Interactions that really matter - and how to manage them

Interactions that
really matter and how to
manage them
Dr Tana Fishman
Department of General Practice and Primary Health
Care, University of Auckland
Linda Bryant
Clinical Advisory Pharmacists Association
Burning issues
Real Life 1
ƒ Please note down one or two ‘burning
issues’ that you came to this session
with that you wanted addressed
Real Life 2
Real Life 3
1
Real Life 4
Real Life 5
Real Life 6
Real Life 7 – a SINGLE patient
Drug – drug interactions
Interactions background
ƒ When the effects of one drug are changed by the presence of
another drug
ƒ Reduces the effect of the ‘target drug” (the drug already there)
ƒ Increases the toxicity of the target drug – often perceived as an
adverse effect of one of the drugs because of increased drug
concentrations
ƒ Range of effects between useful, clinically trivial, increased
morbidity, and fatal
ƒ Variability between individuals makes prediction of absolute
effect very difficult – focus on harm minimisation
ƒ Incidence – up to 10% depending on classification – but
severity of outcome less predictable
ƒ Pharmacodynamic interactions
ƒ Additive effect of similar medicines, or cancelling effect
ƒ Increasing risk of hypotension with
ƒ Two antihypertensives
ƒ An antihypertensive + TCA
ƒ Increasing renal impairment with
ƒ ACE Inhibitor, diuretic and NSAID
ƒ Pharmacokinetic interactions
ƒ Primarily interference with:
ƒ Absorption
ƒ Tetracycline and food, calcium
ƒ Metabolism by enzymes e.g.
ƒ Cytochrome P450
ƒ P-glycoprotein
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Cytochrome P450 enzymes
ƒ In liver, intestines, kidney, lung, brain
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CYP 3A4
CYP 2D6
CYP 2C19
CYP 2C9
CYP 2E1
CYP 2B6
CYP 2A6
CYP 1A2
% drugs
Individual
metabolised
variation
~ 36%
5 - 8 fold
~ 19%
> 50 fold
Polymorphism
P-Glycoprotein (p-gp)
ƒ In intestines, brain, kidney and liver
ƒ Works to ‘pump out’ toxins
ƒ Digoxin is a substrate and quinidine an inhibitor … so if
quinidine inhibits p-gp, more digoxin is absorbed from the
intestine
ƒ If p-gp is inhibited in the kidney, where p-gp tries to excrete
digoxin, more is retained
ƒ P-g prevents drugs crossing the blood-brain barrier - so
inhibition may cause drugs like loperamide to have CNS
effects
5 - 10% Euro
3 - 5% Euro, 15-20% Asian
5 fold
1 - 3% Euro
12 fold
20 fold
Managing interactions
Work time
ƒ Risk assessment
ƒ What is the interaction?
ƒ Is it important?
ƒ How can it be managed?
ƒ How common is the interaction?
ƒ How severe will the interaction be if it occurs?
ƒ Is it a dose-related interaction?
ƒ Management
ƒ An alternative, non-interacting drug
ƒ Stop the target interacting drug temporarily
ƒ Reduce the dosage of the target drug
ƒ Monitor with
ƒ Investigations – INR, blood pressure, liver enzymes
ƒ Clinically – dizziness, muscle aches
Scenario 1
Scenario 2
Mr A, a 76 year old man was investigated for a cough and
breathlessness before an elective operation. His medicines
were:
A 74 year old woman had a history of hypertension and
acute coronary syndrome for which she was taking:
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Metoprolol
Aspirin
Cilazapril
Simvastatin
Omeprazole
Paracetamol
Naproxen
Temazepam
95 mg daily
100 mg daily
2.5 mg daily
60 mg nocte
10 mg mane
1gm tds
750mg daily
10mg nocte prn (about twice a week)
The investigation found an invasive respiratory fungal infection
for which itraconazole 400mg daily was required for 6 to 12
months.
