Category Archives: Toxicology

Off it! Part 4: Synthetic Cannabinoids

Synthetic Cannabinoids

Mental Model – [  ‘UP ‘ – A bad trip ]

There are over 150 different molecules in circulation under this class.  They are sprayed onto plant matter and smoked in a similar way to cannabis, thats pretty much where the similarities end.  They can also be dissolved and injected in their powdered form, snorted, inhaled, or cooked into food.

Synthetic cannabinoids were first produced to investigate the pharmacological potential of the endogenous cannabinoid receptor. They were first found in recreational products in 2008.   They are all analogues of 9-tertrahydrocannabinol (9-THC) the active ingredient in ‘normal’ cannabis, which is a partial CB1 and CB2 agonist.  Newer agonists have much greater affinities for the THC receptors, (being complete rather than partial agonists).  They also seem to last longer than normal cannabis.  CB1 and CB2 receptors are EVERYWHERE in your CNS, and as each molecule in circulation has a different affinity for different receptors, in different locations the toxidrome can be highly variable.

‘Spice’ is the second most popular drug in the US (after cannabis), and it is estimated that the spice industry is worth something like $5 billion.  Its popularity grew initially because of a perception that it is ‘legal’, ‘safe’ and ‘undetectable’.

Patients who come in intoxicated from a synthetic cannabinoid (K2, spice, Kronic etc) are agitated, confused, and paranoid.  There are no generally agreed signs to look for, some case series talk about dilated pupils, conjunctival injection, and hyper-reflexia, but these probably depend on dose, and type taken.  Patients normally seem  tachycardic and diaphoretic.   They may often be brought in by ambulance following ‘seizure-like’ activity, or by the police for erratic behaviour.

16 Cases of AKI reported in the US associated with synthetic cannabis use.  Convulsions have been reported but not proved to be related to synthetic cannabinoids.

Management

Again, this is supportive.  Use titrated IV benzopdiazepines to calm agitation.  IV fluids for dehydration.  Check a CK and a U and E if they are unwell.   If you can get close an ECG is useful for completeness, though no arrhythmia have been reported (but hypokalaemia HAS).

Withdrawl

I witnessed synthetic cannabinoid withdrawal first hand whilst working in ED in New Zealand over the weekend that a nationwide ban came into force.  Patients attend with psychosis, sweating, paranoia and delusions.  Patients were treated with benzodiazepines.

 

Harris, Carson R., and Ashley Brown. “Synthetic cannabinoid intoxication: a case series and review.” The Journal of emergency medicine 44.2 (2013): 360-366.

Spaderna, Max, Peter H. Addy, and Deepak Cyril D’Souza. “Spicing things up: synthetic cannabinoids.” Psychopharmacology 228.4 (2013): 525-540.

Off it! Part 3: GHB

GammaHydroxybutyric Acidghb

[ – Mental model: – Benzos,  ‘DOWN’]

Legal Status:  Class C

Think of GHB as a possibility in patients who are often male, body building and appear ‘drunk’.  GHB patients get VERY flat, very quickly if they get the dose wrong, and alcohol potentiates this.

Other signs of acute toxicity – LOW RR, GCS, BP and Hypersalivation

They are really hard to wake up (no matter what ‘trick’ you use).

GHB binds to GABA and inhibits the release of action potentials from the synapse.  In high enough concentrations GHB gets converted to GABA.  You may hear that someone has taken GBL (or gamma butyrolactone) that’s the precursor and has a delayed affect, especially when take with alcohol.

It seems to be used in social circles of gym fanatics.  There is a belief that it increases human growth hormone release, and improves muscle repair, AND is a calorie free way of getting the buzz people want from alcohol.  It’s also been used as a date rape drug.

Management

Supportive.

These patients sometimes require airway protection.  They will wake up on ICU the next day, thank no one, and leave.   Deaths occur when patients lose their airway control outside of hospital.

Withdrawl

Some people take GHB a lot, if they get their recreational dosing correct can re-dose, and re-dose night after night (or regularly for work outs), when their supply runs out, or changes they can get a rebound effect which is like an alcohol withdrawl, symptoms start 6 hours after the last dose.  It can last much longer (weeks), and is more resistant to benozodiazepines.

The autonomic features are present, but slightly reduced, however the syndrome can last longer (up to two weeks).  Control it with benzodiazepines and baclofen (GABA agonists), and titrate down slowly like with alcohol withdrawl.

Early features – insomnia, tremor, confusion, nausea and vomiting

Late features – tachycardia, hypertension, agitation, seizures and/or myoclonic jerks and hallucinations

Off it! Part 2: Synthetic Cathinones

MCAT/Mephedrone/Bath Salts

[- mental model – amphetamines , ‘UP’]

Legal status: Class B

You will not have spent long in the ED before coming across someone who is off their face on MCAT.  This drug isn’t well described in the literature as it’s only been in the UK since 2008(1).

khatIt is a synthetic derivative of Khat (Catha edulis).  Which is a leafy green plant which in it’s natural form acts as a mild stimulant.  If the leaves are chewed, or put into tea it delivers a feeling somewhere between a big coffee and a small dose of speed.

