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/ promethazine- excessive 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 stored…toxic 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

2 D6

Omeprazole, SSRI

Amniodarone, cimetidine

Quinidine, SSRI

Phenytoin, warfarin

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

Risk of toxicity due to inhibition of metabolism of these drugs

Ketoconazole and other azoles

Benzodiazepines, cisapride, cyclosporine, fluoxetine, lovastatin, omeprazole, quinidine, tolbutamide, warfarin

Risk of toxicity due to inhibition of metabolism of these drugs

MAO inhibitors Catecholamine releasers (amphetamine, ephedrine)

Tyramine-containing foods and beverages

Increased NE in sympathetic nerve endings released by the interacting drugs

Hypertensive crisis

Nonsteroidal anti-inflammatory drugs

Anticoagulants

ACE inhibitors

Loop diuretics, thiazides

Increased bleeding tendency because of reduced platelet aggregation

Decreased antihypertensive efficacy

of ACE inhibitor

Reduced diuretic efficacy

Phenytoin Doxycycline, methadone, quinidine, steroids, verapamil

Increased metabolism due to enzyme induction; decreased efficacy

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

Sulfinpyrazone

Additive toxicity to gastric mucosa

Increased bleeding tendency

Decreased clearance causing greater methotrexate toxicity

Decreased uricosuric effect

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

Lithium

Increased risk of digitalis toxicity because thiazides diminish potassium stores

Increased plasma levels of lithium due to decreased total body water

Warfarin Cimetidine, erythromycin, lovastatin, metronidazole

Anabolic steroids, aspirin, NSAIDs, quinidine, thyroxine

Barbiturates, carbamazepine, phenytoin, rifampin

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

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