Health & Management / Ruminants Pain Management / Techniques and protocols OVERVIEW:
< > Understanding Pharmacokinetics for Pain Management in Ruminants:

Introduction and General Information

"The aim of drug administration is to produce a desired clinical response (i.e. therapeutic effect), which most likely will be obtained by establishing and maintaining, for a certain period of time, an effective concentration of drug at its site of action." (B333.1.w1)

Pharmacodynamics describes how a drug acts on the body, while pharmacokinetics describes how the body acts on drugs. An understanding of the basic principles of pharmacodynamics and pharmacokinetics is advantageous for rational choice and use of drugs for analgesia or any other purpose.

  • The action of a drug is, for most drugs, dependent on its concentration at the appropriate effector site, generally at a specific drug receptor. In general, as concentrations of drugs cannot usually be measured at the effector site, the concentration of drug in plasma is assumed to represent the concentration in the target tissue. As the concentration of drug increases, the number of receptors occupied increases and so does the effect of the drug, up to a maximum effect. (J234.7.w1)
  • The plasma concentration of a drug depends on the size of the dose, rate and extent of its absorption from the site of administration, drug distribution into different body compartments, binding to proteins in plasma and tissues and elimination of the drug by metabolism (biotransformation) and excretion. (J234.7.w1, B333.1.w1)
  • Appropriate routes of administration of a drug depend on the translocation of drug molecules across biological membranes, and the absorption and distribution of the drug in the body. (B327.7.w7)
  • Appropriate dosing regimes depend on the characteristics of absorption, distribution, metabolism and excretion of a drug from the body, these being the factors which determine the time course of the drug concentration in the body. (B327.7.w7)

It is important to recognise that there are considerable variations in drug absorption, distribution and elimination between species. There are also important variations between individuals, effects of disease, interactions between drugs given concomitantly, and factors related to drug formulations. (B330.15.w15)

Ideally every individual animal requiring analgesics would be given an analgesic treatment based on drugs of known efficacy and pharmacokinetics. However this is not always possible even with the domestic ruminants and certainly not with the many species of non-domestic ruminant.

  • For many species there is a lack of adequate information on either the pharmacology or the efficacy of analgesics. (B325)
  • Because of the species-specific factors which affect pharmacokinetics and pharmacodynamics of drugs it is not advisable to extrapolate between species. However extrapolation is necessary when treating non-domestic animals for which there is no species-specific information available. (J213.4.w1)
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Drug Action and Effects - Pharmacodynamics

  • Drug action is "the process by which the chemical agent induces a change in some preexisting physiological function or biochemical process of the living organism." (B333.1.w1)
  • The site of action of a drug is "the location in the body at which the drug initiates the series of events (measured or observed as effects) that are produced by the drug." (B333.1.w1)

Drugs and their receptors

A drug receptor is "the macromolecular component of body tissue with which a drug interacts to initiate its pharmacological effects." This may be a protein, enzyme, nucleic acid, ion channel etc. (B270.2.w2)

  • Most receptors are proteins. (B331.2.w2)
    • An important group of drug receptors are proteins which normally act as receptors for endogenous substances such as neurotransmitters and hormones. Drugs reacting on such receptors often are very selective. (B331.2.w2)
  • Certain drugs, such as osmotic diuretics, have their therapeutic effect without a clear macromolecular tissue receptor on which the drug acts. (B270.2.w2)

An agonist is a drug which possesses affinity for a particular receptor and when bound to that receptor causes a change in the receptor which results in an observable effect. (B270.2.w2, B327.2.w2, B331.2.w2) The action of a drug is the initial consequence of the interaction of that drug with its receptor; further drug effects may follow from this action. (B270.2.w2)

  • A drug has a high affinity if it has a great tendency to combine with a particular type of receptor. The term efficacy or intrinsic activity reflects the maximum effect which the drug can produce. A full agonist produces a maximal effect when it occupies all or a fraction of receptors while a partial agonist produces a less-than-maximal (submaximal) effect even when it occupies all receptors. (B270.2.w2, B327.2.w2)
  • If maximum tissue response occurs when not all the receptors of the tissue are occupied by the drug then there are said to be spare receptors. (B270.2.w2)

A drug's potency reflects the dose that must be administered in order to produce a particular effect of given intensity: if a drug has high potency then a lower dose is required in order to produce a given response. (B270.2.w2) In general, a drug of high potency has a high affinity and therefore will occupy a significant proportion of receptors even when the drug is present at a low concentration. (B327.2.w2)

  • The potency of a drug is affected by the affinity of the drug for its receptor sites and by pharmacokinetic processes (see below) that determine the concentration of the drug in the immediate vicinity of its site of action. (B270.2.w2)
  • Potency is relative, not an absolute measurement. The potency of a drug is generally determined relative to a known standard which produces the stated action by the same mechanism of action. (B270.2.w2)
  • Potency does not necessarily correlate with efficacy or safety. However, a drug with very low potency may be too costly or too cumbersome to administer. (B270.2.w2)

The chemical structure of a drug determines its affinity for its receptor and also its efficacy or intrinsic activity. (B331.2.w2)

  • Small changes in chemical structure may result in large changes in the pharmacological properties of a drug. (B331.2.w2)
  • A change in molecular configuration does not necessarily change all the actions of a drug equally; this allows development of drugs with different selectivities and higher ratios of therapeutic to toxic effects. (B331.2.w2)

Antagonists:

An antagonist is a drug that interacts with a receptor or another component of a drug effector mechanism but does not cause an effect. By its presence an antagonist reverses or blocks the effects of the receptor's agonist. (B270.2.w2, B327.2.w2)

There are several types of antagonists 

  • A competitive antagonist binds selectively to a particular receptor without activating the receptor, but in a way such that it prevents the binding of an agonist. (B327.2.w2)
    • The effects of a competitive antagonist are reversible and can be reversed by an increase in the concentration of the agonist in the immediate vicinity of the site of action. (B270.2.w2)
      • At a given concentration of agonist, if a quantity of the antagonist is present then the occupancy of the receptor by the agonist will be decreased. However, if the concentration of the agonist is increased then its occupancy of the receptor can be restored. (B327.2.w2)
      • For this type of antagonism, in the presence of a fixed concentration of antagonist, the log concentration-effect curve of the agonist is shifted to the right, but the slope of the curve and its maximum are not changed. (B327.2.w2)
      • The dose ratio is the ratio by which the agonist must be increased in order to restore a given level of response; this increases linearly as the concentration of the antagonist is increased. (B327.2.w2)
  • An irreversible (non-equilibrium) competitive antagonist binds to the same receptor as the agonist and, having bound to the receptor, dissociates from it very slowly or not at all. This means that there is no change in occupancy of the receptor by the antagonist in the presence of the agonist. (B327.2.w2) This form of antagonist is also sometimes described as a non-competitive antagonist (see below). (B327.2.w2)
    • A non-competitive antagonist effectively removes the receptor or response potential from the system; further addition of agonist will not influence the degree of antagonism. The maximum effect of the agonist is reduced. (B270.2.w2)
    • An irreversible antagonist reduces the slope and the maximum of the log concentration-effect curve of the agonist. (B327.2.w2)
  • Non-competitive antagonism occurs when the antagonist blocks the production of the response by the agonist at some point after the agonist-receptor interaction, i.e. it interrupts the linkage between receptor and effector. This will usually reduce the slope and the maximum of the log-concentration-response curve of the agonist; it may also cause some degree of right shift in the curve. (B327.2.w2)

Other forms of antagonism are Chemical antagonism, pharmacokinetic antagonism and physiological antagonism. (B327.2.w2) 

Selectivity and specificity:

  • The selectivity of a drug depends on its capacity to preferentially produce a particular effect without other effects being produced at the same dose; a totally selective drug produces only one single effect. (B270.2.w2)
    • Selectivity of action may be produced in some cases by route of administration (e.g. topical administration) or by the pattern of drug distribution (e.g. lack of central nervous system effects due to the drug not reaching the CNS). (B270.2.w2)
  • A drug is specific if all its effects are due to action at only one type of receptor. It should be noted that a specific drug may nevertheless produce multiple effects, due to location of receptors in various organs. (B270.2.w2)

Mathematical (Quantitative) aspects of the drug-receptor interaction

The presence of a drug at its receptor results in an interaction, usually reversible, between the drug and the receptor. The result of the drug-receptor interaction is the formation of a response or stimulus. As more drug is administered and interacts with receptors, the intensity of the response is increased. (B270.2.w2)
  • In general there is a graded dose-response relationship of the drug-receptor interaction at receptor level. (B270.2.w2).
    • The drug-receptor-response relationship can be summarised as: drug + receptor ↔ drug-receptor complex → response. (B270.2.w2)
    • The dose-response relationship (the response of a patient to different doses of a drug) may be plotted graphically as response (Y-axis) against dose (X-axis) or more commonly as response (Y-axis) against logarithm of dose (X-axis). (B270.2.w2)
    • The slope of the log-dose response curve, which is sigmoidal,  indicates the range of doses (from a minimally detectable response to maximally effective) over which the drug acts. (B270.2.w2)
  • There are two interpretations of the dose-response relationship: 
  • A frequency distribution curve can be obtained, for a population (group of individuals), showing the dose required in order to produce a defined response or effect. Plotting the percentage responding (Y-axis) against the logarithm of the dose (X-axis) gives a normal distribution. The dose required to produce the required effect in 50% of individuals in a population is the median effective dose (ED50). The standard deviation (SD) is a useful measure of the variability of the normal distribution curve. The area under the curve enclosed by 1 SD either side of the median represents about 68% of the total area under the curve; thus 68% (or approximately two thirds) of the population would respond to a dose lying within 1 SD of the ED50. (B270.2.w2, B331.3.w3)
  • At a given dose the cumulative quantal log dose-response curve gives the percentage of animals responding to that dose and to all lower doses. This curve is sigmoidal and expresses individual variation in the dose required to produce a specific, predetermined effect. The steeper the slope of the curve the narrower the range of doses covering the majority of the population. (B270.2.w2)
  • NOTE: Different individuals within a population vary in their response to a given concentration of a drug. Additionally, the response of a given individual may vary relating to changes in physiology, pathology, or drug-induced changes. (B270.2.w2, B331.3.w3)

Therapeutic Index

  • For most drugs undesirable effects or side effects of a drug become more common as the dose increases and at high doses these may include severe toxicity and even lethal effects. The LD50 is the median lethal dose: the dose which is fatal to half the population. The therapeutic index is the ratio of the dose which produces an undesired effect (side effect) and the dose which produces the desired effect. This indicates the selectivity of the drug. (B270.2.w2, B331.3.w3)
    • The therapeutic index is indicated by the ratio of the LD50 to the ED50. (B331.3.w3)
  • The slope of the cumulative frequency curve is important for the separation of desirable and undesirable effects, i.e. whether the higher end of the dose required for a desired therapeutic effect will overlap with the lower end of the dose which will cause an undesirable or toxic effect: for two drugs with the same ED50 and LD50, the one with the steeper curve is less likely to show such an overlap. (B270.2.w2)
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Movement of Drug across Membranes - Basis Principles

Passage of drug across cell membranes is required for drug absorption, distribution and elimination, therefore it is essential to have an understanding of the processes by which drugs move across membranes, and the drug and membrane factors which affect this movement. (B331.1.w1)

In order for a drug to have its effects it must achieve an adequate concentration in its target tissue(s), where it has its site of action. The concentration of a drug at any moment and in any given body region is determined by movement of drug molecules and by chemical transformation of the drug. (B327.2.w2, B333.1.w1)

Drugs are transported in the body in the bloodstream and this movement is not affected by the chemical nature of the drug. However, over short distances, and between body compartments, drug molecules are moved by mechanisms such as diffusion, which are greatly affected by the size and chemical nature of the drug molecules. (B327.7.w7)

Aqueous diffusion
  • Aqueous diffusion is required for drug molecules to be delivered to, and moved away from, non-aqueous barriers.
    •  The rate of aqueous diffusion of a drug depends mainly on its molecular size. (B327.7.w7)
    • The diffusion coefficient for small molecules is inversely proportional to the square root of the molecular weight of the molecule. (B327.7.w7)
    • Many drugs are in the molecular weight range 200-1,000; their overall pharmacokinetic behaviour is affected in only a minor degree by variations in aqueous diffusion. (B327.7.w7)

Movement of drugs between compartments

Movement of drugs between compartments, which generally involves penetration of non-aqueous, hydrophobic diffusion barriers by the drug, is very important in determining where a drug will be present in the body and for how long it will be present. (B327.7.w7) 

  • Penetration of hydrophobic diffusion barriers (phospholipid membranes) is greatly affected by the chemical nature of a drug.(B327.2.w2, B328.1.w1)
  • The four main methods by which small molecules cross cell membranes are:
    • Direct (passive) diffusion through the lipid membrane;
    • Diffusion through aqueous pores traversing the lipid membrane;
    • Combination with transmembrane carrier proteins which bind a molecule on one side of the membrane, change conformation, and release the molecule on the other side of the membrane;
    • Pinocytosis.
    (B327.7.w7)
  • Of these, the two methods which are most important in terms of drug pharmacokinetics are direct diffusion and carrier-mediated transport. (B327.7.w7)

Passive diffusion

  • The most important mechanism for passage of drugs across membranes is passive diffusion of drug molecules down a concentration gradient, without cellular energy expenditure. (B270.3.w3, B333.1.w1)
  • The rate of diffusion is affected by the lipid solubility of the drug molecule and by the relative concentration of drug on either side of the membrane (concentration gradient) (B333.1.w1):
    • A drug with a higher lipid solubility will diffuse more rapidly across a lipid membrane than will a drug with low lipid solubility. (B327.7.w7, J234.7.w1)
    • Diffusion will occur from the compartment with a higher concentration to the compartment with lower concentration, and will be faster if there is a large concentration gradient across the membrane. (B327.7.w7)
    • Nonpolar lipid-soluble compounds, and polar compounds with a sufficient degree of lipid solubility, can cross lipoidal membranes. (B333.1.w1)

Molecular weight is a much less important factor in determining movement of drugs across membranes. (B327.7.w7)

pH, pKa and ion trapping:

Most drugs are weak organic acids or bases, existing as both ionized and non-ionized forms in solution at physiological ranges of pH. The proportion of the total that exists in each of the two forms depends on the pH of the drug's immediate environment and on the pKa of the drug. When pH equals pKa, 50% of the drug is in the ionized form and 50% in the unionized form. (B270.3.w3, J289.1.w2) When the pH is greater than the pKa of an acidic drug the drug will be ionized, and basic drugs will be ionized when the ambient pH is lower than the drug's pKa: weak acids are most highly ionized at alkaline pH while weak bases are most highly ionized at acid pH. (B327.7.w7, B333.1.w1, J234.7.w1)

The Henderson-Hasselbalch equation describes the non-ionized to ionized ratio (B270.3.w3, B333.1.w1): 

pH - pKa = log ((conc. ionized) / (conc. nonionic)) for an acidic drug

pH - pKa = log ((conc. nonionic) / (conc. ionized)) for a basic drug. (B270.3.w3, B333.1.w1)

As the pH falls, the percentage of an acid drug that is non-ionic increases, while that of a basic drug decreases. Because the equation is logarithmic, a pH one unit below the pKa of an acidic drug produces a situation in which 9% of the drug is ionized, 91% nonionic. Conversely a base would be 91% ionized at a pH one unit below its pKa. (B270.3.w3)

  • Small changes in pH, particularly close to the pKa, result in large changes in the proportion of the drug present in a nonionic form. (B270.3.w3)
  • The pKa of a compound is a measure of its intrinsic acidity or alkalinity; it is determined by the arrangement of the atoms in the molecule. (B333.1.w1)
  • Quaternary ammonium compounds are an exception to the general rule; they exist in biological fluids only in the cationic form. (B333.1.w1)

It is the non-ionized form of the drug that diffuses across lipid membranes, at a rate determined by its lipid solubility. Passive diffusion results in an equilibrium in which the concentration of the non-ionized form is the same on both sides of the membrane. However if the pH on the two sides of the membrane differ then the degree of ionization on the two sides will differ also. Therefore at equilibrium (when diffusion in both directions is equal), the total concentration of the drug (ionized plus non-ionic form) will be greater on the side of the membrane on which the degree of ionization is greater. In practical terms this means that a drug which is a weak organic acid will end up in greater concentration in an alkaline than an acidic compartment. (B270.3.w3, B327.7.w7, B328.1.w1, J234.7.w1, J289.1.w2, B333.1.w1)

