Download Drug İnteractions

Yasar Kucukardali
Professor , Internal Medicine
Yeditepe University
Aim of the lecture
Definition………………………………………………3 minute
Epidemiologic determination ………………......... 5
Mechanism of the drug interactions …………… 10
Prevention …………………………………………… 7
Examples of the major drug interactions ………... 15
Mini test ……………………………………………….5
definition
Drug interactions
Definition;
it is the modification of the effect of one drug
(the object drug ) by the prior concomitant administration of
another (precipitant drug).
drug-drug interactions
drug-nutrient interactions
drug-herb interactions
definition
Outcomes of drug interactions
1) Loss of therapeutic effect
2) Toxicity
3) Unexpected increase in pharmacological activity
4) Beneficial effects (additive & potentiation) or
antagonism
DRUG-DRUG INTERACTİONS
Drug-drug interactions can involve
prescription or nonprescription (overthe-counter) drugs.
Types of drug-drug interactions include
duplication
opposition (antagonism)
alteration of what the body does to one
or both drugs
Duplication
their side effects may be intensified
For example,
a cold remedy and a sleep aid, both of which contain diphenhydramine ,
a cold remedy and a pain reliever, both of which contain acetaminophen
Awareness of drug ingredients is important, as is checking each new drug
to avoid duplication.
Opposition (Antagonism)
Two drugs with opposing actions can interact, thereby reducing
the effectiveness of one or both. For example, nonsteroidal antiinflammatory drugs (NSAIDs—see Pain: Nonsteroidal AntiInflammatory Drugs), such as ibuprofen
, which are taken to relieve pain, may cause the body to retain salt
and fluid. Diuretics, such as hydrochlorothiazide
and furosemide, help rid the body of excess salt and fluid. If a
person takes both types of drug, the NSAID may reduce the
diuretic's effectiveness.
Certain beta-blockers (such as propranolol ), taken to control
high blood pressure and heart disease, counteract betaadrenergic stimulants, such as albuterol
, taken to manage asthma. Both types of drugs target the same
cell receptors—beta-2 receptors (see ), but one type blocks them,
and the other stimulates them.
definition
Drug-drug interactions (DDIs) are an important
subgroup of ADEs which are highly prevalent in
patients receiving multiple-drug treatment .
DDIs may lead to severe adverse events which can
result in patient hospitalization.
epidemiology
Epidemiology
Estimates about the incidence of DDIs in different
countries vary from 6% to 70% due to variability in
methodologies and settings .
20% of hospitalized patients were susceptible to DDIs
Some studies have estimated that up to 3% of hospital
admissions are caused by DDIs .
epidemiology
Disease conditions
Four conditions that must be approached with special caution
when prescribing any drug are
heart failure
renal disease
hepatic failure
elderly patient
these are the groups of patients that should be treated with
caution due to a specific heath condition e.g., pregnant women,
malignant cases, diabetic patients, asthmatic patients
As kidney or liver function declines, the renal and hepatic
elimination of drugs decreases, leading to lower dosage
requirements for renally and hepatically cleared agents,
respectively.
epidemiology
following characteristics of patients are important
for drug pharmacokinetics
Age: Most drugs were studied in adult patients and
recommended dosages may vary in different age groups.
Sex: Although data are limited, male and female patients
can metabolize and eliminate drugs differently, so the
optimal drug dosages may differ.
Weight: For patients who are obese or cachectic,
changes in drug clearance or volume of distribution often
necessitate dosage adjustments.
epidemiology
Genetics
Pharmacogenomics is the study of the
relationship of genetics in drug metabolism
and ADRs.
In a systematic review by Phillips and
colleagues, of 27 drugs known to frequently
cause ADRs, 59% were known to be
influenced by individual patient genetic
characteristics.
epidemiology
High-risk drugs
Several drug classes have been consistently associated with ADEs
in studies of hospitalized patients .
Anticoagulants,
anti-hyperglycemic agents,
sedatives,
narcotics,
antibiotics,
antipsychotics,
chemotherapeutic agents
are among the leading drug classes associated with
ADEs in adults .
monitoring has been widely used to guide therapy with specific agents,
such as certain antiarrhythmics, anticonvulsants, and antibiotics
For drugs with a narrow therapeutic window, this
leads to an increased likelihood of dose-related
toxicity.
