THERAPEUTIC

INCOMPATIBILITIE
S
(DRUG
INTERACTIONS)

Learning Objectives:

1. Define and know the causes and effect of drug

interactions.
2. To know the factors that contributes to drug
interaction.
3. Differentiate pharmacokinetics and
pharmacodynamics drug incompatibilities.
4. To be knowledgeable on different drug-drug,
drug-food, and drug-herbal interactions,
including their mechanisms.

Drug Interactions

Pharmacokinetic interactions are those that can affect the

processes by which the drugs are absorbed, distributed,
metabolized, or excreted. AN AGENT ALTERS THE ADME OF
THE SECOND AGENT
SUCH interactions may result in a change in the drug
concentration at the site of action with subsequent toxicity
or decreased efficacy.

Pharmacodynamic interaction are those in which drugs having

similar or opposing pharmacoligical effects are administered
concurrently and situations in which the sensitivity or
responsiveness of the tissues to one drug is altered by the
another.
THERE IS A CHANGE IN DRUG EFFECT BUT NOT IN THE

Drug Interactions
Drug interactions are said to occur when the effects
of one drug are changed by the presence of
another drug, herbal medicine, food, drink or
some environmental chemical agent.
Drug interactions are an increasingly important
cause of adverse drug reactions.

When dispensing medication against a prescription,

pharmacists should always consider the following points:

The patient
Other
medication

The dose of
the
medication

The
patients
condition

Determine who is the patient? Is it for a child, an adult or an

elderly person? This is very important or it needs to be
established because many of the other decisions you may
make about the patients therapy will utilize this
information.
Is the dose of the prescribed item suitable for the patient?
Doses of medication will differ for different patients. For
example, for many drugs, a childs dose will be less than
that for an adult. In addition, there are a number of patientspecific factors that will alter the dose.
The condition of the patient should be determined. Special
considerations for the presence of renal (kidney) or hepatic
(liver) problems.

Food-drug interactions
Drug herbal
supplements
Drug environmental
factors
Drug laboratory test
Drug disease
interactions

The concept of drug interaction often is extended to:

1. Food or certain dietary items influence the activity of a
drug.
2. Herbs or other natural products influence the activity of a
drug.
3. Environmental chemicals or smoking influences the
activity of a drug.
4. A drug causes alterations of laboratory test results
5. A drug causes undesired effects in patients with certain
disease states.
. One of the most important consequences of a drug
interaction is an excessive response to one or more agents

Factors Contributing to Drug

Interaction
Multiple
Prescribers

Multiple
pharmacologi
cal effect

Drug
Interactio
ns

Patient Noncompliance

Use of Non
Prescriptions
Products

Causes of Drug Interactions

Decreased drug activity with diminished efficacy
Increased drug activity with exaggerated or
unusual effects
Drugs with a narrow therapeutic range
Steep dose response curve
e.g. anticoagulant, oral contraceptives,
antiepileptics

Drugs with Narrow Therapeutic

Index
Anticoagulants
(warfarin, heparin)
Aspirin
Carbamazepine
Amino glycoside
antibiotics (gentamicin,
tobramycin)
Hypoglycemic agents

Levothyroxine sodium

Digoxin
Aminophylline

Theophylline
Valproic Acid

Lithium
Phenytoin
Procainamide

Quinidine sulfate

1.
2.
3.
4.
5.
6.

Using Drug-Interaction
Information

Interacting Drugs usually can be used together

Beneficial Interactions
Nature of Reports
Depth of Information
Current Literature
Recommendations and Therapeutic Alternative

Patients Variable

Age
Genetic factors
Disease states
Renal function
Hepatic function
Alcohol consumption
Smoking
Diet
Individual variation

THERAPEUTIC INCOMPATIBILITIES
Classifications:

Drug Interactions
Pharmacodynamics
Pharmacodynamics

Pharmacokinetics
Pharmacokinetics

A therapeutic incompatibility is a problem that occurs when

two or more drugs are administered to a patient.
Aka as drug interaction OBJECT DRUG THE ONE THAT IS
AFFECTED THEN PRECIPITANT OR INTERACTANT IA THE ONE
THAT INDUCES THE INTERACTION

Pharmacodynamic drug interactions are interactions

between drugs that have either similar or antagonistic
actions. Although drug interactions will affect different
patients differently, pharmacodynamic drug interactions are
easy to predict and occur in a majority of patients who take
the drugs affected. These interactions will, for example,
include drugs that compete at the same receptor site or
affect the same body systems. A pharmacist can use their

Pharmacokin
etic
interaction

Absorption

Changes in GI pH

The non-ionized form of the drug (more lipid soluble) will be

absorbed more readily than ionized form (more water
soluble).

Acidic drugs exist primarily in the non-ionized form in the

upper region of the GI tract (having a lower pH).

Common
Inteactions
Common drug
Drug Interaction
Bisacod
yl

Antacids/
H2
antagoni
st/ milk

Severe
irritatio
n

Common Drug Interaction

Ketoconaz
ole

Antacid/mil
k/H2
antagonist

Lessen
therapeuti
c effect

Alteration of Motility/Rate of
Alteration of Motility/Rate of
Gastric Emptying
Gastric Emptying

Common Drug Interaction

Cathartics

Other drugs

Decreased
effect of
drug

Common
Inteactions
Common drug
Drug Interaction
Tetracyclin
es

Metal
containi
ng
products

Poorly
absorbe
d
complex
es

Common
Inteactions
Common drug
Drug Interaction
Fluoroquinolone
s

Metal
containing
products/sucralf
ate

Reduced serum
adsorption

Result: Reduced serum adsorption of flouroquinolones such

as moxifloxacin.
Avoid: antacids, milk, iron supplements, yogurt and
sucralfate.

Common
Commondrug
Drug Interactions
Interaction
Anticholinergi
cs

Other
drugs

Decreas
e drug
absorpti
on

-can decrease GI motility and can influence drug

absorption. The effect may be a decreased in absorption,
since the reduced peristalsis may retard dissolution and the
slowing of gastric emptying may delay absorption from the
small intestine, or increased absorption if the drug is
retained for a longer period of time in the area from which it
is optimally absorbed.

Common
Commondrug
Drug Interactions
Interaction
Metocloprami
de

Other drugs

Decrease
drug
absorption

increases motility of the upper GI track, it should be

anticipated
that it may influence the absorption of other drugs
administered concurrently.

Common
Commondrug
Drug Interactions
Interaction
Antiinfective
agents

Food

Decreas
e drug
absorpti
on

The presence of food in the GI tract will reduce the

absorption of many anti-infective agents (except penicillin
V, amoxicillin, Doxycycline and minocycline).
It is generally recommended that the penicillin and
tetracycline derivatives as well as certain other antiinfective agents be given at least 1hr before meals or 2 hr
after meals, to achieve optimum absorption. For
erythromycin stearate formulations should be administered
at least 1 hr before meals or 2 hr after a meal, whereas
formulations of erythromycin ethylsuccinate may be given
without regards to meals

Pharmacokin
etic
interaction

Absorption

Alteration of GI Flora

The non-ionized form of the drug (more lipid soluble) will be

absorbed more readily than ionized form (more water
soluble).

Acidic drugs exist primarily in the non-ionized form in the

upper region of the GI tract (having a lower pH).

Common
Commondrug
Drug Interactions
Interaction
Antiinfective
agents

Anticoagula
nts

Enhance
effectivenes
s of
anticoagula
nt

Common
Commondrug
Drug Interactions
Interaction
Erythromycin/Tetracy
cline

Digoxin

Increase serum conc

of Digoxin

Effects of Food on Drugs

Acetaminophen, Aspirin, Digoxin

Decreased/delayed drug absorption

ACE inhibitors (captopril, lisinopril)

Significant decrease in serum drug

levels

Fluoroquinolones (ciprofloxacin,
levofloxacin,ofloxacin), Tetracycline

Avoid taking with antacids (esp. Mg

and Al types) and Iron products;
significantly decrease drug
absorption

Didanosine

Food in general and acidic

foods/juices significantly decrease
drug absorption

Saquinavir, Griseofulvin, Itraconazole, Food, especially high fat meals,

Lovastatin, Spironolactone
improves drug absorption; take with
food

Effects of Food on Drugs

Famotidine

Decreased/delayed drug
absorption

Ketoconazole

Acidic foods/juices and sodas

(eg, cola), significantly increase
drug absorption

Iron, Levodopa, most Penicillins,

Tetracycline, Erythromycin

High carbohydrate meals

decrease drug absorption

When the increased or decreased absorption effects of food are

undesirable, take drug on an empty stomach, either one hour before
or two hours after meals.

Common
Commondrug
Drug Interactions
Interaction
Theophylli
ne

Food

Decrease
drug
absorption

-food may have an effect on the absorption of theophylline

(except for controlled release)

Common
Commondrug
Drug Interactions
Interaction
Alendronate/
Risedronate

Food/ orange
juice/coffee/min
eral water

Reduced the
bioavailabilty

Food and even orange juice, coffee, and mineral water may
markedly reduce the bioavailability of alendronate and
risedronate.

Common
Commondrug
Drug Interactions
Interaction
Acarbose
and
Miglitol

Food

Maximum
effectiven
ess

-in this case food is important to obtain maximum benefit of

these drugs. Both are effective in the treatment of diabetes
mellitus because they delay the digestion of ingested
carbohydrates and reduce the elevation of blood glucose
concentrations following meals.
Recommendation: Maximum effectiveness is attained
when doses are administered at the start with the first bite
of each main meal

Common
Commondrug
Drug Interactions
Interaction
Grape fruit Extract

Calcium channel
blockers/ HMG-CoA
reductaseinhibitors/cyclospor
ine

High bioavailabilty

The bioavailability of these agents is generally low,

primarily as a result of extensive first-pass metabolism. lt
has been suggested that components of grapefruit juice
reduce the activity of the cytochrome P-450 enzymes
primarily CYP3A4) in the gut wall. As e result, larger
amounts of un-metabolized drug is absorbed, and serum
concentrations are increased.

DISTRIBUTION
The mechanisms by which drug interactions alter drug
distribution include:
* competition for plasma protein binding
* displacement from tissue binding sites

Displacement from tissue binding sites would tend to

increase the blood concentration of the displaced drug.
Ex: Elevation of serum digoxin concentration by
concurrent quinidine therapy = may lead to digoxin
toxicity

DISTRIBUTION
Protein-bound drugs that are given in large dosage
act as displacing agents
Ex: aspirin, sulphonamides, trichloroacetic acid
binds strongly to plasma albumin.

DISTRIBUTION

Drugs that alter protein-binding additionally reduce

elimination of the displaced drug:
Salicylates (NSAIDs) + Methotrexate
MTX

NSAIDS

free drug
Quinidine/Verapamil/Amiodarone + Digoxin =
displace and inhibit renal excretion of digoxin =
severe dysrhytmias

METABOLISM

ENZYME INDUCTION and ENZYME

ENZYME INDUCTION and ENZYME
INHIBITION
INHIBITION

METABOLISM

Enzyme inducers
Ex. barbiturates, carbamazepine, phenytoin, rifampicin
Enzyme inhibitors
Ex. allopurinol, amiodarone, androgens,
chloramphenicol, cimetidine, ciprofloxacin, diltiazem,
disulfiram, erythromycin, isoniazid

Enzyme induction does not take place quickly; maximal effects usually
occur after 7-10 days and require an equal or longer time to dissipate
after the enzyme inducer is stopped.

METABOLISM

Enzyme Induction drugs/substrates on

repeated administration, have the ability to
induce cytochrome P450
Phenobarbital + Warfarin = decrease in
anticoagulant effect
Levodopa + Pyridoxine = decrease effect of
Levodopa

= thrombus formation
Pyridoxine + Levodopa = levodopa activity (antidote)

increasing or enhancing the rate of the synthesis of

microsomal metabolizing enzymes

reducing the rate of degradation resulting in decrease

in the pharmacological activity of the inducing drug or
other drugs co administered with it
If the drugs are transformed into reactive metabolites, enzyme
induction may exacerbate metabolite-mediated tissue toxicity.

