Toxicology

Toxicology

From Bromley Webinars

General principles

·         How can you reduce absorption?

o   Wash it out (gastric lavage)

o   Make it stick to charcoal

o   Help it rush through gut more quickly

·         Increase elimination – eg large salicylate OD alkalising the urine (not so much these days)

·         Specific antidotes

·         Treat complications as required

·         Mental health care as required

Reducing absorption

·         Activated charcoal

o   Not used so much now

o   OD must have been within the last 1hr (can work for longer in some coated drugs/delayed emptying eg tricyclics)

o   Can absorb 10% its weight – about 10g of poison

o   Unpleasant taste, may induce vomiting – may require antiemetic; small risk of aspiration

o   Not effective for metals like iron and lithium or organophosphates, methanol or ethylene glycol

·         Gastric lavage

o   Even less used now

o   “Stomach pumped” – funnel liquid in, funnel liquid out

o   Only used if what has been taken is in such a quantity is very dangerous, has been taken recently enough and will pass through the tube and funnel

o   Shouldn’t be used for any solvents. Patients can’t protect their airway – may need intubation during gastric lavage

Toxidromes

·         Anticholinergic

o   Seen in antihistamines, tricyclics, atropine

o   Dilated pupils, high temp, dry skin, dry eyes, dilated pupils

·         Cholinergic

o   Organophosphate poisoning, some mushrooms

o   Hypersalivation, sweating, small pupils

·         Hallucinogenic

o   Amphetamines, psychedelics

o   HTN, tachycardia, tachypnoea, dilated pupils, agitation and hallucinations

·         Sympathomimetic

o   Remedies for colds – phenylephrine, glycopyronium, some weight loss drugs, amphetamine sand cocaine

o   Hot, large pupils, sweating, HTN, tachypnoea

·         Opioid

o   Pin point pupils, reduced RR, reduced consciousness, bradycardia

·         Sedative hypnotic

o   Sleeping tablets, benxos

·         Serotonin syndrome

o   SSRIs and MDMA

o   Agitated pt, lots of autonomic activity, tremor, dilated pupils, sweating, agitation, tachycardia, tachypnoea, HTN

Carbon monoxide poisoning

·         Fires and smoke – allow questions on airway burns, CO poisoning, cyanide poisoning

Carbon monoxide poisoning

·         Occurs when combustion occurs with inadequate oxygen – housefires but also car engines, faulty boilers or ovens or gas fires

·         CO binds readily to hb producing carboxyhaemoglobin - 200 times the affinity than oxygen, starves the aerobic metabolism

·         Also binds to myoglobin particularly cardiac myoglobin

·         Also damages lipids in the brain producing some of the neuropsychiatric results of CO poisoning.

·         In pregnancy – the 2 circulations can result in greater accumulation of COHb in the fetus – even higher affinity in foetal hemoglobin and great danger from CO to foetus

·         Symptoms

o   Mild toxicity: nausea, headache, poor memory – often in chronic toxicity, esp in winter, all cracks and drafts excluded

o   Moderate toxicity: hypotension, ataxia, confusion (house fire, suicide etc)

o   Severe toxicity – metabolic acidosis, coma, death

·         Normal people – normal environmental exposure. Heavy smoekrs or highly congested areas – might be as high as in smokers

Management

·         High FiO2 – oxygen will compete with the CO

·         The CO will be breathed out over time; half life of 5 hrs; brought down to 80 minutes with high FiO2

·         May be required for 24 hours to support full excretion of the CO

·         Hyperbaric oxygen in hyperbaric oxygen chambers reduces the CO level very much faster but limited evidence for reduction of long term morbidity. Advocated for in pregnant people

·         CO effects on deep tissues and lipids in brain symptoms can develop long term even despite treatment to lower the levels, especially neuropspych: memory, depression, aggressive behaviour

Cyanide poisoning

·         Released by combustion of carbon and nitrogen containing compounds, especially plastics and fabrics when burnt

·         Cyanide is a potent toxin of aerobic metabolism, very toxic and high levels can cause loss of consciousness in 30 seconds

·         Lower levels cause weakness, confusion, collapse, convulsions and ultimately coma

·         Effect on aerobic metabolism causes characteristic lactate rise – look for this in neurological features after a fire.

·         NO SPECIFIC TEST – look for evidence of exposure eg soot in airway, history of exposure to fire, lactate >8, reduced consciousness and neurological suppression – think cyanide!