An example is digoxin, whose elimination is
dependent on P-glycoprotein; many drugs inhibit
P-glycoprotein activity (amiodarone, quinidine,
erythromycin, cyclosporine, itraconazole) and
coadministration of these with digoxin reduces
digoxin clearance, and increases toxicity unless
maintenance doses are lowered.
BİOAVAİLABİLİTY
When a drug is administered orally,
subcutaneously, intramuscularly, rectally,
sublingually, or directly into desired sites of action,
the amount of drug actually entering the systemic
circulation may be less than with the intravenous
route .
The fraction of drug available to the systemic
circulation by other routes is termed bioavailability.
Bioavailability may be <100% for two reasons:
(1) absorption is reduced,
(2) the drug undergoes metabolism or elimination
prior to entering the systemic circulation.
epidemiology
Drug Interactions
In pharmacokinetic interactions, a drug usually alters
absorption, distribution, protein binding, metabolism, or
excretion of another drug
Thus, the amount and persistence of available drug at receptor
sites change
Pharmacokinetic interactions alter magnitude and duration,
not type, of effect
They are often predicted by monitoring drug concentrations or
clinical signs
In pharmacodynamic interactions, one drug alters the
sensitivity or responsiveness of tissues to another drug by
having the same (agonistic) or a blocking (antagonistic) effect.
These effects usually occur at the receptor level but may
occur intracellularly.
Absorption
Drug absorption is determined by the drug's
physicochemical properties
formulation
route of administration
Dosage forms (eg, tablets, capsules, solutions)
Given by various routes (eg, oral, buccal, sublingualrectal, parenteral,
topical, inhalational)
Unless given IV, a drug must cross several semipermeable cell
membranes before it reaches the systemic circulation
Drugs may cross cell membranes by
passive diffusion
facilitated passive diffusion
active transport
pinocytosis
mechanism
Examples
ORAL ADMİNİSTRATİON
Absorption is affected by
differences in luminal pH along the GI tract,
surface area per luminal volume,
blood perfusion,
the presence of bile and mucus,
and the nature of epithelial membranes
ORAL ADMİNİSTRATİON
Because most absorption occurs in the small intestine, gastric
emptying is often the rate-limiting step.
Food, especially fatty food, slows gastric emptying (and rate
of drug absorption)
The small intestine has the largest surface area for drug
absorption in the GI tract, and its membranes are more
permeable than those in the stomach. For these reasons,
most drugs are absorbed primarily in the small intestine
PARENTERAL ADMİNİSTRATİON
Drugs given IV directly enter the systemic circulation. However,
drugs injected IM or sc must cross one or more biologic
membranes to reach the systemic circulation.
Perfusion (blood flow/gram of tissue) greatly affects capillary
absorption of small molecules injected IM or sc.
Excretion
The kidneys, which excrete water-soluble substances,
are the principal organs of excretion.
The biliary system contributes to excretion to the
degree that drug is not reabsorbed from the GI tract.
Generally, the contribution of intestine, saliva, sweat,
breast milk, and lungs to excretion is small, except for
exhalation of volatile anesthetics.
Hepatic metabolism often makes drugs more polar and
thus more water soluble. The resulting metabolites are
then more readily excreted.
Renal excretion
Renal filtration accounts for most drug excretion.
Polar compounds, which include most drug metabolites,
cannot diffuse back into the circulation and are excreted
unless a specific transport mechanism exists for their
reabsorption (eg, as for glucose, ascorbic acid, and B
vitamins).
With aging, renal drug excretion decreases at age 80,
clearance is typically reduced to ½ of what it was at age 30.
Renal excretion
Urine pH, which varies from 4.5 to 8.0, may markedly
affect drug reabsorption and excretion by determining
whether a weak acid or base is in an un-ionized or
ionized form
Acidification of urine increases reabsorption and
decreases excretion of weak acids and decreases
reabsorption of weak bases. Alkalinization of urine
has the opposite effect.
Metabolism
The liver is the principal site of drug metabolism
Although metabolism typically inactivates drugs,
some drug metabolites are pharmacologically
active
An inactive or weakly active substance that has
an active metabolite is called a prodrug
Drugs can be metabolized by oxidation,
reduction, hydrolysis, hydration, conjugation,
condensation, or isomerization; whatever the
process, the goal is to make the drug easier to
excrete
Metabolism
For many drugs, metabolism occurs in 2 phases.
