23: Adverse Drug Reactions Flashcards
How can you classify adverse drug Reactions?
According to their
- onset
- severity and
- Type A-E
How can you classify ADR (adverse drug Reactions) according to their Onset
- Acute
- Within 1 hour
- Sub-acute
- 1 to 24 hours
- Latent
- > 2 days
How can you classify ADR according to their severity?
- Mild
- requires no change in therapy
- Moderate
- requires change in therapy, additional treatment, hospitalisation
- Severe
- disabling or life-threatening
What are the main characteristics and problems with Severe ADR?
- Results in death
- Life-threatening
- Requires or prolongs hospitalisation
- Causes disability
- Causes congenital anomalies
- Requires intervention to prevent permanent injury
What are type A Adverse Drug Reactions?
- extension of pharmacologic effect –> when you look at effect you can kind of guess what the ADR will be
- 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
Explain the characteristics of Type B ADRs
- idiosyncratic (only occur in some people with unknown cause) 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 –> Show how little we often know about drug mechanisms
Explain the Characteristics of Type C ADRs
•Type C
- associated with long-term use
- –> involves dose accumulation
- e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
Explain the characteristics of Type D ADRs
Delayed effects (sometimes dose independent)
- carcinogenicity (e.g. immunosuppressants)
- teratogenicity (disturb embriological developemnt) (e.g. thalidomide)
Explain the Characteristics of Type E ADR
When stopping the drug:
- Withdrawal reactions
- Opiates, benzodiazepines, corticosteroids
- Rebound reactions
- When stoping the drug the situation will be worst than the time you started
- Clonidine in HTN, beta-blockers, corticosteroids
- When stoping the drug the situation will be worst than the time you started
- “Adaptive” reactions
- Neuroleptics (major tranquillisers) (drug might develop e.g. a tremor as reaction to drug that gets worse when withdrawling the drug again)
How can you classify the different types of ADR (MNemonic for the different types
A Augmented pharmacological effect
B Bizarre
C Chronic
D Delayed
E End-of-treatment
What are pseudoallergies?
Which Role do they play in the ADR?
Pseudoallergies are no allergies (not IgE mediated) but pharmacological interactions –> might e.g. lead to a direct stimmulation of mast cells (no sensitisation required)
E.g.
- Aspirin/NSAIDs – bronchospasm
- ACE inhibitors – cough(15-20%)/angioedema (1%), not immunulogical and normally less severe than anaphylaxis (but in case of angiooedema: might also be fatal)
Explain the correlation between numbers of perscribed drugs and ADR
Not surprising: the more Drugs are perscibred, the more ADR can be seen
Which Drugs Classes cause the most ADRs?
Why?
Mainly because they are very common drugs (commonly perscribed so high numbers but relativels low incidence)
- Antibiotics
- Antineoplastics*
- Anticoagulants
- Cardiovascular drugs*
- Hypoglycemics
- Antihypertensives
- NSAID/Analgesics*
- CNS drugs*
*account for two-thirds of fatal ADRs
How can you detect ADRs?
- Subjective report
- patient complaint
- Objective report:
- direct observation of event
- abnormal findings
- physical examination
- laboratory test
- diagnostic procedure
Why can drugs that casue ADR still be marketed?
- Often ADR are not known before marketing (expecially rare ones –> sample size just are not big enough)
- (still might have necessary effect)
What is the yellow card scheme?
A way to detect and Monitor ADR
- voluntary report of
- serious side effect for estabished drugs
- any ADR for drugs in black triange (<2 years after licensing)
- ADR can be reported by everyone
When a ADR in a newly perscribed (or established drug) is suspected: what would be the further process of investigating this?
- Suspected ADR
- Try to confirm (high propability)
- Estimate frequency
- Accordingly: inform perscriber (or might even lead to withdrawl from market)
What are the problems that might occur in the assesing of the incidence of Drug-Drug interactions?
- very complicated to determine (basically impossible/unknown in complicated patients)
- Difficulty in assessing OvetTheCcounter and herbal drug therapy use
- Therefore
- Lack of availability of comprehensive databases
- Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs
What types of Drug-Drug interactions might occur?
There might be:
- Pharmacokinetic
- e.g. receprot site occupancy
- Pharmacodynamic and
- ADME
- Pharmaceutical drug-drug interactions
- outside the body
What is a pharmaceutical Drug-Drug interaction?
drugs interacting outside the body (mostly IV infusions) –> when giving several medications into an IV infusion bag–> might interact with each other
What are pharmacodynamic drug drug interactions?
They alther the effects at the site of action:
- Additive (Drug1+Drug2= Effects of Drug 1+2) (overlapping toxicities of Benzodiazepines and E2)
- synergistic (parts are working together to enhance their effect) (Drug 1+Drug3= Effects of Drug 1+3 +additional effects) (e.g. ABX)
- or antagonistic effects from co-administration of two or more drugs (amitriptyline and acetylcholinesterase inhibitors)
What are the general sites where Pharmacoinetic Drug interactions can occur?
Interactions can change the … of one or more drugs
- Alteration in absorption
- Protein binding effects
- Changes in drug metabolism
- Alteration in elimination
Explain how Drug-Drug interactions can lead to an alteraltion in Absorbtion
E.g. Chelation
–Irreversible binding of drugs in the GI tract that then form e.g. an insoluble precipitate
–Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
Explain how protein binding interactions can lead to drug-drug interactions
Plasma Protein Drugs can be displaced from other drugs which bind to the same PP –> increase the active dose
- (thougnt to be very important put turns out they are not actually)
- But which is relevant: E.g. Warfarin
Explain how Drug Drug interactions may interefere with Drug Metabolism
E.g. via using the same enzymes for Metabolism. Expecially important: Cytochrome P450
- Though most drugs are metabolised by several P450 enzymes, if other isoforms are inhibited the active one might still metabolise more but no guarantee
- There are known Enzyme Inhibitors and Ezyme enhancers
Name some P450 inhibitors
- Cimetidine (anti-histaminicum)
- Erythromycin and related antibiotics
- Ketoconazole (anti-fungals)
- Ciprofloxacin and related antibiotics
- Ritonavir and other HIV drugs
- Fluoxetine and other SSRIs
- Grapefruit juice
List typical P450 emzyme enhancers
- Rifampicin (ABX)
- Carbamazepine (anticonvulsant)
- (Phenobarbitone)(barbiturate)
- (Phenytoin) (anti-convulsive)
- St John’s wort (hypericin)
How fast du enzmyme inhibitors or P450 enhancers normally take to show their effect
(Not necessarily wanted but)
Inhibition is very rapid
Induction takes hours/days
Explain the role of drug-drug interactions in excretion
Almost always in renal tubule
Can be wanted and unwanted
- probenecid and penicillin (good) –> prolong effect and concentration of Penicillin in body (wanted when it was expensive)
- lithium and thiazides (bad) (might lead to lithium poisoning
Name some examples where drug-drug interactions are wanted and therapeutically ecploited
- levodopa + carbidopa
- ACE inhibitors + thiazides
penicillins + gentamicin
salbutamol + ipratropium
Who runs the yellow card scheme?
Medicines and Healthcare Products Regulatory Agency (MHRA)
How many people do you need to see to see 1) one 2) three ADR with an incidence of 1:1,000
1) one= 3.000 (x3)
2) three: 6.500 (x6.5)