MCAT comes as a powder, or is sprayed onto dead plant matter.  It can be eaten, smoked, snorted, or injected.  With onset times and length of action fluctuating depending on the method.  Dosage depends on delivery, but most people ‘bomb’ (MCAT wrapped in a rizla)  up to a gram.  They may take more than one bomb a night.

Information on the toxidrome for MCAT is limited because nearly all of the published material is from patients reporting what they think they may have taken.   When someone says they have taken MCAT, they may have taken MCAT, or a derivative (there are over 30 described in recent review articles(2).

synthetic cathinones

 

The derivatives have different attributes, mostly in their ability to cross the BBB, but their affinity to certain parts of the brain seems to be different too.  Most commercially available preparations that people seem to buy contain a mixture of lots of different molecules.  So when someone says they’ve taken MCAT what they’ve actually taken is a mixture of random cathinone derivatives.

Cathinone derivatives are thought to work by increasing the concentration of dopamine, serotonin, and noradrenaline in the synaptic cleft(1,3).  They do this by upregulating secretion, and blocking MAO (which breaks them down).  It is therefore theoretically possible I suppose that people on SSRIs and TCAs might get more than they bargained for.

Clinical Features

Patients attend the ED with paranoia, anxiety, agitation, aggression, they can hallucinate.   Look for tachydysrhythmias, diaphoresis and tremor.   Patients on MCAT have HUGE pupils.   One of the metabolites is thought to be an ephedrine derivative, and causes vasoconstriction so in theory you could get all of the sequelae associated with vasospasm (ACS, Dissection, ICH).

Rhabdomyolysis has been reported with mephedrone toxicity so a CK is probably worth sending if you think they are bad enough to require bloods.

A malignant hyperthermia like affect has also been reported probably due to it’s serotonergic effect.  I’ve found a handful of confirmed deaths, some due to renal failure, some due to arrhythmia.  However we are very much in case series territory.

Treatment (consensus)

Agitation – Benzodiazepines (3)

Tachycardia – Beta blockade (3)

Renal Impairment – Fluids and dialysis

Withdrawl

Not been studied well,  most information comes from research on Khat.  People who have become habituated to it, can get anhedonia, paranoia, and psychosis, but little is known about withdrawl from synthetic cathinones.

 

  1. Zaitsu, Kei, et al. “Recently abused synthetic cathinones, α-pyrrolidinophenone derivatives: a review of their pharmacology, acute toxicity, and metabolism.”Forensic Toxicology 32.1 (2014): 1-8.
  2. Valente, Maria João, et al. “Khat and synthetic cathinones: a review.” Archives of toxicology 88.1 (2014): 15-45.
  3. Richards, John R., et al. “Treatment of toxicity from amphetamines, related derivatives, and analogues: A systematic clinical review.” Drug and alcohol dependence 150 (2015): 1-13.

 

Off it! A practical guide to people who are off their face in the ED

 

What medical school, the foundation programme, and by and large the ACCS curriculum does not prepare you for is how to manage the patient who is mashed (I think it should be a major presentation).  These people who attend at a time when the department is at it’s busiest, and when we are at our weakest. These patients are clinically complex with an added legal dimension in terms of consent,  and mental capacity, which sucks up a lot of ED resource.

drugsIn the coming few weeks I’m going to take you through a basic approach to patients who are intoxicated, and talk about some of the less well known/understood intoxicants.  Much of the teaching and learning on the subject is based around the particular drug the patient has taken.  This makes it difficult to apply at 3 am when ‘Harry’ has backed into the corner of one of your cubicles because he is convinced the Dynamap is going to devour him.  He does not know what he has taken.  He is not sure of his own name.

In the ED there are 2 syndromes that you can slide people into, this will give you an idea of what to expect, what to watch out for, and for how long.  The key is often to be relaxed, have an easy friendly manner, and de-escalate as much as you can.  Use the ‘up/down’ as a mental model, gain control/safety, and then go searching for causes.  Know that time is normally on your side, most patients will finish their trip, and some will even apologise for wasting your time.

Rules:

  • ‘Just’ drunk / high / tripping is a diagnosis of exclusion.
  • People do stupid things when drunk/high/tripping too, and may have injuries.  Look for them.

Excited delirium (up)

These are the patients that can come in being held down by 2-3 police officers and couple of paramedics.  The history is normally non-existent or vociferously denied by the individual who just wants to go.  You can’t assume they have capacity, which is frustrating for them, and for you.

Approach

  • ABCs, de-escalate.
  • Glucose and a 12 lead is a good idea, but may be impractical.  A temperature is also useful.
  • D look at the pupils (BIG: amphetamines, MCAT, anticholinergics, serotinergic, neuroleptics. SMALL: opiates, alcohol)
  • If de-escalation, bargaining, and brute force aren’t working consider something to make the situation a little calmer – midazolam, diazepam, or propofol all work well when used in experienced hands.  This lets you work out if there is anything wrong, and also keeps you and your colleagues safe.

