effective nonbenzodiazepine anxiolytic (see Chapter 22). Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the central nervous system, and dexfenfluramine, a selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of cardiac valvulopathy. Lorcaserin, a 5-HT2C agonist, is approved by the FDA for use as a weight-loss medication (see Box: Treatment of Obesity).
The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost exclusively for migraine headache. Migraine in its “classic” form is characterized by an aura of variable duration that may involve nausea, vomiting, visual scotomas or even hemianopsia, and speech abnormalities; the aura is followed by a severe throbbing unilateral headache that lasts for a few hours to 1–2 days. “Common” migraine lacks the aura phase, but the headache is similar. After more than a century of intense study, the pathophysiology of migraine is still poorly understood. Although the symptom pattern and duration of prodrome and headache vary markedly among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases.
Migraine involves the trigeminal nerve distribution to intra-cranial (and possibly extracranial) arteries. These nerves release
TABLE 16–5 Antiobesity drugs and their effects.
Liraglutide GLP-1 agonist Decreases appetite 3 mg/d SC Nausea, vomiting, pancreatitis
Lorcaserin 5-HT2c agonist Decreases appetite 10 mg PO BID Headache, nausea, dry mouth, dizziness, constipation
Naltrexone/ Opioid antagonist Unknown 32 mg/ Headache, nausea, dizziness, constipation bupropion + antidepressant
Phentermine Sympathomimetic Norepinephrine release in CNS 30–37.5 mg/d PO Increased BP, HR; arrhythmias, insomnia, anxiety
Phentermine/ Sympathomimetic Norepinephrine release plus 3.75–15 mg/ Insomnia, dizziness, nausea, paresthesia, topiramate + antiseizure agent unknown mechanism 23–92 mg PO dysgeusia peptide neurotransmitters, especially calcitonin gene-related peptide (CGRP; see Chapter 17), an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and is found in biopsy specimens from migraine patients. This effect probably reflects the action of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of effective therapy is sometimes accompanied by diminution of these pulsations.
The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups and actions. In addition to the triptans, these include ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents, β-adrenoceptor blockers, calcium channel blockers, tricyclic antidepressants and SSRIs, and several antiseizure agents. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack.