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
1.COMPLEXATION & 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.

2.ALTERATION OF GI PH
ANTACIDS ENHANCED DISSOLUTION AND
SULPHONAMIDES, ABSORPTION RATE.
ASPIRIN
SODIUM DECREASED DISOLLUTION AND HENCE
FERROUS SULPHATE BICARBONATE,CALCIUM
CARBONATE ABSORPTION.

3.ALTERATION 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
4.ALTERATION OF GI MICROFLORA
INCREASED BIOAVAILABILITY
DUE TO DESTRUCTION OF
DIGOXIN ANTI BIOTICS BACTERIAL FLORA THAT
INACTIVATES DIGOXIN IN
LOWER INTESTINE.
5.MALABSORPTION 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…….?