Peringatan Keamanan

Oral LD50: 427 mg kg-1 (rat) MSDS.

Overdose/toxicity

Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal L5506, FDA label.

Teratogenic effects

This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus FDA label.

Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose FDA label. Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison FDA label.

Nonteratogenic effects

Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment FDA label.

Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0.8 times the maximum recommended human dose of 360 mg/day FDA label.

The use in breastfeeding/nursing

Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants FDA label.

Codeine

DB00318

small molecule approved illicit

Deskripsi

The relief of pain (analgesia) is a primary goal for enhancing the quality of life of patients and for increasing the ability of patients to engage in day to day activities. Codeine, an opioid analgesic, was originally approved in the US in 1950 and is a drug used to decrease pain by increasing the threshold for pain without impairing consciousness or altering other sensory functions. Opiates such as codeine are derived from the poppy plant, Papaver somniferum (Papaveraceae).A175096

Codeine is utilized as a central analgesic, sedative, hypnotic, antinociceptive, and antiperistaltic agent, and is also recommended in certain diseases with incessant coughing.LABEL,A175096

Struktur Molekul 2D

Berat 299.3642
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours [FDA label].
Volume Distribusi Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues [FDA label].
Klirens (Clearance) Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study [A175099]. Renal impairment may decrease codeine clearance [LABEL].

Absorpsi

Absorption Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration FDA label. Food Effects When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine FDA label. Steady-state concentration The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours FDA label.

Metabolisme

Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6­ glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to norcodeine. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties FDA label.

Rute Eliminasi

About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine FDA label. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine F3658.

Farmakogenomik

9 Varian
CYP2D6 (rs3892097)

Patients with this genotype have reduced metabolism of codeine.

CYP2D6 (rs5030655)

Patients with this genotype have reduced metabolism of codeine.

CYP2D6 (None)

Patients with this genotype have reduced metabolism of codeine.

CYP2D6 (rs35742686)

The presence of this polymorphism in CYP2D6 results in non-functioning enzyme variant and may be associated with reduced drug mtabolism or reduced therapeutic response when treated with codeine.

CYP2D6 (rs3892097)

The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine.

CYP2D6 (None)

The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine and lack of therapeutic response from codeine.

CYP2D6 (rs5030655)

The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine.

CYP2D6 (rs1135824)

The presence of this polymorphism in CYP2D6 results in non-functioning enzyme variant and may be associated with reduced therapeutic response when treated with codeine.

CYP2D6 (rs28371733)

The presence of this polymorphism in CYP2D6 results in non-functioning enzyme variant and may be associated with reduced therapeutic response when treated with codeine.

