Conceptual and Practical Update on Drug-Drug Interactions

 

Chitra Jose, Monica Antony, Jyothi Goutham Kumar, Maheswari C, Venkatanarayanan R, Sam Johnson Udaya Chander J*

RVS College of Pharmaceutical Sciences, Coimbatore, India

 

ABSTRACT:

Recently, the topic of Drug-Drug interactions has received a better attention from the regulatory, scientific, and healthcare community worldwide. Although it is impossible to present all the drug combination causing Drug-Drug Interactions (DDIs), this article will summarize the mechanism of action associated with DDIs. DDIs tends to be more common among certain patients with underlying diseases, co-morbid conditions, etc., and in specific clinical situations such as polypharmacy and usage of drugs with a narrow therapeutic range or low therapeutic index. Therefore, successful prevention requires knowledge on molecular mechanisms of drug interaction, severity classification, management and prevention of drug interaction and sources of information on drug interaction, coupled with vigilance, reporting of drug interaction and early intervention. Surprisingly, little information is available to guide us with respect to avoiding complications in critical situation. Therefore, it is necessary to focus more on the concept of drug interaction. Software checkers for identifying drug interactions are widely available. Since the sorting out of clinically significant drug interaction is impossible with these software’s, it has limited clinical utility. As it is no longer practical for physicians to memorize the list of drug interactions to avoid potential drug interactions, it is an important part of clinical practice of knowing how drug-drug interactions occur and how to manage them. Hence, this review aims to present the conceptual framework of drug-drug interactions and their path physiology.

 

 

 

INTRODUCTION:

“Drugs are double-edged weapons”.¹ Uses of these drugs concomitantly may lead to some degree of drug interaction. Combination of more than two drugs with a potential to interact may be beneficial or result in increased toxicity and failure of the treatment.^2,3 But only a small proportion of this interaction is clinically significant which may sometimes causes life threatening, serious, moderate or mild adverse reactions. Many studies have proven that the chance of drug interaction is more in patients with poly pharmacy and multiple diseases.⁴

 

Some studies show that physicians have a poor knowledge about drug interaction^5,6 and many cases were reported in which the patient had some life-threatening conditions. Deficiencies in the knowledge of drug interaction could result in inappropriate patient counseling, disruption in therapy and leads to treatment failure and adverse medical consequences. It is difficult to assess the overall clinical importance of many drug interactions. Often, drug interaction reports are based on anecdotal or case reports, and their mechanisms are not clearly defined. In addition, determining clinical significance requires an assessment of the severity of potential harm. This makes an unequivocal determination of “clinically significant” difficult. Drug interactions, particularly with drugs having a narrow therapeutic range, may have serious adverse consequences. Therefore, in the evaluation and clinical application of drugs, appropriate efforts should be made to predict the nature and degree of drug interactions so that patients will not be adversely affected. The genetic variability and co-morbid disease conditions contribute to the varying degrees of drug interactions. It should, therefore, be kept in mind that drug interactions might readily cause clinically significant changes in blood drug levels (concentration in whole blood, plasma, or serum) and other conditions in patients having pharmacokinetic parameters markedly deviating from those of the standard population. Drug interactions have been studied, interpreted and managed ever since medicines have been concomitantly administered to patients. Currently, thousands of drug interactions are studied each year, contributing to an enormous knowledge base describing simple and complex alterations that occur when drugs are used in combinations. Every year a large number of drugs are introduced and new interactions between medications are increasingly reported. Similarly, it is no longer practical for physicians to depend on memory alone to avoid potential drug interactions.^{7, 8} So, basic knowledge on mechanism of drug interaction will be helpful to manage complications associated with it. Increasing drug regimens or polypharmacy carry the risk of adverse interactions.

 

Definitions:

·        Drug interaction:

A drug interaction occurs when a patient’s response to a drug is modified by food, nutritional supplements, formulation, excipients, environmental factors, and other drugs or disease (or) it is the modification of response to one drug by other drug simultaneously or given in a quick succession. Drug interaction may enhance or diminish the effect of one drug or the other.⁹

 

·        Precipitant drugs:

Precipitant drugs is the medication which modifies the pharmacokinetic (absorption, distribution, metabolism, excretion) or Pharmacodynamics parameters (actual clinical effect) of object drug. Drugs like NSAIDs, antibiotics and, in particular, rifampin are common precipitant drugs.