·         Antidotes: amyl nitrate and dicobalt edeate. Hydroxycobalamin can also be used.

Paracetamol poisoning

Commonest drug taken in overdose: over 100 deaths/year

·         Mortality coming down in recent years – possibly due to limiting pack size to 32 x 500mg

·         Paracetamol’s metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is actually the toxin responsible for hepatotoxicity

·         We need to understand way in which it is metabolised and the time course of these

o   Paracetamol can be metabolised in 3 ways – glucuronidation is the most common forming a non toxic, more soluble substrate which is easily passed in urine

o   Hydroxylation on the other hand forms a toxic metabolite. Usually glutathione conjugates this toxic metabolite rapidly converting it to a non toxic substance.

§  People who have the hydroxylation enzyme induced (eg alcoholics and those on enzyme inducing drugs) produce more of the toxic hydroxylated substrate

§  Others might have low levels of glutathione (eg starvation, liver disease, AIDS) meaning the toxic hydroxylated substrate can’t be conjugated to a harmless glutathione form

§  Also, glutathione can be used up – there is only a limited amount which means it can be overwhelmed when a patient overdoses. There is a window between overdose and the exhaustion of glutathione reserves before liver damage begins – about 8 hours.

·         High risk patients for build up of toxin:

o   Patients with induced liver enzymes

§  Meds: antiepileptics (carbamazepine, phenobarbitone, phenytoin), St John’s Wort, Rifampicin

§  Alcohol – either alcoholics or those with recent heavy binge

o   Patients with low levels of glutathione

§  Anorexia

§  Pre-existing liver disease

§  HIV

Managing individual patient with paracetamol OD

·         Over 75mg per kg is considered a significant overdose in an adult – around 9 tablets for a 60kg person.

·         Children can tolerate around 150mg per kg

·         Anything over these levels require full paracetamol algorithm

·         If under one hour since the overdose consider activated charcoal

·         Otherwise wait until 4 hours after overdose before taking bloods including liver enzymes and paracetamol levels, INR

·         If they present at 8-15 hours then start treatment immediately; stop again if it turns out the level was not toxic

·         Beyond 15 hours the paracetamol level becomes unreliable so treat if there is evidence of a significant overdose and don’t rely on biochemical level of paracetamol

·         Staggered overdose makes it extremely difficult to interpret paracetamol levels; go by the total amount – if it is significant just give the antidote

·         The decision to treat based on a paracetamol level is based on the 100mg per litre line – to the right of the line and treatment is given

The treatment

·         N-acetylcysteine is the treatment for paracetamol overdoses that meet the criteria: over treatment line at 4-8 hrs, presenting at 8-15 hours until a paracetamol level is available, presenting at over 15 hours regardless of paracetamol levels or staggered overdose

·         NAC is a sulfhydrale group donor.

o   Loading dose 150 mg per kg in 200mls of 5% dextrose over 1 hour

o   Then 50mg per kg in 500mls of 5% dextrose over 4 hours

o   Then 100mg per kg in 1L of 5% dextrose

·         Total time is 21 hours

·         A significant number of patients will react, particularly to the first bag. Skin flushing/rash, nausea and vomiting, angioedema or mild anaphylactoid reaction.

o    Around 20% of patients get this within 30 minutes of infusion

o   Most people can keep having their NAC – just need the rate slowed right down

o   NOT a reason to stop NAC and not a reason someone can’t have NAC in the future

·         At the end of the 21 hour infusion repeat the clotting studies and biochem and decide if treatment can discontinue

·         Give further NAC if any of the following:

o   Transaminase activity over 2 times admission level

o   Transaminase activity 3 times normal maximum

o   INR over 1.3

Salicylate toxicity

Aspirin is the only salicylate used anymore. It used to be a bigger issue, not common now for several decades

Saying that there is a complex pattern of clinical features from respiratory alkalosis to metabolic acidosis and a range of symptoms caused

Early features

·         Tinnitus (direct effect of salicylate on the ear)

·         Nausea

·         Hyperventilation (caused by stimulation effect on respiratory centres in the brain) – causes respiratory alkalosis

Later features

·         Vomiting

·         Hot and sweaty

·         Metabolic acidosis

·         Intracellular hypoglycaemia but serum sugars might be low or high

Very severe overdoses

·         Confusion and coma (especially in children)