The theoretical equilibrium concentration ratio (R x/y) of a drug on opposite sides of a biological membrane may be calculated:

for an acid drug R x/y = (1 + 10 (pHx - PKa)) / (1 + 10 (Phy - pKa)) (B270.3.w3, J289.1.w2)

for a basic drug R x/y = (1 + 10 (pKa - PHx)) / (1 + 10 (PKa - pHy)) (B270.3.w3, J289.1.w2)

The practical results of ion trapping include:

  • Acidic drugs are absorbed well from the acidic environment of the stomach and upper small intestine; basic drugs are absorbed well from the alkaline lower small intestine. (B327.7.w7, B328.1.w1, B333.1.w1)
  • Urinary alkalisation reduces excretion of weak bases and increase excretion of weak acids, while in acidic urine excretion of weak bases is increased. (B327.7.w7, B333.1.w1)
  • Weak organic bases, given parenterally, diffuse passively INTO the rumen of ruminants and the colon of horses. (B270.3.w3)
  • Basic drugs tend to concentrate in fluids that are acidic relative to plasma, including intracellular fluid (which at pH 7.0 has a slightly lower pH than plasma at pH 7.4), while acidic drugs are present in cells at a slightly lower concentration than that found in plasma. (B270.3.w3, B331.1.w1)
  • Increasing the pH of plasma (alkalisation), for example by sodium bicarbonate administration, will increase extraction of weakly acidic drugs from the CNS into plasma while acidification of plasma (decreasing the pH), for example by administration of a carbonic anhydrase inhibitor, will cause weakly acidic drugs to become concentrated in the CNS, which may increase their neurotoxicity. (B327.7.w7)
  • Depending on the drug and the tissue involved, drug trapping may be beneficial (e.g. concentration of a therapeutic drug at the site of its required action), or deleterious (for example increased excretion of a drug or exclusion from a target tissue). (J234.7.w1)

It should be noted that the theoretical concentration gradients produced by ion trapping are unlikely to be produced in vivo because lipid membranes are not totally impervious to the ionic forms and because body compartments rarely actually reach equilibrium, due to factors such as diffusion from a small to a much larger volume and because of removal of the drug (drug elimination). (B327.7.w7, B333.1.w1)

Ion trapping and milk:

  • The mammary gland epithelium behaves as a lipoidal membrane and only the lipid-soluble, non-ionized form of an organic electrolyte can pass through. Milk has a pH of about 6.5-6.8 normally, compared to the pH of plasma of 7.4. This means that weak basic drugs will reach higher concentrations in milk than in plasma while organic acids will be at lower concentration. (B270.3.w3, J234.7.w1, J289.1.w2)
  • In mastitis, the pH of milk may be increased by up to 0.7 of a pH unit, therefore higher than normal concentration ratios will be obtained for organic acid drugs. (B270.3.w3)

Carrier-mediated transport: facilitated diffusion and active transport

  • Facilitated diffusion is carrier mediated i.e. it involves a membrane component, and is faster than simple diffusion, but it is not energy dependent and does not move substances against a concentration gradient. (B270.3.w3, B327.7.w7)
  • Active transport is a carrier-mediated process which requires direct expenditure of energy. (B328.1.w1) This is responsible for rapid transfer of strongly acidic or basic drugs into urine and bile, and of transfer of most drug metabolites into urine and bile, and also for removal from the CNS of certain drugs such as penicillins: this is thought to occur at the choroid plexus by reverse transport from the CSF into plasma by the p-glycoprotein pump. (B270.3.w3, B333.1.w1)
  • The concentration gradient of sodium and potassium ions is determined by active transport, and drugs can interfere with this. (B270.3.w3
  • Because it involves a binding step carrier-mediated transport is subject to saturation: at a high concentration of ligand (molecule to be bound and transported) the carrier sites become saturated. Further increases in concentration of the ligand beyond this point do not result in increased transportation. (B327.7.w7)
  • If more than one ligand is present binding to the same carrier, competitive inhibition of transport may occur. (B327.7.w7, B333.1.w1)
  • The main sites in the body at which carrier-mediated transport is important are the renal tubules, the biliary tract, the blood-brain barrier and the gastro-intestinal tract. (B327.2.w2)

Pinocytosis

  • This, like active transport, requires energy. This mechanism may be responsible for transcapillary passage of macromolecules and for uptake of solutes by epithelial cells of the pulmonary alveoli. Size and charge of macromolecules appear to be important in determining the rate of their uptake by pinocytosis. (B333.1.w1)

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Drug Absorption

Dosage Forms and Drug Properties

"In order for a drug to act and exert its characteristic systemic effects, it must be absorbed and attain an effective concentration at its site of action." (B333.2.w2)

When a drug is given by any route other than intravenously, the solubility of the dosage form and the physicochemical properties of the drug molecule affect drug absorption. (B270.3.w3)

  • Drugs given in aqueous solution mix more readily with the aqueous phase at the site of absorption than do drugs given in oily solution, suspension or solid form, and thus are more rapidly absorbed. (B331.1.w1, B333.2.w2)
  • For drugs which are given in solid form, their rate of dissolution may be the limiting factor for absorption. (B333.2.w2)
  • Drugs given at high concentration are absorbed faster than those given at low concentration. (B331.1.w1)
  • Lipid soluble drugs cross membranes readily; they may enter organisms and penetrate tissues more easily than water soluble or polar drugs. (J234.7.w1)
  • For drugs which are to be given orally a balance is required between water solubility, which is required for the drug to dissolve in intestinal fluid and for distribution in the extracellular fluids of the body, and lipid solubility required to enhance transit of membranes from the gastro-intestinal tract (and across other body membranes). (B270.3.w3)
    • A biopharmaceutical drug classification scheme used for human preparations classifies drugs in four categories according to their oral absorption characteristics: 
      • Class I (high solubility, high permeability). Drugs in this class should show good absorption following oral administration, unless the formulation limits drug dissolution; (J215.25A.w1)
      • Class II (low solubility, high permeability). Drugs in this class (including NSAIDs) should show good absorption following oral administration, so long as the drug is formulated in a manner (e.g. by crushing tablets) such that dissolution is not a rate limiting factor in absorption. (J215.25A.w1)
      • Class III (high solubility, low permeability. Drugs in this class may dissolve well but good absorption cannot be assumed and large interspecies differences are likely in absorption. (J215.25A.w1)
      • Class IV (low solubility, low permeability). Absorption following oral administration is likely to be lowest for drugs in this group. Extreme care is required in extrapolating across species and it should be noted that reformulation of the dug will not necessarily improve absorption. (J215.25A.w1)
  • For drugs given by subcutaneous or intramuscular injection, pharmacological product and drug molecule factors affecting the rate of absorption include:
    • Drug concentration in the parenteral solution. (B270.3.w3)
    • Degree of ionization. (B270.3.w3, B333.2.w2)
    • Lipid solubility of the non-ionized form of the drug. (B270.3.w3, B333.2.w2)
    • Molecular size of substances that are not lipid soluble. (B333.2.w2)
  • Incomplete availability of substances given by the subcutaneous or intramuscular routes may be due to:
    • Low solubility of the drug at tissue pH. (B270.3.w3)
    • Any damaging effect of the preparation at the injection site. (B270.3.w3)
  • Sustained-release parenteral preparations provide prolonged duration of therapeutically effective plasma drug concentrations due to their limited rate of absorption from the site of administration. This may be due to slow dissolution and or slow absorption. (B270.3.w3)
    • The main disadvantage of sustained-release preparations is loss of flexibility of dosage. (B270.3.w3)
    • The main advantage is reduced frequency of dosage, and its associated capture and restraint, which reduces animal stress as well as being more convenient. (B270.3.w3, B333.2.w2)
    • Relatively insoluble salts of drugs may be used to provide slow absorption, or the drug may be provided in an oily, water-immiscible vehicle. (B328.1.w1)
    • For extremely slow absorption, as required with some hormonal preparations, an insoluble drug may be incorporated into a compressed pellet or polymer and implanted subcutaneously. (B270.3.w3, B333.2.w2)
    • Note for food-producing animals: Formulations must be such that their intramuscular injection will not cause significant tissue damage with residual levels persisting at the site of administration at the time when food animals go for slaughter. (B270.3.w3)
  • For percutaneous absorption of drugs:
    • Lipid solubility is the most important physicochemical property of a drug to allow percutaneous absorption, since absorption takes place by passive diffusion. (B270.3.w3)
    • Absorption is affected by drug concentration. (B270.3.w3)
    • Absorption is enhanced from an oil-in-water emulsion base such as an aqueous cream. (B270.3.w3)
    • Absorption from vegetable-based or animal-based oils/fats is greater than from mineral oils. (B333.2.w2)
    • Skin penetration of water-soluble substances is increased by surfactants, possibly by increasing the skin's water permeability. (B270.3.w3)
    • Dimethyl sulfoxide, which passes rapidly through the stratum corneum, also promotes absorption, accelerating percutaneous absorption of water, fluocinolone acetonide, salicylic acid and other substances. It is a skin irritant in humans. (B270.3.w3, B333.2.w2)
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Major Parenteral Drug Administration Routes

