mark (L13) Flashcards
define substance abuse
Substance abuse (WHO) refers to the harmful or hazardous use of psychoactive substances, including alcohol and illicit drugs
define drug dependence
Drug dependence is the body’s physical need, or addiction, to a specific agent
economic cost of drug addiction
Drug addiction —places an enormous burden on society
through its repercussions on crime rate and healthcare.
The economic costs of addiction have been estimated
at 80 billion dollars in the United States alone (1999).
COST OF ILLICIT DRUG USE IS £10.7bn / YEAR
8% health service use
10% enforcement
28% deaths linked to eight illicit substances
54% drug related crime
why are certain drugs addictive?
Hypothesis: they intervene with reward behaviours
Nuclei release dopamine (VTA is the main area that releases reward signals and pleasure signals)
Frontal cortex - decision making
VTA - ventral tegmental area
why do we need reward pathways?
Drugs “kidnap” brain reward circuits
Why do we need reward pathways? To rewards us for signals that promote survival: Food consumption Drinking water Procreation Child nurturing/rearing They reinforce behaviour for repetition So called natural re-inforcers
Most addictive drugs increase dopamine release
dopamine pathways functions
reward and otivation pleasure and euphoria motor function and fine tuning compulsion perseveration
serotonin pathways functions
mood
memory processing
sleep
cognition
effect of drugs on everyday mood (also define salience)
The drugs release high levels of dopamine so that the normal levels of everyday life become too low in comparison
Salience - the feeling of wanting more
(drugs can override the self regulation, if there is strong memories of enjoyment last time they took the drugs, so salience is overcome and increases, drive increases, they take more)
define incentive salience
Incentive salience: cognitive process which confers a “desire”
or “want” attribute, including a motivational component,
to a rewarding stimulus. This is hi-jacked by drugs
Drugs over-ride top-down control
Drive is compulsion
skinner’s box study
Skinner’s box - give the rodent either a drug or a sweet substance
Measure the prevalence score - does it prefer to take the drug or the sweets
Increase the number of times the animal has to activate the lever to get the drug to see how committed they are to getting that drug
You can keep increasing the number of times they have to push the lever to see when the rodents decide that the drug isn’t worth it anymore
You can show the difference between the addictions of different drugs
For example study addiction of heroin VS tobacco
They will be more motivated to push the lever more times for heroin than for tobacco
the 2 types of dependence
- Physical dependence
- Results from adaptation by resetting homeostatic mechanisms in response to repeated drug use
- Withdrawal syndrome: direct evidence of physical dependence
- Withdrawal arises due to abrupt termination of drug use
- Appearance of signs and symptoms during withdrawal are characteristic of the drug category - Psychological Dependence
- Motivational component, craving for the drug
- Not always associated with physical dependence
- Some drugs (cocaine) psychological dependence can persist for very long periods
types of tolerance
Reduction in response to the drug after repeated administrations. Thus need increasing concentrations of
drug to get the same effect.
- Innate tolerance
Genetically determined sensitivity i.e. occurs after first dose - Acquire tolerance
Pharmacokinetic
Changes in metabolism and absorption reduce systemic blood concentration
Pharmacodynamic
Adaptive changes within the system resulting in altered response to the drug i.e. receptor desensitisation
- Cross tolerance
cocaine and amphetamines
benzodiazepines and barbiturates
Pharmacodynamic tolerance and G coupled proteins
Dopamine - works for a G protein coupled receptor
It has 7 transmembrane regions, an alpha subunit and a beta gamma subunit
the agonist binds and when you activate gpcr are the G protein dissociates to the alpha and beta gamma which can both signal
the receptors can be phosphorylated by these GRKs or by B arrestins
arrestins can become desensitised - don’t work anymore
disconnect as a signal so that the receptors can be internalised through endocytosis
the effect of the receptors are very rapid
early desensitisation within a minute or so
this effect on the receptor numbers on the surface and can still happen after an hour but ? can last for many weeks
receptors can be recycled back onto the membrane
there are short term tolerance effects of desensitisation or longer affects where there are less receptors on the cell surface which reduces the effect of the receptors
Principles for the effective treatment of drug addiction
Criteria for effective treatment:
1) Quick and easy access to treatment.
2) Addresses all of the patient’s needs, not just their drug use (including mental health problems etc)
3) Patient must stay long enough in treatment.
5) Requirement for counseling and other behavioral therapies.
6) Medication is often an important part of treatment in combination with behavioral therapies.
7) Drug use during treatment must be monitored continuously.
8) Treatment programs should test patients for HIV/AIDS, hepatitis B and C, tuberculosis, and other infectious diseases as well as teach them about steps they can take to reduce their risk of these illnesses
Pharmacological approaches to treating drug dependence
- Alleviate withdrawal symptoms
methadone to blunt opioid withdrawal - Long term drug substitution
Methadone, buprenorphine, or legal heroin - Blocking response to the drug
Naltrexone to block opioid effects - Aversive therapies
Disulfiram to induce unpleasant response to ethanol - Reducing continued drug use (treat underlying mental health problems)
Benzodiazepines to treat anxiety, anti-depressants etc.
using disulfiram (antabuse)
Not used very often
Treats alcohol addiction
It breaks down alcohol by alcohol dehydrogenase
Aldehyde broken down by aldehyde dehydrogenase
Drinking alcohol will build up the aldehyde in the liver
Accumulation of acetaldehyde: Hot flushed face Pulsatile headache Nausea and vomiting, sweating Confusion Blurred vision Hypotension Orthostatic syncope
Has to be taken daily
Symptoms can occur within 10 minutes and can last several hours
Extremely unpleasant
Very small amounts of alcohol can precipitate reaction ie in mouthwashes, medications etc
COCAINE ADDICTION
define euphoria, dysphoria, paranoia and psychosis
Euphoria: increased cognition, motor
performance, hyperlert, hyperactivity,
insomina, anorexia.
Dysphoria: sadness, apathy, anorexia,
insomnia
Paranoia: suspiciousness, hallucinations,
Insomnia
Psychosis: anhedonia, hallucinations,
sterotypical behaviour, delusions etc
–> Can experience all these stages with single high dose or with chronic lower doses
cocaine addiction - 2 types of uses
DIAGRAM IN L13 S17
naive and chronic use
cocaine modulating reward pathways
Cocaine is an uptake blocker of dopamine - blocks the transport of dopamine and 5HT serotonin Works in the VTA, especially where VTA releases dopamine in the nucleus accumbens (controls euphoria) Local anaesthetic (like any drug that ends in -aine) Most cells are spinal neurons
Changes in prefrontal cortex causes changes in the synapses occurring in the nucleus accumbens
Also changes in the prefrontal cortex because of the release of dopamine up there, and the 5HT pathway which is across the prefrontal cortex
Increase dopamine - increase of the reward from the nucleus accumbens
cocaine modulates synaptic properties
- changes AMPAR levels
- impaired cystine glutamate exchange
- changes in intrinsic membrane excitability of MSN
(( Many homeostatic changes in synapse
Cocaine blocks the uptake transporter
Increases dopamine conc
Has a lot of effects because of adaptation
At first will get an effect, then over time everything will be rewired ))
Cocaine withdrawal
THE CRASH Day 1 to 4 after a binge Lack of energy and motivation. Increased hunger. Irritability. Anxiety. Fatigue. Extreme depression.
WITHDRAWAL Week 1-10 Trouble concentrating. Low energy. Changing moods. Dysphoria (general feeling of dissatisfaction with life). Anxiety. Paranoia. Depression. Cravings. EXTINCTION Indefinite Low mood. Episodic cravings.
Treating cocaine addiction
Currently no specific pharmacological interventions (psychedelic drugs?)
- Contingency management (CM). Use a voucher-based system that rewards patients who abstain from cocaine and other drugs. On the basis of drug-free urine tests, the patients earn points, which can be exchanged for items that encourage healthy living, such as a gym membership, food vouchers etc.
- Cognitive-behavioral therapy (CBT) is an effective approach for preventing relapse. This is a talking therapy that helps with management of problems by changing the way to think and behave.
CBT helps patients develop critical skills that support long-term abstinence—for example recognize the situations in which they are most likely to use cocaine, avoid these situations.
Mechanisms of opioid action
Rush: activate opioid receptors on GABA neurons in the VTA which increase dopamine release Into nucleus accumbens
Chronic consumption: reduces cAMP production (blue): adaptation occurs (red) thus when opioids are stopped
get rebound cAMP leading to hyperactivity.