 

·        Object drugs:

Object drug is the medication whose therapeutic effect is modified leading to misadventure associated with the interactions. The common drugs include warfarin, fluoroquinolones, and antiepileptic drugs etc.^{9, 10} Many other drugs, act as precipitants or objects, and a number of drugs act as both. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions.¹¹

 

Among elderly patients, the risk of a sub-therapeutic effect as a potential DDI was as common as the risk of noxious reactions. Besides drugs, important interactions may occur with other pharmacologically active agents such as alcohol and nicotine.

 

Table 1: Some drugs with a low therapeutic index

Lithium	Digoxin
Carbamazepine	Cyclosporine
Phenytoin	Phenobarbitone
Theophylline (Aminophylline)	Warfarin

(Source: Alessandra Batista et al¹²)

 

Negative Impact of Drug Interaction on Quality of Life of Patient:^12-14

Various negative impact of drug interaction on quality of life of patient and patient outcome are:

·        Death.

·        Life-threatening (Serotonin syndrome is a potentially life-threatening disorder of excessive serotoninergic activity often due to drug interactions).

·        Hospitalization (initial and prolonged)

·        Disability- persistent, significant or permanent impairment, damage.

·        Quality of life.

·        Cost of care, etc.

 

Economic crisis of patient underwent drug interaction:

A study of economic consequences of Drug-Drug Interactions reported a case involving interaction of fluoxetine and selegiline required a 15-day hospitalization, emergency room visit, ambulance services, magnetic resonance imaging, electrocardiogram, laboratory tests and consultations.¹⁵ The resultant total medical expenditures for treatment of this single case of an interaction-induced illness was very high.

 

Net effect of combination of drugs:

v  Synergism or additive effect

v  Antagonism or subtractive effect

v  Alteration of drug effect by idiosyncratic effect

 

Drugs more likely to have drug interaction:

v  Drugs with narrow safety margin like amino glycosides, antibiotics, lithium, and dioxin.

v  Drugs affecting closely regulated body function like antihypertensive and ant diabetic.

v  Highly plasma protein bound drug like NSAIDS and anticoagulant.

v  Drugs metabolized by saturation kinetics like Phenytoin and theophylline.

 

Triggering factors for drug interactions:

·        Aging of the population.

·        Increasing complexity of medication regimen used to treat ambulatory patients.

·        Fragmented healthcare system.

·        Multiple prescribers.

·        Genes and physiology.

·        Lifestyle (diet and exercise).

·        Underlying diseases and co-morbid conditions.

·        Drug doses.

·        Duration of combined therapy.

·        Time and route of administration of drug.

·        Patient’s non-compliance.

·        Irrational polypharmacy.

·        Concurrent use of prescribed and non-prescribed drugs

 

Classification of drug interaction:¹⁶

·        Drug-drug interaction

·        Drug-food interaction

·        Drug-laboratory interaction

·        Drug-chemical interaction

 

The drug interactions can be further classified on the basis of:

Depending upon the effect:

a)      Inhibiting drug interaction

b)     Potentiating drug interaction

c)      Modifying drug interaction

 

Depending upon mechanism of action:

a)      Pharmacokinetic interaction

b)     Pharmacodynamics interaction

·      Synergistic interaction

·      Antagonistic interaction

c)      Pharmaceutical interaction

 

Based on MICROMEDEX Software:¹⁷

a)     Contraindicated – the drugs are contraindicated for concurrent use (most severe)

b)     Major DDIs – the interaction may be life-threatening and/or require medical intervention to minimize or prevent serious adverse effects.

c)     Moderate DDIs – the interaction may result in exacerbation of patient’s condition and/or require a modification in therapy.

^d)          Minor DDIs – the interaction would have limited clinical effects.

 

Contraindicated or significant is the most frequently used classifica­tion for drug interaction as the interactions that require immediate medical intervention due to imminent risk of death.  In turn, mi­nor and moderate drug interactions may produce limited clinical effect without the need to significantly change the therapy.

 

Mechanisms of drug interaction:

Pharmacokinetics studies the absorption, distribution, metabolism and excretion of a drug and Pharmacodynamics studies the relationship between the drug and its receptors, its mechanism of action and therapeutic effect. Both can play a major role in drug-drug interactions.

 

Pharmacokinetic Interactions:

A.     Drug Interactions Affecting Absorption:

Mechanisms of absorption include passive diffusion, convective transport, active transport, facilitated transport, ion-pair transport, and endocytosis. Certain drug combinations can affect the rate or extent of absorption of anti-infective by interfering with one or more of these mechanisms.¹⁸ Generally, a change in the extent of a medication’s absorption of greater than 20% may be considered clinically significant.¹⁹ The most common mechanisms of drug interactions affecting absorption are:

 

·        Changes in pH

The rate of drug absorption by passive diffusion is limited by the solubility, or dissolution of a compound in gastric fluid. Basic drugs are more soluble in acidic fluids and acidic drugs are more soluble in basic fluids. Therefore, solubility of some compounds decrease because they alter the pH of their environment, but these compounds need an opposing environment for their absorption. Medications known to require an acidic environment for solubilising are ketoconazole, itraconazole, and daps one have demonstrated significantly decreased absorption when given concominantly.²⁰ Antacids, histamine receptor antagonists, and proton pump inhibitors all raise gastric pH to varying degrees. Antacids transiently (0.5–2 hours) raise gastric pH by 1–2 units, H₂-antagonists dose-dependently maintain gastric pH above 5.0 for many hours, and proton pump inhibitors dose-dependently raise gastric pH above 5.0 for up to 19 hours. The concomitant administration of these compounds leads to significant alterations in the extent of absorption of basic compounds such as certain azoles, antifungal and β-lactam antibiotics.¹⁹ However, because of large inter-individual variability in the extent of altered gastric pH, significant interactions may not occur in all patients.

 

·        Chelation and Adsorption:

Drugs may form insoluble complexes by chelation in the gastrointestinal tract. Chelation involves the formation of a ring structure between a metal ion (e.g., aluminum, magnesium, iron, and to a lesser degree calcium) and an organic molecule (e.g., anti-infective medication), which results in an insoluble compound that is unable to permeate the intestinal mucosa because of the lack of drug dissolution. A number of examples of the influence on anti-infective exposure by this mechanism exist in the literature, involving primarily the quinolone antibiotics in combination with magnesium- and aluminum-containing antacids, sucralfate, ferrous sulphate or certain buffers. These di- and trivalent cations complex with the 4-oxo and 3-carboxyl groups of the quinolones, resulting in clinically significant decreases in the quinolone area under the concentration–time curve (AUC) by 30 to 50% .^21,22 A second well-documented, clinically significant example of this type of interaction involves the complication of tetracycline and iron. By this mechanism, tetracycline antibiotics AUCs are decreased by up to 80% .²³

 

·        Changes in Gastric Emptying and Intestinal Motility:

The presence or absence of food can affect the absorption of anti-infective by a variety of mechanisms.²⁴ High-fat meals can significantly increase the extent of absorption of fat-soluble compounds such as griseofulvin, cefpodoxime, and cefuroxime axetil. Prolonged stomach retention can cause excessive degradation of acid-labile compounds such as penicillin and erythromycin.¹⁸ Because the primary location of drug absorption is the small intestine, changes in gastric emptying and gastrointestinal motility may have significant effects on drug exposure. Rapid gastrointestinal transit effected by prokinetic agents such as cisapride, metoclopramide, and domperidone may decrease the extent of absorption of poorly soluble drugs or drugs that are absorbed in a limited area of the intestine.²⁵ However, clinically significant effects on anti-infective have not been documented.

