Polypharmacy
and
drug interactions
Polypharmacy
Polypharmacy indicates – using of
unnecesary drug, treatment longer then optimal
period, using over then optimal dose
= overuse of drug(s)
Consequences of polypharmacy:
 Increasing frequency of adverse drug reaction (ADR)
 Increasing frequency of drug interactions.
 Increasing possibility of iatrogenic harm.
 Decreasing patient–compliance as result of complicated
terapeutical regimen.
 Increasing therapeutical costs (farmacotherapy costs and
possible costs of terapeutical harm, e.g. hospitalisation).
Reasons for polypharmacy
1. doctor
a) Low respect of recent therapeutical guidelines.
b) Influence of pharmaceutical lobby (promotion,
bribes/corruption)
c) Respect to patients´will, induced prescription
d) Absence of effective therapy, doctor using
psychological effect of „placebo“
2. Patient
a) Polymorbidity - only acceptable way to polypharmacy
b) Wrong compliance to therapy
– only 11 % of patients precisely respect therapeutical
regimen
– 56 % patients have adequate compliance (they use
more than 80 % doses of their drug)
– the rest (33 %) presents factual non-compliance
(patient use less than 80 % doses of drug) (prof.
Smečka, 2000)
c) Increasing numbers of somatising patients
(hypochondriacs)
ad 2. Patient
Polypharmacy is problem at first in elderly
patients.
Main source? = frequently polymorbidity
In the Czech rep. 17 % people older than 65; they
use more than 50 % prescribed drugs.
Demographic progress escalated to deficiency of
healt insurance systems all over the world!
3. Effects of pharmaceutical business
a) Directly to patients – promotion (TV, press,
net…)
b) To medicians (pharmacists) – congresses,
bribes?
c) Lobbing to government institutions (e.g. drug
payment)
4. National health system, health insurance
a) Number of medicinal providers; increase of
medicians is the reason to increase the
prescription.
b) A lot of specialists and low cooperation is the
reason to increase numbers of using drugs with
often contradictory effects.
c) Patient-friendly funding lead to overuse of health
(pharmaceutical) care.
5. Deficient communication between providers and
patient
Non-effective communication chain
Doctor → Nurse → Pharmacist → Patient
Many partners without central management of
information stream.
patient
pharmacistmedic
Communication is Intersection
Inadequate communication with elderly
Seniors perceived as „gray wave“
↓
Gerontofobia
↓
Reducing the frequency and quality of
communication
↓
Lower quality of care
Disorders of perception
90 % seniors - decrease in visual perception
30 % worsens hearing (mostly presbyacusis =
hearing loss)
± lower intellectual abilities (decrease speed of
decision)
Seniors and health literacy?
Health literacy - ability to understanding
fundamental health information as a basis to
adequate decision.
e.g. information leaflet ?!
→ need to communicate clearly with everyone
→ confirm understanding with everyone
Choice of appropriate terminology and content!
Excellent health literacy only by 12% of the
population - health professionals,
enlightenment chronics, grumblers ☺
↓
Need for public verbalization health problems
„You have to explain like to own grandmother"
Let us express the layman:
interaction
contraindication
generics
take on an empty stomach
enteric-coated tablet
myorelaxans
Another problematic terms?
Understanding dispensation low
Only 52% of patients correctly interpreted the
recommendations „enjoy every 8 hours“!
The Pharmacy Intervention for Limited Literacy Study 2007
What recommendation would be more
appropriate?
 Forward important information, but not to overfill
patient – depends on index of drug information
(information needed to safety use of drug)
 Alert for drugs that the patient does not use
regularly (e.g. antibiotics, expectorants, pain
medication)
 "Teach-back" for products declared as known
 Adapt informations to understanding of the
patient (e.g. not analgesic, but the pain reliever
...)
 Explain the patient how his drug works, if it
has any meaning (e.g. diuretics → increase
urine production = more frequent urination ...)
Complementary problems of polypharmacy
1) Non–compliance
The therm non–compliance means intentional or
unintentional sabotage of recomended therapy.
