FACTORS MODIFYING THE ACTION AND FATE OF DRUGS

Following the selection of a specific therapeutic agent to treat a disease condition that has been diagnosed in a particular patient, an appropriate phar­maceutical form of the drug is administered by a predetermined route at the recommended dose rate and frequency. The expectation is that the desired pharmacological response will occur for a known time period without any ex­traneous reactions. However, unanticipated effects can occur following the de­livery of almost any drug into an animal's body. Drug-induced reactions may be exaggerated (hyperresponsiveness) or of reduced magnitude (hyporesponsiveness) compared to those that would normally result from the dosage employed. Such effects may become evident either immediately or over time, and are not necessarily directly related to the drug's main pharmacodynamic action. Sec­ondary pharmacological actions can become the dominant clinical feature and thereby obscure the primary beneficial effect that is being sought. Alternatively, if the drug acts as an antigen, a complex series of immune-mediated (hypersensitivity) reactions may be precipitated that have no relationship to the original disease syndrome or the pharmacological effects of the drug. Finally, unex­pected and bizarre drug-induced effects may occasionally occur that simply cannot be explained. The term idiosyncrasy is used to cover these unusual reactions.

Two basic types of adverse drug effects are recognized. Type A reactions reflect excessive (or even diminished) but predictable, pharmacological actions of a drug that are generally dose dependent and rarely lead to mortality. The causes of this type of adverse drug effect include:

1) physiological factors such as species, breed, genetics, age, sex, body weight and surface area, diet, nutri­tional status, temperament, relative activity, circadian rhythms, and environ­mental conditions;

2) pharmacological factors such as dosage form, generic equivalence, dose rate and delivery route, time and frequency of administra­tion, direct drug-drug interactions, pharmacogenetic interactions, pharmacody­namic interactions, and drug-diet interactions;

3) pathological states such as fever and pyrexia, shock, electrolyte and acid-base derangements, uremia and renal disease,  hepatopathy, cardiovascular disease, anemia, respiratory dis­ease, gastrointestinal disorders, neurological disturbances, and impaired immunocompetence.

Type B adverse reactions lead to aberrant drug effects that are totally unre­lated to any anticipated responses and are usually independent of the dose employed. Mortality rates may be quite high in these cases. The basic causes of type B adverse drug effects include: 1) Errors in drug formulation or accidental contamination of the preparation with either toxic substances or pathogenic microorganisms. Neither of these possibilities is likely when modern commer­cially prepared products are utilized for medicating animals. However, crudely compounded drug formulations always represent a potential hazard. 2) Unique patient characteristics: Genetic differences between animals of the same spe­cies and even breed may be responsible for dramatic differences between the reactions encountered in various animal subpopulations. Pharmacogenetic variances have been well established in man. Another unique characteristic of an animal is the immune status and whether there has been previous exposure to a particular pharmacological agent that has been recognized as an antigen by the host's immune system. Drug allergy, or hypersensitivity, is the common­est form of type B reaction in veterinary medicine.

PHYSIOLOGICAL FACTORS MODIFYING DRUG ACTION

Species: Although the basic mechanism of action of a drug may be the same, the intensity and duration of the effect produced in various animal species can vary considerably. However, in many cases, the range of therapeutic plasma levels correlate quite closely, even with those found in man. Thus, species vari­ations in the responses elicited by a fixed dose of a drug can be attributed to differences in either pharmacokinetic processes (absorption, distribution, bio-transformation, and excretion) or in the pharmacodynamic sensitivity of spe­cific tissue receptors.

There are substantial anatomical and functional differences between the digestive tracts of the various domesticated and wild animal species. These unique characteristics can influence the disposition of orally administered drugs. The carnivorous species are periodic feeders that have thick-walled, rela­tively short gastrointestinal tracts with intestinal transit times of ~ 6 hours. The pH of the gastric juice in these species is usually between 1 and 3. The scope of the fermentation processes in the colon is minimal. Carnivores have well-devel­oped emetic reflexes and can vomit quite readily. Drug absorption in the cat and dog is relatively uncomplicated, occurring mainly in the upper gastrointes­tinal tract. However, the systemic availability of the drug is dependent on the extent of the first-pass effect through the gut epithelium and liver. This can be sufficiently different between the cat and the dog to reflect in variations in the fraction of an oral dose available systemically.

Monogastric herbivores, e.g., Equidae, guinea pig, and rabbit, have relatively voluminous caeca and colons in which active microbial degradation of cellulose and other insoluble carbohydrates takes place. These hindgut fermentation processes are sensitive to disruption by broad-spectrum antimicrobial agents - with fatal consequences in some instances. Micro floral metabolism of drugs can produce a metabolite profile of very different configuration from those in simple monogastric species. The horse tends to be a continuous feeder, with the stomach serving as a temporary storage organ for ingested feed. The intragastric pH of the horse varies considerably and has been shown to have a range of 1 - 7.  The bioavailability of many preparations dosed orally in the horse is often unpredictable. Feeding can markedly influence plasma-concentration time curves as well as the areas under the curves: e.g. giving phenylbutazone orally prior to feeding or with the ration generally leads to good absorption with peak plasma levels in 2-3 hours. However, if phenylbutazone is administered orally after feeding, absorption may be considerably delayed and is often incomplete. The shortest intestinal transit time expected in the adult horse is ~30 hours. The Equidae, not having gall bladders, excrete bile constantly and active biliary elimination of drugs with notable enterohepatic cycling is quite characteristic for these species. The horse is not capable of effective vomiting; in fact, emetic efforts may prove to be disastrous.

Ruminants (pregastric fermenters) possess a large forestomach, consisting of the ruminoreticulum and omasum, which is never empty and in which active microbial growth and metabolism proceed in the form of continuous flow cul­ture. There is a steady but intermittent delivery of ingesta, containing not only many of the end products of microbial digestion but also the bacteria and protozoa themselves, into the abomasum for further utilization by the host animal. Drug absorption from the ruminoreticulum is typically retarded because of dilution in ruminal fluid. Even though the ruminoreticulum and omasum are lined by stratified squamous epithelium, the basic principles that govern the diffusion of drugs from the gastrointestinal tract into the systemic circulation remain the same as in other species, being mainly dependent on the drug's lipid solubility and concentration gradient. With ruminal stasis the rate of absorption is invariably decreased. Buffering systems maintain the usual pH of ruminal fluid between 6.0 and 6.8 but this is dependent on diet and the time of collection relative to feeding. Animals on high grain diets tend to have intraruminal pH values of 5.5 -6.0, whereas exces­sive protein or NPN intake produces higher than normal measurements even up to 8.0 in extreme cases. Denial of feed for any length of time will also lead to more neutral or even alkaline values for ruminal fluid pH. The bioavailability of orally administered drugs is variable, because of the complexity of the fore-stomach activity in these animals. In addition, the anaerobic micro flora is capable of inactivating several drugs in the ruminoreticulum, chloramphenicol and the digitalis glycosides being 2 well-known examples. The reverse is also possible, however, with broad-spectrum antimicrobial agents destroying the ruminal micro flora with resultant ruminal atony and disruption of other fore-stomach functions. The intestinal transit times in domesticated ruminants are quite long, being ~ 40 hours or more in most species. Though rumination is a normal complex regurgitive reflex, ruminant animals are not capable of vomit­ing in the physiological sense.

