Clinical Drug Interactions: A Holistic View
A. H. Ahmad,
Amit Kumar Verma,
Every time a drug is administered to the animal to treat an
ailment, no matter whether it is acute or chronic manifestation, it usually
goes together with some other prescription medicine, OTC (Over the counter)
formulation, herbs or even food. All the xenobiotics such as drugs, toxins and
food components as well as the endogenous compound that are formed in the animal
body as a routine phenomenon exert a stimulatory or inhibitory effect on the
different physiological and biochemical processes going in the body. These effects
may alter the normal metabolism and/or drug transport or its efficacy drastically
and thus expose the man and animals to the risk of a potentially dangerous interaction.
The present review discusses these potential reactions and their mechanisms
that help in navigating the hazardous combinations of drugs with other medicines,
food, herbs, vitamins and minerals with confidence.
Received: December 15, 2012;
Accepted: January 25, 2013;
Published: April 12, 2013
A drug interaction is said to occur when a drug is administered with any another
xenobiotic and the pharmacological response of the drug gets altered either
in intensity or duration (Rahal et al., 2008;
Davis et al., 2013). Whenever two or more drugs
are taken concurrently, there is a chance of an interaction among the drugs
that could manifest as an increase or decrease in their effectiveness or an
adverse reaction or a totally new side effect that is not seen with either drug
alone that can be severe enough to alter the clinical outcome and warrant hospital
admissions, ranging upto 3.8%. In veterinary clinical practice, occurrence of
new drug-drug interactions (Rodrigues, 2000; Rahal
et al., 2007; Singh et al., 2009)
between a plethora of medications being introduced every day is a common feature,
especially in the chronic ailments subjected to poly pharmacy for the treatment
of a large number of diseases; thus making it difficult for any physician to
remember avoiding potential drug interactions. Such interactions often result
in adverse clinical complications.
Drug interactions should always be differentiated from any unusual response
occurring during drug therapy (Arnaud et al., 2012).
Prior to start a treatment for any such plausible adverse drug interaction,
it is essential to have the history of previous medication as most of the time
patients consult many physician and formulate their own prescription just by
amalgamating or substituting the prescribed drugs as usually seen in case of
antibiotics, painkillers and other over-the-counter medicines (Valiyil
and Christopher-Stine, 2010; Kirking et al.,
1986). Certain drugs show the risk of generating interactions over and over
again through well understood mechanisms (Davis et al.,
2013). When such drugs are started or stopped, the physician needs to be
extra alert to the possibility of drug interactions. While it is impossible
to list every plausible interaction with the currently available drugs or food
(Gysin et al., 2011) but the drugs which have
high protein binding tendency mostly get involve in such interactions (Rahal
et al., 2008). Generally, the problem of drug interaction is most
commonly encountered with certain groups of drugs that are usually used in combination
like Non steroidal anti-inflammatory agents (NSAIDs), and the drugs of low therapeutic
index (e.g., Digoxin) are a massive challenge to physicians. Moreover, the commonly
used antibiotics and antimicrobials viz., Penicillin, Sulfonamides, along with
oral contraceptives and antiepileptic are also responsible for these kind of
challenges. The most common examples of such drugs include aspirin, phenylbutazone,
carbamazepine, phenytoin, rifampicin and griseofulvin that influence either
the protein binding or modulate the process of metabolism and excretion of other
drugs. There are many drugs e.g., allopurinol, metronidazole, chloramphenicol,
cimetidine, ketoconazole, quinolones and MAO inhibitors; which are responsible
for the inhibition of metabolism of other drugs.
EARLY EVALUATION OF DRUG INTERACTIONS
Today drug-drug interaction and the resulting adverse reactions form a topic
of round table discussion among pharmaceutical personnel as well as researchers.
Despite this general awareness and concern of the problem of drug interactions
and widespread efforts to monitor them, the physician society has so far failed
in predicting as well as recognizing them. Because drug interactions could not
be generally predicted, one had to wait till they appeared in literature. Recognition
of potential interactions should really commence early in the development of
new drugs. Now various reliable methods are available to find out the actual
or potential drug interactions and such well established method include the
study of various processes the drugs undergo after entering and before its exit
from the body. Such interactions are studied by pharmaceutical companies during
the initial stages of drug development process but pharmacovigilant monitoring
in later phases could also reveal interactions although the restrictions of
use of concomitant drugs in these phases may not provide optimal information
regarding drug interactions. In present system, advanced techniques are applied
to assess the drug interaction in-vitro to update the clinicians and
to avoid untoward interactions particularly for the specific diseases (Davis
et al., 2013). Based upon the method of the existing methods of evaluating
drug interaction many of these interactions can be avoided. However, in-vitro
studies do not exactly translate always in the clinical scenario, because of
immense in vivo variables that come in to play. Some drugs can be metabolized
by more than one enzyme whereas some others like carbamazepine can not only
induce a particular isoenzyme (CYP3A4) but also get metabolized by it demanding
a gradual dosing, while a few others can inhibit a particular isoenzyme but
not be metabolized by it.
Magnitude of the problem: Drug interactions are multifaceted and chiefly
inconsistent (Ansari, 2010) as a known interaction
may not occur in every individual taking the drug or even a drug in the same
class. There is a huge number of the evidences for drug to drug interaction
but the tendency of fraternity to disregard the magnitude is further aggravating
the condition. There is a common postulation that all drugs in a given class
have a homogenous interaction potential but this is actually rare. For example,
amongst the macrolide class, while erythromycin and clarithromycin inhibit CYP3A4
leading to interactions with other drugs, azithromycin does not. Likewise while
ketoconazole interacts with lovastatin and simvastatin and raises their plasma
levels it does not do so with rosuvastatin or pravastatin. Drug interactions
also vary individual to individual and even upto 5-7 fold differences have been
reported. These variations also change with the change of dose, duration of
treatment and route of inoculation (Rahal et al.,
2006, 2007; Verma et al.,
2009; Kumar et al., 2011, 2012).
The matter is often compounded by patients additionally taking herbal drugs
that interact with their prescribed medication (Singh et
al., 2010) about which the doctor may not know; with other modifiers
of drug elimination and response and genetics. The potency of drug also depends
upon the coadministration of other drugs and depending upon the number of drugs
and interaction potential it may go upto 100%. Another early study reported
an incidence of 7% when 6-10 drugs were prescribed that rose to 40% when 15-20
drugs were given. Clearly drug interactions present a health threat to patients
and a great challenge to the physician as monitoring the patients therapy
is a standard of care expected by the patients and the liability of interactions
rests squarely on the physician who fails to recognize potentially harmful interactions
to avoid extra costs of healthcare (Thaler et al.,
HOW DO DRUG INTERACTIONS OCCUR?
There are various categories of interaction with drugs:
||Drug Environmental interactions
Understanding the mechanism by which a given drug interaction occurs is often
useful in practice, as the mechanism could influence both the time course and
mechanism of evoking the interaction (Rahal et al.,
2008; Kumar et al., 2009, 2011).
The past experiences and gender, age, physical conditions drug recommendation
vary individual to individual. Depending upon the reports and the clinical trials,
the desirable therapeutic regimen of drugs in different possible clinical situations
is indicated. Even then, when these drugs are used in field condition, it might
result in a totally different scenario of interaction and this is a kind of
experience of physician, so the use and indications also depend upon the experience
and exposure of clinician/physician (Davis et al.,
Because of the complexity of pharmacotherapy needed for the treatment of the
basic disease, its underlying causative factors, its complications and accompanying
co-morbid factors such as hypertension, diabetes and dyslipidemia, malignancy
and respiratory disorders, the number of drugs prescribed increases translating
into a major risk factor for potential drug interactions (Thaler
et al., 2013).
Although tremendous advances have occurred in knowledge of the mechanisms of
drug interactions over the last few decades, we still have a long way to go
to fully understand them as more than one mechanism may play a part in some
drug interactions (Garcia Fernandez et al., 2013).