 

·        Effects of Intestinal Blood Flow:

Intestinal blood flow can be modulated by vasoactive agents and theoretically can affect the absorption of lipophilic compounds. However, there is no evidence to date that this results in clinically significant drug interactions.²⁶

 

·        Effects of P-Glycoprotein:

P-Glycoprotein has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure. However, because many drugs have affinities for both P-glycoprotein and CYP3A4/5, it is difficult to determine by which specific mechanism drug interactions occur.²⁷ For some compounds, inhibition of both P-glycoprotein function and CYP3A4/5 activity may be required to produce clinically significant interactions. Many anti-infective have binding affinity for P-glycoprotein. These include erythromycin, clarithromycin, ketoconazole, the nucleoside analog adefovir, the human immunodeficiency virus (HIV)-1 protease inhibitors²⁸, etc. Combination with verapamil (a classic P-glycoprotein inhibitor), significantly decreased P-glycoprotein-mediated efflux, occurred only with erythromycin.²⁹

B.     Drug Interactions Affecting Distribution:

·        Protein Binding and Displacement:

Drug interactions affecting distribution are those that alter protein binding. Redistribution and excretion of drugs generally occurs quickly after displacement and the effects of any transient rise in unbound concentration of the object drug are rarely clinically important³⁰. Depending on relative plasma concentrations and protein-binding affinities, one drug may displace another with clinically significant results. This interaction is much more likely to occur with drugs that are at least 80 to 90% bound to plasma proteins, with small changes in protein binding leading to large relative changes in free drug concentration. Drugs that are poorly bound to plasma proteins may also be displaced, but the relative increase in free drug concentration is generally of less consequence. When a protein displacement interaction occurs, the increased free drug in plasma quickly distributes throughout the body and will localize in tissues if the volume of distribution is large. An increase in unbound drug concentrations at metabolism and elimination sites will also lead to increased rates of elimination. Therefore, many clinically significant drug interactions that have been attributed to protein binding have often involved a second, unrecognized mechanism of interaction. Thus, drug interactions involving albumin-binding displacement may potentially be clinically significant if the compound is greater than 80% protein bound, has a high hepatic extraction ratio, a narrow therapeutic index, and a small volume of distribution. Although temporary increase in drug concentrations may be clinically significant with such drugs as warfare and Phenytoin, the mean steady-state free drug concentrations will remain unaltered.³¹

 

C.     Drug Interactions Affecting Drug Metabolism:

Drug-metabolizing activity can be classified according to non-synthetic (Phase I) and synthetic (Phase II) reactions. Phase I reactions include oxidation, reduction, and hydrolysis and occur in the membrane of hepatocyte endoplasmic reticule. Phase II reactions result in conjugation (i.e., glucuronidation, sulfation) and occur in the cytosol of the hepatocyte.

 

·        Phase I Drug Metabolism:

The majority of oxidative reactions are catalyzed by a super family of mixed-function mono-oxygenizes called the CYP enzyme system. Although CYP isozymes are located in numerous tissues throughout the body, the liver is the largest source of CYP protein. Many significant pharmacokinetic drug interactions involve the hepatic CYP isozymes,^32,33 Approximately 95% of all therapeutic drug oxidation can be accounted for by the activities of CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5. Drug interactions involving these isozymes result from enzyme inhibition or

induction, although genetic polymorphism can attenuate these interactions. Inhibition of drug-metabolizing enzymes may result in more significant effects in those with high initial enzyme activity, and induction of drug metabolizing enzymes may result in more significant effects in those individuals with low initial enzyme activity.

 

Mechanisms of Inhibition:

Enzyme inhibition can result in sudden catastrophic drug interactions. Several mechanisms of inhibition exist, and many drugs can interact by multiple mechanisms.³⁴ Reversible inhibition is most common. Reversible inhibition occurs when compounds quickly form weak bonds with CYP isozymes without permanently disabling them. This can occur both competitively (competition for the same binding site between inhibitor and substrate) and noncompetitively (inhibitor binds at a site on the enzyme distinct from the substrate). The magnitude of this type of inhibition depends both on the affinity of substrate and inhibitor for the enzyme and on the concentration of the inhibitor at the enzyme site.³⁵

 

Mechanisms of Induction:

An increase in CYP activity through induction is less of an immediate concern than inhibition because induction occurs gradually rather than rapidly and generally leads to compromised therapeutic goals rather than profound toxicity, because the time-course of enzyme induction is determined by the half-life of the substrate as well as the rate of isozymes turnover. Clinically significant induction results from a more than 50-fold increase in the number of enzyme molecules. This generally occurs through an increase in P450 synthesis by either receptor-mediated transcriptional activation or mRNA stabilization. Investigators have established that a human orphan nuclear receptor, termed the pregnane X receptor (PXR), binds to a response element in the CYP3A4 promoter region. PXR is activated by a range of drugs known to induce CYP3A4 expression (i.e., rifampicin, clotrimazole, etc.). PXR is expressed most abundantly in the liver, but is also present in the small intestine and colon. CYP3A can also be induced by posttranscriptional message stabilization and protein stabilization with the following anti-infective: macro ides, imidazole antifungal agents and rifampin. The specific mechanisms for this are currently unknown, but most likely involve interaction with a cyclic adenosine 5′-monophosphate-dependent phosphorylation process involved in protein denaturation.

