Drug Overdose Flashcards
What happens to the Paracetamol when is taken at a normal dose?
It gets conjugated
*conjugates are harmless - filtered out by the kidney and completely safe
What happens when normal paracetamol metabolic pathways become saturated?
Normal pathways (safe pathways): 1) glucuronyl transferase 2) phenolsulphotranseferase
When normal pathways get saturated (overwhelmed by OD)-> 3rd pathway activated (it is called N-acetyl-p-benzoquinoneimine) -> NAPQI produced -> it destroys hepatocytes in the liver
How does the body get rid of NAPQI?
It combines with Glutathione -> that conjugates NAPQI and gets rid of it (by removing it from the body)
What do we give in paracetamol OD/ what’s the physiological princple?
We want to increase Glutathione dose -> so we can conjugate NAPQI (harmful metabolites of paracetamol in OD)
For that purpose we give N-acetylcysteine
What is the timeframe to give N-acetylcysteine after paracetamol OD?
within 4 hours from OD
What do the inducers do?
Induced cytochrome P450 -> more metabolism -> other drugs (that are metabolized) are less effective
Cytochrome P450 inducers
CRAP GPS
- *C**arbemazepines
- *R**ifampicin
- *A**lcohol (chronic)
- *P**henytoin
- *G**riseofulvin (anti-fungal)
- *P**henobarbitone
- *S**ulphonylureas / St John’s Wort (alternative remedy for depression)
Cytochrome P450 inhibitors
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- *S**odium valproate
- *I**soniazid
- *C**imetidine
- *K**etoconazole
- *F**luconazole
- *A**lcohol (acute - binge drinking)
- *C**hloramphenicol
- *E**rythromycin
- *S**ulfonamides
- *C**iprofloxacin
- *O**meprazole
- *M**etronidazole
*grapefruit juice
What do cytochrome p450 inhibitors do?
Cytochrome p450 inhibitors -> inhibit liver metabolism -> other drugs are less metabolised -> toxicity (overdose/accumulation may occur)
What is the connection between the inducer of cytP450 and paracetamol OD?
As more liver CytP450 activity -> more activation of pathway that produce NAPQI = more dangerous
Treatment protocol for paracetamol
(to treat or not to treat)
Drug paracetamol level is taken 4 hours after the OD -> to check what blood Paracetamol level is
If it is above the line -> treat with NAC (N-acetylcysteine)
If the blood level of Paracetamol is below -> then do not treat *at that point perhaps enough glutathione to metabolise paracetamol + side effects of having NAC
Side effects of NAC treatment
NAC = N-acetylcysteine
- nausea/ vomiting
- bronchospasm
- anaphylactoid reation* - rash (in about 20% of people)
*anaphylactoid reaction is anaphylaxis - like picture but not mediated by IgE but by direct release of inflammatory mediators from mast cells
Do we treat paracetamol OD if we do not know when a person took OD, confusion about where the levels of Paracetamol fall on the ‘treatment line’?
If there is confusion - we treat
What groups of the patients are at high risk of toxic effects of Paracetamol?
High risk of toxic effects of Paracetamol = due to low glutathione stores
- alcoholics
- immunosuppressed
- malnourished
Best investigations for a person coming with Paracetamol OD
- Paracetamol level
- LFT -> to check liver function and bilirubin
- INR -> to make sure clotting is not affected (synthetic function)
- U&Es -> to ensure that there is no multi-organ failure
- glucose -> if pt has low GCS/mental state - to role out that cause of pt state
- ABG -> always to do with a patient with low GCS
- metabolic flap test -> to check if encephalopathy has happened
Paracetamol OD management
if taken <1 hour ago
Activated Charcoal
MoA: it is going to the stomach and absorbs paracetamol particles
*but effective only if a drug is in the stomach
Main treatment for Paracetamol OD
- how much / when
- what do we do
NAC (N-acetylcysteine)
- take blood (levels of Paracetamol) -> give NAC
- 3 x bags of NAC over 21 hours
- repeat bloods afterwards
* to check if they are in ‘safe zone’
What’s a ‘safe zone’ following NAC treatment?