Besides the considerable variations between species with respect to the gas­trointestinal fate of orally administered drugs, there are also species differences related to the intracorporeal distribution of drugs. Depending on their physico-chemical characteristics, pharmacological agents may or may not diffuse into the large voluminous compartments of the digestive tracts of species like the equids and ruminants. The weight of the content of the ruminoreticulum in cattle may constitute between 10 and 15% of the body weight but may or may not represent a distribution compartment. Ion trapping within the gastrointes­tinal tract will depend on the usual pH values in the various large compart­ments found in these species.

Drugs that are highly lipid soluble will tend to accumulate over time in body fat depots. Thus, in animals such as pigs, fat lambs, and finished steers, adipose tissue may represent a large distribution compartment for those lipid-soluble agents that are slowly metabolized.

There are often notable interspecies variations in the degree of plasma pro­tein binding of drugs, both acidic and basic. Differences in the concentration of the plasma proteins are also recognized. Small changes in the degree of binding of drugs in the plasma and tissues may lead to significant redistribution of highly bound drugs between tissues and plasma. Frequently the tissue distribu­tion of drugs differs qualitatively between species.

The passage of drugs across the placenta in the pregnant animal is another facet of interspecies variation in drug distribution. Though not always predict­able or consistent it seems that species with less intimate placentations (epitheliochorial) tend to exclude drugs from the fetus more than do those animals with more intimate placentations (endotheliochorial, hemochorial, or hemoendothelial). The differences may be more quantitative than qualitative.

Most of the pharmacokinetic differences between species are due to varying rates or different pathways for the metabolic transformation of drugs. In addi­tion, many environmental and nutritional factors can influence both phase 1 and phase 2 reactions in different animal species. As a very general rule, carni­vores tend to conjugate drugs and their metabolites slowly, whereas, these reac­tions in herbivores are rather rapid. Omnivores tend to be intermediate in this regard. Domestic animals appear to be able to oxidize drugs more efficiently than man. Account must also be taken of the contributions made by gastroin­testinal micro flora to the drug biotransformation process and the consequent variations observed between species in this regard.

Marked differences in duration of blood concentrations of salicylate, chloramphenicol, phenylbutazone, amphetamine, phenol, and several other drugs are observed among horses, ruminants, swine, dogs, cats, laboratory rodents and man. This observation has a great influence on dosage regimens: e.g. the plasma half-life of salicylate is 38, 8, 6, ~ 5, 1 and 0.8 hours in cats, dogs, swine, man, horses, and goats, respectively. If the dosage interval recommended for man is followed in cats, they will be poisoned. Conversely, this regimen would not be adequate to treat fever in horses. Dogs and cats metabolize 85-90% of a dose of meperidine within an hour after administration. Consequently, this drug is not very useful for the management of pain because of its short duration of action. Cats metabolize phenol very slowly relative to other animals and thus are much more readily intoxicated by this disinfectant.

Several specific differences are known to exist with respect to drug-metabo­lizing enzymes. The cat is deficient in hepatic glucuronyl transferase. This re­sults in a dependence on different and slow pathways for biotransformation of certain compounds, with frequent increases in the duration of action and potential toxicity of these agents. Dogs have a deficiency of arylamine acetyl transferase and also possess, a hepatic deacetylase that rapidly removes acetyl groups. Thus, acetylated derivatives of sulfonamides are not found in canine urine as they are in other species. The pig is deficient in its ability to carry out sulfate conjugation reactions.

Because of the complexity of the various biotransformation capabilities, and the number of metabolic pathways potentially available or not available as the case may be, there exists an inherent danger in extrapolating information de­rived from studies in 1 animal species (including man) to another without due regard for possible differences in the pharmacokinetic fate of the agent in the second species.

There do not seem to be major deviations among mammals with respect to the mechanisms of drug excretion. However, the avian kidney may be less efficient in its ability to eliminate drugs such as the barbiturates. There is also some evidence that there may be differences in the active tubular secretion of certain drug classes in particular species. Those drugs whose renal excretion may be influenced by the pH of the urine will undergo elimination at different rates in the ruminant (urinary pH 7.0 - 8.0), the horse and pig (urinary pH ~ 7.0) and the carnivores (urinary pH usually 5.0 - 6.5).

The rate of biliary excretion and the presence or absence of an extensive enterohepatic cycle may represent the major reason for variations in the elimi­nation half-life of a drug between species. Various animals utilize biliary excre­tion for different sized molecules, e.g., rat >325 daltons, and man >500 daltons.

Lactating animals may excrete large quantities of drug in milk. Those that produce large volumes of milk such as the dairy cow will then eliminate rela­tively greater amounts of drug via the mammary gland.

Besides the differences encountered between the pharmacokinetic patterns in the various animal species, in many instances, because of variations in bio­chemical, physiological, or integrative processes, unique responses may occur in a particular animal species. A selection of these reactions is listed below to emphasize this aspect of variation in drug response.

Species                                    Drug                                                     Reaction

Horses              Certain phenothiazine neuroleptics                      Extreme excitement

Phenothiazine neuroleptics                                 Permanent penile paralysis

Tetracyclines, macrolides, lincosamides Fatal colitis

Monensin                                                          Fatal cardiac failure

Donkeys           Etorphine/acepromazine                                    Severe respiratory depression and

(at horse dose rate)                                           cardiac irregularities

Cattle                Xylazine                                                            Extreme sensitivity to depressant

                                                            effects

Morphine                                                          Excitatory, aberrant behavior

Dogs                Iodochlorhydroxyquin                            Fatal encephalitis                                 

Cats                 Acetaminophen                                                 Fatal centrilobular hepatic necrosis

(biotransformation dependent)  

Phenolic compounds                                         Marked sensitivity         

Morphine and other Opioid                                Excitatory

analgesics (at usual doses)

Aminoglycosides                                              Especially sensitive to neurotoxic effects

Genetic (Breed) Factor: Certain genetic or breed characteristics may also alter the susceptibility of an animal to a particular pharmacological agent. Several pharmacogenetic factors have been elucidated in man but this aspect of phar­macology has not been well studied in animals. The few examples of known unique breed responses include the following: Shetland and Welsh pony crosses seem to be more susceptible to the effects of xylazine than are the European breeds. Certain strains of sheep lack the esterase en­zyme necessary for the inactivation of the organic phosphate anthelmintic, haloxon, which explains the sporadic neurotoxicity in lambs following drench­ing with haloxon. Greyhounds and Whippets often show prolonged sleeping time after the administration of thiopental sodium, possibly due to limited re­distribution in these lean dogs. Brachycephalic breeds, such as the Pug, Peking­ese, and Bulldog, may exhibit syncope following the administration of acepromazine because of sinoatrial block resulting from vagal overtone.

Age: The neonate (up to ~ 1 month) differs from older individuals of the same species in a number of significant ways. Toxicity as a result of drug therapy during the neonatal period is not uncommon. The blood-brain barrier that pre­vents the diffusion of many drugs and endogenous compounds into the brain of the adult is poorly developed in the fetus and the newborn of many species. This is because of open tubulocisternal endoplasmic reticulum components of cerebral endothelial and choroid plexus epithelial cells. Neonatal animals are susceptible to marked changes in environmental temperature because of a larger surface to body weight ratio and a lesser capacity to limit heat loss. Drugs that impair temperature regulatory mechanisms can easily jeopardize a neonate's well being. Fetal hemoglobin is different from adult hemoglobin, and the neonate undergoes the change early in life. Moreover, the fetal RBC is deficient in methemoglobin reductase and hence there is a sensitivity to oxidant drugs. Several classes of drug may produce methemoglobinemia in the newborn: in­cluded are sulfonamides, nitrofurans, methylene blue, acetylsalicylic acid, acetophenetidin, and the phenothiazines.

Pharmacokinetic parameters may be markedly different in the newborn for a number of reasons. Little, if any, information is available regarding quantita­tive adjustments to dose rates or frequencies in the very young, but the differ­ences in disposition kinetics make it imperative that dose rates be reduced in the neonate - at least for the first 4 weeks of life. There is an increased perme­ability of the small intestine during the period immediately following birth, and the absorption of drugs usually retained in the intestine may be appreciable during this period. Milk, however, may retard the absorption of drugs such as the tetracyclines because of calcium chelation. The ruminant is essentially a monogastric animal until the ruminoreticulum is seeded with micro flora and the fermentation processes commence by about the third or fourth week of life. The increased permeability of the blood-brain barrier was noted above, but another feature of importance is the difference in the body water compart­ments at this early age. Body water makes up a higher percentage of body weight at birth than late in infancy. Furthermore, the extracellular fluid volume is greater than the intracellular volume. This effectively reduces the concentra­tion of drugs that are distributed in the extracellular space and alterations in drug distribution patterns are frequent in the neonate. Hypoproteinemia (mostly due to low albumin levels) is also quite common in the newborn and this in turn may increase the amount of drug available to diffuse into tissues. Because the body content of fat is low (2 - 3%) in the neonate, adipose tissue cannot represent a significant distribution compartment. However, the greatest single factor altering pharmacokinetics during the neonatal period is the defi­ciency of hepatic microsomal enzyme function for the first 4 weeks, and partic­ularly during the first 7 days. This limitation almost invariably leads to prolonged tissue levels and even toxic effects if adult dose regimens are blindly followed. Drugs that have considerably longer half-lives in the neonate, partic­ularly within the first week, include phenytoin, phenobarbital, chloramphenicol, salicylates, and theophylline. Renal function is typically deficient at birth and develops fully only during the first 1 - 2 months; thus, rates of elimination of drugs are slow, and also the neonate or young animal may be more susceptible to toxic effects of drugs on the kidney. For example, foals are more susceptible to Gentamicin - induced nephrotoxicity than are adult horses. However, in rumi­nant species, within 5 - 7 days, renal function is adequate for excretion of xenobiotics, and seems to mature within 1 - 2 weeks.

The stage of growth may also predispose a young animal to certain adverse drug effects. Antianabolic or frankly catabolic drugs will delay growth, as will drugs that suppress or impair appetite. Agents that impede normal calcium absorption and deposition will inhibit bone development. In addition, the ad­ministration of steroids with androgenic properties can lead to premature clo­sure of the epiphyseal growth plates, with consequent lessening of the animal's anticipated adult size.

Appreciation for pharmacokinetic considerations in the geriatric patient has increased during the past few years. Indications are that activity of hepatic microsomal drug enzymes is reduced with aging. The half-lives of some drugs may be increased up to 50% in geriatric patients and this is usually accompa­nied by a reduction in total plasma clearance. These differences are not reliably predictable and depend on the characteristics of the drug and the individual patient. The physiologic changes that occur with aging, and that contribute to alterations in drug disposition, include reductions in lean body mass, total body water, plasma albumin concentrations, cardiac output, hepatic mass, liver blood flow, glomerular filtration rate, and renal plasma flow. Few studies have been conducted in geriatric patients, and no fixed pharmacokinetic guidelines for dosage adjustments are available at this time. However, when administering drugs to very old animals, caution should always be exercised with regard to the dose rates selected.

The efficacy of bacteriostatic drugs is dependent upon a competent immune system. Since both the neonate and very old animal usually are not fully immunocompetent, it is preferable to employ bactericidal drugs to control bacterial infections at these ages.

Sex: The influence of sex on drug effects and the occurrence of adverse drug reactions principally relates to reproductive function. However, the rate of biotransformation and hence elimination of some endogenous and foreign com­pounds may differ between male and female animals, e.g., the sex steroids. There are also occasional variations observed in the response to specific drugs between male and female animals.

The main pharmacotherapeutic concerns associated with the treatment of females are the following: 1) the potential effect of the drugs used on the repro­ductive organs and their function; 2) the possible embryocidal, teratogenic, or abortifacient actions of drugs when administered to a pregnant animal; 3) the potential influence of any of the drugs administered on the parturition process - either to delay or to induce parturition; 4) the possible effects of any of the drugs used on lactation - either inhibitory or stimulatory; 5) the presence of any of the drugs administered as a residue in the milk of a lactating animal - either because of possible harmful effects to the suckling young or because of public health considerations.

In the male, possible adverse actions of drugs would relate to the male reproductive system, both the gonads and the accessory glands, particularly the prostate. Stimulatory or inhibitory effects may be induced by appropriate therapeutic agents.

Body Weight and Surface Area: An approximation of surface area is occasionally employed for determining the dose of exquisitely toxic drugs, e.g., some of the antineoplastic agents, but body weight is the primary determinant in most cases. However, the use of body weight does have several limitations that need to be recognized when particularly powerful therapeutic agents are adminis­tered. Differences between body weight and "true" lean body weight become evident when dealing with the following states: obesity, starvation, ascites or generalized edema, fill of the gastrointestinal tract in herbivores, severe dehy­dration, immaturity, old age, and the presence of large tumors.

Diet and Nutritional Status: Well-nourished animals normally cope with the disposition and elimination of drugs with little difficulty. In animals suffering from protein-calorie malnutrition, absorption, distribution, biotransformation, and excretion processes may all be impaired to a greater or lesser degree for many of the reasons discussed above. The diet of an animal can influence the response to a drug. This is best exemplified by the common regional differences encountered with the toxicity of anthelmintics used in a variety of herbivorous species.

Temperament: The temperament of an animal may influence its response to a drug particularly the CNS-active agents. The response to neuroleptics and tranquilizers often depends in large measure on the animal's mental state prior to and following the administration of the agent. Placebo effects have even been described in animals under certain conditions.

Relative Activity and circadian Rhythms: Many biological "rhythms" have been identified and characterized in domesticated animals. These circadian cy­cles may have diurnal or nocturnal peaks. Their chronopharmacological impor­tance relates to the desirability of designing therapeutic regimens to follow particular cycles rather than to disrupt or inhibit the controlling mechanisms that operate through feedback loops. This approach to restricting the adverse effects of drugs is well illustrated by the long-term use of alternate-day, early morning therapy with short-acting glucocorticoids to limit the potential sup­pression of the hypothalamic-pituitary-adrenal axis.

Environmental Conditions: Besides the role that environmental factors play in determining the forage available for herbivorous species, ambient conditions may directly influence the action of a number of drugs. Extreme heat and cold lead to peripheral vasodilation or vasoconstriction, respectively, with possible effects on drug disposition. High temperatures will increase the rate of volatil­ization of the inhalant anesthetics and will also increase the respiratory rate, thus facilitating inhalant anesthesia when open methods of administration are used. Extreme environmental temperatures may also influence the blood levels of several hormones such as epinephrine, thyroxine, triodothyronine, and the glucocorticoids.

