polyaddiction Flashcards
What is polypharmacy and what are the forms of polypharmacy?
Having more than one drug in the body at the same time
- purposeful
- MDMA followed by cannabis or benzos
- cocaine and heroin
- unintentional
alcohol and cocaine
- medicinal and recreational
SSRI and MDMA
What are the different ‘timings’ for taking multiple drugs?
- concomitant use
cocaine plus heroin- sequential use
MDMA followed by cannabis/benzos - chaotic use
alcohol, cocaine, MDMA etc
- sequential use
4 different mechanisms of interaction?
behavioural
- pharmacological - pharmacokinetic altered absorption altered metabolism - social (alcohol leading to heroin)
Why is mixing cocaine and alcohol dangerous?
cocaine metabolised by carboxylesterases
carboxylesterase 1 cleaves cocaine, producing BE (benzoylcgonine)
carboxylesterase 2 cleaves cocaine, producing EME (ecgonine methyl ester)
neither are particularly toxic and are benign metabolites that are excreted
but in the presence of ethanol, carbocylesterase 1 doesn’t just cleave cocaine but produces this new compound called CE (cocaethylene)
CEis cardiotoxic- 20 times greater risk of sudden death with cocaine and alcohol than cocaine itself
Describe the issue of opioid poisoning
number of deaths from opioid overdose increasing
from 2009 to 2016 people were prescribed with a lot of oxycodone
prescribing was controlled from 2011
fentanyls are a big problem in usa, used largely in cancer and pain relief
Heroin addicts frequently take other drugs including
Alcohol
Benzodiazepines
Cocaine (speedballing)
Pregabalin/gabapentin (new phenomenon)
What were the conclusions of the 2007 NTA report on opioid poisonings?
Ethanol present - morphine levels were 20 -50% lower
(suggests that concurrent alcohol use lowers the lethal heroin overdose threshold)
Cocaine - associated with elevated morphine levels
Benzodiazepines - no correlation with morphine levels
drinking alcohol means less morphine is needed to kill you
when heroin is taken it basically breaks up into morphine
Ethanol present - morphine levels were 20 - 50% lower
(suggests that concurrent alcohol use lowers the lethal heroin overdose threshold)
Inverse relationship between
post-mortem morphine and alcohol levels
- Discounts idea that they get drunk and inject too much
How to explain the low morphine/low ethanol group?
they have synergistic effect so even thought they were in lower concentrations, became fatal
How do opiates and alcohol interact
Additive depressant effects? (the common ‘wisdom’)
Synergistic effects?
Alcohol reduces opioid tolerance?
Alcohol enhances likelihood of relapse in situations
of reduced tolerance (e.g. after detox)?
additive is a bit simplistic
synergistic- opioid and ethanol might together give much bigger effect than just additive
reduced opioid tolerance- bigger effect
if someone is detoxed and then have a drink, the same dose of heroin might give a bigger effect
How to investigate opioid overdose deaths from respiratory depression in animal studies
produce a situ to study effects of alcohol and heroine without impairments of HIV/liver infection- often the case in people so can be easily studied in lab
connect an air canister to a gas flow regulator
attach to mouse inside a plethysmograph generator
connect to transducer and monitor respiratory depression on computer
can also investigate tolerance to morphine as mice who are given morphine earlier have less respiratory depression- producing higher minute volume due to tolerance, compared to mice who were given no morphine beforehand
In the same experiment what was the impact of giving ethanol?
The tolerance to morphine was REVERSED upon giving ethanol
Low dose ethanol has no effect alone
Ethanol does not potentiate or summate with morphine in naïve animals
Low dose ethanol reverses tolerance
However, ethanol does not reverse the effect of
chronic methadone or buprenorphine as it does in morphine
same experiment with opioid subs (daily oral methadone or buprenorophine)
most people on opioid sub treatments will relapse and take heroine
this reduces tolerance and less effect
ethanol DOESNT reverse action of methadone and buprenorphine showing it’s selective to heroine
Ethanol reverses cellular tolerance to morphine
in rat locus coeruleus neurones
How is the mechanism for mu opioid receptor desensitization agonist dependent
the grey circle represents a cell
on the cell you have the mu opioids receptor which is what morphine acts on
DAMGO, P, arrestin and GRK on the left of cell
morphine and PKC binding on the right of cell
we have used DAMGO as an opioid agonist for a prolonged periof time, the receptor desensitises
then we give morphine. The desensitisation is driven by PKC
but when we give DAMGO it is driven by GRK (GPCR) through the binding of arrestin
the differnce between morphine and damgo is that morphine has low efficacy
damgo has high efficacy- full agonist
the ability to produce desensitisation differs with different agonists according to their efficacy
Does ethanol reverse m-opioid receptor
desensitization by inhibiting PKC?
methadone and fentanyl have high efficacy like damgo going through the GRK arrestin mechanism
heroine/morphine. oxycodone go through same efficacy
but ethanol does not reverse the tolerance for methadone but reverses the tolerance for heroin/morphine , oxycodone
what we think is that ethanol doesn’t inhibit PKC directly, but PKC sits around in the cytoplasm and once the receptor has been activated ethanol stops the movement of PKC from the cytoplasm to the receptor
Heroin users taking pregablin and gabapentin?
can pregablin and gabapentin be contributing to heroin overdose
use gabapentin (GABA structure w side chains) to take orally and cross BBB in brain to treat epilepsy as an anticovulsant
pregablin has the GABA structure with chains added on, unsaturable unlike gabapentin- if you take more it is absorbed into the blood
neither gapapentin or pregablin work on GABA receptors
intiially thought that pregablin is good for epilse[sy, then pain then anxiety
so the number of prescriptions dramatically increased over the years
this means increased availability has led to abuse
number of deaths with gabapentanoids present in blood correlate with availaility of drug through prescriptions
but they were not just present alone- they seem to be take WITH other drugs- usually opioids with the gabapentin is what causes opioid overdose deaths
What are some perceived effect of gabapentinoids
- give a buzz on their own (feeling of being drunk)
- gouching
- enhance the effect of the heroin
- caused blackouts and loss of control (zombies)
- increased the risk of overdose
- helps to cope with withdrawal between heroin doses
- reduced craving for heroin
How does low dose pregablin reverse morphine tolerance? Does it have the same effect on methadone?
induce tolerance to morphine and instead of ethanol before giving the morphine channel after 6 days
we gave pregablin instead
so the naive mice who were given saline found that pregablin didn’t depress respiration very much (pregablin doesn’t cause resp depression by itself)
if you give morphine only on the 6th day, you don’t get that much respiratory depression because they are sensitised
but if you give pregablin PLUS morphine on the 6th day- you get severe respiratory depression- reverses sensitisation (red line)
like ethanol, pregablin reverses tolerance to morphine
Tolerance
- pregabalin reversal of tolerance increases danger of
heroin overdose
- pregabalin (low dose) reverses morphine (heroin) tolerance oxycodone tolerance - no reversal of methadone tolerance - pregabalin’s long half life (6 h) will allow reversal of morphine tolerance hours after pregabalin is taken
How to reduce gabapentanoid prescriptions
Diversion of gabapentinoid prescriptions
- Need for greater awareness amongst GPs - Need for alternative treatments for chronic pain
reduce prescription of pregablin and gabapentin as anti anxiety medications because they are contributing to overdose deaths
we need alternative treatments that don’t interact with opioids
