Drug Interaction
Feng Wu 武 峰
Beijing Tongren Hospital, Capital Medical University
E-mail: trdrug@126.com
1 Introduction of DI
Pharmacokinetic interaction
SYNOPSES
3 Pharmacodynamic interaction
4 Pharmaceutical interaction
5 Summary
Introduction of DI
• What is drug interaction?
• How important is drug interaction in
clinical practice?
A real event
• In August 2001, 31 death cases reported about fatal dissolving muscle (i.e.
rhabdomyolysis) in USA
– It resulted from cerivastatin therapy
– 12 cases combined with gemfibrozil
• Cerivastatin has caused 55 deaths, 10 billion economic loss, and manufacturer was
forced to withdraw the drug from the global initiative
J.K. Aronson, Cerivastatin, Elsevier, 2006
• Reasons: ADR
Adverse Drug Interaction
• Statins + Fibrates = ?
– Statins are widely used to regulate blood cholesterol, and fibrates are the main
drugs to lower triglycerides
– Sometimes they are given in combination (Mixed dyslipidemia), but what will
happen when these two drugs are used together?
– cerivastatin + gemfibrozil Fatal
rhabdomyolysis
Definition
Drug interaction is the modification of the action
of one drug by another.
Clinical importance
• Multiple drug use is extremely common, so the potential for drug
interaction is enormous
– The elderly: treated continuously with multiple drugs
• Chronic diseases
hypertension
heart failure
osteoarthritis
……
• Acute events
infections
myocardial infarction
……
Risk Factors
• High Risk Patients
– Multiple drug therapy
– Elderly, young, very sick, multiple diseases
– Renal, liver impairment
• High Risk Drugs
– Narrow therapeutic margin
– Steep dose/concentration–response relationships
– Recognized enzyme inhibitors or inducers
• E.g. penicillin
– There is usually a comfortable safety margin between
plasma concentrations produced by usual doses and
those resulting in toxicity
Some drugs with a narrow therapeutic index
Warfarin Digoxin
Theophylline Carbamazepine
Phenytoin Phenobarbitone
Cyclosporin Lithium
Antiepileptic drugs
Classification
• Broad Classification:
– Drug-drug interaction (typical)
– Drug-nutrient interaction
food, beverages (alcohol, grapefruit juice)
herbal remedies, dietary supplements
• Drug-beverage interactions
– Alcohol increases sleepiness caused by diazepam
– Grapefruit juice can selectively inhibit hepatic enzyme
Drug-Herb interactions
St. John’s wort（圣约翰草、贯叶连翘）:
a hepatic enzyme inducer interact with other drugs by
metabolism induction.
According to effect
• Useful
• Trivial (of no consequence)
• Harmful (Adverse drug interaction)
– of great importance in clinical practice
• Useful
– Increased effect
• Drugs can be used in combination to enhance their effectiveness
– Minimized side effects
• Low doses of two drugs may be better tolerated than larger doses of
a single agent
– E.g. Levodopa + carbidopa
• If levodopa is administered alone, the peripheral side effects are obvious
• But when combined with carbidopa, the same effect is achieved with a lower
dose of levodopa, while dose-related side effects are reduced greatly
Paxlovid (Nirmatrelvir+ Ritonavir)
• Trivial
– Interactions based on in vitro experiments, can’t be
extrapolated to the clinical situation
– Interactions involving drugs with a wide safety
margin are also seldom clinically important
➢ Harmful /Adverse drug interactions
➢ Not uncommon, can have profound
consequences
➢ Death from hyperkalaemia, cardiac
dysrhythmia, unwanted pregnancy,
transplanted organ rejection, et al.
➢ but often avoidable
• Useful drug interactions:
Effect increased / toxicity decreased
• Adverse drug interactions:
Toxicity increased / effect decreased
Take advantage of the useful DIs, and avoid adverse DIs
According to mechanism
Classification
Pharmacokinetic
mechanism Pharmacodynamic
Pharmaceutical
DI can result from one or a combination of these three mechanisms
Pharmacokinetic Interaction
• PK interactions occur when one drug affects the
pharmacokinetics of another
– inhibiting its metabolism or reducing its elimination or
influencing its absorption
PK Drug interaction Sites in vivo
Absorption
• Influence gastric emptying, alter the rate or completeness
of absorption of a second drug
– Inhibit gastric emptying, slow down the absorption
atropine opiates
– Hasten gastric emptying, accelerate the absorption
metoclopramide antacids
• Alter the Gastric pH
– Ketoconazole is a weak base that is only soluble at an acid
circumstance
– Drugs that raise gastric pH impair the dissolution and absorption
of ketoconazole
• PPI (protein pump inhibitors): omeprazole
• Histamine2-receptor antagonists: cimetidine
• Interfere with the entero-hepatic circulation
of other drugs
– EHC may prolong drug action and enhance the
effect
– If the re-absorption is altered, the drug effect is Entero-hepatic
reduced Circulation
– oral contraception + antibiotics
• Antibiotics reduce the recirculation of oral
contraceptions (eg. Oestrogen) unwanted
pregnancy
• Interact in the lumen of the gut
– Ca2+ (and also iron) forms an insoluble complex with
tetracycline and retards its absorption
– Colestyramine binds several drugs (e.g. warfarin, digoxin),
preventing their absorption if administered simultaneously
Distribution
• Compete for binding sites on the plasma or tissue protein,
and displace previously bound drugs
Drugs A and B both bind to the same plasma protein
• Warfarin + Phenylbutazone
• This combination did kill patients ...
– The main mechanism is not only displacement
– Phenylbutazone is able to displace warfarin from its binding site and more
importantly selectively inhibits metabolism of warfarin
Metabolism
• Many drug interactions are due to changes in drug metabolism
• Hepatic cytochrome P450 enzymes (CYP450) play a key role in the metabolism
of a large number of drugs
– CYP 450 can be influenced by many drugs
CYP 450 system
• 12CYPs
– CYP1A1, 1A2, 1B1
– CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1
– CYP3A4, 3A5
• The most active CYPs for drug metabolism are
those in the CYP2C, CYP2D, and CYP3A
subfamilies
• The most important drug enzyme is CYP3A4,
involved in the metabolism of about 50% of
clinically used drugs
The fraction of clinically used drugs metabolized
by the major phase 1 enzymes
Related Definitions
• Substrate:
Drug that is metabolised by the enzyme system
• Inducer:
Drug that will increase the metabolism of a substrate
• Inhibitor:
Drug that will decrease the metabolism of a substrate
Cyclosporin：substrate + inhibitor
Liver
Drug A inhibits the
production of enzymes Induction
to metabolize Drug B
Drug A induces the body to
Inhibition produce more of an enzyme
to metabolized Drug B
This increases the amount of
Drug B in the body and could This reduces the amount of
lead to an overdose or toxic Drug B and may lead to loss
effects of Drug B’s effectiveness
Enzyme inducers
Metabolism of concomitant drug ↑ → drug elimination ↑
→ plasma concentration ↓ → drug effect ↓
Barbiturates
Treat epilepsy
Carbamazepine
Rifampin
Example
• A woman takes carbamazepine to treat epilepsy.
Complain: unplanned pregnancy
• Carbamazepine induces CYP3A4
Most of the oral contraceptives are metabolized by the CYP3A4
• Treatment with carbamazepine could enhance the degradation of oral
contraceptives, reduce their effect, and finally lead to contraception
failure
A: Plasma concentration of warfarin
following a single oral dose.
After the subject was given rifampin the
plasma half-life of warfarin decreased
from 47 hours (red curve) to 18 hours
(green curve)
B: The effect of a single dose of warfarin on
prothrombin time under normal
conditions (red curve) and after rifampin
administration (green curve)
Effect of rifampin on the metabolism
and anticoagulant action of warfarin
O’Reilly Ann Intern Med 1974, 81: 337.
