Adverse drug reactions and interactions Flashcards
Adverse drug event
Preventable or unpredicted medication event with harm to the patient
-includes medication errors and adverse drug reactions
Epidemiology of adverse drug reactions (ADRs)
- substantial morbidity and mortality
- estimates of incidence vary with study methods, population and adverse drug reaction definition
- 4th to 6th leading cause of death among hospitalised patients
- 6.7% incidence of serious adverse drug reactions
- 0.3% to 7% of all hospital admissions
- annual costs in the billions
- 30% to 60% are preventable
ADR classification basis
- onset
- severity
- type
Onset of event
- Acute=within 1 hour
- Sub-acute=1 to 24 hours
- Latent=more than 2 days
Severity of reaction
- Mild=no change in therapy required
- Moderate=change in therapy required, additional treatment and hospitalisation
- Severe=disabling or life-threatening
Severe ADR
- life-threatening/results in death
- requires or prolongs hospitalisation
- causes disability
- causes congenital anomalies
- requires intervention to prevent permanent injury
Type A ADR
-extension of pharmacologic effect
-usually predictable and dose dependent
-responsible for at least two-thirds of ADRs
Example: atenolol and heart block, NSAIDs and peptic ulcers, anticholinergics and dry mouth
Type B ADR
- idiosyncratic or immunologic reactions
- includes allergy and ‘pseudoallergy’
- rare and unpredictable
- examples include: chloramphenicol and aplastic anaemia, ACE inhibitors and angioedema
Type C ADR
- associated with long-term use
- involves dose accumulation
- examples include: methotrexate and liver fibrosis, antimalarials and ocular toxicity
Type D ADR
- delayed effects (sometimes dose independent)
- carcinogenicity (eg: immunosuppressants)
- teratogenicity (eg: thalidomide)
Type E ADR
- withdrawal reactions=opiates, benzodiazepines, corticosteroids
- rebound reactions=clonidine, beta-blockers, corticosteroids
- ‘adaptive’ reactions=neuroleptics (major tranquilisers)
Classification of allergies
-Type 1=immediate, anaphylactic (IgE)
Example: anaphylaxes with penicillin
-Type 2=cytotoxic antibody (IgG, IgM)
Example: methyldopa and haemolytic anaemia
-Type 3=serum sickness (IgG, IgM)=antigen-antibody complex
Example: procainamide-induced lupus
-Type 4=delayed hypersensitivity (T cell)
Example: contact dermatitis
ABCDE classification of ADRs
A=Augmented pharmacological effect B=Bizarre C=Chronic D=Delayed E=End-of-treatment
Pseudoallergies
- Aspirin/NSAIDs leading to bronchospasm
- ACE inhibitors leading to cough/angioedema
Common causes of ADRs
-antineoplastics
-cardiovascular drugs
-NSAIDs/analgesics
-CNS drugs
(account for two-thirds of fatal ADRs)
- antibiotics
- anticoagulants
- hypoglycaemics
- antihypertensives
ADR detection
SUBJECTIVE REPORT -patient complaint OBJECTIVE REPORT -direct observation of events -abnormal findings on physical examination, lab tests or diagnostic procedures
-Rare events will probably not be detected before drug is marketed
The yellow card scheme
- introduced after 1964 thalidomide incident
- run by MHRA
- voluntary
- can be used by healthcare professionals, patients and members of the public
- also includes ADRs to blood products, vaccines and contrast media
- for established drugs, only report serious adverse reactions
- for newly licensed drugs (<2 years=’black triangle’ drugs), report any suspected adverse reaction
ADR frequency by drug use
ADR frequency increases with increased individual drug use (increased number of medications)
Incidence of drug-drug interactions
Incidence is difficult to determine due to:
- data for drug-related hospital admissions do not differentiate drug interactions and only adverse drug reactions
- lack of availability of comprehensive databases
- difficulty in assessing over the counter and herbal drug-therapy use
- difficulty in determining contribution of drug interaction in complicated patients
- sometimes principals causes of adverse drug reactions with specific drugs (eg: statins)
Pharmacodynamic drug interactions
RELATED TO DRUG’S EFFECTS IN THE BODY (receptor site occupancy)
Additive, synergistic or antagonistic effects from co-administration of 2 or more drugs
- synergistic actions of antibiotics
- overlapping toxicity (eg: ethanol and benzodiazepines)
- antagonistic effects (eg: anticholinergic medications)
Pharmacokinetic drug interactions
RELATED TO THE BODY’S EFFECT ON THE DRUG (absorption, distribution, metabolism and elimination)
- alteration in absorption
- protein binding effects
- changes in drug metabolism
- alteration in elimination
Pharmaceutical drug interactions
-DRUGS INTERACTING OUTSIDE THE BODY (eg: in IV infusions)
Protein binding interactions=PHARMACOKINETIC INTERACTION
- competition between drugs for protein or tissue binding sites (increase in free/unbound concentration may lead to enhanced pharmacological effects)
- many interactions previously thought to be protein binding interactions were found to be primarily metabolism interactions
- protein binding interactions are not usually clinically significant but some are (Eg: Warfarin=99% plasma albumin-bound so increase in free warfarin increases anti-coagulative effects)
Phase I metabolism
OXIDATION
- reduction
- hydrolysis
Phase II metabolism
CONJUGATION
- glucuronidation
- sulphation
- acetylation
Drug metabolism interactions
- drug metabolism can be inhibited or enhanced by co-administration of other drugs
- CYP450 system most extensively studied
CYP 450 substrates
Predominantly metabolism by a single isozyme
-few examples of clinically used drugs
-examples of drugs used primarily in research on drug interactions
Metabolism by multiple isozymes
-most drugs metabolised by more than one isozyme
-if co-administered with CYP450 inhibitor, some isozymes may ‘pick up slack’ for inhibited isozyme so metabolic rate unaffected
CYP 450 inhibitors
- Cimetidine
- Erythromycin and related antibiotics
- Ketoconazole
- Ciprofloxacin and related antibiotics
- Ritonavir and other HIV drugs
- Fluoxetine and other SSRIs
- Grapefruit juice
Drug elimination reactions
- Almost always occur in the renal tubule
- GOOD=probenecid and penicillin
- BAD=lithium and thiazides
Inhibition and induction
- Inhibition=very rapid
- Induction=takes hours/days
Deliberate interactions
- Levodopa and Carbidopa
- ACE inhibitors and thiazides
- Penicillins and gentamicin
- Salbutamol and ipratropium
CYP 450 inducers
- Rifampicin
- Carbamazepine
- Phenobarbitone
- Phenytoin
- St John’s wort (Hypericin)
Drug metabolism and elimination=PHARMACOKINETIC INTERACTION
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Alterations in absorption=PHARMACOKINETIC INTERACTION
CHELATION
-irreversible binding of drugs in GI tract
Example: tetracylines, quinolone antibiotics to ferrous sulfate (Fe2+), antacids (Al3+, Ca2+, Mg2+), dairy products (Ca2+)
