Drug Interactions

it is “. . . when medicines fight each

other. . .”,
or “. . . when medicines fizz together in
the stomach . . .”,
or “. . .what happens when one medicine
falls out with another. . .”
 Drug Interactions

Drug interaction refers to an adverse drug

response produced by the administration of
a drug or co-exposure of the drug with
another substance, which modifies the
patient’s response to the drug.
 Drug Interactions

If a drug interaction does occur, any one of

the following scenarios may happen,
depending on the drugs involved.

➢ Additive effects, leading to either beneficial results or

side effects.
➢ Lessened effects, leading to drug failure.

➢ No effect, leading to no changes.

The outcome can be harmful if the interaction causes
an increase in the toxicity of the drug. For example,
there is a considerable increase in risk of severe
muscle damage if patients on statins start taking azole
antifungals.

Patients taking monoamine oxidase inhibitor

antidepressants (MAOIs) may experience an acute and
potentially life-threatening hypertensive crisis if they
eat tyramine-rich foods such as ‘cheese’,
A reduction in efficacy due to an interaction can
sometimes be just as harmful as an increase: patients
taking warfarin who are given rifampicin need more
warfarin to maintain adequate and protective
anticoagulation, while patients taking ‘tetracyclines’,
or ‘quinolones’, need to avoid antacids and milky
foods (or separate their ingestion) because the effects
of these antibacterials can be reduced or even
abolished if admixture occurs in the gut.
 Drug Interactions
Therapeutically desired interactions:
• Antibiotics combination therapy
• Cardiovascular drugs
➢ Antihypertensive drugs
➢ Therapy of congestive heart failure
• Therapy of obstructive pulmonary disease
• Fixed combination of opioid antagonist and
agonist
 Factors affecting Drug Interactions

 Multiple drug therapy

 Multiple prescribers

 Patient compliance

 Long-term treatment for chronic disease

 Narrow therapeutic range of medication

 Factors affecting Drug Interactions
 Patient risk factors
• Older patient are at more risk for drug interaction
• Patient with predisposing illness.
• Pharmacogentic variations
• Acute medical condition (eg, dehydration, infection)
• Metabolic or endocrine condition (eg, obesity,
hypothyroidism)

• Female sex
• Having poor nutrition
 Incidence of Drug-Drug Interactions
 True incidence difficult to determine
 Not all drug interactions are clinically significant or
cause adverse effect
 Data for drug-related hospital admissions do not
separate out drug interactions, focus on ADRs
 Lack of availability of comprehensive and easy to
access databases
 Difficulty in assessing OTC and herbal drug therapy
use
 Difficulty in determining contribution of drug
interaction in morbidity of medically complicated
patients
 Classification of Drug Interactions
 Pharmacodynamic
• Related to the drug’s effects in the body
 Receptor site occupancy
 Pharmacokinetic
• Related to the body’s effects on the drug
 Absorption, distribution, metabolism, elimination
and drug transportation
 Pharmacogenetic
• Related to genetic factors that effect metabolism and
drug transport
 Classification of Drug Interactions
 Pharmaceutical
• Related to physical or chemical incompatibility
when two or more drug mixed together

• Phenytoin precipitates in dextrose solutions .

• Amphotericin precipitates in saline.
• Gentamicin physically/chemically incompitable
with most beta-lactums, resulting in loss of
antibiotic effect.
Pharmacodynamic Interactions
 Pharmacodynamic Drug Interactions
 Pharmacodynamic interactions are those occur when the
effects of two drugs impinge on a common effector.
 Additive, synergistic, or antagonistic effects from co-
administration of two or more drugs
• Synergistic actions of antibiotics, CNS depressant and
antihistamine

• Overlapping toxicities - ethanol & benzodiazepines, thiazide

diuretic and digoxin therapy

• Antagonistic effects- anticholinergic medications

(oxybutinin or amitriptyline w/ acetylcholinesterase
inhibitors)
 Pharmacokinetic Drug Interactions
Pharmacokinetic interaction occur when the
absorption, distribution (protein and tissue binding), or
elimination (metabolism and/or excretion) of the drug is
affected by another drug, chemical or food element.
 Alteration in absorption
 Protein binding effects
 Alteration of drug transport
 Alteration in elimination
 Changes in drug metabolism
 Pharmacokinetic
Absorption Interactions

DI can affect the rate and extent of systemic drug

absorption from the absorption site, resulting in
increased or decreased drug bioavailability
A number of interactions occur in the GI tract and reduce the entry of drugs into the systemic circulation.

