The most common toxic effects of the ergot derivatives are gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved. Since migraine attacks are often associated with these symptoms before therapy is begun, these adverse effects are rarely contraindications to the use of ergot.
A more dangerous toxic effect—usually associated with overdosage—of agents like ergotamine and ergonovine is prolonged vasospasm. This sign of vascular smooth muscle stimulation may result in gangrene and may require amputation. Bowel infarction has also been reported and may require resection. Vasospasm caused by ergot is refractory to most vasodilators, but infusion of large doses of nitroprusside or nitroglycerin has been successful in some cases.
Chronic therapy with methysergide was associated with connective tissue proliferation in the retroperitoneal space, the pleural cavity, and the endocardial tissue of the heart. These changes occurred insidiously over months and presented as hydronephrosis (from obstruction of the ureters) or a cardiac murmur (from distortion of the valves of the heart). In some cases, valve damage required surgical replacement. As a result, this drug was withdrawn from the US market. Similar fibrotic change has resulted from the chronic use of non-ergot 5-HT agonists promoted in the past for weight loss (fenfluramine, dexfenfluramine).
Other toxic effects of the ergot alkaloids include drowsiness and, in the case of methysergide, occasional instances of central stimulation and hallucinations. In fact, methysergide was sometimes used as a substitute for LSD by members of the so-called drug culture.
Contraindications to the use of ergot derivatives consist of the obstructive vascular diseases, especially symptomatic coronary artery disease, and collagen diseases.
There is no evidence that ordinary use of ergotamine for migraine is hazardous in pregnancy. However, most clinicians counsel restraint in the use of the ergot derivatives by pregnant patients. Use to deliberately cause abortion is contraindicated because the high doses required often cause dangerous vasoconstriction.
H1 ANTIHISTAMINES First generation:
Second generation:
Competitive antagonism/inverse agonism at H1 receptors Reduces or prevents histamine effects on smooth muscle,
Reduces or prevents histamine effects on smooth muscle, immune cells IgE immediate allergies; especially hay fever, urticaria • often used as a sedative, antiemetic, and anti-motion sickness drug
IgE immediate allergies; especially hay fever, urticaria
Oral and parenteral • duration 4–6 h • Toxicity:
Sedation when used in hay fever, muscarinic blockade symptoms, orthostatic hypotension • Interactions: Additive sedation with other sedatives, including alcohol • some inhibition of
CYP2D6, may prolong action of some β blockers
Oral • duration 12–24 h • Toxicity: Sedation and arrhythmias in overdose • Interactions: Minimal
Other first-generation H1 blockers: Chlorpheniramine is a less sedating H1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H1 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 H1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine
H2 ANTIHISTAMINES •Cimetidine,others(seeChapter62)
Oral, nasal, parenteral • duration 2 h • Toxicity: