DRUG INTERACTIONS

Endang Windiastuti, dr.,SpA(K)

Satgas Farmasi IDAI
Topics on Drug Interactions
Definition
Types of drug interaction
Pharmaceutical interaction
Pharmacodynamic interaction
Pharmacokinetic interaction
Effects of drug interaction
Definition
Drug interaction can be defined as the
modifications of the effects of one drug by
the prior or concomitant of another drug
(poly-pharmacy)
A drug interaction is a situation in which a
substance affects the activity of a drug, i.e.
the effects are increased or decreased, or
they produce a new effect that neither
produces on its own.
Occurence of drug interactions
In Vitro
In Vivo (in patients) :
Clinically expected or unexpected
Clinically observed or undetected
Clinical effect can be severe or light
In Vitro drug interactions
Drugs Interactant Result
Ceftriaxone sodium Lactated Ringer's solution Ca-Ceftriaxone precipitate
Daptomycin Dextrose solution Daptomycin precipitate
Daptomycin 0.9% saline solution
Lactated Ringer's solution
Compatible
Piperacillin-tazobactam Acyclovir Particle formation
Amphotericin B Flocculent
Mitomycin Blue colour
Theophylline Cefepime Cefepime degrades up to
25%
David W. Newton (2009) Am J Health-System Pharm. 66(4):348-357
Thilo Bertsche et al (2008) Am J Health-Syst Pharm. 65(19):1834-1840
Treatment outcome is the NET result of interaction
the patient, environment, drug and disease
Pharmacokinetics
Pharmacodynamics
Adverse
Effects/
Toxicity
Clinical
Efficacy
Age
Sex
Genetic / ethnic
Drug interaction
Body weight
Environment
Nutritional status
Disease state
Source of viability in
Drug Response
Risk Factors for Drug Interactions
High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy
Renal, liver impairment
High Risk Drugs
Narrow therapeutic index drugs (steroid,
rifampicin, quinidin)
Recognized enzyme inhibitors or inducers
Pharmaceutical Interactions
Interactions that occur prior to systemic
administration.
For example incompatibility between two
drugs mixed in an IV fluid. These interactions
can be physical (e.g. with a visible
precipitate) or chemical with no visible sign of
a problem
Drug Interactions before drug
administration
Phenytoin precipitates in dextrose end of
IV.
Intravesicular amphotericim precipitates in
Saline bladder wall necrosis
Gentamicin bind piperacillin loss of
antibiotic effect
Pharmacodynamic interaction
Definition interaction that one drug may cause changes in
another drug action, effect or response without PK alteration
Pharmacodynamic interaction could result in either
Additive effect
Synergistic effect
Antagonistic effect
Pharmacodynamic interaction can happen at these levels
Level of drug action
Level of drug effect
Level of drug response
At this level, it could be called Physiological interaction
Pharmacodynamic Interactions
One drug causes a change in patient
response to another drug without
altering that drugs pharmacokinetics
Eg increase toxicity of digoxin caused by diuretic
induced hypokalaemia
Additive effects of alcohol and benzodiazepines
Beta-blocker given with beta-agonist
What is Pharmacokinetics (PK)?
Means movement of drugs
Study of the relationship between dose, amount of
drug in the body and therapeutic or toxic effects of
a drug
Pharmacokinetic data help us understand:
dose and schedule (once a day vs. twice a day, etc)
dose adjustments due to drug interactions and other
issues.
How Do Drug Interactions Happen?
They occur due to changes in the pharmacokinetics
of a drug
Changes in the absorption, distribution, metabolism
and excretion (ADME) of a drug
Toxic
Effective
Ineffective
0 6 12 18 24
TIME
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Processes that Determine Drug PK
Absorption: how the drug enters the blood
The amount of acid in stomach or amount of food changes the
amount of drug absorbed
This is why some drugs must be taken with or without food or can not
be taken with antacids
Distribution: how the drug travels in the blood and how it
goes into and out of other areas of the body
Metabolism: how the body changes a drug usually in
intestine and liver
Drug Elimination: how the body gets the drug out:
via kidneys through urine or
via liver though stool
http://www.thebody.com/content/art875.html
Pharmacokinetic interaction
These interactions are characterized by the alteration of
the PK or disposition (ADME) of one drug by another.