Alterations in Absorption

 Chelation / complexation
• Irreversible binding of drugs in the GI tract
Examples:
Tetracyclines, quinolone antibiotics - ferrous
sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy
products (Ca+2)
Effects:
Azithromycin and Levofloxacin complexes with
divalent cation, causing decrease bioavailibility.
 Alterations in Absorption

Trovafloxacin +/- Maalox®

Fasted

With Maalox
Usually separating
administration of
chelating drugs by 2+
hours decreases
interaction effect
 Alterations in Absorption

 Adsorption
• Adsorption of drugs in the GI tract
Examples:
Cholestyramine, Kaolin, Acarbose, Activated
charcoal
Effects:
Cholestyramine decrases bioavailability of
digoxin, levothyroxine, raloxifene
 Alterations in Absorption
 Alteration in GI motility
Example
• Increased motility - cisapride (R.I.P.),
metoclopramide, cathertic, laxative
• Decreased motility – narcotics, anticholinergic
agents
Effects
• Decreases bioavailability of drug from
controlled released product .
• Propenthaline delay absorption of
acetaminophen from small intestine
 Alterations in Absorption
 Altering GI tract pH

Example:
• antacids, omeprazole, cimetidine
Effect
• Increase in GI pH may decrease absorption of
drugs which require acidic pH for optimal
absorption such as ketoconazol, itraconazole
and delaverdine
 Ketoconazole Interactions
Ketoconazole Cp (mcg/ml) pH-dependent absorption

8
7
6
5 Keto
4 K + Sucral
3 K + Ranit
2
1
0
0 0.5 1.5 2.5 4 6 12
Hours

Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771

 Alterations in Absorption

 Alteration of GI flora
Example
• Antibiotic
Effects
• Digoxin have better bioavailability taken after
erythromycin
• Estrogen/progestin birth control pill requires
intestinal flora to facilitate enterohepatic
circulation, antibiotic reduces intestinal flora
and reduce estrogen/progestin level
 Alterations in Absorption

 Inhibition of drug metabolism in intestinal

cells
Example
• MAOI (Phenalzine, tranylcapromine)
Effects
• Inhibit metabolism of albuterol and levalbuterol,
leading to hypertension
 Alterations in Absorption

 Malabsorption caused by drugs

Example
Neomycin causes a malabsorption
syndrome, similar to that seen with non-
tropical sprue. The effect is to impair
the absorption of a number of drugs
including ‘digoxin’, and ‘methotrexate’,
 Pharmacokinetic
Distribution Interactions
Distribution of drug may be affected by plasma
protein binding and displacement interactions
or tissue and cellular interaction
Some drugs can "bump" other drugs off
proteins in the plasma and result in an
increased amount of free drug, but this is
only transient because the usual elimination
mechanisms respond by increasing the rate
of elimination.
 Distribution Interaction
 Problems can arise
• When even a transient increase in unbound
concentrations may be toxic (e.g. lidocaine,
Warfarin, Valproic acid)

• When total plasma concentrations are measured

and used to adjust dose (e.g. phenytoin)

• When the drug interaction includes effects on rate

of elimination (e.g. quinidine plus digoxin)
 Protein Binding Interactions
“…the overall clinical importance of plasma protein
binding displacement interactions continues to be
overstated…”
“Despite the theoretical and experimental data to the
contrary, the concept that plasma protein binding
displacement is a common cause of clinically significant
interactions may still be widely taught in some medical
schools, often appears in textbooks and is accepted by
many in the medical community and by drug
regulators.”
Sansom LN & Evans AM. Drug Safety 1995;12:227-233.
Rolan PE. Br J Clin Pharmacol 1994;37:125-128.
 Pharmacokinetic
Interactions due to Drug Transporter
 Drug transporting proteins have recently
been discovered to be involved with drug
interactions.
 Human (ABC) transporters are responsible for
active transport of drugs, peptides, and
endogenous hormones.
 P-glycoprotein is a cationic transporter found
in the liver, intestine, kidney, and brain. P-
glycoprotein acts as an efflux pump to pump
toxic materials out of the cell.
Interactions due to Drug Transporter
Alterations in Absorption: Drug Transport
• Talinolol (TL) given both IV and PO

• Rifampin given X 9 days to healthy

subjects

• Rifampin ’ed TL AUCiv by 21% and

TL AUCPO by 35%

• Rifampin ’ed duodenal expression

of P-gp by 4.2 fold and (W. blot) and
mRNA ’ed in 6/8 subjects

• Conclusion: rifampin induces P-gp-

mediated excretion of TL in the gut
wall
 Pharmacokinetic
Metabolism Interactions
Some important preventable drug interactions
are due to their effects on drug metabolizing
enzymes
Drug metabolism can be effected by enzyme
induction, enzyme inhibition, Substrate
competition for the same enzyme, and change
in hepatic blood flow.
There are many potential consequences of
changes in drug metabolism for a given drug.
 Pharmacokinetic
Metabolism Interactions
Drug metabolism is generally classified in two
phases, termed Phase I and Phase II.
Phase II reactions generally result in conjugation of a
drug to a water-soluble group, and, because there is a
large excess of these groups in well nourished cells,
these reactions are rarely rate-limiting. Thus, they are
rarely involved in drug interactions.
Phase I reactions carried out by cytochrome P450
enzymes, flavin monooxygenases, and reductases
are more frequently rate-limiting. These are the target
of clinically significant drug interactions
 Drug Metabolism Interactions

 CYP450 system has been the most extensively studied.

There are many different isoforms of CYP450, but 6 have
been especially well characterized in terms of clinically
relevant drug metabolism
• CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19
and others
Drug Metabolism Interactions
Drug Metabolism Interactions

 SUBSTRATE [ ]
CYP SUBSTRATE
 RISK OF TOXICITY
CYP INHIBITOR

 SUBSTRATE [ ]
CYP SUBSTRATE
 SUBSTRATE
CYP INDUCER EFFICACY

, ,  SUBSTRATE [ ]
CYP SUBSTRATE
, ,  IN EFFICACY OR
CYP SUBSTRATE TOXICITY
Proportion of Drugs Metabolized by CYP450
Isozymes

CYP2D6
19% CYP3A4
36%

CYP2C19

CYP2C9

CYP1A2
CYP2E1 CYP2B6 CYP2A6
 CYP 450 Substrates
 Metabolism by a single isozyme (predominantly)
• Few examples of clinically used drugs
 Desipramine/CYP2D6

 Metabolism by multiple isozymes

• Most drugs metabolized by more than one isozyme
 Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
• If co-administered with CYP450 inhibitor, some isozymes
may “pick up slack” for inhibited isozyme

 There is tremendous variability between individuals in terms

of expression of cytochrome P450 isozymes. For example,
CYP2D6 is not present at all in some livers.
 CYP 450 Inhibitors

 Drugs can inhibit a specific CYP even

though they are not metabolized by that
isozyme
• Quinidine - most potent CYP2D6 inhibitor but
metabolized primarily by CYP3A4
 Drugs which are metabolized by a specific
CYP may not potently inhibit that CYP
• Venlafaxine is metabolized by CYP3A4 but is
not a potent inhibitor of CYP3A4
 Examples of CYP 450
Substrates, Inhibitors, & Inducers
Isoenzyme Substrates* Inhibitors Inducers
CYP3A4 Alprazolam Clarithromycin Carbamazepine
Lovastatin Ritonavir Phenobarbital
Quetiapine Ketoconazole Efavirenz