            Tolerance: This means requirement of higher doses to produce a given response. It is widely occurring adaptive biological response. Drug tolerance may be natural, acquired or cross-tolerance. Natural tolerance is one in which a species/individual is inherently less sensitive to the drug. For example, rabbits are tolerant to large doses of atropine, which is toxic to other species, black races are tolerant to mydriatics. Acquired tolerance is one in which repeated use of a drug in an individual who was initially responsive, no response is observed to the same dose of the drug. Body is capable of developing tolerance to most drugs. Cross-tolerance is one in which tolerance develops in pharmacologically drugs. For example barbiturates exhibit tolerance, i.e. if one member of barbiturate exhibits tolerance, all the other members also exhibit tolerance.

            Idiosyncrasy: It is a genetically determined abnormal reactivity to a chemical. Certain adverse effects of some drugs are largely restricted to individuals with a particular genotype. In addition, certain uncharacteristic or bizarre drug effects due to peculiarities of an individual are among idiosyncratic reactions.

            Intolerance: If the subject is a hyper-reactor, the desired effects of the drug will be too intense and dosage will have to be reduced. Keeping un-wanted side effects to an acceptable level may require that the dosage is reduced, whether or not this reduces the intensity of the desired effect also.

PHARMACOLOGICAL FACTORS MODIFYING DRUG ACTION

Drug Dosage and Administration: Typically a standard dose rate is furnished for a drug preparation together with the required route of administration and the appropriate time interval between repeat doses. These recommendations by the pharmaceutical manufacturer are based on pharmacokinetic studies in the target animal species. However, because the test animals are often healthy whereas it is diseased animals that are treated, some clinical judgement is often required with respect to the dose to be used. In most instances the administra­tion of a pharmaceutical preparation at the standard rate and frequency by the advised route produces an anticipated kinetic pattern and a satisfactory therapeutic response when used for a specifically indicated disease condition. There are, however, several facets related to drug dosage forms and their administra­tion that might unexpectedly lead to an alteration in drug response.

The absorption of a drug from the common parenteral injection sites, other than intravascular is determined chiefly by the formulation of the drug, the vascularity of the tissue in which the preparation is deposited, and to a lesser extent by the degree of ionization and lipid solubility of the drug. An additional consideration is the anatomical site of the injection. In cattle, differ­ences have been found between the peak plasma concentrations of oxytetracycline when injected IM in the neck, shoulder, and buttock; the highest levels were found after injection in the shoulder region. Other considerations include tissue reaction at the injection site and the influence this might have on absorp­tion into the systemic circulation. Unintended drug delivery into relatively avascular tissues will delay absorption. This is seen with injection into fascial sheaths between muscle bundles (intermuscular) or into subcut. adipose tissue. The base or salt form of the drug used as well as the vehicles, solubilizers, stabilizers, buffers, and emulsifying agents included in the formulation are all capable of modifying the rate or absorption of the drug from the site of injec­tion. This should be taken into account when comparing different preparations of the same drug.

Many oral drug preparations are solid dosage forms though suspensions, pastes, and even solutions are quite common. Any solid dosage form needs to undergo disintegration and dissolution before absorption can take place. Disso­lution frequently controls the rate of drug absorption and thus, differences between the bioavailability of various pharmaceutical formulations of the same drug may be encountered with consequent temporal and quantitative differ­ences between their pharmacological effects.

In all cases with both parenteral and oral administration, the greater the concentration of a drug in a preparation, the faster will be its rate of absorption into the systemic circulation, and the sooner will its pharmacological effects become evident.

Therapeutic Inequivalence: Although generic preparations of a drug manufac­tured by a variety of pharmaceutical companies would be expected to be equally effective at the same dosage, this is not always the case. The reasons for therapeutic or generic inequivalence between different products that contain the same amount of the same active principle (chemically equivalent) are often complex and obscure. There is usually some form of component reaction or interaction in solid dosage forms that is responsible for the reduced bioavaila­bility of the less effective formulation. Excipient differences have been recog­nized as the cause of the inequivalence encountered between preparations containing tetracyclines, phenobarbital, phenylbutazone, phenytoin, and sev­eral other drugs. Different particle sizes, which influence the rate of dissolution of the active principle, have led to discrepancies between products containing digoxin, nitrofurantoin, griseofulvin, oxytetracycline, chloramphenicol palmitate, and ampicillin (ampicillin trihydrate versus ampicillin). Crystal polymor­phism has been responsible for the therapeutic inequivalence evidenced between preparations containing chloramphenicol as well as those containing aluminum hydroxide. Several chemically equivalent formulations intended for parenteral administration have also revealed diminished bioavailability of the active principle, leading to unpredictable therapeutic responses. Once again, there may be several reasons for the ultimate differences in the blood levels that are obtained. The actual formulation with the particular vehicles and stabi­lizers used, the chemical form of the drug employed and the tissue reactions that occur at the injection site may all be responsible for different rates of absorption. Drug preparations intended for parenteral administration that have shown evidence of therapeutic inequivalence include Chloramphenicol, oxytetracycline, diazepam, and iron dextran.

The clinical significance of generic inequivalence and the possibility of resultant therapeutic failures has become less problematical in recent years; regulatory requirements for the licensing of a new product containing an al­ready approved drug now demand that full bioequivalence of the new formulation be demonstrated. However, it is still wise when changing from one product to another to pay attention to the clinical responses to assure oneself that the preparations are indeed equivalent.

Direct Drug-Drug Interactions: When pharmaceutical preparations are mixed indiscriminately prior to their administration by virtually any route, interac­tions may occur between the active ingredients or between the active ingredi­ents and formulation adjuncts. Incompatibilities that occur may result in precipitation, chemical inactivation, or changes in the color, taste, or physical form of the preparations. The occurrence of drug-drug interactions in the phar­maceutical phase is frequently unpredictable. Detrimental reactions may be obvious but are often subtle and not easily detected. There is considerable variation between specific products with respect to their potential incompati­bilities. The constituents involved in such in vitro reactions could include the active principles, vehicles, stabilizers, correctives, preservatives, solubilizers, and antioxidants. Even the type of container or stopper (glass, plastic, or rub­ber) can play a role. Environmental factors such as temperature, humidity, agitation, and ultraviolet light may also initiate detrimental reactions in in­appropriately mixed formulations. The time between the mixing of products and their subsequent oral, parenteral, or topical administration may also allow a degree of inactivation of incompatible ingredients.

Many drug incompatibilities have been recognized and described. A few select examples are listed below, simply to emphasize the degree of caution that should be exercised whenever pharmaceutical preparations are mixed; thought should be given to the possible consequences.

Drug                                                     Incompatible Preparations

Atropine sulfate                         Barbiturates, diazepam

Chloramphenicol sodium succinate        Hydrocortisone sodium succinate, heparin sodium, chlorpromazine hydrochloride, promethazine hydrochloride, gentamicin sulfate, penicillins, erythromycin, tetracyclines, vitamins B and C

Gentamicin sulfate                                 Carbenicillin (and other semisynthetic penicillins), cephalosporins, Chloramphenicol sodium succinate, sulfonamides, heparin sodium

Tetracyclines                                         Salts of calcium, aluminum, magnesium, and other tri-and divalent cations; penicillins, cephalosporins, tylosin, chloramphenicol sodium succinate, hydrocortisone sodium succinate, sodium bicarbonate

Meperidine                                            Barbiturates, sodium bicarbonate, heparin sodium, methylprednisolone sodium succinate

Calcium gluconate                                 Carbonate, phosphate, and sulfate salts (e.g., sodium bicarbonate, potassium phosphate, streptomycin sulfate); promethazine hydrochloride, tetracyclines, sulfonamide solutions

Semisynthetic penicillins                        }

Sodium benzyl penicillin                        }

Aminoglycosides                                  }

Barbiturates                                          } Many incompatibilities—should not be mixed with

Diazepam                                             }           other drug preparations

Phenothiazine neuroleptics                     }

Vitamin B Complex                                }

           

In addition to the above, many drugs will not retain their integrity and activity over time when diluted in certain commonly used parenteral fluids - either if added alone or in combination with other drugs. Again just a few examples from the many that are known are presented below to illustrate this type of potential interaction.