Interaksi Makanan

2 Data
  • 1. Avoid alcohol.
  • 2. Take with food. Food reduces irritation.

Interaksi Obat

1224 Data
Buprenorphine Codeine may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.
Dronabinol Dronabinol may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Droperidol Droperidol may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Hydrocodone Codeine may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.
Hydroxyzine Hydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Magnesium sulfate The therapeutic efficacy of Codeine can be increased when used in combination with Magnesium sulfate.
Methotrimeprazine Codeine may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.
Metyrosine Codeine may increase the sedative activities of Metyrosine.
Minocycline Minocycline may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Nabilone Nabilone may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Orphenadrine Codeine may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.
Paraldehyde Codeine may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.
Perampanel Perampanel may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Pramipexole Codeine may increase the sedative activities of Pramipexole.
Ropinirole Codeine may increase the sedative activities of Ropinirole.
Rotigotine Codeine may increase the sedative activities of Rotigotine.
Rufinamide The risk or severity of adverse effects can be increased when Rufinamide is combined with Codeine.
Sodium oxybate Codeine may increase the central nervous system depressant (CNS depressant) activities of Sodium oxybate.
Suvorexant Codeine may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
Tapentadol Tapentadol may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Thalidomide Codeine may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
Zolpidem Codeine may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Alvimopan The risk or severity of adverse effects can be increased when Codeine is combined with Alvimopan.
Desmopressin The risk or severity of hyponatremia can be increased when Codeine is combined with Desmopressin.
Morphine The risk or severity of adverse effects can be increased when Morphine is combined with Codeine.
Hydromorphone The risk or severity of adverse effects can be increased when Codeine is combined with Hydromorphone.
Oxycodone The risk or severity of adverse effects can be increased when Codeine is combined with Oxycodone.
Dextropropoxyphene The risk or severity of adverse effects can be increased when Codeine is combined with Dextropropoxyphene.
Naltrexone The therapeutic efficacy of Codeine can be decreased when used in combination with Naltrexone.
Sufentanil The risk or severity of adverse effects can be increased when Codeine is combined with Sufentanil.
Levorphanol The risk or severity of adverse effects can be increased when Codeine is combined with Levorphanol.
Remifentanil The risk or severity of adverse effects can be increased when Codeine is combined with Remifentanil.
Diphenoxylate The risk or severity of adverse effects can be increased when Codeine is combined with Diphenoxylate.
Oxymorphone The risk or severity of adverse effects can be increased when Codeine is combined with Oxymorphone.
Dezocine The risk or severity of adverse effects can be increased when Codeine is combined with Dezocine.
Methadyl acetate The risk or severity of adverse effects can be increased when Codeine is combined with Methadyl acetate.
Dihydroetorphine The risk or severity of adverse effects can be increased when Codeine is combined with Dihydroetorphine.
Diamorphine The risk or severity of adverse effects can be increased when Codeine is combined with Diamorphine.
Bezitramide The risk or severity of adverse effects can be increased when Codeine is combined with Bezitramide.
Etorphine The risk or severity of adverse effects can be increased when Codeine is combined with Etorphine.
Dextromoramide The risk or severity of adverse effects can be increased when Codeine is combined with Dextromoramide.
Desomorphine The risk or severity of adverse effects can be increased when Codeine is combined with Desomorphine.
Carfentanil The risk or severity of adverse effects can be increased when Codeine is combined with Carfentanil.
Dihydrocodeine The risk or severity of adverse effects can be increased when Codeine is combined with Dihydrocodeine.
Alphacetylmethadol The risk or severity of adverse effects can be increased when Codeine is combined with Alphacetylmethadol.
Dihydromorphine The risk or severity of adverse effects can be increased when Codeine is combined with Dihydromorphine.
Ketobemidone The risk or severity of adverse effects can be increased when Codeine is combined with Ketobemidone.
DPDPE The risk or severity of adverse effects can be increased when Codeine is combined with DPDPE.
Lofentanil The risk or severity of adverse effects can be increased when Codeine is combined with Lofentanil.
Opium The risk or severity of adverse effects can be increased when Codeine is combined with Opium.
Normethadone The risk or severity of adverse effects can be increased when Codeine is combined with Normethadone.
Piritramide The risk or severity of adverse effects can be increased when Codeine is combined with Piritramide.
Alphaprodine The risk or severity of adverse effects can be increased when Codeine is combined with Alphaprodine.
Nicomorphine The risk or severity of adverse effects can be increased when Codeine is combined with Nicomorphine.
Meptazinol The therapeutic efficacy of Codeine can be decreased when used in combination with Meptazinol.
Phenoperidine The risk or severity of adverse effects can be increased when Codeine is combined with Phenoperidine.
Phenazocine The risk or severity of adverse effects can be increased when Codeine is combined with Phenazocine.
Tilidine The risk or severity of adverse effects can be increased when Codeine is combined with Tilidine.
Carfentanil, C-11 The risk or severity of adverse effects can be increased when Codeine is combined with Carfentanil, C-11.
Benzhydrocodone The risk or severity of adverse effects can be increased when Codeine is combined with Benzhydrocodone.
Meperidine The risk or severity of adverse effects can be increased when Codeine is combined with Meperidine.
Alfentanil The risk or severity of adverse effects can be increased when Codeine is combined with Alfentanil.
Fentanyl The risk or severity of adverse effects can be increased when Codeine is combined with Fentanyl.
Naloxegol The risk or severity of adverse effects can be increased when Codeine is combined with Naloxegol.
Pegvisomant The therapeutic efficacy of Pegvisomant can be decreased when used in combination with Codeine.
Succinylcholine The risk or severity of bradycardia can be increased when Succinylcholine is combined with Codeine.
Methadone The risk or severity of adverse effects can be increased when Methadone is combined with Codeine.
Linezolid The risk or severity of serotonin syndrome can be increased when Linezolid is combined with Codeine.
Mirabegron The serum concentration of Codeine can be increased when it is combined with Mirabegron.
Mirtazapine Codeine may increase the serotonergic activities of Mirtazapine.
Citalopram The risk or severity of serotonin syndrome can be increased when Codeine is combined with Citalopram.
Sertraline The risk or severity of serotonin syndrome can be increased when Codeine is combined with Sertraline.
Zimelidine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Zimelidine.
Dapoxetine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Dapoxetine.
Seproxetine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Seproxetine.
Indalpine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Indalpine.
Ritanserin The risk or severity of serotonin syndrome can be increased when Codeine is combined with Ritanserin.
Alaproclate The risk or severity of serotonin syndrome can be increased when Codeine is combined with Alaproclate.
Fluvoxamine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Fluvoxamine.
Duloxetine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Duloxetine.
Sibutramine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Sibutramine.
Milnacipran The risk or severity of serotonin syndrome can be increased when Codeine is combined with Milnacipran.
Desvenlafaxine The risk or severity of serotonin syndrome can be increased when Desvenlafaxine is combined with Codeine.
Levomilnacipran The risk or severity of serotonin syndrome can be increased when Codeine is combined with Levomilnacipran.
Paroxetine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Paroxetine.
Azelastine Codeine may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
Brimonidine Brimonidine may increase the central nervous system depressant (CNS depressant) activities of Codeine.
Phentermine Phentermine may increase the analgesic activities of Codeine.
Benzphetamine Benzphetamine may increase the analgesic activities of Codeine.
Diethylpropion Diethylpropion may increase the analgesic activities of Codeine.
Lisdexamfetamine The risk or severity of serotonin syndrome can be increased when Codeine is combined with Lisdexamfetamine.
Mephentermine Mephentermine may increase the analgesic activities of Codeine.
MMDA MMDA may increase the analgesic activities of Codeine.
Midomafetamine Midomafetamine may increase the analgesic activities of Codeine.
2,5-Dimethoxy-4-ethylamphetamine 2,5-Dimethoxy-4-ethylamphetamine may increase the analgesic activities of Codeine.
4-Bromo-2,5-dimethoxyamphetamine 4-Bromo-2,5-dimethoxyamphetamine may increase the analgesic activities of Codeine.
Tenamfetamine Tenamfetamine may increase the analgesic activities of Codeine.
Chlorphentermine Chlorphentermine may increase the analgesic activities of Codeine.
Methylenedioxyethamphetamine Methylenedioxyethamphetamine may increase the analgesic activities of Codeine.
Dextroamphetamine Dextroamphetamine may increase the analgesic activities of Codeine.