Simvastatin
Aspirin
Diltiazem
Inhibace Plus®
40 mg nocte
100 mg daily
90 mg daily
5 mg / 12.5 mg daily
Her osteoarthritis is severe and regular paracetamol is
inadequate, even with codeine. She is started on
naproxen SR 750mg daily
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Scenario 3
Scenario 4
A 59 year old woman has severe CVD requiring:
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Chlorthalidone
Simvastatin
Enalapril
Candesartan
Isosorbide mononitrate
Metoprolol
Aspirin
Omeprazole
25 mg daily
40 mg daily
20 mg daily
16 mg daily
60mg daily
47.5 mg daily
100mg daily
20 mg daily
She is allergic to penicillins (rash) and felodipine (swollen
ankles).
She presented with likely atypical pneumonia for which one
week of erythromycin 800mg twice daily was prescribed.
Scenario 5
A patient with taking metformin 500mg twice daily
for impaired fasting glucose developed angina
and mild hypertension. When metoprolol
23.75mg was prescribed the computer beeps
with a warning of an interaction
A 79 year old woman had severe IDH, with two previous
myocardial infarctions. Post-operatively (CABG) she
developed atrial fibrillation and was initiated on warfarin.
Her regular medicines became:
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Metoprolol
Felodipine
Inhibace Plus®
Aspirin
Warfarin
Calciferol
GTN spray
23.75 mg
5 mg daily
5mg / 12.5 mg daily
150 mg daily
mdu (2 to 3 mg daily usually
50,000 iu monthly
prn
Scenario 6
An 83 year old man has IHD, heart failure and atrial
fibrillation.is on:
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Carvedilol
Quinapril
Frusemide
Digoxin
Aspirin
Isosorbide mononitrate
Omeprazole
Paracetamol
GTN
12.5 mg twice daily
20mg daily
80 mg daily
0.125 mg daily
100mg daily
60 mg daily
20 mg daily
prn
prn
The cardiologist has just started amiodarone, 200mg three
times daily for one week, 200mg twice daily for one week
and then 200mg daily
Scenario 7
A 47 year old woman with Bipolar Affective Disorder is well
managed on lithium 400 mg twice daily (serum concentration
maintained at 0.6 to 0.8 mmol/L), and fluoxetine 20mg daily.
When screened for her cardiovascular risk it was found that
she had blood pressure of 152 / 98 mmHg, and a disturbed
lipid profile that, in conjunction with her family history of
cardiovascular disease, put her at a greater than 15% risk of
a cardiac event in the next five years. Despite five months of
lifestyle alteration, the cardiovascular risk remained high.
Over the next three months it was determined that she could
not tolerate β-blockers (extreme fatigue) or calcium channel
blockers (headache, swollen ankles). Having already
prescribed simvastatin 20mg at night, what are your next
steps?
Scenario 8
A 27 year old woman is being treated with
paroxetine 20 mg daily for depression. She also
experiences severe migraines that have
responded only marginally to prophylactic
treatment. She still gets one to two debilitating
migraines every month. Having tried most other
options, she now wants sumitriptan.
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Scenario 9
A 71 year old woman with diabetes peripheral
neuropathy has been using amitriptyline 50 mg
at nigh to very good effect for neural pain. She
now presents with depression and although CBT
is to be instigated, there is a clinical need for an
antidepressant. Fluoxetine 20mg daily is to be
introduced.
Scenario 10
A 19 year old male had difficult to control seizures. He
had recently had phenytoin 450 mg daily added to his
regime of valproate 1.2 gm twice daily, but had had
another brief seizure. His valproate serum
concentration was 280 μmol/L (350 – 700 μmol/L) and
his phenytoin concentration was 82 μmol/L (40 – 80
μmol/L). His valproate dosage was increased to 1.5
gm in the morning and 1.2 gm at night. He became
very lethargic, ataxic and felt ‘muddled’. His serum
concentrations two weeks after the dosage increase
were valproate 210 μmol/L and phenytoin 110 μmol/L.
Real life - 8
Thank you
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