Headache alkaloids

Xanthines such as caffeine (1)> theophylline (aminophylline) (2), and theobromine (3) are a class of alkaloids that occur in numerous plants. The CNS stimulant activity of aqueous infusions containing these compounds has been recognized since antiquity. This has, of course, led to widespread consumption of such well-known beverages as coffee (Coffea arabica), tea (Thea sinesis), mate, and cola beverages (in part Cola acuminata). The annual consumption of caffeine in the United States alone has been estimated to be in excess of a billion kilos. The pure compounds have found some use in the clinic as CNS stimulants. In addition, caffeine is widely used in conjunction with aspirin in various headache remedies. 

Yohimbine is an indole alkaloid produced in the bark of yohimbe trees. It selectively inhibits a2-adrenergic receptors in the brain that are associated with libido and penile erection. Since there is only limited data supporting its efficacy, yohimbine is not a recommended treatment for any form of ED.22 Adverse effects of the drug include nausea, irritability, headaches, anxiety, tachycardia, and hypertension. 

Vincamine (91) is the major alkaloid of V. minor, a plant used against headache and vertigo. It exerts a sedative CNS action and produces a fall in blood pressure. The principal activity is a moderate cerebral vasodilation. Clinical studies have demonstrated that i.v. administration of 91 to humans reduces the arterial blood pressure and increases cerebral blood flow and oxygen consumption. The improved cerebral hemodynamic conditions significantly and positively affect the state of patients with advanced arteriosclerosis with beneficial effects on memory, concentration, and behavior. It has thereafter been introduced under several trade names as a pharmaceutical in many European countries (232). Vobasine (32) has been widely studied it exhibits a weak CNS depressive, analgesic, and antipyretic action (21). 

Normal doses range from 15 to 30 mg of actual alkaloid (ephedrine), and the lethal dose is in the 1-2 g range. Side effects from ephedra use include headache, irritability, restlessness, anxiety, insomnia, tachycardia, urinary disorders, and vomiting. 

Ergotamine is an ergot alkaloid derivative indicated in the treatment of migraine. Propranolol (a fat-soluble and therefore centrally active beta-blocker) and amitriptyline (tricyclic antidepressant) are used for the prophylaxis of migraine headache. 

A cnp of coffee can contain 50-150 mg of caffeine, and cola drinks can have 35-55 mg. Theophiline,l,3-dimethylxanthine, a principal, characteristic alkaloid of tea, and theobromine, 3,7-dimethylxanthine (23.3.19), a principal alkaloid of cocoa, are among a number of methylxanthines. In small doses, caffeine is a relatively weak psychostimulant and is used for increasing awareness as well as for relieving headaches associated with blood flow disorders of the brain. Caffeine has a stimulatory effect on the respiratory and vasomotor centers, and it stimnlates centers of the vagus nerve. It has a direct stimulatory effect on the myocardium, and in large doses can cause tachycardia and arrhythmia. 

Adverse reactions associated with their administration include hypertension, headache, and possible seizures. Nausea, vomiting, chest pains, difficulties in breathing, and leg cramps also have been reported. These alkaloids should not be used in cases of threatened spontaneous abortion or in patients with known allergies to the drugs. Contraindications generally include angina pectoris, myocardial infarction, pregnancy, and a history of a cerebrovascular accident, transient ischemic attack, or hypertension. 

In spite of their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction, and occasionally in the postpartum patient. 

A group of drugs known collectively as ergot derivatives display some alpha-blocking ability as well as other unique properties. Ergot alkaloids and ergoloid mesylates and are used clinically for diverse problems, including the treatment of vascular headache and improvement of mental function in pre-senile dementia. 

Guarana contains tannins and has been used to treat diarrhea. It also contains a high concentration of caffeine, which, in conjunction with the alkaloids theobromine and theophylline, gives guarana diuretic and stimulant properties. Guarana is used to treat fatigue, mild depression, headache, and migraine. 

Quinine is a naturally occurring alkaloid obtained from Cinchona bark, with a mechanism of action similar to that of chloroquine. Quinine is very useful in treating chloroquine-resistant Plasmodium falciparum. In toxic doses, it may cause cinchonism characterized by tinnitus, headache, nausea, and visual disturbances. 

Rhododendron (Rhododendron ponticum L.) honey has an unpleasant flavor and causes poisoning (general weakness, headache, vomiting, loss of consciousness). There is evidence that the poisoning is due to the presence of alkaloid of andromedotoxin in rhododendron honey. 

Sumatriptan and several other "triptans" are selective agonists for 5-HTiD and 5-HTiB receptors. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors. These drugs have proved to be very effective in the treatment of acute migraine headache. The mechanism of action is discussed in more detail below under Clinical Pharmacology of Ergot Alkaloids. 

Feverfew is most often used as a prophylactic remedy for migraine headache. This action has been related to the serotonin hypothesis for migraine causation (see also Chapter 16 Histamine, Serotonin, the Ergot Alkaloids). In vitro, feverfew and parthenolide inhibit platelet aggregation and serotonin release from platelets. 

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