Clinical Pharmacy 1

Drug interactions

An Thanh Pham, MSc.

Ho Chi Minh City, October, 2023

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 Learning objectives

Understand the concepts of drug-drug interactions

Understand the concepts of drug-food interactions

Understand the concepts of drug-herb interactions

Apply knowledge to prevent and manage drug interactions in

clinical practice

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 Content
• Definition and epidemiology
1

• Drug-drug interactions
2

• Drug-food interactions
3

• Drug-herb interactions
4

• Drug interactions prevention and management

5

3
 1. Definition
“The change in the drug’s effects when the drug is concomitantly
administered with another drug, herbal medicine, food, beverage or
other environmental chemical agents”

https://www.altexsoft.com/blog/drug-interaction-checker-apis/ 4
 1. Definition
Drug interactions severity levels
Level 1

• The most serious, life-threatening interactions

• Require to discontinue the pre-existing, interacting medication order

Level 2

• The moderate severity

• A reason needs to be provided to override the alert

Level 3

• The least serious interactions

• Non-interruptive or information alerts
Partners Healthcare System Medication Knowledge Base (PHS MKB) 5
 1. Definition
Drug interactions severity levels

Major • Life-threatening or cause permanent damage

• Deteriorate patient’s condition

Moderate • Requiring additional care or extended hospitalization

Minor • Bothersome, but otherwise not medically detrimental

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 2. Epidemiology

2.1. Distribution patterns

2.1.1. Worldwide
• In 2020:
o Approximately 10.0% of hospitalized patients had a
clinically manifested DDIs
o Prevalence of clinically manifested DDIs in ICU patients
(64.0%) is higher than among non-ICU inpatients
• In 2023:
o 17.2% of hospitalized patients have clinically evident DDIs

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 2. Epidemiology
2.1. Distribution patterns
2.1.2. Asia
The most prevalent drug-drug interactions:
• ACEIs or ARBs with Potassium-sparing drugs
• Aspirin with Warfarin
• Aspirin with Clopidogrel
• NSAIDs with Warfarin

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 2. Epidemiology
2.1. Distribution patterns
2.1.3. Vietnam
q An Giang general hospital (2016):
• The rate of drug interactions according to Medscape.com was 25%
and according to Thongtinthuoc.com was 30%
q Hue University of Medicine and Pharmacy Hospital (2018):
• The prevalence of prescriptions with drug interactions was 6.7%
• The most commonly drug interaction pair:
o Clopidogrel and Proton pump inhibitor (1.6%)
q Lao Cai General hospital (2021):
• 214 times of DDIs occurring in 157 inpatients, of which 2 were
contraindicated DDIs and 212 severe DDIs
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 2. Epidemiology
2.2. Suscep*ble pa*ents
Patients with hepatic disease, renal disease, HIV infection,
epilepsy, diabetes

Patients in intensive care

Transplant recipients

Patients undergoing complicated surgical procedures

Patients with more than one prescriber

Critically ill and elderly patients

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 3. Drug-drug interactions

Pharmacokinetic interactions

Pharmacodynamic interactions

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions

https://toolbox.eupati.eu/glossary/pharmacokinetics/ 12
 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.1. Absorption
Changes in gastro-intestinal pH
• An alteration in gastric pH due to antacids, histamine H2 antagonists or proton
pump inhibitors ➞ the rate of absorption rather than the extent of absorption
(provided that the drug is acid labile)
Examples:
o Decrease the bioavailability of Ketoconazole and Itraconazole
o The absorption of Fluconazole and Voriconazole is not significantly altered

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 3. Drug-drug interactions

3.1. Pharmacokinetics interactions

3.1.1. Absorption
Chelation and Complexing mechanisms
• Form chelates and insoluble complexes
• Example:
o Tetracyclines and Quinolone + Iron, Antacid
(Calcium, Magnesium, Aluminium)
➞ Reduce plasma Tetracyclin/ Quinolone concentration Pulicharla, R., et al. (2017). Tetracyclines metal complexation:
Significance and fate of mutual existence in the
o Bisphosphonates + Calcium environment. Environmental pollution (Barking, Essex :
1987), 221, 1–14.

➞ Reduce the bioavailability of both drugs

➞Theurapeutic failure
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 3. Drug-drug interactions

3.1. Pharmacokinetics interactions

3.1.1. Absorption
Chelation and Complexing mechanisms
Adsorbents:
• Charcoal
• Kaolin
• Anionic exchange resins: Cholestyramine or
Colestipol
➞ Reduce drug absorption

Hibbard, D. M., et al. (1984). Effects of cholestyramine and colestipol on the plasma
concentrations of propranolol. British journal of clinical pharmacology, 18(3), 337–342.
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 3. Drug-drug interactions

3.1. Pharmacokinetics interactions

3.1.1. Absorption
Effects on gastro-intestinal motility
q Anticholinergic drugs (tricyclic antidepressants, phenothiazines,
antihistamines):
• Decrease gut motility and delay gastric emptying
Example: Tricyclic Antidepressants + Dicoumarol ➜ ?
q Opioids (Diamorphine, Pethidine, Metoclopramide):
• Inhibit gastric emptying
• Example: Diamorphine + Paracetamol
q Metoclopramide + Paracetamol ➜ ?
• Increase gastric emptying

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.1. Absorption
Drug transport proteins induction or inhibitions
Inhibitors of P-gp Inducers of P-gp Substrates of P-gp
Amiodarone Apalutamide Apixaban
Azithromycin (systemic) Carbamazepine Colchicine
Carvedilol Fosphenytoin Cyclosporine
Clarithromycin Lorlatinib Dabigatran
Itraconazole Phenytoin Digoxin
Fostamatinib Rifampin (Rifampicin) Edoxaban
Quinidine Green tea Rivaroxaban
(Camellia sinensis)
Grapefruit juice St. John's wort Tacrolimus
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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.1. Absorption
Malabsorption

Digoxin and Neomycin

Lindenbaum, J., Maulitz, R. M., & Butler, V. P., Jr (1976). Inhibition of digoxin absorption by neomycin. Gastroenterology, 71(3), 399–404. 18
 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.2. Distribution
Drug displacement from protein-binding sites
q A drug displacement interaction
• A reduction in the extent of plasma protein binding of one drug caused by another drug➜ Increased free
or unbound fraction of the displaced drug
q The displacement process
• Rises the concentration of free drug temporarily
• Falls rapidly back to its previous steady-state concentration due to metabolism and distribution
• Depend on the half-life of the displaced drug
• Need to be taken into account in TDM
q Example: Phenytoin

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.2. Distribution
Drug displacement from protein-binding sites
q Example: Valproic acid and Warfarin

Yoon, H. W., et al(2011). Valproic acid and warfarin: an underrecognized drug interaction. Neurocritical care, 15(1), 182–185. Anderson SL, Marrs JC. Probable Interaction Between Warfarin and Divalproex Sodium.
J Pharm Technol. 2014 Feb;30(1):8-12.

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism

üWhat is drug metabolism?

üHow many phases in drug metabolism? Explain each phase.

üWhich is the principal organ of drug metabolism?

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
CYP450 isoenzymes
• Comprises 57 isoenzymes (18 families and 43
subfamilies), derived from the expression of an
individual gene
• Four main subfamilies: CYP1, CYP2, CYP3 and CYP4
• The most extensively studied isoenzyme: CYP2D6
(Debrisoquine Hydroxylase)
• The most important of all drug-metabolising enzymes:
CYP3A Zhao M, et al. Cytochrome P450 Enzymes and Drug Metabolism in Humans.
Int J Mol Sci. 2021 Nov 26;22(23)
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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
CYP450 isoenzymes

• Drugs may be substrates/inhibitors/inducers for a cytochrome 450 isoenzyme

• If a drug is metabolised by several cytochrome 450 isoenzymes: inhibition or induction of

a single isoenzyme would have little effect on plasma drug levels

• If a drug is metabolised primarily by a single cytochrome 450 isoenzyme: inhibition or

induction of this enzyme would have a major effect on the plasma drug levels

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
Enzyme inducers
• Rifampicin
• Antiepileptic drugs
o Barbiturates
o Phenytoin
o Carbamazepine
• Cigarette smoking
• Alcohol drinking
• St John's wort (CYP3A) Barone, G. W., et al (2000). Drug interaction between St. John's wort and cyclosporine.
The Annals of pharmacotherapy, 34(9), 1013–1016.
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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
Enzyme inhibition

• ≥5-fold increase in the plasma AUC value

Strong • >80% decrease in clearance

• ≥2- but <5-fold increase in the AUC value

Moderate • 50 - 80% decrease in clearance

• ≥1.25- but <2-fold increase in the AUC values

Weak • 20 - 50% decrease in clearance

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
Enzyme inhibition

Terada T, Hira D. Intestinal and hepatic drug transporters:

Pharmacokinetic, pathophysiological, and pharmacogenetic roles.
Journal of gastroenterology. 2015;50. 27
 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism
Enzyme inhibition
Drug-related factors
• Dosage
• Alterations in pharmacokinetic properties (half-life)
Patient-related factors
• Disease state

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.3. Metabolism

Enzyme inhibition

Grapefruit juice
Bailey, D. G., et al (2000). Grapefruit-felodipine interaction: effect of unprocessed fruit and
probable active ingredients. Clinical pharmacology and therapeutics, 68(5), 468–477.
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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.4. Excretion
Changes in urinary pH

• The renal clearance of weakly acidic drugs (pKa 3.0–7.5) is increased in alkaline urine

• The renal clearance of weak bases (pKa 7.5–10) is higher in acid urine

• Strong acids and bases are is unaffected by urinary pH changes

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.4. Excretion
Changes in active renal tubule excretion
Drugs using the same active transport system in the kidney tubules
➜ Compete with one another for excretion
➜ Therapeutic advantage
Example: Probenecid – Penicillin
Methotrexate - Aspirin

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https://tmedweb.tulane.edu/pharmwiki/doku.php/probenecid
 3. Drug-drug interactions

3.1. Pharmacokinetics interactions

3.1.4. Excretion
Changes in renal blood flow
• Partially controlled by the production of
renal vasodilatory prostaglandins
Example: Indometacin - Lithium

➞ Central nervous system side effects

https://www.medscape.com/content/2003/00/45/63/456379/456379_fig.html

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 3. Drug-drug interactions
3.1. Pharmacokinetics interactions
3.1.4. Excretion
Biliary excretion and the enterohepatic shunt

Dhurjad, P., et al (2022). Exploring Drug Metabolism by the Gut Microbiota: DeRossi SS, Hersh EV. Antibiotics and oral contraceptives. Dental Clinics of North America.
2002;46(4):653-64.
Modes of Metabolism and Experimental Approaches. Drug metabolism and
disposition: the biological fate of chemicals, 50(3), 224–234. 33
 3. Drug-drug interactions
3.2. Pharmacodynamic interactions
When the pharmacological effects of one drug are altered by the presence of another
drug in a combination regimen at its site of action

Siqueira R, et al. Complex diseases demand novel treatment strategies: understanding drug combination. Drug Comb Ther. 2022;4:5-10.
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 3. Drug-drug interactions
3.2. Pharmacodynamic interactions

Pharmacodynamics interactions
Antagonistic interactions

Additive interactions

Synergistic interactions

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 3. Drug-drug interactions
3.2. Pharmacodynamics interactions
3.2.1. Antagonistic interactions
• A drug with an agonist action at a particular receptor type will interact with antagonists
at that receptor
• Occurs when the effect of one drug is impeded by another
q Examples:
• β2-adrenoreceptor agonists and β-blockers
• 𝛼-adrenergic agonists and 𝛼-adrenergic antagonists
• Anticoagulants and vitamin K
• Levodopa and dopamine antagonist antipsychotics

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 3. Drug-drug interactions
3.2. Pharmacodynamics interactions
3.2.2. Additive interactions
When the therapeutic effect of two or more drugs given in combination equals the sum of
the expected effects of each drug

Cascorbi I. Drug interactions--principles, examples and clinical consequences. Dtsch Arztebl Int. 38
2012 Aug;109(33-34):546-55; quiz 556.
 3. Drug-drug interactions
3.2. Pharmacodynamics interactions
3.2.3. Synergistic interactions
qSynergistic interactions:
• When the combine therapeutic effect of two or more drugs is larger than the sum of their
expected effects when given separately
• Example:
o Barbiturate and Alcohol
o Trimethoprim and Sulfonamide
qPotentiation interactions:
• When one drug does not elicit a response on its own but enhances the response to another
drug
• Example:
o Diazepam and Alcohol
o Benserazide and Levodopa 39
 3. Drug-drug interactions
3.2. Pharmacodynamics interactions
3.2.4. Serotonin syndrome (SS)
Two or more drugs affecting serotonin are given at the
same time or after one serotonergic drug is stopped
and another started
➞ an excess of Serotonin
Example: Linezolid, Amfetamines
q Preventive measures:
• Avoiding using combinations of serotonergic drugs
• Special care is needed when changing from a SSRI
to an MAOI and vice versa
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https://www.lecturio.com/concepts/serotonin-syndrome/
 3. Drug-drug interactions
3.2. Pharmacodynamics interactions
3.2.5. Drug or neurotransmitter uptake interactions
MAOIs and indirectly acting sympathomimetic amines (Amphetamines, Tyramine, MDMA
(Ecstasy), Phenylpropanolamine and Pseudoephedrine)