Phase I reactions involve formation of a new or
modified functional group or cleavage (oxidation,
reduction, hydrolysis)
Phase II reactions involve conjugation with an
endogenous substance (eg, glucuronic acid, sulfate,
glycine)
Cytochrome P-450
The most important enzyme system of phase I metabolism is
cytochrome P-450 (CYP-450), a microsomal superfamily of
isoenzymes that catalyze the oxidation of many drugs
CYP-450 enzymes can be induced or inhibited by many drugs
and substances, helping explain many drug interactions in which
one drug enhances the toxicity or reduces the therapeutic effect
of another drug
For examples With aging, the liver's capacity for metabolism
through the CYP-450 enzyme system is reduced by ≥ 30%
because liver volume and hepatic blood flow are decreased.
Thus, drugs that are metabolized through this system reach
higher levels and have prolonged half-lives in the elderly
Statistically,
if you take six
different drugs,
you have an
80 percent chance of
at least
one drug-drug interaction.
Wayne K. Anderson, Dean,
State University of New York
School of Pharmacy
pharmacodynamic interactions
Pharmacodynamics, described as what a drug does to
the body ( pharmacokinetics-what the body does to a
drug)
involves
receptor binding (including receptor sensitivity)
postreceptor effects
chemical interactions
The pharmacologic response depends on the drug binding to its
target. The concentration of the drug at the receptor site
influences the drug's effect.
Drug-Receptor Interactions
Ability to bind to a receptor is influenced by external factors as well as
by intracellular regulatory mechanisms
drugs,
aging,
genetic mutations,
disorders
increase (up-regulate) or decrease (down-regulate)
the number and binding affinity of receptors
For example, clonidine down-regulates α2-receptors;
thus, rapid withdrawal of clonidine can cause
hypertensive crisis. ( alfa 2 agonist)
Chronic therapy with β-blockers up-regulates βreceptor density; thus, severe hypertension or
tachycardia can result from abrupt withdrawal.
Agonists and antagonists
Agonist drugs activate receptors. Many hormones, neurotransmitters (eg,
acetylcholine, histamine, norepinephrine), and drugs (eg, morphine ,
phenylephrine , isoproterenol act as agonists
Antagonists prevent receptor activation. Preventing activation has many
effects.
Antagonist drugs increase cellular function if they block the action of a
substance that normally decreases cellular function.
Antagonist drugs decrease cellular function if they block the action of a
substance that normally increases cellular function.
Reversible antagonists readily dissociate from their receptor;
Irreversible antagonists form a stable, permanent or nearly permanent
chemical bond
pharmacodynamic interactions
A drug's pharmacodynamics can be affected by
physiologic changes due to
disorders
aging
other drugs
Disorders that affect pharmacodynamic responses include
genetic mutations
thyrotoxicosis
malnutrition
myasthenia gravis
Parkinson's disease
some forms of insulin-resistant diabetes mellitus
These disorders can change receptor binding, alter the level of binding
proteins, or decrease receptor sensitivity.
mechanism
Pharmacodynamic Mechanisms
When drugs with similar pharmacologic effects are administered
concurrently, an additive or synergistic response is usually seen.
The two drugs may or may not act on the same receptor to produce such
effects.
In theory, drugs acting on the same receptor or process are usually
additive, eg, benzodiazepines plus barbiturates.
Drugs acting on different receptors or sequential processes may be
synergistic, eg, nitrates plus sildenafil
Conversely, drugs with opposing pharmacologic effects may reduce the
response to one or both drugs.
Minimizing drug interactions
Prescribers should know
all drugs taken by patients
all OTC drugs
herbal products
nutritional supplements
Asking patients about diet and alcohol consumption
The fewest drugs in the lowest doses for the shortest
possible time should be prescribed.
The effects, desired and undesired, of all drugs taken
should be determined because these effects usually
include the spectrum of drug interactions
Patients should be observed and monitored for adverse
events
prevention
DETECTION METHODS
Voluntary reporting by clinicians detects a small
fraction of ADEs.
Medical record or chart review is a more systematic
method for identifying ADEs, detecting many more
ADEs compared to voluntary reporting (65 versus 4
percent) and computerized surveillance (65 versus 45
percent)
Computerized surveillance detects many events not
captured by voluntary reporting
Direct observation by trained staff is regarded as the
most effective method to detect medication
administration errors
prevention
Examples
Examples
Grapefruit juice can act as an
enzyme inhibitor.
