David Juurlink SMACC Chicago talk 'Drug Interactions That Can Kill (and How to Avoid Them)’ takes us on a journey of drug interactions, case studies, and avoidance strategies.
Juurlink starts by educating us on the two different drug-drug interactions (DDI) - effects of one drug altered by the use of another . First of which is Pharmacokinetic where by one drug alters the level of another, the second Pharmacodynamic being no change in drug levels, and uses this as a basis for his following case studies.
Juurlink speaks of the dreadful literature that is available on the thousands of drug interaction per year, stating that most information comes from case reports and volunteer studies, and suggests that majority of these interaction are avoidable.
Juurlink goes on to discuss the findings of 4 case studies involving the following Drug-Drug Interactions and their effects on the patients.
SMX/TMP + sulfonylureas
Macrolides + digoxin
APAP + warfarin
SMX/TMP + ACEI/ARB
Juurlink provides us with a short list of trigger drugs that we should be aware of, a list of meds that warrant extra caution and list of possible safer alternatives. He also suggests that it is of the up most importance to have a good pharmacist to turn to as they are given more information on drugs interactions then physicians. And, to utilise resources such as pharmacy times - where you can get information on drug interactions at a push of the button.
Juurlink also suggests that an Informed patient is a very useful safety mechanism.
2. Frontmatter
Drug-drug interaction (DDI):
Effect of one drug altered by use of another
Two types
Pharmacokinetic
One drug alters the level of another time ->
Drug B
[DrugA]
3. Frontmatter
Drug-drug interaction (DDI):
Effect of one drug altered by use of another
Two types
Pharmacokinetic
One drug alters the level of another
Pharmacodynamic
No change in drug levels
time ->
time ->[DrugA]
Drug B
Drug B
[DrugA]
4. DDIs -
It’s Mostly Bad News
Bad news:
Thousands of them
Literature: Awful
Terminology: Worse
Can be fatal
Good news:
Avoidable
5. Case 1
72 y.o. woman
Type 2 DM, hypertension
Metformin, glimepiride, chlorthalidone, ramipril
Symptoms of UTI
Rx: SMX/TMP (Bactrim, Septra)
One DS tablet B.I.D. x 7 days
6. Case 1
Day 5:
Confused
GTC seizure
EMS: Capillary glucose low
What happened?
7. The Cytochrome (CYP) P450 System
A group of enzymes
What they do:
Modify some drugs
Substrates
Can be turned off
Inhibitors
Can be revved up
Inducers
% of drugs metabolized
by various CYPs
CYP3A4
CYP2D6
CYP2C9
CYP1A2 other
8. The CYP2C9 Short List
CYP 2C9
Substrates
CYP 2C9
Inhibitors
sulfonylureas SMX/TMP
(S)-warfarin metronidazole
fluvoxamine, fluoxetine
fluconazole
amiodarone
Glimepiride
SMX/TMP
Time
13. P-glycoprotein (P-gp)
Membrane glycoprotein
first identified in chemo-
resistant cancer cells
Expressed in
gut
kidney
bile canaliculi
BBB
14. P-glycoprotein (P-gp)
Membrane glycoprotein
first identified in chemo-
resistant cancer cells
Expressed in
gut
kidney
bile canaliculi
BBB
P-gp:
“natural defense mechanism”
30. Trimethoprim Amiloride
Antibiotic
Admission for ↑K+
O.R. & 95% CI
Co-trimoxazole 6.7 (4.5 to 10.0)
Norfloxacin 0.8 (0.4 to 1.5)
Ciprofloxacin 1.4 (0.9 to 2.2)
Nitrofurantoin 1.1 (0.6 to 2.0)
Amoxicillin (reference) 1.0
Antoniou et al. Arch Int Med 2010
Co-trimoxazole and ↑K+
I underscore that although we think about pharmacokinetic DDIs most often, this is only one type of DDI and that pharmacodynamic DDIs are also s msjor concern. And probably even more common.
I underscore that although we think about pharmacokinetic DDIs most often, this is only one type of DDI and that pharmacodynamic DDIs are also s msjor concern. And probably even more common.
The lists are longer, but shorter is manageable
Pretty much all SUs
Only (S) warfarin is 2C9 (R is 3a4) but S is where the money is
Phenytoin is complex but has some 2C9 and it should probably be under warfarin
An example of a real world study, from my thesis.
I often tell people
The translation of this is that IF you have an older patient on glyburide and you Rx Septra, their risk of hospital admission FOR hypoglycemia in the next 7 days is about 5 to 6 times higher with Septra than with Amox
Surely someone will guess this
You might want to shorten this list / lose the HIV stuff. Up to you
I made this case up.
Maybe you want to tweak it
Clearly doe s not happen to some people (many)
Expression varies
I have seen several instances of INR > 6 with APAP < 4 g per day
Maybe influences by GSH, 2e1 activity, Gilbert’s disease, who knows
But bottom line is that it is wrong and dangerous to assume APAP is safe in a patient on warf
Clearly doe s not happen to some people (many)
Expression varies
I have seen several instances of INR > 6 with APAP < 4 g per day
Maybe influences by GSH, 2e1 activity, Gilbert’s disease, who knows
But bottom line is that it is wrong and dangerous to assume APAP is safe in a patient on warf
Amio – 2C9
Abx
- any, by virtue of gut vitamin K (you can make a case for closer INR monitoring in anybody starting Abx while on warf)
- Septra and Flagyl have dual issue of 2C9 inhib
- Paper not yet submitted looks at RR of UGI bleed in patients on warf
Septra ~ 4 fold risk
Other UTI drugs zero to minimal increae risk
The APAP interaction should make people sit up and listen
I think Septra was the last straw here
Cartoon makes a joke about Drug A x Drug B. The reality is that patients often have multiple drugs and diseases that conspire together
Short list for ER docs should be antibiotic heavy.
Short list for ER docs should be antibiotic heavy.
Short list for ER docs should be antibiotic heavy.