8. Adverse Drug Reactions Flashcards
Why do dentists need to understand these?
- need to fully understand potential for interactions of drugs
- under-reported often as inability to recognise them or not seen
Define ‘adverse drug reaction’
- harmful or seriously unpleasant event
- occurring at a dose intended for therapeutic effect
- calls for reduction of dose or withdrawal of drug
Historical events and dates of major issues
- 1937 - sulphanilamide
- 1961 - thalidomide
- 1971 - diethylstilbestrol (uterine cancer in offspring)
- 2006 - TGN1412 (excess cytokine release)
How does the iceberg theory link to clinical trial?
- tip of the iceberg is what we know at the end of the clinical trial
- below the sea is what happens when drug is in normal practice
Are any drugs fully harmless?
- no
- any drug which is pharmacologically effective carries some hazard
Drug safety is a relative concept and takes into account …
- severity of adverse drug reaction
- disease
- therapeutic alternatives
- individual perception and acceptance of risk
What suggests a cause and effect relationship between drug administration and adverse drug reaction?
- time sequence between taking drug and adverse reaction
- reaction corresponds to known pharmacology of drug
- reaction stops on cessation of drug
- reaction returns on restarting drug
After what is a causal relationship highly probable?
- event has reasonable temporal association with drug
- de-challenge from drug
- observed event abated upon de-challenge
- re-challenge
- reaction reappeared upon re-challenge
What’s the yellow card?
- from Medicines and Healthcare products Regulatory Agency (MHRA)
- filled in after reactions and filed
Define ‘side effect’
- unavoidable consequence of drug administration
- arising as unwanted action is just as integral as therapeutic effect to pharmacology of drug
- can be of clinical benefit sometimes
Define ‘secondary adverse effect’
- indirect causation
- secondary to the drug
- e.g opportunistic infections due to glucocorticoid therapy
How is age a risk factor for ADR?
- 3 fold increase in ADR over 60 compared to under 30
- can be due to increased medications or pharmacokinetic factors
- neonates and children susceptible due to difference in pharmacokinetic factors
How is sex a risk factor for ADR?
- females more likley
- pharmacokinetics and hormone influence
How is medical history a risk factor for ADR?
- if ADR to one drug, more likely to experience it with another
How is disease a risk factor for ADR?
- pharmacokinetics
How is current medication a risk for ADR?
- drug interactions
How is ethnicity a risk factor for ADR?
- intrinsic ones (pharmacokinetics and pharmacodynamics)
- pharmacokinetics - metabolism 90% japanese are fast acetylators, 50% of caucasians
- pharmacodynamics - Ashkenazi Jews susceptible to agranulocytosis after clozapine (20% to 1% in normal pop), response to beta blockers (more in chinese than caucasian than african)
- extrinsic is alcohol, diet, smoking
Classifications of ADRs
- A to E
- augmented pharmacological effect, bizzare effect, chronic effect, delayed effect, end of treatment effect
Define ‘augmented pharmocological effect’
- adverse effect known to occur from primary pharmacology of drug
- usually dose dependent
Define ‘bizarre effects’
- adverse effects that are unpredictable from pharmacology of drug
Define ‘chronic effects’
- due to chronic treatment with drug
Define ‘delayed effects’
- occur remote from treatment
- either in children of treated patients or in patient themselves
Define ‘end of treatment effects’
- adverse effects occur as a result of stopping treatment
- withdrawal effects
Examples of Type A ADR
- bradycardia from treatment with beta blocker - primary pharmacology is to decrease hard rate but is dose is too high, will be bradycardic
- hypoglycaemia from insulin injection
- tachycardia from muscarinic antagonist ipratropium
- common/low mortality
Parasympathetic activation normally
