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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
 Drug interaction can be defined as the
modifications of the effects of one drug by
the prior or concomitant of another drug
 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
Piperacillin-tazobactam Acyclovir Particle formation
Amphotericin B Flocculent
Mitomycin Blue colour
Theophylline Cefepime Cefepime degrades up to
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
• 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
• 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
Phenytoin precipitates in dextrose end of
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 drug’s 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
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
0 6 12 18 24
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
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,
• Didanosine (given
as a buffered tablet)
• Block absorption
of quinolones, tetracycline,
and azithromycin
• Reduce absorption
of ketoconazole, delavirdine
• Reduces ketoconazole
• 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 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
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
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 B’s 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
Enteric transport
Enteric metabolism
Intravascular space
Extravascular space
Protein binding
Hepatic influx transport
Phase I metabolism
Phase II metabolism
Efflux transport
Efflux transport
Nature Reviews/ Cancer
Drug Excretion
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
 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)
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
 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 agents…etc
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