 

·        Phase II Drug Metabolism:

The term Phase II metabolism was developed originally to represent synthetic reactions occurring after Phase I processes. It is now known that many xenobiotics do not require Phase I metabolism before undergoing conjugation reactions. The group of Phase II isozymes consists of uridine 5-diphosphate (UDP)-glucuronosyl transferases, sulfotransferases, acetyl transferases etc. Many of these families of enzymes are still growing in complexity, and drug interactions involving these isozymes are under investigation.

 

Genetic Polymorphism

Many of the Phase II enzymes exhibit polymorphism. Although these polymorphisms have been implicated in selected anti-infective-associated adverse drug reactions (e.g., daps one, ionized, sulfonamides),³⁶ influences of these polymorphisms on anti-infective drug interactions have not been documented.

 

Inhibition:

Phase II drug-metabolizing enzymes do not currently appear to play a prominent role in clinical drug interactions with anti-infective as the CYP enzyme system. This may be because of the large capacity of the conjugation system, in which only profound disturbances result in clinically significant alterations in drug pharmacokinetics. UDP-glucuronosyltransferase represents the most common conjugation reaction in drug metabolism. Many drugs have been characterized as competitive inhibitors of UDP-glucuronosyl transferees, but the roles of these interactions in practical drug metabolism issues are unexplored.³⁷

 

Induction:

Far less is known about the potential for induction of Phase II enzymes than the CYP enzyme system. The increased clearance of zidovudine that has been documented with the co-administration of rifampin suggests that induction of these enzymes may be clinically significant.³⁸ Glutathione-S transferase is also known to be inducible, although these activities rarely exceed two to threefold times baseline and are not involved in anti-infective metabolism.³⁹

 

D.     Drug Interactions Affecting Excretion:

Renal elimination of drugs involves glomerular filtration, tubular secretion, and tubular reabsorption.

 

The examples of various pharmacokinetic interactions are illustrated in table 2.

 

 