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https://tmedweb.tulane.edu/pharmwiki/doku.php/tyramine
 4. Drug-food interactions
4.1. Common drug-food interactions

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 4. Drug-food interactions
4.2. Examples

Paeng, C. H., Sprague, M., & Jackevicius, C. A. (2007). Interaction between warfarin and
cranberry juice. Clinical therapeutics, 29(8), 1730–1735. 43
 4. Drug-food interactions
4.2. Examples

Eagles, S. K., et al (2020). The Effects of Cruciferous Vegetable-Enriched Diets on Drug

Metabolism: A Systematic Review and Meta-Analysis of Dietary Intervention Trials in
Humans. Clinical pharmacology and therapeutics, 108(2), 212–227.
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 5. Drug-herb interactions
5.1. Interaction with Digoxin and Diuretic drugs

Glycyrrhizin glabra Fabaceae (Liquorice)

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 5. Drug-herb interactions

5.2. Interaction with Warfarin

Medicago sativa Fabaceae Angelica archangelica Apiaceae Trifolium pratense Fabaceae

(Alfalfa) (Angelica) (Red clover)
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 5. Drug-herb interactions
5.2. Interaction with Warfarin

Borago officinalis Boraginaceae Ananas comosus Bromeliaceae Ginkgo biloba Ginkgoaceae

(Borage) (Bromelain) (Ginkgo)

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5. Drug-herb interactions

Hypericum perforatum Hypericaceae

St John's wort (Hypericum extract) 48
6. Drug interactions prevention

Appropriate Prescribing and Risk Assessment

Recommend to judicious prescribing concepts

Identify patients at high risk

Obtain a comprehensive medication history

Communication and Patient Engagement

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 6. Drug interactions prevention
6.1. Recommend to judicious prescribing concepts

Principles
of judicious Think beyond drugs
prescribing
Practice more strategic prescribing

Maintain heightened vigilance regarding adverse effects

Exercise caution and skepticism regarding new drugs

Work with patients for a shared agenda

Consider long-term, broader impacts

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 6. Drug interactions prevention
6.2. Identify patients at high risk
Drug-Associated Risk Tool

Kaufmann CP, et al. Drug-Associated Risk Tool: development and validation of a self-assessment questionnaire to screen for hospitalized 51
patients at risk for drug-related problems. BMJ Open 2018;8:e016610.
 6. Drug interactions prevention
6.3. Obtain a comprehensive medication history
The “AVOID Mistakes” Mnemonic
Allergies
○ Identification of medications that should not be prescribed for any reason
Vitamins
○ Including natural products or herbs
Old and new medications
○ Including prescription and OTC medications
Interactions
○ Initial assessment of potential interactions
Dependence
○ The need for a behavioral contract in the case of either drug dependence or adherence to
a therapeutic regimen
Mendel
○ Family history of beneficial or negative outcomes with medications
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 6. Drug interactions prevention
6.3. Obtain a comprehensive medication history
Risk factors for polypharmacy
Patients-related System-related

Inadequate transitions of
Advanced age
care
Poor medical
Cognitive impairment
recordkeeping

Frailty

Several chronic medical

conditions

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 6. Drug interactions prevention
6.3. Obtain a comprehensive medication history
Deprescribing
Obtaining a medication list and determining
indications for medications

Assessing each medication with respect to

potential for drug-related harm

Weighing the current or future benefits against

harms for each medication

Developing a plan to discontinue medications

Discontinuing medications and monitoring

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6. Drug interactions prevention
6.4. Communication and Patient Engagement
• Read labels carefully
➞ Learn about any warnings or major drug interactions
• Store medications in their original container for easy
identification
• Visit a single pharmacy location for all medication
• Maintain a listing of all current and recently discontinued
prescription, OTC, and natural products
• Inform all health care providers about all medicinal
products they may be taking

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7. Drug interactions management

