 88% chance of not responding to therapy by week 8. Synonym: fluoxetine. Chemical name: N-methyl-3-phenyl-3-[4- (trifluoromethyl)phenoxy]propan-1-amine Regarding Description Class Antidepressants

there is intraindividual variability in the degree of inhibition. Fluoxetine does not bind aggressively to histamine, muscarinic, or other receptors Fluoxetine has a pharmacodynamic profile that is different from other SSRIs, namely the property of serotonin 5HT2C receptor antagonism. Blockade of serotonin 5HT2C receptors will result in disinhibition (indirectly increasing) releasenorepinephrineand dopamine. It is this serotonin 5HT2C receptor antagonism that causes this drug to have better tolerance. The increase in dopamine and norepinephrine is activating and many patients experience an increase in energy and reduced fatigue from the start of therapy with fluoxetine, as well as improvements in concentration and attention. This makes fluoxetine suitable for patients who have symptoms of decreased positive affect, hypersomnia, psychomotor retardation, apathy and fatigue. However, in patients with agitation, insomnia, and anxiety, this effect is less beneficial because it can induce irritability and even panic attacks in these patients. C. Pharmacokinetics All SSRI antidepressant drugs, including fluoxetine, have a uniform pharmacokinetic profile: 1

1. Absorption Drugs of this class are completely absorbed by oral administration, reach peak plasma concentrations within 2-3 hours, bind strongly to plasma proteins, undergo hepatic metabolism, and are excreted via the kidneys. Nonetheless, the metabolic profiles of these drugs vary widely.
2. Distribution Fluoxetine has up to 95% binding to plasma proteins with a half-life of 2-6 days.
3. Metabolism and Elimination Fluoxetine is metabolized to an active metabolite (norfluoxetine) which has a higher plasma concentration than the original drug. The elimination half-life for norfluoxetine is approximately three times longer than fluoxetine and is the

longest-lived SSRI metabolite. This is one of the reasons why it takes more than 4 weeks for clearance after stopping therapy with fluoxetine, before a new antidepressant can be started. This is to prevent serotonin syndrome. D. Fluoxetine Indications and Dosage Fluoxetine has been approved by the FDA for depressive disorder, obsessive compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), bulimia nervosa, panic disorder, and bipolar depressive disorder (in combination with olanzapine).

1. Depression The fluoxetine dosage for depression is as follows:  Adult: Initial dose is 20 mg/day. Titrate according to response to therapy up to 80 mg daily in divided doses if there is no clinical response for several weeks after therapy.  In the elderly, the maximum dose is 60 mg per day  Children 8 years of age and older: the initial dose is 10 mg daily and may be increased to 20 mg daily if there is no clinical response until several weeks after therapy.
2. Obsessive Compulsive Disorder Dosage for obsessive compulsive disorder indications  Adults, the initial dose is 20 mg daily. May be increased to 60 mg daily in two divided doses if there is no clinical response after several weeks. The maximum dose is 80 mg per day in two divided doses

The fluoxetine formulation in Indonesia is only available in oral preparations which can be stored at room temperature.

1. Dosage Form Fluoxetine is available in the following formulations:  Capsules: 10 mg, 20 mg, 40 mg, and 90 mg (weekly)  Tablets: 10 mg and 20 mg,  Syrup: 20 mg/5 ml in a 120 ml bottle. In Indonesia, only 20 mg capsules or tablets are available
2. Way of giving Fluoxetine has a long half-life (2-3 days) and has a long-acting active metabolite (norfluoxetine, half-life up to 2 weeks). This causes a change in dose will not immediately cause a change in the concentration of the active drug in plasma. This also causes fluoxetine to require dose titration for a long time before reaching the final dose. Fluoxetine can be given once a day, often in the morning, but it can actually be given at any time the patient tolerates it. Consumption of fluoxetine is not affected by food. F. Fluoxetine side effects and drug interactions
3. Side effects Theoretically, the side effects of fluoxetine result from increased concentrations of serotonin at serotonin receptors at sites not involved in the pathophysiology of depression. Increased serotonin in the sleep center will cause insomnia, in the digestive tract will cause diarrhea. Increased

serotonin will also cause a decrease in dopamine release and in some people can cause symptoms such as emotional dulling, cognitive slowing, and apathy. Although theoretically fluoxetine has a side effect of insomnia, some patients report drowsiness after using fluoxetine. The most common side effects are: 4  Gastrointestinal side effects: decreased appetite, nausea, diarrhea, constipation, dry mouth  Side effects on the central nervous system: agitation, tremor, dizziness, headache  Other Side Effects  Other side effects that are often complained of by male patients:  Difficulty ejaculating (prolonged ejaculation time)  Erectile disorders Although the side effects of fluoxetine vary widely, they usually subside over time. Side effects of sexual dysfunction, weight gain, and sleep disturbances are the most difficult to disappear and difficult to overcome

2. Drug Interactions Fluoxetine drug interactions are as follows:  Increased Plasma Levels of Other Drugs

3. Changes in Activity and Metabolism of Other Drugs Fluoxetine can affect the activity and metabolism of other drugs through inhibition of the CYP450 2D6 enzyme. Via this route fluoxetine may interfere with the analgesic effect of codeine, increase plasma concentrations of beta-blockers (eg propranolol), increase plasma concentrations of thioridazine (rising risk of dangerous arrhythmias). Fluoxetine may also decrease clearance and increase concentrations of diazepam, trazodone, alprazolam, buspirone, and triazolam. Fluoxetine can also increase the concentration of statins such as simvastatin, atorvastatin, and lovastatin, thereby increasing the risk of rhabdomyolysis. G. Use in Pregnancy According to studies conducted on experimental animals showed side effects on the fetus, but there have been no controlled studies in pregnant women. Nevertheless, the use of fluoxetine during pregnancy in patients with suitable indications should be continued and until now there has been no report that fluoxetine is harmful to the fetus. This drug may be used if the expected benefit exceeds the risk to the fetus Animal studies have shown that increased serotonin due to fluoxetine can lead to decreased blood flow to the uterus, resulting in reduced oxygenation and nutrition to the fetus. This can cause disruption of fetal development or premature birth

Doctors must be aware of the risk of neonatal abstinence syndrome (NAS) in neonates of mothers receiving selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine in the third trimester. Use in nursing mothers fluoxetine may be excreted into breast milk. If a baby who is breastfed from a mother receiving fluoxetine experiences symptoms of irritability (fussy) or sedation, it is best to stop breastfeeding or medication (one of them) by considering the effect on the mother's ability to care for her baby. H. Contraindications

1. The use of fluoxetine is contraindicated in:  Patients receiving beta blocker drugs (eg propranolol and atenolol) and thioridazine: can cause arrhythmias and heart problems  Patients receiving statin drugs (eg simvastatin and atorvastatin): increased risk of developing rhabdomyolysis  Patients receiving warfarin or heparin: increased risk of bleeding Administration of fluoxetine is also contraindicated in patients who have a history of hypersensitivity to fluoxetine
2. Serotonin Syndrome Serotonin syndrome is a side effect of using serotonergic drugs, including SSRI class drugs, such as fluoxetine. This syndrome is characterized by altered mental status, neuromuscular hyperactivity, and autonomic nervous hyperactivity. Fluoxetine is one of the drugs that often causes serotonin syndrome because of its long half-life.

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