Drug Interactions

DRUG INTERACTIONS

06/03/2013

Dr Rajesh Basavaraj, PG, Dept. of Pharmacology.

DRUG INTERACTIONS
Def: Modification of response to one drug by another drug when they are administered simultaneously or in quick succession • It may result into beneficial effects or into adverse effects

KD Tripathi, 6th ed.

Drug interactionslikely in following situations
• Self medication
• Treatment by semi qualified paramedics / quacks • Drugs having steep DRC with low safety of margins

• Drugs having enzyme inducing/inhibiting effects
• Drugs having zero order/mixed order kinetics • Drugs that are used for prolonged period with precise maintenance of plasma concentration

Regular medication drugs (likely to be involved in drug interactions)
• Antidiabetics
• Antihypertensives • Antianginal drugs • Antiepileptic drugs • Antiparkinsonian drugs

• Oral contraceptives
• Antiasthamtic drugs • Corticosteroids • Psychopharmacological agents • Anti-TB & anti-HIV drugs

Risky drugs
o affect vital processes - Warfarin, CPZ, morphine o saturable kinetics - phenytoin theophylline salicylates o steep DRC - verapamil, L-Dopa, chlorpropamide

o demonstrate dose dependent toxicity - digoxin, Mtx, lithium aminoglycosides
o prophylactic action - OCPs, cyclosporine

o high PPB ability - NSAIDs oral anticoagulants sulfonylureas

Vulnerable patients
• Elderly pts. receiving many drugs • Pts. with hepatic / renal disease • Pts. with unstable disease
▫ epilepsy, diabetes mellitus, cardiac disease

• Pts. dependent on drug therapy for survival
▫ transplant recipients, Addison’s disease

• Pts with more than one prescribing doctor

Adverse drug-drug interactions
A. In vitro drug interactions B. In vivo drug interactions

In vitro drug-drug interactions
Drugs
Thiopentone sodium + SCh/ morphine

Mixed into
In the same syringe

Result
Precipitation / activation
Inactivation of heparin

Hydrocortisone/gentamicin In the same syringe + Heparin

Hydrocortisone + Penicillin In the same syringe
Penicillin + Gentamicin Noradrenaline In the same syringe In i.v infusion fluid – NS or BT

Inactivation of penicillin
Mutual inactivation Oxidized

IN VITRO DRUG-DRUG INTERACTIONS…
Aminophylline i.v soln. i.v epinephrine, erythromycin or cephalothin In i.v infusion fluid – 5% dextrose Into blood / plasma, amino acid soln., mannitol soln., NaHCO3 soln., heparin i.v These drugs get decomposed at alkaline PH of aminophylline Drugs are precipitated in the acidic PH of dextrose soln. Get inactivated or precipitated

Na+ salts of phenytoin, barbiturates, heparin, penicillin & sulfonamides Almost all drugs (as a rule)

IN VIVO DRUG-DRUG INTERACTIONS
A. Pharmacokinetic interactions B. Pharmacodynamic interactions

Pharmacokinetic interactions
o Alteration of the concentration of object drug that reaches its site of action o consequently the intensity of response will be altered

Pharmacokinetic interactions…
Drug absorption: • Due to formation of insoluble or poorly absorbable complexes in gut
 atropine and its substitutes–delay gastric emptying↓ intestinal absorption of other drugs

 prokinetic drugs- hasten gastric emptying- ↑ intestinal absorption of other drugs
 milk, antacids containing Ca2+, Mg2+, Al3+ and iron↓ absorption of tetracyclines  erythromycin/ tetracyclines- ↑ bioavailability of digoxin  adrenaline + LA  Systemic antacids + Omeprazole

Pharmacokinetic interactions…
Drug distribution: • Mainly due to displacement of one drug by another from its binding site on plasma proteins
▫ sulfonamides displace bilirubin in neonates- kernicterus

▫ salicylates and sulfonamidestolbutamide and Mtx

displace

warfarin,

▫ quinidine, verapamil and amiodarone- displace digoxin and also ↓ its excretion (by inhibiting P-glycoprotein) ▫ direct curtailment of drug distribution  protamine sulfate – heparin  desferrioxamine - iron