Enzyme Inhibition certain drugs may inhibit

cytochrome P450 enzyme activity:
Alcohol + Disulfiram = inhibits activity of
aldehyde dehydrogenase, inhibiting
oxidation of acetaldehyde
Cimetidine +
Diazepam/Carbamazepine/Phenytoin =
increase the effect of Drug B
Allopurinol + Mercaptopurine/Azathioprine =

binding to the cytochrome molecule (heme-iron), and

thereby
competitively inhibiting the metabolism of other drugs
irreversibly inhibits the enzyme by covalent interactions
alkylates the enzyme protein and therefore inactivates
the enzyme

Common
Commondrug
Drug Interactions
Interaction
Theophylline

Macrolides
and
Floroquinolo
nes

Theophylline
toxicity

The bioavailability of these agents is generally low,

primarily as a result of extensive first-pass metabolism. lt
has been suggested that components of grapefruit juice
reduce the activity of the cytochrome P-450 enzymes
primarily CYP3A4) in the gut wall. As e result, larger
amounts of un-metabolized drug is absorbed, and serum
concentrations are increased.

Common
Commondrug
Drug Interactions
Interaction
CCB

Carbamazep
ine

Increase
Carbamazep
ine

Enzyme induction
Examples of powerful enzyme inducers:
Rifampicin
Barbiturates
Carbamazepine
Phenytoin
Cigarette smoking
Chronic alcohol use
St. Johns wort
Phenobarbital

Enzyme inhibition
Inhibitors:
Cimetidine
Ciprofloxacin
Fluoxetine
Omeprazole
Clarithromycin
Erythromycin
Grapefruit Juice

EXCRETION

The most important clinical implications of

altering renal excretion involve the use of drugs
that are excreted in their unchanged form or in
the form of an active metabolite.
Most drug interactions of elimination system
happen at site of active anion and cation
transport with the object drug displaced by the
precipitant drug.

Most drugs and their metabolites are excreted via the kidneys.
Renal elimination of drugs happens by glomerular filtration,
active tubular secretion and by passive tubular re-absorption.

EXCRETION
The main mechanisms by which one drug can affect the rate
of renal
excretion of another are:
by altering protein-binding and hence rate of filtration

Methotrexate NSAIDs = eg. ketoprofen inhibit the active

renal tubular secretion of methotrexate

by inhibiting tubular secretion

Probenecid + Penicillin= secretion to prolong its action.

by altering urine flow and/or urine pH

Diuretics - increase the urinary secretion of other drugs and
lowers the plasma concentrations of the co-administered drugs.
Salicylates = Acidifying Agents
Amphetamines = Alkalinizing Agents
The effect of urinary pH on the excretion of weak acids and bases
is put to use in the treatment of poisoning.

Group Report

Divide the class into 7 groups

COMMON DRUG-DRUG INTERACTION (20 D-D interaction)

Group No. 1 OTC Drugs
Group No. 2 and 3 Cardiovascular Drugs (Anti-thrombotic,
anticoagulant, antihypertensive drugs)
Group No. 4 Oral Hypoglycemic agents
Group No. 5 Oral hypolipidemic agents
Group No. 6 Vitamins and antineoplastic agents
Group No. 7 Antipsychotic, antidepressant, anxiolytic agents

Pharmacodyna
Pharmacodyna
mic
mic
Interaction
Interaction
Are those where the effects of one drug are
Are those where the effects of one drug are
changed by the presence of another drug at its
changed by the presence of another drug at its
site of action.
site of action.

Pharmacodyna
Pharmacodyna
mic
mic
Interaction
Interaction

Antagonistic interactions
Additive or synergistic interactions
Drug or neurotransmitter uptake interactions
Drug-food interactions

Common
Drug-Food
Common drug Interactions
Interaction
MAOIs

Food with
tyramine
content

Hypertensi
ve crisis/
inc release
of NE

Alteration of Metabolism in the Gl Tract. The absorption of

certain agents is influenced by the extent to which they are
metabolized in the GI tract. Tyramine is metabolized by
MAO, and normally these enzymes are found in the
intestinal wall and in the liver. However if these enzymes
are inhibited, large quantities of unmetabolized tyramine
can accumulate and act to release norepinephrine from
adrenergic neurons where greater-than-usual stores of this
catecholamine are concentrated as a result of MAO
inhibition.

