Group C11. DDMDA
Hi there today we’re going to talk about fluoxetine fluoxetine is used by doctors to treat patients who suffer from major depressive disorders this could be major depression bulimia nervosa which is binge eating and vomiting and also obsessive-compulsive disorder commonly known as ocd while these diseases can affect anyone and come in many different strengths today
We will focus on flossing and its use in treating major depression before we proceed it is essential to understand what major depression is once we have an understanding we can see how fluoxetine is used to treat it so what causes depression the first major hypothesis of depression was formulated about 30 years ago and proposed that the main symptoms of depression
Are result of a functional deficiency of the brain’s model m energic transmitters norepinephrine serotonin also known as 5ht and dopamine everything we do relies on neurons communicating with one another when the action potential reaches the end of an axon most neurons release a chemical message a neurotransmitter which crosses the synapse and binds to receptors on
The receiving neurons dendrites this helps in successfully transferring the message between two neurons during depression however neurotransmitters such as serotonin are reabsorbed quickly by the sending neuron consequently less serotonin remains in the synaptic cleft for the receiving neuron to bind on to which ultimately leads to abnormal moods this illustrates
That behavioral consequences of depression may arise from altered synthesis storage or release of the neurotransmitters as well as from disturbed sensitivity of their receptors now that we understand the cause of depression we can begin to understand the history of fluoxetine and how it works while paving the way for antidepressant drugs fluoxetine discovery also
Provided a solution to a common psychiatric disorder that many people have experienced in the early 1970s evidence of the role of serotonin also known as 5-hydroxytryptamine or 5hd for short in depression began to emerge and the hypothesis that enhancing serotonin neurotransmission would be a viable mechanism to mediate antidepressant response was introduced given
This efforts commenced in want to develop agents that inhibit the uptake of serotonin from the synaptic cleft in late 1971 brian moly in eli lilly synthesized a range of new compounds a group of phenol oxy phenol propyl a means from diphenhydramine an antihistamine fountain hit a tree uptake of the neurotransmitter serotonin one of these compounds lily one one
Zero one four zero later in 1975 called fluoxetine was found to be highly selective affecting only the neurotransmitter serotonin this was a huge breakthrough as the selectivity of fluoxetine is what makes it such an effective drug using lily 110 140 and other tricyclic antidepressant agents norepinephrine dopamine and the inhibition of serotonin were measured
And compared in a series of experiments on rat brains using the inhibition constant ki lily 110 140 a secondary amine was found to have a greater affinity for the update sites of serotonin than for the sites of norepinephrine and dopamine uptake in 1973 the cns research committee at eli lilly decided to form a project team on fluoxetine to guide it to product
Development this team would be named psychotropic agent ly 110 140 during safety studies in rats and dogs the team learned that fluoxetine showed the presence of phospholipid doses this flood – pausing the project for nine months because they learn that cationic mo philic molecules could cause a reversible accumulation of phospholipid and tissues after confirming
That several other marketed drugs were known to cause phospholipid osis in humans with no problematic side effects the team continued their work in 1976 lamb burger who was a clinical investigator at the lilly laboratory of clinical research first administered philosophy into humans he found that doses of fluoxetine as high as 90 milligrams were well tolerated by
Volunteers it was truly a rewarding experience to find that for the first time in humans fluoxetine selectively and effectively inhibited 5ht uptake by blood platelets and had no demonstratable adrenergic effects on the cardiovascular system even though both processes were in peripheral systems the clinical results of all the trials were compiled in more than a
Hundred volumes of 2-inch binders for the submission of an nda which is a new drug application to the us fda in 1983 the journey of fluoxetine took more than 16 years and required thousands of work dedication inside and outside eli lilly as well as the participation of thousands of patients can make it to the market in january 1988 fluoxetine was launched under the
Trade name prozac fun fact the name prozac was created by a marketing team where pro stands for professional and ac4 activity while the z brings the two together now that we have laid the historical foundation of fluoxetine we can begin to discuss how it works fluoxetine preferentially acts to inhibit the reuptake transporter for serotonin flossie teen has a high
