NUSCTX 110 Study Guide - Fall 2018, Comprehensive Midterm Notes - Protein, Kidney, Gastrointestinal Tract
12 Oct 2018
School
Department
Course
Professor
NUSCTX 110
MIDTERM EXAM
STUDY GUIDE
Fall 2018
NST 110 Lecture #1
I. Toxicology
A. The study of adverse effects of chemicals on living systems, including:
• Mechanisms of action and exposure to chemicals as a cause of acute
and chronic illness
• Recognition, identification, quantification of hazards from
occupational exposure to chemicals
• Discovery of new drugs and pesticides and characterizing their
safety, ADME, toxicology how it’s metabolized and secreted
• Development of standards and regulations to protect humans and the
environment from adverse effects of chemicals. Safety
B. Branches of Toxicology
• Mechanistic
• Forensic
• Clinical
• Environmental
• Food
• Regulatory
C. Origins of Toxicology
• Earliest humans used animal venoms and plant extracts for use
• 400 BC: Hippocrates compiled a list of poisons and outlines principles
• 1400s, Paracelsus applied scientific method to toxicology, all
substances are poisons and the right dose differentiates poisons from
a remedy
• Dose determines toxicity
D. Examples of Toxicological Cases (LOOK ON SLIDES)
• Socrates died of Hemlock poisoning
• Charles VI died from eating a death cap mushroom
• Benzopyrene in soot of chimney, is a carcinogen
II. Drugs
A. Vioxx: Cyclooxygenase 2 (COX2)-Selective Inhibitors
• Vioxx produced by Merck
• COX2 selective inhibitor with very little gastrointestinal side effects
• Prescribed to over 20 million people as a pain reliever for arthritis
• Was found to be responsible for increased risk of heart attack and
stroke
• Recalled in 2004
• Largest drug recall in history
B. Thalidomide: Morning Sickness Drug
• Thalidomide was an anti-nausea and sedative drug that was
introduced in the 50’s to prevent morning sickness but caused
extreme birth defects
• R-thalidomide stimulates the GABA receptor to cause sedative effects
find more resources at oneclass.com
find more resources at oneclass.com
• S-thalidomide binds to a protein and inactivates a protein called
cereblon (CRBN), an E3 ubiquitin ligase that, when bound to
thalidomide, recruits neo-substrates to ubiquinate and proteasomally
degrade them- including a recently identified transcription factor
called SALL4 which is involved in limb outgrowth and development
• Thalidomide has also been shown to inhibit angiogenesis through
down regulation of angiogenesis related growth factors such as
insulin growth factor 1 and vascular endothelial growth factor,
important for making blood vessels for limbs
• Thalidomide is now currently used for cancer therapy due to its anti-
cancer properties
• Celgene is a basically new way of drug discovery – force proteins to
interact, subsequently degrading them, other companies using this to
develop drugs for the undruggable proteome
• Another approach is targeted protein degradation
III. Dose-Response
A. Curves
• Individual dose response
• Y-axis: % of max. response (linear in middle range)
• X-axis: dose (mg/kg), plotted as log base 10, no zero!
• Can derive lethal dose, toxic dose, effective dose values from dose
response data
• Inhibitory concentration can also be determined from concentration
response curve
• Experience efficacy before toxicity
B. Dose response curves for beneficial substances
• U-shaped
• Therapeutic index: want a bigger index
• Some disadvantages of using TI though is that it does not take in to
effect the shape of the curve
• Account for this by calculating the margin of safety. LD1/ED99, so the
smaller the margin of safety the less safe the drug is. The bigger the
margin of safety the more safe the drug is.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Individual dose response: y-axis: % of max. response (linear in middle range, x-axis: dose (mg/kg), plotted as log base 10, no zero, can derive lethal dose, toxic dose, effective dose values from dose response data. Ld1/ed99, so the smaller the margin of safety the less safe the drug is. The bigger the margin of safety the more safe the drug is. Nst 110 lecture #2 (absorption and distribution: absorption, factors involved in absorbing a chemical, physicochemical properties of chemical: hydrophobic v hydrophilic, 3. organic-anion transporting polypeptide (oatp) hepatic uptake of organic: organic anion transporter (oat) kidney uptake of organic anions, organic cation transporter (oct) kidney, liver and placental uptake of organic. 2+, cu 2+, mg2+, etc. : routes of exposure: oral, absorption can occur anywhere in the gi tract including the mouth and rectum. 2. chloroform, anesthetic that depresses the nervous system, but can also be metabolized to phosgene, a reactive metabolite that modifies proteins and causes toxicity in lung, kidney, and liver.
