8-10 Drug Toxicity Flashcards
asdf
A: Alcoholics are at an increased risk for acetaminophen OD because EtOH in excess causes the INC expression of [CYP2E1]. This Phase 1 enzyme converts acetaminophen into a dangerous [NAPQI] (which normally is conjugated into less dangerous product by Glutathione).
Once the hepatocyte reserve of Glutathione runs out, NAPQI is free to interact w/hepatocell proteins–> Cell death—> Liver Failure
B: Acetaminophen is typically conjugated in Phase 2 (Sulfation or Glucuronidation) but sometimes it is Phase 1 functionalized by CYP2E1
adsf
A: Potentiation = Just the Presence of 1 drug actually makes another separate drug TOXIC
B: [Physiological Antagonism]= 2 drugs have opposing physiological functions (anticoagulant and clotting agent)
C: [Chemical Antagonism] = Chelation = 2 drugs chemically interact & neutralize one another
D: [Dispositional Antagonism] = 1 drug prevents another drug from efficiently absorbing/distributing/metabolizing/excreting
E: [Receptor Antagonism] = 1 drug BLOCKS the receptor for another drug
adsf
*Drugs can also cause Immunotoxicity (4 Types) as Adverse Effects * A - B - C - D
Type 1 = Allergy = Drug produces proteins that are altered by [hapten] 1st, and then bind to IgE on mast cells—> Allergic rxn (wheal-and-flare skin reaction) & hay-fever sx
Type 2 = Body (AntiBody problem) = Drug binds to circulating RBC and [IgG Antibody] inappropriately binds to that Drug on the RBC—> RBC lysis
Type 3 = C = Complex (Immune Complex) = [IgG or IgM Antibody] binds to antigen on the drug and becomes lodged in either the Kidney/ Joints/Lung vascular endothelium. They then activate immune complement—> SERUM SICKNESS!
Type 4 = D = Delayed Hypersensitivity = Exposure to Durg topical on skin causes development of Th1. During SECOND Exposure of that Drug antigen, Th1 activate CD8 and TMMI—> Contact Dermatitis. (i.e. Poison Ivy)
adsf
Red Man Syndrome = Occurs when some drugs are infused via IV. These IV drugs get into blood and DIRECTLY DEGRANULATE MAST CELLS (without the need of IgE)–>
- wheal-and-flare skin rxn
- neck and upper arm urticaria
- hypOtension
- angioedema
B: Red Man Syndrome can be prevented with [Antihistamine prophylaxis]
adsf
A: Gentamicin is an Aminoglycoside Abx that is highly nephrotoxic! As it passes through the PCT it inhibits PCT cell lysosome hydrolases and eventually causes those lysosomes to rupture from having too many under graded renal phospholipids! —> Cell Death–> Nephron necrosis —> Renal Failure
adsf
Pregnancy Teratogenicity Rate of Danger for Drugs:
Category A: Studies done in Women and No risk to fetus in 1st trimester or throughout pregnancy
Category B: Studies DONE IN MAMMALS ONLY and No risk to fetus
Category C: Studies DONE IN MAMMALS ONLY and POSITIVE RISK to fetus
Category D: Some Positive risk to HUMAN Fetus
Category: X: CLEAR POSITIVE RISK TO HUMAN FETUS WITH FETAL ABNORMALITIES OBSERVED
adsf
A: [ No Effect Dose] = Max Dose at which NO EFFECT is seen. Required to be obtained during PRE-Clinical trials
asdf
A: IRB (Institutional Review Board)
-Made of MORE than 5 experts (including Docs, nurses, attorneys, scientist, appropriate laymen)
- Purpose is for this panel to ensure all individuals participating in the clinical trials have respected welfare and rights
- Board should exist and practice in the SAME facility the clinical trials are being conducted
B: Inclusion Criteria: Criteria participants must meet in order to partake in the Clinical Trial (i.e. “You must be Black and Male” )
C: EXclusion Criteria: Criteria that literally excludes the participants from further participating (i.e. “…however, if you are Black, Male AND have HTN you will be Excluded from the trial” )
asdf
A: Open Label = Clinical Trial in which the Doctor AND the participant knows what treatment is being administered
B: Non-inferiority trial = Clinical trial in which a drug is known to not be superior to the current standard BUT maybe exhibits less side effects AND is cheaper to administer
or
if placebo group is unethical for that drug
asdf
Clinical Trial Process
Phase I: (20-100 healthy volunteers) = Pharmacokinetics / Tolerable? / Safety? – Done “inpatient” so that Docs can monitor for any serious adverse effects. Usually give 1/10th of the projected-expected dose
-Is Open Label
adsf
Clinical Trial Process
Phase II: Done with 100-200 sick pts who actually have the targeted disease.
-Further Pharmacokinetic parameters such as discrepancies between genders / renal failure / hepatic failure
- Single OR Double Blinded study
- Crosover or Parallel administration
- Dose Regimen and effective data for presentation at the [End of Phase II meeting] and Phase III
- How effective is it on pt with the actual disease (AKA Proof of Concept) ?
asdf
Clinical Trial Process
Phase III: (500 - 6K people who accurately reflect the target demographic)
-Done at multiple clinical sites (similar to sites expected to be used in real practice)
- Consist of many different ethnicities / gender
- DOUBLE BLINDED CONTROLLED RANDOMIZED
- Varying manifestations of the Dz (from mild to SEVERE)
asdf
Clinical Trial Process
Phase IV: Pharmacovigilance : Careful watch of the drug Post-Market surveillance to test toxicity and efficacy in a HUGE Pt population
- allows for you to ascertain rare adverse effects
- Practicing Docs play a big role because they report the adverse effects