Pharmacodyna
Pharmacodyna
mic
mic
Interaction
Interaction

Drugs Having Similar Pharmacological Effects

CNS Depressants
E.g.sedative hypnotics
Antipsychotics
TCA
Opiod analgesics
Antihistamines
Alcohol-CNS depressants
Drugs Having Anticholinergic Activity
Drugs Exhibiting Hypotensive Effect

 Alteration of Electrolyte Concentrations

Certain drugs can alter the concentrations of
electrolytes such as Na and K.
Digoxin + Diuretics (thiazide) = arrythmia
ACE inhibitors + Potassium Sparing Diuretics =
hyperkalemia
Lithium + Diuretics = Lithium Toxicity

Reducing The Risk of Drug

Identify the patient riskInteractions
factors
Take a thorough drug history
Know the actions of the drugs being taken
Consider therapeutic alternatives
Avoid complex therapeutic regimens when possible
Educate the patient
Monitor therapy
Individualize therapy

DRUGS MEDICINAL HERBS

INTERACTION

Medicinal Herb

Drug

Interaction

Chamomile

Warfarin
Other Anticoagulants

Increase risk of
bleeding

Phenobarbital
Other barbiturates
Other sedatives

Intensifies or
prolongs the sedative
effect

Iron

Reduces iron
absorption

Garlic

Warfarin
Other anticoagulants

Increase risk of
bleeding

Ginkgo

Warfarin
Other anticoagulants
Aspirin
NSAIDS

Increase risk of
bleeding

Phenytoin
Reduces
Other anticonvulsants effectiveness of
anticonvulsant
MAO inhibitors

Intensifies
antidepressant effect
and increase risk of
headache, tremors,

Medicinal Herb

Drug

Interaction

Ginseng

Warfarin
Other anticoagulants
Aspirin
NSAIDS

Increase risk of bleeding

Hypoglycemic drugs

Intensifies hypoglycemic
effect

Corticosteroids

Intensifies SE

Estrogen replacement
therapy

Intensifies SE

Digoxin

Increase serum level of

Digoxin

MAOi

increase risk of
headache, tremors,
manic episodes

Opium and derivatives

Reduces effectiveness

Medicinal Herb

Drug

Interaction

Licorice

Antiarrythmics

Negates antiarrythmic
effect by increasing the
heart rhythm

Digoxin

Increases risk of digoxin

toxicity by lowering
potassium levels
through increased urine
formation

Diuretics

Intensifies diuretic
effect causing rapid loss
of potassium

Primrose oil

Phenytoin

which may lower

seizure threshold

St. Johns wort

Cyclosporin

may decrease level of

the drug

Tamarind

Aspirin

Increase bioavailability
of ASA

Adverse Drug Reaction

Adverse Drug Reaction

is an unwanted or harmful reaction experienced after
the administration of a drug or combination of drugs
under normal conditions of use and suspected to be
related to the drug.
is any undesirable effect of a drug beyond its
anticipated therapeutic effects occuring during clinical
use.
A response to a drug that is noxious and unintended,
and that occurs at doses normally used in humans for
the prophylaxis, diagnosis or therapy of disease or for
the modification of physiological function.

ADR and ADE

ADR- Adverse Drug Reaction
is the result of the intrinsic properties of the drug and
cannot be prevented.
ADE- Adverse Drug Event
is an injury resulting from medical intervention related
to a drug and includes ADRs, but also includes preventable
reactions including those caused by human error.

Types of ADR
Type A Reaction
are extension of the drugs known
pharmacological action and are
responsible for the majority of ADRs.
Type B Reaction
includes idiosyncratic reactions,
immunological or allergic reactions and
carcinogenic/teratogenic reactions.

