Antitussive effects

Benzonatate [104-31 ] (46) is a unique compound which appears to have both central and peripheral antitussive effects. Stmcturally it is a derivative of ji)-aminoben2oic acid and contains a long poly(ethylene glycol) side chain. The peripheral effects ate the result of local anesthetic action on the pulmonary stretch receptors. Clinical activity was first reported in 1955 (65). 

Opioids ( opioid systems) are thought to exert their antitussive effects by acting as agonists at p- and K-opioid receptors in the CNS. Activation of these receptors activates various G-proteins and leads to the inhibition of... 

Both disodium cromoglycate and nedocromil sodium have antitussive effects in humans. In this instance, their activity occurs by increasing the depolarisation of sensory nerves, which increases the threshold for an action potential and therefore inhibits the activity of these neurons. 

Gough-suppression of the cough reflex (antitussive effective) by exerting a direct effect on the cough center in the medulla. Gbdeine has the most noticeable effect on the cough reflex. 

Antitussive effects (tested on cats) have been reported for MGXs from Rudbeckia [147] and mahony [58]. Comparative tests performed under the same conditions with some drugs used in clinical praxis revealed a significantly higher activity than expressed by the non-narcotic synthetic drugs. 

Medazonamide [Medazoamide, L-1777, Catos CAS 300-22-1 (100)] has been reported to exhibit a non-narcotic antitussive effect, which, however, is less than that of codeine [426]. Its toxic side-effects have been studied [427]. 

The cough-suppressant (antitussive) effect produced by inhibition of the cough reflex is independent of the effects on nociception or respiration (antitussives codeine, noscapine). 

The opioids block cough by a mechanism that is not yet understood. No stereoselectivity of the opioids for blockade of the cough reflex has been shown. Thus, the isomers of opioids, such as dextrorphan, are as efficacious as the L-isomers as antitussives. This lack of stereoselectivity prompted the development of the D-isomers of opioids as antitussives since they are devoid of the dependence liability of h-isomers. Drugs with predominantly antitussive effects are described later in this chapter. Certain of the opioids, such as propoxyphene and meperidine, are relatively devoid of antitussive effects. 

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the... 

Meperidine differs from morphine in that it has far less antitussive effect and little constipative effect. The drug is particularly useful in cancer patients and in pulmonary patients, in whom the cough reflex must remain intact. However, it does have more seizure-inducing activity than morphine. Although meperidine produces spasms of the biliary tract and colon, such spasms are of shorter duration than those produced by morphine. 

Certain opioids are used mainly for their antitussive effects. Such drugs generally are those with substituents on the phenolic hydroxyl group of the morphine structure. The larger the substituent, the greater the antitussive versus analgesic selectively of the drugs. 

Dextromethorphan hydrobromide is the D-isomer of levorphanol. It lacks CNS activity but acts at the cough center in the medulla to produce an antitussive effect. It is half as potent as codeine as an antitussive. Anecdotal reports of abuse exist, but studies of abuse potential are lacking. It has few side effects but does potentiate the activity of monoamine oxidase inhibitors, leading to hypotension and infrequently coma. Dextromethorphan is often combined in lozenges with the local anesthetic benzocaine, which blocks pain from throat irritation due to coughing. 

Noscapine is a naturally occurring product of the opium poppy. It is a benzylisoquinoline with no analgesic or other CNS effects. Its antitussive effects are weak, but it is used in combination with other agents in mixtures for cough relief. 

Central nervous system depression is the usual effect of morphine, and sedation and drowsiness are frequently observed with therapeutic doses. When given in the absence of pain morphine may sometimes produce dysphora—an unpleasant sensation of fear and anxiety. The most important stimulatory effects of morphine in man are emesis and miosis. Miosis, due to stimulation of the Edinger-Westphal nucleus of the third nerve, occurs with all opioids. The combination of pinpoint pupils, coma, and respiratory depression are classical signs of morphine overdosage. Stimulation of the solitary nuclei may also be responsible for depression of the cough reflex (antitussive effect). Pharmacokinetics and metabolism... 