Drug                                                     Incompatible Parenteral Fluids

Ampicillin sodium                                  Glucose solution, Dextran solutions

Oxytetracycline hydrochloride    Solutions containing Ca⁺⁺ or Mg⁺⁺ ions

(e.g., Ringer's solution) Glucose solutions

Gentamicin sulfate                                 Any fluid when the concentration of gentamicin exceeds 1g/L

Diazepam                                             Insoluble in most solutions

Methylprednisolone sodium succinate Sodium lactate solutions

Sodium bicarbonate                              Sodium lactate solutions, Ringer's solutions, Other Ca²⁺ containing solutions

The general rule to avoid direct drug-drug interactions is simply not to mix pharmaceutical preparations prior to or during their administration unless it is known for certain that the respective formulations are completely compatible.

A few direct drug-drug interactions of note may even occur within the body after separate administration of the agents involved. Examples include the in­activation of certain penicillins by some aminoglycosides at sites of infection (e.g., kanamycin and methicillin, gentamicin and carbenicillin);  tetracyclines chelate di- and trivalent cations (Ca⁺⁺, Fe⁺⁺, Al⁺⁺⁺, etc); protamine inactivates heparin (used to reverse excessive heparin effects on coagulation); calcium gluconate and sodium sulfonamide solutions, when administered simulta­neously, can form gels in the vein with subsequent embolism and occlusion; kaolin binds rifampin and lincomycin in the gastrointestinal tract.

Drug-Diet Interactions: A dietary component or the actual presence of food may influence the absorption of drugs, and drugs in turn may impair the ab­sorption of nutrients. However, in most cases the absorption of orally adminis­tered drugs is not particularly affected by dietary constituents, and they are well absorbed whether given either with or between meals. There are a few notable exceptions to this generalization. The absorption of the tetracyclines is impaired by milk and milk products because of the presence of calcium ions. The presence of food may also substantially reduce the absorption of sulfisoxazole, ampicillin and some other semisynthetic penicillins (but not amoxicillin), cephalexin, tetracyclines, lincomycin, and rifampin. Conversely, the absorption of griseofulvin is markedly increased when given with fat, cream, or oleomarga­rine. This represents a very useful way of attaining high levels of griseofulvin in the keratin layers of the skin in cases of dermatomycosis. The actual presence of food in the stomach may exert a nonspecific effect in reducing or slowing the absorption of some drugs, e.g., the absorption of phenylbutazone in the horse becomes somewhat unpredictable when it is administered after feeding. In ru­minants, eating and the presence of fresh feed in the ruminoreticulum in­creases ruminal motility and enhance blood flow to the forestomach. Under these circumstances, the rate of absorption of drugs from the ruminoreticulum tends to increase.

Some orally administered drugs may interfere with the absorption of spe­cific nutrients—especially with long-term administration. Chronic anticonvulsant therapy with phenytoin suppresses absorption of dietary folic acid, and daily administration of mineral oil impede the absorption of the fat-soluble vitamins, ultimately leading to deficiency states. Oral dosage of antibiotics, such as the tetracyclines and aminoglycosides, which reach effective antibacterial levels in the lower small intestine and large intestine, can lead to suppression of microbial synthesis of vitamin K and the vitamin B complex. In species that are dependent, at least in part, on the microbial production in their intestinal tracts of these essential nutrients, the chronic administration of broad-spectrum anti­biotics can lead to subclinical avitaminosis.

Pharmacokinetic Interactions: One or several drugs can interfere with the pharmacokinetic fate of concurrently administered drugs in several ways. Such interactions may involve processes involved in the absorption, distribution, biotransformation, or excretion of drugs.

Drug Interactions Involving Gastrointestinal Absorption: There are many mechanisms through which the rate of absorption of drugs from the gastrointestinal tract may be modified by a second drug. Antacids and cimetidine in­crease the intragastric pH and thereby may change the disintegration and dissolution rates of solid oral dosage forms, and also delay the absorption of weakly acidic drugs. Sodium bicarbonate typically reduces the absorption of the tetracyclines. Because the stomach is not a major site of absorption and most drugs are primarily absorbed from the proximal small Intestine by virtue of its much greater surface area, the rate of gastric emptying and the degree of intestinal motility may markedly influence the rate of drug absorption. Gastrointestinal motility will be diminished by agents such as anticholinergics, adrenergics, neuroleptics, antihistaminics, and opioid analgesics. Conversely, cholinergics, metoclopramide, antacids, and some purgatives enhance gastroin­testinal movement. The net effect on the absorption rate of drugs administered orally when the digestive tract is under the influence of motility modifiers de­pends in large measure on whether they are acids or bases and whether they are normally rapidly or slowly absorbed. Drugs dosed orally may complex with each other in some fashion, e.g., they may form ion pairs or chelates, and their absorption may then be diminished or enhanced. Tetracycline absorption is diminished by the formation of insoluble chelates with di- and trivalent cations such as Ca⁺⁺, Fe⁺⁺ and Al⁺⁺⁺. On the other hand, the absorption of dicumarol is increased by magnesium hydroxide because of the greater solubility of the chelate that is formed. Kaolin, activated charcoal, and cholestyramine reduce the gastrointestinal absorption of many drugs concurrently administered orally because of their propensity to bind to other substances (adsorption). Malabsorption syndromes can result from toxic effects of certain drugs on intestinal mucosal cells. For example, chloramphenicol, neomycin, and tetracycline pro­duce characteristic lesions in the intestinal mucosa of calves. The morphological changes include diffuse reduction to villous height and numbers, flattened mucosal epithelium, and multifocal villous fusion. Adrenergic agents with alpha activity induce pronounced splanchnic vasoconstriction, which in turn, will deter the rapid absorption of drugs from the gastrointestinal tract into the portal circulation. Finally, for as yet unknown reasons, high plasma concentrations of insulin facilitate the absorption of meperidine, salicylate, and chlorpromazine from the intestine.

Drug Interactions Involving Absorption From Injection Sites: The rate of absorption following parenteral administration is governed primarily by the anatomical site employed for the injection, the pharmaceutical form of the drug and the vehicle used, and the regional blood flow. Interaction of inadvis­edly mixed injections may lead either to an increased absorption rate if vasodilation occurs or to delayed absorption if a vasoconstrictive response results. This interaction may be deliberate, best illustrated by the combined use of epinephrine and local analgesics to prolong the duration of their effect at the site of administration.

Drug Interactions Involving Distribution: The concurrent administration of 2 or more drugs may alter the intracorporeal distribution pattern of each of them. Competition for plasma protein binding sites is quite common. Acidic drugs that possess the greatest affinity displace less strongly bound agents and the net excess of free drug may then lead to exaggerated or toxic responses. The few examples outlined below serve to emphasize this sometimes-dangerous form of pharmacokinetic interaction.