Pharmacologically
predictable
Dose dependent
Incidence
Morbidity
Mortality
Management

Type A

Type B

Yes

No

Yes
High
High
Low
Dosage
adjustment often
appropriate

No
Low
Low
High
Stop

Types of ADR
Type A
refers to a reaction that occurs from the
known pharmacological action of a drug
given to a patient in therapeutic doses
Type B
refers to totally abnormal effects that are
unrelated to the known therapeutic or
pharmacologic action of the drug.
Type C
is a dose-related reaction that is
observed after long term use of a drug.

Types of ADR

Type D
is a reaction to a drug that is manifested
long after drug exposure
Type E
is manifested by symptoms that result
from termination or sudden
discontinuation of the drug.
Type F
results from lack or insufficiency of drug
products, antimicrobial resistance, drug
instability, patient non-compliance,
expired or fake drugs and drug
interactions.
D= such as carcinogenesis and
teratogenesis.

Risk factors for ADRs

Age
Concurrent medicines
Duration of Therapy
Gender
Comorbid conditions
Narrow Therapeutic Index drugs
Ethnicity and Genetics

Common Adverse Drug

Reaction
Name of Drug

Adverse Reaction

Acetaminophen

Nausea, rash, headache

Naproxen

Dyspepsia, nausea, abdominal

pain, constipation, dizziness,
drowsiness, rash

Celecoxib

May increase risk of serious and

potentially fatal CV thrombotic
events
-headache, dyspepsia, diarrhea,
abdominal pain, nausea and
vomiting, rash, flatulence

Guaifenesin

Rash, vomiting, nausea

Common Adverse Drug Reaction

Name of Drug

Adverse Reaction

Digoxin

Dizziness, headache, diarrhea,

nausea and vomiting, anorexia,
weakness, bradycardia or
tachycardia, confusion, rash,
mental disturbance, apathy

Captopril

Rash, pruritus, taste changes,

hypotension, dizziness, fatigue,
cough, hyperkalemia, nausea and
vomiting

Amlodipine

Peripheral edema, headache,

fatigue, palpitations, dizziness,
nausea, flushing

Metoprolol

Fatigue, dizziness, diarrhea,

pruritus, rash, depression,
dyspnea, bradycardia

Nifedipine

Peripheral edema, headache,

dizziness, flushing, fatigue/
weakness, palpitations

Examples of Serious Adverse Drug

Reaction
Adverse Drug
Reaction

Types of Drugs

Peptic ulcers or
Oral
bleeding from the corticosteroids
stomach

Examples
Hydrocortisone
Prednisone

NSAIDS

Aspirin
Ibuprofen
Ketoprofen
Naproxen

Anticoagulants

Heparin
Warfarin

Examples of Serious Adverse Drug

Reaction
Adverse Drug
Types of Drugs Examples
Reaction
Anemia
Certain antibiotics Chloramphenicol
(resulting from a
decreased
production or
increased
destruction of red
blood cells)
Some NSAIDS
Phenylbutazone
Antimalarial and
anti tuberculosis
drugs in people
with G6PD

Chloroquine
Isoniazid
Primaquine

Examples of Serious Adverse Drug

Reaction
Adverse Drug
Reaction
Decreased
production of
white blood cells

Types of Drugs

Examples

Certain
antipsychotic
drugs
Chemotherapy
drugs

Clozapine

Some drugs used

to treat thyroid
disorders

Cyclophosphamid
e
Mercaptopurine
Methotrexate
Vinblastine
PTU

Examples of Serious Adverse Drug

Reaction
Adverse Drug
Reaction
Kidney Damage

Types of Drugs

Examples

Some anti TB
drugs
Iron supplement
in high dosage
NSAIDS in
repeated use of
excessive dosage

INH

Aminoglycoside
antibiotics
Some
chemotherapy

Gentamicin
Kanamycin
Splatin

Ibuprofen
Ketoprofen
Naproxen

Examples of Serious Adverse Drug

Reaction
Adverse Drug
Reaction
Liver damage

Types of Drugs

Examples

Some analgesics

Confusion and
drowsiness

Sedatives,
including many
antihistamines
Anti-depressants

Acetaminophen in
excessive doses
Diphenhydramine

Confusion and
drowsiness

Amitriptyline
Imipramine