Page 305 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 291

TABLE 16–6 Pharmacokinetics of triptans.

Maximum Dose
Drug Routes Time to Onset (h) Single Dose (mg) per Day (mg) Half-Life (h)
Almotriptan Oral 2.6 6.25–12.5 25 3.3
Eletriptan Oral 2 20–40 80 4
Frovatriptan Oral 3 2.5 7.5 27
Naratriptan Oral 2 1–2.5 5 5.5
Rizatriptan Oral 1–2.5 5–10 30 2
Sumatriptan Oral, nasal, subcutaneous, 1.5 (0.2 for 25–100 (PO), 20 nasal, 200 2
rectal subcutaneous) 6 subcutaneous, 25 rectal
Zolmitriptan Oral, nasal 1.5–3 2.5–5 10 2.8

efficacies in individual patients. The pharmacokinetics and potencies Cisapride, a 5-HT agonist, was used in the treatment of
4
of the triptans differ significantly and are set forth in Table 16–6. gastroesophageal reflux and motility disorders. Because of toxicity,
Most adverse effects are mild and include altered sensations it is now available only for compassionate use in the USA. Tegas-
(tingling, warmth, etc), dizziness, muscle weakness, neck pain, erod, a 5-HT 4 partial agonist, is used for irritable bowel syndrome
and for parenteral sumatriptan, injection site reactions. Chest with constipation (see Chapter 62).
discomfort occurs in 1–5% of patients, and chest pain has been Compounds such as fluoxetine and other SSRIs, which
reported, probably because of the ability of these drugs to cause modulate serotonergic transmission by blocking reuptake of the
coronary vasospasm. They are therefore contraindicated in patients transmitter, are among the most widely prescribed drugs for the
with coronary artery disease and in patients with angina. Another management of depression and similar disorders. These drugs are
disadvantage is the fact that their duration of effect (especially discussed in Chapter 30.
that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan,
Table 16–6) is often shorter than the duration of the headache.
As a result, several doses may be required during a prolonged SEROTONIN ANTAGONISTS
migraine attack, but their adverse effects limit the maximum safe
daily dosage. Naratriptan and eletriptan are contraindicated in The actions of serotonin, like those of histamine, can be antago-
patients with severe hepatic or renal impairment or peripheral vas- nized in several ways. Such antagonism is clearly desirable in those
cular syndromes; frovatriptan in patients with peripheral vascular rare patients who have carcinoid tumor and may also be valuable
disease; and zolmitriptan in patients with Wolff-Parkinson-White in certain other conditions.
syndrome. The brand name triptans are extremely expensive; thus Serotonin synthesis can be inhibited by p-chlorophenylalanine
generic sumatriptan should be used whenever possible. and p-chloroamphetamine. However, these agents are too toxic
Propranolol, amitriptyline, and some calcium channel block- for general use. Storage of serotonin can be inhibited by the use of
ers have been found to be effective for the prophylaxis of migraine reserpine, but the sympatholytic effects of this drug (see Chapter 11)
in some patients. They are of no value in the treatment of acute and the high levels of circulating serotonin that result from release
migraine. The anticonvulsants valproic acid and topiramate (see prevent its use in carcinoid. Therefore, receptor blockade is the
Chapter 24) have also been found to have some prophylactic effi- major therapeutic approach to conditions of serotonin excess.
cacy in migraine. Flunarizine, a calcium channel blocker used in
Europe, has been reported in clinical trials to effectively reduce the SEROTONIN-RECEPTOR
severity of the acute attack and to prevent recurrences. Verapamil
appears to have modest efficacy as prophylaxis against migraine. ANTAGONISTS

Other Serotonin Agonists in Clinical Use A wide variety of drugs with actions at other receptors (eg,
α adrenoceptors, H -histamine receptors) also have serotonin
1
Flibanserin, a 5-HT agonist and 5-HT antagonist, is approved receptor-blocking effects. Phenoxybenzamine (see Chapter 10)
1a
2A
for treatment of hypoactive sexual desire disorder in women. Due has a long-lasting blocking action at 5-HT receptors. In addition,
2
to inadequate evidence of efficacy, it was refused approval in the ergot alkaloids discussed in the last portion of this chapter are
2010 and 2013. The clinical trials that led to its approval in 2015 partial agonists at serotonin receptors.
showed a very small but significant increase in satisfactory sexual Cyproheptadine resembles the phenothiazine antihistaminic
desire and activities over several weeks of daily oral administra- agents in chemical structure and has potent H -receptor-blocking
1
tion. Consumption of alcohol is contraindicated due to increased as well as 5-HT -blocking actions. The actions of cyproheptadine
2
risk of severe hypotension. Other adverse effects include syncope, are predictable from its H histamine and 5-HT receptor affini-
1
nausea, fatigue, dizziness, and somnolence. ties. It prevents the smooth muscle effects of both amines but has