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DRUG INTERACTIONS OF VETERINARY IMPORTANCE WITH

REFERENCE TO FLUID THERAPY

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Drugs interact with foods and a wide variety of drugs viz: injectables, over-the-
counter medications, nutritional supplements etc. which are given simultaneously or
relatively in a shorter period of time. When drugs and certain foods are taken at the same
time they can interact in ways that diminish the effectiveness of the ingested drug or reduce
the absorption of food nutrients. Drug-drug interactions occur when the effect of one drug is
altered by the presence of another drug in the body. Multiple drug therapy in modern
veterinary clinical practice, often with inappropriate combination of drugs, either individually
or with formulations may lead to adverse responses.

The drug-drug interactions occurring in-vitro as a result of having been mixed before
administration is referred as incompatibility. Drug interactions can also occur as the result of
drugs interacting in the patient (in vivo).

Drug interactions can reduces the effect of the ‘ primary/target drug” (the drug already
there) or increases the toxicity of the target drug – often perceived as an adverse effect of
one of the drugs because of increased drug concentrations and on very few occasions these
drug interactions may be beneficial in increasing the overall activity. However, most of the
drug interactions are therapeutically not viable and may produce unfavorable affects/loss of
efficacy. The factor of interference of drug on certain laboratory tests procedures has also
be taken in to consideration while interpreting laboratory results so as to distinguish false
+ve/-ve test results.

Incompatibility

Mixing of certain drugs together in the same syrienge or with intravenous fluids may lead to
physical incompatibility (change in turbidity or colouration) or chemical reactions (viz;
hydrolysis, oxidation, reduction or complex formation) and thereby loss of pharmacological
activity. The vehicle/ stabilizers /preservations used in the product may also cause drug
interaction
Many interactions and incompatibilities are possible considering the vast number of drugs
available that may be used in combination. Interactions can result in a lack of therapeutic
effect or toxicity. A distinction should be made between drug interactions that occur in vitro
(such as in a syringe or vial) from those that occur in vivo (in the patient). Veterinarians
frequently mix drugs together in syringes, vials, or fluids before administration to animals.
These in vitro reactions also have been called pharmaceutical interactions. A drug interaction
of this nature may form a drug precipitate, a toxic product, or inactivate one of the drugs to
unknowingly administer an ineffective compound. Compounding drugs that are incompatible
may cause in vitro drug interactions.

Drugs may be incompatible therapeutically, chemically, and pharmaceutically. Therapeutic


Incompatibility occurs when drugs are combined which have antagnostic physiologic actions.
Chemical Incompatibility occurs when from the combination of two or more drugs a new and
undesired chemical compound results. Pharmaceutical Incompatibility occurs when drugs are
combined which form, either immediately or later, cloudy, precipitated or decomposed
solutions. Chemical and pharmaceutical incompatibility are so closely related as to be
governed many times by the same rule. Such incompatibility is difficult to avoid, and
emphasizes the advisability of adopting simplicity in prescription writing, which is really a
therapeutic gain.

Solutions may be incompatible with other solutions because of ionic interactions. For
example sodium bicarbonate (NaHCO3) will react with calcium-containing solutions,
forming calcium carbonate.

• Fluoroquinolones should not be mixed with cation-containing fluid solutions, when


given by intravenous route.

• Admixing tetracyclines with calcium-containing solutions will result in precipitation.

• It is not advisable to mix salts of hydrochloric acid (HCl) (e.g., dobutamine HCl,
dopamine HCl, and epinephrine HCl) with alkaline solutions.

• Vitamin B1 (thiamine hydrochloride) is unstable in alkaline solutions and should not


be mixed with alkalinizing solutions, carbonates, or citrates.
• Caution must be exercised in the administration of parenteral fluids, especially those
containing sodium ions, to patients receiving corticosteroids or corticotropin.

• Potassium containing solutions should be used with caution in the presence of


cardiac disease, particularly in digitalized patients or in the presence of renal disease.

• Solutions containing lactate ions should be used with caution as excess administration
may result in metabolic alkalosis. The solution has to be clear and container
undamaged. It is always better to discard unused portion of the solution.

Reactions which may occur because of the solution incompatibility include failure to get
desired response, untoward responses like febrile response, venous thrombosis or phlebitis
extending from the site of injection, extravasation and hypervolemia.

Normal saline, comparatively appears to be the most compatible intravenous fluid among
all, for most of the drugs including ampicillin sodium, benzyl penicillin, diazepam,
gentamicin oxytetracycline, sulfonamides etc. The admixture of any drug with other
medications in the same syrienge or intravenous fluid bottle is generally not recommended
as it may result in substantial mutual inactivation and drugs should not be mixed in infusion
containers or syrienges unless the componments are of known compatibility.

Drug-drug Interactions

Broadly, there are mainly two types of interactions: pharmacodynamic and pharmacokinetic.
Pharmacodynamic drug interactions, drugs act agonistically at the same receptor sites
leading to potentiation or may act antagonistically at the same receptor leading to
antagonisim. Pharmacokinetic interactions may ccur at the level of absorption, distribution,
metabolism or excretion of the drug. The net result may be an increase or decrease in the
concentration of primary drug in plasma/blood thereby potentiating /inhibiting action at the
site of action/infection or resulting in the toxicity due to reduced clearance from the body .