Use of any drug is based upon the disease and patients. Many time dose, route
and other indication for the same drug vary in different conditions (Kumar
and Rahal, 2005; Rahal et al., 2009). Whatsoever
drugs are to be given simultaneously, it should be based upon previous experience
and need of the patient (Mahendra Kumar et al.,
2011). The clinically most important adverse drug-drug interactions occur
with drugs that have easily recognizable toxicity and a low therapeutic index,
such that pretty slight change in drug effect can have clinically significant
adverse consequences (Garcia Fernandez et al.,
2013). There are numerous mechanisms by which drugs may intermingle (Hanigan
et al., 2011) but most of them can be classified as:
||Additive or synergistic interactions
||Antagonistic or opposition interactions
Adverse drug reactions resulting from simultaneous medication are commonly
associated with drugs that are chemically or biochemically antagonistic (Garcia-Barrera
et al., 2012). All kind of the interaction of the drug interaction
depends upon various steps of pharmacokinetics as absorption of the drug from
various sites of administration, distribution to different tissues and organs,
biotransformation and finally its elimination (Rahal et
al., 2007) from the host or the interaction of the drug with the receptor,
the actual site of bioaction (Rathore et al., 2012a,
b), ultimately leading to the impact of drug and its
implication (Wachter and Verghese, 2012).
The science of therapeutics does not merely involve testing of new molecules
in medical and veterinary clinical medicine, but it emphasizes upon the treatment
of each patient holistically as an individual and it is widely recognized that
individuals show wide variability in response to the same treatment (Verma
et al., 2011). Pharmacokinetic interactions must always be evaluated
in the context of their clinical biochemical and pathophysiological relevance.
Co administration of two drugs always does not mean any interaction; the interaction
depends upon a mixture of factors including relative affinities of each drug
for the binding site or the xenobiotic metabolizing enzyme; component of plasma
proteins which actually binds the drugs in question like albumin, acidic glycoprotein
and nevertheless, the actual free drug concentration available at the tissue
site for binding to the receptor and produce a response (Garcia
Fernandez et al., 2013).
Effect of drug interaction also depends upon the physical and physiological
condition of patient (Thaler et al., 2013). In
general, pharmacokinetic interactions are considered clinically significant
when at least a 30% change is seen in Cmax, Tmax and AUC (Rahal
et al., 2008). Coadministration of drugs which follow different pathway
of drug metabolism might be useful with certain consideration, such as the prescribed
dose and its fulfillment, the actually administered dose, its rate and extent
of absorption, bioavailability, Tmax, AUC, distribution, metabolism, the rate
of elimination (time 1/2), drug concentration attained at the actual site of
action, genetic polymorphism in the receptor and the effect of the drug at the
DRUG ABSORPTION INTERACTIONS
Since the oral route is the one most frequently used to administer drugs, interactions
influencing absorption are more likely to occur within the gastrointestinal
tract, which more often result in reduced rather than increased absorption.
Different interactions of drugs have different implications. Some of them might
be useful while others might be deadly. Use of different drug combinations at
different dose and route of inoculation always affect these interactions. Various
pharmacokinetic actions of drugs as absorption and eliminations are base of
these interactions. The common examples of absorption interaction include milk
calcium and tetracyclines making calcium unavailable to the body. High doses
of drugs may be required to achieve the drug effect in short duration eg., analgesic
and have its own clinical significance as most clinically important drug interactions
occur due to the following factors:
||Changes in gastrointestinal pH (leading to ion trapping)
||Changes induced by chelation and adsorption (making drug unavailable for
||Changes in gastrointestinal motility (altering its time course of absorption)
||Transporter based interactions (altering the extent of absorption)
||Intestinal metabolism of drugs (modulating the half-life)
DRUG DISTRIBUTION INTERACTIONS
Many drugs interact by displacement of each other binding to plasma proteins
(Rahal et al., 2007). Drugs with acidic nature
are known to have an affinity to bind to plasma proteins, hence when drugs are
administered in combination, competitive binding for the same site or receptor
may displace one drug from the protein binding site increasing the amount of
the displaced free drug in plasma and various tissues setting up an interaction
leading to an enhanced potential for toxicity (Rahal and
Malik, 2010, 2011; Trumic
et al., 2012), such as is seen in the case of concomitant administration
of warfarin with phenylbutazone or other highly protein bound drugs that leads
to increased levels of warfarin and hence its toxicity, with the clinical implication
of frequent and prolonged bleeding. Drug interactions involving alterations
in distribution because of volume changes can be exemplified by the combined
use of gentamicin and frusemide. As gentamicin is well distributed in extracellular
fluid any fall in ECF induced by frusemide reduces the volume of distribution
of gentamicin thus increasing its serum levels with the clinical implication
of nephro- and ototoxicity.
