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PHAR 100 (175)
Lecture

4drugtoxicityandroutes.pdf

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Department
Pharmacology and Toxicology
Course
PHAR 100
Professor
Hisham Elbatarny
Semester
Fall

Description
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 ◦ Iron ▪ 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 CAUTION • Almost all drugs have adverse effects ◦ Dose ◦ 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 • idiosyncrasy ◦ 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 always Therapeutic Index • How do we assess drug toxicity? • Toxic dose 50 : dose toxic to 50% of animals • median effective dose 50: dose effective in 50% of animals • Therapeutic Index = TD50/ED50 Therapeutic Index • TI = TD50/ED50 • a measure of the safety of a drug for that particular toxicity Dose of Drug, Concentrationin Blood and Re
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