Warfarin — NSAIDs
IMPACT: Potential for serious gastrointestinal bleeding
MECHANISM OF INTERACTION: 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.
PREVENTION: Avoid concomitant use of an NSAID with
warfarin. If anti-pyretic effects are desired, then consider
acetaminophen. Acetaminophen in doses less than
2g/day on a short-term basis does not appear to affect
the INR. If anti-inflammatory effects are necessary, then
consider cyclooxygenase-2 (COX-2) inhibitor therapy. If
analgesic effects are desired, caution should also be
exhibited with the use of tramadol;
MANAGEMENT: Prothrombin time and INR should be
monitored every week with co-administration of warfarin
with an NSAID. Signs and symptoms of an active bleed
should be monitored
Warfarin — Sulfa drugs
IMPACT: Increased effects of warfarin, with potential for
bleeding
MECHANISM OF INTERACTION: clinicians
hypothesize that warfarin’s activity is prolonged due to a
decreased production of vitamin K by intestinal flora
affected by systemic antibiotic administration.
PREVENTION: Avoid concomitant use of a sulfa drug
with warfarin, particularly sulfamethoxazoletrimethoprim. Identify microbial pathogen prior to
initiation of antibiotic therapy. If use of a sulfa drug is
imperative, then reduce warfarin dose by 50% during
antibiotic administration and for one week following
completion of the antibiotic.
MANAGEMENT: Prothrombin time and INR should be
monitored every week during co-administration of
warfarin with a sulfa drug. Signs and symptoms of an
active bleed should be monitored
Warfarin — Macrolides
IMPACT: Increased effects of warfarin, with potential
for bleeding
MECHANISM OF INTERACTION: Erythromycin
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.
PREVENTION: Concomitant use of a macrolide with
warfarin should be avoided; switch to an alternative
antibiotic. Microbial pathogen identification prior to
antibiotic initiation will decrease the prevalence of
unnecessary drug interaction risk.
MANAGEMENT: If use of a macrolide is imperative,
then monitor INR every other day and adjust warfarin
dosing as necessary. Signs and symptoms of an
active bleed should be monitored
Warfarin — Quinolones
IMPACT: Increased effects of warfarin, with potential for
bleeding
MECHANISM OF INTERACTION: Reduction of intestinal
flora responsible for vitamin K production by antibiotics is
probable as well as decreased metabolism and clearance of
warfarin.
PREVENTION: Culture and identify microbial pathogen prior
to initiation of antibiotic therapy. Consider culture sensitivity
screening. quinolone selection should focus on one of the
newer agents that has not demonstrated significant
impairment of warfarin metabolism.
MANAGEMENT: Prothrombin time and INR should be
monitored during co-administration of warfarin with a
quinolone. If use of ciprofloxacin is imperative, then monitor
INR every other day and adjust warfarin dose as necessary.
Signs and symptoms of an active bleed should be monitored
Warfarin — Phenytoin
IMPACT: Increased effects of warfarin and/or phenytoin
MECHANISM OF INTERACTION: Currently unknown, but
one theory suggests a genetic basis involving liver
metabolism of warfarin and phenytoin.
PREVENTION: Obtain baseline phenytoin levels prior to
initiation of warfarin. Monitor INR during co-administration.
Target INR should be towards the lower end of the
therapeutic range.
MANAGEMENT: Prothrombin time, INR , and phenytoin
levels should be monitored during co-administration. Signs
and symptoms of an active bleed should be monitored daily
with particular attention to the appearance and patterns of
bruises.
ACE inhibitors — Potassium
supplements
IMPACT: Elevated serum potassium
MECHANISM OF INTERACTION: Inhibition of ACE
results in decreased aldosterone production and potentially
decreased potassium excretion.
PREVENTION: Draw potassium level prior to initiation
of ACE-inhibitor in a patient.
MANAGEMENT: Potassium levels greater than 5 should
be monitored carefully due to risk of severe hyperkalemia
and EKG changes. Watch renal function (BUN, SCr) also.
Adjust potassium supplementation if levels increase.
ACE inhibitors — Spironolactone
IMPACT: Elevated serum potassium levels
MECHANISM OF INTERACTION: Unknown, possibly an additive
effect.
PREVENTION: Draw potassium level prior to initiation of
spironolactone in a patient.
