Fluoxetine (Prozac): Mechanism of Action and Side Effects

The Fluoxetine , Better known as prozac, Is an antidepressant that falls within the category of selective serotonin reuptake inhibitors (SSRIs). Better known as Prozac, it is one of the most prescribed antidepressants worldwide.

Although it has numerous beneficial effects to treat disorders such as depression wave anxiety Can not be taken lightly, as it can also cause adverse effects.

The emergence of SSRIs in the late 1980s revolutionized psychopharmacology up to six prescriptions per second.

Although originally born as Antidepressants , Are also prescribed for other less serious conditions such as premenstrual dysphoric disorder, anxiety disorders Or some eating disorders.

Within the SSRI group there are six types of compounds that share many effects, but also have unique properties that differentiate them ( See table 1 ). In this article we will see the common and proper effects of flouxetine.

Table 1. Types of SSRIs

Mechanism of action of SSRIs

To understand how SSRIs work before we must know what happens in brain Of a person with depression at the cellular level.

According to the monoaminergic hypothesis, people with depression Suffer from a serotonin deficiency in serotonergic presynaptic neurons, both in the somatodendritic areas and in the axonal terminal.

Figure 1. Serotoninergic neuron of patient with depression (Stahl, 2010).

All antidepressants work by increasing the Serotonin Until they reach their previous levels, prior to the disorder, and thus attempt to alleviate or eliminate depressive symptoms.

In addition to acting on axonal receptors, SSRIs Act on serotonin receptors in the somatodendritic area (5HT1A receptors), and this triggers a series of effects that end up with increased serotonin.

To understand the following section is necessary to have basic notions of psychopharmacology, if you have never studied psychopharmacology or want to refresh your knowledge I recommend that you read the box Description of a Synapse from the article Introduction to Psychopharmacology .

The mechanism of action of SSRIs will be explained step by step:

1. SSRIs block the serotonin receptors in the somatodendritic area, also called TSER (serotonin transporters) pumps. This blockade prevents serotonin molecules from binding to receptors and therefore serotonin can not be recaptured (hence the name of SSRIs) and remains in the somatodendritic area. After a while the levels of serotonin are raised due to their accumulation. Serotonin levels also increase in unwanted areas and the first side effects begin to appear ( See figure 2 ).

Figure 2. Step 1 - blockade of somatodendritic serotoninergic receptors (Stahl, 2010).

2. When the receptors are blocked for a long time without the neuron, they are identified as unnecessary, therefore they cease to function and some disappear, these effects are known as desensitization and down regulation and are produced through a genomic mechanism ( See figure 3 ).
   

Figure 3. Step 2- sensitization and down regulation of somatodendritic serotoninergic receptors (Stahl, 2010).

3. As there are fewer receptors the amount of serotonin that arrives within the neuron is lower than before regulation, therefore, the neuron"believes"that there is very little serotonin and begins to produce more amounts of this neurotransmitter and its flow is activated Towards the axons and their release. This mechanism explains most of the antidepressant effects of SSRIs ( See figure 4 ).
   

Figure 4. Step 3- activation of serotonin production and release (Stahl, 2010).

4. Once the neuron has already begun to segregate higher levels of serotonin, another mechanism of action of SSRIs that has not been effective so far is becoming relevant. This mechanism is blocking the axonal receptors, which are also desensitized and downregulated and, therefore, less serotonin is recaptured. This mechanism causes the SSRI side effects to begin to slow down as serotonin levels are lowered to normal levels ( See figure 5 ).

Figure 5. Step 4- sensitization and down regulation of the serotonergic axonal receptors (Stahl, 2010).

In short, SSRIs act by progressively increasing serotonin levels in all brain areas where there are serotonergic neurons, not only where they are needed, which causes both beneficial and detrimental effects. Although the side effects or unwanted effects are improving over time.

Mechanism of action of fluoxetine

In addition to the mechanism explained above, common to all SSRIs, Fluoxetine It also follows other mechanisms that make it unique.

Figure 6. Schematic of a fluoxetine molecule (Stahl, 2010).

This drug not only inhibits serotonin reuptake, it also inhibits the reuptake of Norepinephrine Y Dopamine In the prefrontal cortex, blocking the 5HT2C receptors, which increases the levels of these neurotransmitters in that area. Drugs that have this effect are called DIND (norepinephrine and dopamine inhibitors), therefore, fluoxetine would be a DIND in addition to an SSRI.

This mechanism may explain some of the properties of fluoxetine as an activator, thus helping to decrease fatigue in patients with reduced positive affect, Hypersomnia , Psychomotor retardation and apathy . In contrast, it is not advisable for patients with agitation, insomnia And anxiety, since they may experience undesired activation.

The mechanism of fluoxetine as DIND may also act as a therapeutic effect on the anorexy and the bulimia .

Finally, this mechanism may also explain the ability of fluoxetine to increase the antidepressant actions of Olanzapine In patients with bipolar depression, since this drug also acts as DIND and would add both actions.

Other effects of fluoxetine are weak blockade of norepinephrine reuptake (IRN) and, at high doses, inhibition of CYP2D6 and 3A4, which may increase the effect of other psychoactive drugs in an undesired way.

