Module 39 Flashcards
What is the mechanism by which naltrexone appears to be effective in the treatment of alcoholism? What are the other treatment options for alcoholism?
- It appears that an important component of any addiction is dopamine release. Although it is the µ-opioid receptor that naltrexone blocks, it appears that this modulates the dopaminergic mesolimbic pathway, possibly through endogenous opiates that are augmented in alcoholics when they drink alcohol. As with most things it is complicated. Naltrexone has limited effectiveness unless the patient is highly motivated to quit.
- Disulfiram works by inhibiting aldehyde dehydrogenase, so if patients are willing to take it regularly, but then they drink alcohol, they become very sick; a type of aversion therapy. Other treatments include acamprosate and benzodiazepines, which treat the symptoms of withdrawal.
What is the difference between metabolism of alcohol in men and women?
- There really is very little difference.
- On average, women do have higher levels of blood alcohol given the same dose, but this is mostly a function of body weight. Alcohol distributes very well to all parts of the body, and therefore size matters.
Why do many individuals of Asian decent exhibit facial flushing when they drink alcohol?
- On average, individuals of Asian decent have low, but not absent levels of aldehyde dehydrogenase. Therefore, they have a small amount of acetaldehyde build up; not enough to make them sick, but enough to cause vasodilation, especially in the face.
What is melatonin promoted for? Is the observation that it scavenges hydroxy radicals important? What is the evidence of efficacy and safety?
- Melatonin is promoted as a sleep aid. There is some evidence that it has some efficacy for jet lag, but its effectiveness is limited. Most melatonin is synthetic, but some is derived from cattle brains, and that raises the concern of bovine spongiform encephalitis. The usual dose of melatonin used as a sleep aid is much higher than the amount produced by the body
The claim that it scavenges hydroxy radicals, and is therefore a good antioxidant is ludicrous. Hydroxy radicals are so reactive they react with everything. It would be extraordinary if melatonin did not react with hydroxy radicals. Given that the reaction of hydroxy radicals is nonselective, the only way that melatonin could decrease the reaction of hydroxy radicals with other endogenous molecules is if it were present at a higher concentration, and it is impossible to achieve melatonin levels higher than other molecules in the body such as proteins, fats, etc.
What natural product originating in the South Sea islands has been claimed to be effective for the treatment of anxiety? What serious toxicity has been associated with this agent? What structural feature suggests that it may lead to drug interactions?
- Kava is produced as a aqueous extract from the roots of the shrub Piper methysticum. It contains kava lactones, which have sedative and euphoriant effects. Its use by local populations sometimes leads to abuse.
- Its traditional use is often associated with mild liver injury as determined by an increase in serum ALT, but it did not appear to cause liver failure with traditional use. Its chronic use is also associated with a characteristic rash.
Some of the kava lactones have a methylenedioxy structure, a classic inhibitor of P450.
- Its traditional use is often associated with mild liver injury as determined by an increase in serum ALT, but it did not appear to cause liver failure with traditional use. Its chronic use is also associated with a characteristic rash.
What other “natural” product is used for sleep, and contaminants in the product led to many cases of eosinophilia-myalgia syndrome?
- Tryptophan has been used to promote sleep. It is the precursor of serotonin and melatonin.
What “social” drug is likely responsible for more deaths than any other?
- Tobacco.
- Cigarettes are responsible for ~40% of all cancers in North America. Alcohol comes next, and can cause many other problems such as the breakup of families
What are the possible medical uses of marijuana, and what is the evidence of its efficacy?
- Marijuana has been promoted for the treatment of many different conditions including seizures, to increase appetite, especially in cancer patients, pain, and glaucoma. Unfortunately there is little data to support its use for most indications, especially because it has been illegal and very hard to do well designed studies. It is likely that most of the touted benefits are greatly overstated.
- We simply do not have good data on its possible long-term effects when used by young people.
What other component of cannabis does not have the intoxicating effect of THC and has been approved for the treatment of seizures?
cannabidiol
What drug candidate targets the marijuana receptor but has very different pharmacological effects? What side-effect prevented its approval?
Rimonabant is a reverse agonist (it binds to the receptor, but it has the opposite effect as an agonist) for the cannabinoid receptor CB1, which was developed to treat obesity (The reverse of the “munchies”). It also appeared to have efficacy to help with smoking cessation. However, it caused an unacceptable risk of severe depression with suicidal thoughts, and it was not approved.