CYP2D6 Risperidone Quinidine Phenytoin

Desipramine Fluoxetine Ethanol
Donepezil Paroxetine Carbamazepine

CYP1A2 Clozapine Fluvoxamine Smoking

Theophylline Ciprofloxacin Omeprazole
Caffeine Ticlopidine Carbamazepine

*Primary metabolic pathway

 Examples of CYP 450
Substrates, Inhibitors, & Inducers
Isoenzyme Substrates* Inhibitors Inducers
CYP2C9 Tamoxifen Cimitidine Carbamazepine
Losartan Fluoxetine Phenytoin
Celecoxib Voriconazole Rifampin

CYP2C8 Paclitaxel Gemfibrozil Phenobarbital

Repaglinide Rifampin

CYP2C19 Diazepam Ketoconazole Carbamazepine

Lansoprazole Ticlopidine Rifampin
Clomipramine Fluxetine

*Primary metabolic pathway

 CYP 450 Inducers

 The “usual suspects”

• Rifampin
• Rifabutin
• Carbamazepine
• Phenobarbital
• Phenytoin
Drug Interactions - Enzyme induction

Figure 51.5 Effect of rifampicin on the

metabolism and anticoagulant action of
warfarin. A Plasma concentration of warfarin
(log scale) as a function of time following a
single oral dose of 5 µmol/kg body weight.
After the subject was given rifampicin (600
mg daily for a few days), the plasma half-life
of warfarin decreased from 47 hours (red
curve) to 18 hours (green curve). B The effect
of a single dose of warfarin on prothrombin
time under normal conditions (red curve) and
after rifampicin administration (green curve).
(Redrawn from: O'Reilly 1974 Ann Intern
Med 81: 337.)
 CYP 450 Inhibitors

 The “usual suspects”

• Cimetidine
• Erythromycin
• Ketoconazole

• Ritonavir
• Fluoxetine, paroxetine (CYP2D6)
• Nefazodone (CYP3A4)
 Drug Metabolism Interactions

 Nonhepatic enzymes can be involved in drug

interactions. Serotonin syndrome has been
reported in patient receiving antidepressants
similar to citaploram in combination with MAOI.

 A decrease in hepatic blood flow can decrease

the hepatic clearance for high excretion drugs
such as propanolol and morphine.
 Pharmacokinetic
Drug elimination Interactions

Renal drug clearance can be affected by

changes in glomerular filtration, tubular
reabsorption, active drug secretion and renal
blood flow
 Pharmacokinetic
Drug elimination Interactions

 GFR and renal blood flow:

➢ Methylxanthine increases renal blood flow and
GFR, decrease time for reabsorption of various
drugs, leading to more rapid urinary drug
excretion
 Drug elimination Interactions

 Active tabular secration:

Probenecid block the active tubular secration of penicilline
and some cephalosporin antibiotic
 Pharmacokinetic
Drug elimination Interactions

 Tubular reabsorption and Urine pH:

➢ Alkalization of the urine pH increases the
reabsorption of amphetamine and decreases its
clearance

➢ Alkalization of the urine pH increases the

ionization of salicylates, decreases reabsorption
and increases its clearence
 Pharmacogenetic Drug Interactions

An individual's genetic makeup can alter their

response to a drug.

Genetics affect pharmacokinetics and

pharmacodynamics. Unrecognized mutations can
affect the magnitude of a drug interaction.

Pharmacogenetics applies to inherited traits and

genetic polymorphisms. Polymorphism refers to
stable allelic variations found in the population
(occurring at a frequency > 1%) that result in altered
protein activity.
 Pharmacogenetic Drug Interactions

Genetic differences in drug metabolism are result of variation

in alleles for genes that code for enzyme responsible for the
drug metabolism

Polymorphism can occur in any enzyme system, including the

Cytochrme P450 hepatic enzymes and mixed oxidase and
N- acetyltransferase system.

