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Pharmacology > 25-26 - Toxicity & Adverse Drug Reactions > Flashcards

25-26 - Toxicity & Adverse Drug Reactions Flashcards

1
Q

Toxicology is the study of the noxious effects…

A

Of chemicals on living systems

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2
Q

Biochemical toxicology studies interactions of the body with xenobiotics such as (5)…

A
  • Drugs (theraputic and recreational)
  • Occupational exposure
  • Environmental agents
  • Natural toxins
  • Engineered materials (such as novel toxins and nanomaterials)
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3
Q

LD50

a) is useful as it provides insight into mechanism and effects of poisons
b) represents 50% of the concentration required to kill
c) has limited use as it does not provide insight into mechanisms and effects other than death
d) represents the concentration at which 50% of test animals are harmed

A

LD50

a) is useful as it provides insight into mechanism and effects of poisons
b) represents 50% of the concentration required to kill

c) has limited use as it does not provide insight into mechanisms and effects other than death

d) represents the concentration at which 50% of test animals are harmed

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4
Q

Acute toxicity

A
  • Rapid (occurs while toxin is still present in the body)
  • Easily identifiable
  • May have an antidote
  • Requires single/ short-term exposure
  • e.g. cyanide, VX
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5
Q

Chronic toxicity

A
  • Delayed symptoms (occuring after excretion)
  • Cumulative effect
    • May require long-term exposure
    • Single exposure may be sufficient
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6
Q

Which 5 properties make an organ particularly succeptible to toxic effects?

A
  • Highly perfused organs
  • Biological role
    • Lungs - exposure to O2
    • Kidney tubule cells - exposure to concentrated luminal fluid
  • High energy demand
  • Dynamic tissues
  • Metabolic activity
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7
Q

Name the 3 reactive oxygen species (ROS) and outline the ways in which they damage cells…

A

O2–• (superoxide anion) , O• (oxygen radical), OH• (hydroxyl radical)

  1. Oxidative DNA damage
  2. Oxidative protein damage
  3. Oxidative lipid damage
  4. Glutathione (GSH) depletion (usually remvoes ROS)
  5. Loss of cell homeostasis
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8
Q

Name a reactive nitrogen species (RNS)…

A

NO2 (nitrogen dioxide)

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9
Q

Paraquat

A
  • Hydrophilic
  • Mimics putresine
    • Uptake via putresine receptors
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10
Q

Scrotal cancer in chimney sweeps was caused by benzoapryrene which has toxic effects by…

A

DNA binding - forms DNA adduct with guanine

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11
Q

Other than in DNA, where is adduct formation involved in toxicity?

A

Protein adduct formation

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12
Q

Toxins may also work by interactions with specific targets. For example…

A
  • Organophosphorus insecticides (OPs)
  • Neurotoxins
    • Irreversibly bind to esteric site of Ach esterase
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13
Q

Describe the mechanism of liver damage due to paracetamol overdose…

A
  1. Paracetamol is metabolised by 3 routes, one of which produces hepatotoxic intermediate (NAPQI)
  2. GSH converts NAPQI into non-toxic compounds
  3. In overdose, GSH (glutathione) is depleted, leading to build of NAPQI
  4. NAPQI causes damage to liver cells

N-Acetyl cysteine is given to replenish GSH in paracetamol overdose

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14
Q

In the case of aspirin overdose, excretion becomes zero order therefore the ________ increases. This means further small doses can lead to big increases in ____________.

A

In the case of aspirin overdose, excretion becomes zero order therefore the half life (5hrs to 12-15hrs) increases. This means further small doses can lead to big increases in plasma concentration.

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15
Q

Describe the mechanism of aspirin overdose…

A
  • Initially stimulates respiratory centre in hypothalamus
    • Hyperventilation
    • Respiratory alkalosis
  • Accumulation of lactate and pyruvate lead to metabolic acidosis
  • Acid conditions un-ionise more salicylate = positive feedback
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16
Q

An adverse drug reaction (ADR) is a…

A

Harmful or seriously unpleasant event occuring at a dose intended for theraputic effect calling for reduction or withdrawal of the drug

17
Q

Give 4 significant historical examples of ADRs…

A
  • 1930s - Elixir sulphanilamide (mass poisoning)
  • 1960s - Thalidomide (birth defects)
  • 1970s - Diethylstilbestrol DES (uterine cancer in offspring)
  • 2006 - TGN1412 trial (cytokin storm)
18
Q

No pharmacologically effective drug is entirely safe. Therefore drug safety is a matter of…

A

Relative risks

(e.g. severity of ADRs, severity of the disease, alternatives, perceptions and acceptance of risk by involved parties)

19
Q

Identifying an ADR…

A
  • Plausible time sequence between drug administration and the reaction
  • Reaction corresponds to pharmacology of the drug
  • Cessation of drug stops reaction ( & restarting of drug causes return of reaction)
20
Q

The Yellow Card

A
  • MHRA (medicine and healthcare products regulatory agency) form for suspected ADRs
  • New drugs monitored more closely for first 2yrs
21
Q

Side effects

A

Unavoidable consequences of drug administration or pharmacology.

Can sometimes be of clinical benefit.

22
Q

Secondary adverse effects…

A

Indirect causation

e.g. opportunistic infection due to immunosuppressive effect of glucocorticoids

23
Q

List 7 potential risk factors for ADRs…

A
  • Old age (>60)
    • 3x increase in risk
    • Reduced glomerular filtration rate, P450 activity
    • Other medications
  • Youth (neonates & children)
    • Lack conjugating enzymes
  • Sex
    • Female- hormonal influences
  • Medical history
    • Previous ADRs
  • Disease
  • Other medications
    • Drug interactions
  • Ethnicity
    • Intrinsic (pharmacokinetic/-dynamics)
    • Extrinsic (cultural - diet, alcohol, smoking)
24
Q

ADRs are classified according to 5 categories…

A
  • A ugmented
    • too much of intended effects
    • common, low mortality
  • B izzare
    • unexpected reaction
    • uncommon, high mortality
  • C hronic
  • D elayed
    • ADR occurs remotely from treatment or in offspring of patient
  • E nd of treatment Effects
    • withdrawal effects
25
Q

Give an example of a type A (augmented) ADR…

A

Bradycardia from β-blockers

26
Q

Give an example of a type B (bizzare) ADR…

A

Anaphylaxis due to penicillin

27
Q

Give an example of a type C (chronic) ADR…

A

Iatrogenic Cushing’s syndrome from chronic glucocorticoid therapy

n.b. is also considered a side effect

28
Q

ADRs can involve either ________ or ________ of effects

A

ADRs can involve either potentiation↑ or attenuation↓ of effects

29
Q

ADRs may result from pharmacodynamic interactions, such as alcohol (ethanol) with…

A

Antihistamines, leading to increased sedative effects

30
Q

Carbamazepine induces its own metabolism as it is both product and inducer of…

A

CYP3A3/4

31
Q

Carbemazepine has many potential…

A

Drug interactions

These can involve potentiation or attentuation of CYP3A3/4 or epoxide hydrolase

Pharmacology (23 decks)

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