·         Pulmonary oedema

·         AKI

·         Complex electrolyte disturbances

Approach of aspirin overdose

·         Significant overdose = 150mg per kg (half a tablet per kg)

·         Activated charcoal or gastric lavage if early – within 1 hour of overdose

·         Check salicylate levels at 2 hours If asymptomatic and 4 hours if symptomatic

·         Large doses may clump together delaying absorption – must repeat levels multiple times as the level may continue to rise

·         Levels should not guide management – it is the combination of clinical features and levels that are important

Interpreting salicylate levels

·         Typical level at onset of symptoms is around 300mg/L

·         Typical level with severe symptoms is around 500mg/L

·         Typical level with life-threatening poisoning is around 800-900mg/L – this is when dialysis might be required

Interpreting the ABG in Salicylate poisoning

·         Respiratory stimulant – first change is a drop in CO2 and rise in pH – resp alkalosis

·         Later on the uncoupling of oxidative phosphorylation and increased fatty acid metabolism to generate ketone bodies results in metabolic acidosis

Management of salicylate poisoning

·         If symptoms are mild supportive measures with IV fluids may be enough

·         With salicylate levels over 500mg/L giving 200ml of 8.4% sodium bicarbonate over 60mins (a process known as “alkalinisation of the urine”) to promote excretion

o   Salicylate is then not resorbed in the tubule and excreted much faster

o   Maintaining the pH of the urine at 7.5 to 8.5 promotes maximum excretion, a good target

·         Very severe toxicity will not be adequately managed by renal excretion and haemodialysis will be required

·         Manage salicylate overdoses more aggressively in children, they are more likely to have confusion and coma

·         Potassium tends to fall with salicylate overdoses so might need to be monitored frequently maintained with IV treatment

·         Give glucose readily,  monitor it regularly – especially if there are symptoms of hypoglycaemia

·         Be wary of aspirin toxicity in elderly patients - often they may be exposed to chronic overdose from regular medications

Tricyclic Antidepressant (TCA) Overdose

Becoming less common since introduction of SSRI family but still does occur

Typical question: 22 year old woman has taken 50 amitriptyline tablets 25mg each 2 hours ago

Mechanisms of toxicity

1.       Anticholinergic atropine like symptoms

2.       Blocks pre-synaptic re-uptake of amines

3.       Antagonism of apla1 adrenergic receptors

4.       Blocks cardiac fast sodium channels – wide QRS complexes

Clinical features

·         Anticholinergic features are often the earliest

o   Dilated pupils

o   Tachycardia from prevention of vagal inhibition of the heart

o   Dry mouth

o   Urinary retention

o   Confusion and hallucination

·         CNS features

o   Confusion

o   Drowsiness

o   Seizures – often short lived and tend not to require treatment, self limiting

o   COMA

o   Respiratory depression

o   Ophthalmoplegia with divergent strabismus – eyes looking in different directions

·         Metabolic features

o   Metabolic acidosis

·         Cardiovascular features – often the most dangerous features

o   Initially hypotension

o   Progresses to widening of the QRS complex

o   This results in tachyarrhythmias

o   Ultimately bradyarrhythmia and cardiac arrest

Management of TCA overdose

·         Significant (7-10mg per kg) overdose within the last hour – give activated charcoal to prevent absorption. Or gastric lavage. Must have a secure airway or have been intubated already

·         Put the patient on cardiac monitoring early to pick up any cardiac toxicity

·         Arterial blood gases, or venous blood gases instead if there is no concern about hypoxia or respiratory depression

·         Intubation if GCS is under 8 to protect the airway

·         ECG: looking for QRS morphology changes that could be the prelude to fatal arrhythmias

o   QRS widening to over 100 mSec (over 2.5 asmall squares on the ECG)

o   QTc of over 430 mSec

o   aVR (which should be predominantly negative) might have an R/S ratio of over 0.7

*Calculating a corrected QTc

·         QT interval is from start of Q to end of T

·         Count the number of small squares – 40mSecs each gives you the QT interval

·         BUT needs correcting for rate as it lengthens or shortens depending on HR

·         So next calculate R-R interval in mSecs

·         Bazett’s formula QTc = QT/√R-R interval

·         Normal QTc is less than 440

Management of TCA continued

·         Give fluids for hypotension – 20ml/kg bolus

·         Bicarbonate should also be given for TCA – it is a specific treatment for TCA overdose and reduces toxicity through a number of pathways

o   Give if there is any hypotension

o   Give if there is wide QRS or any arrhythmias

o   Give if there are any seizures

o   Give if there is metabolic acidosis

o   100mls at a time of 8.4% bicarbonate – repeat this dose until the pH is normal