"In order for a drug to act and exert its characteristic systemic effects, it must be absorbed and attain an effective concentration at its site of action." (B333.2.w2)

Drug absorption, the passage of a drug from its site of administration into the bloodstream, is affected by the route of administration. (B270.3.w3)

  • If systemic effects are required, a drug may be given orally or parenterally (by injection or inhalation). (B270.3.w3)
    • Parenteral administration generally gives more rapid availability of the drug and a more predictable availability than with oral administration. (B331.1.w1)
    • Parenteral injection requires asepsis and may cause pain. (B331.1.w1)
    • Cost of parenteral drug formulations may be greater than that of oral formulations. (B331.1.w1)
  • Site of injection, regional blood flow and previous injections at the same site can all affect absorption of drugs injected other than intravenously. (J234.7.w1)
    • Increasing blood flow to the site of administration enhances the rate of absorption. (B331.1.w1, B333.2.w2)
    • A larger area of absorbing surface increases the rate of absorption. (B333.2.w2)

Intravenous injection

Advantages:

  • Generally provides a rapid effect since there is no delay while the drug is absorbed. (B327.7.w7, B328.1.w1)
  • Provides full bioavailability. (B333.2.w2)
  • Compared to other systemic routes of injection this gives a more predictable concentration of drug in plasma and produces immediate plasma concentrations which can produce a pharmacological effect. (B270.3.w3, B331.1.w1, B333.2.w2)
  • This route allows titration of a drug to effect. (B270.3.w3, B333.2.w2)
  • This may be the only route by which some irritating and hypertonic solutions can be given. (B270.3.w3, B333.2.w2)
  • This may be required for drugs of high molecular weight. (B331.1.w1)
  • Suitable route for administration of large volumes. (B331.1.w1)
  • Intravenous infusion may be used to maintain therapeutic levels of drugs with short half-lives and relatively low safety margins. (B333.2.w2)

Notes:

  • The infusion rate of a drug being given by intravenous infusion is determined by fixing the rate of flow of the infusion ad the concentration of drug in the infusion solution. (B270.3.w3)
  • The time taken to reach a steady state using continuous intravenous infusion is determined by the overall elimination half-life of the drug. A drug with a shorter half life (eliminated more rapidly) reaches steady state in a shorter time than a drug with a longer half-life. (B270.3.w3)
  • Administrating a loading dose as a bolus, followed by an infusion at a steady rate, is often used to rapidly establish the desired drug concentration. (B270.3.w3)

Disadvantages/Limitations/Precautions:

  • Except in exceptional circumstances (such as induction of anaesthesia by a bolus of thiopental), intravenous injection should be performed slowly. (B270.3.w3, B331.1.w1, B333.2.w2)
    • Ideally the injection is given over the length of time equal to a complete circulation of the blood. (B333.2.w2)
  • This route is not suitable for either oily solutions or insoluble suspensions. (B331.1.w1)
  • With irritating and hypertonic solutions it is essential that the tip of the needle is in the vein lumen, allowing injection of drug solution without causing damage to the intima or perivascular tissues. (B270.3.w3)
  • There is an increased risk of adverse effects when this route is used. (B331.1.w1)
    • Rapid intravenous injection results in transiently high concentrations of the drug in the bloodstream and therefore in other tissues, which increases the likelihood of acute toxicities, most importantly to tissues such as the CNS. (B270.3.w3, B328.1.w1)

Subcutaneous injection

Advantages:

  • Concentrations of drug in the bloodstream may be maintained for longer than following intravenous injection. (B328.1.w1)
  • This route is generally more convenient and less hazardous than intravenous inoculation. (B328.1.w1)
  • Provides prompt absorption of aqueous solutions and slow, sustained absorption of repository preparations. (B331.1.w1)
  • Is suitable for some insoluble preparations and for solid pellet implantation. (B331.1.w1)

Further notes:

  • Following subcutaneous or intramuscular injection, drug is provided to the bloodstream, and thus to body tissues, more slowly than following intravenous injection. (B328.1.w1)
  • Absorption of most drugs is rapid from subcutaneous or intramuscular sites when the drug is given as an aqueous solution, with the rate of absorption being determined mainly by the vascularity of the injection site. (B270.3.w3, B328.1.w1, B333.2.w2)
  • Peak concentration of drug in serum is usually achieved within 30 to 60 minutes. (B270.3.w3, B333.2.w2)
  • There may be differences in absorption rates between subcutaneous and intramuscular sites, and even between different intramuscular sites. (B270.3.w3, B328.1.w1)
  • The rate of absorption and uptake of a drug, and of other drugs administered simultaneously at the same site, may be affected if a drug alters local blood supply or capillary permeability. For example adrenaline (epinephrine) given at very low concentrations in local anaesthetic solutions causes local vasoconstriction at the injection site, delaying absorption of the local anaesthetic, thereby prolonging the duration of analgesia, reducing the required amount of local anaesthetic drug and reducing the risk of systemic toxicity from the local anaesthetic drug. (B270.3.w3, B333.2.w2)
  • The rate of absorption may be affected by the area of absorbing surface exposed to the drug, and therefore by bolus size. Drug uptake from insoluble oily boluses is proportional to the surface area of the bolus, therefore drug uptake may be increased by dividing the dose between sites, which increases the available surface area of the absorbing surface. (B270.3.w3, B328.1.w1)

Disadvantages:

  • Severe pain, necrosis or sloughing of tissue may occur if irritating substances are administered by this route. (B331.1.w1)

Intramuscular injection

Advantages:

  • Concentrations of drug in the bloodstream may be maintained for longer than following IV injection. (B328.1.w1)
  • This route is generally more convenient and less hazardous than intravenous inoculation. (B328.1.w1)
  • Provides prompt absorption of aqueous solutions and slow, sustained absorption of repository preparations. (B331.1.w1)
  • Is suitable for moderate volumes. (B331.1.w1)
  • Is suitable for drugs in oily vehicles and for some irritating substances. (B331.1.w1)

Notes:

  • See notes above under Subcutaneous Injection.