And selective affinity for these serotonin transporters and therefore blocks serotonin from binding to the transporters and being absorbed into the presynaptic cells as a result of the excess serotonin in the synaptic cleft which we mentioned earlier to be the region of space between two neurons where nerve impulses are transmitted by a neurotransmitter there is
An over activation of the postsynaptic receptors in other words a lot of serotonin is received by the postsynaptic receptors and these signals help improve the mood of the individual long-term administration of fluoxetine causes a reduction in the production of the reuptake transporters and their binding sites these responses at the receptors and to transporters
Are thought to produce the antidepressant effects of fluoxetine now you might be wondering how fluoxetine does this to better understand that let’s take a look at its structure activity relationship compounds containing an airlock see propyl aiming motif in their structure demonstrated in figure a are known as mono amine reuptake inhibitors drugs containing this
Privileged structural motif where r1 and r2 are arrows or hetero arrows preferably phenol possess a selectivity profile for norepinephrine transporters and serotonin transporters while compounds containing a substituent in the two part of the arousal ring of the structure as you can see in figure b this selectivity in high affinity for norepinephrine transporters
Generally works on nor panetta and reactive inhibitors whereas compounds such as fluoxetine has a substituent in the four prime position which has selectivity and high affinity for serotonin transporters and is therefore generally considered a selective serotonin reuptake inhibitor and yep you guessed it that’s why it’s categorized as an ssri as you can see fluoxetine
Is based on this and as such has a substituent on the fourth carbon of the ring we’re now going to take a look at the synthesis of fluoxetine clinical fluoxetine is a racemic mixture of the rns enantiomers and they are of equivalent pharmacologic activity hence the velocity in synthesis we consider here refers to the formation of racemic fluoxetine the synthesis
Employed a manic reaction with acetophenone to provide a beta dimethyl amino propio fee known it was then dissolved in a t hf solution of four equivalent diborane an acetic workup then provides a racemic secondary alcohol the alcohol was dissolved in chloroform and saturated with in hydras hydrochloric gas while sulfuryl chloride was added after evaporation of the
Solvent the mixture was collected as a crystalline hydrochloride salt the salt was added to an alkaline solution of four tri fluoro phenol to afford a phenoxyethanol derivative in the presence of cnb r benzene and toluene basic hydrolysis of the n sino derivative gives racemic fluoxetine as a free base like most medicines one fluoxetine is administered it can have
Both on target and off target side-effects one of the main on target side effects results from excessively increasing doses of fluoxetine this causes nerve cell over activity due to the accumulation of serotonin in the brain leading to a collection of symptoms known as serotonin syndrome this can also occur within hours when the patient starts the medication the
Most common serotonin syndrome symptoms are headache vomiting diarrhea tremors and a rapid heart rate for the off target side effects of fluoxetine promising study indicates that fluoxetine can reduce the risk of colon cancer it was found to inhibit the development of carcinogen induced pre neoplastic lesions in colon tissues but the mechanisms of action are not
Well understood fluoxetine was able to reduce the development of mmg induced dysplasia and vascularized related dysplasia in colon tissue taken together these findings explain partially why there is a local in cancer risk with patients under antidepressant therapy moving on the half-life fluoxetine is long lasting approximately two to three days it is metabolized
And likely to remain in the body for several weeks after discontinuation this is important information to be considered when counseling a patient philosophy should not be used during pregnancy unless the benefits outweigh the risks and should also be avoided during breastfeeding since it is known to cross the placenta and enter the breast milk finally just to go
Over the forms of fluoxetine that are available there are capsules tablets oral suspensions and oral solutions fluoxetine was cleverly discovered carefully analyzed and is a revolutionary pharmaceutical used to tree among other things major depression while we enjoyed discussing the history and the use of this antidepressant we hope our discussion has given the
Appropriate credit due to this medicinal masterpiece
Transcribed from video
The Story of Fluoxetine By Ali Majed
