B3: Drug Addiction Flashcards
What is ‘addiction circuitry’?
Where drug-evoked synaptic plasticity outlasts the presence of the drug in the brain.
This contributes to neural circuit reorganization and is the proposed basis of addiction
What is the common target zone of addictive drugs?
All target the Mesocorticolimbic Dopamine (DA) System
This system originates in the Ventral Tegmental Area (VTA) and projects mainly to the Nucleus Accumbens (Nac) and to the Prefrontal Cortex (PFC)
So addictive drugs all increase dopamine (DA) concentration in the projection areas of the VTA, as well as within the VTA itself
How does cocaine increase DA levels?
Increases amount of DA at synapses by directly inhibiting DA transporter (and thus preventing reuptake of DA from synaptic cleft)
How do amphetamines increase DA levels?
Amphetamines are transporter substrates. They are taken up into the cell and enhance the nonvesicular release of DA into synapse
How does nicotine increase DA levels?
Nicotine binds to Nicotinic Receptors on DA neurons
Stimulates presynaptic release of DA in the Nuc (nucleus Accubens(( by stimulating presynaptic cholinergic receptors
How do opioid agonists (e.g. opioids, cannabinoids, GHB etc) increase DA levels?
Opiod agonists target GABAergic interneurons in the VTA that normally inhibit DA release in the Nuc (nucleus accubens)
Loss of GABAergic suppression of DA release from DA neurons = increased DA release into VTA and Nuc
What is interesting about alcohol addiction?
Can occur in the absense of DA mechanisms
Main indications for medical use of benzodiazepines
Anxiety
Sleep Disorders
Sometimes in Epilepsy
Chronic use can lead to addiction
How do Benzodiazepines increase DA levels?
Benzodiazepines bind to GABAa receptors on Interneurons
This prevents normal inhibition of DA release from DA neurons
This there is increased DA release
What is zolpidem and what is it usually used for?
A non-benzodiazepine hypnotic, that works in the same way as benzodiazepines:
Binds to GABAa receptors of Interneurons
This prevents their normal inhibitory action on DA neurons
Thus leading to increased DA release
Usually used for insomia and various brain disorders
What were the warning alerts about Zolpidem released in 2008 and 2013?
May be associated with complex sleep-related disorders: sleep walking, sleep driving and other bizarre behaviours
In 2013, recommended that zolpidem dosages be reduced by 20% due to next-morning alertness impairments
Describe cocaine and amphetamine neuroplasticity changes
Found to increase dendritic sine density, and increase dendritic branching
Found to affect medium spiny GABAergic neurons in the Nuc (nucleus accubens)
And Glutaminergic pyramidal neurons within the PFC
These changes were evidence within 24 hours of drug administration, and persisted for 3-4 months
What is the outcome of repeated exposure to methamphetamine?
Causes long-lasting presynaptic corticostriatal depression (LTD)
-> i.e. affects forebrain functioning
This is relieved by readministration of methamphetamine
Describe the LTD that occurs with long-term methamphetamine use
Synaptic changes - involving alterations in DA and cholinergic receptor systems
Synaptic changes persist long after withdrawal of drug from system
Without the drug, there is long-term corticostriatal depression (depressed forebrain functioning) which is relieved by readministration of methamphetamines
What are the chief pharmacological treatments for alcohol addicion?
Acamprosate
Naltrexone
Disulfiram
Describe the use of Acamprosate in alcohol withdrawal
Outcomes of this therapy in people?
Acamprosate: mixed antagonist of NDMA and mGluR5 glutamate receptors
Thus, it helps to reduce the neuronal hyperexcitability associated with alcohol withdrawal
In some, it redces alcohol craving - some of these people remain abstinent, while others drink less alcohol
Neuronally, what occurs with alcohol withdrawal
List the drug which is used to deal with each of these effects, in the treatment of alcohol addiction
Neuronal hyperexcitability (Acamprosate)
Release of endogenous opioids - enkaphalins and endorphins (Naltrexone)
Guidelines for Acamprosate therapy: initiation of treatment, contraindications, adverse effects
Should be initiated 1 week after cessation of drinking
Contraindicated if significantly impaired hepatic or renal impairment
Diarrhoea, rashes, abdo pain, vomiting, nausea
Long-term benefits/adverse events unclear
Describe the use of Naltrexone in alcohol and opioid withdrawal
Naltrexone competitively inhibits all opioid receptors
remembering that alcohol causes release of endogenous opioids enkaphalins and endorphins
What will happen if drinking alcohol whilst on naltrexone?
Patient will feel less pleasurable effects: naltrexone blocks opiod receptors, thus preventing endogenous opioids released by alcohol (enkephalins and endorphins) from having effect
But alcohol induced impairment remains
Efficacy of Naltrexone?
