The traditional analeptics are a group of potent and relatively nonselective CNS stimulants. The convulsive dose lies near their analeptic dose. They can be illustrated by picrotoxinin and pentylenetetrazole. Both are obsolete as drugs but remain valuable research tools in determining how drugs act. Newer agents, modafinil and doxapram, are more selective and have use in narcolepsy and as respiratory stimulants.
Picrotoxinin, the active ingredient of picrotoxin, has the following structure:
According to Jarboe et al.,1 the hydroxylactonyl moiety is mandatory for activity, with the 2-propenyl group assisting. Picrotoxinin exerts its effects by interfering with the inhibitory effects of y-aminobutyric acid (GABA) at the level of the GABAa receptor's chloride channel. The drug is obsolete medically. Pharmacologically, it has been useful in determining mechanisms of action of sedative-hypnotics and anticonvulsants. Butyrolactones bind to the picrotoxinin site.
Pentylenetetrazole, 6,7,8,9-tetrahydro-5h-tetrazolo[1,5-a]azepine, 1,5-pentamethylenetetrazole (Metrazol), has been used in conjunction with the electroencephalograph to help locate epileptic foci. It is used as a laboratory tool in determining potencies of potential anticonvulsant drugs in experimental animals. The drug acts as a convulsant by interfering with chloride conductance.2 It binds to an allosteric site on the GABAa receptor and acts as a negative modulator. Overall, it appears to share similar effects on chloride conductance with several other convulsive drugs, including picrotoxinin.
Modafinil (Provigil) has overall wakefulness-promoting properties similar to those of central sympathomimetics. It is considered an atypical ^-norepinephrine (NE) receptor stimulant and is used to treat daytime sleepiness in narcolepsy patients. Adverse reactions at therapeutic doses are reportedly not severe and may include nervousness, anxiety, and insomnia. Modafinil is used by oral administration.
Doxapram, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone hydrochloride hydrate (Dopram), has an obscure molecular mechanism of action. Overall, it stimulates respiration by action on peripheral carotid chemoreceptors. It has use as a respiratory stimulant postanesthetically, after CNS depressant drug overdose, in chronic obstructive pulmonary diseases, and in the apneas. Dopram is administered exclusively by intravenous injection. Because of the benzyl alcohol content of the injectable formulation, Dopram must never be given to neonates.
TABLE 15.1 Chemical Structures of the Xanthine Alkaloids
The naturally occurring methylxanthines are caffeine, theophylline, and theobromine. See Table 15.1 for their structures and occurrence and Table 15.2 for their relative potencies.
Caffeine is a widely used CNS stimulant. Theophylline has some medical use as a CNS stimulant, but its CNS-stimulant properties are encountered more often as sometimes severe, and potentially life-threatening, side effects of its use in bronchial asthma therapy. Theobromine has very little CNS activity (probably because of poor physico-chemical properties for distribution to the CNS).
Caffeine is often used as it occurs in brewed coffee, brewed tea, and cola beverages. In most subjects, a dosage of 85 to 250 mg of caffeine acts as a cortical stimulant and facilitates clear thinking and wakefulness, promotes an ability to concentrate on the task at hand, and lessens fatigue. As the dose is increased, side effects indicating excessive stimulation (e.g., restlessness, anxiety, nervousness, tremulous-ness) become more marked. (They may be present in varying degrees at lower-dose levels.) With further increases in dosage, convulsions can occur. A review of the actions of caffeine in the brain with special reference to factors that contribute to its widespread use appears to be definitive.3
The CNS effects of theophylline at low-dose levels have been little studied. At high doses, the tendency to produce convulsions is greater for theophylline than for caffeine. In addition to being cortical stimulants, theophylline and caffeine are medullary stimulants, and both are used as such. Caffeine may be used in treating poisoning from CNS-depressant drugs, although it is not a preferred drug.
The important use of theophylline and its preparations in bronchial asthma is discussed elsewhere. Caffeine also is reported to have valuable bronchodilating properties in asthma. Finally, because of central vasoconstrictive effects, caffeine has value in treating migraine and tension headaches and may have actual analgesic properties in the latter use.
The CNS-stimulating effects of the methylxanthines were once attributed to their phosphodiesterase-inhibiting ability. This action is probably irrelevant at therapeutic doses. Evidence indicates that the overall CNS-stimulant ac
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