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Pharm Block 1 > Drug Toxicity > Flashcards

Drug Toxicity Flashcards

1
Q

What are some factors affecting drug toxicity?

A

Drug pharmacological properties

Drug dosing

Age/gender

Genetics

Body weight/fat distribution

Smoking/drinking

Pre-existing conditions/health status

polypharmacy (drug-drug interactions)

allergy (hypersensitivity reactions)

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2
Q

What are the 5 mechanisms of drug toxicity?

A

on target effects
off target effects

harmful metabolites (mainly in the liver)

allergic responses

idiosyncratic responses (rare adverse effects)

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3
Q

What is an on-target adverse effect?

A

high drug concentration or chronic receptor activation/inhibition of the intended receptor

-Can be within the intended tissue (correct tissue, correct receptor) or in an uninteneded tissue (correct receptor, incorrect tissue)

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4
Q

What is an off target adverse effect?

A

high drug activation or activation/inhibition of incorrect receptor

-can be in the intended tissue (correct tissue, wrong receptor) or an unintended tissue (unintended receptor, unintended tissue)

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5
Q

what can on target adverse effects in the correct tissue be due to?

A
  • changes in exposure
  • changes in sensitivity
  • alteration in drug PK parameters (impaired kidney/liver or drug interactinos)
  • change in drug PD parameters (increase in receptor umber)
  • extended exposure
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6
Q

What is a class effect?

A

Since the effect is caused by the drugs desired mechanism of action, the effect will be shared by all members of the drug class

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7
Q

How does diphenhydramine work?

A

Histamine H1 receptor antagonist (antihistamine)

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8
Q

What is an on-target adverse effect of diphenhydramine?

A

Can cross the BBB where it blocks H1 receptors causing drowsiness

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9
Q

How does lidocaine work?

A

blocks Na+ channels in neurons at site of

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10
Q

What is an on-target adverse effect of lidocaine?

A

overdose or inappropriate administration can cause channel blockade in the CNS causing tremors, seizures and even death

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11
Q

How does Haloperidol work?

A

antipsychotic that blocks dopamine D2 receptors in the mesocorticol/mesolimbic regions

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12
Q

What is an on-target adverse effect of haloperidol?

A

D2 blockade in the pituitary results in Hyperprolactinemia, whereas D2 blockade in the nigrostriatal region promotes EPS symptoms

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13
Q

What is a common example of a drug binding to an unintended site of action?

A

Numerous compounds have been shown to be capable of interacting with the cardiac hERG channels and blocking their activity

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14
Q

What is hERG?

A

hERG is a subunit of cardiac potassium channels critical for the cardiac action potential

Inhibition of hERG channels can result in serious toxicity

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15
Q

What can binding to hERG result in?

A

long QT syndrome

cardiac arrhythmias

sudden cardiac death

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16
Q

What can be a consequence of racemic mixtures of drugs being administered?

A

While one enantiomer is pharmacologically active and promotes the desired effect, the other can be completely inactive, but in some cases can bind to an alternative target to cause adverse effects

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17
Q

What does the R enantiomer of Thalidomide cause?

A

(R )-thalidomide causes sedation to treat morning sickness

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18
Q

What does the S enantiomer of THalidomide cause?

A

birth defects (limb defects)

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19
Q

What does the S,S (+) enantiomer of ethambutol do?

A

treats TB

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20
Q

What does the R,R (-) enantiomer of ethambutol cause?

A

blindness

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21
Q

What are three drugs that have harmful metabolites?

A

cyclophosphamide
Ifosamide
Nitrosurea

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22
Q

What is the reactive intermediate of cyclophosphamide, and what is its target organ?

A

alpha,beta-unsaturated aldehyde

bladder

23
Q

What is the reactive intermediate of Ifosamide, and what is its target organ?

A

alpha halo aldehyde

Kidney

24
Q

What is the reactive intermediate of Nitrosurea, and what is the target organ?