After treatment with NAC -> we check the bloods
‘safe zone’ is:
- INR <1.3
- ALT <2 X upper limit abnormal
Then, they are likely to recover - not dangerous state for the liver
*if not within ‘safe zone’ limit -> give more NAC over 16 hours and keep patient for another day
What do we need to do before discharging a patient with Paracetamol OD?
We need to arrange psychological review (mental health team)
What is the last resort in the treatment of Paracetamol OD?
Liver transplant
What criteria are used to determine who should be referred for an immediate liver transplant?
King’s criteria
to determine who should receive a liver transplant after acute or chronic paracetamol induced severe liver injury
What are the most important King’s College criteria for liver transplant
- pH <7.3 or lactate >3.5 after fluids -> indicates metabolic acidosis due to liver failure
OR all 3 of:
- INR >6.5
- Creatinine >300 -> renal dysfunction
- hepatic encephalopathy - grade III or IV -> low GCS and liver flap
*All these are signs of severe liver damage
Common examples of benzodiazepines
- Diazepam
- Lorazepam
- Midazolam
- Zopiclone
- Flunitrazepam / Rohypnol
Uses of benzodiazepines
- anxiolytic
- sedative
- hypnotic
- anticonvulsant
- muscle relaxant
What is the clinical picture of benzodiazepine OD?
- confusion
- retrograde amnesia
- low GCS
- altered mental state
- altered balance
Investigations in benzodiazepines OD
- glucose
- ABG
- U&E
- FBC
- urine toxicity -> to role out other drugs OD (the person would be unconscious so no Hx provided)
- ECG
Is there a risk to life in benzodiazepine OD?
No risk to life as their breathing of heart rhythm would not be affected (although low GCS)
Management of benzodiazepine OD
- support airway and respiration (if low)
- watch and wait for GCS to recover
- Flumazenil - competitive antagonist
Flumazenil
- MoA
Flumazenil
*antidote for benzodiazepine OD
MoA: selective GABA-A antagonist (competative inhibitor)
Side effects of Flumazenil
Side effect:
- promote seizures (that may be resistant as we cannot treat it with benzodiazepines - due to already OD on them) - so often just ‘watch and wait’ approach
- arrhythmias
Common Tricyclic anti-depressants
- Amitriptyline
- Imipramine
- Nortriptyline
- Doxepin
- Clomipramine
What is side effect of TCAs?
Anticholinergic
Result: less PNS -> more SNS activity
Examples:
- dilated pupils
- tachycardia
- dry mouth
- urinary retention
- blocks alpha1 adrenal receptors in blood vessels -> lower blood pressure as vasoconstriction is blocked -> more vasodilatation
- coma
- fast sodium channels in the heart are blocked -> arrythmais
- seizures -> due to GABA antagonist
Signs of TCAs OD on ECG
ECG with TCAs OD
- tachycardia
- R axis deviation (lead I and aVF - ‘returning/reaching’)
- widen QRS
Investigations in TCAs OD
- ECG
- ABG
- glucose
- U&E
- FBC
- urine toxicology
Management of TCAs OD
TCAs OD:
- ECG (signs of TCAs OD)
- activated charcoal if presented <2 hours
- sodium bicarbonate -> if ECG changes (to increase the bioavailability of sodium, as sodium channel blocked) + buffer against seizures and acts against acidosis
- fluids -> for hypertension
- seizures treatment -> benzodiazepines (NOT PHENYTOIN! )
What drug and why is contraindicated in the treatment of TCAs OD induced seizures?
Phenytoin is contraindicated
This is because it acts as Na+ channel blocker and in TCAs OD we have already blocked Na+ channels -> risk of arrhythmias would be increased
Would haemodialysis work in management of TCAs OD?
