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Med Chem Test 4 > Toxicity > Flashcards

Toxicity Flashcards

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1
Q 
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
A

D. Lack of protein binding

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2
Q

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

A

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

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3
Q

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

A

True

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4
Q

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

A

True?

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5
Q

What are the sites of toxicity?

A

Hepatic

Extra-hepatic

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6
Q

What are the types of toxicity?

A

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

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7
Q

The extent of DME related toxicity depends on…

A

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

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8
Q

What are the risk factors for Drug-Induced Hepatotoxicity?

A 
Ethnicity: DME polymorphisms
Genetics: Polymorphisms
Age: Elderly
Gender: F>>M
Alcohol
Liver disease
Pharmacokinetics
Pharmacodynamics
Herbal remedies
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9
Q

What is an example of a DME polymorphism?

A

African American & Hispanics are more susceptible to Isoniazid toxicity

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10
Q

What are examples of polymorphisms?

A

metabolizer phenotypes like PM, UM

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11
Q

How does age affect drug-induced hepatotoxicity?

A

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

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12
Q

How does gender affect drug induced hepatotoxicity?

A

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

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13
Q

How does alcohol affect drug induced hepatotoxicity?

A

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

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14
Q

How does liver disease affect drug induced hepatotoxicity?

A

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

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15
Q

How does Pharmacokinetics affect drug induced hepatotoxicity?

A

SR-drugs, long-acting drugs

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16
Q

How does Pharmacodynamics affect drug induced hepatotoxicity?

A

Dose(overdose), Distribution (narrow TI drugs)

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17
Q

How does Herbal remedies affect drug induced hepatotoxicity?

A

Increase risk of inducing liver toxicity.

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18
Q

Ethanol toxicity affects what organ?

A

Liver mostly

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19
Q

Chronic consumption of ethanol induces what enzyme?

A

2E1 (two to four times)

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20
Q

Ethanol toxicity leads to elevated what?

A

acetaldehyde levels which can form protein adducts and decrease DNA repair

21
Q

APAP is safe at what dose per day?

A

less than 4 grams per day

22
Q

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

A

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

23
Q

What type of drug is Troglitazone?

A

Anti-diabetes drug (withdrawn in 2000)

24
Q

What are sites of extra-hepatic toxicity?

A

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

25
Q

What drug causes cardiotoxicity(hERG & free radicals)?

A

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

26
Q

What drugs cause hematotoxicity?

A

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.

27
Q

What drug causes pulmonary toxicity?

A

Amiodarone (antiarrhythmic drug)

excessive accumulation of amiodarone and its des-ethyl metabolite in lung tissue.

28
Q

What drug causes Neurotoxicity?

A

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.

29
Q

What drug causes genitourinary toxicity?

A

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

30
Q

What causes pro-carninogen bioactivation?

A

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.

31
Q

What are some teragenic xenobiotics?

A

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

32
Q

Teratogenesis includes oxidative damage to….

A

DNA
Protein
Lipid

33
Q

What are the toxicity Mechansims?

A

Existing: Electrophilic Carbons (Halogenated Carbons)

Bioactivated:
Electrophilic Bonds, Electrophilic Double Bond
Allylic Carbocation
Free Radical

Oxidative Stress Toxicity

Hypersensitivity

34
Q

What are drug examples of Electrophillic Double Bond toxicity mechanism?

A

Carbamazepine
Paroxetine
Tolcapone
Diclofenac

35
Q

What are drug examples of Allylic Carbocation toxicity mechanism?

A

Tamoxifen

36
Q

What are drug examples of Free radical toxicity mechanism?

A

Isoniazid (Anti-TB drug)

Captopril (ACE inhibitor)

37
Q

What are drug examples of oxidative stress toxicity mechanism?

A

free radicals

on-free radicals

38
Q

What are the types of hypersensitivity?

A

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

39
Q

What is Type 1 hypersensitivity?

A

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

40
Q

What is Type 2 hypersensitivity?

A

IgG-mediated cytotoxicity

involves erythrocytes/leukocytes/platelets Methyldopa, Aminopyrine, Heparin

41
Q

What is Type 3 hypersensitivity?

A

Immune complex deposition

Binding to endothelial cells Beta lactams, Qunidine, minocycline

42
Q

What is Type 4 hypersensitivity?

A

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

43
Q

What does hepatic hypersensitivity involve?

A

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

44
Q

What is the intervention or rescue to APAP Toxicity?

A

NAC (APAP mercapturic acid conjugate)

45
Q

What is the intervention or rescue to DME defense?

A

Electrophile deactivation by GSTs and EHs

46
Q

What is the intervention or rescue to Oxidative Stress?

A

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

47
Q

What is the intervention or rescue to organophosphate toxicity?

A

2-PAM or Pralidoxime antidote

Oxime used to regenerate ChEs (AChE/BuChE). Have to administer before aging occurs

48
Q

What are DDIs implicated in toxicity?

A

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

Med Chem Test 4 (6 decks)

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