Target Protein

Mu-type opioid receptor OPRM1
Kappa-type opioid receptor OPRK1
Delta-type opioid receptor OPRD1

Referensi & Sumber

Synthesis reference: Nagaraj R. Ayyangar, Anil R. Choudhary, Uttam R. Kalkote, Vasant K. Sharma, "Process for the preparation of codeine from morphine." U.S. Patent US4764615, issued May, 1912.
Artikel (PubMed)
  • PMID: 15495019
    Schroeder K, Fahey T: Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001831.
  • PMID: 11092114
    Vree TB, van Dongen RT, Koopman-Kimenai PM: Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Pract. 2000 Jul-Aug;54(6):395-8.
  • PMID: 15102399
    Srinivasan V, Wielbo D, Tebbett IR: Analgesic effects of codeine-6-glucuronide after intravenous administration. Eur J Pain. 1997;1(3):185-90.
  • PMID: 23781422
    Bhandari M, Bhandari A, Bhandari A: Recent updates on codeine. Pharm Methods. 2011 Jan;2(1):3-8. doi: 10.4103/2229-4708.81082.
  • PMID: 2049245
    Chen ZR, Somogyi AA, Reynolds G, Bochner F: Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991 Apr;31(4):381-90.
  • PMID: 9218689
    Takahama K, Wakuda I, Fukushima H, Isohama Y, Kai H, Miyata T: Differential effect of codeine on coughs caused by mechanical stimulation of two different sites in the airway of guinea pigs. Eur J Pharmacol. 1997 Jun 18;329(1):93-7.
  • PMID: 25234029
    Straube C, Derry S, Jackson KC, Wiffen PJ, Bell RF, Strassels S, Straube S: Codeine, alone and with paracetamol (acetaminophen), for cancer pain. Cochrane Database Syst Rev. 2014 Sep 19;(9):CD006601. doi: 10.1002/14651858.CD006601.pub4.
  • PMID: 22747535
    Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A: Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18(37):5994-6004. doi: 10.2174/138161212803582469.
Menampilkan 8 dari 12 artikel.

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  • Coderpina — Frycia Centro América

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