Depressants Codeine

Morphine is a strong agonist that crosses easily into the CNS. It is highly potent with regard to CNS effects, such as euphoria and medullary respiratory depression. Codeine is also a strong to moderate agonist, but does not cross the blood-brain barrier well. Thus, higher doses are needed to achieve CNS effects. Loperamide has little ability to cross into the CNS and is unlikely to produce CNS effects at any dose. It is thus sold over-the-counter. 

CODEINE In contrast to morphine, codeine is -60% as effective orally as parenteraUy as an analgesic and as a respiratory depressant. Codeine analogs such as levorphanol, oxycodone, and methadone have a high ratio of oral-to-parenteral potency. The greater oral efficacy of these drugs reflects lower first-pass metabolism. Once absorbed, codeine is metaboUzed by the liver, and its metabolites are excreted chiefly as inactive forms in the urine. A relatively small fraction (-10%) of administered codeine is O-demethylated to morphine, and free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, its antitussive actions may involve distinct receptors that bind codeine itself. The tj of codeine in plasma is 2-4 hours. 

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. 

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). 

A characteristic feature of the action of the opium alkaloids is their simultaneous depressing and exciting action on the central nervous system. In this respect there is no clear line of demarcation between the morphine group—morphine, codeine and thebaine—and the papaverine-narcotine group, and as the series is ascended in the order, morphine, papaverine, codeine, narcotine, thebaine, narcotic action diminishes and power of rellex stimulation increases until in thebaine a strychnine-like effect is exhibited. 

Codeine (morphine methyl ether) resembles morphine in its general effect, but is less toxic and its depressant action less marked and less prolonged, whilst its stimulating action involves not only the spinal cord, but also the lower parts of the brain. In small doses in man it induces sleep, which is not so deep as that caused by morphine, and in large doses it causes restlessness and increased reflex excitability rather than sleep. The respiration is slowed less than by morphine (cf. table, p. 261). Cases of addiction for codeine can occur but according to Wolff they are rare. The best known ethers of morphine are ethylmorphine and benzyl-morphine [cf., table, p. 261), both used to replace morphine or codeine for special purposes. 

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. 

Tramadol is a pain reliever (analgesic). Its action is similar to opioid narcotics such as codeine and morphine, but it does not depress breathing the way the others can, and less often leads to abuse and addiction. 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

The answer is c. (Hardman, pp 528-537.) Morphine is a pure agonist opioid drug with agonist activity toward all the opioid subtype receptor sites. In high doses, deaths associated with morphine are related to the depression of the respiratory center in the medulla. Morphine has a high addiction potential related to the activity of heroin or dihydromorphine. Codeine has a significantly lower addiction potential. 

Pharmacological clinical activity bias. An AE that is already present due to the disease may be increased if it is also an ADR of the drug or vice versa. For example, the diarrhea of gastroenteritis may be alleviated by codein-containing preparations given to relieve pain while the inertia of a severely depressed patient may be sufficiently resolved by an antidepressant to enable the patient to commit suicide. 

Some 2-benzylindenes based upon the benzimidazole analgesics have been reported, several of which, for example, (LVIIIa, R = H) have potencies in the codeine-pethidine range [178]. Their relationship to the benzimidazoles as analgesics is doubtful, however, because insertion of a para-ethoxy group (R= OEt in LVIIIa) depresses potency, in marked contrast to its influence in the heterocyclic series. 

There are some additional choices in patients with refractory arthritis despite the use of NSAIDs or paracetamol (acetaminophen), alone or in combination. Narcotics can be used with little risk of addiction, but with the caveat that they can cause cognitive changes, constipation, urine retention and respiratory depression (see section on analgesics). Codeine... 

Adverse effects and drug interactions with codeine are similar to those reported for morphine, although they are less intense. Overdose in children results in the same effects as overdose of morphine, such as respiratory depression, miosis, and coma these symptoms are treated with naloxone administration. 

Propoxyphene (dextropropoxyphene Darvon) is structurally related to methadone but is much less potent as an analgesic. Compared with codeine, propoxyphene is approximately half as potent and is indicated for the treatment of mild pain. It is not antipyretic or antiinflammatory like aspirin and is less useful than aspirin in most cases of mild pain. Toxicity from propoxyphene, especially in combination with other sedatives, such as alcohol, has led to a decrease in its use. Death following ingestion of alcohol in combination with propoxyphene can occur rapidly (within 20 minutes to 1 hour). The drug is not indicated for those with histories of suicide or depressive illnesses. 

Codeine Empirin with Codeine, Fiorinal with Codeine, Robitussin AOC, Tylenol with Codeine Captain Cody, Cody, schoolboy II, III, IV Injected, Swallowed Drowsiness/respiratory depression and arrest, nausea, confusion, constipation, sedation, unconsciousness, coma, tolerance, addiction... 

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