Disadvantages:

  • Cannot be used in individuals on anticoagulant medication. (B331.1.w1)
  • May interfere with interpretation of some diagnostic tests, such as serum creatine kinase. (B331.1.w1)
  • Not all drugs are completely available from all intramuscularly injected parenteral products. For example diazepam is not completely available. (B270.3.w3, B333.2.w2)
  • Some parenteral preparations cause pain when injected intramuscularly, including ketamine. This effect is due to the formulation of the drug. (B270.3.w3)
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Oral Administration

Oral administration may be considered the safest, most convenient and most economical route of drug administration. (B331.1.w1)

Absorption of drugs administered by the oral route requires:

  • Release from the dosage form (for drugs administered in a solid dosage form). (B270.3.w3, B333.2.w2)
  • The drug is stable in GIT fluids, i.e. not chemically or enzymatically inactivated in either the stomach or small intestine. (B270.3.w3, B333.2.w2)
  • The drug has a sufficient degree of water solubility and lipid solubility. (B270.3.w3, B333.2.w2)
  • The drug is at least partially in a non-ionized state. (B331.1.w1, B333.2.w2)
  • Diffusion and/or transport across the mucosal barrier of the gastro-intestinal tract into the portal circulation. (B270.3.w3, B333.2.w2)
    • Passive non-ionic diffusion is the main method by which most drugs are absorbed following oral administration. (B329.12.w12)
  • Passage through the liver. (B270.3.w3)
The rate-limiting step determining release of drug from a solid dosage form is dissolution. Frequently this step controls the rate of absorption of the drug. (B270.3.w3, B333.2.w2)
  • Particle size can have a marked effect on drug dissolution and therefore rate of drug uptake; this may be important when different proprietary brands of drugs with the same concentration have different particle sizes, and thus considerable differences in their rates of dissolution, and thus differences in absorption rates. (B328.1.w1)
  • Decreasing the size of the particles, for example by micronization, enhances dissolution. (B270.3.w3, B333.2.w2)
  • Dissolution can be enhanced by administration of the drug in the form of a salt. (B270.3.w3, B333.2.w2)

Further information on effects of the drug's properties and dosage forms on oral absorption are provided above in the section: Dosage Forms and Drug Properties.

Effect of species:
  • In the dog, cat and pig, absorption from the gastrointestinal tract is generally fast and relatively complete, while it is much more variable in equines and slow in ruminants. (B333.2.w2)
    • If a drug is absorbed more slowly than it is eliminated, then the rate of removal of the drug from the body is determined by absorption rather than by elimination. (B333.2.w2)
  • Predicting oral absorption in species for which there is no available specific pharmacokinetic data is difficult. (J215.25A.w1)
  • When extrapolating between species the oral absorption characteristics of a drug should be considered. Cross-species assumptions about absorption are particularly difficult for drugs with low gastro-intestinal permeability; large interspecies differences in absorption should be expected for such drugs. (J215.25A.w1) See section above, Dosage Forms and Drug Properties for more information. 

Effect of pH

pH gradients between plasma and GIT fluids play an important role in determining extent of absorption of drug products following oral administration of weak organic acids and bases. (B270.3.w3)

  • The effective pH in the microenvironment at the mucosal surface of the intestinal epithelial barrier is 5.3 (compared with pH 6.6 within the intestinal contents). Therefore very good absorption occurs of weak acids with pKa above 3 and weak bases with pKa less than 7.8. (B270.3.w3, B333.2.w2)
  • Absorption of strong acids, strong bases and quaternary ammonium compounds is poor and variable as these compounds are virtually completely ionized over the whole range of physiological pH. (B333.2.w2)
  • Polar drugs may not be well absorbed. (B331.1.w1)

Effects of gastro-intestinal motility and blood flow

  • For all orally administered drugs, including weak acids, weak bases and pH neutral drugs, the small intestine, due to its large surface area and rich blood supply, is the principle site of absorption. Drug absorption is therefore affected by rate of gastric emptying. This in turn is affected by not only the volume and composition of gastric contents but also physiologic factors such as autonomic nervous system activity and hormonal activity. (B270.3.w3, B333.2.w2)
  • Drugs which are poorly soluble, enteric-coated or in slow-release preparations are most affected by changes in gastric emptying or intestinal mobility. (B270.3.w3)
  • The rate of absorption of lipid-soluble drugs from the intestine is altered by changes in intestinal blood flow. (B270.3.w3)

First-pass through the liver

Other factors

  • Some drugs with physicochemical properties which would be expected to provide good absorption across biological membranes are affected by a reverse transport system and metabolising enzymes in the intestinal mucosa. (B270.3.w3)
  • Some drugs may be destroyed by either digestive enzymes or low pH in the stomach. (B331.1.w1)
Absorption of orally-administered pharmaceutical products in ruminants

The reticulorumen in the adult has a volume of about 100 to 225 litres in cattle, six to 10 litres in sheep and goats. Its contents are semisolid, acidic (pH 5.5-6.5) and it never totally empties. (B333.2.w2)

A variety of factors, both animal based and dependent on the properties of the drug in its dosage form, affect the absorption of orally administered drugs. "The concentration of a weak organic electrolyte in ruminal fluid is influenced by the dose administered, route of administration, lipid solubility and pKa of the drug, relative rates of uptake from and passage into the ruminal fluid (both of which take place by nonionic diffusion), rate of salivary flow (for organic acids), extent of drug binding to plasma proteins, and efficiency of elimination (biotransformation and excretion) processes." (B270.3.w3)

Drug characteristics and dosage forms

  • Non-ionised lipid-soluble forms of weak organic acids will normally be absorbed well from the rumen. (B270.3.w3)
  • Some drugs may be inactivated by indigenous microflora of the rumen, either by hydrolysis or reduction. (B270.3.w3, B333.2.w2)
  • Drugs may be administered in a number of formulations including liquids (solutions or suspensions), additives in food or water, solid tablets, boluses, capsules or specialised delivery devices. (B329.14.w14)
    • Different dosage forms result in different sites of arrival in the rumen and different distribution patterns. (B329.14.w14)
    • Drugs administered in liquids arrive in greater concentration in the reticulum and adjacent areas, therefore may pass through the reticulo-omasal orifice to a considerable extent before mixing with the main contents of the reticulorumen. This decreases ruminal degradation and provides drug for intestinal absorption sooner than would occur otherwise. (B329.15.w15)
    • Either to protect the drug from the action of the ruminal microflora or prevent effects of the drug on that microflora, dosage forms may be used which protect drugs from microbial degradation in the rumen and allow release of the drug in the abomasum or small intestine. (B329.14.w14)
    • Special oral dosage forms for ruminants, as boluses or pellets of zero buoyancy, or as devices which lodge temporarily within the rumen, may be suitable for drugs for which long-lasting drug concentrations are desired and which are resistant to or designed to act upon the microflora of the rumen. (B329.14.w14)
    • POTENTIAL LOCAL TOXICITY: For drugs administered orally to ruminants in solid form, the product should be checked for potential local irritation of the mucosa, which is more likely to occur if normal mixing contractions are reduced. (B329.15.w15)
Sources of drug entering the reticulo-rumen
  • In addition to oral dosing, drugs may enter the rumen by diffusion through the wall from the bloodstream or in saliva. (B329.15.w15, J234.7.w1)
    • Due to ion trapping concentrations of weak acids including salicylates and pentobarbital in the rumen rise above the concentration in plasma following intravenous inoculation if the pH of the rumen is higher than that of the plasma while if rumen contents are more acidic than plasma (as is normally the case) then weak bases become concentrated in the rumen. (B329.15.w15)
    • Following parenteral administration of a drug its concentration in ruminal contents reflects both salivary processes and diffusion across the ruminal epithelium. (J234.7.w1B333.2.w2)
    • The concentration of a drug in saliva is dependant on the concentration of the drug in plasma, its lipid solubility and whether it is a weak acid or base, and its pKa. (J234.7.w1) Ruminant saliva has a higher pH than plasma, thus acidic drugs with a pKa less than salivary pH will be more ionised in saliva, will accumulate in saliva and may be delivered to the rumen in substantial quantities by this route. (J234.7.w1, B333.1.w1)
    • The amount of drug in the rumen following parenteral administration depends on the respective rates of delivery to the rumen in saliva, and removal from ruminal fluid by diffusion across the rumen epithelium. Weak bases tend to accumulate in the rumen by diffusion but are diluted by addition to the rumen of large quantities of saliva in which they are present at only low concentration. The relative rates of the two processes (transfer of drug by the parotid salivary gland and diffusion across the ruminal epithelium) are important in determining drug distribution. (J234.7.w1)

Routes by which drug leave the reticulo-rumen

  • Drugs may leave the rumen by passive diffusion of drug in solution through the wall of the rumen (i.e. through lipid membranes) or in the outflow of ingesta. (B329.12.w12, B329.15.w15, J234.7.w1)
  • There may also be some absorption from the bucco-pharynx during rumination; this has not been much considered. (B329.15.w15).

