Drug interactions

Drug Interactions

Topics covered• Introduction

• Drugs likely to be involved

• Drug food interaction

• Drug alcohol interaction

• Drug drug interaction

1. Pharmacokinetic

2. Pharmacodynamics

• Drug interaction during drug development

• Drug disease interaction

• Drug herb interaction

Drug interaction can be defined as the modifications of

the effects of one drug by the prior or concomitant

administration of another drug

Drug that precipitates the interaction - Precipitant drug

Drug whose action is affected - Object drug

Type of interactions

DI

Food

DrugDisease

Drugs likely involved in interactions

• Drugs highly bound to plasma

proteins

• Used for long term

• Enzyme inducers or inhibitors

• Two drugs simultaneously given

for same disease

Precipitating drugs

• Narrow therapeutic index

• Zero order kinetics

• Steep dose response curves

Object Drugs

Patient factors

• Hepatic damage

• Renal failure

• Elderly patients

• Multiple diseases

• Critically ill patients

Useful Interactions• Adrenaline with lignocaine• Probenecid wid penicillin

Increase duration of action

Synergistic effects

• Atropine in organophosphate poisoning• Naloxone in opiod poisoning

Reverse toxic symptoms

• Protamine with heparin• Desferroxamine with iron Neutralise the action

• Sulfamethoxazole with trimethoprim

Drug Food

Interactions

How drugs effect food???

Food intake

Alteration in gut flora

Nutrient absorption

Nutrient metabolism

Nutrient excretion

How food can effect drugs

Increase absorpti

on

Decrease

absorption

Irritation of

digestive tract

No effect

• Rifampicin- without food• Rifabutin- with food• Rifapentin- no effect of

food

Milk Fruit juice

Tea/coffee Alcohol

Swallowing of the medicine

• Erythromycin• Ketoconazole• celiprolol• Grapefruit

juice

• Tetrcayclines • Bisacodyl• Iron

supplements• Mercaptopurin

• Wine-tyramine reaction

• iron absorbtion

• theophylline

Drug Alcohol Interactions

In the absence of alcohol

After moderate alcohol consumption

In chronic heavy drinkers who are sober

In chronic heavy drinkers who are intoxicated

Class Names Interaction Effect

1. Analgesics AspirinAcetaminophen

Increase gastric emptyingInhibition of gastric ADHToxic metabolite of acetaminophen

Faster alcohol absorbtion

Liver damage

2. Anticonvulsant Phenytoin Induces phenytoin breakdown

Decrease effect

3. Antihistamines Chlorpheniramine Increase CNS effect sedation

4. Antidiabetics ChlorpropamideGlyburideMetformin

Increase risk of hypoglycemia

UnconsciousnessDisulfiram like reactionLactic acidosis

5. BZDs Diazepam Increase effect Sedation

6. H2 Antagonists Cimetidine Inhibits ADH Increases BAL levels

Drug Drug Interactions

DI

Outside the body

Syringe Iv fluids

Inside the body

Pharmacokinetic

Pharmacodynamic

Interactions outside the body• Mixing of the drugs in the same syringe

1. Thiopentone and succinylcholine

2. Carbenicillin inactivate aminoglycosides

3. Hydrocortisone inactivates penicillins

Interactions outside the body

• Mixing of the drugs in the same syringe

• Giving drug in i.v infusion

1. Quinopristin and Dalfopristin

2. Ampicillin, sodium salts of phenytoin, heparin

Unstable Infuse within

2-4hrs

Stable for 6-8 hrs

Stable for 12 hrs

Photosensitive drugs

Not infused after 6 hrs

Ampicillin Benzylpenicillin Fluoxacillin Amphoterecin CephaloridineErythromycin Diazepam Tetracycline Dacarbazine colistin

