Lavoro svolto da Alessandro Malatesta ed Emanuele Turbil
Description
Disulfiram (tetraethylthiuram) is used in the pharmacotherapy of cronic alcoholism. It used like deter to drinking because causes extreme discomfort to patients who drink alcoholic beverages.
Indications
Compliance with disulfiram therapy is often low, and both compliance and clinical outcome can be improved by supervised administration. When the drug is prescribed, the alcohol content of common nonprescription medications should be communicated to the patient. Management with disulfiram should be initiated only when the patient has been free of alcohol for at least 24 hours. The drug may cause mild changes in liver function tests.
The safety of disulfiram in pregnancy has not been demonstrated.
The duration of disulfiram treatment should be individualized and determined by the patient's responsiveness and clinical improvement.
The usual oral dose is 250 mg daily taken at bedtime.
Pharmacokinetics
Disulfiram is rapidly and completely absorbed from the gastrointestinal tract; however, a period of 12 hours is required for its full action. Its elimination rate is slow, so that its action may persist for several days after the last dose
Molecular Mechanism
The drug interferes with ethanol metabolism because Disulfiram inhibits aldehyde dehydrogenase , alcohol is normally metabolized to acetaldehyde but not beyond,therefore it accumulates.This mechanism is responsible of effect of alcohol ingestion during therapy with this drug. Infact alcohol induces several effects: sedation, slurred speech, ataxia and respiratory depression up to coma (with an high concentration of substance in blood)by increasing the activity of GABA on his receptor (isoform A) and by inhibition of NMDA channel of glutamate (the major excitatory neurotransmitter of SNC). This can cause also “blackout”, a period of memory loss. Acetaldehyde acts like a vasodilator(relaxes smooth muscle and depresses the vasomotor center in brain),so decreases blood pressure causing hypotension and tachycardia. Moreover this metabolite damages gastroenteric mucosal determining vomit and gastric pain. All this symptoms are present when patience drinks alcol during therapy with Disulfiram.
This drug is also used for the treatment of cocaine abuse because it seems to enhance cocaine-induced-seizures (CIS) frequency by inhibiting dopamine-beta hydroxylase (enzyme that catalyzes the conversion of dopamine to norepinephrine) .
This inhibition causes significantly attenuated basal extracellular DA levels in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC). The decrease in dopaminergic tone was associated with a profound increase in the density of high-affinity state D1 and D2 DA receptors in the NAc and CP, while DA receptors in the PFC were relatively unaffected. As a behavioral consequence of these neurochemical changes, using Disulfiram the patient becomes hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine.
Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures. 2008
Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine. 2006
Disulfiram also inhibits proteasome (a citoplasmatic structure that degrades regulatory proteins of the cell) and NF-kappaB (it is a protein complex that controls the transcription of DNA and that it's involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation and bacterial or viral antigens. So it plays a key role in regulating the immune response to infection).An impaired function of them can lead to abnormal cell proliferation and therefore to develop tumors.
Recent studies have suggested that Disulfiram is are able to bind with tumor cellular copper, forming an active complex with proteasome-inhibitory, apoptosis-inducing and anti-cancer activities, although the detailed molecular mechanisms remain unclear. Copper has been shown to be essential for tumor angiogenesis processes. Consistently, high serum and tissue levels of copper have been found in many types of human cancers, supporting the idea that copper could be used as a potential tumor-specific target.
Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006
Disulfiram significantly inhibited the tumor growth (by 74%), associated with in vivo proteasome inhibition (as measured by decreased levels of tumor tissue proteasome activity and accumulation of ubiquitinated proteins and natural proteasome substrates p27 and Bax) and apoptosis induction (as shown by caspase activation and apoptotic nuclei formation).
In conclusion, inhibitions of proteasome induces cell death, especially in the tumors, as metastatic ocular melanoma.
Disulfiram inhibited both NF-kappaB nuclear translocation and DNA binding activity. The inhibition of NF-kappaB contrasts its protective effect toward apoptosis hence facilitates it.
Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. 2003
Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram. 2006
Pharmacogenomics
Persons of Asian descent possess an ALDH2*2 genetic variant of the ALDH enzyme that metabolizes acetaldehyde slowly and allows it to accumulate. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a flushing reaction similar to that seen with the combination of disulfiram and ethanol. In fact, this ALDH2*2 allele variation is the best-characterized genetic factor protecting against the development of alcohol dependence. Pharmacogenomic research suggests that it is highly unlikely that disulfiram will be helpful in treating a patient who has genetically compromised ALDH function.
Side Effects
Disulfiram given by itself to nondrinkers has little effect; however, flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after drinking alcohol. The effect may last 30 minutes in mild cases or several hours in severe ones.
HANGOVER
When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache.
The drug inhibits the metabolism of many other therapeutic agents:
Several other drugs inhibit aldehyde dehydrogenase and can cause a disulfiram-like reaction if combined with ethanol:
- Cephalosporins: Disulfiram-like reactions noted with cefamandole, cefoperazone, cefotetan, and moxalactam.
- Chloral hydrate: Mechanism not established.
- Metronidazole: Mechanism not established.
- Sulfonylureas: Chlorpropamide is most likely to produce a disulfiramlike reaction; acute alcohol intake may increase hypoglycemic effect (especially in fasting patients).
- Trimethoprim
Patients should be warned to avoid drinking ethanol while taking these drugs and for several days after they discontinue them.
Toxicity
The combination of naltrexone plus disulfiram should be avoided since both drugs are potential hepatotoxins.
Naltrexone is an orally available opioid receptor antagonist that blocks the effects of exogenous and, presumably, endogenous opioids that alter brain responses to alcohol, eg, by decreasing the craving of abstinent alcoholics for alcohol or by blunting the pleasurable "high" that comes with renewed drinking.
