Drug Interactions
DR MICHELLE MUNYORO
MBCHB, MCPH (UZ)
6 February 2019
OUTLINE
• DEFINITION
• CLASSIFICATION OF DRUG INTERACTIONS
• PREVENTION AND MANAGEMENT OF ADVERSE DRUG NTERACTIONS
• RULES FOR PRESCRIBERS
• MEDICOLEGAL ASPECTS
DEFINITION
• “Two or more drugs administered at the same time or in close
sequence may :
1. act independently
2. interact to increase or decrease the intended/unintended effect of
one or both drugs
3. may cause a new and unexpected reaction
Types of drug interactions
• Drug- Drug interaction : Nevirapine and Rifampicin
• Drug – Food interaction : Cheese & MAOI’s
• Drug – Beverage interactions : Alcohol & Metronidazle.
• Drug – Lab Test interactions : I-DOPA & Uric acid.
• Drug – Infusion fluid interaction : Ampicillin & Glucose.
• Drug – Disease interaction : Digoxin & Heart failure.
• Drug – Host interactions : Barbiturates & Age.
• Drug – Parasite interaction : Phenothiazines & Photoallergy.
• Drug – Echochemical interaction : DDT & Enzyme induction
• Drug- Herb interactions : ARVs and Moringa
Classification of Drug interactions
• Hansten’s Classification
-Pharmacokinetic
-Pharmacodynamic
Pharmacokinetic Interactions
• ABSORPTION
• DISTRIBUTION
• METABOLISM
• ELIMINATION
INTERACTIONS AT ABSORPTION LEVEL
• Mainly occur due to :
1. Formation of complexes
2. Direct effect on membrane transport
Interactions at absorption level
• Complex formation
-complexes may considerably reduce bio-availbility of drugs
-e.g Bisphosphonates bioavailability very low (0.5-2%)
- When taken with milk or mineral water – bioavailbility is reduced by
chelation with Ca2+ ions.
Interactions at Absorption Level
• Membrane Transport
- Multi drug efflux transporters e.g P-Glycoprotein (P-gp, ABCB1)
-P-gp inducers therefore can reduced bioavailability of substrates e.g
Rifampicin and Protease Inhibitors.
-P-gp inhibitors may increase bioavailability of substrate e.g digoxin and
Verapamil.
-inhibition of uptake transporters- reduced bioavailability e.g
repaglinide and metformin
Other Mechanisms of absorption interactions
• Alteration in GI pH
• Alteration in gut motility
• Inhibition of GI enzymes
• Alteration of GI microflora
• Malabsorptive syndromes
OBJECT DRUG PRECIPITANT DRUGS INFLUENCE ON OBJECT DRUG
ABSORPTION INTERACTION
[Link] & ADSORPTION
ANTACIDS,FOOD & MINERALS FORMATION OF POORELY SOLUBLE
CEPHROFLOXACINE, SUPPLEMENTS CONTAINING AND UNABSOBABLE COMPLEX WITH
PENCILLAMINE AL,Mg,Fe,Zn & Ca IONS SUCH HEAVY METAL IONS.
[Link] OF GI PH
ANTACIDS ENHANCED DISSOLUTION AND
SULPHONAMIDES, ABSORPTION RATE.
ASPIRIN
SODIUM DECREASED DISOLLUTION AND HENCE
FERROUS SULPHATE BICARBONATE,CALCIUM
CARBONATE ABSORPTION.
[Link] OF GUT MOTILITY
ASPIRIN DIAZEPAM, RAPID GASTRIC
LEVODOPA, METOCLOPRAMIDE EMPTYING,INCREASED RATE
MEXILETINE OF ABSORPION.
LEVODOPA, LITHIUM DELAYED GASTRIC
CARBONATE, ANTI CHOLINERGICS EMPTYING;DECREASED RATE
MEXILETINE OF ABSORPTION.
OBJECT DRUG PRECIPITANT DRUGS INFLUENCE ON OBJECT DRUG
[Link] OF GI MICROFLORA
INCREASED BIOAVAILABILITY
DUE TO DESTRUCTION OF
DIGOXIN ANTI BIOTICS BACTERIAL FLORA THAT
INACTIVATES DIGOXIN IN
LOWER INTESTINE.
[Link] SNDROME
VITAMIN NEOMYCIN INHIBITION OF ABSORPTION
A,B12,DIGOXIN DUE TO MAL.
DISTRIBUTION INTERACTIONS
•The major mechanism for distribution interaction is alteration in
protein-drug binding.
e.g. Tolbutamide given in combination with a sulphonylurea = increased
hypoglycemic effect
INTERACTIONS AT METABOLIC LEVEL
• Inhibition of drug metabolism is a significant cause of drug
interactions.