Crixivan and St John’s Wort: Induction Interaction
12
10 Crixivan
alone
Concentration (g/mL)
4
Crixivan +
2 SJW
0
0 1 2 3 4 5
Time (hours)
St Johns wort lowers crixivan to ineffective levels and results in development of resistance
Piscitelli et al, Lancet 2000
Auto-induction
• If the inducing agent is itself a substrate for the induced
enzymes, the process can result in slowly developing
tolerance
• E.g carbamazepine
– Usually initiated at a low dose to avoid toxicity
– Over a period of a few weeks, when liver enzymes are induced,
the dose should be gradually increased
• Enzyme induction can increase action of a second drug if the
effects are mediated by an active metabolite
• E.g. Paracetamol toxicity
– The toxicity of hepatic injury is caused by N-acetyl-p-benzoquinone
imine, which is formed via CYP450
– In patients whose CYP system has been induced, risk of serious
hepatic injury is increased
Enzyme inhibitors
Metabolism of concomitant drug ↓ → drug elimination ↓
→ plasma concentration↑ → drug effect ↑
Erythromycin (antibacterial drugs)
Ketoconazole (antifungals)
Cimetidine (histamine receptor antagonists)
Example
• Theophylline has serious (sometimes fatal) dose-related
toxicities
• ciprofloxacin or clarithromycin (CYP inhibitors)
– Asthmatic patients are often caught by chest infections, they
may have the chance to use these drugs together
– The toxicity of theophylline may be enhanced
20 Control
Clearance (ml/min)
Cimetidine
15
10
Drug effect ↑
5
0
D DZD CZD OXM
Effect of cimetidine on the clearance on diazepam (D), desmethyldiazepam
(DZD), chlordiazepoxide (CZD) and oxazepam (OXM).
CZD values are x10, while OXM values are 1/10.
Somogyi A, Gugler R. Clin Pharmacokinet 7:23, 1982.
• Grapefruit juice
– Inhibit CYP 3A4, reduces the metabolism of concomitant
drugs, finally lead to increasing toxicity of these drugs
– including ciclosporin, terfenadine and several calcium
channel antagonists
• Amiodarone inhibit CYP2C9
– the principal enzyme that eliminates warfarin
• Atrial fibrillation patients
– Treated with amiodarone also receiving warfarin to prevent
thrombosis
• If warfarin is accumulated in plasma, the major bleeding complications
may occur
Excretion
• Many drugs can enhance or inhibit the excretion of
other drugs
• The main mechanisms
– inhibiting tubular secretion
– altering urine flow
– altering urine pH
• Inhibit tubular secretion
– Many drugs share a common transport mechanism in the proximal
tubules and reduce one another’s excretion by competition
• E.g. probenecid inhibit the active secretion of penicillin and thus prolong its action
– Special case:
• Diuretics lead to increased reabsorption of lithium, reducing its clearance,
and leading to lithium accumulation and toxicity
• Alter urine flow
– Diuretics tend to increase the urinary excretion of other drugs, but
this is seldom clinically important
• Alter urine pH
– Alter the excretion of drugs that are weak acids or bases
• Administration of systemic alkalinizing or acidifying agents can influence
reabsorption of such drugs
• E.g. Sodium bicarbonate (basic salt) enhances the excretion of phenobarbital
(weak acid) especially in barbital toxicity
Pharmacodynamic Interaction
Definition
• The response of the drug target is modified by a
second drug
– Increase the effect of another
e.g. alcohol increases sleepiness caused by diazepam
– Reduce the effect of another
e.g. indometacin increases BP in patients and makes the
antihypertensive drug such as losartan less effective
Drug interaction of PD
synergia
DRUG A
Same receptor or
biochemical process adding
DRUG B
rivalry
• PD Interactions are non-specific
– Depends broadly on the effect of a drug, rather than its specific
chemical structure, PK character…
• PD interactions are often predictable from the actions of the
interacting drugs
• There are many mechanisms, the practical examples are
probably more useful than classification
• NSAIDs+ Antihypertensive drugs
– NSAIDs inhibit biosynthesis of prostaglandins (PG) , cause
a variable but sometimes marked increase in BP
– Antihypertensive drugs are made less effective, such as
