Drug Interaction:

Pharmacokinetic

Tri Widyawati

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 Learning Objectives
You should be able to describe:
• definition of drug interaction
• types of drug interaction.
• mechanisms of pharmacokinetic interaction

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 Do we
really need to
study drug
interactions?
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www.fda.gov
 Lethal Combination of Tramadol and
Multiple Drugs Affecting Serotonin
Ripple MG. et al. Am J For Med Path. 21(4):370-4,2000

• The threshold for seizures is lowered by

tramadol. In addition, the risk for seizure is
enhanced by the concomitant use of tramadol
with selective serotonin reuptake inhibitors or
neuroleptics.
• The cause of death in this individual was
seizure activity complicating therapy for back
pain and depression
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“…drug interactions represent 3-5% of
preventable ADRs and are an important
contributor to ER visits and hospital
admissions.” < JAMA 1995;274(1):35–43>

“…elderly patients with digoxin

toxicity were 12 times more likely
to have been treated with
clarithromycin” < JAMA 2003;289 (13):1652>
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Potential Drug Interactions
Number of Number of
Interactions
Drugs Interactions
1   0
2 A+B 1
3 A+B A+C 3
B+C
A+B A+C
4 A+D B+C 6
B+D C+D
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 Patients in high risk of drug interactions

• Polypharmacy people (elder)

• Hepatic disorders • Renal disorders • Genetic factors

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 Definition
• Drug interactions occur when one drug
modifies the actions of another drug in the
body
• A drug interaction occurs when either the
pharmacokinetics or the pharmacodynamics of
one drug is altered by another
• “Alteration either in the pharmaco-dynamics
and/or kinetics of a drug, caused by
concomitant drug treatment, dietary factors or
social habits such as tobacco and alcohol”
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Outcomes of Drug Interactions: Adverse
• Toxicity
– Torsade de pointes: terfenadine, astemizole, cisapride
– Rhabdomyolyis: HMG-CoA reductase inhibitors
(antihiperlipidemia)
– Hypotension: calcium channel blockers,
sildenafil (Viagra®)
– Excessive sedation/respiratory depression:
benzodiazepines
• Drug resistance
• Therapeutic failure
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Outcomes of Drug Interactions: Beneficial
• Additive desirable pharmacodynamic
effects:
Combination antiretroviral therapy
– Use of 2NRTIs + PI or NNRTI
•  potency
•  resistance

• Penicillin : probenicid is a competitive

inhibitor for tubular secretion
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 Types
• Drug - drug interactions.
• Herbal - drug interactions.
• Food - drug interactions.
• Drink - drug interactions.
• Pharmacogenetic interactions.

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 Mechanisms
Pharmacokinetics :
 Absorption interactions
 Distribution interactions
 Metabolism interactions
 Excretion interactions
Pharmacodynamics :
 Synergistic interactions
 Antagonistic interactions

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Pharmacokinetic Interactions

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 Absorption interactions
Mechanisms :
Altered local pH.
Altered bacterial flora.
Formation of drug chelates or insoluble
complexes.
Altered GIT motility.
P-glycoprotein transporter

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 Altered local pH
• Some drugs are absorbed from stomach (acidic
media), so when this media become neutral or
alkaline, this will affect the absorption of drug.
• Vice versa
Drug (A) Drug (B) Effect
NaHCO3 Aspirin Dissolution rate (aspirin)   absorption
rate 
Antasid Penicillin G, Solubility drug B   total absorption 
Erythromycin
Antasid Fe Gastric pH   absorption of Fe 

Vitamin Fe Gastric pH   absorption of Fe 

C
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 Altered bacterial flora
• Bacterial flora has a marked role in
metabolization of some drugs.
• Long term antibiotics may kill normal flora and
affect drug absorption.
• Ex :
erythromycin and digoxin

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 Formation of drug chelates or insoluble
complexes
Drug (A) Drug (B) Effect

Tetracyclin Cation multivalent (Ca2+, Chelating   absorption of

e Mg2+, Al3+ in antacid, Ca2+ tetracycline and Fe2+
in milk, Fe2+ in Fe
preparation
Digoxin, Kaolin-pektin Drug (A) absorbed by drug (B)  
Lincomycin absorption of drug (A)

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 Altered GIT motility
• Some drugs increase or decrease GIT motility 
increase/decrease time of absorption and absorbed
amount.

Drug (A) Drug (B) Effect

morphine like Paracetamol GET >>  absorption time of
drugs drug B >>
metoclopramide Paracetamol, GET <<  absorption time of
propanolol drug B <

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 Drug absorption:
effect of inhibition of P-gp
P-gp action: reduced
absorption of
substrate

Inhibitor: Inhibition of p-gp

Ex. grapefruit juice  More drug enters
= ↑ absorption

Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distributioin: Focus on H1-Receptor
Antagonists. Clin Drug Invest 21 (8):587-596, 2001. Posted to Medscape 8/1/01
 Interactions
Based on Distributions & Binding

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 Distribution interactions

• There is an important factor :

Vd
• Protein binding interactions :
- unbound molecules remain free and
pharmacological active.
- bound molecules are pharmacological inactive.
• Some drugs may compete others for binding to
protein depending on affinity and concentration.