Pharmacokinetic interactions…
Drug metabolism: Enzyme induction: 1-2 wks to develop
Enzyme inducer Phenobarbitone Phenytoin, CBZ Glucocorticoids Pioglitazone Rifampicin Phenobarbitone Enzyme induced CYP3A4 Drugs affected Midazolam, alprozolam Barbiturates Ritonavir, CCBs Macrolides OCPs, Warfarin, Losartan Ibuprofen, Tamoxifen

CYP3A4 CYP2C9

Smoking Omeprazole
INH Chronic alcohol intake

CYP1A2
CYP2E1

Theophylline, Warfarin Imipramine, PCT
Halothane, PCT Ethanol

Effect of rifampicin on the metabolism and anticoagulant action of warfarin

Pharmacokinetic interactions…
 Microsomal enzymes- liver, but also in lungs CYP1A2 in smokers Clinical significance of enzyme induction: • Consequences of ↑ drug metabolism  ↓ plasma levels – ↓ therapeutic effect of coadministered drug  Inactive metabolite  Active metabolite

• Enzyme induction- toxicity
• Therapeutic benefits

Pharmacokinetic interactions…
Enzyme inhibition: • Hepatic microsomal mixed function oxidase (MFDs), MAO, xanthine oxidase, aldehyde dehydrogenase
Inhibitors Cimetidine Enzyme inhibited Hepatic microsomal MFDs Drugs affected Phenytoin, warfarin Antidepressants, Diazepam Theophylline, quinidine Phenytoin, Primidone Phenobarbitone Theophylline, CBZ Warfarin, Cyclosporine Theophylline

Sodium valproate Erythromycin Fluoroquinolones except ofloxacin

Hepatic microsomal MFDs Hepatic microsomal MFDs Hepatic microsomal MFDs

Pharmacokinetic interactions…
Chloramphenicol Verapamil, diltiazem Allopurinol Hepatic microsomal MFDs Terfenadine Phenytoin, warfarin Hepatic microsomal MFDs Theophylline, CBZ Cyclosporine Xanthine oxidase 6-MP, azathioprine

MAO-Is
Disulfiram Metronidazole Chlorpropamide Cefoperazone Carbidopa Ecothiophate

MAO
Aldehyde dehydrogenase

Morphine, pethidine
Alcohol, phenytoin Warfarin

Peripheral dopa decarboxylase AChE

L-Dopa Suxamethonium

Pharmacokinetic interactions…
Clinical significance of enzyme inhibition: • Potentially adverse consequences  Cimetidine + dicumarol- enhanced bleeding  MAO-Is + Morphine - severe respiratory depression  Dicumarol/ chloramphenicol + Phenytoin - severe ataxia, drowsiness  Chloramphenicol/ ketoconazole + Terfenadine precipitate cardiac arrhythmias

• Therapeutically beneficial consequences  L-Dopa + carbidopa
 d-TC + neostigmine  Alcohol + disulfiram

Pharmacokinetic interactions…
Drug excretion

• Altering protein binding, and hence filtration
• Inhibiting tubular secretion • Altering urine flow &/or urine pH

Inhibition renal tubular secretion:
Drug(s) causing inhibition Probenicid, Phenlybutazone Sulfonamides, Aspirin Thiazide diuretics Verapamil Quinidine Amiodarone Indomethacin Aspirin NSAIDs Drug(s) affected Penicillin Indomethacin

Digoxin Furosemide Methotrexate

Pharmacokinetic interactions…
Alteration of urine flow and pH:

• Alkalinization of urine by NaHCO3 – ↑ excretion of acidic drugs
• Acidification of urine by ammonium chloride/ ascorbic acid- ↑ excretion of basic drugs • Loop and thiazide diuretics- ↑ proximal tubular reabsorption of lithium

Pharmacodynamic interactions
• Modification of the pharmacological effect of a drug without altering its concentration in tissue fluid • May result in  Synergism

 Antagonism
 Abnormal response

o Abnormal response
 Propranolol + Insulin / oral hypoglycemic drugsmasks symptoms of hypoglycemia→ predispose to hypoglycemic coma

Pharmacodynamic interactions…
Synergism
• Aspirin + Warfarin
• BZDs + Antihistaminics+ CPZ + Morphine+ Alcohol • d-TC + Aminoglycosides

