Adverse reactions to drugs Flashcards
Define adverse drugs event
preventable or unpredicted medication event—with harm to patient
ADR can be classified according to what
Onset
Severity
Type
Classify ADR according to onset of event
Acute Within 1 hour Sub-acute 1 to 24 hours Latent > 2 days
Classify ADR according to severity
Severity of reaction: Mild requires no change in therapy Moderate requires change in therapy, additional treatment, hospitalisation Severe disabling or life-threatening
What might be the consequences of a sever ADR
Results in death
Life-threatening
Requires or prolongs hospitalisation
Causes disability
Causes congenital anomalies
Requires intervention to prevent permanent injury
Outline type A ADR
extension of pharmacologic effect
usually predictable and dose dependent
Give examples of type A ADR
e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
Differentiate the ADR with paracetemol and digoxin
Digoxin the ADR steadily increases, throughout the therapeutic window
With paracetemol, there is low ADR throughout the therapeutic window, but dramatically increases following even a small amount over the therapeutic dose
Outline type B ADR
idiosyncratic or immunologic reactions
includes allergy and “pseudoallergy”
Give examples of type B ADR, including pseudoallergy
e.g., chloramphenicol and aplastic anemia,
PSEUDOALLERGY: ACE inhibitors and angioedema
Aspirin/NSAIDs – bronchospasm
Differentiate the commonality of type A and type B ADR
A- 2/3 of ADR
B- very rare and unpredictable
Outline type C ADR
associated with long-term use
involves dose accumulation
Example of type C ADR
e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
Give an example of acute onset ADR
Anaphylaxis
Outline type D classification of ADR
delayed effects (sometimes dose independent)
carcinogenicity
teratogenicity
Type D. What is carcinogenecity. Give an example
Cancer causing (immunosuppressant)
Type D what is teratogenecity. Give an example
Damage to foetus… thalidomide
Outline type E reactions
Withdrawal reactions
Rebound reactions
“Adaptive” reactions
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Give examples of withdrawal reaction (type E)
Opiates (cold turkey), benzodiazepines (can lead to fitting), corticosteroids
Give examples of rebound reactions (type E)
Clonidine, beta-blockers, corticosteroids
Give example of adaptive reactions
Neuroleptics (major tranquillisers)
Movement reactions (i.e. the EPS)
reactions don’t go away when you remove the drug, and can get worse
When are antimalarial drugs given
In some rheumatic disease
Outline rebound reactions with clonidine
BP reduces during
But missing a couple of doses results in rebound
You end up worse than before you started
Memoire for dverse drug reactions
A Augmented pharmacological effect B Bizarre C Chronic D Delayed E End-of-treatment
Classify the 4 hypersensitivity reactions
I- Immediate, anaphylactic
II- cytotoxic antibody (IgG, IgM)
III- serum sickness (IgG, IgM)
IV- delayed hypersensitivity (T cell)
Give an example of a drug allergy associated with each hypersensitivity type
I- anaphylaxis with penicillins
II- methylopa and haemolytic anaemia
III- procainamide-induced lupus
IV- contact dermatitis
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Give examples of pseuoallergies
Aspirin/NSAIDs – bronchospasm
Block COX and thus prostanoids….. more leukotrienes produced.
They are pro-inflammatory and bronchoconstrictor
Only happens in a minority of patients, but NSAIDs not used
ACE inhibitors – cough/angioedema
Pharmacoloical… due to build of bradykinin which causes cough, swelling of tongue, lips, etc.
Bradykinin is pro-inflammatory.