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 Distribution interactions
Only drugs with low Vd will be affected.
•Ex :
Warfarin (99% bound) and Phenytoin (90%
bound)

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2 units 18 units

AA A A A AAAAAAAAAAAAAAAAA Vd=20/2=10

Vascular
Compartment Extravascular compartment of the body

BBBBB B Vd=20/18=1.1
BBBB BB
BBB

18 units 2 units

Vd = Amount of drug in the body

Concentration in the blood
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 Mefenamic
acid Albumin-Warfarin Warfarin level  Bleeding

Sulphonamide Albumin-Tolbutamide Tolbutamide level  Hipoglycemia

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 Interactions
Based on Metabolic Clearance
• Most drugs are chemically altered within Liver
• Hepatic metabolism has two pathways :
– Phase 1 (modification)
– Phase 11 (conjugation)

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CYP450 most important isoenzymes responsible
for liver metabolism.

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isoform CYP450.doc
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Types of drug metabolism interaction
1. Enzyme induction:
• Onset slow (days – 2weeks).
• Increase the dose or frequent of administration
2. Enzyme inhibition:
• Most common than enzyme induction
• Takes 2-3 days
• Decrease drug metabolism  increase the
serum concentration

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– If serum levels within therapeutic ranges so it is
not clinically important.
– Some drugs can be metabolized by more than one
of CYP450 isoenzymes, so the reaction may be not
clinically important.

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  Inhibition of drug metabolism   effect of the object
drug  toxicity

Eg : inhibitor CYP1A2   toxicity risk of klozapin and

teofilin.

 Inhibition of enzym  effect 

 Inhibition of prodrug metabolism   active drug  
therapeutic effect
 Eg : analgetyc and toxic effect of codein  result of
convertion of codein to morphine by CYP2D6

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 Induction of enzyme  effect 
Drug that metabolism by CYP3A4 or CYP2C9  induction
of enzim.
Especially : FPE >> by CYP3A4 at intestinal walls and hepar
 serum concentration of object drug <<.

 Induction of enzym  toxic metabolite

Eg. : convertion of analgetyc acetaminofen to non-toxic and
toxic metabolite.
Enzyme inductor   toxic metabolite and hepatotoxicity
risk

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 Interactions
Based on Metabolic Clearance
• Drug that reduce hepatic blood flow  reduce
the clearance of other drugs metabolized in
the liver
Eg. propranolol + morphine

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 Excretion Interaction
• Most drug are excreted in Urine or Bile.
• Some drugs are reabsorbed from renal
tubules or enterohepatic recirculation.
• Some drugs are excreted in acidic urine, so
changing urine pH will affect there serum
level.
• These interaction is rare.

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 Interactions during excretion
Excretion by bile and enterohepatic circulation

Drug (A) Drug (B) Effect

Probenecid Rifampicin, Excretion of drug B by bile duct   effect of drug
Indometacin B
Neomycin, Oral Drug (A) suppressed intestinal bacteria  inhibit
Rifampicin contraception enterohepatic circulation of drug B   effect of
drug (B)

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 Interactions during excretion
Tubular secretion
Drug (A) Drug (B) Effect
Probenecid Metothrexate, Penicillin,
Indometacin, Dapson Drug A inhibit drug B
Furosemide Gentamycin,
secretion in tubular 
sefalosporin clearens drug B  
effect/toxicity drug B 

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 Interactions during excretion
Altering of pH urinary
Drug (A) Drug (B) Effect
Base drug : Amonium chloride (drug B) pH urinary   clirens of
amfetamin, efedrin, drug A  effect of drug A 
quinidine
Bic-nat, asetazolamide (drug B) pH urinary   clirens of
drug A  effect of drug A 
Acid drug : Bic-nat, antasid (drug B) pH urinary   clirens of
salicylate, (Al(OH)3 and Mg()H)2 drug A   effect of drug A 
fenobarbital

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 How to overcome an interaction ?

•Binding interactions can be avoided if the two drugs are taken an hour or two apart
• Tetracyclines: Do not take milk, iron preparation or indigestion remedies at the same
time of day as this medicine
If the previous solutions don’t work ?!!!
Adjust drug dosage with monitoring of drug level and physiological functions

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 Online Drug Interaction
Checker
http://reference.medscape.com/drug-
interactionchecker
,,,,,,,
https://online.epocrates.com/u/1300/MultiChe
ck?ICID=search-DDI
,,,,,,
http://www.drugs.com/drug_interactions.html

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 Refferences

Omar, A.Drug interaction, ppt.

E-mail: tw_rozan@yahoo.com

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