Pharmacology 23 - Adverse Drug Reactions Flashcards
Define adverse drug event
Preventible or unpredicted medication event with harm to patient
Describe the epidemiology of adverse drug reactions
- Substantial morbidity and mortality
- Estimates of incidence vary with study methods, population, and ADR definition
- 4th to 6th leading cause of death among hospitalized patients
- 6.7% incidence of serious ADRs
- 0.3% to 7% of all hospital admissions
annual costs in the billions ($120 billion in US) - 30% to 60% are preventable
How are adverse drug reactions classified?
- Onset (how quickly they happen)
- Severity (how bad they are)
- Type
List the different onsets of ADRs
- Acute (within 1 hour eg. anaphylaxis)
- Subacute (1 to 24 hours)
- Latent (more than 2 days)
List the different severities of ADRs
- Mild (requires no change in therapy)
- Moderate (requires change in therapy, additional treatment and hospitalisation)
- Severe (disabling or life-threatening)
List characteristics of severe adverse drug reactions
- Results in death
- Life-threatening
- Requires or prolongs hospitalisation
- Causes disability
- Causes congenital anomalies
- Requires intervention to prevent permanent injury
List characteristics of type A adverse drug reactions
60-70% of adverse reactions
- Extension of pharmacologic effect
- Usually predictable and dose dependent
List examples of type A adverse drug reactions
- Atenolol and heart block (or bradycardia)
- Anticholinergics and dry mouth, constipation or visual disturbances
- NSAIDS and peptic ulcer
- Digoxin has a linear relationship between adverse reaction and dose
- Paracetamol is harmless at a wide dose range, but beyond a certain dose there is a sharp increase in toxicity (resulting in liver damage and even need for transplant)
List characteristics of type B adverse drug reactions
- Idiosyncratic (will happen in some people but not others) or immunologic reactions
- Includes allergy and “pseudoallergy”
- Rare (even very rare) and unpredictable
List examples of type B adverse drug reactions
- Chloramphenicol and aplastic anemia (total bone marrow failure, tends to not be survived)
- ACE inhibitors and angioedema (swelling of the lips and lung, rarely heart failure non immunological form of anaphylaxis)
- Herceptin and cardiac toxicity (totally unexpected)
List characteristics of type C adverse drug reactions
- Associated with long-term use
- Involves dose accumulation over a period of time
List examples of type C adverse drug reactions
- Methotrexate (immunosuppressant/ cancer use) and liver fibrosis
- Antimalarials and ocular toxicity
List characteristics of type D drug reactions
Delayed effects, sometimes dose independent
List examples of type D drug reactions
- Carcinogenicity (e.g. immunosuppressant)
- Teratogenicity (e.g. thalidomide)
List characteristics of type E adverse drug reactions and give examples
- Withdrawal reactions (opiates, benzodiazepines, corticosteroids)
- Rebound reactions where the drug is stopped and people become worse than before they started it (clonidine, beta blockers, corticosteroids)
- Adaptive reactions *(neuroleptics)
List the types of adverse drug reactions
- Type A (augmented pharmacological effect)
- Type B (bizarre)
- Type C (chronic)
- Type D (delayed)
- Type E (end of treatment)
List types of allergic reactions and give examples
- Type 1 - immediate anaphlactic (IgE mediated - eg. anaphylaxis and penicillin)
- Type II - cytotoxic antibody (IgM and IgG mediated, eg. methyldopa and haemolytic anaemia)
- Type III - serum stickiness with antigen-antibody complex cormation (IgG, IGM medaited, eg. procainamide induced lupus)
- Type IV - delayed hypersensitivity (t cell eg. contact dermatitis)
Give examples of pseudoalleragies
- Aspirin/ NSAIDS causing bronchospasm (care with asthmatics)
- ACE inhibitors causing cough (15-20%)/ angioedema (1%)
List the common causes of ADRs
- Antibiotics
- Antineoplastics *
- Anticoagulants
- Cardiovascular drugs *
- Hypoglycaemics
- Antihypertensives
- NSAID/ analgesics *
- CNS drugs *
- = cause 2/3rds of fatal ADRs
How are ADRs detected?