Strongly bound drug	Displaced drug	Effect of interaction
Phenylbutazone	Coumarins (especially warfarin)	Hemorrhage due to excessive Inhibition of the synthesis of Vit-K-dependent clotting factors
NSAID	Sulfonamides	Enhanced sulfonamide activity and toxicity
NSAID	Methotrexate	Increased methotrexate toxicity
Valproic acid	Phenytoin	Increased plasma phenytoin levels

Besides the effects on drug disposition that may result from displacement from protein binding sites, the pharmacodynamic effects of 1 drug may affect the tissue distribution of another. Examples include drug-induced alterations in cardiac output, blood shunts and changes in capillary permeability.

Drug Interactions Involving Biotransformation: Of all the pharmacokinetic factors that control drug action, the rate of metabolic transformation is 1 of the most important. Hence, interactions that result in changes in the rate of drug metabolism can be of great clinical significance. One drug can alter the metabo­lism of a second drug either by stimulating (inducing) or inhibiting the microsomal enzyme systems. The extent to which drug-metabolizing enzymes may be induced varies with the species and with the degree of previous exposure to inducing agents. The usual consequence of microsomal enzyme induction is an abbreviated effect of the second drug because it is biotransformed much more rapidly. However, in those cases in which prodrugs are converted to active compounds by metabolic transformation, toxic effects may become evident because of the facilitation of the activation process. Inducing agents need to be administered repetitively over a period of several days in order to stimulate microsomal enzyme activity maximally. In veterinary medicine, few therapeu­tic agents are administered for prolonged time periods but there are some im­portant exceptions such as anticonvulsants, nonsteroidal anti-inflammatory drugs, sex steroids and antifungal agents. A selection of drugs that induce microsomal enzyme activity and the compounds whose rate of biotransformation is increased are set out below.

 

Inducing agent             Compounds whose rate of Biotransformation is increased

Phenobarbital                Barbiturates, Phenytoin, Phenylbutazone, Warfarin, Cortisol, Testosterone Progesterone, Bilirubin

Phenylbutazone             Phenylbutazone, Corticosteroids, Sex steroids

Phenytoin                     Corticosteroids, Sex steroids

Griseofulvin                  Warfarin

Phenothiazine neuroleptics, diazepam, diphenhydramine, mitotane, estradiol, progestogens, androgens, and other barbiturates are also capable of inducing microsomal enzyme activity.

Some drugs are capable of inhibiting the biotransformation of others. The mechanism usually involves competitive enzyme inhibition and, unlike induc­tion, occurs immediately after the inhibitor reaches the enzyme. Even though the effect may be observed very quickly, in some cases it may take several days before the clinical evidence of microsomal (or other) enzyme inhibition of drug metabolism becomes apparent. Microsomal enzyme inhibitors that are of clini­cal importance include chloramphenicol, cimetidine, quinidine, and prednisolone. The suppression of barbiturate and phenytoin metabolism by chloramphenicol is of particular concern because of the serious consequences of this interaction. Allopurinol, a xanthine oxidase inhibitor, reduces the hepatic inactivation of several agents including 6-substituted purines such as azathioprine and mercaptopurine.

Drug Interactions Involving Excretion: Drug interactions can affect the ef­ficiency of the organs involved in the excretion of drugs and their metabolites. Several mechanisms may be responsible for interactions affecting renal excre­tion. Any drug that modifies renal blood flow can potentially alter the renal clearance of other drugs by changing both the glomerular filtration rate and the tubular transport process. Increased renal blood flow will generally promote the renal excretion of drugs and/or their metabolites. The reverse is true for renal ischemia induced by vasoconstrictive agents. Increased urine flow rates resulting from the administration of diuretics may increase the renal excretion of concurrently administered drugs - though in some cases the diuretics them­selves will compete with other agents for tubular transport carriers and this will reduce their renal elimination. Alteration of urinary pH will change the rate of excretion via the kidneys, principally when the pKa’s of the drugs are within the range of the urine pH. Even minor deviations in urine pH will then substan­tially modify the degree of ionization of either acids or bases, thus hindering or facilitating their reabsorption from the tubules. Weak bases, such as morphine, meperidine, procaine, and several antihistaminics, are excreted more rapidly at lower and more slowly at higher urine pH values. The opposite applies for weak acids such as nalidixic acid, nitrofurantoin, several sulfonamides, some barbitu­rates, and many nonsteroidal anti-inflammatory drugs. Urinary alkalinizing agents that are capable of influencing the excretion rate of concurrently admin­istered drugs include sodium bicarbonate, sodium citrate, and sodium acetate. The carbonic anhydrase inhibitors that act as diuretics also alkalinize the urine. Urinary acidifiers (with opposite effects from those of the alkalinizing agents on the renal excretion of drugs) include ascorbic acid, methionine, sodium acid phosphate, and ammonium chloride. The carriers responsible for the tubular transport of drugs have a limited capacity, and competition for secretion can occur between similar organic ions. Anions compete with anions and cations with cations for transport sites. Clinically significant interactions of this type usually involve anions since organic cations are generally potent molecules that are not given in doses high enough to saturate the transport mechanisms. Ex­amples of drugs that are acidic in nature and which undergo renal elimination by a shared carrier-mediated transport system include: penicillins; cephalosporins; probenecid; sulfonamides; acetazolamide; furosemide; nonsteroidal anti-inflammatory drugs such as aspirin, phenylbutazone, naproxen, mefenamic acid and ibuprofen; and phase II drug metabolites such as glucuronic acid, glycine, and sulfate conjugates. Basic drugs that utilize a tubular carrier-medi­ated transport process include procainamide, dopamine, trimethoprim, triamterene, thiamine and several opioid agents such as morphine and dihydrocodeine.

Drug interactions associated with biliary excretion seem to be relatively un­important. Pharmacological agents that influence hepatic blood flow can im­pact on the efficiency of bile production and flow. In addition, enterically active antimicrobial agents can modify normal enterohepatic cycling by preventing bacterial hydrolysis of drug conjugates in the gastrointestinal tract.

Pharmacodynamic Interactions: There are many recognized pharmacodynamic interactions that occur when 2 or more drugs are administered simultaneously. In many instances the resultant effects are indeed desired and beneficial - good examples being premedication with neuroleptics prior to in­duction of general anesthesia to reduce the dose of the anesthetic (functional potentiation); the reversal of narcosis with opioid antagonists such as naloxone (competitive antagonism); the treatment of digitalis overdosage with propranolol (functional antagonism). However, in some cases the combined effects of 2 or more drugs may induce or increase toxicity (additive effects or potentiation).

There are simply too many interactions of this nature to review here and only certain aspects of a few examples are presented.

1) Aminoglycoside antibiotics are ototoxic, nephrotoxic, and may precipi­tate acute peripheral vasodilation following IV administration. In addition, they have a curare-like effect at the neuromuscular junction and exert a negative inotropic effect on the heart. The ototoxic and nephrotoxic effects are potenti­ated by loop diuretics such as furosemide. The neuromuscular and cardiac effects are potentiated by most general anesthetics, especially halothane and thiopental. Calcium ions and short-acting acetylcholinesterase antagonists re­verse these latter effects.

2) Lincomycin, clindamycin, and polymyxins exert a neuromuscular block­ing effect, and care should be taken when any non-depolarizing neuromuscular blocking agent is used concurrently with these antibiotics.

3) Tetracycline antibiotics also possess a neuromuscular blocking effect that may be potentiated by general anesthetics or hypocalcemic states.