Source of decreased therapy efficiency, with a lot of
negative consequences (clinical, psychological,
economical…)
Impacts of non-compliance:
 clinical (uneffective therapy, increase of ADR,
intoxication)
 psychological (stress in relationship patient –
medic, mistrust, wrong communication)
 economical (increase therapy costs, decrease
effectivity of medical service)
Types of therapeutic non–compliance:
1st. – Patient dont´ get drug.
In social systems in EU is this secondary problem,
Problem? Strictly economic-oriented states (USA,
China etc.) Possible 20 % patients without drugs.
Economic crisis and future in EU???
2nd. – Misunderstanding treatment rules? Sabotage
rules? The core is in communication of
patients´problem → need to upgrade
patients´motivation.
Formation pharmaceutical care to health couching
2) Drug error
Drug error definition: undesirable mistake of
healthcare chain: doctor – nurse (paramedic) –
pharmacist.
Many potential conflict points: prescription,
preparation, dispensation of drugs (patient
education), service/administration, etc.
To greatest risk are exposed patients with
polypharmacy – exponential risk increase,
which depends on number contemporary
using drugs.
Risk management – way to reduce problematic
points of therapy
identification risk → prevention risk
Progress of medicine and pharmaceutical
scieces
With progress of sciences we can use more
and more new drugs (problem to investigate)
vs
Clinical studies and new guidelines for
safety and effective therapy management
(answer to practice).
Risk of drug interactions
Study of emergency cases (Goldberg, USA)
 target group – patients with two and more
together using drugs
 target parameter – potencional risk of drug
interactions
 results: 47 % of patients were endangered with
risk of drug interaction. Incidence of drug
interactions increased from 13 % for two drugs
till 82 % for seven and more drugs.
By more then 50 % patients were drug
interactions main reason to emergency
visit!
Attention
General practice (Hanlon, 2002)
target - epidemiological study focused to general
practice and incidence drug interactions by elderly
patients (more 65 years)
findings – total incidence 13 % of potential drugdrug
or drug-disease interactions!
– moreover, 11 % of patients used their drugs
longer than optimal period or used inadequate
doses! (they are underdosed or overdosed).
Drug interactions increase risk of
hospitalization (Doucet, USA)
result: at least 6 % of all hospitalizations in US
were straight caused by drug interaction
(billions USD expenditures)
Moreover, twice frequent are harms and manifest
disorders due to drug interactions.
Bedell et al. (2000) – more together
participate medics caused significant increase of
drug interactions.
reasons – duplicate therapeutic interventions
– medication with opposite effects
Prescribing medic often hasn´t accurate
information about participation other medics on
therapy
76 %! of personal health documentation at
registers of cardiologists and internists contains
incorrect pharmacotherapeutic informations.
Significant common points of this mistakes were
higher patients age and associated
polypharmacy.
Procentual incidence of drug interactions
70,7
85,7
69,2
74,2
78,3
65
70
75
80
85
90
5 6 7 8+ Sum
Number drugs
Incidence
Interaction
Number drugs 5 6 7 8 + Sum
Number patients 39 41 23 21 124
Patients with interact. 27 29 18 18 92
Incidence (%) 69,2 70,7 78,3 85,7 74,2
ÚAF FaF Brno, 2005
Distribution drug interactions according to ATC groups
4,64%
0,50%
0,50%
2,63%
0,13%
55,14%
13,91%9,65%
12,91%
A – GIT, metabolism
B – blood system
C – cardiovascular system
H– systemic hormones
J – systemic antiinfectives
M – musculosceletal system
N – CNS
R – respiratory system
V– varia
Study ÚAF FaF Brno, 2007
172 patients used 5 and more drugs
Mechanisms of drug interactions
For simple and rapid (effective) identification
of drug interactions is useful to remember some
basic principles
let's summarize them
Modulated absorption
– drug absorption can be altered by using other
pharmacological or physical substance at the
same time
– model example can be tetracycline with Ca,
Mg,.. ions or antacids.