·         Sedate with diazepam if there is agitation

·         Any convulsions will likely self terminate but treat any hypoxia, correct acidosis and give benzos if seizures don’t self-terminate

·         AVOID phenytoin as it exacerbates the effect of TCA overdose on the cardiovascular system

Iron overdose

Body determines how much iron is needed to be absorbed from the gut – only small amounts are evr absorbed, even from iron supplements

·         Iron is a very important substance in the body – it can be both an electron donor and electron receiver as it moves between ferrous Fe2+ and ferric Fe3+ states

·         It is transported bound to the protein ferritin as unbound iron can have peroxide hence free radical effect on systems and can therefore be very destructive on an intracellular level

Iron overdose sees excessive absorption of iron result in the binding capacity of iron transport proteins being overwhelmed and free iron becoming more abundant

·         Various iron salts contain different amounts of elemental iron – usually around 12-30% of the mass of salts like ferrous sulphate, ferrous fumarate.

o   Of this only around 10% is absorbed

o   20-60mg/kg of elemental iron is mildly to moderately toxic

o   These quantities are easier to achieve in children; children have a higher susceptibility to iron overdose and also iron tablets look like sweets often

o   Iron toxicity is greatest in gastrointestinal cells and liver cells

Classically, 5 different stages of iron toxicity have been described:

1.       Initial gastrointestinal stage with Diarrhoea and vomiting early after ingestion. Sometimes bloody diarrhoea; possibly severe hypotension

2.       Latent stage for 12-24 hours where patient seems to improve and stop vomiting

3.       Wider distribution of iron then results in metabolic acid and cardiovascular (hypotension) effects as well as hypoglycaemia from 12-48 hours – the most dangerous stage and where most mortality occurs

4.       Hepatic toxicity now becomes dominant with raised bilirubin and raised liver enzymes – this can go on for days

5.       Delayed stage then sees scarring and fibrosis that can cause obstruction and the liver can also become scarred and cirrhosis develop.

Managing iron overdose

·         X-ray can actually show iron tablets in the stomach or gut (as they are radio-opaque); if there is a large number yet to be absorbed then whole bowel irrigation can was them through

·         After 4-6 hours serum iron levels can be recorded

·         Beyond 6 hours metabolism of the iron makes blood tests less reliable and likely to underestimate the overdosage

·         Serum iron:

o   Less then 3mg/L (55micromol/L) – likely to only cause mild toxicity

o   3-5mg/L (55-90micromol/L) – moderate toxicity will occur

o   More than 5mg/L (90micromol/L) – severe toxicity

·         Treatment:

o   Desferrioxamine, an iron chelating agent should be given IV if:

§   levels are >3mg/L and the patient is symptomatic

§  Levels are >5mg/L regardless of symptoms

o   15mg/kg/hr. It causes Iron to be excreted in the urine turning the urine pink. Can also cause hypotension so ensure adequate hydration

o   Monitor glucose regularly due to hypoglycaemic effect of iron

Methaemoglobinaemia

Can cause a profound cyanosis in patients who are otherwise symptomatic or can cause a respiratory distress

·         Caused by change in iron state from Fe2+ ferrous state to Fe3+ ferric state – just one of the 4 iron molecules in each haemoglobin molecule changing to ferric state causes higher oxygen affinity than normal in the other 3 haem groups

·         This means oxygen is less easily given up to the tissues causing tissue hypoxia

·          Normally, there is <1% methaemoglobin in the blood

·         Various precipitants can cause oxidative stress shifting more groups towards Fe3+ but this results in relatively asymptomatic change until methaemoglobin reaches 15% of total blood

o   As it gets higher, the patient gets more cyanotic, breathless, headache develops and confusion can start

o   Once 50% Methaemoglobinaemia is reached seizures and coma result

o   >70% Methaemoglobinaemia is fatal

A range of drugs can cause this state:

·         Nitrates such as amyl nitrate (poppers – especially when drunk instead of sniffed)

·         Some local anaesthetic agents

·         Rarely, trimethoprim can cause Methaemoglobinaemia

·         Dapsone can also cause it

Methaemoglobinaemia can be genetic due to a lack of the required enzyme to keep iron in the ferrous state – famously a family from Kentucky suffered from recessive allele with multiple family members being blue

Treatment for acute Methaemoglobinaemia

·         Oxygen

·         Methylene blue

o   Facilitates the enzyme that reduces the ferric back to the ferrous state

Methanol and ethylene glycol

Both cause a metabolic acidosis, both are organic solvents and treated in a similar way due to alcohol dehydrogenase being responsible for producing the toxic metabolite.