No, as TCAs are protein bound
Example (1) of typical antipsychotic
Haloperidol
Examples (4) of atypical antipsychotics
- Clozapine
- Olanzapine
- Quetiapine
- Risperidone
Uses of anti-psychotics
- schizophrenia
- bipolar
- dementia
What are effects of anti-psychotic drugs?
Anticholinergic
- dry mouth
- increased HR
- low BP (as no vasoconstriction -> vasodilation)
- dilated pupils
- serotonin blocked -> low GCS
- arrhytmias and seizures -> as block of Na+ channels
How to differentiate anti-psychotics OD from TCAs?
Anti-psychotic meds also block dopamine-2 receptors -> involuntary movements are not blocked
Involuntary movements: pseudoparkinsonism, acute dystonia, tardive dyskinesia
Investigations for anti-psychotic OD
- ECG
- ABG
- glucose
- urine toxicology
- INR
- U+E
- FBC
- INR
Neuroleptic Malignant Syndrome
- what is this?
- clinical presentation
A possible outcome of anti-psychotic OD -> neuroleptic malignant syndrome
Clinical presentation:
- hyperthermia -> temp keeps going up
- autonomic dysfunction -> sympathetic effects are out of control (pupils dilated all the time, BP keeps going down)
- muscle rigidity -> uncontrolled muscle contraction -> leads to rhabdomyolysis
- reduced GCS
How do we test for Neuroleptic Malignant Syndrome
- check the urine -> will be red due to muscle breakdown (myoglobin)
- CK levels -> creatinine raised of thousands
Management of Neuroleptic Malignant Syndrome
Mx of Neuroleptic Malignant Syndrome
- stop anti-psychotics
- rapid cooling and anti-pyretic (Ice packs, cold fluids and paracetamol)
- IV fluids
- drugs (Dantrolene, Bromocriptine, Benzodiazepine, Procyclidine)
- haemodialysis -> to get rid of myoglobin
Drugs used in Rx of Neuroleptic Malignant Syndrome (4)
Dantrolene -> muscle relaxant
Bromocriptine -> D2 antagonist (to reverse effects of anti-psychotics)
Procyclidine -> anti - muscarinic (help with muscle rigidity)
Benzodiazepine -> muscle relaxants
Opioids examples
- codeine
- morphine
- tramadol
- fentanyl
- buproprione
- methodone
Side effects of morphine/ opioids
- nausea a vomiting
- abdominal pain -> due to constipation
- low GCS
- respiratory depression (in OD)
- marked pupil constriction (in OD)
Investigations in opioid OD
- ABG
- glucose
- urine toxicology
- U&E
- FBC
- ECG
Management of opioid OD
- support airway and respiration (ABCD)
- monitor GCS
- charcoal if OD <2 hours (if can be taken orally)
- Naloxone IV
What do we need to know about dosing of Naloxone?
Naloxone IV has a rapid onset of action but also very short half-life -> needs repeated dosing
Opiate withdrawal symptoms
Naloxone may induce opioids withdrawal symptoms:
‘everything is running’ - fluid out
- muscle aches
- insomnia
- runny nose
- fever
- abdominal cramps
- diarrhoea
- vomiting
- tachycardia
The antidote to iron OD
Deferoxamine IV - chelating agent (to absorb and excrete iron molecules)
Antidote for anti-freeze (glycol) poisoning
Glycol / anti-freeze poisoning
Antidote: alcohol -> Ethanol IV or Fomepizole
Alcohol is a competitive antagonist
Symptoms of Carbon Monoxide poisoning
- headache
- nausea
- dizziness
- collapse
- breathlessness - but sats are 100% (as CO misinterpreted as O2 by sats probe); with ABG CO2 will be very low
- loss of consciousness
Management of CO poisoning
Carbon Monoxide poisoning Mx:
- hyperbaric O2 chamber (to get rid of CO and allow O2 to bind to RBCs again)