Other often used substances with absorption
principle - charcoal (activated coal), psyllium
Changing GIT motility by one of using drugs
– quite often unidentified mechanism of drug
interactions
– gastrointestinal motility deceleration leads to
slower absorption other drugs and delayed start of
their effects (e.g. opiates, loperamid)
– gastrointestinal motility acceleration leads to
faster absorption or elimination (e.g. prokinetics
and some laxatives)
Changing of gastric acidity
– by changing of gastric acidity is modulated
disociation drugs (weak acids or bases)
– impact on disolution enterosolvent peroral drug
forms → cause premature disolving drug form
→ gastrotoxicity
→ deactivation of drug (e.g. digestive enzymes)
– important because of frequently use gastric acid
inhibitors (e.g. omeprazole, ranitidine…)
Changing distribution parameters
– most often situation is modificate relation drug to
binding plasmatic albumine. Mechanism is
competition for binding capacity this protein
fraction of blood plasma.
– result is increase free fraction drug, which is
responsible for main pharmacological effect
– clinical importance has this interaction by drugs
with strong binding to albumine, and on other
hand with close therapeutic profile.
well-known example = warfarin + NSAID –
minor change free fraction of warfarin can
caused increase INR (Quick test) and this way
risk of fatal hemorrhage (bleeding).
– by drugs without close therapeutic profile
(safety drugs) is complication faster clearance.
This situation cause, that drug is faster
eliminated and to adequate therapy we have to
use higher doses.
Fraction binding to albumine creates depot,
which can supply therapeutic needs for longer
time.
If depot function is impaired, biological
halftime is reduced all at once with effectivity
of pharmacotherapy.
Changing of metabolism drugs
Most clinical significant group of drug
interactions.
Crucial is in this metabolic way family of
cytochrome P450 (CYP450).
In human genome were found at least 59
cytochromes P450.
The most important are CYP3A4 a CYP2D6.
Cytochromes P450 are responsible for
majority of drug metabolism (its´ estimated at
least 55 %).
Highest levels have P450s in liver, but they
are represented all over body - GIT (small
intestine), lung, kidneys, brain…
More than 50 % drugs are metabolized by way
the CYP3A4!
This cytochrome is also most frequevent
form, in human liver represent 30 % contained
cytochromes.
Importance CYP3A4 represents by elderly
patients, because his activity decreases with
every decade by 8 %.
A lot of drugs have potencial to induce
CYP3A4 activity (e.g. dexametasone,
barbiturates, BZD). Result is faster metabolism
drug, which is substrate of this cytochrome.
On other hand, we can often observe
competition different drugs for binding place
of enzyme – result is slowdown of metabolism
both.
We can investigate two extremes:
- failure therapy – low concentration of drug
- toxic harm – high concentration of drug
Main inhibitors CYP3A4:
 macrolide ATB – erytromycine,
claritromycine, roxitromycine (azitromycine
using other metabolic way; no interaction)
 azol antimycotics – mostly clotrimazole,
ketoconazole
 bergamotine and his derivates (grapefruit) –
deactivates only small intestine fraction
CYP3A4 (cause higher intake of drug). Liver
fraction without impact.
Other examples at table 1.
Main inductors CYP3A4:
 rifampicin (ATB, antituberculotic)
 fenytoin (antiepileptic)
 karbamazepin (antiepileptic)
 fenobarbital (antiepileptic, hypnotic)
 hyperforin (Hypericum perforatum,
antidepressant)
Most often
significant
interactions
CYP3A4
Second significant cytochrome is CYP2D6,
which funkcion we estimate 25 % metabolised
drugs.
Conditions are complicated by the way of
genetic polymorphism, which can significantly
change metabolic operations. This fact worsens
study of potential drug-drug interaction risk.
In present time we can calculate (based on
studies), that european population (with Caucasus
progenitors) contains 7 % slow metabolisers (this
lead to increase of plasmatic drug concentration).
On other hand, east Asian population contains about
50 % slow metabolisers!
Little satisfaction – based on recent studies isn´t
CYP2D6 inducible.
Typical substrates are some antidepressants and βblockers,
in which we can observe the most of
interactions.
Most important substrates and inhibitors of
CYP2D6 are contained in table 2.