Methanol

·         The most simple alcohol – one C molecule. It is added to methylated spirits in order tot render it poisonous to prevent people drinking the pure ethanol

·         In the body, methanol is converted to formic acid which is not metabolised or excreted very well so builds up

·         It is toxic to a number of structures but particularly the optic nerve leading to blindness; it also interferes with aerobic metabolism leading to metabolic acidosis

o   It smells like alcohol and to begin with people who drink will be similarly intoxicated but the toxicity will then come on over hours as the methanol is metabolised to formic acid

o   The patient may develop tachypnoea due to metabolic acidosis, blindness will result in dilated pupils.

o   Up to 30% of those poisoned with methanol have died in multiple overdose situations usually from bootlegged alcohol, and may have permanent visual impairment

·         The latent phase of toxicity provides an opportunity for treatment

o   Alcohol dehydrogenase mut be inhibited to prevent conversion of methanol – a not very toxic substance – to the dangerous formic acid

o   This can be done with either fomepizole or ethanol itself

Ethylene glycol (found in antifreeze)

·         A sweet syrupy substance quite appealing to children; it is again the metabolites that confer toxicity – in this case oxalic acid

o   Oxalic acid binds to calcium which then precipitates out in a number of body tissues, esp kidneys and can then cause renal failure

·         3 stages of toxicity:

o   In the first 12 hours, the patient seems intoxicated similar to alcohol – slurred speech, incoordination, confusion, nausea, vomiting

o   In the next 12 to 36 hours as the conversion to oxalic acid occurs the patient develops metabolic acidosis, hyperventilation, tachycardia (most deaths occur in this stage)

o   The third stage over 1-3 days sees the calcium oxalate crystals precipitating out into he tissues most notably causing kidney failure

·         Treatment: like methanol there is a window of opportunity to treat as the metabolite is what causes the toxicity

o   Treatment is once again by inhibition of alcohol dehydrogenase with either fomepizole or ethanol

o   Renal failure may need support with dialysis

o   Survivors make a full recover

MUDPILES

·         Methanol and ethylene glycol are both in the mnemonic MUDPILEs which is a list of causes of a RAISED ANION GAP ACIDOSIS:

·         Anion gap = [(Na+K) - (Cl+HCO3)], normal range is 12 – 16; this accounts for the anions in the serum that we don’t measure.

o   If the anion gap is increased it implies that anions have been added to the serum

§  M – methanol

§  U - uraemia

§  D – diabetic ketoacidosis

§  P – paraldehyde, propylene glycol

§  I – isoniazid, iron overdose

§  L – lactic acidosis

§  E - ethylene Glycol

§  S – salicylates

Serotonin syndrome

Particularly associated with some antidepressants

Arises from the accumulation of certain amines, particularly 5-hydroxytryptamine and other drugs that are active at the serotonin receptors

Main symptoms are:

·         Autonomic hyperactivity - sweating, tachycardia tachypnoea, dilated pupils, high temp

·         Neuromuscular abnormality with rigidity and twitching progressing to seizures

·         Mental status changes with agitation

Associated with a number of drugs:

·         SSRIs

·         TCAs

·         Monoamine oxidase inhibitors (5-hydroxytryptamine is metabolised by MOA so inhibition of it can allow serotonin to accumulate)

·         Alagesics like tramadol and fentanyl can cause it

·         Dextromethorphan (from cough syrup) can cause it

·         Antiemetics such as ondansetron and metoclopramide can also result in serotonin syndrome

·         Recreational drugs such as cocaine MDMA etc

Symptoms of serotonin syndrome:

·         Autonomic disturbance caused by serotonin:

o   Hypertension

o   Tachycardia

o   Hyperthermia

o   Diarrhoea

o   Dilated pupils

o   Sweating

·         Neuromuscular dysfunction:

o   Tremor

o   Hypertonicity (leading to rigidity)

o   Hyperreflexia

·         Mental state change

o   Anxiety

o   Agitation

o   Confusion

o   Coma

·         These may progress to:

o   Seizures

o   Malignant hyperthermia with consequent muscle damage and kidney failure

o   DIC coagulopathy

*high mortality, mostly in the first few days

Management of serotonin syndrome

·         Stop the drugs – in mild cases this may be all that is required

·         Fluid resuscitation to raise BP and increase urine output

·         Measure creatinine kinase for rhabdomyolysis

·         Cyproheptadine is a possible antidote without immense evidence but worth giving in severe cases; only available as an oral tablet meaning in comatose pts it must be crushed and given down a nasogastric tube

·         If the pt has seizures then treat with benzodiazepines or phenobarbitone

·         Aggressive management of thermal disturbance; paralyse if the temp exceeds 40.5 degrees

·         Manage rhabdomyolysis with fluids and renal support If necessary

·          

Cocaine

Example question: a 26 year old office worker presents with chest pain which started at a party; his ECG shows ST segment abnormalities

1.       What toxidrome may account for his symptoms?

2.       How would you manage his toxicity?

3.       What drug must you avoid when treating this?

Cocaine is an adrenergic stimulant. It causing ischaemic type chest pain even in young patient

·         This is multifactorial and results from:

o   Coronary vasospasm

o   Accelerated atherosclerosis from continued cocaine use

o   Increases platelet adhesion

o   Stimulant effect of cocaine increasing myocardial oxygen demand

·         The pain is very characteristic of typical ischaemic pain and mimics ACS but is often in much younger patients following use of cocaine in social settings

·         Diazepam reduces agitation, heart rate and oxygen demand making it a very helpful agent

·         Nitrates can also be used to reduce the vasospasm

·         Aspirin for someone with evidence of ischaemic heart disease should be considered

If someone has progressed to developing full blown NSTEMI or STEMI then they should be managed in the typical way, with primary PCI or what have you, but NOT thrombolysis as this would result in higher risk of stroke

Critically, AVOID BETA BLOCKERS – this would remove the beta adrenergic effect on the heart resulting in unopposed alpha adrenergic effects which would WORSEN the vasospasm. Evidence supports this as a reasonable position

Cocaine is typically referenced due to the chest pain it causes but it could come up in the exam in relation to the adrenergic effect:

·         Agitation

·         Tachycardia

·         Paranoid

·         Sweaty

·         Breathless

·         Seizures

It can be very scary if someone is experiencing this

·         Again benzodiazepines are a key part of managing the cocaine toxidrome as they reduce

Ecstasy

Apparently it’s use is declining now – less popular. Ok then.

Mild hallucinogenic and mood enhancing factors

Associated with long term psychiatric and cognitive sequelae after even only one exposure…?

There have been deaths from ecstasy; can come from:

·         Hyperthermia, dancing all night in a hot club – leads to rhabdomyolysis, renal failure, DIC

·         Another hazard is dilutional hyponatraemia – increases anti-diuretic hormone and people are encouraged to drink lots in clubs, can be severe enough to cause seizures and coma and death

·         Also some cardiac failure in possible from fluid overload, some direct toxicity

Management of ecstasy toxicity

·         Benzodiazepines for agitation

·         Cooling aggressively for hyperthermia: even paralyzed, intubated, ventilated if needed to bring temperature down

·         Manage rhabdomyolysis, renal failure, cardiac faulure and DIC as appropriate

·         Otherwise supportive measures, it will clear the system in about 12 hours

Opiate toxicity

Could be caused by:

·         Codeine

·         Dihydrocodeine

·         Diamorphine

·         Heroin

·         Morphine

·         Fentanyl

·         Tramadol

Can all cause opioid toxicity

Question might open with management of opioid toxicity but go on to the complications of IV drug abuse:

·         Endocarditis

·         HIV

·         Hep C

·         Etc

People who take IV drugs are more likely to be at risk of serious adverse effects if taken in combination with benzodiazepines or alcohol

Opiate toxicity presentation:

·         Decreased respiratory rate

·         CNS depression

·         Pin-point pupils

Management of opiate toxicity:

·         Naloxone 0.4-2mg - The dose might need to be titrated quite high depending on how much the patient has taken

·         This might need to be followed on by naloxone infusion 10mg in 50mls of saline, 200mcg/ml given at 60% (or 2/3rds) of initial dose per hour – as most opiates have a longer half life than naloxone itself