MANAGEMENT: Potassium levels greater than 5 should be
monitored carefully due to risk of severe hyperkalemia and EKG
changes. Watch renal function (BUN, SCr) also. Avoid potassium
supplements in patients taking this combination of medications,
unless the need is documented and the patient is monitored closely
for hyperkalemia.
Digoxin — Amiodarone
IMPACT: Digoxin toxicity
MECHANISM OF INTERACTION: 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.
PREVENTION: Obtain digoxin level prior to initiation of
amiodarone therapy. Then, decrease dose of digoxin by 50%
and monitor digoxin levels once weekly for several weeks.
MANAGEMENT: Maintain digoxin level between 1-2. Monitor
for signs and symptoms of digoxin toxicity (abdominal pain,
anorexia, bizarre mental symptoms in the elderly, blurred
vision, bradycardia, confusion, delirium, depression, diarrhea,
disorientation, drowsiness, fatigue, hallucinations, halos
around lights, reduction in visual acuity, mydriasis nausea,
neuralgia, nightmares, personality changes, photophobia,
restlessness, vertigo, vomiting, and weakness).
Digoxin — Verapamil
IMPACT: Digoxin toxicity
MECHANISM OF INTERACTION: Synergistic effect of
slowing impulse conduction and muscle contractility, leading
to bradycardia and possible heart block.
PREVENTION: Monitor heart rate and EKG–PR interval.
Evaluate selection of verapamil and digoxin. If patient has
CHF, note that verapamil has no proven benefit in reducing
mortality or morbidity; furthermore, digoxin offers no additional
benefit in mortality, but does improve symptomatology.
MANAGEMENT: Monitor heart rate and EKG–PR interval.
Monitor for signs and symptoms of digoxin toxicity
Theophylline — Quinolones
IMPACT: Theophylline toxicity
MECHANISM OF INTERACTION: Inhibition of hepatic
metabolism of theophylline by the quinolones.
PREVENTION: Obtain theophylline level prior to initiation of a
quinolone. Of the quinolones, enoxacin and ciprofloxacin reduce
theophylline clearance by 30-84%. Consider switching to
gatifloxacin, levofloxacin, moxifloxacin, or trovafloxacin; these
agents appear not to inhibit theophylline metabolism.
MANAGEMENT: Monitor theophylline levels. Maintain level
within targeted range of 5-15mcg/mL; however, theophylline toxicity
may result even when the level is within the targeted range. Signs and
symptoms of theophylline toxicity include seizures, nausea, and
vomiting.
Summary
The benefits of drug therapy / risk
The smallest dosage necessary to produce the desired effect should be
used.
The number of medications and doses per day should be minimized.
Electronic tools to search databases of literature and unbiased opinion will
become increasingly commonplace.
Genetics play a role in determining variability in drug response and may
become a part of clinical practice.
Electronic medical record and pharmacy systems will increasingly incorporate
prescribing advice, such as indicated medications not used; unindicated
medications being prescribed; and potential dosing errors, drug interactions,
or genetically determined drug responses.
Prescribers should be particularly wary when adding or stopping specific
drugs that are especially liable to provoke interactions and adverse reactions.
Prescribers should use only a limited number of drugs, with which they are
thoroughly familiar.
Following conditions that must be approached with special caution when
prescribing any drug. Which one is wrong?
A-heart failure
B-renal disease,
C-rheumatismal disease
D-hepatic failure
E-elderly patient
Following factors contrubuting factors to drug interactions Which one is
wrong
A-Multiple drug therapy
B-Poor patient compliance
C-Enviremental factors
D-Multiple diseases
E-Drug related factors
Which one is the mechanism of the pharmacodynamic
grug interactions ?
A-Reduced plasma protein binding
B-Altered tissue distribution
C-Altered hepatic metabolism
D-Altered renal excretion
E-Potentiation/antagonism at target receptor
Following measures should be take to reducing the risk of drug interactions.
Which one is wrong ?
A-İdentify the patients risk factors
B-Take throught drug history
C-Consider therapeutic alternatives
D-Use low dose drug
E-Monitor therapy
Which one is correct related to serious drug interactions ?
A-Warfarin plus ciprofloxacin (increased effect of warfarin)
B-Sildenafil plus nitrates ( dramatic hypotension)
C-Statin plus gemfibrosil ( Rhabdomyoliysis
D-SSRI plus Monoamin oxidase inhibitors ( hypertansive
crisis)
E-All