Morphine Codeine phosphate

Opioids. Reactions to morphine, codeine phosphate, meperidine, fentanyl and its derivatives are uncommon. Because of their direct histamine-releasing properties, especially regarding morphine and codeine, distinction between anaphylaxis and non-immune-mediated histamine release is not always easy. Only 12 cases were recorded in the last 2 years epidemiologic survey in France, 9 of them being related to morphine administration [9]. 

Opiates can effect serum levels of enzymes and other substances whose homeostatic control depends on clearance through the liver (F8, G12, M15, N4, S19). In one reported case, the aspartate aminotransferase was within normal limits before the administration of codeine, but within 2 hours after the drug, the enzyme activity had risen to two times the normal value by 8 hours to eight times the normal activity, and within 24 hours it had returned to normal (F8). Increases in transaminase to levels 5-85 times the control value have been reported in 6 of 16 patients with disease of the biliary tree following the administration of codeine phosphate (2 grains) (B7, F8). Gross has shown that morphine, codeine, or mepheridine administration produce elevations of serum amylase or lipase (G12). These elevations have been attributed to constriction of the sphincter of Oddi and increased intraductal pressure on the pancreatic duct (G12, N4). 

Codeine phosphate is still used for diarrhea predominantly based on hypermotility but the longer-acting loperamide is more convenient and has less central nervous system effects. Codeine has an exceptionally low affinity for opioid receptors and its effects are due to the fact that it is converted for approximately 10% to morphine. The active metabolite of morphine, morphine-6-glucuronide, may also accumulate during repeated administration of codeine to patients with impaired renal function. 

Natural opium alkaloids codeine phosphate hydromorphone hydrochloride morphine hydrochloride morphine sulfate oxycodone hydrochloride oxymorphone hydrochloride... 

Opium derivatives, such as morphine and codeine phosphate, have been used for a iong time, but the piperidine derivatives loperamide (Imodium) and diphenoxylate (Lomotii) are now preferred. Both are p-receptor agonists, iargeiy devoid of centrai opiate-iike effects, and reiativeiy insoiubie in water, so that parenterai use and abuse are aimost impossibie. 

THC augments opioid activity. Thus, administration to mice of zf8-THC (3 mg/kg) together with morphine (1 mg/kg) or codeine phosphate (3 mg/ kg) potentiated the activity of the opioids 4-5 times [146], Intrathecal administration of zf9-THC (3.13 fig and 6.26 fig) to mice caused a 4- and 12-fold shift in the dose response curve of morphine [147]. While the administration... 

After a single oral dose of 60 mg of codeine phosphate in combination with 650 mg of aspirin, administered to 12 subjects, peak plasma concentrations of 0.11 to 0.23 pg/ml (mean 0.16) of codeine were attained in 0.5 to 1.5 hours, and peak plasma concentrations of morphine of0.0003 to 0.014 pg/ml (mean 0.007) were reported at 1.5 hours (J. W. A. Findlay etal, Clin. Pharmac. Ther., 1978,24, 60-68). 

There is of course no bathochromic shift here in alkaline solutions (difference between morphine hydrochloride [111] and codeine phosphate [801]). In many compounds the relatively weak phenol ether band is considerably overshadowed and barely discernible (mepyramine maleate [306], noscapine hydrochloride [805], papaverine hydrochloride [2408]). 

Kronstand R, Jones AW. Concentration ratios of codeine-to-morphine in plasma after a single oral dose (100mg) of codeine phosphate. J Anal Toxicol 2001 25 486-7. 

Fig. 5-30. Separation of epinephrine, ephedrine, and opium alkaloids. - Separator column IonPac NS1 (10 pm) eluent 0.005 mol/L sodium octanesulfonate + 0.05 mol/L KH2P04 (pH 4.0) / acetonitrile (89 11 v/v) flow rate 1 mL/min detection UV (220 nm) injection volume 50 pL solute concentrations 10 mg/L epinephrine, 10 mg/L morphine sulfate, 20 mg/L ephedrine hydrochloride, and 20 mg/L codeine phosphate.

Morphine and certain other central analgesics have a contractile action on the sphincter of Oddi (M18). Increased biliary pressure arrests the secondary phase of BSP disappearance from the circulation the initial rapid phase is unaffected. This effect is not demonstrable in patients with intact gallbladders since the gallbladder has some capacity to regulate pressure. Codeine phosphate has a similar effect to morphine in cholecys-tectomized patients, causing biliary colic and elevated BSP retention. Pholcodine and l-(2,12-benzylphenoxyl-l-methylethyl) piperidine has no such effect. Papaverine exerts a counter-effect, relieving colic and BSP stasis (H26). 