Some gentic changes inactivate or reduce enzymatic

activity(resulting PM) Leading to increase in the substrate drug

Gene duplication may increase enzymatic activity(resulting EM/UM)

Leading to lower level of substrate drug.
Pharmacogenetic Drug Interactions
 Pharmacogenetic Drug Interactions

Isoenzyme Inhibitor Substrate Effect of EM/UM Effect of PM on

on the substrate the substrate

CYP2D6 Diphenhy Metoprolol Increased 61% Little change

dramine

CYP2D6 Quinidine Venlafexin Increased 12 No change

times

CYP2D6 Fluxetine Resperidone Increased 4 Increased 1.3

times times
Herb - Drug Interactions
 Herb-Drug Interactions Limitations
 Since not regulated by FDA, safety & efficacy not
required
• Little information available regarding drug interactions
 Extrapolation of data to available products difficult
• Independent lab tests many products
(http://www.consumerlabs.com/)

 Drugs with narrow therapeutic windows are at grater

risk
 Drug- herbal interaction can occur as pharmacokinetic
or pharmacodynamic interaction
 Herb - Drug Interactions
Herbal Interacting Proposed Mechanism Clinical Effect
Product Drug
Denshen Warfarin Decreased warfarin metabolism Increased effects of
warfarin
Dong Quai Warfarin ? Increased INR
Ginkgo Warfarin Inhibition of platelet aggregation Increased warfarin effects
Kava Alprazolam Additive effects Increased CNS depression
Melatonin Fluvoxamine Increased melatonin serum Increased drowsiness
concentration
Epidrine Coticosteroids Increased metabolism Decreased concentration
Green tea Warfarin Green tea contains vitamin K Decreased anticoagulation
St. John's wort Indinavir, Enzyme induction by St. John's Decreased concentration
cyclosporine, wort of substrate
warfarin
St. John's wort Digoxin Induction of p-glycoprotein Decreased serum digoxin
levels
 St. John’s wort: CYP3A4 Induction Effects

Indinavir Indinavir + SJW

 8 normal volunteers
18

16
 Indinavir AUC determined
Indinavir Cp (µg/ml)

14

12 before and after 14 days

10
SJW 300 mg TID
8

6  Indinavir AUC decreased

4

2 by 57 ± 19% in presence
0
0 0.5 1 2 3 4 5
of SJW
Time

Piscitelli SC et al. Lancet 2000;355:547-8

 Garlic - Saquinavir Interaction

 N = 10 healthy subjects
3500
 Saquinavir 1200 mg TID x
3d - AUC 3000

AUC (h*ng/mL)
2500
 Garlic caplets BID x ~3
weeks 2000

 Repeat saquinavir AUC 1500

 Discontinue garlic x 10 1000

days 500

 Repeat saquinavir AUC 0

Saq + Saq
Saq Garlic

Piscitelli S et al. Clin Infect Dis 2002;34:234-238

Food – Drug/nutrient
Interactions
 Food – Drug Interactions
Food – drug interaction can occur as pharmacokinetic
or pharmacodynamic interaction
 Food-Drug Interactions

 Food can influence the bioavailability of a drug.

• Quinolone antibiotics complexes calcium(found in
milk product)
• Indinavir - rapidly absorbed in fasted state, AUC
and Cmax decreased by ~80% with high
calorie/fat/protein meal
• Saquinavir - administration with high fat meal
increases AUC by ~570% for this low F drug (4%)
 Food-Drug Interactions

Indinavir +/- food Itraconazole caps +/- food

With food

Fasted

Pharm Res. 1999 May;16(5):718-24. Antimicrob Agents Chemother.

1993 Apr;37(4):778-84.
 Food-Drug Interactions
 Food can be metabolized by the same liver enzymes
that metabolize drugs
• Flavinoids in grapefruit juice can inhibit gastro-
intestinal CYP3A4 and first pass metabolism

 Can increase concentrations of various CYP3A4

substrates - esp. those with low F
• Saquinavir AUC increases 50 - 200%
• Benzodiazepines
• Calcium channel blockers
• Lovastatin
 Food-Drug Interactions

 Food can pharmacodynamically antagonize the

effect of some drug:
• Spinach, broccoli provides dietary sources of
vitamine K, which antagonizes the effect of warfarin.

