4. Drug Overdose: Prescribed and Therapeutic Drugs Flashcards
Antidepressants
Mechanisms:
(TCAs) such as amitriptyline and imipramine
serotonin re-uptake inhibitors (SSRIs) such as
fluoxetine (Prozac), paroxetine (Seroxat), sertraline (Lustral),
citalopram (Cipramil) and escitalopram (Cipralex)
SSRIs
SSRIs are relatively selective for 5-HT uptake, have fewer anticholinergic side effects
than TCAs and are safer in overdose
They can cause a ‘serotonin syndrome’ if used in
combination with drugs such as monoamine oxidase inhibitors. Its features include
hyperthermia, muscular rigidity and cardiovascular collapse.
TCAs
TCAs are tertiary amines and are related chemically to phenothiazines.
They act by blocking the re-uptake of amines, primarily noradrenaline and 5-HT
competitive inhibition of a transport protein binding site
They have minimal influence on dopaminergic synapses but
do affect muscarinic ACh and histamine receptors.
Features of overdose: Adeprs - CVS
major problems are cardiovascular and neurological.
Ventricular arrhythmias are common and are associated particularly with QT interval
prolongation.
In high doses they appear to block a specific
cardiac potassium channel (the HERG channel)
Ventricular fibrillation may supervene. Other potential
arrhythmias include heart block and ventricular tachycardia
CNS effects include features of overdose: Adeprs
agitation and excitability,
grand mal convulsions and coma.
The muscarinic effects
resemble those of atropine poisoning,
with flushing, dry mouth,
mydriasis and gastrointestinal stasis.
Features of poisoning with SSRIs are analogous, but are generally less severe.
Management Adepress OD
Largely supportive.
Benzodiazepines may abort convulsions.
Cardiac arrhythmias should be treated only with extreme caution,
if at all, because the combination of effects can be fatal.
Magnesium is probably the least dangerous
treatment, although intravenous lidocaine and amiodarone have been used.
ECG monitoring is mandatory for at least 24 hours after ingestion.
Induced alkalosis (plasma pH > 7.5) by the use of hyperventilation a
nd intravenous NaHCO3 may
reduce the amount of free drug that is present.
NaHCO3 - 1-2mEq/Kg
Paracetamol
Mechanisms
Mechanisms: paracetamol probably acts as an inhibitor of central prostaglandin
synthesis, although its exact subcellular mechanism of action remains unclear.
peripheral anti-inflammatory action is conflicting
absorbed from the small intestine
liver enzymes which catalyze the normal
conjugation pathways rapidly become saturated.
A dose of 8–10 g in adults is toxic. The alternative metabolic pathway via mixed
function oxidases produces a metabolite (N-acetyl-p-benzoquinine imine) which is
toxic to cells both of the liver and of the renal tubules
normally conjugated with glutathione,
but will accumulate when glutathione stores are
depleted to cause centrilobular hepatic necrosis and renal tubular damage.
Features Paracetamol
Management
Features of overdose: nausea and vomiting occur early; symptoms and signs of
hepatic failure appear later.
Management:
definitive early treatment is with agents that will replenish glutathione
stores and prevent hepatic damage.
Methionine, which is a glutathione precursor, can be given orally, although the more common treatment is
intravenous N-acetylcysteine.
Fulminant hepatic failure can be treated only by hepatic transplantation.
Benzodiazepines Mechanism
Mechanism of action:
benzodiazepines facilitate the opening of GABA-activated
chloride channels and thereby enhance fast inhibitory synaptic transmission within
the CNS.
They bind to a separate receptor, which effects an allosteric change that
increases the affinity of GABA for the GABAA receptor.
Features of overdose benzos
Features of overdose: these drugs are relatively safe in overdose because, taken alone,
they cause profound sedation but without respiratory depression, haemodynamic
instability or secondary toxicity. In combination with other CNS depressants,
however, they may be associated with marked respiratory depression.
Management
: flumazenil (Anexate) is a specific benzodiazepine antagonist which
displaces benzodiazepines from the binding sites and reverses their effects.
The effective duration of action of flumazenil is shorter than that of many of the drugs
which it antagonizes, and so the dose (typically up to 500 μg intravenously) may
need to be repeated.
The incautious use of flumazenil may also unmask convulsions caused, for example, by TCAs, otherwise suppressed by the benzodiazepine overdose
Tramadol
Features of overdose:
Tramadol has relatively low activity at μ-receptors, but it also acts by inhibiting the
re-uptake of noradrenaline and 5-HT within the CNS
Features of overdose: although activity at μ-opioid receptors is weak, after overdose
patients may demonstrate typical features of sedation and respiratory depression. Of
greater interest are the signs of a ‘serotonin syndrome’, which include agitation,
tachycardia and hypertension, diaphoresis and muscular rigidity.
Tramadol Mx
Management:
in general, the treatment of a tramadol overdose is supportive.
Naloxone can be used to treat the opioid side effects,
but the optimal management of a serotonin syndrome remains uncertain.
The 5-HT2A antagonist cyproheptadine has been used,
as have drugs such as dantrolene, propranolol and diazepam
Alcohol
included because alcohol ingestion frequently complicates overdose with other
drugs. TCAs, for example, can dangerously enhance the depressant effects of acute
alcohol intake.
Mechanism of action: ethanol facilitates the
opening of GABA-activated chloride channels to
increase fast inhibitory synaptic transmission within the CNS.
It also acts to inhibit the NMDA receptor.
Alcohol
included because alcohol ingestion frequently complicates overdose with other
drugs. TCAs, for example, can dangerously enhance the depressant effects of acute
alcohol intake.
Mechanism of action: ethanol facilitates the
opening of GABA-activated chloride channels to
increase fast inhibitory synaptic transmission within the CNS.
It also acts to inhibit the NMDA receptor.
