Codeine pharmacology

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). 

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). 

Comprehensive summaries of the pharmacological information available regarding codeine, apomorphine and thehaine are given in the report already referred to. ... 

Noyes R, Brunk SF, Avery DAH and Canter AC (1975b). The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clinical Pharmacology and Therapeutics, 18, 84-89. 

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. 

Axelrod, J. (1955) The enzymatic conversion of codeine to morphine. Journal of Pharmacology and Experimental Therapeutics, 115 (3), 259-267. 

Many pharmacologically active organic chemicals fonnd in natnre are alkaloids. In general, these componnds contain one or more nitrogen atoms, which in turn impart some basicity to the molecnle. Well-known alkaloid examples are caffeine, cocaine, codeine, ephedrine, morphine, nicotine, qninine, and scopolamine. Heroin is derived from morphine by a chemical modification that increases lipophilicity, making the heroin molecnle inherently more pharmacologically potent than morphine. The exhibition of its basic properties by an alkaloid (Aik) involves (by definition) the acceptance of a proton H+ according to ... 

Soaking plants parts in alcohol (ethanol) creates a tincture. In this process, pharmacologically active constituents of the plant are extracted by the alcohol. Tinctures do not contain the complete spectrum of substances that exist in the plant or crude drug, only those that are soluble in alcohol. In the case of opium tincture, these ingredients are alkaloids (i.e., basic substances of plant origin) including morphine, codeine, narcotine = noscapine, papaverine, narceine, and others. 

Codeine (12) and morphine (13), both major active constituents of opium resin, the dried latex from the immature fruits of Papaver som-niferum L., are pharmacologically important drugs as analgesic agents with considerable use today. Like other opiates, morphine and codeine... 

Nabitan (39) is a cannabis-inspired analgesic whose nitrogen atom was introduced in order to improve water solubility and perhaps to affect the pharmacological profile as well. The phenolic hydroxyl of benzopyran synthon is esterified with 4-(l-piperidino)butyric acid under the influence of dicyclohexyl carbodi mi de. In addition to being hypotensive and sedative-hypnotic, nabitran (39) is a more potent analgesic than codeine. The preparation of synthon begins with aceto-... 

Pharmacology Dextromethorphan is the d-isomer of the codeine analog of levorphanol. Its cough suppressant action is due to a central action on the cough center in the medulla. Dextromethorphan 15 to 30 mg equals 8 to 15 mg codeine as an antitussive. 

Hydrocodone (Hycodan), oxycodone (Roxicodone), dihydrocodeine, hydromorphone (Dilaudid), and oxy-morphone (Numorphan) are derivatives of codeine and morphine. All are indicated for the relief of mild to severe pain or for their antipyretic effects they are often used in combination with nonopioid analgesics. The drugs vary in potency, but their pharmacological effects do not differ significantly from those of codeine or morphine. 

The usual codeine dose and timing of dose separation for children is 1 to 1.5 milligrams (mg) of codeine per body weight (in kilograms) per day, but given as several doses every 4 to 6 hours. The accepted medical or pharmacological shorthand is 1-1.5 mg/kg/day, q4-6h, where q stands for every, and h represents hours. The usual adult (older than 13 years of age) dose and schedule is 10-20 mg, q4-6h, as needed, although 60-mg doses may occasionally be needed. 

Together, the chemistry of codeine and the drug s absorption into the bloodstream, distribution to various compartments and tissues in the body, metabolism (breakdown of the parent compound into smaller molecules, or metabolites), and excretion are intimately related to how codeine exerts its medicinal or therapeutic effects. Codeine s chemical properties and pharmacologic characteristics explain how, figuratively speaking, a spoonful of codeine can relieve pain, suppress cough, or act as an antidiarrheal. 

The medicinal chemistry and pharmacology of codeine can also shed light on why specific side effects (the unintended, undesirable, and unwanted effects) associated with codeine occur. Codeine s side effects, or toxicities, are discussed in the next chapter. 

Codeine, either alone or in combination with other drugs, is given orally as a tablet or capsule or in liquid form (including as syrup). Codeine can also be delivered via intramuscular injection, usually for patients unable to swallow because of a medical condition such as throat cancer. One of the interesting pharmacologic characteristics of codeine is the drug s potency... 

The pharmacological action of codeine is increased by induction as this increases demethylation to morphine. Induction by phenobarbital decreases the toxicity of organo-phosphates, but increases that of phosphorothionates. Studies with the drug warfarin have shown that induction by both phenobarbital and 3-methylcholanthrene will change the stereochemistry of the product, as can be seen in Table 5.24. Thus, hydroxylation in the 8-position in the R-isomer is increased 12 times compared with only 4 times with the S-isomer following 3-methylcholanthrene induction. 

Members of the group of natural, semisynthetic, or synthetic alkaloid compounds prepared from opium are referred to as opioids. This group includes natural compounds usually denoted opiates, such as morphine and codeine, and the synthetic and semi synthetic compounds such as oxycodone, buprenorphine, fentanyl, methadone, and tramadol. The pharmacological effects and pharmacokinetic parameters of these drugs share many common characteristics and are illustrated with the prototypic drug in this class, morphine. 

The diethyl compound without the iodine is 2,5-dimethoxy-N,N-diethylamphetamine, which was prepared by the reductive alkylation of DMA with acetaldehyde and sodium cyanoborohydride. This product, DEDMA, was a clear white oil, bp 82-92 °C at 0.15 mm/Hg which did not form a crystalline hydrochloride. An interesting measure of just how different these N,N-dialkylated homologues can be from the psychedelic primary amines, pharmacologically, can be seen in the published report that the beta-hydroxy derivative of DEDMA is an antitussive, with a potency the same as codeine. 

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