4) The toxicity of cardiac glycosides is enhanced by hypercalcemia, hypomagnesemia, hypokalemia, and hypothyroidism. Serum concentration and tox­icity of digoxin are increased by co-administration of quinidine; at the same time the inotropic effects of digoxin are lessened. Coadministration with furo­semide results in elevation of serum digoxin. Propranolol ameliorates cardiac glycoside intoxication and also lessens the positive inotropic effect

5) Halothane and methoxyflurane sensitize the myocardium to the arrhythmogenic effects of catecholomines. Fatal ventricular fibrillation can be reliably produced by the release or administration of epinephrine in halothane-anesthetized dogs. Induction of anesthesia with thiobarbiturates potentiates this effect. Premedication with acepromazine, lidocaine, or propranolol prevents this dan­gerous interaction.

6) Diamidines such as diminazene and phenamidine are inhibitors of acetyl­cholinesterase. If an animal is treated with 1 of these antiprotozoal agents soon after being dipped in an organophosphate insecticide, signs of intoxication may occur.

7) Succinylcholine, the depolarizing muscle relaxant, is hydrolyzed in vitro by serum cholinesterases. Organophosphorus and carbamate insecticides inhibit cholinesterase, thus potentiating succinylcholine's action.

8) Propranolol, a β receptor blocker, precipitates hypoglycemia in insulin-dependent diabetics.

9) The antiarrhythmics, quinidine and procainamide, potentiate the action of muscle relaxant drugs and may cause recurarization.

10) Fatal renal failure following the combined use of methoxyflurane and tetracyclines has been reported.

11) When amphotericin B and digitalis glycosides are administered concur­rently there is an enhanced potential for cardiac arrhythmias.

12) Long term use of phenytoin and phenobarbital or primidone leads to cholestatic hepatopathy.

13) Verapamil and propranolol given IV together may cause a high degree of heart block.

14) Phenobarbital enhances digoxin toxicity but the mechanism is not un­derstood.

15) Diphemanil methylsulfate can precipitate fatal ventricular fibrillation in thiamylal-anesthetized dogs.

PATHOLOGICAL FACTORS MODIFYING DRUG ACTION

Pathological lesions in major organ systems, or pathophysiological changes within body fluids, can substantially alter both the pharmacokinetic fate and the pharmacological action of many drugs. However, the potential influence of the disease state on the fate and action of drug administered to sick animals is rarely taken into account during the therapeutic management of cases. This is understandable simply because there is a dearth of experimental and clinical data to serve as a basis for rational dosage adjustments in the presence of pathological states. The clinical approach must still be empirical in this regard. Nevertheless, there are several pathological conditions that are known to mod­ify drug action in a number of species, especially in man.

Gastrointestinal Disease: Several conditions may alter the absorption rates of orally administered drugs. Increased, decreased, or even unpredictable absorption patterns may be evident, depending on the lesions and pathophysiological changes present. The presence of the following disease conditions or clinical signs could well be responsible for deviations in the usual drug absorption processes - and the possibility should always be taken into account when treat­ing such cases.

Vomiting (many causes), Gastritis, Gastric ulceration, Achlorhydria or hypochlorhydria, Ruminoreticular stasis, Ruminal lactacidosis, Ruminitis, Diarrhea (many causes), Enteritis (many forms), Duodenal ulceration, Steatorrhea, Pancreatic disorders, Other malabsorption syndromes, Ileus, Gastrointestinal obstructions, Ulcerative colitis, Peritonitis,  Post-laparotomy, Gatrotomy or enterotomy.

Hepatic Disease: Either acute or chronic liver disease can alter the disposition and elimination of many drugs. There are also several pharmacokinetic deter­minants that may be affected by lesions associated with hepatic disease. The most important facets of drug disposition and elimination affected by liver disease are the following:

1) impairment of the activity of drug-metabolizing enzyme systems due to hepatocyte damage;

2) limitation of the efficiency of the hepatobiliary secretory system due to hepatocellular failure;

3) changes in he­patic blood flow, particularly in circulatory shock, cirrhosis, and portal-systemic venous shunting;

4) reduced synthesis of plasma proteins, especially albumin, and alteration in their drug-binding capacity;

5) development of ascites and peripheral edema with consequent enlargement of the volume of distribution for many drugs and resultant prolongation of their elimination half-lives.

Besides the influence of hepatic dysfunction on the kinetic fate of agents that usually undergo biotransformation, the reduced metabolic transformation of those drugs whose systemic bioavailability is generally restricted by first-pass metabolism may be sufficient that serious toxic effects occur very quickly.

Many disease states may impact on the liver's role in drug clearance. Exam­ples include viral, bacterial, and toxic hepatitis; various hepatopathies; cirrhosis due to a number of causes; Liver abscessation; and derangements (congenital and acquired) in the circulation of blood through the liver. In treating cases with impaired hepatic blood flow or function, it is often necessary to reduce the doses of drugs used that are usually metabolically transformed, and to increase the intervals between doses in order to avoid excessive systemic concentrations. The responses should be carefully monitored clinically.

Renal Disease: If urinary excretion is an important route of elimination, renal failure results in decreased drug clearance and thus slower removal of the drug from the body. A usual dosage regimen in such cases will lead to accumulation and, ultimately, to toxicity. In addition, animals with renal insufficiency often react abnormally to a number of drugs, irrespective of the alterations in elimi­nation. This increased sensitivity may be due to changes in plasma protein binding, increased receptor responsiveness, derangements of acid-base bal­ance, uremia, hyper- and hypokalemia, hyper- and hyponatremia, dehydration, etc.

A number of disturbances may take place within the failing kidney, all of which may influence in 1 way or another the excretion and renal clearance of drugs. Changes in the pH of the filtrate will also alter the excretion rates of drugs with appropriate pKa values. Renal ischemia, glomerular lesions, tubular damage, impaired intrarenal perfusion, functional disabilities of the tubular cells, and obstructive lesions in the tubules, collecting ducts, and ureters may all influence the effective renal clearance of drugs and/or their metabolites. The slower removal of the drug from the body will result in accumulation and increased likelihood of toxicity if administration according to the usual dosage regimen is followed. Drugs such as aminoglycosides, penicillins, cephalosporins, colistin, tetracyclines (except doxycycline), sulfonamides, nitrofurantoin, 1, 5 -fluorocytosine, methotrexate, procainamide,  methenamine, digoxin, and barbiturates are examples of agents that are wholly or largely eliminated by the kidney. Adjustment of dosage is necessary when using these drugs in patients with renal insufficiency.

There are several approaches to establishing a dose schedule. First, if feasible, a regimen may be individualized for a particular patient. Actual plasma concentrations may be used to control drug therapy and the kinetic parameters discussed earlier can be calculated to determine optimal dose rates and frequencies. Second, when an agent has a fairly wide therapeutic index, halving the standard dose or doubling the usual dosage interval should be sufficient in uremic patients to maintain therapeutic plasma levels without serious danger of accumulation. Finally, when potentially toxic drugs, such as gentamicin, kanamycin, and other aminoglycosides, cephaloridine, sulfonamides, digoxin, and some antineoplastic agents are administered and renal insufficiency is present, more refined modification of dosage regimens is necessary.

Since both renal clearance and the renal fractional rate constant are directly proportional to creatinine clearance, one approach is to calculate the fraction of the normal dose to be given at the usual dosage interval:

                                                D x Cl cr (Patient)

D(ri) = -----------------------

                                                Clcr (Normal)

where    D(ri) is the dose in the presence of renal insufficiency

D is the usual maintenance dose, and

Clcr is the creatinine clearance.