Band, C.J. Band, P.R. Deschamps, M. Besner, J.-G. Goldman, A.J. Human pharmacokinetic study of immediate-release (codeine phosphate) and sustained-release (codeine contin) codeine. J.Clin. Pharmacol., 1994, 34, 938-943 [electrochemical detection SPE plasma ethylmorphine (IS)] Papadoyannis, I. Zotou, A. Samanidou, V. Theodoridis, G. Zougrou, F. Comparative study of different solid-phase extraction cartric es in the simultaneous RP-HPLC analysis of morphine and codeine in biological fluids. J.Liq.Chromatogn, 1993,16, 3017—3040 [simultaneous caffeine, morphine, quinine, strychnine SPE urine plasma LOD 10-20 ng/mL]... 

Fig, 4. Analgesic effect (reflex depression) of 3-oxy-iV-methylmorphinan hydrochloride (I), morphine hydrochloride (II), and codeine phosphate (III) on white mice. Thermal irradiation of constant intensity was applied to the tail until a flick was obtained or up to twice the duration required without medication. Drugs were administered subcutaneously. On the ordinates are plotted on a linear scale the per cent of the mice not reacting to the thermal irradiation. Dosage is plotted on the abscissa on a logarithmic scale. (Copied from W. Wirth (45).)... 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

Thomapyrin containing acetaminophen, caffeine and acetylsalicylic acid Antiviral drug suramin Amino group containing drugs codeine phosphate, ephedrine hydrochroride, thebaine, berberine, hydrochloride, jatrorrizine hydrochloride, cocaine hydrochloride Isradepin and by-products Morphine alkaloids Barbiturates (barbital, phenobarbital, secobarbital, thiopental)... 

A number of medicines derived from opium are clinically very important. Morphine hydrochloride, purified from opium powder, is used as an analgesic and an anesthetic, and codeine phosphate and noscapine hydrochloride are used in cough medicines. Papaverine hydrochloride is used as a smooth muscle relaxant. 

Morphine, codeine, oripavine, thebaine Industrial liquors (fiom extraction processes) CD-CZE 100 mM Tris-phosphate (pH 2.8) + 30 mM HP-PCD UV at 214 nm [47]... 

Cyclodextrin (CD)-modified CZE with the same detection system has proven successful to increase both sensitivity and specially selectivity in this type of analysis [114, 115]. The most frequently background electrolyte (BGE) employed both in CZE-UV and CZE-CD-UV is sodium phosphate at acidic pH in the presence of a small percentage of organic solvents, such as methanol or acetonitrile (MeCN), to increase the selectivity of the CE separation. A good separation of morphine, codeine, and thebaine in different opium poppy plants can be seen in Fig. 33.3 [114]. 

The only South African-based API manufacturer. Fine Chemicals Corporation (FCC) was foimded in 1962 in Cape Town. At inception, FCC produced codeine phosphate, morphine sulphate and paracetamol exclusively for the South African market. The product range was expanded in the 1980s with the development of a number of generic APIs, primarily for the US market. In the 1990s, FCC invested heavily to meet emerging international standards of GMP production. Since then, the company has been successfully inspected by various regulatory authorities including the USFDA in 1996, 1999, 2002 and 2006. 

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. 

Codeine, also known as methylmorpliine, C H2 NOt H20, is a colorless white crystalline substance, mp 154.9 C, slightly soluble in water, soluble in alcohol and chloroform, effloresces slowly in dry air. Codeine is derived from opium by extraction or by the methylation of morphine. For medical use, codeine is usually offered as the dichlotide, phosphate, or sulfate. Codeine is habit forming. Codeine is known to exacerbate urticaria (familiarly known as hives). Since codeine is incorporated in numerous prescription medicines for headache, heartburn, fatigue, coughing, and relief of aches and pains, persons with a history of urticaria should make this fact known to their physician. Codeine is sometimes used ill cases of acute pericarditis to relieve severe chest pains in early phases of disease. Codeine is sometimes used in drug therapy of renal (kidney) diseases. 

