Lecture 27- Poisoning Flashcards
adverse reactions can be due to
dose, person, disease related
What is seen as a beneficial effect in one situation may be an undesirable side effect in another and vice versa
- Loperamide (mu opioid agonists) - antidiarrheal effects, other opioids constipation in pain management
- Chlorpromazine – antipsychotic sedative, anti-emetic in palliation
Side effects lead to successful use of drugs too-context and condition being treated is important
e.g. Viagra originally developed for angina, one side effect was vasodilation –> used as an erectile dysfunction drug
- Pharmacological toxicity often a predictable extension to desired effect
e.g. excessive toxic responses
- Warfarin
- Sweet spot- anticoagulant
- Too much= bleeding
- Insulin
- Too much= hypoglycaemic state
e.g. Off target response
e.g. statins = rhabdomyolysis
e.g. thalidomide= birth defects
e.g. effect normally on seen in large overdose
Large therapeutic index difference between therapeutic and toxic response
e.g. an effect normally only seen in a small overdose
Narrow therapeutic index difference between therapeutic and toxic response
Biochemical toxicity
- A drug or active metabolite which causes cellular damage - macromolecules inc. structural proteins and enzymes
- Most drugs that reach market have been tested extensively for toxicity BUT - at supra therapeutic levels build up of toxic metabolites possible
- Balance of elimination of a drug or metabolites will dictate the potential harm that may be caused
Overcoming biological toxicity
Understanding the mechanism of toxicity has in some cases allowed us to develop suitable pharmacological treatments
e.g. 1 Overcoming biological toxicity in overdose scenario
- during paracetamol overdose - thiol group found on endogenous glutathione can prevent cell damage caused by highly reactive chemical metabolites
- When glutathione gets overwhelmed
- acetylcysteine – thiol donating in paracetamol overdose administered in three successive infusions at different conc. Over 21h
- Mechanism supported by observations
- hepatic necrosis
- CYP inducers inc. alcohol
- patients with low hepatic reserves of glutathione
e.g 2 Overcoming biological toxicity drugs used at therapeutic levels
- Cyclophosphamide typically used in severe rheumatoid presenting with other systemic manifestations
- Highly toxic metabolites – eliminated in urine and cause haemorrhagic cystitis due to cell damage in bladder
-
Use of Mesna alongside cyclophosphamide
Mesna – thiol group for cytoprotection and polar group – high renal excretion and protection at bladder epithelium – p.o. 2 hours before or i.v. with cyclophosphamide
Management principles
Immediate actions
- Remove person from contact with poison – typically you will be presented with somebody significantly after the event(s)
- Vital signs and injury
- History – from the patient if you can, chaperone, evidence – packaging, written notes
Supportive measures to address:
Prevention of absorption
- Gastric lavage almost never recommended due to risk of aspiration
-
Activated charcoal – large absorbent area given as suspension in water large quantities needed - 10:1
- Timing of overdose makes the efficacy of charcoal unpredictable – later for modified release preparations and antimuscarinics
- Not suitable for drowsy or comatose patients
Antidotes
- Competitive antagonists
- Naloxone
- Atropine
- Chelating agents – complex with poison – reduced free drug
- e.g. cyanide, lead, iron salts
- Manipulating drug metabolism
- Fomepizole
- Acetylcysteine
- Antibodies antivenom
- digoxin-specific antibody – binds to digoxin