Table 2: List of some important pharmacokinetic interactions

Object drug (s)	Precipitant drug (s)	Influence on  object drug (s)
ABSORPTION INTERACTIONS
1. Complexation and adsorption
Tetracycline, Fluoroquinolones like ciprofloxacin, penicillamine	Antacids, food and minerals supplements containing Al, Mg, Fe, Zn, Bi and Ca ions.	Formulation of poorly soluble and unabsorbable complex with such heavy metal ions.
Cephalexin, sulphamethoxazole, trimethoprim, warfarin and thyroxine	Cholestyramine	Reduced absorption due to adsorption and  binding
2. Alteration of GI Ph
Sulphonamides, aspirin	Antacids	Enhanced dissolution and absorption rate
Ferrous sulphate	Sodium bicarbonate, calcium carbonate	Decreased dissolution and hence absorption
Ketoconazole , tetracycline atenolol	Antacids	Decreased  dissolution and bioavailability
3. Alteration of Gut motility
Aspirin, diazepam, levodopa, lithium carbonate, paracetamol, mexiletine	Metoclopramide	Rapid gastric emptying; increased rate of absorption
Levodopa, lithium  carbonate, mexiletine	Anticholinergics (atropine)	Delayed gastric emptying ; decreased rate of absorption
4. Inhibition of GI enzymes
Corticosteroids, oral contraceptives, theophylline, cyclosporine	Phenytoin	Decreased plasma levels; decreased efficacy of object drugs
5. Alteration of GI microflora
Digoxin	Antibiotics (erythromycin, tetracycline)	Increased bioavailability due to destruction of bacterial flora that inactivates digoxin in lower intestine
Oral contraceptives	Antibiotics( ampicillin)	Decreased reabsorption of drugs secreted as conjugates via bile in intestine
6. Malabsorption Syndrome
Vitamin A, B12, digoxin	Neomycin (and colchicines)	Inhibition of absorption due to malabsorption /steatorrhea caused by neomycin
DISTRIBUTION INTERACTIONS
Competitive displacement interactions
Displaced drug(s)	Displacer (s)
Anticoagulants (warfarin)	Phenylbutazone, chloral hydrate, salicylates	Increased clotting time; increased risk of haemorrhage
Tolbutamide	Sulphonamides	Increased hypoglycaemic effect
Methotrexate	Sulphonamides, salicylic acid	Increased methotrexate toxicity
Phenytoin	Valproic acid	Phenytoin toxicity
METABOLISM INTERACTIONS
1. Enzyme induction
Corticosteroids, oral contraceptives, coumarins, Phenytoin, tolbutamide, tricyclic antidepressants	Barbiturates	Deceased plasma levels; decreased efficacy of object drugs
Corticosteroids, oral contraceptive, theophylline, cyclosporine	Phenytoin	Deceased plasma levels; decreased efficacy of object drugs
Corticosteroids, oral  hypoglycaemic agents, coumarins	Rifampicin	Deceased plasma levels; decreased efficacy of object drugs
2. Enzyme inhibition
Tyramine, rich food (cheese , liver , yeast products)	MAO inhibitors(phenelzine, pargyline)	Enhanced absorption of unmetabolised tyramine; increased pressor activity; potentially fatal risk of hypertensive crisis
Drugs that undergo extensive hepatic first pass metabolism(eg: propanolol, calcium channel  blockers etc)	Grapefruit juice	Enhanced absorption of drugs; increased risk of toxicity
Folic acid	Phenytoin	Decreased absorption of folic acid due to inhibition of an responsible for its absorption
Tricyclic antidepressants	Chlorpromazine, haloperidol	Increased plasma half life of tricyclics , increased risk of sudden death from cardiac disease in such patients
Coumarins	Metronidazole, phenylbutazone	Increased anticoagulant activity risk ; risk of haemorrhage
Oral hypoglycemics	Phenyl butazone, sulphaphenazole, chloramphenicol	Hypoglycemia may be precipitated
Alcohol	Disulfiram ,metronidazole, tinidazole	Disulfiram like reactions due to increase in plasma acetaldehyde levels
AZT, mercaptopurine	Xanthine oxidase inhibitors (allopurinol)	Increased toxicity of anti neoplastics
Alcohol  ,benzodiazepines, warfarin, Phenytoin, phenobarbital	Cimetidine	Increased blood levels of object drug

(Source: Remington’s Pharmaceutical Sciences⁴⁰, Biopharmaceutics and Pharmacokinetics-A Treatise⁴¹)

 

Table 2: continued

Object drug (s)	Precipitant drug (s)	Influence on  object drug (s)
EXCRETION INTERACTIONS
1. Changes in active tubular secretion
Penicillins, cephalosporins, PAS, methotrexate , dapsone	Probenecid (acid)	Elevated plasma levels of acidic drugs ; risk of toxic reaction
Procainamide ,ranitidine	Cimetidine(base)	Increased plasma levels of basic object drugs; risk of toxicity
Acetohexamide	Phenylbutazone	Increased hypoglycaemic effect
2. Changes in urine pH
Amphetamine , tetracycline, quinidine	Antacids .thiazides, acetazolamide	Increased passive reabsorption of basic dyes; increased risk of toxicity
3. Changes in renal blood flow
Lithium bicarbonate	NSAIDs (inhibitors of prostaglandin synthesis; the latter control renal blood flow partially by vasoconstriction)	Decreased renal clearance of lithium; risk of toxicity

(Source: Remington’s Pharmaceutical Sciences⁴⁰, Biopharmaceutics and Pharmacokinetics-A Treatise⁴¹)

 

Pharmacodynamics drug interactions:

The activity of object drug at its site is altered by the precipitant. Such interactions may be direct or indirect.

 

A.     Direct Pharmacodynamics Interactions: is the one in which drugs having similar or opposing pharmacological effects are used concurrently. The three consequences of direct interactions are:

·        Antagonism: The interacting drugs have opposing actions, e.g.: acetylcholine and nor adrenaline have opposing effects on heart rate.

