6/19- Alcohol/Substance Abuse 4: Flashcards
What kind of drugs are used to treat alcoholism relapse prevention?
Opioid antagonists
What treatments (3) are used to treat nicotine dependence?
- Varenicline
- Selegiline
- Nicotine vaccine
What is the priming effect?
Think: Lay’s potato chips
- Once you start, it’s hard to stop; start craving more rather than satisfying the craving
What are the mechanisms for Naltrexone’s efficacy in the treatment of alcohol dependence?
- Craving reduction
- Modifying experience of intoxication
- Inhibition of the priming effect of the initial drink
What is the process in which alcohol stimulates ___ receptors?
Opiate receptors
- Alcohol raises beta endorphin, stimulating mu opiate receptors
- Stop alcohol, beta endorphin drops and craving starts
- Continued alcohol use or withdrawal starts
- Alcohol raises…
How does Naltrexone alter the process in which alcohol stimulates opiate receptors?
- Naltrexone raises beta endorphin
- Alcohol can not raise BE
- Relapse prevented
Which patients are more responsive to Naltrexone?
- More complex and severely dependent patients may be better for naltrexone Genetics may play a role
- Strong family history of alcoholism
- Get biggest response in group that have > 50% of relatives with alcoholism
- Genetic responsivity: mu opiate receptor polymorphism
What was found in the relative BE levels in sons of people with alcoholic fathers?
- Much much lower levels than control
- Lower even than the BE levels of someone who was abstinent after being alcohol dependent
How does B-endorphin level change after alcohol consumption in sons of alcoholics?
Get a significant raise for relatively small amount of alcohol
Comparison between family history positive and negative people on Naltrexone?
- Left: half a glass of beer on placebo
- Placebo did not have much effect on FH+
- Right: 2 glasses of beer on Naltrexone
- Response of FH+ group was normalized!
What are pharmacogenetics?
Effects of genetic polymorphisms on pharmacological effects of drugs or medications
- Matching patients to treatments based on genetics
- Personalized medicine
Mice without u opiate receptors will not do what?
Self-administer alcohol
What gene was found to be relevant for alcoholism and beta endorphin?
Human Mu opioid receptor gene
- Can make normal levels of beta endorphin, but receptor is 3-4x more sensitive than normal
- OPRMI1 gene sequence: 118 A -> G exon 1 SNP increases OPRMI affinity for BE
What gene was found to predict Naltrexone response in alcoholics?
Again, mu-opiate receptor involved
- Asn40Asp variant
- 24-36% of Europeans; associated with alcoholism in Swedes (accounting for 11% of inheritence)
- Functional polymorphism -> 3x increase in beta endorphin binding to mu receptor
- Best response (non-relapse) with polymorphism (95%)
What is an endophenotype?
Endorphin dependent alcoholism
- Alcohol -> increase in endogenous opioids
- Euphoria/stimulation
- Sensitive mu receptors
- Family history
- Alcohol craving
What are some strategies that have had limited efficacy for nicotine dependence?
- Nicotine replacement therapies
- Buproprion
Best quit rates come with what treatment (early on)?
- Both Buproprion and Nicotine patch seem to help the most
- However, at a year, they’re all about the same (20%)
Approved medications for treating nicotine addiction?
- Nicotine patch, gum, lozenge, inhaler, spray
- Buproprion (anti-depressant)
- Varenicline (Chantix): partial nicotinic receptor agonist (a4B2 receptor)
(Nicotine vaccine promising; on the way)
Most new drugs are what class? Mechanism?
Partial agonists
- Agonists at low doses
- Antagonists at high doses
Nicotine stimulates what pathway?
Varenicline stimulates what?
- Mesolimbic path (from VTA -> nucleus accumbens)
- Same is stimulated by Varinicline; main action is at VTA (results in lesser amount of DA release from VTA at nAcc as well as prevention of nicotine binding at the a4B2 receptors)
T/F: Varinicline continues to have a significant effect/benefit after a year?
True
What is the mechanism of Bruproprion?
Its a reuptake inhibitor at the DA receptor; perhaps reducing some of the DA deficit occurring with addictions (but not entirely sure why it works)
- Primarily an anti-depressant
What is the mechanism of Varenicline use for nicotine addiction?
- Mu-opiate receptor and DRD2 (dopamine D2 R)
- Varenicline is like nicotine replacement therapy (NRT), but PARTIAL rather than full agonist
What genetic variations may affect response to Nicotine addiction treatments?
- Mu-opioid receptor OPRM1: Asn40Asp variant predicts response to NRT; having it means you’re more likely to respond to NRT and Varenicline
- DRD2 141 ins/del: del C allele predicts better response to NRT (nicotine replacement therapy) than buproprion
What is Selegeline? How is it used in the treatment of nicotine dependency?
- Monoamine oxidase inhibitor
- One of the initial anti-depressants
- One of the components in tobacco smoke is a MAOI (A and B types); MAO-B decreases DA (need to increase it to treat nicotine dependence and to give up smoking)
- Selegeline is used to replace this
- Now used to treat Parkinson’s disease
Rationale/mechanism for anti-nicotine vaccine?
- Nicotine is not immunogenic; in this case bound to cholera toxin
- Vaccine generates Abs against nicotine
- Abs mop-up nicotine in the blood
- Nicotine is unable to reach the brain
- Applicable to therapy and prevention
So, Abs can reduce drug’s brain concentrations (retained in blood)
- Animals will stop self-administrating
T/F: Drugs of abuse easily enter the brain?
True
- There are binding receptors in the brain
- Suck out of bloodstream and drive equilibrium
T/F: Taking drug slowly prevents abuse-enforcing behavior
True
What are the different human nicotine vaccines?
- Xenova product: TA-Nic
- NABI nicotine vaccine
- Cytos product
Conclusions:
- Nicotine replacement and bupropion have limited utility for sustained abstinence,
- But pharmacogenetic matching is promising for varenicline –nicotine partial agonist
- Selegiline may improve abstinence
- Nicotine vaccine entering phase 3 testing with good efficacy at sufficient antibody response
- Alcohol relapse prevention is effective using naltrexone – opiate antagonist
- Pharmacogenetic matching based on opiate pathophysiology of disease defining an endophenotype is critical for efficacy
- Nicotine replacement + varenicline developing pharmacogenetic matching
- Nicotine vaccine and selegiline promising
(:
