Adverse Drug Reactions Flashcards
simple definition of adverse drug effect
preventable or unpredicted medication events with harm to the patient.
describe the epidemiology of ADRs
o 4th-6th leading cause of death amongst patients.
o 6.7% incidence of serious ADRs.
o 0.3%-7% of all hospital admissions and costs a lot of money.
o 30-60% are preventable.
what are ADRS classed based on?
- onset
- severity
- type
what are the different onsets of ADRs?
o Acute <1 hour.
o Sub-acute 1-24 hours.
o Latent >2 days.
what are the different severities of ADRs? what changes should take place following?
o Mild
-no change in therapy required.
o Moderate
- change in therapy required, additional treatment and hospitalisation.
o Severe
- disabling, life-threatening, prolongs hospitalisation, causes congenital abnormalities,
requires intervention to prevent further injury.
what are the different types of ADRs?
- Type A: Augment/extend the pharmacological effect.
- Type B: Bizarre – Idiosyncratic or Immunologic reactions.
- Type C: Chronic – Long-term use side effects.
- Type D: Delayed – Delayed effects.
- Type E: End of treatment side effects.
what is Type A?
Augmented effect:
- 60-70% of ADRs
- can be expected from the pharmacology
- Usually predictable and dose-dependent
- the pharmacology of the drug is not necessarily fully understood
e.g. Paracetamol has a threshold below which it has minimal side effects (and then exceeding this, side effects rapidly increase).
Digoxin just has a dose-dependent line with constant increasing SEs.
what is Type B?
Bizarre:
Unpredictable, rare (totally unexpected)
and include allergy and “pseudo-allergy”.
name drugs with their Type A reactions
Augmented reactions:
Atenolol–> heart block
NSAIDs–>peptic ulcers.
name drugs with Type B reactions
Bizarre/Idiosyncratic reactions:
Chloramphenicol–>aplastic anaemia
ACE inhibitors–>angioedema
Herceptin–> cardiac toxicity
- new cancer drugs are tested for cardiac toxicity pre-clincially
what is Type C?
Chronic:
Involves dose accumulation over time associated with chronic use
name drugs with Type C reactions
chronic use reactions:
Methotrexate –> liver fibrosis
antimalarial–> ocular toxicity
methotrexate is immunosuppressive for IBD
what is Type D?
Delayed effects of drugs
name drugs and their Type D reactions
delayed reaction:
Carcinogenicity – e.g. immunosuppressants.
Teratogenicity – e.g. thalidomide.
what is 3 reactions make up Type E?
End of treatment side effects consists of 3 reactions:
1) Withdrawal reactions
– patient cannot make endogenous supply
2) Rebound reactions
– disease gets worse when drugs stopped
3) “Adaptive” reactions
– adapted body reactions to drugs
name drugs that cause a withdrawal reaction?
opiates
corticosteroids
benzodiazepines
name drugs that cause a rebound reaction
- clonidine (BP increases again after stoppage but higher to how it worse before treatment)
- beta-blockers
- corticosteroids
Type E (due to stoppage)
name drugs that cause an “adaptive reaction”
Type E
neuroleptics (tranquilisers) used in schiz
what is the effect of stopping clonidine treatment?
BP increases again after stoppage but higher to how it worse before treatment
Clonidine hydrochloride is an anti hypertensive
classification overview of ADR types
o A – augmented pharmacological effect. o B – bizarre. o C – chronic. o D – delayed. o E – end-of-treatment.
what are the types of allergic reactions (hypersensitivity)
Type 1 – immediate, anaphylactic
Type 2 – cytotoxic antibody.
Type 3 – serum sickness (antibody-antigen complex)
Type 4 – delayed-type hypersensitivity
what are the mediators of the different allergic reaction types?
- type 1–> IgE
- type 2–> IgG, IgM
- type 3–> IgG, IgM
- type 4–> T-cell
Type B ADR involves allergic reactions:
types of allergic reaction (hypersensitivities) and examples of drugs that cause them?
type 1: anaphylaxes with penicillin
type 2: methyldopa and HA.
type 3: procainamide-induced lupus.
type 4: contact dermatitis
type 1 is immediate and anaphylactic (IgE)
type 2 is mediated by cytotoxic antibody (IgG, IgM)
type 3 involves immune complexes (IgG, IgM)
type 4 is delayed type (T cell)
what are pseudo-allergies?
they are not allergies because they have no associated immune response
they are pharmacological reactions
what is the pseudo-allergic reaction to aspirin and NSAIDs in general?
bronchospasm :
Aspirin/NSAIDs inhibit COX so less prostaglandin synthesis and more leukotrienes made.
some asthmatics need to avoid NSAIDs
what is the pseudo-allergic reaction to ACEis?
1) angioedema:
ACEi inhibit production of AngII (in Afro-Carribean patients particularly)
2) cough:
stop the breakdown of inflammatory mediators such as bradykinin which stimulate the cough receptors in the lungs.
the drug needs to be removed in this case
what drugs are the most common causes of ADRS?
