DRUG INTERACTIONS

ARLENE M. DIAZ M.D , FPSECP

Department of Pharmacology
MHAM SWU COLLEGE OF MEDICINE

DRUG INTERACTIONS
The administration of one drug (A) can alter
the action of another (B)
PHARMACODYNAMIC INTERACTIONS
> modification of the pharmacologic effect of
B without altering its concentration in the
tissue
PHARMACOKINETIC INTERACTIONS
> alteration of the concentration of B that
reaches its site of action

PHARMACODYNAMIC INTERACTIONS
I. INTERACTIONS BASED ON OPPOSING ACTIONS OR
EFFECTS

1. Beta adrenoreceptor antagonists VERSUS beta

adrenoreceptor agonists
2. Antimuscarinics e.g atropine on ACH VERSUS
competitive or on inhibitor of
acetylcholinesterase e.g neostigmine on
nondepolarizing neuromuscular blocking agents
e.g tubocurarine
3. Mixed agonist-antagonist
(pentazocine) ;
VERSUS pure agonist e.g naloxone

PHARMACODYNAMIC INTERACTIONS
II. INTERACTIONS BASED ON ADDITIVE EFFECTS
Tricyclics PLUS diphenhydramine/ promethazineexcessive atropine like effects
H1 receptor antagonists + alcohol> marked
sedation
Sedative hypnotics + opiates/alcohol
Warfarin PLUS aspirin, quinidine, thrombolytics,
thyroid hormones

PHARMACODYNAMIC INTERACTIONS

Antihypertensives plus another

antiHPN

Diuretics lower plasma potassium

concentration> cardiac glycoside
action> glycoside toxicity
MAOI ..> noradarenaline
storedtoxic effects with ephedrine or
tyramine

Pharmacodynamic Interactions
SYNERGISTIC EFFECT
Sulfonamides & trimetoprim
Pyrimethamine + sulfadoxine
POTENTIATING EFFECT
> Clavulanic acid + Amoxycillin

PHARMACOKINETIC INTERACTION
I ABSORPTION

GIT absorption slowed by

inhibit gastric emptying(atropine/opiates)
Accelerated by drugs which hasten gastric
emptying (metoclopramide)
Pharmaceutical interactions: calcium/iron
forms insoluble complex with tetracycline &
retards absorption

PHARMACOKINETIC INTERACTION
Cholestyramine binds with digoxin &
warfarin: prevent absorption
Epinephrine + local anesthetic
injection,,,>slows absorption & prolongs
its local effect

PHARMACOKINETIC INTERACTION
II. DISTRIBUTION
Displacement of a drug from binding sites
Sulfonamides can displace methotrexate,
phenytoin, sulfonylureas, & warfarin
Phenylbutazone displaces warfarin
ASA displaces methotrexate
Quinidine, verapamil & amniodarone displace
DIGOXIN

PHARMACOKINETIC INTERACTION
III. DRUG METABOLISM
ENZYME INDUCTION
ENZYME INHIBITION

Drugs that significantly induce P450

mediated drug metabolism in humans
CYP
family
induced

IMPORTANT
INDUCERS

Drugs Whose
Metabolism is
Induced

1A2

Carbamazepine
Phenobarbital, Rifampin
Omeprazole

Acetaminophen, clozapine
Haloperidol, tricyclics
theophylline

2C9

Phenytoin, rifampin,
phenobarbital, primidone

Barbiturates, chloramphenicol
Ibuprofen, phenytoin, steroids
Tolbutamide, warfarin

2C19

Carbamazepine,
phenobarbital, phenytoin

Tricyclics, phenytoin
topiramate, warfarin

Drugs that inhibit P450 mediated drug metabolism in

humans
CYP
family
induced

INHIBITORS

Drugs Whose
Metabolism is Inhibited

1A2

Cimetidine,
fluoroquinolones,
grapefruit
Macrolides, INH, zileuton

Acetaminophen, clozapine,
haloperidol. Theophylline,
tricyclic, warfarin

2C19

Amniodaron,e, isoniazid
chloramphenicol,
metronidazole, SSRI

Barbiturates, ibuprofen
chloramphenicol, phenytoin
Steroids, chlorpromazine

2C19

Omeprazole, SSRI

Phenytoin, warfarin

2 D6

Amniodarone, cimetidine
Quinidine, SSRI

antidepressants, opioids
Lidocaine, flecainide

PHARMACOKINETIC INTERACTION
IV. DRUG EXCRETION
1. By altering protein binding and hence
filtration
2. By inhibiting tubular secretion
3. By altering urine flow and/or urine pH

Drugs that inhibit renal tubular secretion

DRUGS CAUSING INHIBITON
DRUGS AFFECTED
====================================
Probenecid, Sulfinpyrazone
PENICCILLIN
Phenylbutazone, Sulfas
INDOMETACIN
ASA, Thiazides
AZIDOTHYMIDINE
Indomethcin
====================================
Verapamil, Quinidine
DIGOXIN
Amiodarone
====================================
ASA, NSAID
METHOTREXATE

