1. The management of adverse drug reactions I Ralph Edwards
Diagnosis
Procedures
Management
Therapy
Often no clear separation...

2. The management of adverse drug reactions
Is the patient taking drugs?
OTC OC
Herbal/traditional
Abused drugs
Long term prescription
Check with medical history

3. A patient
An 81 year old man with an old valve replacement and recent heart failure.
Digoxin mg daily
Warfarin 4mg daily
Frusemide 80 mg daily
Potassium supplements

4. The patient
Develops a deep bleeding ulcer
Eventually looks like this:

5. The management of adverse drug reactions
Could the symptoms and signs be due to drugs?
Yes!
When there is polypharmacy, this becomes difficult
WHICH DRUG?!

6. The management of adverse drug reactions
How serious is the patient's clinical state?
If very serious:
Stop all drugs which may POSSIBLY cause condition
Treat, as necessary
Consider step-wise re-introduction, later
If not serious:
Proceed logically

7. Patient Diagnosis Possible bleeding tendency: over-anticoagulated
Een heel andere vorm van necrose van de huid door een geneesmiddel. Het is al heel lang bekend dat het gebruik van cumarine anticoagulantia in zeldzame gevallen wordt gecompliceerd door het ontstaan van grote necrotische plekken, met name van adipeuze gebieden zoals mammae of nates. Microscopisch ziet men vooral trombosevorming in de kleine bloedvaten. Men heeft lang gedacht dat het om een immunoallergische reactie ging (een ‘Schwartzmann Sagnarelli reactie’). Niet daarbij passend en onbegrepen was waarom deze complicatie meestal al tijdens de eerste dagen van de toediening ontstaat. Tegenwoordig weten we dat cumarinederivaten bij patiënten met een (erfelijk) tekort aan proteïne C in het plasma (een trombolytische factor die ook vitamine K afhankelijk is) eerst een korte periode van toegenomen coagulabiliteit veroorzaken, met een kans op ‘spontane’ vaatafsluiting en necrose. Waarom het voornamelijk de adipeuze huidgedeelten betreft is nog niet opgehelderd. De dia toont een vroeg stadium bij een adipeuze vrouw. Na korte tijd werd het hele aangedane gebied necrotisch en ontstond een groot gat dat met behulp van plastisch-chirurgische operaties moest worden hersteld
Ron: was dit niet de fixed drug eruption van Marcel op noroxin??

8. Patient
Action
Stop warfarin
Check prothrombin ratio

9. The management of adverse drug reactions
Time relationships
Do they make sense?
Drug before disease?
Timing of drug and reaction?
Kinetics-steady state
Withdrawal reaction?
Allergy type
Previous exposure?
Pregnancy stages
Neoplasia kinetics

10. The management of adverse drug reactions
YES,BUT WHICH DRUG?
Known pharmacology
Of single drug
Of class
Known idosyncracy

11. Patient
Prothrombin ratio normal and patient has been stabilised for a long time
New diagnosis
Possible coumarin necrosis
During chronic treatment?

12. The management of adverse drug reactions
Are there any special tests which may help?
Blood levels of medicines (therapeutic monitoring)
Other clinical tests to help establish
The disease entity eg. allergy testing, skin biopsy
Baseline state eg. liver and kidney function
Follow up of response following discontinuation of medicine or reduction of dose

13. Patient Consider skin biopsy
Result likely to be available in two weeks !

14. The management of adverse drug reactions
Now decide the likelihood of patients condition being drug related
Frequency, related to drug(s) versus background
With sound clinical benefit/risk judgement decide to stop relevant drug(s)

15. Patient
Could these be emboli with infarction and ulcer due to failed anticoagulation ?
Septic emboli ?
Both unlikely explanations

16. The management of adverse drug reactions
BUT THE PATIENT REALLY NEEDS SOME OF THESE DRUGS!
Try some options:
Stop non essential drugs
Consider dose - reduce where suitable
Consider interactions
Stop those likely to be causing serious reactions and whose benefit/risk balance in this situation is not good

17. Patient
Patient needs anti-coagulation, so start heparin until biopsy result available
N.B. Patient stays in hospital because he cannot manage injections and no short term support can be arranged

18. The management of adverse drug reactions
NOW WHAT?
Wait (dechallenge)
Is it plausible in onset and duration?
Patient is improving/well
Start alternative therapy if necessary
Report your suspected ADR, if 'interesting'

19. The management of adverse drug reactions
THE PATIENT IS NOT WELL
Sorry, wrong drug!
Try the next most likely drug(s)
Sorry, patient cannot manage without this drug
Try a suitable substitute
Watch cross reaction of any sort!
Could try re-instituting same drug
If you stopped more than one, and one seems to be essential
At lower dose?

20. Patient
Patient is certainly NOT well. He develops several more very painful bleeding ulcers

21. The management of adverse drug reactions
THE PATIENT IS STILL NOT WELL
Well, it's possible that you will have to treat this reaction
In fact there are some ADRs that you should have treated ages ago
Eg. Anaphylaxis
Syncope
There is a need to manage the patient clinically !!

22. Patient
Start paracetamol for pain

23. The management of adverse drug reactions
When treating an ADR:
Do not confuse the picture unnecessarily!
Have a clear objective
Do not treat for longer than is necessary
Review patient

24. Patient Pain very severe Start morphine
Biopsy result surprisingly available and shows vasculitis with much bleeding

25. The management of adverse drug reactions
Finally:
Reconsider interactions
Consider rechallenge for drugs which are or will be important to the patient
Ethics
Same dose? Same route?Same preparations?
Safeguards!
Send in report

26. Patient
Frusemide considered as cause of vasculitis with bleeding super-imposed because of anti-coagulation
But consider long ½ life of Warfarin
Frusemide stopped
Pain continues

27. Patient
The dose of morphine is increased and mild heart failure occurs
This is followed by bronchopneumonia
And the patient dies in a few days
of a morphine adverse reaction?

28. The management of adverse drug reactions
Potassium supplements
Frusemide 80 mg daily
Warfarin 4mg daily
Digoxin mg daily
A 76 year old man with an old valve replacement and heart failure.
THE END