10.03.1 5-HT and Migraine
Excessive cranial blood vessel dilation and inflammation underlies the pain of migraine. Ergotamine has gone from being a poison to therapy for migraine. Ergot alkaloids are the product of a fungus that grows on corn. In biblical times, when they ate contaminated corn, it caused plague. The symptoms of the plaque were due to the ergot alkaloids causing intense vasoconstriction of the extremities leading to gangrene, and stimulation of the uterus causing abortion. Ergotamine is one of the ergot alkaloids. The actions of ergotamine include being a partial agonist at 5-HT1B/1D receptors. Stimulation of the 5-HT1B/1D receptors on cranial blood vessels causes vasoconstriction. The vasoconstriction with ergotamine overcomes the excessive vasodilation of migraine.
Sumitriptan is a 5-HT1B/1D agonists also used in the treatment of migraine attacks, and has two mechanisms, one of which is similar to ergotamine. The central nervous system is involved in the excessive vasodilation of migraine. Stimulation of 5-HT1B/1D receptors in the central nervous system may decrease the release of neurotransmitter onto the cranial blood vessels, and the excessive vasodilation (Figure 10.9). Secondly, as with ergotamine, the triptans cause a direct stimulation of the 5-HT1B/1D receptors on the cranial blood vessels to cause vasoconstriction to overcome the excessive vasodilation.
Figure 10.9 Mechanisms of triptans (Copyright QUT, Sheila Doggrell)
In an attack of migraine, need a drug that acts quickly to relieve the attack. When used orally, the bioavailability of sumatriptan is low (15%). Also, after oral administration of sumitriptan, peak plasma concentrations are not reached for 1-2 hours, and onset of action may take up to 30 minutes, which is too slow for somebody who is having a migraine attack. Thus, we need a quicker effective route of administration for sumatriptan. After subcutaneous or nasal spray administration of sumatriptan, the bioavailability is increased and the onset of action may occur in 15 minutes.
Drugs used to prevent migraine attacks include the serotonin receptor antagonist (predominantly 5-HT2 receptor antagonist) e.g. pizotifen. The action of pizotifen in preventing migraine is unknown. However, it has been shown that two-thirds of patients, who regular suffer migraine attacks, have a 50% reduction in frequency of headache with pizotifen. Unfortunately, pizotifen cause drowsiness, which makes it unpopular for continued use in patients.