Drug Interactions
Principles and Examples
By
Prof. Dr. Nehal Afifi
Head of Pharmacology Dept.
Cairo university
Drug Interactions
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Drug interactions occur when the pharmacological actions
of a drug is modified by the presence of other drugs.
A drug-drug interactions defined as the phenomenon that
occur when the pharmacological action or pharmacokinetic
of a drug are altered by Prior administration or Coadmin.
(concurrent) administration of a second drug.
Drug interactions can have desired, or unwanted effects.
Drug–drug interactions have contributed significantly to
adverse drug reactions.
Drug interactions may be dangerous or even cause deaths
in both man & animals (Adverse interactions).
Prof. Dr/ Nehal Afifi 3/25/2017
Drug–drug interactions (DDIs)
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The probability of interactions increases with the number of
drugs taken.
Evaluating drug–drug interactions is very important during
drug development.
Drug interactions occur on pharmacodynamic and
pharmacokinetic levels.
Drug–drug interactions (DDIs) can be classified into:
Pharmacodynamic interactions (ie, additive, synergistic, or
antagonistic effects that occur despite unaltered plasma
levels of the drugs),
pharmacokinetic interactions (ie, alterations in drug
absorption, volume of distribution, metabolism, or excretion),
Pharmaceutical incompatibility (eg, combinations of acids
and bases),
Prof. Dr/ Nehal Afifi 3/25/2017
Pharmacodynamic
interactions
Drug
interactions
in vivo
Pharmacokinetics
Drug interactions
interactions
Interactions In- vitro
incompatibilities
In - vitro
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Interactions in vitro (incompatibilities)
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Incompatibilities include interactions by mixing of Two drugs
before admin., or the addition of a drug to iv infusion fluids.
This reduce therapeutic potency of the drugs.
Chemical alteration to the active ingredients has
occurred due to chemical reactions .
Change in color and/ or turbidity occurred when
physically incompatible compounds are mixed.
Example: Mixing thiopentone+ suxamethonium PPT
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Incompatibility of drugs with i.v. fluids
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Normal saline with pH around 4, must used as a diluents.
Drugs Incompatible i.v. fluids
Ampicillin sodium Dextrose sol. & dextran
Adrenaline Sodium bicarbonate
Benzyl penicillin Dextrose solution
Oxytetracycline Sol. contain Ca² or Mg²
Heparin sodium Dextrose sol.
Prof. Dr/ Nehal Afifi 3/25/2017
Drug-drug interactions(DDI) in vivo
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DDI is Classified according to the mechanism of
interactactions into:
1. Pharmacodynamic interactions
One drug induce a change in drug effect without altered its
plasma conc. E.g.; concurrent use of two drugs with the
same , similar or opposing pharmacological actions.
2. Pharmacokinetic interactions
One drug may alter absorption, distribution, metabolism or
excretion of a second drug.
Prof. Dr/ Nehal Afifi 3/25/2017
Pharmacodynamic interactions
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This term refers to interactions in which drugs influence each
other’s effects directly.
Pharmacodynamic interaction is actually desired (Benficial), if
potentiating effects in the same direction (synergistic effects).
The desired interactions can improve the therapeutic effect.
for example, sedatives can potentiate each other.
When the effect of one drug is impeded by another, the effects of
these drugs are antagonistic → undesired ( Adverse) Effects.
Interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) are
demonstrated as an example of pharmacodynamic interactions.
Prof. Dr/ Nehal Afifi 3/25/2017
Pharmacokinetic interactions
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Pharmacokinetic interactions occur at the levels of
absorption , elimination, transport and metabolism.
pharmacokinetic interactions at the drug metabolism level,
chiefly of cytochrome P450 enzymes.
The systematic knowledge of Pharmacokinetic interactions
help to prevent adverse effects.
Prof. Dr/ Nehal Afifi 3/25/2017
Drug
interactions
Adverse
Drug interactions
Beneficial
Drug interactions
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Beneficial (desired) drug interactions
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Drugs combined to achieve a synergistic effect or to
limit the occurrence of side- effects (Beneficial interac)
Pharmacodynamic interactions may be clinically useful.
Examples:
Combination of Sulpha drugs & Trimethoprim .
Atropine treat the organophosphorus comp. toxicity .
Co administration of Probenecid & Penicillin enhances
effectiveness of penicillin.
Sedatives can potentiate each other.
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Clinical Importance of Beneficial Interactions
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Potentiate and enhance drug effects.
Broader the spectrum of activity.
Reduce the recommended dose of each drug.
Minimize the side effects.
Decrease drugs residues.
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Adverse Drug interactions
If fluoroquinolones combined with macrolides; erythromycin,
this result in QT prolongation( cardiac arrythmia).
The combination of ACE inhibitors with potassium-sparing
diuretics as spironalactone can increase potassium retention
→ hyperkalemia
Co administration of Cardiac glycosides & potassium-
wasting diuretics → increase digoxin toxicity.
Adverse drug interaction with NSAIDs is Pharmacodynamic
The concurrent administration of NSAIDs with anticoagulant
warfarin increase the risk of bleeding.
If Antidepressant drugs as selective serotonin reuptake
inhibitors (SSRIs) co administer with NSAIDs →result in
increased GI bleeding .
NSAIDs reduced antihypertensive effects of ACE Inhibitors.
