Mechanism Of Sumitriptan Ibuprofen The Treatment Of Migraine Biology Essay
Migraine is a weakening condition and occurs three times more in women than men. Patients have described the symptoms as a moderate to severe headache coupled with nausea. One major difference between a migraine and a headache is that the pain associated with migraine is felt on one side of the brain (unilateral). This unilateral pain, spreads and increases in severity over time, is pulsating in nature and may last between 4 and 72 hours. 
One third of migraine sufferers have some kind of sensory experience known as “aura” indicting that the migraine will occur soon. Other symptoms include vomiting, increased sensitivity to light and sound. Hands and feet may feel cold and sweaty while some odours are intolerable. In migraines the pain worsens when head movement occurs whereas in tension-type headaches no such effect occurs. 
Neurologist use aura to distinguish between migraines and headaches, however the cause for migraines is not yet known. One common theory is that there is a disorder related to the neurotransmitter serotonin. Migraines in women may be linked to changes in hormones and hormone levels. Anxiety, stress, altered sleep patterns are amongst the most common factors that trigger a migraine attack. For many years, scientists where under the impression that migraines were linked to dilation and constriction of blood vessels in the head however now believe migraine attacks may be due to genetic abnormalities in the control of certain cells within the brain. 
Studies of twins have shown that a 60-65% genetic influence plays a role in the ability to develop migraines. Furthermore, one report suggests 75% of adult migraine sufferers are women indicating the causes are linked to hormones and hormone levels. In the US, the female to male ratio of migraine sufferers increases from 2.5:1 at puberty to 3.5:1 at 40 after which it declines possibly due to menopause. Finally, the frequency of migraines has known to decrease in pregnant women while some pregnant women have an increased frequency indicating the cause to be due to changes in hormones and hormone levels. 
Over the past 50 years the causes of migraine have been hypothesised by 3 main theories. This is due to the vast mechanisms and different sensory elements associated with migraine.
The Vascular Theory
This theory is based purely on the basis that when a person suffers from migraines changes in the vessels causes the symptoms. During an attack the cerebral vessels are dilated and the constriction of intracerebral vessels causes aura. Dilation of extracerebral vessels causes the headache by activating the fifth cranial (trigeminal) nerve. 
The Cortical Spreading Depression Theory
Figure adapted from Centre for Neuro SkillsThis theory was developed purely for the early symptoms indicating the onset of a migraine attack. The thinking behind this phenomenon is a short lasting wave of depolarisation which spreads across the surface of the brain. This starts from the back, occipital region, of the brain and moves towards the front at a speed of 3.5mm/min making the neurons excited and then depressed causing symptoms such as aura. Therefore this condition is known as Cortical Spreading Depression (CSD) and is the basis of the theory. 
The Neurovascular Hypothesis
This theory doesn’t explain how small protein like molecules (neuropeptides) used by neurons to communicate with each other, are released from the trigeminal nerves. However, when released, these neuropeptides cause inflammation and vasodilatation by inverting blood vessels in the extracranial arteries and in the circle of Willis. Furthermore, it is unknown how this mechanism causes aura however these neuropeptides are being researched for treatment purposes. 
Figure adapted from Webanatomy.netAs discussed the different theories indicate that one common hypothesis for migraine attacks is very difficult to achieve. However, a combination of these hypotheses is a more suitable approach. Trigger factors such as glare, stress or loud noises activate certain parts of the brain stem causing the release of neuropeptides from the nerves to alter blood flow in this central region. This causes CSD and activates the trigeminovascular fibres which release the neuropeptides intern causing inflammation and headache pain. 
There are two main types of treatments for migraines, acute and prophylactics. Acute treatment is used to reduce the severity of the attacks where as prophylactics are used to reduce the attacks. This essay will only detail the acute treatments. Acute treatments can be divided further in to two sections: treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or treatment with serotonergic modulators.
