Drug toxicity and routes of administration
• Drug Toxicity
◦ (Acute [usually one large dose] and Chronic [occurs from long-term use ~3mnths)
• Poisoning and Suicide
◦ ASAand Acetaminophen - Common
▪ Cause of poisoning in children – iron tablets
▪ children far more susceptible to iron (adults block iron overdose)
◦ Household chemicals
◦ Barbiturates cause of poisoning – less so in 2013
◦ Benzodiazepines – often with alcohol
• Almost all drugs have adverse effects
◦ Individual - may be genetic
◦ Age; ex: newborn should not be treated like a small adult
◦ Disease state; ex: live cirrhosis (most drugs metabalized by liver)
• CategorizeAdverse effects.
Types of Adverse Effects of Drugs
• Extension of therapeutic effect
◦ over sedation with barbiturates or benzodiazepines
◦ nonselective action of the drug
• unrelated to main drug action
◦ digitalis and nausea
◦ NSAID – GI erosions → Non-steroidal anti-inflammatory drug: gastrointestinal erosions
◦ usually genetically mediated – ex: lack of an enzyme or changes in the manner in which the
drug is handled
◦ outside of normal population response: need only a small or a much larger dose
• drug allergy
◦ need prior exposure to form antibodies to the drug – penicilin (15%)
What Michael Jackson was administered On June 25th 2009.
Michael Jackson was given a series of sedatives by Dr. Conrad Murray on June 25, the day the singer
died, according to an affidavit released yesterday (August 24, 2009) in Houston.
• 1:30AM: 10 mg tablet of diazepam (valium)
• 2 AM: 2 mg lorazepam, IV
• 3 AM: 2mg midazolam , IV
• 5AM: 2mg lorazepam, IV
• 7:30AM: 2mg midazolam, IV
• 10:40AM: 25mg of propofol (general anaesthetic → never used outside of medical facility or
outside of hands of anaesthetist) given IV and diluted with lidocaine. • 10:50AM: “Doctor leaves Jackson’s room; returns minutes later to find Jackson not breathing.
• Begins CPR and gives 0.2mg flumazenil IV
Michael Jackson Dies!
Why did Michael Jackson die?
• drugs acted synergistically
◦ all benzdiazepines – CNS depressants; all act on same receptor, same site
◦ propofol acts on same system but different binding site
• category of toxicity: extension of therapeutic response
Why is toxicity difficult to predict? Why adverse responses?
• toxicity is a rare event: chloramphenicol – 1 in 50,000 patients died from blood dyscrasias
◦ rare event not detected in tests
• toxic event appears after years of use
◦ long term use may cause toxicity not detected in tests, e.g. hearing loss with streptomycin
• toxic effect not detected in animals: headache, insomnia, depression not detected in animals
• toxic effect unique to a certain period: thalidomide was not detected in tests.
◦ used incorrect species of test animal.
• Are animals a good test system? Seem to be
• How well do they reflect toxicity in humans? Don't
• How do we assess drug toxicity?
• Toxic dose 50 : dose toxic to 50% of animals
• median effective dose 50: dose effective in 50% of
• Therapeutic Index = TD50/ED50
• TI = TD50/ED50
• a measure of the safety of a drug for that particular
Dose of Drug, Concentrationin Blood and Re