Alternatively, the dose may be kept constant and the dosage intervals increased:

                                                T x Clcr(normal)

T(ri) =-------------------------

                                                Clcr (Patient)

where    T(ri) is the dosage interval in the presence of renal disease and

T is the usual dosage interval

The term I/serum creatinine (mg/dL) has been substituted for the creati­nine clearance ratios when these were not obtainable. However, in man, the relationship between t 1/2 and serum creatinine is not linear above the value of 4 mg/dL. Thus the formulas may be somewhat less reliable at higher serum creatinine levels.

Diseases and Drug-Protein Binding: In a number of pathological states, a de­crease in the plasma protein binding of drugs, usually acids, is observed. This may be due to many factors related either to the protein or to the drug or to the binding conditions. A decrease in the extent of drug plasma protein binding does not invariably lead to enhanced drug effects.

Hyperalbuminaemia will alter the binding capacity of many drugs. Common clinical conditions associated with hypoalbuminaemia, including aging, burns, neoplasia, cardiac failure, protein-losing enteropathy, inflammatory diseases, injury, liver disease, nephrotic syndrome, renal failure, and nutritional deficiency. Con­ditions resulting in the modification of the albumin compartment volume may also lead to discrepancies in the anticipated distribution of drugs. The predomi­nant disease states resulting in sequestration of plasma proteins in the intersti­tial compartment include inflammatory states, pregnancy, septic shock, cardiogenic shock, and pulmonary edema.

In several disease conditions there is decreased affinity of drugs for plasma albumin. There may be several reasons for this phenomenon, including the release of endogenous binding inhibitors and the presence of Metabolic acidosis. The pathological states associated with decreased affinity of drugs for albumin include liver disease, chronic renal failure with uremia, the nephrotic syndrome, malnutrition, and cardiac failure.

The plasma protein binding of basic drugs differs somewhat from acidic drugs, which bind largely to albumin. Basic drugs interact with a number of plasma constituents including α-acid glycoprotein (an acute phase protein), lipoprotein, and albumin. Whereas the trend for albumin is almost always to decrease in concentration, α-acid glycoprotein and lipoprotein show large fluctuations due to physiological and pathological conditions. Associated with changes in the plasma levels of these specific proteins, both decreases and increases in the binding of basic drugs have been recorded.

Cardiovascular Disease: Cardiovascular insufficiency, due to either cardiac fail­ure or circulatory shock, is often associated with disturbances in cardiac out­put, autonomic nervous system activity, central and systemic venous pressures, and sodium and water metabolism. These disturbances may in turn influence the extent and pattern of tissue perfusion and may lead to tissue hypoxia and visceral congestion. Gastrointestinal motility may also be altered. Cardiac failure potentially affects the disposition of drugs, which may then necessitate adjustment in dosage regimens for optimum therapy. However, no ready guide­lines are available.

A few special features need emphasis. Redistribution of the cardiac output to preserve blood flow to the heart and brain will lead to a diminished volume of distribution as well as decreased renal and hepatic perfusion with resultant delay in drug elimination. Both of these factors will tend to lead to increased plasma levels of any parenterally administered drug. Splanchnic vasoconstriction encountered in shock will delay the gastrointestinal absorption of any orally administered agent.

In cases of congestive heart failure with marked ascites and dependent edema, the accumulated fluid may or may not represent a distribution compartment. If it does, the total weight of the animal can be used to calculate a dose rate, provided there is not a concurrent rapid loss of the fluid due to appropriate therapy. Moreover, in such cases, hypoalbuminemia and reduced binding capacity are often features that could alter the normal distribution patterns of a drug.

As a general rule, when cardiovascular dysfunction is present, loading doses should be conservative and continued therapy monitored closely either by watching for clinical signs of overdosage or by measuring plasma levels of the drugs being employed.

Pulmonary Disease: Acute hypoxemia appears to decrease intrinsic hepatic clearance while chronic hypoxia appears to increase intrinsic clearance. The free fraction of some basic drugs is decreased in plasma taken from patients suffering from chronic hypoxemia. Blood gas disturbances also can affect drug disposition by decreasing hepatic and renal perfusion.

It appears that respiratory disease can significantly change drug disposition through a number of interacting mechanisms. These nave not been adequately studied to provide a basis for clinical dosage adjustment. Drugs showing flow-dependent hepatic clearance (e.g., lidocaine, meperidine, propoxyphene) and those with predominantly renal clearance (e.g., aminoglycosides, digoxin) should be used with caution when respiratory disease is present. Theophylline doses should also be reduced on an empirical basis.

Neurological Disturbances: A large number of neurological disorders may po­tentially alter the effect of many drugs - both those with CNS activity as well as several that do not normally act within the CNS. Clearly lesion-induced changes in CNS functions will influence an animal's response to CNS depressant agents. Moreover, in the presence of meningoencephalitis many drugs that do not nor­mally do so may penetrate the blood-brain barrier producing unusual effects, e.g., penicillin G may act as a convulsant. Damage to autonomic or vital medullary centers may also influence the response of specific target tissues to either stimulant or depressant drugs. In idiopathic canine epilepsy and epileptiform conditions in general, phenothiazine neuroleptics can precipitate seizures and should not be used as tranquilizers or for premedication prior to general anes­thesia in affected animals.

Other Pathological States: Several other pathological states may influence ei­ther the pharmacokinetic fate or the pharmacodynamic effects of a number of specific drugs. A selection of these are presented to emphasize the significant impact that disease conditions can have on drug action.

1) Anemia: Tissues may be hyper- or hyporesponsive when anemia and hy­poxemia are present. The myocardium may become especially sensitive to the action of positive inotropic and chronotropic agents. Biotransformation and excretion processes can also be seriously disrupted.

2) Toxemia:  The disposition and elimination of many drugs as well as their toxicity may become altered in toxemic states.

3) Electrolyte disturbances: Even minor deviations from the normal electro­lyte values in plasma can lead to significant changes in the response to certain drugs, hypocalcemia as well as hypo- and hyperkalemia being prime examples. The digitalis glycosides are much more toxic in the presence of hypokalemia.

4) Acid-base derangements: Alkalosis often enhances the response of excit­able tissue to provocative drugs. Conversely, systemic acidosis tends to depress the reactions of excitable tissue such as nerves, skeletal muscle, the myocar­dium, and smooth muscle. Tissue acidosis limits the diffusibility of many local anesthetics to their site of action. The bactericidal action of the aminoglycoside antibiotics is less efficient in the presence of acidosis. Systemic acidotic states also tend to change the plasma protein binding of drugs. The pH of the urine can change during acid-base derangements with subsequent alterations in the usual renal excretion rates of many of those drugs with appropriate pKa values.

5) Endocrine and metabolic disturbances: Several endocrine and metabolic derangements may be exacerbated by the administration of exogenous agents. For example, incipient diabetes mellitus may be precipitated by the administra­tion of glucocorticoids and by the progestogen, megesterol acetate. Hyperthyroidism often increases the responsiveness of an animal to a variety of drugs and such cases should be managed very carefully.

6) Impaired immunocompetence: When, for whatever reason, host defense systems are not fully functional, the successful clinical use of several antimicro­bial drugs is placed in jeopardy. This is especially true for the bacteriostatic group of agents.