People who are screaming and shouting and fighting off police officers and nurses may have serious pathology (I have found a frontal lobe tumour in a guy fighting off police officers).  Rapidly expanding space occupying lesions can make some people get very fighty.  Don’t assume they are just being annoying.

If someone can’t calm down enough for you to have a conversation with them, they probably don’t have capacity.

Hypoactive delirium (down)

These patients are brought in cold often being ‘found’ by some unlucky member of the general public.  Sometimes the police bring them in, sometimes ‘friends’.

  • ABCs
  • Glucose, 12 lead, temp.
  • GCS – A GCS of <8 only counts if it’s done by an ED sister or ED spr.  We are brutal.  We will teach you our tricks if you ask nicely, or give us cake.
  • Pupils: BIG: amphetamines, MCAT, anticholinergics, serotinergic, neuroleptics. SMALL: opiates, alcohol

Be more concerned with patients with big pupils and hypoactive delirium, this means they’ve taken A LOT, and are closer to the final common pathway of all toxicology which is SEIZURE->COMA->DEATH.

 

Next week MCAT!

At the end of an algorithm with no where to go..

Pre-alert at 4am: “Status 1 23 yo male, seizures, now GCS 3, BM 6.4, HR 130 BP 90/60 Sats 95% on 15L, NPA insitu.  Given 15mg IM midazolam.  Seizures have stopped ETA 10 minutes”

On arrival, slightly sheepish paramedic, also says ‘errr he’s in VT but we only found out as we were driving in’

On arrival I do a quick assessment, while the boss takes over the airway.

A, patent, NPA insitu, B equal AE, sats 95% on 15LNRB, good respiratory effort, C BP 80/50 HR 180, monitor looks like broad complex tachy.

1 x 200 J synched shock – Still VT.

I look to the boss  “s***” we say together.

Here is the ECG:

vt
click to enlarge

What are you going to do?

 

 

 

We got an anaesthetist to manage the airway, and we gave a series of further shocks, and changed the positions of the pads, and we loaded him with Amiodarone.

I pulled up his past medical history, he was involved in a RTC when he was a teenager, had had ORIFs of his right tib and fib, and right femur.  No heart conditions.

His girlfriend, who was (understandably) distraught said he was not on any regular medications, and though he had been depressed in the past, wasn’t depressed now.  I then asked her if she was on any medication he might have taken.  She was taking dothiepin (a TCA).

He’d been in the department now for 30 minutes, still in VT, still not responding to the medications we had.  In the end we decided that he was behaving like a TCA overdose, and we had enough evidence to try treating him as such.

The treatment for TCA OD is sodium bicarbonate, as it provides a sodium load for the Na+ channel blocking affect of the TCA (which is why TCAs affect cardiac conduction).

Start with 50ml of 8.4% NaHCO3- over 15 minutes.  We used about 6 vials of this stuff, and his ECG turned into this:

click to enlarge
click to enlarge

After an infusion of HCO3- 4 hours later his ECG looked like this:

norm

About TCA OD:

– TCAs – [STEM]”line” or [STEM]”mine”.  Commonest UK ones –  Amitriptyline, Nortriptyline.

TCAs [tricyclics – 3 actions] block the reuptake of noradrenaline centrally and peripherally, they have an anticholinergic effect, and also block Na channels in brain and myocardium.

Patients who have taken TCAs get anticholinergic effects: warm, dry, hyperthermia, tachycardic, agitation, blurred vision, hallucinations, urinary retention, ileus.  At higher concentrations the symptoms get worse, then affect their consciousness level, then their cardiac conduction.

All ODs need an ECG, look for a long QRS; >100ms increases the risk of fits and coma.  Greater than 160ms is associated with ventricular arrhythmias.

Treatment (ABCs as given)

50mmol of 8.4% over 15 minutes, repeated as required, infusions of bicarbonate can be given.  If you’ve ventilated the patient you can also hypoventilate them to a pH of 7.45-7.5, which seems to decrease the affinity of the TCA to myocardial Na+ channels.

Addendum:

What happens if the bicarb isn’t working?  [thanks to @bedrocteam] for pointing this out:

– Mg2+ is recommended if the bicarbonate isn’t working, though the evidence is getting quite thin at this point[1].  There is also case reports of intralipid being used, when all else has failed [2].

  1. Emamhadi, Mohammadali, Babak Mostafazadeh, and Marzieh Hassanijirdehi. “Tricyclic antidepressant poisoning treated by magnesium sulfate: a randomized, clinical trial.” Drug and chemical toxicology 35.3 (2012): 300-303.
  2. Engels, Paul T., and Jonathan S. Davidow. “Intravenous fat emulsion to reverse haemodynamic instability from intentional amitriptyline overdose.” Resuscitation81.8 (2010): 1037-1039.