Antineoplastics – cytotoxic drugs. Cardiovascular drugs. NSAIDs/analgesics. CNS drugs. These 4 account for 2/3rds of fatal ADRs.
Antibiotics.
Anticoagulants.
Hypoglycaemics.
Antihypertensives.
ADR frequency increased with increased individual use
how can ADRs be detected and recorded?
subjective and objective reports:
1) Subjective reports:
o Patient complaints – yellow-card system.
2) Objective reports:
o Direct observations of events.
o Abnormal findings – physical examination, lab tests, diagnostic procedures.
Rare events will probably NOT be detected before a drug is marketed.
what is the Yellow Card Scheme? how should it be used?
Reporting of adverse effects:
This was a scheme introduced after the 1964 incident with thalidomide and is run by the Committee on Safety of Medicines (branch of medicines control agency).
Voluntary, can be used by any healthcare professional, and includes blood products, vaccines and contrast media.
Established drugs should only report serious adverse reactions.
“Black triangle” drugs (newly licensed) should report ANY suspected adverse reactions.
why is it difficult to ascertain the incidence of drug-drug interaction?
o Data for drug-related hospital admissions do not differentiate out drug interactions, only ADRs.
o There is a lack of available comprehensive databases.
o Difficulty in assessing OTC drug use.
o Difficulty in determining drug contribution to interactions in complicated patients.
o Sometimes the principal causes of ADRs is with specific drugs – e.g. statins which enhances toxicity of other drugs with co-administration
what are the 3 classifications of drug interactions?
pharmacodynamic
pharmacokinetic
pharmaceutical
what are pharmacodynamic drug interactions?
drug’s effects on the body
– e.g. receptor site dynamics.
Additive, synergistic, or antagonistic effects from co-administration (looks at drug’s properties)
give examples of pharmacodynamic drug interactions
• Synergistic actions of antibiotics
– use of two ABs will increase the effect more than their separate contributions (i.e. 2+2=5) OR they antagonise each other.
• Overlapping toxicity
– ethanol and benzodiazepines.
• Antagonistic effects
– anticholinergic medications.
what are pharmacokinetic drug interactions?
body’s effects on the drug
– e.g. absorption, distribution, metabolism, excretion
give examples of pharmacokinetic drug interactions?
Involves aspects of ADME (pharmokinetics)
1) Alteration in absorption – chelation 2) Protein-binding interactions – e.g. warfarin 3) Drug metabolism and excretion
what is the effect of chelation on drug absorption?
Irreversible binding in the GI-tract, for example, antibiotics to metal ions or calcium to form chelates that prevent absorption of the antibiotic.
e.g. drugs with milk
what is the significance of PPB in the effects of warfarin?
Warfarin is 99% albumin-bound so anything to decrease that (competing drug) will increase the free warfarin so there is more anti-coagulative effects.
how can drugs be excreted after going through the phases of metabolism?
Drugs can be
(1) directly excreted
(2) undergo Ph1 metabolism and be excreted,
(3) undergo Ph1 and Ph2 and then be excreted
(4) only undergo Ph2 and then be excreted.
what are pharmaceutical drug interactions?
drug interactions outside the body – e.g. in IV infusions.
what are the reactions that occur in phase 1 metabolism?
oxidation
reduction
hydrolysis
what are the reactions that occur in phase 2 metabolism?
conjugation (glutathione, amino-acid) glucuronidation sulphation acetylation methylation.
produce polar, water soluble excretable product
how are most drugs metabolised in the CYP450 system?
by multiple isoenzymes
Thus, co-administration of a CYP450 inhibitor may not affect metabolism rate as some isoenzymes can pick-up the slack for the inhibited isoenzyme.
name inhibitors of CYP450
- Cimetidine [H2 receptor antagonist used in peptic ulcer]
- Erythromycin (and related ABs)
- Ketoconazole [anti fungal and Cushing’s]
- Ciprofloxacin (and related ABs)
- Ritonavir (and other HIV drugs).
- Grapefruit juice.
- Fluoxetine (and other SSRIs).
the inhibition effect is very rapid
name inducers of CYP450
- Rifampicin
- Carbamazepine
- St John’s wort (hypericin)
- Phenobarbitone.
- Phenytoin.
the induction take hours/days
compare the onset of effects of inhibitors and inducers of CYP450 enzymes
inhibitors are rapid
inducers take hours/days
where do drug elimination interactions almost always occur?
renal tubules
name a good elimination interaction? why was this good?
GOOD: Probenecid + penicillin
Probenecid reduced excretion of penicillin and penicillin used to be expensive.
example of bad elimination interaction
why is this bad?
BAD: Lithium and thiazides
thiazides lead to toxic accumulations of lithium
name some deliberate drug interactions
Levodopa + carbidopa
- can use lower doses of levodopa as carbidopa reduced peripheral metabolism of levodopa so more can cross BBB
ACEi + thiazides
- treat HF.
Penicillin’s + gentamycin
- treat severe staph. infections.
Salbutamol + ipratropium
- beta-agonists and anti-muscarinics used in inhalers to treat asthma.