Also get a fall in dopamine receptors (leads to tolerance)
Very similar to cocaine
Doesn’t block dopamine release, but blocks receptors on GABA neurones in the VTA (so it isnt inhibited as much as normally so releases even more dopamine than normal)
Opioid receptors reduces cAMP
When you take morphine, you will get a fall in cAMP
This recovers slowly because you get tolerance to morphine
So the manocyclic amp that neurons are producing slowly increases
If you take naloxone, the reason you recover is because of the increased expression of adenyl cyclase - increases camp and you start getting some tolerance
If you immediately withdraw, you have more adenyl cyclase than normal conditions, you will get a massive overshoot of camp
This produces the withdrawal effects
opiate withdrawal timeline
6-12h short acting opiates, symptoms begin
30h long acting opiates
72h symptoms peak
SYMPTOMS AT 72H nausea vomiting stomach cramps diarrhea goosebumps depression drug cravings
Untreated withdrawal: symptoms occur within 8 hours: peak symptoms at 36-72 hours
Symptoms subside after 5 days
Treating opiate addiction
Alleviate withdrawal symptoms
methadone to blunt opioid withdrawal
Long term substitution
Methadone, buprenorphine, or legal heroin
Methadone is the medication with the longest history
of use for opioid use disorder treatment, having been
used since 1947.
Patients on methadone had 33 percent fewer opioid-positive drug tests and were 4.44 times more likely to stay in treatment compared to controls
–> Methadone is reasonable effective, no withdrawal, no high, can be taken orally
Use of methadone for maintenance and withdrawal (UK)
- Initiate at least 8 hours after last heroin dose
- Long half life means plasma concentration will rise during initial treatment (takes 3-10 days to stabilise). Thus may need to reduce dose
- Withdrawal time: 4 weeks as impatient; 12 weeks in community
- Enforced withdrawal is ineffective: if patient cannot tolerate withdrawal remain on maintenance therapy
- Following withdrawal need support for at least a further 6 months
- If miss 3 days or more of regularly prescribed methadone at risk of
overdose because of loss of tolerance - If more than 5 days test for illicit drugs (very important for buprenorphine as precipitated withdrawal, next slide )
Buprenorphine
- Preferred by some patients (i.e. if driving/skilled tasks for living) as less sedating than methadone
- Can be given on alternate days and has fewer drug interactions than methadone. Lower risk of overdose than methadone
- Can precipitate withdrawal in patients dependent on high doses of opiates
- Currently available in two forms: alone (Subutex) and in combination with the opioid receptor antagonist naloxone (Suboxone).
- Suboxone is designed to deter misuse: naloxone has no effect so long as the drug is taken orally, (poor absorption). If it is crushed, dissolved, and injected, the naloxone blocks the effect of the buprenorphine.
(( PARTIAL AGONIST SO doesn’t make the patient very sedated (good if they have a job)
Suboxone has naloxone in it (naloxone isn’t active orally, only by injection). So if you take this tablet, only buprenorphine will be absorbed and naloxone wont
If you crush the tablets and inject them, then the naloxone will be active and will block the effects of buprenorphine ))
Naltrexone (opioid receptor antagonist)
- Naltrexone is an antagonist that does not produce tolerance but precipitates withdrawal.
- Poor adherence limits its effectiveness. As a result, there is insufficient evidence that oral naltrexone is an effective treatment for opioid use disorder.
- Is given to patients to be used in case of accidental overdose
- It is prescribed as an aid to prevent relapse in formerly opioid-dependent patients.
(( This can be used to prevent relapse because if the patient has completely withdrawn, and they did relapse, it wont have any effect because they have the antagonist there ))
symptoms of nicotine addiction
In active smokers, a lack of nicotine produces a wide range of withdrawal symptoms, including:
Headache. Nausea. Constipation or diarrhea. Fatigue, drowsiness and insomnia. Irritability. Difficulty concentrating. Anxiety. Depression.
Symptoms wane after about 2 weeks
Treatment of nicotine addiction
NICOTINE REPLACEMENT
Reducing craving and physical withdrawal symptoms
Nicotine is poorly absorbed orally and short half life need to take oral preparations several times a day (chewing gum)
Transdermal patches replaced daily
E- cigarettes- mimic cigarettes. The dose of nicotine delivered is unclear and effectiveness has still not be determined. However recently been approved as withdrawal method by NHS
VARENICLINE - partial nicotine agonist
BUPROPION - nicotine antagonist
Ethanol
Complex effects across many neurotransmitter systems
Alcoholism is common: 4-5 % of the population
PHARMACOLOGICAL TREATMENT
- Acamprosate calcium SR tablets : used along with counselling.
- Used after abstinence has been achieved
- Weak NMDAR antagonist reduces craving
When used alone, acamprosate is not an effective therapy for most individuals;
works best when used in combination with psychosocial support since
DISULFIRAM (not used very much)
- Alleviate withdrawal symptoms: benzodiazepines, clomethiazole, clonidine, propranolol
- Opioid receptor antagonists reduce the effects of endorphins that play a role in the reward properties of alcohol.
Do drugs of addiction share a common pathway?
DIAGRAM IN L13 S37