Not in everyone (ethnic differences)
THESE ARE PHARMACOLOGICAL NOT ALLERGIC
Which drugs are most common cause of ADRs
Antineoplastic, CVS, NSAIDs/Analgesics, CNS drugs
account for 2/3 of fatal ADRs
Also: ABs, Anticonvulsants, Hypoglycaemics, Antihypertensives
are common causes of ADRs
All cuases of ADR
Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs*
Why is there lots of ADR with CVS and CNS drugs
Cos so many take them
What causes increase in ADR
Giving more drugs
How are ADR detected
Subjective report
-patient complaint
Objective report:
- direct observation of event
- abnormal findings
What abnormal findings might help with ADR
physical examination
laboratory test
diagnostic procedure
What is the problem with ADR detection
Stastically, large numbers needed to detect rare events
1 in 100 needs 300 to detect
1 in 100 X 3 needs 650 people to detect
ie rare events will probably not be detected before
drug is marketed
What is the yellow card scheme
for established drugs only report serious adverse reactions
(fatal, life-threatening, needing hospital admission, disabling)
for “black triangle “ drugs (newly licensed, usually <2 years) report any suspected adverse reaction
Who can yellow card scheme be used by
can be used by doctors, dentists, nurses, coroners and
pharmacists, and members of the public
voluntary
What should happen if ADR is suspected
Should be confirmed (high probability)
Estimate frequency
Inform prescribers
Why is it hard to work out drug drug interactin
Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs
Lack of availability of comprehensive databases
Difficulty in assessing OTC and herbal drug therapy use
Difficulty in determining contribution of drug interaction in complicated patients
Sometimes principal cause of ADRs with specific drugs
eg statins
Outline the three types of drug interactios
Pharmacodynamic
Related to the drug’s effects in the body
Pharmacokinetic
Related to the body’s effects on the drug
Pharmaceutical
- drugs interacting outside the body (mostly
IV infusions)
What does pharmacodynaic drug interaction relate to
Related to the drug’s effects in the body
Receptor site occupancy
What does pharmacokinetic drug interaction relate to
Related to the body’s effects on the drug
Absorption, distribution, metabolism, elimination
Outline pharmacodynamic drug interactions
give examples
Additive, synergistic, or antagonistic effects from co-administration of two or more drugs
Synergistic actions of antibiotics
Overlapping toxicities - ethanol & benzodiazepines
Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
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What are the pharmacokinetic drug interactions
Alteration in absorption
Protein binding effects
Changes in drug metabolism
Alteration in elimination
Give an example of alterations in absorptions as a cuase of drug drug interactions
Chelation
Irreversible binding of drugs in the GI tract
Tetracyclines, quinolone antibiotics (i.e. those used for COMPLICATED gastric ulcer!!!)
can bind to:
- ferrous sulfate (Fe+2), - antacids (Al+3, Ca+2, Mg+2),
- dairy products (Ca+2)
So that you absorb less of these ions and you absorb NO antibiotic!
Outline protein binding interactions
Competition between drugs for protein or tissue binding sites
Increase in free (unbound) concentration may lead to enhanced pharmacological effect
Why have protein binding interactiosn been overestimated
Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions
PB interactions are not usually clinically significant
but a few are
Give an example of a clinically significant protein binding interactions
PB interactions are not usually clinically significant
but a few are (mostly with warfarin)
How can a drug be handled by the kidney
- Excreted unchanged by kidney (furesomide)
- Phase 1 reaction in liver / kidney. Excreted OR in kidney:
- Phase 2 reaction (with or without previous phase 1) nand excreted by kidney
Examples of phase 1 metabolism
Oxidation
Reduction
Hydrolysis
T/F Phase I must happen before Phase II
F
Examples of phase II metabolism
Conjugation:
Glucoronidation
Sulphation
Acetyation
Outline drug metaboism interactions
Drug metabolism inhibited or enhanced by coadministration of other drugs
Phase 2 metabolic interactions (glucuronidation, etc.) occur, research in this area is increasing
T.f most drugs are metabolised by a single isoenzyme predominantly
Few examples of clinically used drugs
Examples of drugs used primarily in research on drug interactions
Most drugs metabolized by more than one isozyme
What is the problem with targeting CYP 450
If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme
Give examples fof CYP 450 inhibitors
Cimetidine
Erythromycin and related antibiotics
Ketoconazole etc
Ciprofloxacin and related antibiotics
Ritonavir and other
HIV drugs
Fluoxetine and other SSRIs
Grapefruit juice
Give examples of CYP 450 inducers
The “usual suspects”
Rifampicin
Carbamazepine
(Phenobarbitone)
(Phenytoin)
St John’s wort (hypericin)
Differentiate change in CYP450 activity
Inhibition is very rapid… due to enzyme inhibiton
Induction takes hours/days (new enzyme synthesis and protein making etc.)
Outline the drug elimintation interactions with examples
Almost always in renal tubule
- probenecid and penicillin (good),
- lithium and thiazides (bad)
Explain - probenecid and penicillin (good)
Good
Giving probenecid with penicillin allows you to give smaller doses of penicillin as the probenecid reduces elimintation of the penecillin
Exmplain - lithium and thiazides (bad)
the thiazide will increase the excretion of sodium at the expense of the lithium
Lithium retained and circulating levels increased
Give examples of deliberate drug interactions
levodopa + carbidopa
salbutamol + ipratropium
ACE inhibitors + thiazides
penicillins + gentamicin (particulary staphylococcal)