- pupils constrict
- lens of eye readjust for closer vision
- airways in lungs constrict
- heart rate decreases
- blood vessels to limb muscles constrict
- blood vessels to visceral organs more dilated
- salivary secretions normalise
Effect of a muscarinic antagonist on parasympathetic activation
- pupils dilate (relaxation of constrictor pupillary muscle/blurred vision)
- increased focal length of lens (relaxed ciliary muscle)
- bronchodilation
- increased cardiac output (rate and force)
- decreased GI motility
- decreased exocrine grand secretion (dry mouth, decreased sweating)
Muscarinic antagonists are known as …
parasympatholytic
Pupil dilation can be an ADR to … and a therapeutic effect to …
- atropine
- tropicamide
Bronchodilation can be an ADR to … and a therapeutic effect to …
- nothing
- ipratropium
Increased heart rate can be an ADR to … and a therapeutic effect to …
- ipratropium
- nothing
Decreased gut motility can be an ADR to … and a therapeutic effect to …
- nothing
- hyoscine
Decreased exocrine secretions/dry mouth can be an ADR to … and a therapeutic effect to …
- iprapropium
- atropine
Examples of bizarre type B reactions
- anaphylaxis due to penicillin
- bone marrow suppression due to chloramphenicol
- uncommon so often have high mortality
Explain the TGN1412 Clinical trial
- phase 1 clinical trial - autoimmune/leukaemia treatment
- ADRs included decreased blood pressure, nausea, pain, soft tissue damage and multi-organ failure
- caused excess cytokine release (cytokine storm) and indiscriminate immune response
Example of type 3 chronic ADR
- iatrogenic Cushing syndrome from chronic glucocorticoid therapy
Explain hypercortisolaemia
- Cushing’s syndrome
- caused by adrenal/pituitary tumour (Cushing’s disease)
- side effect of chronic glucocorticoid therapy
Examples of delayed type D ADRs
- diethylstilbestrol given to pregnant mother (causes high incidence of avginal cancer in offspring in 20s)
- isotretinoin (accutane) causes birth defects
- second cancers in response to Hodgkin’s disease treatment
Example of type E end of treatment ADR
- adrenal insufficiency after glucocorticoid therapy
Regulation of metabolism by corticosteroids
- hypothalamic nuclei
- with CRH goes to anterior pituitary
- with ACTH and negative feedback goes to adrenal cortex
- produces cortisol
Explain adrenal atrophy in response to glucocorticoid treatment
- exogenous glucocorticoids used for anti-inflammatory or immunosuppressive therapy
- act of HPA axis negative feedback system and over time adrenal atrophy
- on termination of treatment, atrophied adrenals cannot produce enough cortisol so results in adrenal insuffiency
Symptoms of adrenal insufficiency
- general weakness
- weight loss
- nausea
- Addinson’s disease
When one drug modifies the action of another, the modification can be … or …
- potentiation
- attenuation
What are the pharmacodynamic interactions of drugs?
- similar of opposing pharmacological effects
- ethanol increasing sedative effect of antihistamine drugs or some antidepressants
What are the pharmacokinetic interactions of drugs?
- one drug interferes with disposition (e.g metabolism or excretion) of other
- monoamine oxidase inhibitors blocking metabolism of dietary amine
- many drugs inhibit CYP450 (like fluvoxamine) so can interfere with metabolism of other drugs
CBZ is what?
carbamazepine
Stages of carbamazepine metabolism?
- CBZ is the parent drug (active)
- with CYP3A3/4 becomes CBZ-Epoxide (an epoxide metabolite which is also active)
- with epoxide hydrolase, becomes CBZ-diol (a diol metabolite - inactive)
What increases metabolism of CBZ?
- carbamazepine
- phenobarb
- phenytoin
- primidone
Things that decrease CBZ metabolism
- cimetidine
- danazol
- fluozetine
- verapamil
- diltazem
- antiretrovirals
Things that increase CBZ-E to CBZ-diol stage
- SAME AS CBZ TO CBZ-E
- carbamazepine
- phenobarb
- phenytoin
- primidone
Things that decrease CBZ-E to CBZ-diol
- lamotrigine
- valproate
