Adverse Drug Reactions Flashcards
What can too much vitamin C give you
Kidney stones
What is important to remember about clinical pharmacology
All substances are poisons: there is none that
is not a poison. The right dose differentiates
a poison from a remedy.
What is meant by an adverse drug event
preventable or unpredicted medication event—with harm to patient
could be due to an adverse drug reaction or due to a medication error ( wrong drug or wrong dose prescribed)
Describe the importance of adverse drug reactions
They are costly and cause a lot of morbidity and mortality in patients.
Describe the epidemiology of ADRs
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
Generally, how can we classify ADRs
Onset
Severity
Type
Summarise the classification of ADRs based on onset
Acute - most commonly anaphylactic immune reactions
Within 1 hour
Sub-acute
1 to 24 hours
Latent
> 2 days
Summarise the classification of ADRs based on the severity of the reaction
Mild
requires no change in therapy
Moderate
requires change in therapy, additional treatment, hospitalisation
Severe
disabling or life-threatening
Outline the consequences of a severe ADR
Results in death
Life-threatening
Requires or prolongs hospitalisation (LIVER DAMAGE)
Causes disability
Causes congenital anomalies
Requires intervention to prevent permanent injury (ANTIDOTES, AVOID THE DRUG ALTOGETHER)
Describe type A ADRs
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 (also visual problems and constipation), NSAIDS and peptic ulcer
Augmented and often predictable effect of the pharmacology of the drug- but sometimes we don’t understand why the side effects are produced.
How can we reverse type A ADRs
In many instances, this type of unwanted effect is reversible, and the problem can often be dealt with by adjusting the dose to obtain a more favourable balance between efficacy and safety.
This may be problematic in patients who have developed tolerance for opiods.
Compare the relationship between the incidence of ADRs (y-axis) and dose (x-axis) for digoxin and paracetemol
§ Paracetamol has a threshold below which it has minimal side effects (and then exceeding this, side effects rapidly increase). Digoxin just has a dose-dependent line with constant increasing SEs. (linear relationship with digoxin)
Summarise type B ADRs
Examples of such ADRs, which are often immunological in nature, include drug-induced hepatic or renal damage, bone marrow suppression, carcinogenesis and disordered fetal development. Uncommon but severe unpredictable adverse effects that have been mentioned in earlier chapters include aplastic anaemia from chloramphenicol and anaphylaxis in response to penicillin. They are usually severe – otherwise they would go unrecognised – and their existence is important in establishing the safety of medicines. The unpredictable nature of such reactions means that adjustment of the recommended therapeutic regimen (e.g. using a lower dose) may not prevent them.
Outline the classification for 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
Many serious ADRs are totally unexpected eg Herceptin
and cardiac toxicity
What is meant by aplastic anaemia
Total bone marrow failure
Describe angioedema
Similar to anaphylaxis:
Swelling of lips and tongue, heart failure, breathlesness to bronchoconstriction.
Nowadays, what are all anti-cancer drugs tested for
cardiac toxicity
Outline type C ADRs
associated with long-term use
involves dose accumulation
e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
What is the key factor in type C ADRs
how much of the drug has accumulated over time
What is methotextrate used to treat
Immunosupressant
anti-cancer drug
Give an example of some antimalarial drugs
Chloroquinolone and hydrochloroquinolone
Outline the type D classification of ADRs
delayed effects (sometimes dose independent) carcinogenicity (e.g. immunosuppressants) teratogenicity (e.g. thalidomide)
Outline the type E ADRs
End of treatment side effects. BDP = benzodiazepines.
§ Withdrawal reactions – patient cannot make endogenous supply – opiates (cold turkey reaction), corticosteroids, BDPs.
§ Rebound reactions – disease gets worse when drugs stopped – clonidine, b-blockers, corticosteroids.
§ “Adaptive” reactions – adapted body reactions to drugs – neuroleptics (tranquilisers). and anti-psychotics for schizophrenia.
Why is it important not to stop prescribing corticosteroids immediately to a patient who has been on them for a long period of time
The patient will have lost the ability to make steroids
Therefore their CVS may collapse after sudden withdrawal.
Describe and explain the clonidine rebound
Clonidine is an alpha-2 agonist so it suppresses the release of noradrenaline
Long-term use of clonidine leads to an upregulation in adrenergic receptors on the post-synaptic membrane
If the dose of clonidine is missed once or twice, it will cause an increase in noradrenaline release, which then acts on an increased number of receptors so has a greater effect
This causes a large increase in blood pressure
Summarise the Rawlins and Thomson classification for ADRs
A Augmented pharmacological effect B Bizarre C Chronic D Delayed E End-of-treatment
Essentially, what are the two types of hypersensitivity reactions
Hypersensitivity reactions of types I, II and III (Ch. 7) are antibody-mediated reactions, while type IV is cell mediated.
Outline the types of allergic reactions
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
What is important to remember about anaphylactic reactions
They are a medical emergency and thus require treatment immediately.
Give examples of pseudoallergies
Aspirin/NSAIDs and bronchoconstriction
• This occurs because aspirin and NSAIDs inhibit the production of prostaglandins, which are bronchodilators and pro-inflammatory -caution when given to asthmatics
• They promote the production of leukotrienes, which are bronchoconstrictors
ACE inhibitors and cough/angioedema
• ACE inhibitors prevent the breakdown of kinins
• Kinins accumulate in the sensory nerves in the lungs and trigger cough
Substitute for another type of drug
More common in afro-carribeans
Angioedema- a milder and non-immunological version of anaphylaxis.
