86. Drug intoxications. Mechanisms, symptoms, treatment
According to the lecturer the most important drugs to know here are sedative hypnotics, opioids, digitalis, sympathomimetics, anticholinergics, iron and paracetamol.
Types of intoxications according to mechanism of death
- Intoxication with decreased level of consciousness
- Sedative hypnotics
- Tricyclic antidepressants
- Antipsychotics
- Opioids
- Intoxication with excitatory drugs
- Sympathomimetics
- Ketamine and PCP
- Anticholinergics
- Theophylline
- Intoxication with cardiac dysfunction
- Digitalis glycosides
- Beta blockers
- Calcium channel blockers
- Intoxication with metabolic dysfunction
- Salicylates
- Oral antidiabetics
- Sodium nitroprusside
- Intoxication with tissue necrosis
- Paracetamol
- Iron
Intoxication with sedative hypnotics
Compounds
- Benzodiazepines
- Z-drugs
- Barbiturates
- Ethanol
Mechanism of intoxication
These drugs bind to an allosteric binding site on the GABAA receptor, increasing its affinity for Cl–. This hyperpolarizes the nerve cell.
Symptoms
- Gradual decrease in consciousness
- Disinhibition -> sleepiness -> lethargy -> stupor -> coma
- Vasomotor centre depression -> hypotension
- Respiratory centre depression -> hypoventilation
- Decreased muscle tone -> hypothermia
- Decreased intestinal motility -> paralytic ileus
- Myosis
- Snoring
The cause of death is respiratory or circulatory failure.
Treatment
- Supportive
- Respiratory support
- Circulatory support – norepinephrine, fluids
- Maintenance of body temperature
- Specific treatment
- For ethanol intoxication: thiamine
- For phenobarbital intoxication: bicarbonate infusion, activated charcoal administration for days
- For benzodiazepine or Z-drug intoxication: flumazenil
By administering bicarbonate, we alkalinize the urine of the patient, which will increase the excretion of the weak acid phenobarbital. By giving many doses of oral activated charcoal over days we can interrupt the enterohepatic circulation of phenobarbital.
Flumazenil does not reverse benzodiazepine-induced respiratory depression, which makes its use in treating intoxication limited. It may also precipitate seizures in people who:
- took a pro-convulsive drug like tricyclic antidepressants, theophylline together with the benzodiazepines
- have been taking benzodiazepines chronically
- are epileptic
- have had head trauma
Also, the duration of action of flumazenil is short, only 90 minutes. As such, the patient may become re-sedated after this time.
Intoxication with tricyclic antidepressants
Mechanism of intoxication
Tricyclic antidepressants are dirty drugs. In addition to inhibiting the serotonin and norepinephrine reuptake they inhibit:
- α1 adrenergic receptors
- -> hypotension
- Muscarinic acetylcholine and Histamine H1 receptors
- -> gradual decrease in consciousness
- -> sleepiness -> lethargy -> stupor -> coma
- -> respiratory depression
- -> vasomotor centre depression
- -> gradual decrease in consciousness
- GABAA receptors
- -> convulsion
- Myocardial sodium channels
- -> impaired repolarization, arrhythmia
The cause of death can be one of the 3 C’s: Coma, cardiac arrhythmia or convulsions.
Symptoms
- Hypotension
- Tachycardia
- Dry, hot skin
- Impaired consciousness
- Arrhythmia
- Convulsions
Treatment
- For convulsions
- Benzodiazepines or barbiturates
- For arrhythmias
- Sodium bicarbonate infusion (counters the sodium channel blockade)
- For hypotension
- Fluids
- Norepinephrine
Intoxication with classical antipsychotics
Compounds
- Chlorpromazine
- Fluphenazine
- Haloperidol
Mechanism of intoxication
Blockage of:
- Dopamine receptors
- -> extrapyramidal symptoms
- α1 adrenergic and muscarinic acetylcholine receptors
- -> hypotension
- -> tachycardia
- GABAA receptors
- -> impaired consciousness
Symptoms
- Coma
- Hypotension
- Tachycardia
- Extrapyramidal symptoms
- “Cogwheel rigidity”
- Dystonia – abnormal movement of muscles
Treatment
There is no specific treatment, only symptomatic.