In addition, both fluoxentin and its metabolite have a long half-life (2 or 3 days for fluoxetine and 2 weeks for its metabolite), which helps decrease the withdrawal syndrome observed when withdrawing some SSRIs. But it must be taken into account that this also implies that it will be a long time before the drug disappears completely from the organism when the treatment is finished.

Side Effects of SSRIs

Side effects that all SSRIs share include the following:

• Mental agitation, nervousness, anxiety and even panic attacks . This effect occurs due to the acute blockade of the 5HT2A and 5HT2C receptors in the serotonergic projection of the raphe to the amygdala and the limbic cortex to the ventromedial prefrontal cortex.
• Akathisia, psychomotor retardation, mild parkinsonism, dystonic movements and, as a consequence of these, joint pain. This effect is caused by the acute blockade of 5HT2A receptors in the basal ganglia.
• Sleep Disorders , Myoclonus, awakenings. This effect is caused by the acute blockade of 5HT2A receptors in the sleep centers.
• Sexual dysfunction. This effect is due to the acute blockade of 5HT2A and 5HT2C receptors in the spinal cord .
• Nausea and vomiting. This effect appears as a consequence of the acute blockade of the 5HT3 receptors in the Hypothalamus .
• Intestinal motility, cramps. This effect is a consequence of the blockade of 5HT3 and 5HT4 receptors.

In addition to the aforementioned effects, fluoxetine may produce other side effects of its own which can be seen in the table below.

Table 2. Side effects of fluoxetine.

Overdose of fluoxetine may lead to instability, confusion, lack of response to stimuli, dizziness, fainting or even coma, in addition to previous side effects.

In addition, a pre-marketing clinical trial found that some of the younger participants (younger than 24 years) developed suicidal tendencies (thought or attempted to harm themselves or commit suicide) after taking fluoxetine. Therefore, young people should be especially cautious with this drug.

Precautions Before Taking Fluoxetine

First of all, I would like to make it clear that psychotropic drugs can be very dangerous for health in general and especially for mental health, so they should never be self administered, they must always be taken after medical prescription and during their take To the doctor if any mental or physical changes are noticed.

It is important to tell the doctor if you are taking, or have just stopped taking, another drug as it may interact with fluoxetine and cause harmful effects.

Below you will find a list of medications that may be potentially dangerous if combined with fluoxetine:

• Medications for tics such as Pimozide (Orap).
• Medications to treat schizophrenia Such as thioridazine, clozapine (Clozaril) and haloperidol (Haldol).
• Some antidepressants IMAO (Monoamine oxidase inhibitors), such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar) and tranylcypromine (Parnate).
• Medications to treat anxiety such as alprazolam (Xanax) or diazepam (Valium).
• Anticoagulants, such as warfarin (Coumadin) and ticlid (ticlopidine).
• Some antifungals like fluconazole (Diflucan), ketoconazole (Nizoral) and voriconazole (Vfend).
• Other antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin, imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), fluvoxamine (Luvox), lithium , Lithobid), and trimipramine (Surmontil).
• Some non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, or paracetamol.
• Medications for cardiac disorders such as digoxin (Lanoxin) and flecainide (Tambocor).
• Some Diuretics .
• Medicines to treat infections such as linezolid.
• Medications to treat cardiovascular diseases such as fluvastatin (Lescol), and to treat hypertension like torsemide (Demadex).
• Medications to treat gastric ulcers and disorders such as cimetidine (Tagamet) and proton pump inhibitors such as esomeprazole (Nexium) and omeprazole (Prilosec, Prilosec OTC, Zegerid).
• Treatments for HIV such as etravirine (Intelence).
• Anticonvulsants such as phenytoin (Dilantin), carbamazepine (Tegretol) and phenytoin (Dilantin).
• Hormonal treatments such as tamoxifen (Nolvadex) and insulin.
• Medications for diabetes like tolbutamide.
• Methylene blue, used to treat Alzheimer disease .
• Medications for migraines such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex) and zolmitriptan (Zomig).
• Sedatives, tranquilizers and sleeping pills.
• Medications to treat obesity such as sibutramine (Meridia).
• Analgesics like tramadol (Ultram).
• Treatment for cancer such as vinblastine (Velban).

It is also advisable to tell the doctor if you are taking vitamins, such as tryptophan, or Herbal products , as the Grass of San Juan .

In addition, special care must be taken with fluoxetine if you are receiving electroconvulsive therapy, if you have diabetes , Seizures or liver disease, and if you have recently had a heart attack.

You should not take fluoxetine if you are pregnant, especially in the last months of gestation. It is also not recommended that people over 65 years of age take this medicine.

References

1. American Society of Health-System Pharmacists. (November 15, 2014). Fluoxetine . Obtained from MedlinePlus.
2. Faculty of Medicine UNAM. (S.f.). Fluoxetine . Retrieved on May 13, 2016, from Faculty of Medicine UNAM.
3. Stahl, S. (2010). Antidepressants. In S. Stahl, Stahl's etiology and psychopharmacology (Pages 511-666). Madrid: AULA MEDICA GROUP.
4. Stahl, S. (2010). Antidepressants. In S. Stahl, Stahl's etiology and psychopharmacology (Pages 511-666). Madrid: AULA MEDICA GROUP.