Most often significant interactions CYP2D6
Substrates CYP2D6
Typical inhibitors
CYP2D6
Ajmalin
Amitriptylin
Bufuralol
Bupranolol
Cinarizin
Citalopram
Debrizochin
Deprenyl
Dezipramin
Dextrometorfan
Dexfenfluramin
Enkainid
Flekainid
Fluoxetin
Fluvoxamin
Flunarizin
Flufenazin
Galantamin
Haloperidol
Hydrokodon
Chlorpromazin
Imipramin
Kaptopril
Klomipramin
Kodein
Melperon
Metipranol
Metoxyamfetamin
Metoprolol
Mexiletin
Mianserin
Nortriptylin
Ondansetron
Paroxetin
Perhexilin
Perfenazin
Propafenon
Propranolol
Risperidon
Spartein
Tioridazin
Timolol
Tramadol
Trifluperidol
Tropisetron
Tomoxetin
Venlafaxin
Amiodaron
Buproprion
Celecoxib
Cimetidin
Difenhydramin
Doxorubicin
Fluoxetin
Chinidin
Chlorpromazin
Klemastin
Klomipramin
Kokain
Levomepromazin
Metoklopramid
Metadon
Mibefradil
Moklobemid
Paroxetin
Perfenazin
Ranitidin
Ritonavir
Sertralin
Terbinafin
Changing of drug elimination by kidney
Two drugs can compete to secretory
mechanism. Result of this situation is slowdown
of elimination, increase drug(s) concentration and
this way increase risk of toxic harm.
Change of pH of urine can cause slowdown
elimination too. Alkalisation of
urine decreases elimination of drugs on the
base of weak bases and conversely.
Problem of this interaction is the most significant by
elderly patients. The reason is, that this patients
have lower glomerular filtration and often lower
drinking regimen.
Optimal drinking regimen?
Farmacodynamic interactions
Caused by aditive/synergic, or on other hand
antagonistic effects of drugs
Frequently we don't understand this relations exactly
→ increase risk ADR, side effects
X
These effects are often used, because combination
of two or more drugs can be more effective or
safety than higher dose of one drug (therapy of
hypertension, diabetes NID, painful conditions…)
Issues of natural products in therapy
Todays trend in self care medicine is comeback to
the nature products.
Often patients underestimated potential risk –
„nature is holy, perfect, safety…“ Botulinum
toxine? Viperatoxine? St. John's Wort?
Other potential risks are:
-wrong replacement of mother plant by
unprofessional preparation
- contamination – aflatoxines, other plants, drugs…
Specific problem of „natural“ products in
chinese medicine – „upgrade“ with use external
chemical substances.
e.g.: acetaminophene (paracetamolum)
indomethacin
hydrochlorothiazide
prednisolone
caffeine (Huang 1997).
Moreover, these substances are not declared on the
final product.
It was found that 24 %! from 2609 specimens
traditional herb mixtures from Taiwan
hospitals contained chemical compounds.
Non-steroidal antiinflamatory drugs (e.g.
diclofenac) and benzodiazepines (e.g.
diazepam) were identified in many chinese
patented herb mixtures outside Asia (Gertner
2005).
warfarine – garlic (Allium sativum) → increase INR
(International Normalization Ratio – Quick test =
protrombine time). Garlic decrease agregation of
trombocytes and can caused bleeding.
ASA – Ginkgo biloba → increase bleeding;
ginkgolides are strong inhibitors of PAF (Platelet
Activatig Factor)
lithium – psyllium (Plantago ovata) → decrease of
blood serum concentration of lithium; psyllium
effects like absorbent stuff
digoxine – St. Johns´wort → decrease AUC and
maximal concentration of digoxine; induction
CYP 3A4
digoxin - hawthorn (effective in reducing angina
attacks by lowering blood pressure and cholesterol
levels). Should never be taken together → mix
can lower heart rate too much (possible heart
failure)
antihypertensives, caffeine - ginseng → increase
the risk of overstimulation, hypertension and
gastrointestinal upset. Ginseng, when taken with
the blood-thinning drug (warfarin) can caused
bleeding!
Top ten drug interactions most dangerous to
seniors in long-term care
Numerous studies have shown, that senior
citizens are the most prone to danger from drug
interactions.