Examples of drug-drug interactions of veterinary importance


Drug Interacting agent (drug) Result/adverse effect
Fluoroquinolones Na+ and Cl-. Aluminum, Iron, Decrease absorption
calcium, and Mg+2 , antacids
Theophylline(methyl xanthines) CNS stimulation-Convulsions
NSAIDS Increased risk of seizures
CNS Depressants Antihistamines, opioid analgesics, Enhanced depressant effets
Phenothiazine derivatives
Tetracyclines (oral) Antacids , Calcium supplements, Chelation and reduced
Milk, Iron supplements, tetracycline absorption
Magnesium-containing laxatives,
Sodium bicarbonate

Phenobarbital or
Microsomal enzyme inducers,
Reduce efficacy
Digitalis Phenolphthalein (laxative), Abnormal rhythmicity
antihypertensives
Acid labile drugs like Anticholinergic drugs (eg: Decrease absorption
erythromycin atropine)
Linocomycin Antidiarrhoeals-kaolin, pectate Decreased absorption
Chloramphenicol, erythromycin, Antagonistic-reduced efficacy
neostigmine Potentiate respiratory
Opioid analgesics depression
Antibiotics Large dose of atropine Decreased bioavailability
administered per os
in ruminants
Aminoglycoside Cephaloridine, cephalothin Nephrotoxicity,
polymixins, furosemide, curare neuromuscular blockade
like drugs, anaesthetics,
amphotericin
Chloramphenicol Dicoumarol, barbiturates Prolonged anesthesia,
Cyclophosphamide Phenytoin, anticoagulation/ bleeding
Salicylates
Griseofulvin Dicoumarol, barbiturates Reduced anticoagulant effect
Monensin Tiamulin Neurotoxicity
Rifampin Theophylline Enhanced theophylline
clearance
Sulfonamides Oral anticoagulants Prolonged anticoagulation
effect
Oral Salicylates ,Chloramphenicol Severe hypoglycemic effect
hypoglycaemics(eg: Phenylbutazone, long acting
tolbutamide) sulpha drugs
Beta blockers

Corticosteroids Acetazolamide Increased hypokalemic risk


Antidiabetic drugs Antagoniosm of
hypoglycaemia
Increased risk of
Barbiturates
hypokalemia
Diuretics
Antagonism of diuretic
effect,Increased risk of
Metoclopramide hypokalemia
Aggression
NSAIDS Risk of gastrointestinal
ulceration
Phenobarbitone Barbiturates Chloramphenicol Cross tolerance can exist
Corticosteroids Progesterone between many of them
Testosterone
Thyroxin,Griseofulvin,Phenytoin
,Phenylbutazone
Cyclophosphamide
Warfarin phenylbutazone,phenytoin Increased warfarin toxicity
salicylate,sulphinpyrazone
Decongestants in Diuretics Aggravate high blood
cold and cough pressure
(antihistaminics)
Antihistamines used Barbiturates, tranquilizers, CNS Increased sedative effects
for allergies and depressants
colds,
NSAIDS Anticoagulants, corticosteroids Risk of excessive bleeding
Diuretics,beta blockers,ACE Reduced antihypertensive
inhibitors effect
Sulfonylureas Increased hypoglycaemic
effect
Ketoconazole Antacids , H2 receptor
antagonists ,Sucralfate Reduced absorption and
Omeprazole,Isoniazid Rifampin, efficacy
Phenytoin , Carbamazepine
Phenobarbital
Antidiarrhoeal tranquilizers (e.g., diazepam), increased effect of
medication (e.g., sedatives tranquilizers, sedatives
diphenoxylate)
Fat-soluble Mineral oil Reduced absorption of the
vitamins vitamins
Cephalosporins Antacids, H2 recpetor Reduced efficacy
amatagonists
Nephrotoxci mediactions- Potentiate nephrotoxicity
Aminoglycosides, Diuretics
Potentiate bleeding
anticoagulants
Macrolides(eg: Chloramphenicol , Florfenicol, Antagonistic: - Reduced
azithromycin Lincosamides, penicillins efficacy
eryhthromycin) xanthines
Increased toxicity
Penicillins Chloramphenicol, tetracyclines , Antagonistic: - Reduced
sulfonamides; phenyl butazone efficacy; reduced distribution
Oral- Antacids Decrease absorption
Levamisole Organophosphorous compounds, Enhanced toxicity
diethylcarbamazine
Metoclopramide Antimuscarinic drugs, opioid Antagonism
analgesics,
butyrephenones, phenothiazines, Increased Extrapyramidal
corticosteroids signs risk
aspirin, paracetamol Increased absorption
Zinc salts Iron salts, tetracyclines Reduced absorption
Many therapeutic agents are lipophilic and their half-lives are largely determined by the rate of
their enzymatically catalysed metabolism to a more hydrophilic product. The reabsorption
from renal tubules fluid is greater for lipophilic than water-soluble compounds on their
metabolites. Normally, metabolism of a relatively non-polar drug to a polar derivative
facilitates its elimination in urine. A variety of therapeutic agents and environmental / good
contaminants affect these biotransformation reactions. Many therapeutic agents induce hepatic
microsomal enzyme systems. Prolonged use of such drugs (sometime with short exposure
also) would lead to development of tolerance and therapeutic failure and this can be
attributable to ‘enzyme induction’. On the contrary to this, serious adverse effects for a given
drug may be observed even after the administration of therapeutic dose due to ‘enzyme
inhibition’ following continuous exposure to certain class of drugs or agrochemicals and food
contaminants. Knowledge of specific pathway drug metabolism of a therapeutic agent can aid
in overcoming drug interactions in the clinical practice.

