Mechanism of Action:
Codeine Sulfate is an opioid analgesic, accompanying to morphine, but with beneath almighty analgesic properties. Codeine is careful for the mu receptor, but with a abundant weaker affection than morphine. The analgesic backdrop of codeine accept been speculated to appear from its about-face to morphine, although the exact apparatus of analgesic action charcoal unknown.
Effects on the Central Nervous Arrangement (CNS) :
The arch ameliorative action of Codeine Sulfate is analgesia. Although the absolute apparatus of the analgesic action is unknown, specific CNS analgesic receptors and autogenous compounds with morphine-like action accept been articular throughout the academician and analgesic bond and are acceptable to comedy a role in the announcement and acumen of analgesic effects. Some added CNS furnishings of codeine accommodate anxiolysis, euphoria, and animosity of relaxation/relax condition. Codeine Sulfate is responsible for respiratory depression, in allotment by a absolute aftereffect on the brainstem respiratory centers. Codeine Sulfate and added accompanying opioids abase the ahem reflex by absolute aftereffect on the ahem centermost in the medulla. Codeine Sulfate may additionally account miosis.
Effects on the Gastrointestinal Amplitude (GIT) and on Added Smooth Muscle :
Gastric, biliary and pancreatic secretions may be decreased by codeine. Codeine additionally causes a abridgement in action and is associated with an access in accent in the antrum of the abdomen and duodenum. Digestion of aliment in the baby civil is delayed and active contractions are decreased. Active peristaltic after-effects in the colon are decreased, while accent is added to the point of spasm. The end aftereffect may be constipation. Codeine can account a credible access in biliary amplitude burden as a aftereffect of the access of the sphincter of Oddi. Codeine may additionally account spasms of the sphincter of the urinary bladder.
Codeine produces borderline vasodilation which may aftereffect in orthostatic hypotension and fainting. Absolution of histamine can occur, which may comedy a role in opioid-induced hypotension. Manifestations of histamine absolution and/or borderline vasodilation may accommodate pruritus, flushing, red eyes, and sweating.
Endocrine Arrangement :
Opioid agonists such as Codeine Sulfate accept been credible to accept a array of furnishings on the beard of hormones. Opioids arrest the beard of ACTH, cortisol, and luteinizing hormone (LH) in humans. They additionally activate prolactin, advance hormone (GH) secretion, and pancreatic beard of insulin and glucagons in bodies and added species, rats and dogs. Thyroid aesthetic hormone (TSH) has been credible to be both inhibited and angry by opioids.
Immune Arrangement :
Codeine has been credible to accept a array of furnishings on apparatus of the allowed arrangement in in vitro and beastly models. The analytic acceptation of these allegation is unknown.
Codeine concentrations do not associate with academician assimilation or abatement of pain.
The minimum able assimilation varies broadly and is afflicted by a array of factors, including the admeasurement of antecedent opioid use, age and accepted medical condition. Able doses in advanced patients may be decidedly college than in opioid-naive patients.
Codeine is captivated from the gastrointestinal amplitude with best claret assimilation occurring 60 account column administration.
Food Furnishings/Effects –
When 60 mg of the Codeine Sulfate was administered 30 account afterwards ingesting a aerial fat/high calorie meal, there was no cogent change in the amount and admeasurement of assimilation of codeine.
Administration of 15 mg of the Codeine Sulfate every/each four hours for 5 canicule resulted in steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) aural 48 hours.
Codeine has been appear to accept an credible aggregate of administration of about 3-6 L/kg, advertence all-encompassing administration of the biologic into tissues. Codeine has low claret protein bounden with about 7-25% of codeine apprenticed to claret proteins.
About 70-80% of the administered dosage of codeine is metabolized by alliance with glucuronic acerbic to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively/separately. UDP-glucuronosyltransferase (UGT) 2B7 with 2B4 are the above enzymes mediating glucurodination of codeine to C6G. Cytochrome P450 2D6 is the above agitator amenable for about-face of codeine to morphine and P450 3A4 is the above agitator mediating about-face of codeine to norcodeine. Morphine and norcodeine are added metabolized by alliance with the glucuronic acid. The glucuronide metabolites of the morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are accepted to accept analgesic action in humans. The analgesic action of C6G in bodies is unknown. Norcodeine and M3G are about not advised to acquire analgesic properties.
Approximately 90% of the absolute dosage of codeine is excreted through the kidneys, of which about 10% is banausic codeine. Claret half-lives of codeine and its metabolites accept been appear to be about 3 hours.
Carcinogenesis, Mutagenesis, Impairment of Fertility :
Carcinogenesis: Two year carcinogenicity studies accept been conducted in F344/N rats and B6C3F1 mice. There was no affirmation of carcinogenicity in macho and changeable rats, respectively, at comestible doses up to 70 and 80 mg/kg/day of codeine (approximately 2 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis) for two years. Similiarly there was no affirmation of carcinogenicity action in macho and changeable mice at comestible doses up to 400 mg/kg/day of codeine (approximately 5 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis) for two years.
Mutagenesis: Codeine wasn’t mutatgenic in the in- vitro bacterial about-face alteration appraisal or clastogenic in the in vitro Chinese hamster ovary corpuscle chromosome abnormality assay.
Impairment of fertility: No beastly studies were conducted to appraise the aftereffect of codeine on macho or changeable fertility.
Reproduction And Adorning Toxicology –
Studies on the changeable and adorning furnishings of codeine accept been appear in the appear abstract in hamsters, rats, mice and rabbits.
A abstraction in hamsters administered 150 mg/kg bid of codeine (PO; about 7 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis) appear the development of cranial malformations/deformities (i.e., meningoencephalocele) in several of the fetuses examined; as able-bodied as the ascertainment of increases in the allotment of resorptions per clutter examined. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as approved by decreased fetal anatomy weight. In an beforehand abstraction in hamsters, doses of 73-360 mg/kg akin (PO; about 2-8 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis), reportedly producing the cranioschisis in all of the fetuses examined.
In studies in rats, doses at the 120 mg/kg akin (PO; about 3 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis), in the baneful ambit for the developed animal, were associated with an access in antecedent absorption at the time of implantation.
In abundant mice, a distinct 100 mg/kg dosage (SC; about 1.4 times the recommended circadian dosage of 360 mg/day for adults on a mg/mg2 basis) reportedly resulted in delayed ossification in the offspring.
No teratogenic furnishings were empiric in rabbits administered up to 30 mg/kg (approximately 2 times the best recommended circadian dosage of 360 mg/day for adults on a mg/m2 basis) of codeine during organogenesis.