NUSCTX 110 Midterm 1
On-Target Toxicity - ✔✔Toxic effect due to the drug interacting with
the intended therapeutic target
Off-Target Toxicity - ✔✔Toxic effect due to the drug interacting with an
unintended biological target or unintended tissue
Idiosyncratic drug reactions - ✔✔drug reactions that occur rarely and
unpredictably
Idiopathic drug reactions - ✔✔when the cause of toxicity in a drug is
unknown
Rosiglitazone - ✔✔•It was prescribed as an insulin sensitizer for
diabetics by binding to PPAR-gamma receptors in adipocytes•First
released in 1999, annual sales peaked at 2.5 billion in 2006 and use has
declined dramatically after drug was found to increase risk of heart
attacks.•Adverse effects subject to over 13,000 lawsuits and has been
estimated to have caused 83,000 heart attacks in the US•Rosiglitazone
causes on-target edema which can put people at risk for congestive
heart failure—occurs through reduced renal excretion of sodium and
increase in sodium and water retention
,Non-Steroidal Anti-Inflammatory Drugs - ✔✔Non-Steroidal Anti-
Inflammatory Drugs—Aspirin, Ibuprofen, Diclofenac, Naproxen,
acetaminophen•Used for pain relief, inflammation, fever reduction and
swelling, arthritis, headache•Acetylsalicilic acid (active ingredient of
aspirin) is produced by plants including willow bark and spiraea
Rofecoxib (Vioxx) - ✔✔•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; Financial damage: nearly
$6 billion in litigation•Largest drug recall in history•Merck and FDA
criticized for ignoring evidence of dangers of Vioxx before its eventual
recall•140,000 people could have suffered serious coronary heart
disease from taking the drug in just the U.S.•Studies have shown that
COX2 is responsible for synthesis of prostacyclins in the vasculature
which are cardioprotective•COX2-selective inhibition reduces the
cardioprotective prostacyclin and causes cardiac events
Diphenhydramine - ✔✔•Diphenhydramine also crosses the blood brain
barrier where H1 histamine receptor antagonism causes
sleepiness.•Modern antihistamines, such as claritin, do not cross the
blood brain barrier
Toxicology - ✔✔Toxicology is 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.•Development of standards and
regulations to protect humans and the environment from adverse
effects of chemicals.
Terfenadine - ✔✔a non-sedating antihistamineformerly used for
treatment of allergic conditions by Sanofi Aventis•Was used by over
100 million patients by 1990 and made over $440 million•Replaced by
fexofenadine in the 1990s due to risk of cardiac arrhythmia
Thalidomide - ✔✔•Thalidomide was an anti-nausea and sedative drug
that was introduced in the late 1950s to be used to help with morning
sickness•1950s to 1960s: more than 10,000 children in 46 countries
were born with deformities such as phocomelia involving shortened
limbs R-thalidomide stimulates the GABA receptor to cause sedative
effects. •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 ubiquitinate and proteasomally
degrade them—including a recently identified transcription factor
called SALL4 which is involved in limb outgrowth and development
1.How do most small-molecule drugs that are in the clinic work to exert
their therapeutic action? - ✔✔a.Most small-molecule drugs bind to a
pocket in a protein and inhibits or activates that protein, but that
protein is not degraded
b.Most small-molecule drugs bind to a gene and turn on or turn off that
gene
c.Most small-molecule drugs edit your genome to repair inborn errors
On-Target Toxicity - ✔✔Toxic effect due to the drug interacting with
the intended therapeutic target
Off-Target Toxicity - ✔✔Toxic effect due to the drug interacting with an
unintended biological target or unintended tissue
Idiosyncratic drug reactions - ✔✔drug reactions that occur rarely and
unpredictably
Idiopathic drug reactions - ✔✔when the cause of toxicity in a drug is
unknown
Rosiglitazone - ✔✔•It was prescribed as an insulin sensitizer for
diabetics by binding to PPAR-gamma receptors in adipocytes•First
released in 1999, annual sales peaked at 2.5 billion in 2006 and use has
declined dramatically after drug was found to increase risk of heart
attacks.•Adverse effects subject to over 13,000 lawsuits and has been
estimated to have caused 83,000 heart attacks in the US•Rosiglitazone
causes on-target edema which can put people at risk for congestive
heart failure—occurs through reduced renal excretion of sodium and
increase in sodium and water retention
,Non-Steroidal Anti-Inflammatory Drugs - ✔✔Non-Steroidal Anti-
Inflammatory Drugs—Aspirin, Ibuprofen, Diclofenac, Naproxen,
acetaminophen•Used for pain relief, inflammation, fever reduction and
swelling, arthritis, headache•Acetylsalicilic acid (active ingredient of
aspirin) is produced by plants including willow bark and spiraea
Rofecoxib (Vioxx) - ✔✔•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; Financial damage: nearly
$6 billion in litigation•Largest drug recall in history•Merck and FDA
criticized for ignoring evidence of dangers of Vioxx before its eventual
recall•140,000 people could have suffered serious coronary heart
disease from taking the drug in just the U.S.•Studies have shown that
COX2 is responsible for synthesis of prostacyclins in the vasculature
which are cardioprotective•COX2-selective inhibition reduces the
cardioprotective prostacyclin and causes cardiac events
Diphenhydramine - ✔✔•Diphenhydramine also crosses the blood brain
barrier where H1 histamine receptor antagonism causes
sleepiness.•Modern antihistamines, such as claritin, do not cross the
blood brain barrier
Toxicology - ✔✔Toxicology is 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.•Development of standards and
regulations to protect humans and the environment from adverse
effects of chemicals.
Terfenadine - ✔✔a non-sedating antihistamineformerly used for
treatment of allergic conditions by Sanofi Aventis•Was used by over
100 million patients by 1990 and made over $440 million•Replaced by
fexofenadine in the 1990s due to risk of cardiac arrhythmia
Thalidomide - ✔✔•Thalidomide was an anti-nausea and sedative drug
that was introduced in the late 1950s to be used to help with morning
sickness•1950s to 1960s: more than 10,000 children in 46 countries
were born with deformities such as phocomelia involving shortened
limbs R-thalidomide stimulates the GABA receptor to cause sedative
effects. •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 ubiquitinate and proteasomally
degrade them—including a recently identified transcription factor
called SALL4 which is involved in limb outgrowth and development
1.How do most small-molecule drugs that are in the clinic work to exert
their therapeutic action? - ✔✔a.Most small-molecule drugs bind to a
pocket in a protein and inhibits or activates that protein, but that
protein is not degraded
b.Most small-molecule drugs bind to a gene and turn on or turn off that
gene
c.Most small-molecule drugs edit your genome to repair inborn errors
