Top Gene Interactions
- Metabolism: Hepatic. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. CYP3A4 and CYP2B6 facilitates the biotransformation of tramadol to N-desmethyl-tramadol. CYP2D6 facilitates the biotransformation of tramadol to O-desmethyl-tramadol. Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%.The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to five different metabolites. Of these, M1 (O-Desmethyltramadol) is the most significant since it has 200 times the affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. In the 6% of the population that have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment (A308, L1160). Route of Elimination: Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. Half Life: Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively.
- Uses/Sources: Indicated in the treatment of moderate to severe pain. Consider for those prone to constipation or respiratory depression. Tramadol is used to treat postoperative, dental, cancer, and acute musculosketetal pain and as an adjuvant to NSAID therapy in patients with osteoarthritis (A308).
- Health Effects: Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. The respiratory depressant effects include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients (RxList, A308). Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.
- Symptoms: Overdose symptoms of a tramadol overdose may include drowsiness, shallow breathing, slow heartbeat, extreme weakness, cold or clammy skin, feeling light-headed, fainting, or coma. (L1328)
- Treatment: In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with ULTRAM, the risk of seizures is also increased with naloxone administration. (L1712)
- Route of Exposure: Inhalation. Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults.
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: LD50: 300-350 mg/kg (Oral, Rat) (A2833)
Mechanism of Action
|Target Name||Mechanism of Action||References|
Glutamate receptor ionotropic, NMDA 3A
Muscarinic acetylcholine receptor M3
Delta-type opioid receptor
Alpha-7 nicotinic cholinergic receptor subunit
5-hydroxytryptamine receptor 2C
Sodium-dependent serotonin transporter
Sodium-dependent noradrenaline transporter
Mu-type opioid receptor
Kappa-type opioid receptor
|Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. The analgesic properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord. The (+) enantiomer has higher affinity for the OP3 receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha(2)-adrenergic receptors.||
Tramadol Interacts with Diseases
|Disease||Inference Score||References/Inference Genes|
|Diabetes Mellitus, Experimental||21.38||
|Diabetes Mellitus, Type 2||14.22||
|Radiation Injuries, Experimental||13.3||
|Alcoholic liver cirrhosis||12.55||
|Basal Ganglia Diseases||10.79||