Drugs and compounds can increase the activity of the cytochrome P-450 (CYP) enzymes.
Some of these enzymes also may reside in the intestine. As a result of this increase in activity
(induction), drugs metabolized by the same enzymes will be cleared faster. The enzymes most
commonly affected by induction are the mixed-function oxidases, reactions. Examples of
enzyme inducers include omeprazole,phenobarbitone,
carbamazepine,ethosuximide,glucocorticoids,phenobarbitonerifampicin,sulfadimidine,nevirapine
,sulfinpyrazone, phenyl butazone, phenobarbitone ,isoniazid etc.

Hepatic microsomal biotransformation enzymes also may be inhibited by certain drugs and
compounds. The inhibition occurs via a competitive binding to form an inactive drug-enzyme
complex. The time for inhibition to occur is almost immediate. In many cases it is actually a
metabolite of the drug that is responsible for enzyme inhibition. However, noncompetitive
inhibition also is possible when the drug is not a substrate for the enzyme.

Examples of enzyme inhibitors are cimetidine,fluoroquinolones,chloramphenicol, fluconazole,


isoniazid,omeprazole,sertraline,clrithromycin,clotrimazole, diltiazem,
erythromycin,fluoxetine,fluvoxamine,itraconazole,ketoconazole,metronidazole, miconazole,
paroxetine, protease inhibitors (indinavir, nelfinavir, ritonavir).

Certain drugs are known to displace drugs from protein binding sites and increase the
fraction of drug unbound. For most drugs, the amount of protein in the plasma (and subsequently
the number of available drug binding sites) greatly exceeds the concentration of drug in the
plasma and binding is rarely saturated. Interactions that involve displacement of protein-bound
drugs are therefore rare unless there is severe hypoproteinemia or the drug is so highly protein
bound that it occupies most of the binding sites. Only drugs that are highly protein bound
(approximately greater than 85%), exhibit high clearance, and have a low therapeutic index are
likely to be involved in protein binding interactions of clinical significance

Drug interactions affecting laboratory test results: Mostly, hepatotoxic and nephrotoxic
drugs can cause this type of drug interaction, resulting in alteration of hematological,
biochemical or urologic test results Therefore, sound clinical judgement must be exercised in the
interpretation of certain laboratory test results when the patient in under medication. Some of the
drugs also interact directly with the chemistry of test procedure, but most of them may be caused
by pathological changes in organs or alteration in enzyme systems by certain drugs

Food drug interactions: When drugs and certain foods are taken at the same time they can
interact in ways that diminish the effectiveness of the ingested drug or reduce the absorption of
food nutrients. Additionally, vitamin and herbal supplements taken with prescribed medication
can result in adverse reactions

Generally, food may delay or reduce the absorption of the drug resulting in their reduced efficacy
and slower onset of action. However for very few agents, food may help in increasing the
absorption of the drugs. Drugs in turn may alter/hinder the nutrients absorption from the food

The impact of food-drug interactions will depend on a variety of intervening factors like the
dosage of the drug, age, size and state of health of the patient and the time of food and medicine
intake. Avoidance of drug interactions does not necessarily mean avoiding drugs or foods. In the
case of tetracycline and dairy products, these should simply be taken at different times, rather
than eliminating one or the other from the diet.. As a general rule, irritant drugs are to be taken
along with food and for other drugs, it is better to be administered 1-2 hours after food intake.
The suggested oral administration in animals in relation to feeding is as per the following
guideline .

a. Drugs preferably administered with food for enhancing bioavailability/reducing the gastric
irritation .eg:chloramphenicol palmitate(cats), doxycycline, erythromycin estolate, erythromycin
ethyl succinate, griseofulvin, ketoconazole, metronidazole, nitrofurantoin, Irritant drugs.
b. Drugs preferably administered on an empty stomach( 2 hours before or after food intake) eg:
erythromycin base, erythromycin stearate,isoniazid, lincomycin,rifampin,most of the penicillins,
cephalosporins sulphonamides and tetracyclines
c. The drugs having no effect of food on their bioavailability .eg: chloramphenicol caps and
tabs, palmitate (dog), erythromycin coated formulations, ethambutol, fluoroquinolones, hetacillin