Adverse Drug Reactions (20.02.2020) Flashcards
Epidemiology of adverse drug reaction
- 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
UK prevelaance 6.5%
What criteria can you use to classify ADRs?
Onset
Severity
Type
Onset of event - classification of ADRs
Acute
- Within 1 hour
Sub-acute
- 1 to 24 hours
Latent
- > 2 days
SEVERITY - classification of ADRs
Mild
- requires no change in therapy
Moderate
- requires change in therapy, additional treatment, hospitalisation
Severe
- disabling or life-threatening
Severe ADRs
- Results in death
- Life-threatening
- Requires or prolongs hospitalisation
- Causes disability
- Causes congenital anomalies
- Requires intervention to prevent permanent injury
- > you might have to stop the drug, give an antidote..
Type A ADR
- extension of pharmacologic effect
- usually predictable and dose dependent
- responsible for at least two-thirds of ADRs
- > 66% of ADRs
- e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
Different type A ADRs (examples)
- digoxin: very linear dose dependance
- paracetamol: not a problem at a lower dose when you get above a certain dose you get a sharp increase of toxicity and you may get liver damage.
Type B ADRs
- idiosyncratic (you don’t really know why) or immunologic reactions
- includes allergy and “pseudoallergy”
- rare (even very rare) and unpredictable
- e.g., chloramphenicol and aplastic anemia (=total BM failure, people tend not to survive it; other ABs available so people don’t use it), ACE inhibitors and angioedema (swelling of lips, tongue, breathlessness, rarely HF)
=> Many serious ADRs are totally unexpected eg Herceptin
and cardiac toxicity
Type C ADRs
- associated with long-term use
- involves dose accumulation (how much of the drug has accumulated over time?)
- e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
Type D reactions
- delayed effects (sometimes dose independent)
- carcinogenicity (e.g. immunosuppressants)
- teratogenicity (e.g. thalidomide)
Type E reactions
Withdrawal reactions
-> Opiates, benzodiazepines (fitting), corticosteroids (patients collapse if you stop suddenly)
Rebound reactions
-> Clonidine, beta-blockers, corticosteroids (when you stop the drug and then the situation is worse than when you started)
“Adaptive” reactions
-> Neuroleptics (major tranquillisers) ????
Clonidine withdrawl
- after treatment the BP goes up again, higher than it was before treatment
- can cause stroke, death..
- pharmacological explanation of why it happens
ABCDE classification of ADRs
A Augmented pharmacological effect B Bizarre C Chronic D Delayed E End-of-treatment
Types of allergic reactions
Type I - immediate, anaphylactic (IgE)
e.g., anaphylaxis with penicillins
=> this is the most important one in this context because you have to be able to recognise it and treat it right away
Type II - cytotoxic antibody (IgG, IgM)
e.g., methyldopa and hemolytic anemia
(less common)
Type III - serum sickness (IgG, IgM)
antigen-antibody complex
e.g., procainamide-induced lupus
(less common)
Type IV - delayed hypersensitivity (T cell)
e.g., contact dermatitis
Examples of peudoallergies
Aspirin/NSAIDs – bronchospasm
ACE inhibitors – cough in a large number of patients/angioedema
What are pseudoallergies?
- similar presentation to a true allergy, though due to different causes.
- Aspirin/NSAIDs – bronchospasm
- ACE inhibitors – cough in a large number of patients/ angioedema (milde, non-immunological version of anaphylaxis, tongue and mouth swelling etc.)
List some common drugs that cause ADRs
Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs*
*account for two-thirds of fatal ADRs
=> many people take these drugs, the total numbers are very large even thought the incidence is not very large.
Frequency of drug reactions in multipharmacy
the more medications, the more adverse reactions
How are ADRs detected?
Subjective report
- patient complaint
Objective report:
- direct observation of event
- abnormal findings
- physical examination
- laboratory test
- diagnostic procedure
There is a statistical problem: rare events will probably not be detected before the drug is marketed because you need a large number of participants for this.
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) - there might not be a full picture for the adverse reactions of the drug.
- > report any suspected adverse reaction
What happens when an ADR is suspected?
ADR SUSPECTED -> ADR CONFIRMED (HIGH PROBABILITY) -> FREQUENCY ESTIMATED -> PRESCRIBERS INFORMED (by MHRA) - if it is dangerous and life threatening it might be withdrawn
Incidence of drug-drug interactions
- True incidence difficult to determine (because there are so many possible interactions and so many people)
- 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
What are the types of drug interactions?
Pharmacodynamic
Pharmacokinetic
Pharmaceutical
Pharmacodynamic drug interactions
- Related to the drug’s effects in the body
- Receptor site occupancy
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)
Pharmacokinetic drug interactions
Related to the body’s effects on the drug
Absorption, distribution, metabolism, elimination
- Alteration in absorption
- Protein binding effects (e.g. albumin)
- Changes in drug metabolism
- Alteration in elimination
Pharmaceutical drug interactions
drugs interacting outside the body (mostly IV infusions)
Alterations in absorption (example)
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)
Protein Binding interactions
- Competition between drugs for protein or tissue binding sites (binding to albumin)
- 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)
Drug Metabolism and Elimination
a) Excretedunchangedby kidney
b) Ph1 metabolism in liver or kidney (mainly oxidation)
c) Ph2 metabolism -> kidney (usually made. water soluble)
Ph1 metabolism reactions
Mainly: oxidation
less frequent: reduction and hydrolysis
Ph2 metabolism reactions
Mainly conjugation
also:
Glucuronidation
Sulphation
Acetylation
ionised compound added that is easily excreted
???????
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, research in this area is increasing
CYP 450 Substrates and drug interactions
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
Name some CYP inhibitors
The “usual suspects”
- Cimetidine
- Erythromycin and related antibiotics
- Ketoconazole etc
- Ciprofloxacin and related antibiotics
- Ritonavir and other HIV drugs (often involved in drug interactions)
- Fluoxetine and other SSRIs
- Grapefruit juice (there is a natural compound in grapefruit that is a CYP450 inhibitor)
Name some CYP inducers
The “usual suspects”
- Rifampicin
- Carbamazepine
- (Phenobarbitone)
- (Phenytoin)
- St John’s wort (hypericin) -> antidepressant, similar to SSRIs
There might be some more in plants
What is the difference in how fast the action is in (CYP) inhibitors and inducers?
Inhibition is very rapid
Induction takes hours/days
Drug elimination interactions
Almost always in renal tubule
- probenecid and penicillin (good) - lithium and thiazides (bad) -> given together you have increased excretion of sodium at the expense of lithium so you have high levels of lithium
Deliberaate drug interactions
- levodopa + carbidopa (BBB)
- ACE inhibitors + thiazides (stronger BP reducing effect together, the ACE will stop the natural renin increase from thiazides)
- penicillins + gentamicin
- salbutamol + ipratropium
Summary
- much of therapeutics is about avoiding or detecting ADRs
- most are avoidable
- drug interactions are an important added
risk for ADRs - more drugs = more trouble