Intoxication with atypical antipsychotics
Compounds
- Clozapine
- Olanzapine
- Risperidone
Mechanism of intoxication
Blockage of:
- Histamine H1 receptors
- -> lethargy
- -> sedation
- α1 adrenergic receptors
- -> hypotension
- -> myosis
- Muscarinic acetylcholine receptors
- -> confusion
- -> sedation
- -> tachycardia
Symptoms
- Lethargy
- Sedation
- Myosis
- Hypotension
- Tachycardia
- Confusion
Treatment
There is no specific treatment, only symptomatic.
Intoxication with opioids
- Morphine
- Buprenorphine
- Methadone
- Fentanyl
- Tramadol
- Codeine
- Heroin
Mechanism of toxicity
These drugs are agonists for the opioid receptors. An important contributing factor to opioid intoxication is the fact that the tolerance to the respiratory depressive effect lasts only a few days.
Activation of opioid receptors cause:
- Respiratory depression
- Vasomotor centre depression
- Inhibition of inhibition of the nucleus of the oculomotor nerve
- Decreased intestinal motility
- Decreased urinary bladder motility
- Histamine release
Symptoms
- Gradual decrease in consciousness
- Disinhibition -> sleepiness -> lethargy -> stupor -> coma
- Hypoventilation
- Pinpoint pupils
- Urine retention
- Paralytic ileus
- Itching
The cause of death is often respiratory depression, but in the case of heroin it can be ARDS also.
Treatment
- Naloxone
- Respiratory support
- Catheterization of the urinary bladder
Intoxication with sympathomimetics
Compounds
- Amphetamine
- Amphetamine derivatives
- MDMA
- Ecstasy
- Methamphetamine
- Bupropion
- Cocaine
Mechanism of intoxication
These drugs are indirect sympathomimetics and psychostimulants by different mechanisms. Amphetamines enter the adrenergic nerve ending by acting as false substrates for NET. They are also taken up into the vesicles by VMAT. This causes noradrenaline to be leave the cytosol into the synaptic cleft through NET.
Cocaine inhibits NET, so that noradrenaline cannot be removed from the synaptic cleft.
Symptoms
- Psychosis
- Rhabdomyolysis
- Convulsions
- Hyperthermia
- Hypertension
- Tachycardia
- Arrhythmia
- Mydriasis
The cause of death can be one of many:
- Haemorrhagic stroke
- Due to severe hypertension
- Arrhythmia
- Myocardial infarction
- Convulsions
- Brain oedema
- Due to extreme thirst -> water intoxication -> hyponatraemia
Treatment
- Symptomatic
- Cooling
- α1 antagonist (urapidil)
- For hypertension
- Beta blockers
- For arrhythmia
- Benzodiazepines
- For convulsions
- Antipsychotics
- Continuous aspiration of gastric juice
- As amphetamine is a weak base and will be ion trapped there
- Hypertonic solutions or vasopressin antagonists
- For hyponatraemia
Intoxication by centrally acting anticholinergics
Compounds
- Atropine
- Scopolamine
- Diphenhydramine (antihistamine)
- Benztropine (antiparkinson)
Mechanism of intoxication
These drugs inhibit muscarinic acetylcholine receptors, causing the symptoms below:
Symptoms
- Excitement
- Hallucination
- Delirium
- Coma
- Tachycardia
- Dry skin
- Hyperthermia
- Dry mouth
- Mydriasis, photophobia
- Cycloplegia (loss of accommodation)
- Urinary retention
Treatment
- Symptomatic
- Cooling
- Benzodiazepines
- Beta blockers
- Antidotes
- Physostigmine
- Rivastigmine
Intoxication by digitalis glycosides
Compounds
- Digoxin
- Digitoxin
Etiology
The toxicity of digitalis can be increased by many factors, like:
- Diuretic treatment
- Clarithromycin treatment
- It kills the gut bacteria which metabolizes glycosides
- It is also a Pgp inhibitor
- Hypokalaemia
- Renal failure
- Concomitant use of drugs which are Pgp inhibitors
- Verapamil
- Amiodarone
- Quinidine
Mechanism of toxicity
The glycosides inhibit Na-K-ATPase, which causes hypopolarization of the cell, increasing their excitability. However, they’re not specific for the heart and can act on neurons as well. By acting on other tissues they cause a multitude of other effects:
- On the heart
- -> faster but incomplete repolarization
- -> slower depolarization
- On visual cortex
- -> visual disturbances
- On chemoreceptor trigger zone/area postrema
- -> vomiting
- On vagus nerve
- -> bradycardia
- -> decreased conduction in heart
Symptoms
- Bradycardia
- Extrasystoles
- Nausea, vomiting
- Visual disturbances
- Headache
- Hyperkalaemia
The cause of death is either ventricular arrhythmia or AV block.