 Food can contain pharmacologically active

compounds:
• MAOI inhibit the metabolism of tyramine from
tyramine-containingfoods such as red wine and
cheese. The increase level of tyramine cause
hypertensive crisis.
Food – nutrient Interactions
 How Might Drugs Affect Nutritional
Status?
 Drugs that Affect Intake
• Loss of Appetite or taste
 Drugs that Affect Nutrient Absorption
 Drugs that Affect Nutrient Metabolism
• Antivitamins
• Monoamine Oxidase Inhibitors(MAOI)
• Excretion of Nutrients
• Drug-Induced Electrolyte Alterations
 Drugs that Affect Intake

 Appetite suppressants:
• Ritalin used with hyperactive children
 long-term use may result in growth-retardation
 catch-up growth may occur when discontinued

• Cisplatin: a cytotoxin agent used in cancer

therapy
 causes nausea, vomiting, and reduced food intake
Drugs That Affect Nutrient Absorption

 Luminal Effects:
• Influencing Transit Time
 Laxatives
• Bile Acid Activity
 Cholestyramine sequesters bile acids
» inhibits fat digestion
• Change of pH
 Antacids change pH and reduce absorption of Ca,
Mg, Fe and Zn
Drugs that Affect Nutrient Metabolism

 Inhibition of Synthesis of Certain

Enzymes by Competing for vitamins or
Vitamin Metabolites necessary for their
structure
• Methotrexate used in treatment of leukemia
and rheumatoid arthritis
 This breaks down folate and induces a folate
deficiency
– DNA synthesis is stopped
 Monoamine Oxidase Inhibitors
 Common Interaction: MAOI and pressor amines in foods
• Two classes of biologically active amines
 psychoactive: neurotransmitters
– norepinephrine and dopamine
 vasoactive: pressor amines
– tyramine, serotonin, histamine
 these are found in many foods but are rarely a problem because
they are quickly deaminated

 However, with drugs that inhibit amine removal, some

foods containing these substances aren’t as well tolerated
• eg: tyramine containing foods eaten while on MAOI
 Increases blood pressure
• Antidepressant: Phenelzine sulfate
 Pt needs to avoid tyramine containing foods
– cheese, smoked fish, chianti wines
– meat extracts, beer, ale,
 Excretion of Nutrients

 Some drugs displace a nutrient from

plasma binding site and make it available
for kidney filtering
• D-penicillamine is used to treat heavy metal
poisoning
 It chelates the intended metal and makes it
available for kidney removal
 This also chelates other metals and removes them
from the circulation and induces a deficiency
– eg: Zinc
 Electrolyte Alterations

 Thiazide: a loop diuretic that enhances Na

loss
• also increases K loss
• K supplements may be required
 Recognizing Drug Interactions

 High index of suspicion

• Patient’s demonstrating exaggerated toxicity or
drug effects
 Patient could also be poor metabolizer of dependent
isozyme
 Genotyping may aid in future, but would not pick up
“phenocopy” effects
• Patient’s demonstrating treatment failure or
loss of drug effect
 Induction vs. absorption interactions
 Management of Drug Interactions

Every pharmacist should develop a plan

for handling potential or known drug
interactions.
Here are some suggestions to use for
evaluating medications and patient profiles
for known and potential drug interactions
 Management of Drug Interactions

 Develop a list of medications that are commonly

associated with DI.

 Review the patient profile, including drug history

and patient risk factors
 Management of Drug Interactions
 Next, look at the medication regimen and try to
ascertain the therapeutic plan. Some things to look
for:
➢ Is the new medication at a high dose?
➢ How long is the medication going to be used?
➢ What route is being used?
➢ Will adjusting the dosing times avoid the interaction?
➢ In what sequence are the interacting medications being
started?
 Management of Drug Interactions

 Determine the probability of a clinically

significant drug interaction.
 Suggest a different drug if there is a high
probability for a clinically significant drug
interaction.
 Monitor the patient for adverse events.
 Reevaluate the patient profile and drug
history when changing drug therapy
 Drug Interaction

 Evaluate the risks of drug therapy with

respect to patient’s possible genotype and
status of drug metabolism

 Educate patient, patient’s family and other

health care practitioners caring for patient
about the importance of drug compliance,
about the sign of toxicity, the risk of
concomitent herbals and the use of OTC
medication