Principles of Drug Toxicity and Adverse Effects

Question 1

What is toxicology?

Answer 1

Study of adverse effects of chemicals on living systems

Question 2

What are the five basic types of adverse drugs?

Answer 2

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

Question 3

Describe Type A adverse drug.

Answer 3

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

Question 4

Describe Type B adverse drugs.

Answer 4

– 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

Question 5

What are Type A adverse drugs induced by?

Answer 5

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

Question 6

What interventions are there for Type A Adverse Effects?

Answer 6

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

Question 7

What preventions are there for Type A Adverse Effects?

Answer 7

Dose titration, adverse effects monitoring, pharmacotherapy monitoring

Question 8

How do Type B adverse effects develop?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

• troublesome, avoiding certain drugs with known risk of reactions

Question 11

Describe Type B (allergic) adverse effects.

Answer 11

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

Question 12

Describe Type B (idiosyncratic) adverse effects.

Answer 12

• 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

Question 13

Describe Type C adverse effects?

Answer 13

• 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

Question 14

Describe the treatment of Type C adverse effects

Answer 14

Troublesome - largely irreversible in higher cumulative doses

Question 15

Describe the general prevention of Type C adverse effects.

Answer 15

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

Question 16

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

Answer 16

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

Question 17

What are the possible consequences of teratogenesis?

Answer 17

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

Question 18

Describe Type E adverse effects.

Answer 18

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

Question 19

Describe the preventative measures for Type E adverse effects.

Answer 19

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

Question 20

Describe preclinical Toxicology Evaluation.

Answer 20

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?

Question 21

What are the goals of preclinical safety assessment?

Answer 21

• 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

Question 22

What is meant by dose-response?

Answer 22

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

Question 23

Define primary pharmacodynamics effects.

Answer 23

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

Question 24

Define secondary pharmacodynamic effects.

Answer 24

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

Question 25

Define safety pharmacology

Answer 25

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

Question 26

What is the hERG channel?

Answer 26

- 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

Question 27

What is cardiac repolarisation?

Answer 27

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

Question 28

Why study the hERG channel?

Answer 28

* 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

Question 29

Why is hERG important?

Answer 29

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

Question 30

What is meant by inter-individual differences in toxicity?

Answer 30

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.

Question 31

Describe absorption of drugs in elderly.

Answer 31

↓ 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 )

Question 32

Describe distribution of drugs in elderly people

Answer 32

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

Question 33

Why do neonates have susceptibility to toxicity?

Answer 33

↑ 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