- Via subjective reports, eg. patient complaints
- Objective report (direct observation of events, with abnormal findings on physical examination, lab tests and diagnostic procedures)
What is the yellow card screen?
- Introduced post thalidomide
- Used by HCPs and members of the public
- For black triangle drugs, which are newly licensed (2 years), any suspected adverse reaction is reported
- For established drugs, only serious adverse reactions are reported
- Used as it is unlikely rare events will be detected before the drug is marketed
- Prescribers informed once ADR confirmed and frequency is estimated
Why is incidence of drug-drug interactions difficult to determine?
- 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
List the three types of drug interactions
- Pharmacodynamic (drugs effect in the body)
- Pharmacokinetic (body effects on the drug, ADME)
- Pharmaceutical (drugs interacting outside the body, mostly IV infusions)
Describe pharmacodynamic drug interactions
- Additive (similar affects by different mechanisms), synergistic (one drug potentiates another drug to increase its function), or antagonistic effects from co-administration of two or more drugs
- Synergistic actions of antibiotics
- Overlapping toxicities - ethanol and benzodiazepines
- Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
Describe pharmacokinetic drug interations
- Alteration in absorption (chelation)
- Protein binding effects
- Changes in drug metabolism
- Alteration in elimination
Describe chelation
- Alteration of absorption
- Irreversible binding of drugs in the GI tract, altering absorption making active drugs insoluble
- Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
Describe protein binding interactions of drugs
- Competition between drugs for protein or tissue binding sites
- Increase in free (unbound) concentration may lead to enhanced pharmacological effect
- 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 a few are (mostly with warfarin)
Describe drug metabolism interactions
- Drug metabolism inhibited or enhanced by coadministration of other drugs
- CYP 450 system has been the most extensively studied (CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others).
- Phase 2 metabolic interactions
(glucuronidation, etc.) can occur
Describe metabolism of CYP450 substrates
- Metabolism by a single isozyme (predominantly - few examples of clnically used drugs)
- Metabolism by multiple isozymes (most drugs - therefore, isozymes will take over metabolism when one isozyme becomes inhibited)
Give an example of drugs metabolised by multiple isozymes
Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
List CYP450 inhibitors
- Cimetidine
- Erythromycin and related antibiotics
- Ketoconazole etc
- Ciprofloxacin and related antibiotics
- Ritonavir and other HIV drugs
- Fluoxetine and other - SSRIs
- Grapefruit juice
List CYP450 inducers
- Rifampicin
- Carbamazepine
- (Phenobarbitone)
- (Phenytoin)
- St John’s wort - mood altering drug (hypericin)
Compare inhibition and iduction
- Inhibition is very rapid
- Induction takes hours/ days
Describe drug elimination interactions. Give examples
- Almost always occur in the renal tubule
- Probenecid and penicilin (good - increased plasma penicillin)
- Lithium and thiazides (bad - due to increased sodium excretion at the expense of lithium, lithium is retained to toxic levels)
List deliberate drug interactions
- Levodopa and carbidopa (increase efficacy of levodopa in CNS)
- ACE inhibitors and thiazides (anti-hypertensives)
- Penicillins and gentamicin (staphylococcal infections)
- Salbutamol and ipratropium (beta agonist + anticholinergic)
Describe adverse drug reaction to clonidine
- Used in hypertension (a2 receptor agonist)
- During use, blood pressure is decreased
- After use, blood pressure increases to a point where there is large risk of stroke
What are pseudoallergies?
- Not allergies
- Not associated with immune response
- Pharmacologically mediated
Describe relationship between increased medications and ADRs
Positive correlation
Describe the three drug metabolism and elimination pathways
- Some drugs excreted unchanged by the kidney
- Some phase 1 metabolism (oxidation most common, also reduction or hydrolysys. Liver/kidney excretion follows)
- Can be phase 2 metabolism (conjugation via glucorinidation/ sulphation/ acetylation. Excreted from the kidney in water soluble form)