Despite the factors described above for distribution interactions, recent research
recommend that although in-vitro many commonly used drugs are capable of being
displaced by others, in the body, these effects/interactions seem to be so well
buffered that the outcome may not normally be clinically important. Moreover,
as some interactions which were originally assumed to be due to protein binding,
have later on been shown to have other mechanisms involved, it has been suggested
that the importance of this plasma proteins alone being responsible for the
interaction has been overstated.
DRUG METABOLISM INTERACTIONS
The animal or human body is constantly exposed to foreign substances (drugs)
not found naturally in the body. These compounds alter the body function to
achieve a therapeutic end and are modified or metabolized by a plethora of enzymes.
The processes by which the enzymes alter an active drug inside the body to an
inactive one or two active or toxic metabolites are commonly referred to as
drug metabolism or biotransformation (Thaler et al.,
2013). To exert their systemic effect, most drugs need to reach a site of
activity and for this they need to be lipid soluble so as to be able to penetrate
the lipid plasma membrane barrier. The lipophilic drugs after they fulfil their
pharmacological role, further need to be converted into a water soluble form
to be excreted efficiently by the renal route. Liver has the chief responsibility
of metabolism and enables these processes in two phases-phase 1 and 2.
In phase I, oxidation/reduction reactions convert the drugs into a more hydrophilic
form, while phase 2 reactions provide another set of mechanisms involving conjugation/hydrolysis
with substances like glucuronic acid, aminoacids and other endogenous metabolites
for modifying drugs into inactive compounds to enable their excretion. The cyotchrome
p 450 family present in the hepatic microsomes are mainly responsible for carrying
out these modifications in drug molecule and together account for 90-95% of
xenobiotic biotransformations taking place in the body; the complete cytochrome
P450 family is a collection of diverse subfamily of enzymes with substrate specificity
and nonspecificity and shows high genetic variability. Therefore exact proportion
of role for different subfamilies in the biotransformation of a single drug
entity is highly unpredictable.
A drugs action on a molecular already results in a biological complex
that could be influenced further by disease. In addition to all these factors,
genetic polymorphisms that influence change in this biological complex can greatly
influence drug response. These differences in the variability to metabolize
different drugs could account for a few persons manifesting toxicity with interacting
drugs while others do not exhibit any symptoms. The clinical implication of
this polymorphism is exemplified by omeprazole, where poor metabolisers having
higher drug levels with standard dosages had markedly high healing rates 100%
compared to otherwise normal metabolizers; highlighting the need for identification
of such polymorphisms early in a drugs development. Although, significant
metabolism takes place in the liver, other organs like the kidney and gut are
also involved. On the basis of the extent to the drug gets metabolized in liver,
the drugs are categorized as high extraction drugs, moderate extraction drugs
and low extraction drugs. The high extraction drugs have shorter half-life,
shorter therapeutic index and productive life in comparison to the low extraction
drugs. However, lower the therapeutic index of a drug, greater is the risk to
turn out into a grave clinical outcome owing to metabolism and excretion pattern
changes (Garcia Fernandez et al., 2013).
To predict drug interactions well it is mandatory that a proper understanding
of drugs influencing CYP 450 enzyme induction and inhibition be made. Interactions
involving drug metabolism can alter the amount of drug available for action
by inhibition or induction of metabolism. Inhibition is usually more predictable
than induction which is influenced by genetic differences between patients.
Inhibitors battle with other drugs for a particular enzyme thus affecting the
optimal rate of metabolism of the substrate drug that then accumulates in the
body resulting in toxicity (Lynch and Price, 2007).