Stability of drugs in Saline or Dextrose solution

Prevention of Pharmaceutical Interactions

1. Give iv drugs by bolus

2. Do not add infusion solutions

3. Avoid mixing of drugs in the same infusion

4. Mix the drug thoroughly in the infusion

5. Use 2 separate infusion sites if drugs administered simultaneously

Interactions inside the body

Absorbtion Distribution

Excretion Metabolism

Surface area

Motility

Alter acidity

Alter P gp

Chelation

Absorbtion

• Chemical Interaction 1. Chelation Al 3+ , Mg 2+ + Prednisolone Insoluble Complexes Ca2+ + TC Formation of chelating compounds

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH

PPI Impair absorbtion of Ketoconazole

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer Cholestyramine inhibits absorbtion of Digoxin,warfarin

Sucralfate interferes with absorbtion of Phenytoin

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer • Altered Gut flora Broad spectrum antibiotics potentiate anticoagulants

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer • Altered Gut flora• Altered gastric emptying

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer • Altered Gut flora• Altered gastric emptying

Atropine/opiods reduce absorption of drugs

Purgatives decrease absorbtion of digoxin

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer • Altered Gut flora• Altered gastric emptying• Presence of food

Absorbtion

• Chemical Interaction 1. Chelation 2. Alteration in pH 3. Forming an absorbtive layer • Altered Gut flora• Altered gastric emptying• Presence of food• Alteration of drug transporters

Oral drug inhibitor transporterDigoxin quinidine P gpPaclitaxel Cyclosporin P gpmethotrexate Omeprazole BCRPirinotecan gefitinib BCRP

Effect on Transporters

Beneficial absorbtion interactions

Metoclopramide

Increases gastric emptying

Increases absorbtion of analgesic in treatment of acute attack of migraine

Distribution 1. Displacement from tissue binding sites

Distribution1. Displacement from tissue binding sites2. Displacement from plasma protein binding

Can be clinically important if 2 criteria are fulfilled

1. Drug should be highly protein bound (>90%) 2. Low apparent volume of distribution

Precipitant drugs involved3. Sulfonamides4. Salicylates5. Phenylbutazone

Clinical Relevance of PP Displacement???

10% 20%

20%

Unbound fraction

Bound fraction

12

Metabolism

Enzyme InductionS No. Precipitant drug Object drug

1. Alcohol Warfarin, Phenytoin2. Barbiturates Chlorpromazine, OCPs, Phenytoin3. Phenytoin Tolbutamide, OCPs4. Rifampicin Warfarin, Tolbutamide5. St. John’s Wort Carbamazepine, SSRIs, Warfarin

Metabolism

Metabolism

Enzyme Inhibition

S No. Precipitant Drug Enzyme Object drug1. Allopurinol Xanthine Oxidase Azathioprine2. Carbidopa Dopa decarboxylase L-Dopa3. Disulfiram Aldehyde

