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Pharmacotherapy - Coggle Diagram
Pharmacotherapy
Treatments for
Alcohol
acamprosate
- alcohol increases the inhibitory neurotransmitter GABA and decreases the excitatory neurotransmitter glutamate.
- results in reduced activity broadly across the brain
- chronic occupancy of these receptors following chronic alcohol consumption results in downregulation and desensitisation.
- withdrawal produces the converse changes in neurotransmitter activity > dangerous increase in brain excitation > can cause neurotoxicity convulsions, and death.
- can oppose the neural effects of withdrawal
- boismare et al 1984: showed that rats reduced their alcohol consumption over 15 days given daily co-administration of acamprosate
- not clear if acamprosate reversed withdrawal or competed with the direct rewarding effects of alcohol, or both.
naltrexone
- a competitive antagonist of opioid receptors, which blocks the function of endogenous endorphins.
- naltrexone should not be confused with naloxone, which is for opioid overdose.
- initial reports showed that naltrexone reduced alcohol consumption in animal models, and has shown to have clinical efficacy.
- naltrexone and acamprosate combined produce additive treatment effects.
- taken together, they have different mechanisms of action and they combine to produce a broader protection from relapse.
- maisel et al (2013): *acamprosate increased the number of abstinent days to a greater extent than naltrexone. however, naltrexone reduced craving and heavy drinking sessions whereas acamprosate did not.
- acamprosate promotes abstinence by ameliorating withdrawal, whereas naltrexone promotes abstinence by blocking the euphoric effects of alcohol consumption produced by endorphin release.
disulfiram (antabuse)
- was once the only medication for treatment of alcoholism
- blocks acetalhyde dehydrogenase, which is the liver enzyme that breaks down alcohol in the liver
- results in an increase in sensitivity to alcohol consumption, and an array of aversive symptoms.
- flushing of the skin, accelerated heart rate, shortness of breath, nausea, vomiting, headaches, visual disturbances,
- idea was not that the addict would experience these symptoms and stop their alcohol use (taking disulfram and drinking is dangerous, so those who cannot stop drinking are not allowed to take disulfram)
- compliance is low > people on disulfram tend to just stop taking it so they can have a drink.
- depo treatment > slowing the release of disulfram in the body so it doesn't need to be taken every day.
- doesn't maintain adequate plasma concentrations of disulfram
- doubt being casted on the efficacy of disulfram in promoting abstinence
Treatment for
Nicotine
nicotine replacement therapy
- nicotine replacement, like gum, patches, etc, were found to have efficacy in improving abstinence following a quit attempt.
- 1967: Dr. Claes Lundgren suggested oral nicotine as a substitute for tobacco based on the observation that sailors sometimes switched from smoking to chewing tobacco without any difficulty when assigned to submarine duty.
- ove ferno recognised the commercial potential of nicotine replacement and embarked on a research program to desin a means to orally administer nicotine with delayed absorption (gum).
- fixing the nicotine into an ion exchange resin and putting that into a chewing gum to enable the chewer to control the rate of release.
- stead et al. (2008): NRT group was 58% more likely to remain abstinent than the control group
- wang et al (2008): NRT appears to be effective at reducing the frequency with which individuals smoke, and so should be used long term until full abstinence is finally achieved.
- absolute quit rates remain low > somewhere between 6-16% if NRT participants remained abstinent after six months, whereas about 2-10% of placebo participants remained abstinent.
- the proportion of those reducing their cigarette smoking by more than 50% at 6 months is 23.7% for NRT patients and 13.5% for placebo patients.
- effective at reducing the frequency at which individuals smoke > should be used long-term until abstinence is achieved.
bupropion (zyban)
- tobacco withdrawal syndrome is characterised by an increase in depression, which is linked to an inability to quit smoking.
- antidepressant agents might protect relapse by ameliorating depression.
- similar to other antidepressants where it acts as a dopamine and noradrenaline reuptake inhibitor. antagonist for acetylcholine receptors.
- blocks the primary neural target for nicotine, and thereby may improve abstinence by blocking the rewarding effects of nicotine, rather than by reversing withdrawal-induced depression.
- claim is supported by the observation that antidepressants with no affinity for acetylcholine receptors have no efficacy for smoking cessation.
- small superiority over nicotine replacement therapies in promoting abstinence.
- hurt et al (1997) bupropion found to produce superior quit rates compared to placebo.
varenicline (champix)
- pfizer rationalised that a partial agonist would combine both properties and be more effective as a treatment, rather than either alone.
- acetylcholine partial agonist would serve as a weak nicotine replacement agent, activating acetylcholine neurons to reverse withdrawal related hypofunction, but would also block the acute stimulating effects of smoking by competing with nicotine from smoking.
- varenicline appears to be slightly more effective as a smoking cessation agent than either NRT or bupropion.
- absolute quit rates remain low > short term abstinence = 25% for varenicline vs 15% for placebo.
Antagonists and
Agonists
agonists
- activate receptors to increase their function, either exciting or inhibiting the cell, depending upon which ions the associated channel allows across the membrane.
- full agonist: activate the receptor to its maximal response
- partial agonist: activate the receptor to less than its full response.
- function as competitive antagonists, by eliciting a submaximal response.
- thought important to ameliorate withdrawal, and block the full effect of the addictive drug
- indirect agonist: enhance the function of endogenous neurotransmitters indirectly without activating the receptors for that neurotransmitter themselves > blocking transporters, inducing neurotransmitter release, and/or inhibiting neurotransmitter metabolism
antagonists
- fit a receptor imperfectly, and thus, block the action of the endogenous neurotransmitter that would otherwise act upon that receptor.
- the antagonist has no direct effect on the channel itself.
Treatment for
Opiates
methadone
- opioid agonist with high oral bioavailability and long half-life (takes a longer time to be broken down by the body)
- developed in germany in the 1930s > similar biochemical process to those in the manufacture of heroin and morphine.
- longer half-life makes it useful in therapy
- morally tolerance harm reduction strategy, which effectively ameliorates heroin withdrawal, weans addicts from straight heroin, reduces black market distribution, reduces overdose or poisoning from impurities, and reduces disease transmission from needle sharing.
- politically polarising
- oral administration must be carefully supervised in-house by treatment clinics > treatment is limited by distance, and how close a person is to a clinic.
suboxone
- combination of buprenophrine (partial opioid receptor agonist) and naloxone (opioid receptor agonist).
- naloxone has poor bioavailability, so oral administration of suboxone is effectively rewarding, because the buprenophrine effect dominates.
- cannot be injected > not rewarding, because the naloxone counters the opioid agonist effects.
- reduces fear of addicts taking large amounts of suboxone home and injecting themselves for the rewarding effects.
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Background
- behavioural therapies persuade or empower addicts to remain abstinent, whereas pharmacotherapies seek to modify the biological processes underpinning the motivation to take drugs.
- some compounds block the neural substrates of reward and thus block the euphoric effect of the drug.
- other compounds provide a weak analogue of the drug to ameliorate withdrawal symptoms and perhaps transfer dependence to wean the addict off the drug.