Antidotes

Beta blocker overdose

They block beta adrenoreceptors

Beta adrenergic activation causes:

·         Beat 1 receptors increase cardiac output

·         Beta 2 receptors cause bronchodilation (smooth msulce relaxation), release metabolites (gluconeogenesis, glycogenolysis, lipolysis), vasodilate muscles

*cardioselective beta blockers

**labetalol is not card selective and also has alpha blocking effects

***Sotalol is antiarrhythmic as well and can be used in re-entrant tachycardias

Therefore, if the overdose is with a non cardioseletive beta like propanol then as well as the beta 1 blockade causing hypotension, bradycardia and AV block patients will also get hypoglycaemia from the metabolic effects and bronchospasm from the smooth muscle blockage

Managing beta blocker overdose

·         Sympathomimetics like adrenaline tend not to be effective in beta blocker overdose because their mechanism of action ahs been deactivated by the beta blocker

·         Atropine may help by preventing any vagal slowing of the heart thereby improving AV conduction

·         Glucagon has a direct effect on cardiac cells which bypasses the beta adrenoreceptor improving HR, force of conduction and AV condution

·         50 MCG/kg/hr – typically 3-4mg/hr which is a LOT of glucagon

·         There are some new approaches:

·         high dose insulin euglycemic therapy (HIET) to counteract hypoglycaemic, requires a LOT of glucose to be given simultaneously

·         Lipid therapy for lipophilic drugs such as propranolol – 20% intralipid infusion

Calcium channel blocker overdose

Verapamil and diltiazem are the most toxic and their main features in overdose are hypotension and

Bradycardia

Can be very serious toxicities

Management

·         Adding calcium IV to counteract Ca channel blockade

·         Giving fluid to maximise preload

·         Atropine to counteract AV blockade

·         Transcutaneous pacing if unable to improve bradycardia

·         Catecholamines (adrenaline and noradrenaline) to speed up the heart

·         High dose insulin therapy again

·         Lipid therapy again

Anti-coagulant toxicity

This relates more to the over-anticoagulated patients usually with warfarin which presents with prolonged INR and heightened risk of bleeding – particularly intracranial bleeding

In brief:

·         Stop the drug

·         Reverse with vitamin K

·         Give fresh frozen plasma which contains coagulation factors

·         Give coagulation factor concentrates if necessary but these are very expensive

Benzodiazepines

CNS depressants – drowsiness, respiratory depression and coma

·         Saying that, even large overdoses have low risk of mortality

·         Problems tend to arise with CNS depressant co-ingestions eg benzodiazepine + alcohol

·         Flumazenil is a competitive antagonist of benzodiazepines and tends to be used for reversal in procedural sedation with benzodiazepines

·         It’s role in overdose is less clear and those with long term use of benzos may develop seizures in withdrawal which could be precipitated by flumazenil

·         It is therefore usually not recommended in overdose with benzos

Management tends to be supporting with intubation and ventilation in rare cases when required.

GHB

Gamma hydroxybutyrate

·         Easily made in the kitchen with basic equipment

·         Similar to ecstasy: euphoria, disinhibition, empathogenic state

·         Dosing is often poorly controlled; larger doses and cause sedation and coma quite readily

·         Classically reversal is very quick and sudden with rapid regaining of consciousness

·         Effect lasts 2-4 hours

·         Can be used as a date-rape drug as it is very salty

·         Popular amongst body builders as it doubles growth hormone and can help with muscle bulk

Drug and alcohol abue

Addiction – the uncontrollable craving – is the disease, resulting in imbibing the substance regardless of the negative effects it has on the individual’s health and life

Dependence is the body’s specific need and reliance on this substance in order to maintain normal functioning; the absence leading to withdrawal symptoms

Many patients may experience physical dependence without addiction eg patients in chronic pain

Withdrawal symptoms vary drug to drug:

·         Opiates: anxiety, sweating, diarrhoea, vomiting

·         Alcohol: irritability, tremor, hypertension, sensitivity to light, anxiety

·         Delirium tremens (DT)

·         This is the progression to more extreme alcohol withdrawal within 2-3 days of stopping alcohol: confusion, shaking, shivering, sweating, frightening visual hallucinations eg insects crawling on them

·         Progresses to convulsions – seizures, coma and death.

·         DT is a medical emergency and needs to be managed with benzodiazepines – chlordiazepoxide has a long half life and is the one used in the UK