Toxicity

Question 1

All of the following factors can and do alter how drugs are eliminated, except:
A.  Entero-hepatic circulation
B. Transporter induction
C.  Urinary pH
D.  Lack of protein binding

Answer 1

D. Lack of protein binding

Question 2

True/False: Molecular oxygen is an essential co-factor in CYP mediated toxicities of xenobiotics.

Answer 2

True: CYP enzymes need the molecular oxygen to interact with their heme group.

Question 3

True/False: Toxicity can be an outcome at either stage (phase I and II) of metabolism.

Answer 3

True

Question 4

True/False: It is preferable that a drugs is metabolized by one single DME versus being metabolized by several DMEs.

Answer 4

True?

Question 5

What are the sites of toxicity?

Answer 5

Hepatic

Extra-hepatic

Question 6

What are the types of toxicity?

Answer 6

Dose-dependent (overdose, narrow TI drugs)
Reactive metabolites (electrophiles, ROS)
Idiosyncratic reactions (unpredictable toxicity)
Hypersensitivity and immune response related
Teratogenic and Carncinogenic
Drug-Drug Interactions related

Question 7

The extent of DME related toxicity depends on…

Answer 7

Tissue expression of DMEs
Presence of deactivating DMEs & cofactors
Cellular structure with which metabolites can react
Reactive metabolites ability to access the toxicity site.

Question 8

What are the risk factors for Drug-Induced Hepatotoxicity?

Answer 8

Ethnicity: DME polymorphisms
Genetics: Polymorphisms
Age: Elderly
Gender: F>>M
Alcohol
Liver disease
Pharmacokinetics
Pharmacodynamics
Herbal remedies

Question 9

What is an example of a DME polymorphism?

Answer 9

African American & Hispanics are more susceptible to Isoniazid toxicity

Question 10

What are examples of polymorphisms?

Answer 10

metabolizer phenotypes like PM, UM

Question 11

How does age affect drug-induced hepatotoxicity?

Answer 11

Elderly are vulnerable to liver toxicity due to decreased clearance/liver mass & blood flow, poor diet, etc.

Question 12

How does gender affect drug induced hepatotoxicity?

Answer 12

Females are greater than men. Acetaminophen, Halothane, Nitrofurantoin, Diclofenac, & Sulindac.

Question 13

How does alcohol affect drug induced hepatotoxicity?

Answer 13

It induces liver injury/cirrhosis, GSH depletion (APAP, Statins)

Question 14

How does liver disease affect drug induced hepatotoxicity?

Answer 14

HIV patients afflicted with hepatitis B or C are at risk for hepatotoxicity.

Question 15

How does Pharmacokinetics affect drug induced hepatotoxicity?

Answer 15

SR-drugs, long-acting drugs

Question 16

How does Pharmacodynamics affect drug induced hepatotoxicity?

Answer 16

Dose(overdose), Distribution (narrow TI drugs)

Question 17

How does Herbal remedies affect drug induced hepatotoxicity?

Answer 17

Increase risk of inducing liver toxicity.

Question 18

Ethanol toxicity affects what organ?

Answer 18

Liver mostly

Question 19

Chronic consumption of ethanol induces what enzyme?

Answer 19

2E1 (two to four times)

Question 20

Ethanol toxicity leads to elevated what?

Answer 20

acetaldehyde levels which can form protein adducts and decrease DNA repair

Question 21

APAP is safe at what dose per day?

Answer 21

less than 4 grams per day

Question 22

What is the difference in metabolites from a normal dose and a high dose?

Answer 22

Normal dose: APAP forms Sulfate and glucuronide conjugates are major metabolites.
High dose: APAP exhaust these pathways allowing more parent drug to undergo phase I bio activation to toxicity

Question 23

What type of drug is Troglitazone?

Answer 23

Anti-diabetes drug (withdrawn in 2000)

Question 24

What are sites of extra-hepatic toxicity?

Answer 24

Cardiotoxicity, Hematotoxicity, Pulmonary toxicity, Nuerotoxicity, Geneitourinary (Nephrotoxicity, bladder, genital) toxicity, skin hypersentitivity

Question 25

What drug causes cardiotoxicity(hERG & free radicals)?

Answer 25

Doxorubicin (Anticancer Anthracycline looks like 4 rings together and another ring to the side) Induces Congestive Heart Failure(CHF) with 2-3 days.

Question 26

What drugs cause hematotoxicity?

