Page 304 - Basic _ Clinical Pharmacology ( PDFDrive )

290 SECTION IV Drugs with Important Actions on Smooth Muscle

TABLE 16–5 Antiobesity drugs and their effects.

Drug or Drug Possible Mechanism
Combination Drug Group of Action Dosage Toxicity
Orlistat GI lipase inhibitor Reduces lipid absorption 60–120 mg TID PO Decreased absorption of fat-soluble
vitamins, flatulence, fecal incontinence
Liraglutide GLP-1 agonist Decreases appetite 3 mg/d SC Nausea, vomiting, pancreatitis
Lorcaserin 5-HT 2c 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 360 mg PO TID
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
BID, twice daily; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart rate; PO, by mouth; SC, subcutaneously; TID, three times daily.

peptide neurotransmitters, especially calcitonin gene-related structure to that of the 5-HT nucleus can be seen in the structure
peptide (CGRP; see Chapter 17), an extremely powerful vaso- below. These receptor types are found in cerebral and meningeal
dilator. Substance P and neurokinin A may also be involved. vessels and mediate vasoconstriction. They are also found on neu-
Extravasation of plasma and plasma proteins into the perivascular rons and probably function as presynaptic inhibitory receptors.
space appears to be a common feature of animal migraine models
and is found in biopsy specimens from migraine patients. This CH 3
effect probably reflects the action of the neuropeptides on the CH 2 CH 2 N CH
vessels. The mechanical stretching caused by this perivascular CH 3 NH SO 2 CH 2 3
edema may be the immediate cause of activation of pain nerve N
endings in the dura. The onset of headache is sometimes associated
with a marked increase in amplitude of temporal artery pulsations, Sumatriptan
and relief of pain by administration of effective therapy is some-
times accompanied by diminution of these pulsations. In population studies, all of the triptan 5-HT agonists
1
The mechanisms of action of drugs used in migraine are poorly are as effective or more effective in migraine than other acute
understood, in part because they include such a wide variety of drug treatments, eg, parenteral, oral, and rectal ergot alkaloids.
drug groups and actions. In addition to the triptans, these include However, individual drugs in this class may have different
ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents,
β-adrenoceptor blockers, calcium channel blockers, tricyclic
antidepressants and SSRIs, and several antiseizure agents. Further-
more, some of these drug groups are effective only for prophylaxis 100
and not for the acute attack. Persistent Persistent Photophobia
Two primary hypotheses have been proposed to explain the 80 pain nausea
actions of these drugs. First, the triptans, the ergot alkaloids, and
antidepressants may activate 5-HT 1D/1B receptors on presynaptic 60
trigeminal nerve endings to inhibit the release of vasodilating Percent of patients
peptides, and antiseizure agents may suppress excessive firing of
these nerve endings. Second, the vasoconstrictor actions of direct 40
5-HT agonists (the triptans and ergot) may prevent vasodilation
and stretching of the pain endings. It is possible that both mecha- 20
nisms contribute in the case of some drugs.
Sumatriptan and its congeners are currently first-line therapy
for acute severe migraine attacks in most patients (Figure 16–3). 0 P S P S P S
However, they should not be used in patients at risk for coronary Treatment (P = placebo, S = sumatriptan)
artery disease. Anti-inflammatory analgesics such as aspirin and
ibuprofen are often helpful in controlling the pain of migraine. FIGURE 16–3 Effects of sumatriptan (734 patients) or placebo
Rarely, parenteral opioids may be needed in refractory cases. (370 patients) on symptoms of acute migraine headache 60 minutes
For patients with very severe nausea and vomiting, parenteral after injection of 6 mg subcutaneously. All differences between
metoclopramide may be helpful. placebo and sumatriptan were statistically significant. (Data from
Sumatriptan and the other triptans are selective agonists Cady RK et al: Treatment of acute migraine with subcutaneous sumatriptan. JAMA
and 5-HT receptors; the similarity of the triptan
for 5-HT 1D 1B 1991;265:2831.)