American Society of Consultant Pharmacists
identified ten drug interactions most commonly
associated with dangerous reactions by residents
in long-term care.
warfarin – NSAIDs → NSAIDs increase gastric
irritation and erosion of the protective lining of
the stomach, assisting in the formation of a GI
bleed. Additionally, NSAIDs decrease the
cohesive properties of platelets necessary in clot
formation. Prothrombin time and INR should be
monitored every week with co-administration of
warfarin with NSAID.
warfarin – sulfa drugs (e.g. sulfamethoxazole)
→ increased effects of warfarin, with potential
for bleeding.
Currently, the mechanism for interaction with
sulfa drugs is unknown; however, clinicians
hypothesize that warfarin’s activity is
prolonged due to a decreased production of
vitamin K by intestinal flora affected by
systemic antibiotic administration.
warfarin – macrolides (clarithromycin)
→ Increased effects of warfarin, with potential
for bleeding.
Macrolide inhibits the metabolism and subsequent
clearance of warfarin from the body. The activity
of warfarin may also be prolonged due to
alterations in the intestinal flora and its
production of vitamin K for clotting factor
production.
Possible solution is using of azithromycin (other
metabolism)
warfarin – quinolones (ciprofloxacine)
→ Increased effects of warfarin, with potential
for bleeding.
The exact mechanism for warfarin-quinolone drug
interaction is unknown. Reduction of intestinal
flora responsible for vitamin K production by
antibiotics is probable as well as decreased
metabolism and clearance of warfarin.
warfarin – phenytoin (antiepileptic) → increased
effects of warfarin and/or phenytoin.
Mechanism of interaction is currently unknown,
but one theory suggests a genetic basis involving
liver metabolism of warfarin and phenytoin.
ACE-inhibitors – potassium supplements →
elevated serum potassium.
Inhibition of ACE results in decreased
aldosterone production and potentially
decreased potassium excretion (risk of
cardiovascular failure)
ACE-inhibitors – spironolactone (diuretic) → both
elevated serum potassium levels, additive effect.
digoxin – amiodarone (antidysrhythmic) → increase
digoxin toxicity.
Multiple theories exist, but actual mechanism is
unknown. Amiodarone may decrease the
clearance of digoxin, resulting in prolonged
digoxin activity. There may also be an additive
effect on the sinus node of the heart.
digoxin – verapamil (antihypertensive) → increase
digoxin toxicity.
Synergistic effect of slowing impulse conduction
and muscle contractility, leading to bradycardia
and possible heart block.
theophylline – quinolones → increase theophylline
toxicity.
Inhibition of hepatic metabolism of theophylline
by the quinolones.
Criteria drug suitability by elderly patients
1991 – team of Dr. Beers (US specialist) realized
first list of not recomended drugs for elderly
(more then 65). This drugs are not only
dangerous; possible is little theraeutical benefit
or potential drug interactions.
This list most important revisions were realized
2003, 2007. Last 2012
http://www.americangeriatrics.org/files/documents/beers/2012Be
ersCriteria_JAGS.pdf
Main problematic drugs:
 Non–COX-selective NSAIDs (especially
piroxicam a indomethacin)
 Long acting benzodiazepines
 Sedative antihistaminics
 Sedative antipsychotics
 Anticholinergic acting antidepressants
 Barbiturates
 High dose of digoxin (not antiarhytmic use)
 pentoxiphylline
Etc.
Similar to Beers criteria exists in Canada list of
McLeods´criteria (1997)
Problematic of inappropriately drug using was
studied by multicentric european AdHOC study
(Aged in HOme Care)
8 european countries (representative groups of
home-care elderly from Czech rep., Denmark,
Finland, Iceland, Italy, Netherland, Norway and
GB).
Average prevalence using of inappropriate drugs was the
same in Europe and US (about 20 %)
! international european differences was deep !
Most inappropriate drugs - Czech rep. – 41 % users !!!
(last years improvement; todays about 20 %)
Least - Denmark – 5,8 % users
Fialová D, Topinková E, Gambassi G. et al.: Potentially
inappropriate medication use among elderly home care
patients in Europe. JAMA, 2005, 293(11):1348-58.
Thank you for your attention