A common NSAID used in the treatment of migraines is Ibuprofen. Its mechanism of action is inhibition of cyclo-oxygenase (COX) enzymes. There are two types of COX enzymes, COX-1 and COX-2. COX-1 is present in most tissue and is involved in tissue homeostasis and cell-cell signalling. COX-2 is an enzyme which is responsible for production of prostanoid mediators in inflammation and the anti-inflammatory action is mainly due to inhibition of COX-2. Most NSAIDs inhibit these enzymes however with each drug they differ in the inhibition of each of these enzymes. Ibuprofen is non-selective COX enzyme inhibitor and therefore may produce unwanted side effects. 
Prostaglandin is one of a number of hormone-like substances which help in a number of bodily functions such as assist the transmissions of pain signals to the brain, dilation and constriction of blood vessels and control of blood pressure, and are derived from a chemical called arachidonic acid.  Ibuprofen inhibits COX-2 thus inhibiting the production of prostaglandin H2 (PGH2) from arachidonic acid. PGH2 is normally converted, by several other enzymes, in to other prostaglandins which are responsible for inflammation and transmission of pain signals within the brain. Therefore, inhibition of COX-2 causes anti-inflammatory effects which prevent a pressure build up and pain signalling thus relieving symptoms of the headache in migraines.
Serotonergic modulators (Sumatriptan)
Studies have shown that both plasma and platelet levels of serotonin fluctuate during migraine attacks. This suggests that serotonin plays a key role in the pathogenesis of migraine. Furthermore, serotonin (5-HT) and its metabolites (5-hydroxyindoleacetic acid) have elevated concentration in a person’s urine during these attacks. The changes in plasma concentration of serotonin imply that it could also be due to fundamental changes in the brain serotonin concentration and activity. This strong link between serotonin and migraine attacks has lead to the development of drugs which interact with the serotonin receptor. 
Sumatriptan was the first drug developed specifically to interact with certain 5-HT (5-HTID and 5-HTIB) receptors to treat migraines. Sumatriptan has very similar structural properties that are very similar to serotonin and is a 5-HT receptor agonist.  It is a highly effective drug against migraines and cluster headaches. Current research is vital to the pharmacological actions of Sumatriptan while future research will provide information on key mechanism of the pathophysiology of migraines. 
Adapted from anatomy and physiology websiteThe key concepts that are already known about Sumatriptan are that it can’t cross the blood brain barrier easily indicating it has a peripheral point of action. Secondly, it causes vasoconstriction of the large cerebral arteries and dural vessels (venous channels which are found between dura mater in the brain) by acting via 5-HT-1-like/5-HT1d receptor which reduces “swelling” of brain tissue intern reducing pressure. Finally, it blocks the pathway of dural inflammation via the 5-HT1d autoreceptor-mediated inhibition of vasoactive neuropeptides within the trigeminovascular system. 
Sumatriptan selectively binds to the 5-HT1-like receptors e.g. 5-HT1b which make it an effective treatment for acute migraines. However, placebo-controlled clinical trials have shown that, when administered via subcutaneous, oral, intranasal or rectal routes there was a significant effectiveness then the placebo in relieving migraine headaches. Furthermore, it reduced or removed other symptoms such as nausea, photophobia and phonophobia making it an ideal treatment for migraines. It also improved workplace productivity as patients ranged from 12.1 to 89.8 hours per year.  Sumatriptan has been developed based on the vascular theory and its high efficacy indicates that dilation of the cranial blood vessels causes vascular headache. 
Ibuprofen is a suitable over the counter medication which can be used to treat mild to moderate migraine headaches. Its mechanism of action is inhibiting the synthesis of prostaglandins which are the precursor molecules for inflammatory response and pain signalling. Sumatriptan is very expensive however due to its excellent workplace productivity, society benefit overall and reduce the cost. Its activation of 5-HT receptors reduces symptoms such as nausea and vomiting as well as migraine headaches. Therefore, Sumatriptan is the ideal candidate drug for first or second line treatment for migraine sufferers.
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