Salbutamol and Propranolol

Tetracycline and Iron Preparations

Valproic acid and Warfarin

Ciprofloxacin and Erythromycin

https://www-uptodate-com./drug-interactions/ 56
 7. Drug interactions management
7.1. Pharmacokinetics
7.1.1. Absorption
Changes in gastro-intestinal pH
PPIs and Ketoconazole
• Severity: Moderate
• Risk Rating: D: Consider therapy modification
• Consequence: ?
• Patient management:
o Administration with an acidic beverage
o Prescribe alternative medications that do not interact
o Dose adjustment to safely use

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.1. Absorption
Chelation and Complexing mechanisms
Tetracycline and Iron Preparations
• Severity: Moderate
• Risk Rating: D: Consider therapy modification
• Consequence: ?
• Patient management:
o Administering oral Iron preparations at least 2 hours
before, or 4 hours after, the dose of the oral Tetracycline Neuvonen PJ, Turakka H. Inhibitory effect of various iron salts on
the absorption of tetracycline in man. Eur J Clin Pharmacol.
o Monitor for decreased therapeutic effect of Tetracycline 1974 Aug 23;7(5):357-60.

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.1. Absorption
Effects on gastro-intestinal motility
Amitriptyline and Warfarin
• Severity: Moderate
• Risk Rating: C: Monitor therapy
• Consequence: ?
• Patient management:
o Monitor for increased vitamin K antagonist effects (INR, bleeding)

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.2. Distribution
Valproic acid and Warfarin
• Severity: Moderate
• Risk Rating: C: Monitor therapy
• Consequence: ?
• Patient management:
o Monitor for increased vitamin K antagonist effects (INR, bleeding)

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.3. Metabolism
St John's Wort and Cyclosporine
• Severity: Major
• Risk Rating: D: Consider therapy modification
• Consequence: ?
• Patient management:
o Consider alternatives to St. John's wort
o Monitor for serum concentrations of Cyclosporine following St. John's wort initiation
o Increased serum concentrations following St. John's wort dose decrease

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.3. Metabolism
Felodipine and Grapefruit juice
• Severity: Moderate
• Risk Rating: C: Monitor therapy
• Consequence: ?
• Patient management:
o Monitor hemodynamic response (eg, blood pressure, heart rate) to Felodipine
o Dose adjustment

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 7. Drug interactions management
7.1. Pharmacokinetics
7.1.3. Metabolism
Penicillin and Probenecid
• Severity: Minor
• Risk Rating: C: Monitor therapy
• Consequence or benefit: ?
• Patient management:
o Prolong coadministration of Penicillin and Probenecid
o Increase exposure of Penicillin

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 7. Drug interactions management
7.2. Pharmacodynamics
7.2.1. Antagonistic interactions

Salbutamol and Propranolol

• Severity: Major

• Risk Rating: X: Avoid combination

• Consequence: ?

• Patient management:

o Avoid coadministration

o If used concomitantly, monitor closely for Minton NA, et al. Modulation of the effects of salbutamol by propranolol and atenolol. Eur J Clin Pharmacol.
1989;36(5):449-53.

diminished bronchodilatory effects of

Salbutamol
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 7. Drug interactions management
7.2. Pharmacodynamics
7.2.2. Additive interactions

Angiotensin-Converting Enzyme Inhibitors

and Potassium-Sparing Diuretics

• Severity: Major

• Risk Rating: C: Monitor therapy

• Consequence: ?

• Patient management:

o Monitor for blood electrolytes https://www.gov.uk/drug-safety-update/spironolactone-and-renin-angiotensin-

system-drugs-in-heart-failure-risk-of-potentially-fatal-hyperkalaemia

(increased incidence of hyperkalemia)

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 7. Drug interactions management
7.2. Pharmacodynamics
7.2.3. Synergistic interactions
Diazepam and Alcohol

• Severity: Moderate

• Risk Rating: C: Monitor therapy

• Consequence: ?

• Patient management:

o Avoid or limit the use of alcohol while being treated with Diazepam

o Do not use more than the recommended dose of Diazepam

o Monitor for increased central nervous system (CNS) depression

o Avoid activities requiring mental alertness (driving, operating hazardous machinery)

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 8. References
1. Roger Walker, [2012], Clinical Pharmacy and Therapeutics, 5rd edition, Churchill Livingstone,
England.
2. Gabay, M. (2019). Drug Interactions: Scientific and clinical principles. Am Fam Physician, 99,
558-64.
3. https://www-uptodate-com/drug-interactions/
4. https://reference.medscape.com/drug-interactionchecker
5. https://www.drugs.com/drug_interactions.html

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Thank you for your attention!
Any questions?

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