The prototype antihistamine of this group is diphenhydramine. It has antimuscarinic and pronounced central sedative properties and also an antitussive effect. The mechanism of the latter is unclear, but diphenhydramine is a common ingredient of propriety preparations for the treatment of coughs and colds. It is an effective anti-emetic, especially useful for prevention and treatment of motion sickness. Because of its anticholinergic properties it is occasionally used in the treatment of mild forms of Parkinson s disease. It is also of use in the treatment of drug-induced extrapyramidal effects. Piperazine derivatives... 

The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). 

In addition to their use as pharmacological tools, selective 8 opioid antagonists may have clinical potential in the treatment of a variety of disorders where endogenous opioids play a modulatory role, e.g. disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, drug addiction and immune function (Spetea et al., 2001). It is also worth mentioning that 8 antagonists have been shown to possess an antitussive effects in rodents, thus indicating another possible clinical application for these compounds (Kamei et al., 1994). 

Kamei, J., Iwamaoto, Y., Suzuki, T., et al. Involvement of 8-,-opioid receptor antagonism in the antitussive effect of S-opioid receptor antagonists, Eur. J. Pharmacol. 1994, 257, 291-294. 

Dimethoxanate [477-93-0] (47) and pipazethate [2167-85-3] (48) are related phenothiazine derivatives that have shown antitussive activity. Unlike many phenothiazines, these do not produce central nervous system depression or analgesia at therapeutic doses. They are both somewhat less potent than codeine. It has been suggested that the unique side chain that is similar to, but shorter than, the one on benzonatate, may be at least pardy responsible for the antitussive effects. Both dimethoxanate and pipazethate are the result of molecular modifications of classical phenothiazines, such as promethazine [60-87-7], which possess antitussive activity in addition to central nervous system depressant activity. Dimethoxanate can be prepared by the reaction of phenothiazine- 10-carboxylic acid chloride with p-dimethylaminoethoxyethanol (66). 

The calcium ion antagonists nifedipine 21829-25A] (62), verapamil [52-55-9] (63), and flunarizine [52468-60-7] (64) exhibit antitussive effects in a dose-dependent manner in guinea pigs (91). Pretreatment with a subthreshold dose of nifedipine also markedly increased the antitussive effects of morphine, dihydrocodeine, and dextromethorphan. However, none of the calcium ion antagonists are used clinically as antitussive agents. They are used in the treatment of angina and hypertension (see Cardiovascularagents). 

Dihydrohydrastinine has an antitussic effect which resembles that of narcotine (10). 

Morphine has been, and remains, an important drug even though codeine is used to a larger extent than morphine and, while its analgesic action is only one-sixth of morphine, it is employed for its antitussive effect, as a cough repressant. 

Capon DA, Bochner F, Kerry N, et al. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther 1996 60 295-307. 

Aside from the demonstrated antinociceptive effect produced by agonist interactions at 8 receptors [174], NTI has been employed to demonstrate that 8 opioid receptors are involved in the antinociceptive effects of cholecys-tokinin octapeptide in mice [183] and in swim stress-induced antinociception in adult rats [184, 185]. NTI was found to produce a marked and long-lasting antitussive effect in mice and rats which was not antagonized by the irreversible n antagonist /i-FNA [186],... 

Dextromethorphan hydrobromide is an antitussive drug with no analgesic or addictive action. Its antitussive effect is similar to codeine. The recommended oral dose for adults is 10-30mg three to six times a day, not to exceed 120mg daily. It is absorbed rapidly and completely when taken orally with a lag time of 15-30 min [72]. 

Yanaura S, Fujikura H, Hosokawa T, Kitagawa H, Kamei J, Misawa M. Antitussive effect of RU-20201-central and peripheral actions. Jpn J Pharmacol 1984 34(3) 289-98. 

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