A

Isocyanate

Lung

25
Where will harmful metabolites mostly cause their toxic effects?
the liver
26
What will happen at high levels of Acetaminophen?
hepatotoxicity
27
How does hepatotoxicity happen with acetaminophen?
phase II enzymes will become saturated at high doses, resulting in metabolism by CYP2E1, CYP3A4, CYP1A2, forming N-acetyl benzpquinoneimine (NAPQI) which is highly reactive
28
How do we normally metabolize NAPQI?
detoxified via glutathione
29
If NAPQI overwhelms the glutathione system, what happens?
protein conjugation and hepatotoxicity
30
How do we treat acetaminophen induced hepatotoxicity, what does it do, and what is the time window?
Treatment within the first 8-12 h is with N-acetyl Cysteine, which elevates glutathione levels
31
How does drug induced hepatotoxicity normally occur?
production of harmful metabolites by CYP450 enzymes
32
What are some renal toxic drugs?
ACE inhibitors, NSAIDs, aminoglycosides, | antivirals, antibiotics
33
What are some mechanisms of renal toxicity
altered intraglomerular hemodynamics (changes in GFR and vasoconstriction) tubular toxicity (conc. of drug toxins in tubules) inflammation crystal nephtopathy (formation of insoluble crystals)
34
What is a major mechanisms of cardiovascular toxicity?
interactions of drugs with the hERG channel promoting long QT syndrome
35
What is an example of direct toxicity of the heart?
doxorubicin (chemotherapy) - dose limiting
36
what is the mechanism of cardiovascular toxicity of doxorubicin?
Doxorubicin can be metabolized by complex I of the mitochondrial respiratory chain resulting in a highly reactive superoxide radical capable of direct damage to cardiomyocytes
37
how can drugs affect the immune system?
Some drugs (or their metabolites) are chemically very reactive and can covalently modify patient proteins creating a haptenated-protein complex that can stimulate the immune response
38
How can drug induced immune responses result in hypersensitivity?
create drug allergies by making patients hypersensitive to drug re-exposure or to a structurally related drug (e.g. beta lactams)
39
How can drugs result in damaging immune responses?
promote damaging immune responses causing significant pathology to various tissues most commonly the skin, liver & blood cells - skin rashes - Stevens Johnson Syndome - hemolytic anemia - hepatocellular liver injury
40
What kind of hypersensitivity reactions can drugs induce?
I, II, III, IV
41
define idiosyncratic drug reactions
Idiosyncratic drug reactions are those that are unpredictable and appear in a very small number of patients
42
What is the risk of developing an idiosyncratic disease?
strong genetic component NOT related to either the drugs dose or mechanism of action
43
What is the most common reason for drug withdrawals?
idiosyncratic toxicity
44
What are the most frequent organs affected by idiosyncratic toxicity?
liver, skin, blood cells
45
what is a likely mechanism of idiosyncratic toxicity?
immune mediated, linked to MHC/HLA genes
46
What will occur with most drugs that induce idiosyncratic toxicity?
give rise to highly reactive drug metabolites
47
What are some examples of teratogens?
ACE inhibitors, Acne medication, tetracycline & doxycycline antibiotics, warfarin, carbamazepine, phenytoin, valproate, thalidomine
48
What does exposure to a tertogen before the 3rd week of gestration result in?
usually fetal death
49
What does exposure to a teratogen between 3rd and 8th week of gestation?
developmental defects (this is when organogenesis occurs)
50
Category A
Adequate and well controlled studies have failed to demonstrate a risk to the fetus in the 1st trimester and no evidence of risk in later trimesters
51
Category B
Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no well-controlled studies in pregnant women
52
Category C
Animal reproduction studies have shown an adverse effect on the fetus, and there are no controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
53
Category D
There is positive evidence of human fetal risk, but potential benefits may warrant use in pregnant women despite the risk
54
Category X
Studies in animals and humans have demonstrated fetal abnormalities, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits

Pharm Block 1 (8 decks)

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