In whom is it most effective?
Reduced cravings for alcohol, and reduced consumption and relapse rates in some not all patients
Some evidence suggests naltrexone most effeective when used in combination with acamprosate
Most effective in:
Patients with history of binge drinking
Those drinking heavily for 20 years or less
Those with stable social support and living situation
When is Naltrexone contraindicated?
Some states of chronic/acute pain -> as blocks opioid receptors, opioid analgesics will be ineffective. However, NSAIDS and other non-opioid analgesics can still be used to treat pain
How is Disfulfiram used to treat alcohol addiction?
Prevents the metabolism of alcohol by blocking acetaldehyde breakdown
This causes unpleasant and potentially serious effects if alcohol is consumed:
intense flushing, sweating, palpitations, tachycardia, dyspnoea, nausea, vomiting, hyperventilation, pounding headache, chestpains, restlessness, sense of impending doom
Associated steep rise in BP followed by hypotension
Severe reactions may affect the hears, or cause convulsions of LOC
Occasionally death from cardio-respiratory failure -> treatment of the interaction = intensive supportive therapy
Efficacy of and indications for Disulfiram treatment
Commencement
Used only in highly motivated, compliant patients whom understand fully the dangers of taking alcohol during treatment with disufiram
There is marked variation in the extent of resposne to alcohol
Alcohol must not have been consumed for 24 hours prior to commencement of disufiram
After cessation, should remain abstinent for at least 1 week
Doses should be dispensed under supervision of clinic or trusted person
Drugs used to treat Opioid Addiciton
Naltrexone
Methadone
Buprenorphine
Describe naltroxine use in opioid withdrawal
If used on someone physically dependent, will precipitate severe withdrawal reactions -> because is pure opioid receptor blocker
Thus, patients must first go through a gradual withdrawal program, and undergo a ‘naloxone challenge; to confirm abstinence from opioids
I.e. if try to take opioids after that -> they won’t feel the effects of them, because they will be blocked
Why can naltrexone precipitate risk of overdose after cessarion of treatment?
Naltrexone can accelerate the loss of tolerance that occurs with absinence from opioids
Thus, if person tries to take opioids like the used to, after cessation of treatment, they can OD because they will have lost their tolerance
Withdrawal signs associated with opiates?
Sweating, restlessness, vomiting, Pilerection, Rhinorrhoea
How is methadone used for opioid addiction
Methadone = orally active opioid designed to remove the need for IV administration
Idea: take opioid administration from ‘street-scene’ to clinical scene
Indications for methadone use
Short-term use in opioid withdrawal
Long-term substitution for heroin and other opiods
*Thought to be easier to wear addict from methadone compared with heroin or morphine
Advantages of methadone treatment, compared with other treatments for opioid addiction?
High acceptibility, especially in comparison to withdrawal and abstinance-based approaches
Proven effectiveness in reducing illicit opioid use
Features of Methadone Drug
S8
Can be as dangerous as heroin
Variable half life: 15-60hrs
Active for ~4-6 hours. With repeated dosing can extend to 72 hours, but takes several days to reach this steady state
Describe Buprenorphine use in opioid withdrawal
Partial opioid agonist
Effective in reducing illicit opioid use
Dose administered depends on recent opioid use of individual: May precipitate ithdrawal syndrome if have had recent large dose of opioid and buprenorphine dose not properly matched
Benefits of buprenorphine compared with methadone
Lower overdose risk
Less dependence
(by virtue of it being a partial opioid agonist)
Effects can be reersed with high doses of naltrexone -> will block effects of opioid analgesics
Aims of pharmacological nicotine addiction therapy
Reduce severity of tobacco withdrawal symptoms
To increase likelihood of smoking cessation
Drugs used for nicotine addiction
Bupropion
Varenicline
Use of Bupropion in nicotine addiction
+ a contraindication
Possible action due to its inhibition of neuronal reuptake of dopamine (DA) and noradrenaline (NA)
Can worsen psychiatric conditions
Varenicline for nicotine addiction
+ a contraindication
Blocks nicotine from binding to ACh nicotinic receptors
This prevents pleasurable effects of smoking
Has partial agonist activity which reduces symptoms of withdrawal
Post-marketing reports of worsening psychiatric conditions
Describe the steps of the approach to addiction
Precontemplation: no thoughts about changing behaviour
Contemplation: Thoughts about the need/desire to change but no action yet taken
Preparation: Ready to take action
Action: Attempts made to change behavious and avoid environmental ‘triggers’
Maintenance: Behaviour has been changed and the person is adjusting to these changes and working to prevent relapse