CYP isozymes escalate the rate of metabolism in the presence of inducers and
that lead to rapid clearance of substrate from the system. Because of the dependency
on enzyme synthesis and time 1/2 of the inducing drug, these type of interactions
occur slowly. Attainment of steady state concentrations always reported to increase
CYP enzymes. However, if the half-life (time 1/2) of the affected drug is long,
it may take a week to reach steady state levels. This inhibition leads to decreased
metabolism of drugs acted upon by the enzyme, prolonging its time 1/2 and reducing
clearance, thus growing plasma levels that lead to interactions (Alavijeh
et al., 2005). Some drugs are converted to toxic endproducts by enzymes
(Farukbhai, 2010) and enzyme inducers can increase the
formation of these toxic metabolites. Paracetamol is primarily converted to
nontoxic metabolites but a small amount is converted to toxic metabolites; however
if administered with an enzyme inducer it could lead to hepato-toxicity.
DRUG ELIMINATION REACTIONS
The major routes for elimination of drugs remain the kidney and gastrointestinal
tract. There are no noteworthy drug-drug interactions through bile elimination,
except for drug-disease ones. There are many modes of interaction for the drugs
excreting out through renal route and theses interactions are mainly because
of urinary pH alteration and passive reabsorption at renal tubule. Other common
causes include glomerular filtration alteration and drug to drug interaction
(Freudenthaler et al., 1998). Active secretion
into the renal tubules is an important excretion pathway for a few drugs (Ip
et al., 1988), which get affected by the co-administration of certain
other drugs, thereby affecting their therapeutic response. The capacity of a
drug to inhibit the renal excretion of another is dependent on an interaction
at active transport at reabsorption sites. The beneficial probenecid- penicillin/amoxicillin
interaction exemplifies one of the many reported interactions at the anion transport
site; the two drugs competing for excretion by modifying active transport in
the renal tubules resulting in probenecid being excreted and the antibiotics
being retained and reabsorbed, with the clinical implication of increasing their
plasma levels to a desirable level to increase its therapeutic effect and prolonging
the plasma time 1/2. The interaction between quinidine and digoxin is reported
to have severe consequences due to the reduction of renal excretion of digoxin
even upto 50% and that includes reduction of about 50% in digoxin excretion
in bile as well as by its P-gp mediated inhibition of transcellular transport
and also inhibition in the gut.
The rate of excretion of a drug or its metabolites can be influenced by other
drugs that increase or decrease glomerular filtration due to changes in renal
blood flow. A mild increase in renal clearance may lead to a clinically significant
decrease in the plasma levels of drugs with low therapeutic index. An alteration
in the urinary pH can also significantly modulate the excretion pattern of the
drug. The repercussion of this mechanism is reflected in the management of salicylate
or amphetamine poisoning by alkalinizing with antacids or acidifying the urine,
respectively. The drugs which have acidifying nature e.g., ascorbic acid, might
lead to increased levels of phenobarbitone.
Pharmacodynamic interactions are reasonably common in practice and occur when
a precipitant drug alters the clinical effects of the object drug at its site
of action. One drug may alter the normal physiological milieu whereby it can
increase or decrease the effects of another drug. This may be illustrated by
the interaction produced by diuretic induced hypokalemia with the simultaneous
use of digoxin resulting in digoxin toxicity. Synergistic and additive reaction
are the outcome of interaction of similar active principle or due to the simultaneous
administration of drugs of similar action. The drugs used in combination may
or may not act on the same class receptor to produce these effects and the effect
is one of duplication where the clinical effect is intensified. There are numerous
examples of such a response like that is seen when a cold remedy and a pain
reliever (both containing paracetamol) are taken together. Likewise the simultaneous
use of two nephrotoxic drugs can aggravate renal damage, where the dose of either
drug may have been insufficient to produce toxicity. Many allopathic drugs have
serious hazardous effects as amphotericin when applied with pentamidine it may
lead to severe nephrotoxicity. Whereas, interaction of gancyclovir and zidovudine
might be the cause of bone marrow depression. The simultaneous prescription
of potassium supplements to patients already on spironolactone or triamtrene
and those on ACE inhibitors leads frequently to severe hyperkalemia.
Clinically important interactions of drugs acting at different sites are seen
with the combined use of certain antibiotics in managing infections or combinations
of cytotoxic drugs in management of malignancies. Drugs with conflicting or
antagonistic pharmacodynamic effects reduce response to either drug. NSAIDs
especially the COX-2 inhibitors that would normally increase blood pressure
tend to inhibit the hypotensive action of diuretics, ACEIs and beta blockers.