Effect of dilution

  • The extent of absorption is not necessarily affected by the diluting effect of the rumen, although it may decrease the rate of absorption. (B270.3.w3)
Effects of reticulo-rumen pH
  • The pH of the reticulo-rumen is maintained at about 5.5-6.5. (B329.14.w14) i.e. less than that of plasma.
    • Weak bases are rapidly ionized on entering ruminal fluid and will be trapped in the rumen, while weak acids tend to diffuse out of the rumen. (J234.7.w1)
  • The rate of absorption from the rumen is dependent on the concentration of the unionized form of a drug. This is affected by the pH of the rumen and the pKa of the drug (weak acid or weak base). (B329.15.w15)
  • If the pH within the reticulo-rumen is not conducive to production and diffusion of the non-ionised form of the drug then absorption will depend on the rate of flow to other parts of the digestive tract where a more favourable pH is found. (B329.14.w14)
  • High-grain diets result in a lower ruminal pH, starvation results in higher pH, which may affect drug distribution in the rumen. (J234.7.w1)

Effects of feeding and diet

  • Blood flow to the mucosa of the reticulorumen is increased after feeding; this may increase absorption of drugs from the reticulorumen at this time; starvation and changes in diet may also affect drug absorption. (B329.15.w15)
  • Feeding dry foods, or starvation, both are associated with delayed passage of fluid from the rumen. (J234.7.w1)
  • Within the reticulo-rumen, drugs are subject to considerable dilution; this may decrease the efficiency of drug absorption from the rumen. (B329.14.w14, B329.15.w15) Additionally this may lead to accumulation of drug and the rumen acting as a reservoir of sequestered drug and affect the elimination rate of a drug. (J234.7.w1)
  • Binding of drug to ingesta slows absorption, as does increased dilution of drug in rumen fluid. (J234.7.w1)
  • Drug binding to ingesta and degradation by ruminal microflora both may decrease the efficiency of drug absorption. (B329.14.w14)

Effects of varying gastrointestinal activity

  • Slow mixing of ingesta may retard disintegration of solid dosage forms and thus the rate at which solubilized drug comes into contact with the surface of the ruminal mucosa where it may be absorbed. (B329.14.w14)
  • Increased motility increases contact of rumen fluid with the papillae and thus increases drug absorption from the rumen. (J234.7.w1)
  • Increased reticuloruminal motility increases rate of passage of ingesta and thus drugs into the abomasum and intestine and therefore increases absorption rate; ruminal stasis decreases absorption. (J234.7.w1)
  • In ill animals with ruminal stasis, ruminal outflow, and thus transportation of drug to the abomasum and intestine for absorption, are greatly reduced. (B329.15.w15)
    • Drug in the rumen of a sick inappetant ruminant may not be readily available for systemic absorption. (J234.7.w1)

Bypassing the reticulo-rumen

  • Orally administered drugs usually enter the reticulo-rumen, but if the reticular groove closes they may bypass this compartment and go directly to the abomasum via the omasum. (B329.14.w14, B329.15.w15)
  • Good absorption of drugs may be obtained by delivery direct to the abomasum, as occurs following closure of the reticular groove. (B329.14.w14)

Absorption from the abomasum and intestines

  • pH in the contents of the abomasum is about 2 to 3, which favours absorption of weak acids, and in the intestine the pH varies from about 2.7 at the pylorus rising to about 7.5 in the ileum. Absorption of weak bases is favoured by intestinal pH; the large surface area of the intestine favours absorption of all drugs with sufficient lipid solubility for diffusion across lipid membranes. (B329.14.w14)
NOTE:
  • Either slow absorption or incomplete absorption may prevent achievement of effective blood concentrations. If the rate of absorption is slow then, even if the extent of absorption is complete the drug may never reach effective blood concentrations. If only a small fraction of the administered dose is absorbed then, even if the rate of absorption is high, effective blood concentrations may not be achieved. (B329.14.w14)

Effects of age - absorption in neonatal ruminants:

  • In young ruminants the postnatal development of the reticulorumen can have an important influence on drug absorption. (B330.16.w16)
    • Species vary in their degree of maturity at birth and in their rate of postnatal development. (B330.16.w16)
  • Anatomically the reticulorumen is underdeveloped, with reduced volume and surface area at birth compared to the adult. (B329.12.w12)
  • Gastro-intestinal motility develops after birth. (B330.16.w16) 
    • In lambs, while the small intestine shows patterns of motor activity similar to that seen in adults, the reticulorumen begins to develop functional activity after birth with full functionality of the forestomach developed only after several weeks. (B330.16.w16)
    • In calves, reticulorumen activity is absent at birth and in the first two weeks, with slight movements noted at three weeks old and active diphasic contractions by six weeks in calves fed roughage. While mixing movements are absent, the rate of transfer of material to the omasum, abomasum and duodenum is enhanced, which affects bioavailability and absorption. (B329.12.w12)
  • The blood flow in the ruminal veins and portal vein increases in the first weeks of life, enhancing absorption from the digestive tract. (B329.12.w12)
  • The reticulorumen is relatively non-functional in the neonatal ruminant; function is approximately equal to that in adults by about eight to twelve weeks old. (B329.12.w12)
  • The pH of the reticulorumen is higher in neonates than in adults; for example in calves it is 6.0 to 8.0 at three weeks old compared to 5.5 to 6.5 in adults. (B329.12.w12)
  • The pH of the abomasum in calves is 7.5 at birth, dropping to 4.0 within a few hours then falling gradually to 2, with temporary rises when milk is ingested. As solid food is consumed the pH becomes about 3.5 to 3.6. (B329.12.w12, B330.16.w16)
  • Gastrointestinal flora
    • Bioavailability of some drugs will be higher in neonatal ruminants than in adult ruminants following oral administration, due to the absence of the microbial population of the reticulorumen. (B330.16.w16)
    • As the microbial population develops, metabolisation of drugs by the gastrointestinal flora becomes possible, as well as chemical reduction of drugs. (B329.12.w12)
  • Drug absorption may be modified by changes in the absorbing area of the intestinal mucosa and the regional blood flow after birth. (B330.16.w16)
  • Milk feeding may affect the absorption of some drugs. (B330.16.w16)

 

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Other Drug Administration Routes

If local effects are required the drug may be given by topical, intramammary, intrauterine or parenteral routes such as tissue infiltration, intra-articular, subconjunctival or epidural injections. (B270.3.w3)

Topical application to the skin and percutaneous (transdermal) absorption

Topical application to the skin is generally used when local effects are required. (B333.2.w2)

Application to the skin for percutaneous absorption, as in pour-on formulations, is a convenient route for treatment of large animals such as cattle. (B328.1.w1)

  • Percutaneous absorption requires that the drug:
    • Dissolves and is released from the vehicle in with it was applied; (B270.3.w3, B333.2.w2)
    • Penetrates the stratum corneum, the keratinised layer of the skin; (B270.3.w3, B333.2.w2)
    • Is taken up by the capillary blood supply to the area. (B270.3.w3)
  • For many drugs surprisingly rapid penetration of intact skin occurs. (B328.1.w1)
  • Species and site of application both affect the barrier properties of skin. (B333.2.w2)
  • Once a drug penetrates the stratum corneum (the keratinised layer) and reaches the stratum granulosum, it can readily reach local sites of action. (B333.2.w2)
  • This route has the advantage of by-passing intestinal and hepatic first-pass effects. (J215.25A.w1)
  • There may be considerable intra- and inter-specific variation in transdermal drug absorption; this has been noted for example with fentanyl. (J13.60.w1)

Notes:

  • It is important to remember that percutaneous absorption of drugs may be hazardous to the person administering a drug, particularly when working with very potent drugs (e.g. etorphine) or for women of childbearing age, if working with prostaglandin preparations. (B328.1.w1)
  • If action in the dermis or deep in the epidermis is required (as for fungal infections), systemic administration may be more effective than topical administration. (B333.2.w2)

Pulmonary absorption (Inhalation)

  • Absorption of gaseous and volatile liquid anaesthetic agents, which are highly lipid soluble, occurs rapidly across the alveolar epithelium. Inhalation anaesthetics vary widely in their blood solubility and their blood/brain partitioning. These properties determine the rate of induction, ease of changing the depth of anaesthesia and speed of recovery. (B270.3.w3)