Treatment
- Symptomatic
- Pacemaker
- Atropine
- Antidote
- Digitalis antibody
- K+ infusion
- Activated charcoal or cholestyramine administration
Intoxication by beta blockers
Compounds
- Propranolol
- Metoprolol
- Atenolol
- Pindolol
Mechanism of toxicity
These drugs inhibit β adrenergic receptors. Some are specific for β1 in therapeutic doses, however if overdosed that can act on β2 receptors as well.
Symptoms
- Due to β1 receptor blockage
- Hypotension
- Bradycardia
- AV block
- Due to β2 receptor blockage
- Bronchoconstriction
- Peripheral vasoconstriction
- Hypoglycaemia
- Hyperkalaemia
Treatment
- Isoprenaline – overcomes beta antagonism
- Glucagon – has positive heart effects
- Atropine – increases heart rate
- β2 agonist – relieves bronchospasm
Glucagon acts on its own receptor on the heart but has the same intracellular effects as the beta-adrenergic receptor; both increase intracellular cAMP.
Intoxication by salicylates
Compounds
- Aspirin (acetylsalicylic acid)
- Salicylic acid
Mechanism of toxicity
Acetylsalicylic acid is rapidly hydrolysed by butyrylcholinesterase to salicylic acid in the body. Salicylic acid is eliminated partly by unchanged renal excretion and partly by biotransformation.
Salicylic acid is toxic by three mechanisms:
- It is an irritant
- It uncouples oxidative phosphorylation
- It depletes glycine and CoA from the mitochondria of the liver and kidney
The result of the latter two is the depletion of ATP, which stimulates glycolysis and metabolism. However, pyruvate can’t be converted into acetyl-CoA as the cells are depleted of CoA. Pyruvate will instead be reduced to lactate.
Symptoms
- Abdominal pain
- Vomiting
- Haematemesis
- Hyperventilation -> respiratory alkalosis
- Tinnitus
- Hyperthermia
- Hypoglycaemia
- Lactic acidosis
Multiple organs can fail due to salicylate toxicity:
- Liver failure
- Rhabdomyolysis
- Pulmonary oedema
- Proteinuria
Treatment
- NaHCO3 infusion
- Alkalinisation of urine -> increases excretion
- Corrects acidosis
- Oral glycine
- Provides glycine for the biotransformation of salicylates
- Haemodialysis
Intoxication by oral antidiabetics
Compounds
- Sulfonylureas
- Glimepiride
- Glipizide
- Metformin
Etiology
Sulfonylurea overdose can be caused by CYP inhibitors like amiodarone and fluconazole, or by strongly plasma protein-drugs like loop diuretics or NSAIDs.
Metformin overdose rarely occurs in the absence of contraindications for metformin. The most common cause is metformin use in impaired renal function.
Mechanism of toxicity
The mechanism of toxicity is different for the two types of antidiabetic. Sulfonylureas block ATP-gated K+ channels on β cells, directly stimulating exocytosis of insulin. Because this effect directly stimulates insulin secretion there is high risk of secreting too much insulin, causing hypoglycaemia.
Metformin inhibits the oxidative phosphorylation, which activates AMPK, which inhibits the transcription of gluconeogenetic enzymes and stimulates GLP-1 production. The toxicity of metformin is related to its inhibition of the oxidative phosphorylation.