The overdosing of drugs being treated with their physiological or pharmacological
antagonist also demonstrate the beneficial effects of antagonism. The physiological
antagonism can best be evidenced in the control of involuntary activities of
the body. Atropine is an excellent example of pharmacological antagonist of
muscarinic effects. The effects of benzodiazepines get inhibited with the concurrent
administration of theophylline.
Drug-disease interactions can occur when a medication has the potential to
worsen a disease. The effect a drug has in certain patients may be unexpected
not related to the drug per se but because of the patients disease pattern
(Thaler et al., 2013). It is important for the
physician to know the patients entire disease profile to plan a suitable therapeutic
regimen to avoid drug interactions carefully balancing the need to ensure that
the patient is given appropriate medicines to cover his ailments and simultaneously
at the same time, selecting such drugs from various therapeutic categories that
do not or have a lesser potential for inducing drug interactions.
The myth that natural products are completely harmless, creates a need for
responsible, public/physician education specially as they are widely used by
our rural/semi-urban population (Mahima et al.,
2012a); hence the need to be fully aware of these interactions and as a
large number do not inform the physicians about their intake, the potential
and true incidence of these interactions is largely unknown (Kumar
and Rahal, 2005). In majority of cases multiple reasons are responsible
for these kind of interaction and most common among them are the presence of
contamination, lack of standardization of the application of faulty or improper
methods of standardization. The mechanisms of food-induced interactions are
essentially the same as that of drug interaction; however these occur chiefly
due to alterations in absorption that may impair their nutritional benefit and
to some extent due to altered metabolism. Many nutrients affect the metabolism
of other nutrients and drugs. There interaction may be synergistic or antagonistic
for example Calcium, phosphorous and vitamin D; Zinc and vitamin A; Selenium
and vitamin E; calcium, manganese and vitamin K; iron and vitamin B6; cobalt
and vitamin B12; sulphur and other vitamins (Chaudhary et
al., 2010; Mahima et al., 2012b).
The nature of drug interactions is complex and not an exact science due to
interplay of multiple mechanisms that requires the prescribers care in
choosing or changing medication when necessary; adjusting the dose, time and
sequence of administration as maybe required or continue the treatment regimen
recognizing the significance of the interaction weighing the therapeutic risks
versus benefits to the patient. Moreover, the use of newly designed drugs and
its interaction with other drugs are always challengeable to physician and this
interaction depends upon the age, sex, nutritional and physiological status
of patient. It is impossible to remember or document all clinically significant
drug interactions but this article attempts to cover the broad mechanisms and
principles of the manner in which these interactions occurs exemplifying significant
ones that are governed by these principles that clinicians may find useful in
their practice. Of particular importance in assessing such adverse reactions
that result after addition of any new drug to a formerly stable regimen that
could possibly account for the adverse effect or alteration in the patients
physiological functions in handling the administered drugs. Diseases apart,
physiological changes in renal and hepatic function with advancing age, malnutrition
and reduced homeostatic mechanisms makes the elderly more responsive to the
additive effect of two or more drugs rendering them more prone to serious drug
interactions. Whenever drugs are to be indicated there should be a balance between
the positive and negative interaction and balance is a key for the successful
Ansari, J.A., 2010.
Drug interaction and pharmacist. J. Young Pharmacist, 2: 326-331.CrossRef | Direct Link |
Arnaud, L., A. Mathian, J. Boddaert and Z. Amoura, 2012.
Late-onset systemic lupus erythematosus: Epidemiology, diagnosis and treatment. Drugs Aging, 29: 181-189.CrossRef | PubMed |
Chaudhary, M., A.K. Garg, G.K. Mittal and V. Mudgal, 2010.
Effect of organic selenium supplementation on growth, se uptake and nutrient utilization in guinea pigs. Biol. Trace Elem. Res., 133: 217-226.CrossRef | Direct Link |
Davis, M.W., S. Wason and J.L. Digiacinto, 2013.
Colchicine-antimicrobial drug interactions: What pharmacists need to know in treating gout. Consult. Pharm., 28: 176-183.CrossRef | PubMed |
Farukbhai, N.M., 2010.
