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pharmacology > Principles of Drug Toxicity and Adverse Effects > Flashcards

Principles of Drug Toxicity and Adverse Effects Flashcards

1
Q

What is toxicology?

A

Study of adverse effects of chemicals on living systems

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2
Q

What are the five basic types of adverse drugs?

A
  • Type A (augmented)
  • Type C (continuing)
  • Type E (end of treatment)
  • Type B (bizarre)
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3
Q

Describe Type A adverse drug.

A

– Can be predicted from the pharmacology of the drug
– Are directly dose-dependent
- Have relatively less dangerous outcomes with lower rate of mortality

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4
Q

Describe Type B adverse drugs.

A

– Cannot be predicted on the basis of known pharmacology of the drug
– Can affect almost any organ system
- Have more serious clinical outcomes with higher overall mortality

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5
Q

What are Type A adverse drugs induced by?

A
  • Same pharmacological mechanisms as the therapeutic effects
  • By increase of the therapeutic or other pharmacological effect of the drug
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6
Q

What interventions are there for Type A Adverse Effects?

A

Dose reduction in most cases, use of antagonists in serious circumstances

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7
Q

What preventions are there for Type A Adverse Effects?

A

Dose titration, adverse effects monitoring, pharmacotherapy monitoring

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8
Q

How do Type B adverse effects develop?

A
  • Immunological reaction on a drug (allergy)
  • Genetic predisposition (idiosyncratic reactions)
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9
Q

What interventions are put in place for Type B adverse effects?

A
  • Instant drug withdrawal, symptomatic treatment
  • Pharmacological approach in allergy: antihistamines, adrenalin (epinephrine)
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10
Q

What preventions are put in place for Type B adverse effects?

A
  • troublesome, avoiding certain drugs with known risk of reactions
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11
Q

Describe Type B (allergic) adverse effects.

A
  • Based on immunological mechanism
  • Require previous exposition before actual manifestation
  • Immunogenicity can be acquired
  • Molecular weight does not have direct effect on immunogenicity
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12
Q

Describe Type B (idiosyncratic) adverse effects.

A
  • Do not require any prior sensitisation
  • Rare and unpredictable reactions
  • Genetically determined deviations in the human metabolism or biotransformation of the drugs
  • Do not occur in most patients at any dose
  • Effects not related to pharmacological properties of the drug
  • Can be very severe
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13
Q

Describe Type C adverse effects?

A
  • Not as frequent as type A
  • Mostly associated with cumulative-long term exposure inducing toxic response
  • Mostly the accumulation is not immune but is functional and/or ultrastructural
    changes induced by a drug
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14
Q

Describe the treatment of Type C adverse effects

A

Troublesome - largely irreversible in higher cumulative doses

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15
Q

Describe the general prevention of Type C adverse effects.

A
  • Cumulative dose reduction
  • Limitation of time of exposure
  • Monitoring
  • Prevention of non-compliance and drug abuse
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16
Q

how do Type D (delayed) adverse effects manifest themselves?

A

With significant delay:
– Teratogenesis,
- Mutagenesis/carcinogenesis
– Tardive dyskinesis
- Leucopoenia

17
Q

What are the possible consequences of teratogenesis?

A
  • embryo/fetus death, morphologic malformations,
    functional defects and defects (incl. behavioral), developmental retardation etc.
18
Q

Describe Type E adverse effects.

A
  • Drug withdrawal syndromes and rebound phenomenons
  • Due to up-regulation of the receptors during chronic treatment
19
Q

Describe the preventative measures for Type E adverse effects.

A
  • Avoid abrupt withdrawals
  • Slow decrease in dose
  • Avoid long term treatment with such drugs.
20
Q

Describe preclinical Toxicology Evaluation.

A
  1. Efficacy assessment - does it work?
  2. ADME profiling - how can it be delivered and what does the body do to it?
  3. Toxicology/Safety Pharmacology assessment - is it safe?
  4. Pharmaceutics - is its manufacture viable and controllable?
21
Q

What are the goals of preclinical safety assessment?

A
  • To be sure (within reasonable limits) that the products we develop are not
    harmful to humans
  • Establish dose-response and exposure-response relationships
  • Allow informed assessment of risks
  • Develop safer drugs and medicines
22
Q

What is meant by dose-response?

A

Response of an individual organism to varying doses of a chemical e.g. enzyme activity, blood pressure

23
Q

Define primary pharmacodynamics effects.

A
  • Studies on the mode of action and/or effects of a substance in
    relation to its desired therapeutic target
24
Q

Define secondary pharmacodynamic effects.

A
  • Studies of the mode of action and/or effects of a substance not
    related to its desired therapeutic target
25
Q

Define safety pharmacology

A
  • Studies that investigate the potential undesirable
    pharmacodynamic effects of a substance on physiological
    functions in relation to exposure in the therapeutic range.
26
Q

What is the hERG channel?

A
  • hERG = ‘human ether-a-go-go related
    gene’
  • Encodes for Kv11.1 Potassium channel
  • Activation causes prolongation of
    electrical impulses regulating heart beat
  • Can lead to fatal arrhythmias
27
Q

What is cardiac repolarisation?

A

The hERG channels
appear to allow a
potassium current to pass
that corresponds to Ikr
(rapidly activating delayed
rectifier K+ current)

28
Q

Why study the hERG channel?

A
  • Inhibition of Ikr = decreased K+ efflux = Long QT
  • Stimulation of Ikr = increased K+ efflux = Shortened QT
  • Acquired or congenital long QT syndrome may cause cardiac arrhythmias
    and sudden death in otherwise young and healthy persons
29
Q

Why is hERG important?

A

Lots of marketed drugs bind to it, with apparently diverse structures.

30
Q

What is meant by inter-individual differences in toxicity?

A

We express different gene versions: Polymorphisms
Single Nucleotide Polymorphisms (SNPs) results in alteration of amino acid
sequence of protein
* Distinct protein structures could result in phenotypic differences between the
subjects, such as variation in response to medication.

31
Q

Describe absorption of drugs in elderly.

A

↓ inhalation capacity
↑ dermal absorption - thinner skin
(↓ resistant to chemical spilled on skin)
↓ gut absorption (malabsorption,
impaired gut wall function)
↓ expression of metabolic enzymes and plasma
protein transporting drugs (free drug ↔ bound drug )

32
Q

Describe distribution of drugs in elderly people

A
  • Altered blood flow & ↓ clearance
  • Change in Volume of
    distribution: fat/water ratio
    changes as we age (hydrophobic
    chemicals stored in fat tissue)
33
Q

Why do neonates have susceptibility to toxicity?

A

↑ dermal absorption:
(underdeveloped skin,
not as protective)
↓ gut absorption
Reduced excretion
immature renal
function
Metabolic enzymes expression: underdeveloped for
some metabolic enzymes
- Distribution of chemicals
* Different fat/water ratio

pharmacology (40 decks)

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