Antitussives Codeine

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

Antitussives Codeine, 10-20 mg every 4-6 hours, not to exceed 120 mg in 24 hours (with guaifenesin) Guiatuss AC, Mytussin AC, various generic Acts centrally to increase the cough threshold. In doses required for cough suppression, the addiction liability associated with codeine is low. Many codeine-containing antitussive combinations are schedule V narcotics, and OTC sale is restricted in some states. 

Smith J, Owen E, Earis J et al, (2006) Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease, J AUergy Chn Immunol 117 831-835 Takahama K, Shirasaki T (2007) Central and peripheral mechanisms of narcotic antitussives codeine-sensitive and -resistant coughs. Cough 3 1-8 Undem BJ, KoUarik M (2005) The role of vagal afferent nerves in chronic obstructive pulmonary disease, Proc Am Thorac Soc 2(4) 355-360... 

Takahama K, ShirasaM T (2007) Central and peripheral mechanisms of narcotic antitussives codeine-sensitive and -resistant coughs. Cough 3 8... 

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Codeine, mol wt 299.3, is a significantly less potent analgesic than morphine, requiring 60 mg (0.20 mmol) to equal the effectiveness of 10 mg (0.04 mmol) of morphine. However, codeine is orally effective, and it is less addictive and associated with less nausea than morphine. Codeine is used as an antitussive agent, although newer, nonaddictive agents are preferred (see Expectorants, antitussives, and related agents). 

Narcotic Antitussives. Since its isolation in 1832, codeine [76-57-3] (27) has been one of the most widely used and effective compounds for the treatment of cough. Though less potent than morphine [57-27-2] (28), it has become the reference against which most antitussives are measured. 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

Hydromorphone [466-99-9] (31) and hydrocodone [125-29-1] (32) are isomers of morphine and codeine, respectively. Hydromorphone can be prepared by catalytic rearrangement of morphine (49) or by oxidation of the aliphatic hydroxyl group of dihydromorphine (50). Hydrocodone can be similarly prepared. As an antitussive, hydromorphone is several times more active than morphine and hydrocodone is slightly more active than codeine. Hydromorphone has a much higher addiction potential than hydrocodone. 

Modifications of the morphine skeleton have produced butorphanol [42408-82-2] (35) and drotebanol [3176-03-2] (36), which in animal models have demonstrated antitussive activity much greater than that of codeine (51,52). Butorphanol is also a potent analgetic of the narcotic antagonist type (51). Both compounds possess a unique 14-hydroxyl group. 

Nonnarcotic Antitussives. The most centrally active, noimarcotic antitussive is dextromethorphan [125-71-3] (39). It is similar to codeine in terms of potency and mechanism of action, ie, it is a direct depressant of the cough center. It is unique in that even though it is stmcturaHy related to codeine, it is not addictive. 

Levopropoxyphene [2338-37-6] (42), the optical antipode of the dextrorotatory analgetic propoxyphene, is an antitussive without analgetic activity. The 2-naphthalenesulfonate salt has a less unpleasant taste than the hydrochloride salt, and is widely used. Clinical effectiveness has been demonstrated against pathological and artificially induced cough, but the potency is somewhat less than codeine. The compound is reported not to cause addiction. Levopropoxyphene can be prepared (62) by first resolving [ -dimethylamino-CX-methylpropiophenone with dibenzoyl-(+)-tartaric acid. The resolved... 

The citrate salt of isoaminile [77-51-0] (50) is a nitrile used as an antitussive in numerous European countries. In clinical trials it was shown to be as effective as codeine or chlophedianol, with few mild side effects. Isoaminile citrate is longer acting than chlophedianol and does not cause the respiratory depression of codeine (68). 

Diphenhydramine [58-73-1] (55) was originally developed as an antihistamine and was first used clinically for this purpose in 1946 (see HiSTAMlNE AND HISTAMINE antagonists). In addition to this primary effect, however, central antitussive activity has also been demonstrated in animals (75,76) and in humans (77). Its antitussive activity is about half that of codeine. Drowsiness is the most frequent side effect. Diphenhydramine can be prepared as follows (78) ... 

Another antitussive with weak antihistaminic activity is the Japanese compound picoperine [21755-66-8] (56). This compound is a stmctural isomer of the weU-known antihistamine tripelennamine and is more potent than codeine. The chemistry (79) and pharmacology (80) of picoperine have been reported. 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

Dia2epam [439-14-5] (60) and clona2epam [1622-61 -3] (61) suppress cough induced by electrical stimulation of the lower brainstem of cats (90). Clona2epam and dia2epam adrninistered intravenously are about thirty-five times and six times more potent than codeine, respectively. Nevertheless, the compounds have not been widely used as antitussives in humans. Dia2epam is used in the treatment of anxiety, and clona2epam as an anticonvulsant. 

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9)an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. 

Examples small amounts of narcotics (codeine) used as antitussives or antidiarrheals... 

Use of codeine may result in respiratory depression, euphoria, light-headedness, sedation, nausea, vomiting, and hypersensitivity reactions. The more common adverse reactions associated with the antitussives are listed in the Summary Drug Table Antitussive, Mucolytic, and Expectorant Drugs. When used as directed, nonprescription cough medicines containing two or more ingredients have few adverse reactions. However, those that contain an antihistamine may cause drowsiness. 

Other central nervous system (CNS) depressants and alcohol may cause additive depressant effects when administered with antitussives containing codeine. 

Morphine and related opiates are known to suppress the cough reflex these compounds have thus been used extensively in antitussive preparations. Since this activity is not directly related to the analgesic potency, the ideal agent is one that has much reduced analgesic activity and thus, presumably, lower addiction potential. The weak analgesic codeine (4) is... 

Alkaloids Glycoside Morphine Codeine Digitalis glycosides Sennosides Analgesic, Antitussive Cardiovascular diseases, Laxatives... 

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]. 

Codeine, dextromethorphan and pholcodine are opioid cough suppressants indicated for dry cough. Sedating antihistamines, such as diphenhydramine, tend to have an antitussive action as well. Vitamin C is not used in the management of cough but may be used as a prophylaxis against colds. 

Dextromethorphan is an opioid antitussive similar in action to codeine and pholcodine. Codeine and pholcodine are considered to be more potent than dextromethorphan. Dextromethorphan tends to cause less constipation and dependence than codeine. Cough suppressants are not usually recommended in children under 2 years. 

Asthma is managed by the use of an inhaled bronchodilator prescribed on an as-required (p.r.n.) basis to relieve acute attacks and administration of an inhaled corticosteroid as maintenance therapy. Budesonide is available as inhaled corticosteroid. Amoxicillin or another antibacterial agent may be required for short-term periods. Codeine, being an antitussive, should be used with caution in asthmatics and certainly not routinely. 

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