A study of Druf-drug interaction between lercanidipine and glipizide inrats. Msater's Thesis, VL College of Pharmacy, Raichur, India
Freudenthaler, S., I. Meineke, K.H. Schreeb, E. Boakye, U. Gundert-Remy and C.H. Gleiter, 1998.
Influence of urine pH and urinary flow on the renal excretion of memantine. Br. J. Clin. Pharmacol., 46: 541-546.CrossRef | PubMed |
Garcia Fernandez, V., M. Garrido Arevalo, E. Labrada Gonzalez and F.J. Hidalgo Correas, 2013.
Fatal drug-drug interaction between 5-fluorouracil and brivudine. Farmacia Hospitalaria, 37: 72-73.PubMed | Direct Link |
Garcia-Barrera, T., J.L. Gomez-Ariza, M. Gonzalez-Fernandez, F. Moreno, M.A. Garcia-Sevillano and V. Gomez-Jacinto, 2012.
Biological responses related to agonistic, antagonistic and synergistic interactions of chemical species. Anal. Bioanal. Chem., 403: 2237-2253.CrossRef | PubMed |
Hanigan, M.H., B.L. Dela Cruz, S.S. Shord, P.J. Medina, J. Fazili and D.M. Thompson, 2011.
Optimizing chemotherapy: Concomitant medication lists. Clin. Pharmacol. Ther., 89: 114-119.CrossRef | PubMed |
Ip, T.K., P. Aebischer and P.M. Galletti, 1988.
Cellular control of membrane permeability. Implications for a bioartificial renal tubule. ASAIO Trans., 34: 351-355.PubMed | Direct Link |
Kumar, A. and A. Rahal, 2005.
Relevance of oral xenobiotic in ruminants. Proceedings of the 2nd Round Table Conference on Rumenology, April 6-7, 2006, Bhubneshwar, India, pp: 57-58
Kumar, A., A. Rahal, R. Ragvendra, A. Prakash, R. Mandil and S.K. Garg, 2012.
Pharmacokinetics of levofloxacin following intravenous and intramuscular administration in cattle calves. Asian J. Anim. Vet. Adv., 7: 1006-1013.CrossRef | Direct Link |
Kumar, P., A.H. Ahmad, A. Rahal and K.P. Singh, 2009.
Bioavailability and pharmacokinetics of ketoprofen in buffalo calves. J. Vet. Pharmacol. Toxicol., 8: 52-55.
Kumar, P., A.H. Ahmad, A. Rahal and K.P. Singh, 2011.
Bioavailability bioequivalence and pharmacokinetics of florfenicol in buffalo calves. Online J. Pharmacol. Pharm., 7: 1-9.
Lynch, T. and A. Price, 2007.
The effect of cytochrome P450 metabolism on drug response, interactions and adverse effects. Am. Fam. Physician, 76: 391-396.Direct Link |
Mahendra Kumar, B.J., M. Kumaraswamy and L. Mahadevamma, 2011.
Incidence and pattern of potential drug interactions of antimicrobial agents in the department of medicine in a tertiary care teaching hospital: A prospective study. Asian J. Pharm. Clin. Res., 4: 31-36.Direct Link |
Mahima, A. Rahal, R. Deb, S.K. Latheef and H.A. Samad et al
Immunomodulatory and therapeutic potentials of herbal, traditional/indigenous and ethnoveterinary medicines. Pak. J. Biol. Sci., 15: 754-774.CrossRef | Direct Link |
Mahima, A.K. Verma, A. Kumar, A. Rahal, V. Kumar and D. Roy, 2012.
Inorganic versus organic selenium supplementation: A review. Pak. J. Biol. Sci., 15: 418-425.CrossRef | Direct Link |
Alavijeh, M.S., M. Chishty, M.Z. Qaiser and A.M. Palmer, 2005.
Drug metabolism and pharmacokinetics, the blood-brain barrier and central nervous system drug discovery. NeuroRX, 2: 554-571.CrossRef | PubMed | Direct Link |
Rahal, A. and J.K. Malik, 2010.
Pharmacokinetics, urinary excretion and plasma protein binding of 2,3-butanedione monoxime in goats. Small Rumin. Res., 93: 19-23.CrossRef | Direct Link |
Rahal, A. and J.K. Malik, 2011.
