Principles of Drug Toxicity and Adverse Effects Flashcards
What is toxicology?
Study of adverse effects of chemicals on living systems
What are the five basic types of adverse drugs?
- Type A (augmented)
- Type C (continuing)
- Type E (end of treatment)
- Type B (bizarre)
Describe Type A adverse drug.
– Can be predicted from the pharmacology of the drug
– Are directly dose-dependent
- Have relatively less dangerous outcomes with lower rate of mortality
Describe Type B adverse drugs.
– 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
What are Type A adverse drugs induced by?
- Same pharmacological mechanisms as the therapeutic effects
- By increase of the therapeutic or other pharmacological effect of the drug
What interventions are there for Type A Adverse Effects?
Dose reduction in most cases, use of antagonists in serious circumstances
What preventions are there for Type A Adverse Effects?
Dose titration, adverse effects monitoring, pharmacotherapy monitoring
How do Type B adverse effects develop?
- Immunological reaction on a drug (allergy)
- Genetic predisposition (idiosyncratic reactions)
What interventions are put in place for Type B adverse effects?
- Instant drug withdrawal, symptomatic treatment
- Pharmacological approach in allergy: antihistamines, adrenalin (epinephrine)
What preventions are put in place for Type B adverse effects?
- troublesome, avoiding certain drugs with known risk of reactions
Describe Type B (allergic) adverse effects.
- Based on immunological mechanism
- Require previous exposition before actual manifestation
- Immunogenicity can be acquired
- Molecular weight does not have direct effect on immunogenicity
Describe Type B (idiosyncratic) adverse effects.
- 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
Describe Type C adverse effects?
- 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
Describe the treatment of Type C adverse effects
Troublesome - largely irreversible in higher cumulative doses
Describe the general prevention of Type C adverse effects.
- Cumulative dose reduction
- Limitation of time of exposure
- Monitoring
- Prevention of non-compliance and drug abuse
how do Type D (delayed) adverse effects manifest themselves?
With significant delay:
– Teratogenesis,
- Mutagenesis/carcinogenesis
– Tardive dyskinesis
- Leucopoenia
What are the possible consequences of teratogenesis?
- embryo/fetus death, morphologic malformations,
functional defects and defects (incl. behavioral), developmental retardation etc.
Describe Type E adverse effects.
- Drug withdrawal syndromes and rebound phenomenons
- Due to up-regulation of the receptors during chronic treatment
Describe the preventative measures for Type E adverse effects.
- Avoid abrupt withdrawals
- Slow decrease in dose
- Avoid long term treatment with such drugs.
Describe preclinical Toxicology Evaluation.
- Efficacy assessment - does it work?
- ADME profiling - how can it be delivered and what does the body do to it?
- Toxicology/Safety Pharmacology assessment - is it safe?
- Pharmaceutics - is its manufacture viable and controllable?
What are the goals of preclinical safety assessment?
- 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
What is meant by dose-response?
Response of an individual organism to varying doses of a chemical e.g. enzyme activity, blood pressure
Define primary pharmacodynamics effects.
- Studies on the mode of action and/or effects of a substance in
relation to its desired therapeutic target
Define secondary pharmacodynamic effects.
- Studies of the mode of action and/or effects of a substance not
related to its desired therapeutic target
Define safety pharmacology
- Studies that investigate the potential undesirable
pharmacodynamic effects of a substance on physiological
functions in relation to exposure in the therapeutic range.
What is the hERG channel?
- 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
What is cardiac repolarisation?
The hERG channels
appear to allow a
potassium current to pass
that corresponds to Ikr
(rapidly activating delayed
rectifier K+ current)
Why study the hERG channel?
- 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
Why is hERG important?
Lots of marketed drugs bind to it, with apparently diverse structures.
What is meant by inter-individual differences in toxicity?
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.
Describe absorption of drugs in elderly.
↓ 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 )
Describe distribution of drugs in elderly people
- Altered blood flow & ↓ clearance
- Change in Volume of
distribution: fat/water ratio
changes as we age (hydrophobic
chemicals stored in fat tissue)
Why do neonates have susceptibility to toxicity?
↑ 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
