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PHARM 141 > Toxicity > Flashcards

Toxicity Flashcards

1
Q

Define toxicokinetics

A

How toxins are absorbed, distributed, metabolized and excreted

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2
Q

What is the difference between toxin and toxicant

A

Toxin = natural (plant or some shit)

Toxicant = man-made

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3
Q

What are the levels on which a toxicologist researcher examines the nature of adverse effects?

A
  1. Molecular mechanisms of whole body, system/organ, cellular or macromolecule damage
  2. Short and long term harms associated with toxic effects (including costs associated with preventing or treating the adverse effects)
  3. Probability of occurrence of toxic effects in groups of patients, in the environment, in the workplace etc
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4
Q

What is the difference between acute, sub-acute, sub-chronic and chronic exposure to a toxin?

A

Acute = minutes to 48 hours

Sub-acute = repeated exposure <1 month

Sub-chronic = repeated exposure for 1-3 months

Chronic = >3 months

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5
Q

What is EC50?

A

Concentration at which 50% of the maximal effect is observed

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6
Q

What is TC50?

A

Concentration at which 50% of a toxic maximal effect is observed in cells

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7
Q

What is ED50?

A

The dose at which 50% of the maximal therapeutic effect is observed

or

50% of subjects experience a particular therapeutic effect

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8
Q

What is is TD50?

A

The dose at which 50% of the maximal toxic effect is observed

or

50% of subjects experience a particular toxic effect

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9
Q

What is LD50?

A

The dose at which 50% of subjects experience mortality due to the drug or toxin/toxicant

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10
Q

What is the therapeutic window/index a ratio of?

A

TD50 : ED50
**gives sense of the difference in dose between where you would expect an effective dose vs starting to observe toxicities

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11
Q

What is the margin of safety?

A

Ration of the lethal dose in 1% of the population vs the effective dose in 99% of the population

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12
Q

What is the difference between NOAEL and LOAEL?

A

NOAEL = no observed adverse effect level → “threshold dose”

LOAEL = Lowest observed adverse effect level

***these will be fairly close together on a graph

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13
Q

What are the types of non-dose related ADRs and what can you do?

A

Allergic responses and idiosyncratic

Must d/c these products

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14
Q

How can ADRs be classified?

A
  1. Dose-related
  2. Non-dose related
  3. Extension effects
  4. Off-target effects
  5. Reversibility
  6. Organ specificity
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15
Q

How is acetaminophen metabolized and how does it relate to hepatotoxicity?

A

Acetaminophen is metabolized by 3 different pathways: sulfation, glucoronidation, CYP450 enzymes

Sulfation and glucoronidation products are excreted in urine

CYP450 metabolizes it to a chemically-reactive toxin that is neutralized by glutathione; glutathione reserves are limited and so if a toxic amount (10g at once or >4g over multiple doses) is ingested there is not going to be enough glutathione to neutralize it and it will start reacting with proteins causing dysfunction and cell death

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16
Q

What are the symptoms of acetaminophen overdose and what is the antidote?

A

N/V with improvement prior to liver failure

Antidote: IV N-acetylcystine within 8 hours → augments glutathione reserves

17
Q

How is Ethanol metabolized?

A

Undergoes significant 1st pass metabolism in the GI tract and in the liver → requires NAD+

  1. Ethanol → acetaldehyde by alcohol dehydrogenase
  2. Acetaldehyde → acetic acid by aldehyde dehydrogenase

Acetic acid is then used in the production of fatty acids

18
Q

Why is alcohol metabolism saturated at relatively low concentrations and why does this cause AEs?

A

NAD+ is required in both steps but is rapidly used up and produced at a limited rate

Acid aldehyde is the metabolite that causes the AEs from alcohol consumption and if it can’t be metabolized further it stays in your system

19
Q

What is the metabolism of methanol, which metabolite causes toxicity and what is the antidote?

A
  1. Methanol → formaldehyde by alcohol dehydrogenase
  2. Formaldehyde → formic acid by aldehyde dehydrogenase

BOTH of the metabolites are much more toxic than those of ethanol and may cause blindness, respiratory depression and death

Antidote: administer ethanol; it has higher affinity for the enzymes used in metabolism, out-competes methanol which increases the amount of methanol excreted unchanged

20
Q

How is MPTP a neurotoxin?