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Pharmacodynamics Interactions at drug-
Receptor-sites
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1. Amino glycoside antibiotics produce skeletal neuromuscular
Relaxant effect. Thus the Combination of Aminoglycoside &
non-depolarizing neuromuscular blockers (curare, gallamine)
leads to excessive skeletal muscle relaxation.
Curare is not recommend in patients TTT with antibiotics.
2. General Volatile anesthetics (Ether, Halothane, Enflurane ,
methoxyflurane) potentiate effect of neuromuscular Relaxants
Reduced does of neuromuscular Relaxants must be used in
patients anaesthetized with General Volatile Agents.
Prof. Dr/ Nehal Afifi 3/25/2017
Pharmacokinetic interactions
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The desirable & undesirable effects of a drug are related
to its conc. at the sites of action, to the dose
administered and to the drug’s absorption, distribution,
metabolism, and/or excretion (ADME).
All these influenced by the concurrent administered drugs.
Observed changes arising from pharmacokinetic drug–
drug interactions such as a decrease or increase in blood
Conc. of a drug, formation of complexes, or inhibition and
induction of metabolizing enzymes.
Pharmacokinetic drug interactions lead to adverse effects.
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I. Interactions at the Absorption level
a. formation of complexes:
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Complexes reduce the bioavailability of drugs after oral
administration.
Multivalent cations such as di- or tri valent (Ca²-, Mg²-, Al³-,
& Fe³-). Form Nonabsorbable complex by Chelation with
Tetracyclines or quinolones → reduce drugs absorption.
Concurrent intake of calcium-containing foods, Laxatives
or Antacids containing aluminum or magnesium ions,with
Tetracyclines or quinolones must therefore be avoided.
Multivalent cations reduce absorption of levothyroxine.
The concurrent intake of alendronate(for osteoporosis) with
proton pump inhibitors at the same time resulting in a
reduction of alendronate absorption.
Prof.. Dr/ Nehal Afifi 3/25/2017
II.Transporter-based drug–drug interactions:
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Interactions between drugs and transporter are of increasing
interest in clinical development.
P-glycoprotein (P-gp) is the Multidrug efflux transporters
[membrane transport] .
P-glycoprotein is expressed in many tissue barriers such as
intestine, liver, kidney, and blood–brain barrier,
Example of a typical drug interaction at P-gp level is the
much higher absorption of the cardiac glycoside digoxin
when acompanied by oral admin. of the calcium antagonist
verapamil.
Examples of transporter-based interactions include:
the interactions between digoxin and quinidine,
penicillin and probenecid.
Prof. Dr/ Nehal Afifi 3/25/2017
III. Interactions at the Metabolic level
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Inhibition of drug metabolism is a frequent cause of DDI.
pharmacokinetic interactions at the drug metabolism level, chiefly
due to competition for the cytochrome P450 enzs.
cytochrome P450 enzyme (CYP), is expressed in the liver and
catalyzes the phase I oxidation of all medical drugs .
Interactions at the cytochrome P450 enzyme level: , when used in
combination with inhibitors or inducers of the same enzyme,
either increased effects and increased occurrence of unwanted
effects,(in case of inhibitors) .
or reduced effects or loss of effect (in case of inducers)
Prof. Dr/ Nehal Afifi 3/25/2017
Interactions with the most important
cytochrome P450 enzymes Inhibitors
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1. Anticoagulants—with a narrow therapeutic spectrum,
such as ciclosporin or phenprocoumon and warfarin .
vitamin K antagonists cause life-threatening hemorrhage .
The cause is interactions with macrolide antibiotics as
erythromycin , clarithromycin, which inhibit cytochrome P450
3A4, important in metabolization of warfarin, phenprocoumon.
2. The calcium channel blockers verapamil and azole
Antimycotics can be highly potent CYP3A4 inhibitors.
Ketoconazole, Fluconazole inhibits the cytochrome P450
system so strongly that it is now used as a standard inhibitor .
In this case, the increased bioavailability of verapamil is due
to fluconazole-mediated inhibition of CYP2C9 .
Prof. Dr/ Nehal Afifi 3/25/2017
Antidepressants—Selective serotonin reuptake inhibitors
(SSRIs) are potent inhibitors of CYP2D6 and CYP1A2 .
Interactions between antidepressants and beta-
blockers(metoprolol),→ inhibit metabolism of metoprolol
cause lowering of blood pressure,& bradycardia.
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Prof. Dr/ Nehal Afifi 21 3/25/2017
IV- Interactions affecting drug Excretion
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a- Reduction in urinary elimination
Altered active transport in the tubules
Probenecid block excretion of penicillin
Aspirin block excretion of methotrexate
b- Change in urine PH :
Influence elimination of weak acids & bases (passive
reabsorption to un-ionized) , e.g. Acetazolamide , sod.
Bicarbonate (urinary alkalinizer) increase acids
excretion.
Urinary alkalinizer increase sulfa excretion prevent
crystal urea.
Prof. Dr/ Nehal Afifi 3/25/2017
Reducing the Risk of drug interactions
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Drug interactions can be avoided if adequate precautions
are taken.
Monitoring therapy & make adjustment to the drug dose
regimen.
Avoid multiple-drug therapy & complex therapeutic
regimens & Use individualized therapy.
Hepatic & kidney functions must be tested firstly.
Knowledge on the pharmacology of drugs used in therapy.
Prof. Dr/ Nehal Afifi 3/25/2017
