Adverse drug reactions Flashcards
Define an adverse drug event
A preventable (medication errors) or unpredicted (ADR) medication event with harm to the patient.
What are the classifications of ADRs?
Onset
Severity
Type
What are the different categories of onset in ADRs?
Acute - within 1 hour. e.g anaphylaxis
Sub-acute - 1 to 24 hours
Latent > 2 days
What are the different categories of severity in ADRs?
Mild - requires no change in therapy
Moderate - requires change in therapy
Severe - disabling or life-threatening
Describe severe ADR?
Life threatening - results in death
Requires or prolongs hospitalisation
Requires intervention to prevent permanent injury
Severe ADR can causes:
- Disability
- Congenital anomalies
What are the different types of ADRs?
Type: A - Augmented pharmacological effect B - Bizarre C - Chronic D - Delayed E - End-of-treatment
Describe type A ADRs?
- Extension of pharmacological effect = usually predictable and dose dependent
- Responsible for at least 2/3s of ADRs
e.g e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
Give examples of a relationship of ADR and dose?
Type A reactions:
Paracetamol - sudden increase in ADR at specific dose.
Digoxin - linear increase
Describe type B ADRs?
- idiosyncratic or immunologic reactions
- includes allergy and “pseudoallergy”
- rare (even very rare) and unpredictable
e.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema (pseudo-allergy)
Describe type C ADRs?
- associated with long-term use
- involved dose accumulation
e.g., methotrexate and liver fibrosis - dependent on the total amount of methotreaxate given, antimalarials and ocular toxicity - the more you give the more damage
Describe type D ADRs?
- delayed effects (sometimes dose independent)
- carcinogenicity (e.g. immunosuppressants)
- teratogenicity (e.g. thalidomide)
Describe type E ADRs?
Withdrawal reactions
- Opiates, benzodiazepines, corticosteroids (fits)
Rebound reactions
- Clonidine - if you miss a dose your hypertension could get even worse (slide 17), beta-blockers, corticosteroids
“Adaptive” reactions
- Neuroleptics (major tranquillisers) You get abnormal random movements
Classify the types of allergies and give examples.
Type I - immediate, anaphylactic (IgE)
e.g., anaphylaxis with penicillins
Type II - cytotoxic antibody (IgG, IgM)
e.g., methyldopa and hemolytic anemia
Type III - serum sickness (IgG, IgM)
antigen-antibody complex
e.g., procainamide-induced lupus
Type IV - delayed hypersensitivity (T cell)
e.g., contact dermatitis
Give some examples of pseudoallergies?
Aspirin/NSAIDs – bronchospasm (induction into proinflammatory compounds - block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased)
ACE inhibitors – cough/angioedema (due to bradykinin not being broken down) Angioedema similar to anaphylaxis.
List the common causes of ADRs?
Antibiotics Antineoplastics* - Acting to prevent, inhibit or halt the development of a neoplasm (a tumor). Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs*
- account for 2/3s of fatal ADRs
What is the correlation between ADR and drug use?
The greater the number of medications taken the greater the frequency of ADR
What are the two stages in ADR detection?
Subjective report
- patient complaint
Objective report:
- direct observation of event
- abnormal findings
1) physical examination
2) laboratory test
3) diagnostic procedure
Rare events will probably not be detected before the drug is marketed.
What is the Yellow Card Scheme?
- introduced in 1964 after thalidomide.
- run by the Medicines and Healthcare Products Regulatory Agency (MHRA)
- entirely voluntary: can be used by doctors, dentists, nurses, coroners and pharmacists, and members of the public
- includes blood products, vaccines, contrast media
- 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
What are the different types of drug interactions?
Pharmacodynamic - related to the drug’s effects in the body. Receptor site occupancy
Pharmacokinetic - related to the body’s effects on the drug. Absorption, distribution, metabolism, elimination
Pharmaceutical - drugs interacting outside the body (mostly IV infusions 0 reactions inside transfusion bags)
Describe pharmacodynamic drug interaction?
Examples of pharmacodynamic interactions can be additive, synergistic, or antagonistic effects from co-administration of two or more drugs
- Synergistic actions of antibiotics
- Overlapping toxicities - ethanol and benzodiazepines (CNS depressants)
- Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
What are the four different pharmacokinetic drug interactions?
- Alteration in absorption
- Protein binding effects
- Changes in drug metabolism
- Alteration in elimination
Describe alterations in absorption
Chelation
- Irreversible binding of drugs in the GI tract
- Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe2+), antacids (Al3+,Ca2+, Mg2+), dairy products (Ca2+)
- The antibiotics and ferrous sulfate/antacids are not absorbed because they bind together.
What are protein binding interactions?
Competition between drugs for protein or tissue binding sites:
- Increase in free (unbound) concentration may lead to enhanced pharmacological effect
PB interactions are not usually clinically significant
but a few are (mostly with warfarin - very protein pound. Displacing that is bad)
Summarise drug metabolism and elimination
See slide 35
What reactions are involved in phase I and II metabolism?
Phase I: molecule is structurally changed.
- oxidation
- reduction
- hydrolysis
Phase II: Stick another molecule onto the drug
- Glucuronidation
- Sulphation
- Acetylation
Describe drug metabolism interactions?
Drug metabolism is inhibited or enhanced by coadministration of other drugs.
Describe the CYP450 substrates?
Metabolism by a single isozyme (predominantly)
- Few examples of clinically used drugs
- Examples of drugs used primarily in research on drug interactions
Metabolism by multiple isozymes
- Most drugs metabolized by more than one isozyme
Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
- If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme
What can inhibit CYP450?
- Cimetidine
- Erythromycin and related antibiotics
- Ketoconazole (anti-fungal)
- Ciprofloxacin and related antibiotics
- Ritonavir and other HIV drugs
- Fluoxetine (SSRI antidepressant) and other SSRIs
- Grapefruit juice
Inhibition is very rapid
What can induce CYP450?
Antiepileptic drugs:
- Rifampicin
- Carbamazepine
- (Phenobarbitone)
- (Phenytoin)
- St John’s wort (hypericin): Antidepressant
Induction takes hours/days
Describe some drug elimination interactions?
Renal tubule:
GOOD: Probenecid and penicillin (prevented penicillin from being excreted keeps it around for longer)
BAD: Lithium and Thiazides (increases excretion sodium at the expense of lithium. We need lithium)
What are some deliberate interactions?
- levodopa + carbidopa
- ACE inhibitors + thiazides
- penicillins + gentamicin
- salbutamol + ipratropium