Some important drug interactions

Drug or Drug
Group

Drugs Involved

Comment

Alcohol

Sedative hypnotics, opioid analgesic,

tricyclic antidepressants, antihistamines

Additive CNS depression,

sedation, ataxia , increased risk
of accidents

Aminoglycosides

Loop diuretics

Enhanced ototoxicity

Antacids

Iron supplements, fluoroquinolones,

Ketoconazole, tetracyclines

Decreased gut absorption, due

either to reaction with the drug
affected or to reduced gut acidity

Antibiotics

Estrogens, including oral contraceptives

Many antibiotics lower estrogen

levels and reduce contraceptives
effectiveness

Antihistamines
(H1-blockers)

Antimuscarinics, sedatives

Additive effects with the drugs

involved

Antimuscarinic
drugs

Drugs absorbed from the small intestine

Slowed onset of effect because

stomach emptying is delayed

Some important drug interactions

Drug or Drug
Group

Drugs Involved

Comment

Barbiturates,
especially
phenobarbital

Azoles, calcium channel blockers,

propanolol, quinidine, steroids,
warfarin, and many other drugs
metabolized in the liver

Increased clearance of the affected

drugs due to enzyme induction,
possibly leading to decreases in drug
affectiveness

Beta-blockers

Insulin
Prazosin

Masking of symptoms of hypoglycemia

Increased first-dose syncope

Bile-acid-binding
resins

Acetaminophen, digitalis, thiazides,

thyroxine

Reduced absorption of the affected

drug

Carbamazepine

Doxycycline, estrogen, haloperidol,

theophylline, warfarin

Reduced effect because of induction

of metabolism

Cimetidine

Benzodiazepines, lidocaine,
phenytoin, quinidine, theophylline,
warfarin

Increased effect due to inhibition of

hepatic metabolism

Disulfiram,
metronidazole,
certain
cephalosporins

Ethanol

Increased hangover effect of ethanol

because aldehyde dehydrogenase is
blocked

Some important drug interactions

Drug or Drug Group
Drugs Involved

Comment

Erythromycin

Cisapride, quinidine, sildenafil,

theophylline

Ketoconazole and
other azoles

Benzodiazepines, cisapride,
Risk of toxicity due to inhibition of
cyclosporine, fluoxetine,
metabolism of these drugs
lovastatin, omeprazole, quinidine,
tolbutamide, warfarin

MAO inhibitors

Catecholamine releasers
(amphetamine, ephedrine)
Tyramine-containing foods and
beverages

Nonsteroidal antiinflammatory drugs

Anticoagulants

Increased NE in sympathetic nerve

endings released by the interacting
drugs
Hypertensive crisis

Loop diuretics, thiazides

Increased bleeding tendency because

of reduced platelet aggregation
Decreased antihypertensive efficacy
of ACE inhibitor
Reduced diuretic efficacy

Doxycycline, methadone,
quinidine, steroids, verapamil

Increased metabolism due to enzyme

induction; decreased efficacy

ACE inhibitors

Phenytoin

Risk of toxicity due to inhibition of

metabolism of these drugs

Some important drug interactions

Drug or Drug
Group

Drugs Involved

Comment

Quinidine

Digoxin

Increased digoxin levels due to

decreased clearance; displacement
may play role

Rifampin

Azole antifungal drugs,

corticosteroids, methadone,
theophylline, tolbutamide

Decreased efficacy of these drugs

due to induction of hepatic P450
isozymes

Salicylates

Corticosteroids
Heparin, warfarin
Methatrexate

Additive toxicity to gastric mucosa

Increased bleeding tendency
Decreased clearance causing
greater methotrexate toxicity
Decreased uricosuric effect

Sulfinpyrazone

Some important drug interactions

Drug or Drug Group
Drugs Involved

Comment

Selective serotonin
reuptake inhibitors

MAO inhibitors, meperidine,

tricyclic antidepressants

Serotonin syndrome, hypertension,

tachycardia, muscle rigidity,
hyperthermia, seizures

Thiazides

Digitalis

Increased risk of digitalis toxicity

because thiazides diminish
potassium stores

Lithium

Warfarin

Cimetidine, erythromycin,
lovastatin, metronidazole
Anabolic steroids, aspirin,
NSAIDs, quinidine, thyroxine
Barbiturates, carbamazepine,
phenytoin, rifampin

Increased plasma levels of lithium

due to decreased total body water
Increased anticoagulant effect via
inhibition of warfarin metabolism
Increased anticoagulant effect via
pharmacodynamic mechanisms
Decreased anticoagulant effects
due to increased clearance of
warfarin via induction of hepatic
P450 isozymes

ASSIGNMENT :
IN TABULATED FORM GIVE THE DIFFERENT DRUG INTERACTIONS AND WRITE IN
THE FOLLOWING :
IST COLUMN: DRUG OR DRUG GROUP

2ND COLUMN : PROPERTIES PROMOTING DRUG INTERACTIONS

3RD COLUMN : CLINICALLY DOCUMENTED INTERACTION

SOURCE : BASIC AND CLINICAL PHARMACOLOGY BY KATZUNG

CHAPTER 66 PAGE 1138- 1149

 For the Lord is good and

His love endures forever,
His faithfulness continues
through all generations.
Psalm 100:5