Intramammary administration 

  • Intramammary administration of drugs is generally utilised when a local effect is required. (B333.2.w2)
  • Drugs are transferred from plasma to milk, and from milk to plasma, by passive diffusion. Therefore drugs given by the intramammary route may pass into the circulation. (B328.1.w1)
  • In acute mastitis, systemic administration of drugs gives a more reliable drug concentration throughout the udder than does intramammary infusion, particularly when the udder is inflamed or fibrosed. (B328.1.w1)
  • The formulation of an intramammary preparation given (i.e. the nature of the vehicle in which the drug is given) affects the persistence of the drug in the udder. (B329.17.w17)

Intrathecal administration

  • This route is suitable when local rapid effects are required on the meninges or cerebrospinal axis. (B331.1.w1)
  • This may be used for e.g. administration of opioid analgesics. (B327.7.w7)
  • This route may be used in acute CNS infections. (B331.1.w1)

Sublingual administration

  • This may be useful when a rapid response to a drug is required, particularly if the drug is unstable at gastric pH or is rapidly metabolised by the liver so that first-pass effect would greatly reduce bioavailability. (B327.7.w7)

Application to epithelial surfaces (rectal, vaginal, nasal mucosa, cornea)

  • Rectal administration is used both to produce local effects and in some cases for systemic absorption. (B327.7.w7)
    • Rectal absorption is often unreliable; absorption is often both irregular and incomplete. (B327.7.w7, B331.1.w1, J215.25A.w1)
    • May cause irritation of the rectal mucous membrane. (B331.1.w1)
    • A presumed advantage of rectal administration, compared to oral administration, is that hepatic first-pass effects should be avoided. (J215.25A.w1)
      • About half of the absorbed drug bypasses the liver and therefore does not undergo first-pass removal. (B331.1.w1)
      • There may be considerable variation between species in venous drainage routes of the rectum. (J215.25A.w1)
    • A major disadvantage for the use of this route in large animals is the volume of drug preparation required, which is likely to be considerable. (J215.25A.w1)
  • Ocular administration can allow local action without undesirable systemic side effects. (B327.7.w7)
    • Some absorption into the systemic circulation does occur following ocular administration and may result in side-effects. (B327.7.w7, B331.1.w1)
  • Nasal administration, as with sublingual administration, allows absorption without passage of a drug through the gastro-intestinal tract. It is thought that drugs are absorbed through the mucosa overlying lymphoid tissue. (B327.7.w7)
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Bioavailability and the Mathematics of Drug Absorption

Quantification of drug absorption involves both a rate component (how fast the drug is absorbed) and an extent component (what proportion of the administered drug is absorbed). Frequently the plasma concentration observed over time following administration of one or more doses is described.

The area under the curve (AUC) created by a plot of plasma concentration (on the Y-axis) versus time (on the X-axis) curve is proportional to the systemic exposure to a drug. (B270.3.w3)

The AUMC is the area under the first statistical moment curve: a curve produced by plotting (plasma drug concentration multiplied by the time of the sample) on the Y-axis against time on the X-axis. (B270.3.w3)

The rate of absorption may be estimated by the time of the peak in the plasma concentration versus time curve (B270.3.w3, B333.2.w2). The half-life of absorption is the time taken for half of the drug waiting to be absorbed to reach the systemic circulation (B270.3.w3)

Bioavailability

The extent of absorption or bioavailability is the extent to which a drug administered as a particular dosage form enters the systemic circulation. (B270.3.w3)

  • It must be remembered that the rate of absorption is important as well as the total absorption; slow absorption may result in the drug not reaching effective (therapeutic) levels. (B333.2.w2)

Bioavailability may be affected by:

  • Poor dissolution of drug product in GIT fluids (for drugs given in solid dosage form); (B270.3.w3)
  • Instability of drug or inactivation of drug substance in GIT luminal contents; (B270.3.w3)
  • Poor passage of drug through the mucosal barrier; (B270.3.w3)
  • Metabolism in the intestinal mucosa or liver prior to entry of drug into the systemic circulation (first pass effect). (B270.3.w3)

The bioavailability of a drug can be calculated by comparing the area under the blood concentration versus time curve for the orally administered drug with that of the same drug administered intravenously. (B329.14.w14) The systemic availability F = AUC oral / AUC iv .(B270.3.w3)

  • The relative bioavailability of two orally administered formulations of a given drug can be calculated by comparing their graphs of area under the blood concentration versus time curve. (B329.14.w14)
  • If a drug formulation or route of administration has a lower bioavailability, less drug will reach the required site of action unless the dosage is adjusted. (J234.7.w1)
  • Two drug products are considered to be bioequivalent when the rates and extents of absorption of the active ingredient in the two products are statistically equivalent to one another, according to predetermined criteria under controlled test conditions. (B270.3.w3)

It should be noted that for some drugs, particularly if high doses are given, absorption, distribution and elimination do not follow first-order kinetics. This may be related to factors such as protein binding with saturation at high drug concentrations, or capacity-limited biotransformation (metabolism) mechanisms. (B330.15.w15)

Species variations in bioavailability:

  • There are considerable variations in bioavailability of drugs from oral dosage forms, particularly when monogastric animals are compared with ruminants. Some drugs are not available for absorption in ruminants due to inactivation by rumen microflora (e.g. chloramphenicol). (B270.3.w3)
  • For aspirin a much higher dose (100 mg/kg rather than 10 mg/kg for dog and cats) is required in cattle; this may be attributed to the diluting effect of ruminal fluid. Dosage interval (12 hours) for this drug is based on the rate of absorption of salicylate (absorption half life 2.9 hours) rather than on its elimination half life (t1/2 β = 0.54 hour). (B270.3.w3)
  • If the plasma concentration-time curves in two species following oral administration are to be compared, it is important first to compare the plasma concentrations in the two species following intravenous inoculation of the drug, since the shape of the plasma concentration-time curve following oral administration is dependent not only on absorption characteristics but also on drug distribution and elimination. (B330.15.w15)

    • The plasma concentration following oral administration reflects not only initial absorption from the gastro-intestinal tract but also subsequent first-pass effect through the liver. (B330.15.w15)
    • The time at which peak plasma concentration of a drug is achieved is greatly influenced by the speed of elimination of the drug. (B330.15.w15)
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Distribution

Body Compartments and the Mathematics of Drug Distribution

Drugs reach the tissue of each organ of the body in an amount determined by blood flow and blood concentration to the organ. The concentration of drug reached in the tissues depends on the ability of the drug to penetrate capillary epithelium and diffuse across cell membranes. (B270.3.w3)

  • The pattern of distribution describes the relative amount or concentration of drug entering each organ or tissue. Inter-species variability in drug distribution is largely accounted for by variations in the contribution of the GIT and its contents, and skeletal muscle, to the percentage of body weight. (B270.3.w3)
  • The kinetics of drug distribution depend on dose, route of administration, lipid solubility, extent of plasma protein binding and binding to extravascular tissue constituents, and the rate of blood flow through organs and tissues. (B270.3.w3)

In order to simplify calculations, the body is considered to consist of several interconnected compartments with different properties. (J234.7.w1)

  • Each pharmacokinetic compartment is a tissue or group of tissues with similar blood flows and drug affinity (not real anatomical or physiological regions). (J234.7.w1)
    • Initially, drug distributes rapidly into the central compartment consisting of the blood plus highly perfused tissues such as the heart, liver and spleen. (J234.7.w1, B331.1.w1)
    • The drug then distributes into peripheral compartments (tissues such as muscle, most of the viscera, skin and fat) more slowly and at variable rates. (J234.7.w1, B331.1.w1)
  • Following intravenous administration of a drug, the initial rapid drop in blood drug concentration corresponds to the first distribution phase in which the drug equilibrates within the central compartment and also between the central compartment and peripheral compartments. After this, changes in concentration are a result of continuing equilibration but also elimination of drug from the body. (J234.7.w1)
  • The apparent volume of distribution of a drug is the volume of fluid in which it would be necessary to dilute a given amount of the drug to give a concentration equal to the concentration of that drug measured in the blood following intravenous administration of that amount of drug. (J234.7.w1)
    • This value is useful for relating blood drug concentration to the total amount of drug in the body. (J234.7.w1)
    • This value does not have any meaning in terms of an actual anatomical space. (J234.7.w1)
    • The value provides an indication of the drug's distribution throughout body fluids and its uptake by tissues. (J234.7.w1)
    • A drug with an apparent volume of distribution of less than 1 L/kg may be restricted in its movement out of the vasculature and extracellular fluid while one with an apparent volume of distribution greater than 1 L/kg is generally bound to or concentrated within one or more tissues. Drugs which are highly bound to plasma proteins tend to remain in the vascular system and have a small apparent volume of distribution, although the fraction of the drug that is unbound may have good penetration into tissues. (J234.7.w1)
    • The apparent volume of distribution of a drug may be affected by: (J234.7.w1)
      • Physicochemical properties of the drug (e.g. pKa, ionization, lipid solubility, polarity, molecular weight);
      • pH of fluid or tissue;
      • Tissue composition;
      • Permeability of membrane barriers;
      • Cardiac output, blood flow and capillarization of tissues;
      • Plasma protein binding;
      • Hydration, ration of lean to fat body mass and changes in total body water or extracellular fluid volume;
      • Age and sex of the individual animal;
      • Disease processes (e.g. renal disease, liver disease, diabetes, endotoxaemia, electrolyte disorders);
      • Drug interactions.
    • (J234.7.w1)