Change in absorption
Change in distribution
Change in Metabolism
Change in Excretion
Important PK interactions are those associated with
Altered drug metabolism
Drug transporters
Protein binding
Altered Absorption
Change in gastrointestinal pH
Ketoconazole needs acidic conditions in gut
Drug binding in GI tract (E.g. tetracycline and calcium)
Change in gastrointestinal flora
Antibiotics with digoxin (increased toxicity)
Change in gastrointestinal motility (metoclopramide)
Drug induced mucosal damage (antineoplastic agents)
Displaced protein binding
Phenytoin displaced by aspirin / sulfonamide
Altered metabolism (liver enzyme CYP450 family)
In the GI Tract
Sucralfate, antacids, and oral
iron preparations
Omeprazole, lansoprazole,
H2-antagonists
Didanosine (given
as a buffered tablet)
Cholestyramine
Block absorption
of quinolones, tetracycline,
and azithromycin
Reduce absorption
of ketoconazole, delavirdine
Reduces ketoconazole
absorption
Binds raloxifene,
thyroid hormone, and digoxin
Pharmacokinetic Drug Interactions : Absorption
Alteration Action
Drug binding in GI tract
Iron may chelate ciprofloxacin, resulting in
decreased absorption
GI motility
Increased GI motility caused by metoclopramide
may decrease cefprozil absorption
GI pH
GI alkalinization by omeprazole may decrease
absorption of ketoconazole
GI flora
Decreased GI bacterial flora caused by an antibiotic
admin could decrease bacterial production of
vitamin K augmenting anticoagulant effect of
warfarin
Drug metabolism in wall
of intestine
MAO in the wall of GI tract may be inhibited by MAO
inhibitors resulting in increased blood pressure to
phenylephrine
PK interaction associated with
drug transporters
Transporters Playing Key Roles in Drug Absorption
and Excretion
Important drug transporters
P-glycoproteins (PgP)
very important for excretion processes
Other transporters : Albumin
Interaction usually result in
Inhibit function of transporters
And inhibit drug excretion
And finally cause AUC of a drug to increase or more
drug in the body
Drug Metabolism
Many drug interactions are due to changes in
drug metabolism:
How the body changes a drug (usually in
intestines and liver)
Breaks drug down to make it easer to pass into
urine or stool
Main system involved in drug metabolism
interactions is CYP P450 enzymes found
in liver and intestines
Drug Interactions Via Liver
Interactions that happen through CYP enzymes are either based on enzyme
induction or inhibition
Induction:
Drug A induces the body to produce more of an enzyme
which metabolized Drug B .
This reduces the amount of drug B, which may lead to
loss of drug Bs effectiveness
Inhibition:
Drug A inhibits the production of enzymes to metabolize
Drug B.
This increases the amount of Drug B in the body and could
lead to an overdose or toxic effects
Drug administration
Absorption
Enteric transport
Enteric metabolism
Distribution
Intravascular space
Extravascular space
Protein binding
Metabolism
Hepatic influx transport
Phase I metabolism
Phase II metabolism
Biliary
excretion
Efflux transport
Intestinal
excretion
Renal
excretion
Efflux transport
Nature Reviews/ Cancer
Drug Excretion
Definition
The removal of a drug
molecule from the body
without chemical modification.
Generally in urine, but
occasionally in bile , intestine.
Processes involved in renal excretion: 1
Filtration
Passive process (Pressure driven)
20% of plasma volume is filtered
Small molecules - Yes
Large molecules No
Most proteins not filtered.
Drugs which are extensively protein
bound will also not be filtered.
Acids
Furosemide
Penicillins
Probenecid
Bases
Quinine
Quaternary
ammonium salts
Probenecid and penicillins share same mechanism.
- Probenecid competes with penicillins.
-Penicillin clearance reduced.
Processes involved in renal excretion: 2
Active secretion
Excretion Interaction
Change in renal blood flow
Methotrexate and NSAIDs
NSAIDS can decrease renal blood flow by
inhibition of renal prostaglandins.
Reduced clearance of MTX and active (toxic)
metabolite
Onset of drug interaction
It may be seconds up to weeks for example in case
of enzyme induction, it needs weeks for protein
synthesis, while enzyme inhibition occurs rapidly.
The onset of action of a drug may be affected by the
half lives of the drugs e.g., cimitidine inhibits
metabolism of theophylline.
Cimitidine has a long half life, while, theophylline has a short
one.
When cimitidine is administered to a patient regimen for
Theophylline, interaction takes place in one day.
Effect of Drug interaction
Therapeutic drug interaction could be used in 2 objectives
1. To produce synergistic therapeutic effects
Examples are found by several antibiotic combinations
Penicillin-Sreptomycin
Penicillin-Probenecid
Sulfa-trimethoprim
2. To detoxify or lower toxic effects
Examples are those antidotes of certain toxic agents
Outcomes of drug interactions
1) Loss of therapeutic effect
2) Toxicity
3) Unexpected increase in pharmacological activity
4) Beneficial effects e.g additive & potentiating
(intended) or antagonism (unintended).
5) Chemical or physical interaction
e.g I.V incompatibility in fluid or syringes mixture
* Prevention of drug interaction
1) Monitoring therapy and making adjustments
2) Monitoring blood level of some drugs with narrow
therapeutic index e.g., digoxin, anticancer agentsetc
3) Monitoring some parameters that may help to characterize
the the early events of interaction or toxicity e.g., with
warffarin administration, it is recommended to monitor the
prothrombin time to detect any change in the drug activity.
4) Increase the interest of case report studies to report
different possibilities of drug interaction
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