A

MPTP is converted to MPP+ by MOA which causes it to be selectively taken up by cells in substantia nigra through the same process as dopamine

MPP+ inhibits mitochondiral complex 1 and oxidative phosphorylation resulting in neuronal death in the dopaminergic neurons of the substantia nigra → causes Parkinson’s disease symptoms except neuronal cell death is rapid (unlike Parkinson’s)

21
Q

What is the MPTP-like environmental toxin?

A

Herbicide → rotenone

Used to induce Parkinson’s like symptoms in animals to study them

22
Q

How does Oseltamavir work?

A

ANTIVIRAL

Inhibits neuraminidase and as a result, inhibits the viral particles from leaving the infected host cell

Viruses accumulate at the cell surface and attract WBCs which destroy the cell

23
Q

How does Remdesivir work?

A

ANTIVIRAL

Mimics natural nucleosides (specifically monophosphate nucleoside GS-441524) to disrupt replication of viral RNA and DNA

24
Q

What are the possible ways an antibiotic can work?

A
  1. Folate synthesis inhibitors
  2. RNA polymerase inhibitor
  3. Cell membrane inhibitor
  4. Cell wall inhibitors (beta-lactam antibiotics like penicillins)
  5. DNA gyrase inhibitors (fluoroquinalones)
  6. Protein synthesis inhibitors
25
Q

What is the difference between gram-negative and gram-positive?

A

Gram-positive → thick cell wall

Gram-negative → thin cell wall with outer membrane that is resistant to antibiotics

26
Q

How do beta-lactam antibiotics work?

A

interfere with bacterial cell wall synthesis by binding transpeptidase (penicillin binding protein) → interferes with the joining/cross-linking of two cell wall building blocks

(peptidoglican and glycopeptide)

27
Q

What advantages does amoxicillin have over ampicillin?

A
  • better oral absorption
  • easier to formulate into palatable df
  • slightly more gram-neg antibacterial effects
28
Q

How do you get an allergy to penicillin?

A

During penicillin metabolism; metabolites bind to host protein to form antigen identified as non-self by the immune system

29
Q

How do the -azoles work and what is an important possible AE?

A

ANTIFUNGAL

Inhibit ergosterol synthesis → reduces total ergosterol and production of toxic sterols accumulating in the membrane and causing disruption

Inhibit CYP450 enzymes contributing to their efficacy but they can do this in host cells too and may cause drug interactions

30
Q

How does hydroxychrolorquine work?

A

Antimalarial effect remains unclear → theory is it interferes with heme group metabolism and causes accumulation of heme groups in Plasmodium cells

31
Q

How do chemotherapeutics target cancer cells and what other cells does this effect? What are the outcomes?

A

Target rapidly dividing cells like cancer cells but also effect the rapidly dividing bone marrow, hair follicles and epithelial cells

This causes immunosuppression (reduction in WBCs), hair loss and disruption of epithelial tissues (inflammation and pain, seen in mouth and GI tract)

32
Q

How do cancer cells mutate and increase their resistance to chemotherapeutics?

A

p53 gene is mutated on cancer cells which allows them to keep dividing and growing despite being damaged

Resistance:

  • mutations in the drug target
  • increased drug metabolism
  • efflux pumps
33
Q

How do vinca alkaloids work?

A

Bind to tubulin to inhibit polymerization → work during the M phase of division and disrupts assembly of mitotic spindle so the daughter cells can’t split and they die

34
Q

How do immune cells communicate with each other?

A

Mainly cytokines

35
Q

What is methotrexate, how does it work and what are some common ADRs?

A

Methotrexate = cytotoxic immunosuppressant with some anti-cancer activity

Inhibits folic acid synthesis which disrupts the production of purine bases → primarily dihydrofolate reductase inhibitor but other mechanisms contribute to its efficacy

ADRs: nausea, mucosal ulcers, hair loss, bone marrow supression, hepatotoxicity, pulmonary fibrosis and folic acid deficiency

36
Q

What is Infliximab, what does it do and what are the AEs?

A

Infliximab = anti TNFa antibody (part mouse, part human)

Binds to soluble TNFa and cell-surface TNFa to inhbit immune system signalling and causes apoptosis in TNFa expressing cells

Patients may develop anit-infliximab antibodies so it is usually used in combination with methotrexate

Infusion reactions: uticaria, chills, headache, rash, pjaryngitis, cough, chest pain

RARE: serious infection/sepsis (usually occurs in patients with additional immunosuppressive therapies)

PHARM 141 (8 decks)

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