Answer 26

Dapsone & Sulfamethoxazole (anti-infectives) 3A4, 2C9, &2E1 lead to -NOH metabolites Methemoglobinemia & agronulocytosis Clozapine-agronulocytocytosis(a form of leukopenia, lowered white blood cell count). Electrophilic imine implicate din covalently binding neutrophils.

Question 27

What drug causes pulmonary toxicity?

Answer 27

Amiodarone (antiarrhythmic drug) | excessive accumulation of amiodarone and its des-ethyl metabolite in lung tissue.

Question 28

What drug causes Neurotoxicity?

Answer 28

Designer drugs MPTP induce parkinsons like symptoms due to DA neurotoxic MPP+ ion via MAO-B. Organophosphate ester toxicity (in drugs, nerve poisons, insecticides) Increased ACh accumulations leads to ACh toxicity.

Question 29

What drug causes genitourinary toxicity?

Answer 29

Ethylene Glycol A sweet and odor-less liquid Readily absorbed from the GI-tract Metabolized by ADH & ALDH to toxic species Diethylene Glycol Coutnerfeit for glycerin(widely used in drug formulations) or Glyrcerol

Question 30

What causes pro-carninogen bioactivation?

Answer 30

Aflatoxin B1, a fungal mycotoxin hepatocarcinogen that forms covalent adducts with DNA(genotoxic response). Exposure from eating moldy foods (corn, peanuts). AAF N-hydroxylation is 1 stpe in carninogen formulation N-OH AAF- Phase II leads to the ultimate carcinogen.

Question 31

What are some teragenic xenobiotics?

Answer 31

Thalidomide, Carbamazapine, Diethylstilbesterol, Cyclophophamide, Ethanol, Phenytoin, Retinoic Acid, Warfarin, Valproic Acid

Question 32

Teratogenesis includes oxidative damage to....

Answer 32

DNA Protein Lipid

Question 33

What are the toxicity Mechansims?

Answer 33

Existing: Electrophilic Carbons (Halogenated Carbons) Bioactivated: Electrophilic Bonds, Electrophilic Double Bond Allylic Carbocation Free Radical Oxidative Stress Toxicity Hypersensitivity

Question 34

What are drug examples of Electrophillic Double Bond toxicity mechanism?

Answer 34

Carbamazepine Paroxetine Tolcapone Diclofenac

Question 35

What are drug examples of Allylic Carbocation toxicity mechanism?

Answer 35

Tamoxifen

Question 36

What are drug examples of Free radical toxicity mechanism?

Answer 36

Isoniazid (Anti-TB drug) | Captopril (ACE inhibitor)

Question 37

What are drug examples of oxidative stress toxicity mechanism?

Answer 37

free radicals | on-free radicals

Question 38

What are the types of hypersensitivity?

Answer 38

Type 1: IgE-mediated drug hypersensitivity Type 2: IgG-mediated cytotoxicity Type 3: Immune complex deposition Type 4: T-Cell-mediated drug hypersensitivity

Question 39

What is Type 1 hypersensitivity?

Answer 39

IgE-mediated drug hypersensitivity (involves mast cells penicllins, cephalopsorins)

Question 40

What is Type 2 hypersensitivity?

Answer 40

IgG-mediated cytotoxicity | involves erythrocytes/leukocytes/platelets Methyldopa, Aminopyrine, Heparin

Question 41

What is Type 3 hypersensitivity?

Answer 41

Immune complex deposition | Binding to endothelial cells Beta lactams, Qunidine, minocycline

Question 42

What is Type 4 hypersensitivity?

Answer 42

T-Cell-mediated drug hypersensitivity (involve T-cell stimulation by drug)

Question 43

What does hepatic hypersensitivity involve?

Answer 43

Involves formation of immunogens: ethanol, thiol containing xenobiotics (penicillins, cephalosporins, etc) can form haptens.

Question 44

What is the intervention or rescue to APAP Toxicity?

Answer 44

NAC (APAP mercapturic acid conjugate)

Question 45

What is the intervention or rescue to DME defense?

Answer 45

Electrophile deactivation by GSTs and EHs

Question 46

What is the intervention or rescue to Oxidative Stress?

Answer 46

Antioxidant enzymes; Catalase, Glutathione peroxidase, Glutathione reductase, speroxide dismutase, cytochrome C

Question 47

What is the intervention or rescue to organophosphate toxicity?

Answer 47

2-PAM or Pralidoxime antidote | Oxime used to regenerate ChEs (AChE/BuChE). Have to administer before aging occurs

Question 48

What are DDIs implicated in toxicity?

Answer 48

Displacement of narrow therapeutic index drugs from albumin (warfarin) DME Induction/Inhibition Transporter induction/inhibition