• CYP 450 Enzyme system catalyses phase I oxidation of almost 50% all
medical drugs
• CYP4503A4 has a broad substrate spectrum.
Clinical Examples
● Bioavailability can be increased by inhibition of cytochrome P450 enzymes
– Risk of renal toxicity with cyclosporin if clarithromycin is given
– Risk of bleeding if verapamil is given to patients on phenprocoumon anticoagulation
therapy
– Myalgia due to simvastatin if fluconazole is also given
– Increase in theophylline toxicity if ciprofloxacin is given
● Bioavailability can be reduced by induction of cytochrome P450 enzymes
– Transplant rejection in patients on cyclosporin for immune suppression who are co-
medicated with rifampicin
– Thrombosis risk in patients on phenprocoumon anticoagulation therapy who are co-
medicated with carbamazepine
– Efficacy of ethinylestradiol contraceptives is at risk if Efavirenz is given at the same time.
Interactions at Elimination level
excretion pattern of a drug is altered.
Major mechanisms of excretion interactions are ;
•Alteration in renal blood flow
•Alteration of urine PH
•Competition for active secretions
•Forced diuresis
Pharmacodynamic Interactions
• Direct effects of the drugs on one another
• Polypharmacy most common cause
• Common in the elderly
Pharmacodynamic Interactions
• Antagonism
• Addition / summation
• synergism / potentiation
Antagonistic Interactions
• The interacting drugs have opposing actions
• Example: Acetylcholine and noradrenaline have opposing effects on
heart rate.
Additive interactions
• The interacting drugs have similar actions and the effect is the some
of individual drug responses or a combination of both.
Example : hypnotic sedatives
Synergystic interactions
• It is an enhancement of action of one drug by another
• Example: Amphotericin B and Flucytosine
PREVENTION OF DRUG INTERACTIONS
• Individualised approach is imperative
• A minimum number of essential drugs for the shortest necessary
duration must used.
• Appropriate monitoring is mandatory when drugs known to interact
are prescribed concurrently.
• A change of therapy calls for enhanced pharmacovigilance.
Prevention of Drug interactions
• Timing of medication, genetic difference, and concurrent pathology
are contributory factors that must be catered for.
• The clinician must not be complacent and must anticipate variability
in the occurrence and magnitude of interactions.
• Severity and type of interaction are two important determinants of
the management of interaction and their adversities.
• Withdrawal of interacting drugs, substitution by another drug,
dosage reduction, and specific therapy of adverse interaction are the
common principles of management.
Rules for a good prescriber
• Do not prescribe contraindicated combinations.
• Know the components of the generic formulation.
• Develop an order of priority of need
• Prescribe drugs for limited period only to the patient.
• Be sure of hepato-renal function.
• Do not be misled if a multiple drug combination is tolerated by one patient.
• Know which patients are seeing other physicians and what medications
have been prescribed.
• Know what OTC drugs the patient is taking.
• Record proper drug history of the patient in notes particularly and history
of allergic or other drug interactions.
Medico-Legal Aspects
• There will always be error produced by failure of human perception
• There will always be occasions on which a drug may be mis-labelled,
an improper does administered, or the wrong drug given to patient
• Injury from such situation generally = NEGLIGENCE
• In the event of litigation, clinician has to substantiate why he/she
deviated from the limitations described in the package insert and in
best interest of patient and doctor a clinician has substantial freedom
to use any drug.
Medico-Legal Aspects
• Injury caused to patient: clinician’s judgment will be related to the general
standard OF CARE.
• A clinician failing to read the fine print of drug warning may find to his dismay
that a known adverse reaction does exist, when the warning is magnified in the
slide projected in the court-room at his/her trial for malpractice
Role of Pharmaceutical industry
• many brand names of same generic name are made available by
industry with different bioavailability, and physico-chemical properties
and hence the association of pharmaceutical industries must initiate
and create facilities for registry of drug interactions as they occur.
• Bioequivalence
• An effort to study possible and probable interactions with all new
drugs must be made involving both preclinical and clinical
pharmacology especially when are used in combination.
References
• Greiner B, Eichelbaum M, Fritz P, et al.: The role of intestinal P-
glycoprotein in the interaction of digoxin and rifampin. J Clin Invest
1999; 104: 147–53
• Rang and Dale’s Clinical pharmacology
• BNF 63
• Li L, Yu M, Chin R, Lucksiri A, Flockhart DA, Hall SD: Drug-drug
interaction prediction: a Bayesian meta-analysis approach. Stat Med
2007; 26: 3700–21
Questions…….?