Antagonism
• CNS stimulants + Depressants
• Thiazides + Oral hypoglycemic drugs • NSAIDs + β-blockers/ ACE-Is • Atropine + ACh / Anti-ChEs • d-TC + Ach • ACE-Is + Spironolactone • L-dopa + Antipsychotics • Bacteriostatic + Bactericidal (tetracycline + penicillin)

• TCAs + Atropine
• Metoclopramide + Phenothiazines • Halothane + Adrenaline • Sildenafil + Organic nitrates • 2 bactericidal agents (penicillin + gentamicin) • Bacteriostatic + Bactericidal (Rifampicin + Dapsone)

Interactions due to change in fluid and electrolyte balance
• Hypokalaemia (Thiazide / Loop diuretics) + Digoxin/d-TC • Hypokalaemia + Lignocaine, quinidine, procainamide

• ACE-Is + K+ sparing diuretics
• Sodium depletion – lithium toxicity

Beneficial drug-drug interactions
Interactions leading to therapeutic effects

• Sulfamethoxazole + Trimethoprim (Cotrimoxazole)
• L-Dopa + Carbidopa • Nitrates + β blockers – angina

• Nitrates + CCBs – angina
• Thiazides + K+ sparing diuretics + β blockers – HTN • Probenicid + penicillin / cephalosporins • Amoxicillin + β-Lactamase inhibitor • ACE-Is + SGLT-2 cotransporter inhibitors

Beneficial drug-drug interactions…
Interactions providing advantage in management of poisoning and drug overdose • Naloxone- morphine poisoning / addiction • Protamine sulfate – heparin toxicity

• Physostigmine- atropine poisoning
• Neostigmine- reversal of muscle relaxation due to d-TC • Ethanol- methanol poisoning • Desferrioxamine / deferiprone- iron poisoning

Drug-laboratory test interactions
• Cephalosporins- false + ve urine glucose test • Cephalosporins- spurious serum creatinine levels • Diuretics- serum electrolyte tests, blood sugar levels • ACE-Is – hypokalaemia • MAO-Is- ↓ urinary VMA levels

Drug-food interactions
• Tyramine containing food items + MAO-Is – Cheese reaction • Spinach, broccoli- rich in Vit K – antagonize effects of warfarin • Food- ↑ bioavailability of griseofulvin, metoprolol, propranolol, phenytoin, dicumarol • Food- ↓ bioavailability didanosine of NSAIDs, tetracyclines,

• Protein rich diet- acidic urine- promotes excretion of basic drugs and vice-versa

Drug-food interactions…
• Grape, orange, garlic → inhibit CYP3A4 → ↑ bioavailability of indinavir, saquinavir, nimodipine, nifedipine, simvastatin, lovastatin • Acarbose - inhibits α-glucosidase- taken at the start of each meal- delays carbohydrate absorption • Tetracyclines complex with milk Ca2+ • Milk → ↓ iron absorption

Drug-herbal products interactions
• Ginger, Garlic & Ginkgo biloba- ↑ risk of bleedinganticoagulants and antiplatelet drugs • St. John’s wort  phototoxicity when sulfonamides and PPIs used with tetracyclines,

 summation effects with CNS depressants  ↓ plasma concentration of digoxin, cyclosporine, warfarin and protease inhibitors

Drug-herbal products interactions…
• Chinese ginseng  potentiates effects of caffeine, anticoagulants, antiplatelets, MAO-I and CNS stimulants  ↓ effects of antihypertensives, cardiac glycoside

• Aloevera’s latex  laxative properties, ↓ blood sugar- concurrent use of laxatives and hypoglycemics should be avoided  ↓ intestinal absorption of Vit K

REFERENCES:
• Essentials of medical pharmacology; KD Tripathi, 6th edition • Pharmacology and pharmacotherapeutics; RS Satoskar, SD Bhandarkar, Nirmala N Rege, 21st edition

• Rang and Dale’s pharmacology; HP Rang, MM Dale, JM Ritter, RJ Flower, 6th edition
• Basic and clinical pharmacology; Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition • Principles of pharmacology; HL Sharma, KK Sharma, 2nd edition