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
 Food

DI
Disease Drug
 Drugs likely involved in interactions
Precipitating drugs Object Drugs

• Drugs highly bound to plasma

proteins
• Used for long term
• Enzyme inducers or inhibitors
• Two drugs simultaneously given
for same disease
• Narrow therapeutic index
• Zero order kinetics
• Steep dose response curves
 Patient factors

• Hepatic damage

• Renal failure

• Elderly patients

• Multiple diseases

• Critically ill patients

 Useful Interactions
Increase duration of • Adrenaline with lignocaine
action • Probenecid wid penicillin

• Sulfamethoxazole with trimethoprim

Synergistic effects

Reverse toxic • Atropine in organophosphate poisoning

symptoms • Naloxone in opiod poisoning

• Protamine with heparin

Neutralise the action • Desferroxamine with iron
Drug Food
Interactions
How drugs effect food???
Food intake

Nutrient Alteration
excretion in gut flora

Nutrient Nutrient
metabolism absorption
 How food can effect drugs

Increase Decrease
• Rifampicin- without food
absorption absorption • Rifabutin- with food
• Rifapentin- no effect of
food
Irritation
of
No effect
digestive
tract
• Tetrcayclines • Erythromycin
• BisacodylMilk • Ketoconazole
Fruit juice
• Iron • celiprolol
supplements • Grapefruit
• Mercaptopurin juice
Swallowing of
the medicine
• Wine-
• iron
Tea/coffee Alcohol
tyramine
absorbtion reaction
• 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 Aspirin Increase gastric Faster alcohol
Acetaminophen emptying absorbtion
Inhibition of gastric
ADH
Toxic metabolite of
acetaminophen Liver damage
2. Anticonvulsant Phenytoin Induces phenytoin Decrease effect
breakdown
3. Antihistamines Chlorpheniramine Increase CNS effect sedation
4. Antidiabetics Chlorpropamide Increase risk of Unconsciousness
Glyburide hypoglycemia Disulfiram like
Metformin reaction
Lactic acidosis
5. BZDs Diazepam Increase effect Sedation
6. H2 Antagonists Cimetidine Inhibits ADH Increases BAL levels
 Drug Drug Interactions

DI

Outside Inside the

the body body

Pharmaco Pharmaco
Syringe Iv fluids
kinetic dynamic
 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

 Stability of drugs in Saline or Dextrose
solution

Unstable Stable for Stable for Photosensitive Not infused

Infuse within 6-8 hrs 12 hrs drugs after 6 hrs
2-4hrs
Ampicillin Benzylpenicillin Fluoxacillin Amphoterecin Cephaloridine
Erythromycin Diazepam Tetracycline Dacarbazine colistin
 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
 Alter
acidity

Surface Motility
area

Alter P Chelation
gp
 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
 Effect on Transporters

Oral drug inhibitor transporter

Digoxin quinidine P gp
Paclitaxel Cyclosporin P gp
methotrexate Omeprazole BCRP
irinotecan gefitinib BCRP
 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
 Distribution
1. Displacement from tissue binding sites
2. 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 involved

1. Sulfonamides
2. Salicylates
3. Phenylbutazone
Clinical Relevance of PP Displacement???
12
10% 20%

20%

Unbound fraction
Bound fraction
 Metabolism
Metabolism

Enzyme Induction
S No. Precipitant drug Object drug
1. Alcohol Warfarin, Phenytoin
2. Barbiturates Chlorpromazine, OCPs, Phenytoin
3. Phenytoin Tolbutamide, OCPs
4. Rifampicin Warfarin, Tolbutamide
5. St. John’s Wort Carbamazepine, SSRIs, Warfarin
Metabolism Metabolism
Enzyme Inhibition
S No. Precipitant Drug Enzyme Object drug
1. Allopurinol Xanthine Oxidase Azathioprine
2. Carbidopa Dopa decarboxylase L-Dopa
3. Disulfiram Aldehyde Alcohol
dehydrogenase
4. MAO Inhibitors Monomine Oxidase Amine containing
foods
 Metabolism
Enzyme Inhibition
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
Excretion
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
 Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
● Opiates with Naloxone

● Warfarin with Vitamin K

 Pharmacodynamic Interactions
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

 Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism 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

 Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites

B) Indirect Pharmacodynamic Interactions

1. Cardiovascular system
Loss of Antihypertensive action of ACEI with NSAIDS
Bradycardia- beta blockers + verapamil
 Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites

B) Indirect Pharmacodynamic Interactions

1. Cardiovascular system
2. Fluid and electrolyte imbalance
Thiazide and loop diuretics - hypokalemia
 Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
2. Synergism at same site
3. Summation of similar effects at different sites

B) Indirect Pharmacodynamic Interactions

1. Cardiovascular system
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 Label as such based on vitro
substrate studies

Presence of significant interactions??

Conduct in vivo studies with other

drugs based on co administration

Dose adjustment required or not?

Drugs in Liver Diseases
1. 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
 Betel Nuts Ginkgo Biloba
Area Catechu • Inhibits PAF
• Contains • spontaneous
arecoline Subarachnoid
• Extrapyramidal hemorrhage
symptoms
HERBS

St. Johns Wort

Garlic Hypericum
Allium sativum perforatin
• Increases INR Liquorice • Inducer of
• Post operative Glycyrrhizin CYP3A4
bleeding • Inhibits • May elevate
degradation serotonin
of cortisol
 Alteration in appetite

appetite
TCA Methylphenidate

Antipsychotics Fenfluramine

Corticosteroids Dexfenfluramine

Sulfonylureas Sibutramine

appetite
Orlistat
 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
Alteration in absorption

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 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+
 Increase duration of action

• Increases duration of
action
• Bloodless field OAT
• Lesser systemic S/E
• Increase
concentration at site
Synergistic Action
Reversal of Toxic Symptoms
Neutralisation of action