Page 310 - Basic _ Clinical Pharmacology ( PDFDrive )

296 SECTION IV Drugs with Important Actions on Smooth Muscle

cavity, and the endocardial tissue of the heart. These changes was sometimes used as a substitute for LSD by members of the
occurred insidiously over months and presented as hydronephro- so-called drug culture.
sis (from obstruction of the ureters) or a cardiac murmur (from Contraindications to the use of ergot derivatives consist of the
distortion of the valves of the heart). In some cases, valve damage obstructive vascular diseases, especially symptomatic coronary
required surgical replacement. As a result, this drug was with- artery disease, and collagen diseases.
drawn from the US market. Similar fibrotic change has resulted There is no evidence that ordinary use of ergotamine for
from the chronic use of non-ergot 5-HT agonists promoted in the migraine is hazardous in pregnancy. However, most clinicians
past for weight loss (fenfluramine, dexfenfluramine). counsel restraint in the use of the ergot derivatives by preg-
Other toxic effects of the ergot alkaloids include drowsi- nant patients. Use to deliberately cause abortion is contrain-
ness and, in the case of methysergide, occasional instances of dicated because the high doses required often cause dangerous
central stimulation and hallucinations. In fact, methysergide vasoconstriction.

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot
Alkaloids

Mechanism Clinical Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Applications Interactions

H 1 ANTIHISTAMINES
First generation:
• Diphenhydramine Competitive Reduces or prevents histamine IgE immediate Oral and parenteral • duration 4–6 h • Toxicity:
antagonism/inverse effects on smooth muscle, allergies; especially Sedation when used in hay fever, muscarinic
agonism at H 1 immune cells • also blocks hay fever, urticaria blockade symptoms, orthostatic hypotension
receptors muscarinic and α adrenoceptors • often used as a • Interactions: Additive sedation with other
• highly sedative sedative, antiemetic, sedatives, including alcohol • some inhibition of
and anti-motion CYP2D6, may prolong action of some β blockers
sickness drug
Second generation:
• Cetirizine Competitive Reduces or prevents histamine IgE immediate Oral • duration 12–24 h • Toxicity: Sedation and
antagonism/inverse effects on smooth muscle, allergies; especially arrhythmias in overdose • Interactions: Minimal
agonism at H 1 immune cells hay fever, urticaria
receptors
• Other first-generation H 1 blockers: Chlorpheniramine is a less sedating H 1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H 1 blocker, is available
over-the-counter in many sleep-aid formulations and in Diclegis (in combination with pyridoxine) for use in nausea and vomiting of pregnancy
• Other second-generation H 1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine

H 2 ANTIHISTAMINES
• Cimetidine, others (see Chapter 62)
SEROTONIN AGONISTS
5-HT 1B/1D :
• Sumatriptan Partial agonist at Effects not fully understood Migraine and cluster Oral, nasal, parenteral • duration 2 h • Toxicity:
5-HT 1B/1D receptors • may reduce release of headache Paresthesias, dizziness, coronary
calcitonin gene-related peptide vasoconstriction • Interactions: Additive with
and perivascular edema in other vasoconstrictors
cerebral circulation
• Other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action);
much more expensive than generic sumatriptan

5-HT 2C :
• Lorcaserin Agonist at 5-HT 2C Appears to reduce appetite Obesity Oral • duration 11 h • Toxicity: Dizziness,
receptors headache, constipation

5-HT 4 :
• Tegaserod (see Chapter 62)

(continued)