·        Addition or Summation: The interacting drugs have similar actions and the resultant effect is the sum of individual drug responses, e.g.: CNS depressants like sedatives, hypnotics, etc.

·        Synergism or Potentiation: It is enhancement of action of one drug by another, e.g.: alcohol enhances the analgesic activity of aspirin.

 

B.     Indirect Pharmacodynamics Interactions:

Both the object and the precipitant drugs have unrelated effects, but the latter in some way alters the effects of the former. e.g: salicylates decreases the ability of the platelets to aggregate thus impairing the homeostasis of warfare-induced bleeding occurs.

 

Prevalence of drug interaction:

Globally:

It is evident that up to 8% of hospital admissions are due to adverse drug reactions and over 20% of these are due to drug interactions, which show the clinical relevance of drug interaction.⁴⁷ The incidence of drug interactions is difficult to quantify, as this may depend on the “clinical significance” of the interaction. However, the greater the number of drugs taken inevitably increases the risk of a drug interaction occurring. A recent study shows polypharmacy and major and moderate Drug-Drug Interactions are more prevalent in females and in age group of 61-80 years.^3,6 Some studies are upcoming with the effect of educational programme in management of drug interaction and adverse drug reactions.⁴⁸

In India:

On the basis of recently published study, 1% of total hospital admissions are caused by DDIs and 0.05% of the emergency department visits, 0.1% of re-hospitalizations and 0.6% of the hospital admissions are caused by adverse drug reactions (ADRs) due to DDIs.⁴² Many studies have been conducted on prevalence of drug interactions in various parts of the country or in various departments of the hospital. Some studies showed that the age, gender, polypharmacy and co-morbidities are known as the risk factors for developing DDIs.^43-45 Another study showed that the prevalence of potential DDIs in medicine department is found to be 19.5%.^46,5,6

 

Identification and management of drug–drug interactions:

The potential for an interaction is often predictable, but there are usually many variables involved in whether the interaction will be clinically significant. Also, medicines in the same class do not interact to the same extent. For example, Simvastatin versus atorvastatin.¹⁶

 

Risk assessment:

·        How common is the interaction?

·        How severe will the interaction be if it occurs?

·        Is it a dose-related interaction?

 

Management:

·        Prescribe an alternative, non-interacting drug.

·        Stop the target interacting drug temporarily.

·        Monitoring: Early detection with investigations-INR, blood pressure, liver function tests, etc.; clinically- seeing symptoms of dizziness or muscle aches.

·        Spacing the dosing interval/time.

 

Why knowledge of DDIS is important to healthcare professionals (lack of knowledge):

The ability of prescribers to identify and manage accurately potential DDIs has not been well defined.⁴⁸ Every year, a large number of drugs are introduced and new interactions between medications are increasingly reported.⁸ Consequently, it is no longer practical for physicians to rely on memory alone to avoid potential drug interactions. Multiple drug regimens carry the risk of adverse interactions. Identifying and managing drug interactions are a challenging job for family physicians, and remembering all potential interactions has become virtually impossible.

 

Sources of information on drug interactions

Information on clinically significant DDIs can be obtained from the following sources:

§  British National Formulary (BNF)

§  Summary of Product Characteristics / Data Sheet Compendium

§  Martindale - The Complete Drug Reference

§  Drug Interactions, Stockley

§  National Medicines Information Centre (NMIC)

§  Micromedex

§  Medscape.

 

CONCLUSION:

According to the present Indian scenario, drug interaction in one of the reasons for hospitalization and increased economic burden of the patients.^15,47 Considering the importance of management of these drug interactions, we have concluded that most of potential drug interactions can be recognized by applying principles of clinical pharmacology. An explanation of the mechanisms of interactions will enable practitioners to understand more fully the nature of the interactions and thus enable them to manage better for effective clinical outcome. Also, such studies will need to emphasize on area of the molecular mechanism by which drug interacts, importance of drug interaction management and their influence in the betterment of patient care and for the excellent therapeutic outcome, as it is the need of time to explore this area of Drug-Drug Interactions.

 

CONFLICT OF INTEREST:

None declared

 

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Received on 24.10.2015          Modified on 17.11.2015

Accepted on 21.11.2015        © RJPT All right reserved