Toxicity

Question 1

Define toxicokinetics

Answer 1

How toxins are absorbed, distributed, metabolized and excreted

Question 2

What is the difference between toxin and toxicant

Answer 2

Toxin = natural (plant or some shit)

Toxicant = man-made

Question 3

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

Answer 3

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

Question 4

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

Answer 4

Acute = minutes to 48 hours

Sub-acute = repeated exposure <1 month

Sub-chronic = repeated exposure for 1-3 months

Chronic = >3 months

Question 5

What is EC50?

Answer 5

Concentration at which 50% of the maximal effect is observed

Question 6

What is TC50?

Answer 6

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

Question 7

What is ED50?

Answer 7

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

or

50% of subjects experience a particular therapeutic effect

Question 8

What is is TD50?

Answer 8

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

or

50% of subjects experience a particular toxic effect

Question 9

What is LD50?

Answer 9

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

Question 10

What is the therapeutic window/index a ratio of?

Answer 10

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

Question 11

What is the margin of safety?

Answer 11

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

Question 12

What is the difference between NOAEL and LOAEL?

Answer 12

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

LOAEL = Lowest observed adverse effect level

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

Question 13

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

Answer 13

Allergic responses and idiosyncratic

Must d/c these products

Question 14

How can ADRs be classified?

Answer 14

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

Question 15

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

Answer 15

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

Question 16

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

Answer 16

N/V with improvement prior to liver failure

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

Question 17

How is Ethanol metabolized?

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

How is MPTP a neurotoxin?

Answer 20

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)

Question 21

What is the MPTP-like environmental toxin?

Answer 21

Herbicide → rotenone

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

Question 22

How does Oseltamavir work?

Answer 22

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

Question 23

How does Remdesivir work?

Answer 23

ANTIVIRAL

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

Question 24

What are the possible ways an antibiotic can work?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

How do beta-lactam antibiotics work?

Answer 26

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)

Question 27

What advantages does amoxicillin have over ampicillin?

Answer 27

* better oral absorption * easier to formulate into palatable df * slightly more gram-neg antibacterial effects

Question 28

How do you get an allergy to penicillin?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

How does hydroxychrolorquine work?

Answer 30

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

Question 31

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

Answer 31

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)

Question 32

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

Answer 32

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

Question 33

How do vinca alkaloids work?

Answer 33

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

Question 34

How do immune cells communicate with each other?

Answer 34

Mainly cytokines

Question 35

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

Answer 35

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

Question 36

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

Answer 36

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)