Pharmacokinetics, urinary excretion and plasma protein binding of pralidoxime in goats. Small Rumin. Res., 95: 179-183.CrossRef | Direct Link |
Rahal, A., A. Kumar, A.H. Ahmad and J.K. Malik, 2008.
Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep. Res. Vet. Sci., 84: 452-456.CrossRef | PubMed | Direct Link |
Rahal, A., A. Kumar, A.H. Ahmad, and J.K. Malik, 2007.
Pharmacokinetics of ciproﬂoxacin in sheep following intravenous and subcutaneous administration. Small Ruminant Res., 73: 242-245.CrossRef |
Rahal, A., A. Kumar, A.H. Ahmad, J.K. Malik and V. Ahuja, 2006.
Pharmacokinetics of enroﬂoxacin in sheep following intravenous and subcutaneous administration. J. Vet. Pharmacol. Therap., 29: 321-324.CrossRef |
Rahal, A., V. Singh, D. Mehra, S. Rajesh and A.H. Ahmad, 2009.
Prophylactic efficacy of Podophyllum hexandrum
in alleviation of immobilization stress-induced oxidative damage in rat. J. Nat. Prod., 2: 110-115.Direct Link |
Rathore, R., A. Rahal and R. Mandil, 2012. Cimicifuga racemosa
potentiates antimuscarinic, anti adrenergic and antihistaminic mediated tocolysis of buffalo myometrium. Asian J. Anim. Vet. Adv., 6: 300-308.Direct Link |
Rathore, R., A. Rahal, R. Mandil, A. Prakash and S.K. Garg, 2012.
Comparative anti-inflammatory activity of Cimicifuga racemosa
and Mimosa pudica
. Aust. Vet. Practitioner, 42: 274-278.
Rodrigues, R.J., 2000.
Information systems: The key to evidence-based health practice. Bull. World Health Organ., 78: 1344-1351.PubMed | Direct Link |
Singh, V., A. Rahal, K.P. Singh and A.H. Ahmad, 2009.
Effect of ethanolic extract of Withania somnifera
roots on antioxidant defence in mercury induced toxicity in HepG2 cell line. Online J. Pharmacol. Pharm., 5: 65-72.
Singh, V., A. Rahal, K.P. Singh and A.H. Ahmad, 2010.
Evaluation of prophylactic potential of Withania somnifera roots extract on mercury-induced oxidative damage in various rat tissues. J. Vet. Pharmacol. Toxicol., 9: 64-67.
Gysin, S., M. Salt, A. Young and F. McCormick, 2011.
Therapeutic strategies for targeting ras proteins. Genes Cancer, 2: 359-372.CrossRef | Direct Link |
Thaler, S., C. Neumeier and G. Flury, 2013.
Drug-induced malignant arrhythmias: IT prevents lethal drug mixtures. InternistDirect Link |
Kirking, D.M., J.W. Thomas, F.J. Ascione and E.L. Boyd, 1986.
Detecting and preventing adverse drug interactions: The potential contribution of computers in pharmacies. Soc. Sci. Med., 22: 1-8.PubMed | Direct Link |
Trumic, E., N. Pranjic, L. Begic, F. Becic and M. Asceric, 2012.
Idiosyncratic adverse reactions of most frequent drug combinations longterm use among hospitalized patients with polypharmacy. Med. Arh., 66: 243-248.PubMed | Direct Link |
Valiyil, R. and L. Christopher-Stine, 2010.
Drug-related myopathies of which the clinician should be aware. Curr. Rheumatol. Rep., 12: 213-220.CrossRef | PubMed |
Verma, S., A.H. Ahmad, A. Rahal and K.P. Singh, 2009.
Pharmacokinetics of Florfenicol Following Single Dose Intravenous and Intramuscular Administration in Goats. J. App. Anim Res., 36: 93-96.CrossRef | Direct Link |
Verma, S., A.H. Ahmad, K.P. Singh and A. Rahal, 2011.
Acute toxicity study of albendazole formulations in rats. Indian J. Vet. Pharmacol. Toxicol., 10: 58-60.
Wachter, R.M. and A. Verghese, 2012.
The attending physician on the wards finding a new homeostasis. JAMA, 308: 977-978.CrossRef | PubMed |