The codeine that occurs naturally in small amounts in opium is isolated from the aqueous morphine alkaloid mother liquors by immiscible extraction with a nonaqueous solvent. Dilute sulfuric acid is employed to extract the codeine sulfate from the nonaqueous solvent. This solution is evaporated, crystallized, and recrystallized. The alkaloid is precipitated from a sulfate solution by alkali and purified, if necessary, by alcoholic crystallization. It is converted into the phosphate by solution in phosphoric acid, evaporation, crystallization, centrifugation, and drying. 

Wash kinetic/digestion profile of 6-monoacetylmorphine ( ), morphine (A), and codeine (O) in the hair of a heroin user. All samples received an initial wash with dry ethanol ( ). This was followed by washes with phosphate buffer (pH 5.5) and release of remaining drugs by enzymatic digestion. 

Wernly and Thormann (1991) used a phosphate-borate buffer pH 9.1 with 75 mM SDS for the qualitative determination in urine of many drugs of abuse (and their metabolites), including benzoylecgonine, morphine, heroin, 6-monoacetylmorphine, methamphetamine, codeine, amphetamine, cocaine methadone, methaqualone, and benzodiazepines. 

Many drugs and excipients (cephalexin monohydrate, quinidine sulfate dihydrate, ampicillin trihydrate, codeine sulfate trihydrate, morphine sulfate dihydrate, dicalcium phosphate trihydrate, raffinose pentahy-drate, lactose monohydrate) utilize water as an integral part of their crystal structure. Solids that form specific crystal hydrates tend to sorb relatively small amounts of water to their external surface below a characteristic relative humidity, when initially dried to an anhydrous... 

Fig. 1 Capillary electrophoretic separation of opiates. Running conditions 100 mM phosphate buffer pH 6.0. Electrokinetic injection with field-amplified sample stacking after solid-phase extraction of spiked urine using double mechanism cartridges. Precision of migration times 1.2% R.S.D. (relative standard deviation), resolution >2 with all peaks shown. Within the day and day-to-day repeatability 1-4% R.S.D., respectively detection by UV at 200 nm. Peak identification pholcodine (P), MAM (6-M), heroin (H), codeine (C), morphine (M), dihydrocodeine (D), and levallorphan (I.S.) E represents an unidentified endogenous compound present in urine (see inset). (From Ref. 9 with permission.)...

Fig. 7.6. Separation of heroin and some common adulterants and contaminations Column amino-propyl bonded silica (S5NH.)(Phase-Sep) (250x4 mm ID), mobile phase acetonitrile - 0.005 M tetrabutylammoniurn phosphate (85 15), flow rate 1 ml/min, detection UV 284 nm. Peaks 1, noscapine 2, papaverine 3, caffeine 4, heroin 5, acetylcodeine 6, 6-0-acetyl-morphine 7, codeine 8, strychnine 9, morphine, (Reproduced with permission from ref. 93, by the courtesy of Journal Chromatographic Science)...

Fig. 7.7. Separation of some opium alkaloids Column Zorbax NH (250x4.6 mm ID), mobile phase acetonitrile - 07025 M potassium dihydrogen phosphate (3 1), flow rate 2.0 ml/min, detection UV 286 nm. Peaks 1, papaverine 2, thebaine 3, narceine 4, codeine 5, morphine 6, tyrosine (internal standard).

Morphine and related drugs possessing potent narcotic analgesic properties, are used in clinical practice. A few examples belonging to this class of compounds are morphine sulphate diamorphine hydrochloride codeine dihydrocodeine phosphate hydromorphone hydrochloride hydrocodone tartrate oxymorphone hydrochloride. 

An early key intermediate in benzylisoquinoline biosynthesis is (57), which by decarboxylation affords (59) this in turn leads to (61) and on to alkaloids (Scheme 2). Confirmation of this pathway has come from a study using cell-free preparations of P. somniferum stems and seed capsules. It was found that this preparation catalysed the formation of (57), (59), and (61) from dopamine (54) plus 3,4-dihydroxyphenylpyruvic acid (55) without the addition of 5-adenosyl-methionine, NADPH, and pyridoxal phosphate, the reaction stopped at (57). The formation of the alkaloids reticuline, thebaine, codeine, and morphine, produced by whole plants, could not be detected with this cell-free system. The results confirm not only the intermediacy of (57) and (59) in benzylisoquinoline biosynthesis, but also the involvement of (54) and (55). 

---