Symptoms
The symptoms of sulfonylurea toxicity are the same as for hypoglycaemia:
- Symptoms caused by sympathetic activation
- Nausea
- Sweating
- Tachycardia
- Symptoms caused by decreased glucose supply to the brain
- Confusion
- Dizziness
- Seizures
The symptoms of metformin toxicity are the same as for lactic acidosis:
- Nausea
- Confusion
- Hypotension
- Tachycardia
- Tachypnoea
Treatment
For sulfonylurea:
- Glucose
- Octreotide (SST analogue)
For metformin:
- Supportive therapy
- Bicarbonate infusion
- Haemodialysis
Intoxication of sodium nitroprusside
Etiology
Intoxication occurs if sodium nitroprusside infusion is given in high dose or over a long time. Sodium nitroprusside is usually used to treat hypertensive emergencies and so overuse can occur.
Mechanism of toxicity
Sodium nitroprusside releases cyanide ions in the body. Cyanide inhibits complex IV of the oxidative phosphorylation, causing histotoxic hypoxia. As the oxidative phosphorylation is inhibited cells will be unable to perform aerobic metabolism and must perform the much less efficient anaerobic metabolism. Symptoms occur due to ATP deficiency in the CNS and heart, and due to lactic acidosis.
Symptoms
- Confusion
- Excitement
- Convulsions
- Bradycardia
- Hypotension
- Arrhythmias
- Lactic acidosis
Pharmacokinetics
Cyanide is eliminated by an enzyme called rhodanase, which is found in the liver and muscle. This enzyme converts cyanide into thiocyanate, which isn’t toxic.
Methaemoglobin binds to cyanide in the body. By stimulating haemoglobin conversion into methaemoglobin, we can inactivate cyanide.
Treatment
Either of the following options, in decreasing order of preference:
- Hydroxycobalamin + sodium thiosulphate
- Amyl nitrite + sodium nitrite + sodium thiosulphate
- 4-DMAP
- Cobaltous EDTA
Hydroxycobalamin and cobaltous EDTA bind to and inactivate cyanide directly.
Thiosulphate is the substrate for rhodanase, and by providing this substrate we increase the rate at which rhodanase will eliminate cyanide.
Amyl nitrite, sodium nitrite, and 4-DMAP stimulate conversion of haemoglobin into methaemoglobin.
Intoxication of paracetamol
Etiology
The hepatotoxic dose of paracetamol is 12 g. The dose is lower in alcoholics as they have decreased GSH (glutathione) and induced CYP2E1.
Mechanism of toxicity
Paracetamol is biotransformed partly by UGT and partly by CYP2E1. The metabolite formed by CYP2E1 is called NAPBQI and is toxic. NAPBQI is usually detoxified by GSH. NAPBQI binds covalently to proteins and is toxic by three mechanisms:
It inhibits the calcium pump in the sarcoplasmic reticulum, which causes intracellular Ca2+ to increase. This activates enzymes which will degrade the cell, and it inhibits oxidative phosphorylation.
It forms reactive oxygen species in the liver mitochondria.
It releases Fe2+ from lysosomes in liver cells. Fe2+ catalyses the Fenton reaction, which produces reactive oxygen species.
The cause of death is often hepatocellular necrosis.
Symptoms
- Initially malaise, then transient improvement
- 2-4 days later:
- Hepatocellular necrosis
Survivors generally recover completely, without cirrhosis.
Treatment
The antidote is N-acetylcysteine. This compound is converted into glutathione, which increases the liver’s ability to eliminate NAPBQI and the reactive oxygen species formed by it.
Intoxication by iron
Mechanism of toxicity
Fe2+ catalyses the Fenton reaction, which produces reactive oxygen species. These radicals cause cellular injury.
Symptoms
- Initially
- Haemorrhagic gastroenteritis
- Possibly haemorrhagic shock
- Then
- Acidosis
- Hyperthermia
- Cyanosis
- In 2 – 4 days
- Hepatic necrosis
- In 1 – 2 months
- Intestinal scarring
Treatment
- Deferoxamine
- Whole bowel irrigation
- Supportive treatment
The antidote is deferoxamine, a chelating agent which binds iron with very high affinity.