dehydrogenaseAlcohol

4. MAO Inhibitors Monomine Oxidase Amine containing foods

Metabolism

S.no Precipitant drug Object drug Effect

1. Cimetidine Diazepam CNS effects

2. Macrolides Theophylline Cardiac toxicity

3. Metronidazole Alcohol Disulfiram like action

4. Chloramphenicol Tolbutamide Hypoglycemia

Metabolism

Enzyme Inhibition

Excretion

S. No. Precipitant Drug Object Drug Result

1. Probenecid Penicillin Penicillin Retention

2. Quinidine Digoxin Digoxin Toxicity

3. Salicylates Methotrextate Methotrexate toxicity

4. Salicylates Uricosuric Drugs Reduced Uricosuria

Excretion

Pharmacodynamic Interactions

A) Direct Pharmacodynamic Interactions

1. Antagonism at same site

● Opiates with Naloxone

● Warfarin with Vitamin K


A) Direct Pharmacodynamic Inteactions 1. Antagonism at same site

2. Synergism at same site

● Effects of depolarising skeletal muscle relaxants potentiated by

antibiotics like aminoglycosides, polymixin B


A) Direct Pharmacodynamic Interactions 1. Antagonism at same site


3. Summation of similar effects at different sites

● Effect of alcohol as a depressant potentiated by other

centrally acting drugs

● Effect of trimethoprim and sulfamethoxazole





B) Indirect Pharmacodynamic Interactions

1. Cardiovascular system

Loss of Antihypertensive action of ACEI with NSAIDS

Bradycardia- beta blockers + verapamil







2. Fluid and electrolyte imbalance Thiazide and loop diuretics - hypokalemia







2. Fluid and electrolyte imbalance

3. CNS Sedation- BZD+ Alcohol

Drug Interaction studies during drug developement

• Main objectives:

1. Any interaction large enough to require dose adjustment

2. Any interaction calls for therapeutic monitoring

3. Contraindication to concomitant use of any medication

• Interactions between

1. new drug and existing drug

2. metabolic enzymes (CYP1A2, CYP2B6, CYP3A4)

3. metabolites of the investigational drug

4. Transporter based interactions

Conduct in vitro metabolism and drug drug interaction studies

Conduct in vivo studies with specific substrate

Label as such based on vitro studies

Presence of significant interactions??

Conduct in vivo studies with other drugs based on co administration

Dose adjustment required or not?

-+

Drugs in Liver Diseases1. Pharmacokinetic level

• Decrease the activity of drug metabolising enzymes

• Changes in the blood flow

1. Drugs undergoing extensive hepatic first pass metabolism

2. Drugs which are inactivated in the liver

3. Drugs which are activated in the liver

4. Drugs which are partly metabolised

5. Due to reduced synthesis of albumin

Drugs in Liver Diseases

1. Pharmacokinetic level

2. Pharmacodynamic level

• CNS sensitivity of sedatives, opioids is increased

• Effect of anticoagulant is enhanced

• Altered fluid and electrolyte balance

Drugs in Renal Disease

• Drugs which are excreted unchanged

• Drugs which are partly metabolised, partly excreted unchanged

• Drugs which are completely metabolised and then excreted

DRUG HERB

INTERACTION

HERBS

Betel NutsArea Catechu

• Contains arecoline

• Extrapyramidal symptoms

Ginkgo Biloba• Inhibits PAF• spontaneous

Subarachnoid hemorrhage

St. Johns WortHypericum perforatin

• Inducer of CYP3A4

• May elevate serotonin

GarlicAllium sativum

• Increases INR• Post operative

bleeding

LiquoriceGlycyrrhizin

• Inhibits degradation of cortisol

TCA

Antipsychotics

Corticosteroids

Sulfonylureas

Methylphenidate

Fenfluramine

Dexfenfluramine

Sibutramine

Orlistat

app

eti

te

ap

petite

Alteration in appetite

Alteration in gut flora

• Antibiotics can effect normal flora and cause vitamin B depletion

• Antibiotics like cefamendole, cefoperazone, cefotetan can

interfere with vit K producing bacteria

Interfere with absorbtion of Fe, Ca, fat

Loss of fat-soluble vitamins,

Ex. Vit A and E

Antacids decrease the absorbtion of Ca 2+,vit C

Alteration in absorption

Alteration in nutrient metabolism

• Eg.

Anticoagulant drug warfarin and vitamin K

Statins inhibit HMG –CoA Reductase inhibitor – precursor for

cholesterol and coenzyme Q10

Alteration in nutrient excretion

• D- penicillamine & EDTA binds metals Zn2+ and eliminates it via urine

• Diuretics cause loss of ions such as Mg 2+ ,K+ ,Na+ , Ca 2+

OAT

Increase duration of action

• Increases duration of

action

• Bloodless field

• Lesser systemic S/E

• Increase

concentration at site

Synergistic Action

Reversal of Toxic Symptoms

Neutralisation of action

Drug interactions

Health & Medicine

Transcript of Drug interactions