ACEI, angiotensin-receptor antagonists (ARB)
• NSAIDs+ warfarin
– NSAIDs cause gastric and duodenal ulcers
– Concurrent administration with warfarin increases the risk of
gastrointestinal bleeding almost fourfold compared with
warfarin alone
• Sildenafil + organic nitrates
– If a patient takes sildenafil as he is receiving organic nitrates
for coronary heart disease (CHD)
– The combination can cause profound and potentially
catastrophic hypotension
• Interruption of physiological control loops
Eg. Insulin + beta blockers
– Insulin-requiring diabetic patients may depend on some special
sensations (palpitation) to warn them of hypoglycaemia
– Interruption of beta blockers may lead to serious consequences
• Alterations in water/ electrolyte balance
Eg. diuretics + digoxin
• Thiazide commonly cause mild hypokalaemia, which is usually of
no consequence
• Toxicity of digoxin is increased when blood potassium is low
• Concurrent use increases the risk of digoxin toxicity
• Hyperkalaemia-- one of the most common causes in fatal adverse DIs
• Potassium-sparing diuretics + ACEI
– Potassium-sparing diuretics such as spironolactone may increase
plasma potassium
– Combined ACEI with potassium-sparing diuretics
• Especially in patients with renal impairment, it can cause severe
complication of hyperkalaemia
Pharmaceutical interaction
• Pharmaceutical interactions occur by chemical
reaction or physical interaction when drugs are mixed
E.g.
– Vitamin C (acidic)+ amphotericin B (alkaline)
the chemical reaction will take place when mixed together
• Most of the pharmaceutical interactions occur outside the body due to
in vitro incompatibilities
– Inactivation (chemical reaction) and precipitation (physical reaction)
when drugs are mixed in a bag of intravenous solution, or in the port
of an intravenous cannula
– E.g.
• ceftriaxone + infusion fluid containing calcium (Ringer’s solution)
• Precipitation may be formed and lead to severe adverse reaction
Interaction outside the body
• Issues of compatibility are complex
Specific sources of information are available in
manufactures’ package inserts, formularies or from the
hospital pharmacy
• Consult these sources before adding a drug to an infusion
fluid or mixing in a syringe
Summary
Summary
• Drug Interactions may be pharmacokinetic or pharmacodynamic or
pharmaceutical
• PK interactions involve four main sites:
– Absorption (eg. the antibiotics interfere with entero-hepatic recirculation and
cause failure of oral contraception)
– Distribution (competition for protein binding can displace previously bound drugs)
– Metabolism (many important interactions stem from enzyme induction or
inhibition)
– Excretion (eg. probenecid inhibit the active secretion of penicillin and thus
prolong its action）
Summary
• PD interactions are often predictable from the actions
of the interacting drugs
• Pharmaceutical interactions are due to in vitro
incompatibilities
Key Points
• DI Classification according to mechanisms
• Main sites of PK interaction
• Important drug interactions in clinical practice
Quiz
(1) Which agent or nutrient in combination with statins will result in PK drug interaction?
A. Grapefruit B. Erythromycin C. Ketoconazole
D. Ciclosporin E. All of the above
(2) Which agents below combined with warfarin that needs adjusting its dose?
A. Phenobarbital B. Cimetidine C. Phenylbutazone
D. Vitamin K E. All of the above
(3) In intravenous therapy, which solutions can NOT concomitant use with ceftriaxone sodium?
A. Saline B. Glucose C. Ringer's solution
D. Water for injection E. All of the above
(4) In available combination therapy, which may NOT increase clinical effects on patients?
A. Losartan + HCT
B. Amoxicillin + Clavulanate Potassium
C. Salmeterol + Fluticasone
D. Clopidogrel + Omeprazole
E. All of the above
(5) Which combination therapies do NOT lead to Adverse drug interaction?
A. Gemfibrozil + Cerivastatin
B. Terfenadine + Ketoconazole
C. Benazepril + HCT
D. Cisapride + Erythromycin
E. All of the above
Useful resources
• https://go.drugbank.com/
• https://dailymed.nlm.nih.gov/
Thank you everyone!
