Codeine pharmacological properties

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

In contrast to 14-hydroxydihydrocodeine-B the C-isomer is converted by phosphorus pentachloride to substances containing phosphorus. The difference in behaviour of the two isomers is similar to that of the epimeric pair dihydrocodeine and dihydroisocodeine, and there is nothing about the chemical or pharmacological properties of the two isomers incompatible with the view that 14-hydroxydihydrocodeine-B has the codeine and the C-isomer the isocodeine arrangement of groups at C-6 [6]. 

Codeine is an analgesic that is effective in the treatment of mild to moderate pain. It is often combined with other analgesic products and enjoys a popularity that makes it the standard for other oral opioids. Unfortunately, codeine has the same propensity to produce tolerance, dependence, and constipation as morphine. Hydrocodone, a derivative of codeine, also is seen most often in combination products and has pharmacologic properties similar to those of morphine. Oxycodone has a similar potency to morphine and is an excellent oral analgesic for moderate to severe pain. This is especially trne when the product is used in combination with nonopioids however, its predilection for causing tolerance and dependence, along with its basic opioid characteristics, likens it to morphine. It shonld be noted that sustained-release oxycodone is also available. 

The next correlation was found in Scotland where Crum Brown and Fraser (1869) made a major discovery. They showed that several alkaloids, when quaternized, lost their characteristic pharmacological properties (many of them spasmogenic or convulsant) and acquired the muscle-relaxing powers of tubocurarine (2.6) (itself a quaternary amine), whose site of action had been shown to lie at the jimction between nerve and voluntary muscle, a few years earlier, by Claude Bernard (1856). Strychnine, bruceine, thebaine, codeine, morphine, nicotine, atropine, and coniine were quaternized into curarimimetic substances, by reaction with methyl iodide. The Scottish authors wrote There can be no reasonable doubt that a relation exists between the physiological action of a substance and its... 

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). 

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). 

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. 

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 ... 

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 family of the Papaveraceae includes 31 genera and approximately 700 species (2). The alkaloids contained therein are derivatives of the 1-benzyltetrahydroisoquinoline alkaloid reticuline (1). For the classification and chemical data of the described alkaloids (3-5) as well as for the pharmacodynamic properties of morphine and codeine (6, 7) see reviews. Some pharmacological aspects have been dealt with by Shamma (5) and Krueger et al. (8). 

With respect to treatment, depending on the particular biotransformation pattern and the activity of the metabolites, several therapeutic approaches are evident. For example, EMs (93 percent of the Caucasian population) could receive an inhibitor as part of a therapeutic regimen. Such inhibition will alter the kinetics, toxicity, drug-reinforcing properties, and physical dependence liability of some drugs of abuse (e g., hydrocodone, oxycodone, codeine) and make the drug less pharmacologically attractive. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

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