Which four classes of drug account for over 2/3rds of ADRs
Antineoplastics
Cardiovascular drugs
NSAIDs/analgesics
CNS drugs
This is because so many patients are taking these drugs- so the NUMBER is large but the INCIDENCE is small.
List some other drugs which commonly cause ADRs
Hypoglycemics
Antihypertensives
Antibiotics
Antiocagulants
What does ADR frequency increase with
Increasing drug use
Describe the two ways in which we can detect ADRs
Subjective report patient complaint (yellow card scheme)- clinician will then determine whether this ADR is likely (based on his knowledge of the pharmacology of the drug).
Objective report: direct observation of event abnormal findings physical examination laboratory test diagnostic procedure
Explain why rare ADRs will probably not be detected before the drug is marketed
Even is the expected incidence is 1 in 100
You will probably need to see more cases (i.e 300) to pick up one event.
And 650 cases to pick up 3 events.
Summarise 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
Outline what should happen if an ADR is suspected
Try and confirm it (to a high probability)
The try and estimate the frequency
Then report it to the prescribers- who should withdraw the drug overnight if it appears to be a high risk to the patient.
Why are drug interactions almost inevitable
Because of the issue of polypharmacy
Explain why the true incidence of ADRs is difficult to determine
True incidence difficult to determine
Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs
Lack of availability of comprehensive databases (lots of different drug combinations and lots of different patients).
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 is important to remember about statins
Much of the toxicity of statins is due to the combination with other drugs- by enhancing their toxicity by blocking their metabolism.
Outline the 3 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)- things being added to IV. lines that shoudln’t be.
What are the 3 types of pharmacodynamic drug interactions
Additive, synergistic, or antagonistic effects from co-administration of two or more drugs
Additive- drugs result in the same result but work via different mechanisms
Synergistic- one drug potentiates the effect or toxicity of another
Give some examples of pharmacodynamic drug interactions
· Synergistic actions of antibiotics – use of two ABs will increase the effect more than their separate contributions (i.e. 2+2=5) OR they antagonise each other.
Overlapping toxicities - ethanol & benzodiazepines (additive)
Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
Describe how pharmacodynamic drug interactions are often deliberate
B2 agonists and bronchodilators often given to asthmatics- same result- but work via different mechanisms
Additive.
Summarise the different types of pharmacokinetic drug interactions
Alteration in absorption
Protein binding effects (albumin binding)
Changes in drug metabolism
Alteration in elimination
Give an example of an alteration in drug absorption
Chelation
Irreversible binding of drugs in the GI tract to form something insoluble or something that cannot be absorbed
Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
What is meant by protein binding interactions
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
What is a key protein binding interaction to remember
PB interactions are not usually clinically significant
but a few are (mostly with warfarin)
· Warfarin is 99% albumin-bound so anything to decrease that will increase the free warfarin so there is more anti-coagulative effects.
Describe the different paths of drugs for elimination or metabolism
Can be excreted unchanged by the kidney – furosemide (diuretic)
Can undergo phase 1 metabolism in the liver, kidney or gut and then be excreted
Can undergo phase 2 metabolism in the kidney and then be excreted.
What different reactions can occur in phase 1 metabolism
Phase 1 metabolism = oxidation, reduction, hydrolysis.
What reactions occur in phase 2 metabolism and what is its purpose
§ Phase 2 metabolism = conjugation (glutathione, amino-acid), glucuronidation, sulphation, acetylation and methylation.
Convert the drug into a water-soluble polar form (often mean that the drug is ionised).
What can drug metabolism be inhibited or enhanced by
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
Describe CYP450 metabolism by a single isoenzyme
Metabolism by a single isozyme (predominantly)
Few examples of clinically used drugs
Examples of drugs used primarily in research on drug interactions
Describe CYP450 metabolism by multiple isoenzymes
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
Imipramine is an anti-depressant
Which CYP450 enzymes are responsible for over half of drug metabolism
CYP2D6
CYP3A4
CYP 3A4 is the most common in humans
Which CYP450 is responsible for the metabolism of paracetemol
CYP1A2
List some CYP450 inhibitors
Cimetidine (a2 antagonist in peptic ulcers)
Erythromycin and related antibiotics (macrolides)
Ketoconazole etc
Ciprofloxacin and related antibiotics (quinolones)
Ritonavir and other HIV drugs
Fluoxetine and other SSRIs
Grapefruit juice (furanocoumarins- CYP 3A4)
What are the CYP450 inducers
Rifampicin (nati-TB) Carbamazepine (anti-epileptic) (Phenobarbitone) (CNS suppressant) (Phenytoin) (anti-epileptic) St John’s wort (hypericin) (anti-depressant)
Compare the time course of action between CYP450 inhibitors and CYP450 inducers
Inhibitors- instantaneous and rapid effect
Inducers- slow effect- needs to alter mRNA and thus gene expression.
Give some examples of drug elimination interactions
Almost always in renal tubule
- probenecid and penicillin (good)- prevents the elimination of penecillin- so high levels remain in the plasma - lithium and thiazides (bad)- sodium lost at expense of lithium in DCT- lithium builds up- more toxicity
What is lithium often prescribed for
A mood stabiliser
Give some examples of deliberate drug interactions
Levodopa + carbidopa can use lower doses of levodopa as carbidopa reduced peripheral metabolism.
§ ACEi + thiazides treat HF and HTN
§ Penicillin’s + gentamycin treat severe staph. Infections.
§ Salbutamol + ipratropium beta-agonists and anti-muscarinics used in inhalers to treat asthma.
What else is important to remember
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