What is an adverse drug reaction?
Preventable/unpredicted medication event with harm to patient
What are the 3 kinds of classification of adverse drug reactions?
Onset (acute <1h, sub-acute 1-24h and latent >2d), severity (mild = no change in therapy, moderate = change in therapy, additional treatment and hospitalisation, severe = disabling/life threatening) and type (A, B, C, D, E)
What occurs in a severe adverse drug reaction?
Results in death, life-threatening, requires/prolong hospitalisation, causes disability, causes congenital abnormalities in foetus, requires intervention to prevent permanent injury
What is Type A adverse drug reaction?
Most common. Extension of pharmacologic effect usually predictable and dose dependent responsible for at least two-thirds of ADRs e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
What is Type B adverse drug reaction?
Idiosyncratic or immunologic reactions includes allergy and “pseudoallergy” rare (even very rare) and unpredictable e.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema
What is Type C adverse drug reaction?
Associated with long-term use involves dose accumulation e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity (build up is toxic)
What is Type D adverse drug reaction?
Delayed effects (sometimes dose independent) carcinogenicity (e.g. immunosuppressants) teratogenicity (e.g. thalidomide)
What is Type E adverse drug reaction?
Withdrawal reactions: Opiates, benzodiazepines, corticosteroids (due to body not being able to produce its own). Rebound reactions: Clonidine, beta-blockers, corticosteroids “Adaptive” (not good for you) reactions: Neuroleptics (major tranquillisers), psychotropic drugs mainly -> lots of different involuntary movements which can be disabling
What is a rebound reaction - use Clonidine as an example?
Used as alpha 2 agonist, can make patients drowsy and tired; missing one or 2 doses of clonidine can lead to substantial rise in BP -> long term use of clonidine causes long term suppression of peripheral NA production, leading to compensatory upreg in adrenergic receptors on post synaptic neurone -> meaning when NA inhibition is removed and NA is released, it will have more receptors to act on, causing a greater effect, rise in BP
What are the different types of adverse drug reactions?
Augmented pharmacological effect Bizarre Chronic Delayed End-of-Treatment/Dosage
What are the 4 types of allergies?
Type I - immediate anaphylactic (IgE - anaphylaxis with penicillin), type II Ab-dependent cytotoxicity (IgG+IgM - methyldopa and haemolytic anaemia), type III serum sickness (IgG+IgM), type IV delayed hypersensitivity (T cells)
What are the pseudoallergies that can occur?
Aspirin/NSAIDS -> bronchospasm (inhibit protanoids and increase leukotriene production occurs as the precursors are shoved down the leukotriene pathway, which are bronchoconstrictors); ACE inhibitors -> cough/angioedema (stop (brady)kinin breakdown, which triggers coughing when accumulated)
What are the common drugs causing adverse drug reactions?
Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs* *account for two-thirds of fatal ADRs
How are adverse drug reactions detected?
Subjective report = patient complaint; objective report = direct observation of event, abnormal findings (physical examination, lab test, diagnostic procedure) -> problem with detection = Rare events will probably not be detected before drug is marketed
What is the yellow card scheme?
What is the incidence of drug-drug interactions?
What are the 3 types of drug interaction?
Pharmacodynamic (drug's effect in body), pharmacokinetic (body's effect on drug) and pharmaceutical (drugs interacting outside body - IV infusions)
What are the 3 effects of pharmacodynamic drug interactions?
Additive effects - two drugs add together E.g. overlapping toxicities of ethanol and benzodiazepines Synergistic effects - two drugs potentiate each others' actions to get a great effect than expected E.g. synergistic actions of antibiotics Antagonist effects - drugs that antagonise each others' actions E.g. amitriptyline and acetylcholinesterase inhibitors
What are the 4 pharmacokinetic drug interactions?
Alteration in absorption Protein binding effects Changes in drug metabolism Alteration in elimination
How do you alter the absorption of a drug?
Chelation -> Irreversible binding of drugs in the GI tract Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
How do you alter protein binding interactions of a drug?
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 PB interactions were found to be primarily metabolism interactions PB interactions are not usually clinically significant but a few are (mostly with warfarin)
How do you alter the elimination of a drug?
Almost always altered in renal tubule -> probenecid and penicillin = good, lithium (mood stabilising drug) and thiazides = bad as you get increase excretion of Na with lithium being retained, causing build up which can be toxic. Usually most drugs are cleared by the kidney unchanged. When undergoes phase I reaction can be excreted in liver/kidney. When undergoes p1 then p2 or just straight to p2, then excreted only in the kidney.
What are the deliberate interactions of certain drugs?
Levodopa + carbidopa = lower doses of levodopa used as it isn't broken down in the periphery ACE inhibitors + Thiazides = increase anti hypertensive effects Penicillins + Gentamicin = staph infections Salbutamol + ipratropium = asthma
How is drug metabolism altered?
- 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.) occur.
- CYP450 substrates -> Metabolism by a single isozyme (predominantly)
- 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 are some CYP450 inhibitors (very rapid)?
Cimetidine Erythromycin and related antibiotics Ketoconazole etc Ciprofloxacin and related antibiotics Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice
What are some CYP450 inducers (takes hours/days)?
Rifampicin Carbamazepine (Phenobarbitone, Phenytoin - psych drugs) St John’s wort (hypericin) May be many more but haven't been identified yet
What is pharmacogenetics?
The study of genetically determined inter individual differences in therapeutic response to drugs and susceptibility to adverse effects -> few genes of interest
How do we determine genotype of a patient?
How can you determine phenotype?
Determination of metabolic rate (original level of drug/metabolite in urine); after admin of drug given can check parameters= half life, clearance, plasma levels
How are the phenotypes distributed in the population?
Multimodal, bimodal, trimodal