Mathematics of Distribution

Distribution rate and half life:

  • The rate of distribution depends on the ability of the drug to distribute from the bloodstream into extracellular fluids and tissues. (B270.3.w3)
  • The half-life of distribution is the time taken for 50% of the drug present in plasma to distribute outside the bloodstream. (B270.3.w3)

Volume of distribution:

  • The volume of distribution is the volume of fluid that would be required to contain the amount of drug in the body if it were uniformly distributed at a concentration equal to that in the plasma. This value does not distinguish between a drug that is widely distributed and one with high affinity binding with restricted distribution. The volume of distribution is more properly termed the apparent volume of distribution as it does not correlate to any actual body volume. (B270.3.w3, B327.7.w7)
  • The apparent volume of distribution Vd (mL/kg) can be calculated as Vdarea = (D x F) / AUC x β (B270.3.w3)
    • (AUC = area under conc./time curve from t=0 to t= infinity; F = the bioavailability for a drug administered by a given route; D = the dose administered; β = the slope of the terminal disappearance portion of the plasma concentration-time profile when plotted as a natural logarithm of concentration on the Y axis versus time on the X axis).(B270.3.w3)
  • Vd is also equal to the total amount of drug in the body divided by the concentration of drug in the plasma. (B327.7.w7, B331.1.w1)
  • As an approximation, Vd = D/Cmax . (J234.7.w1)
  • The volume of distribution at steady-state (Vdss) is independent of elimination processes and is most useful for predicting plasma concentrations of drug following multiple dosing to a pseudo-equilibrium. (B270.3.w3, J234.7.w1)
  • The volume of distribution is required in order to calculate the dose (D) of a drug that must be given in order to provide a required concentration of drug in plasma:

D (mg/kg) = Cther (mg/L) x ((Vdarea / F) (L/kg)).  (B270.3.w3) (The inclusion of the bioavailability term in this equation allows for drugs administered by routes other than the intravenous route).

  • The initial concentration of the drug in plasma, shortly after it has been injected intravenously, can be calculated: Cp0 (g/ml) = D (mg/kg) / Vdarea (L/kg). (J215.11.w1)

N.B. It should be noted that drug distribution within the body is in a dynamic state. Equilibration of drug between tissues and elimination by excretion and/or metabolism occur simultaneously, not sequentially. (J234.7.w1)

An alternative method of considering body compartments is to divide into plasma (5% of body weight), interstitial fluid (16%), intracellular fluid (35%), transcellular fluid (CSF, intraocular, peritoneal, pleural and synovial fluids) (2%) and fat (20%). Extracellular fluid includes plasma, interstitial fluid and lymph (about 1.2%). Within each aqueous compartment, drug may be found bound or free and, for weak acids or bases, ionized or unionized. (B327.7.w7)

  • A drug may remain confined to plasma due to size (too large to easily cross the capillary wall, for example heparin) or more commonly due to strong binding to plasma proteins. (B327.7.w7)
  • Relatively lipid soluble drugs that readily cross cell membranes may have an apparent volume of distribution of 0.55 L/kg, equivalent to total body water. (B327.7.w7)
  • Drugs which bind outside the plasma, or distribute into fat will have a larger Vd. (B327.7.w7)
  • Drugs which are highly polar and cannot easily enter cells may have a Vd equivalent to the total extracellular volume, about 0.2 L/kg. (B327.7.w7)
  • Higher than expected accumulation in tissues may occur due to pH gradients (ion trapping), binding to intracellular constituents, or partitioning into fat. (B331.1.w1)
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Plasma Protein Binding and Tissue Protein Binding

  • On entering the bloodstream some molecules of a drug may bind reversibly to plasma proteins. (B333.1.w1)
  • Plasma protein binding of a drug restricts its distribution, which limits its receptor availability. (B270.3.w3, B331.1.w1)
  • Plasma protein binding can limit drug elimination from the body. (B270.3.w3, B331.1.w1)
  • Binding to plasma proteins or other macromolecules results in a higher total concentration on the side of a lipoidal membrane where the greater binding occurs. (B333.1.w1)
  • Bound drug is pharmacologically inactive and acts as a reservoir of drug from which the concentration of free drug in body water is maintained. (B330.18.w18)
  • Drug bound to plasma proteins or tissues is not available for metabolism in the liver or excretion in glomerular filtrate in the kidneys. (B328.1.w1, B327.7.w7)
    • Binding limits glomerular filtration. (B331.1.w1)
    • Binding does not usually limit biotransformation or active renal tubular secretion, since these processes will immediately decrease the concentration of free drug, thus further drug will become dissociated from the drug-protein complex. (B331.1.w1)
  • Factors affecting equilibrium between free drug and bound drug include protein (mainly albumin) concentration, drug affinity for binding sites, presence of disease states altering certain free fatty acids in plasma and presence of other drugs/metabolites in the plasma. (B270.3.w3)
  • There may be wide variation in the percentage plasma binding of different drugs within a chemical class. (B270.3.w3)
  • Qualitatively the relationship between drug and plasma proteins is described by the binding capacity (moles per gram of protein) and the dissociation constant of the drug-protein complex (moles/L). (B270.3.w3)
  • Only the lipid-soluble nonionic drug, present unbound in the plasma, can penetrate cell membranes, diffuse into transcellular fluids such as CSF and enter milk. The transcellular drug concentration approximates at equilibrium to the free drug concentration in the plasma. (B270.3.w3)
  • Plasma albumin mainly binds acidic drugs; approximately two molecules may be bound per molecule of albumin. (B327.7.w7)
  • β-globulin and α1-acid glycoprotein may bind basic drugs. (B327.7.w7)
  • The fraction of drug that is bound depends on the concentration of the drug, its affinity for binding sites and the number of binding sites available. (B331.1.w1)
    • When the drug is present in low concentration (lower than the plasma protein-binding dissociation constant) the fraction of drug bound is a function of the concentration of binding sites and the dissociation constant. (B331.1.w1)
    • When the drug is present in high concentration (higher than the plasma protein-binding dissociation constant) the fraction of drug bound is a function of the drug concentration and the number of binding sites. (B331.1.w1)
  • Steady-state unbound concentrations are not affected by the extent of protein binding. (B331.1.w1)
  • Occasionally clinically important drug interactions may result from competition between drugs for protein binding. (B327.7.w7)
  • Reactive drugs such as alkylating agents may occasionally become covalently bound to plasma proteins. (B331.1.w1)
  • For drugs in which therapeutic levels approach protein binding saturation concentrations, including salicylates and phenylbutazone, the percentage binding decreases with increasing drug concentration, therefore there is a disproportionate increase in free drug concentration as total drug concentration increases. (B330.18.w18, B327.7.w7)

Both plasma protein binding and tissue binding affect drug distribution. (B330.15.w15)

  • Tissue binding of drugs, which is usually reversible, is usually to proteins, phospholipids or nucleoproteins. (B331.1.w1)
    • This may represent a sizeable reservoir of drug. (B331.1.w1)

Effects of species, age, illness and physiological state.

  • Species differences in binding may be related to differences in the composition and conformation of plasma albumin. (B270.3.w3)
  • In general the extent of binding is of the same order of magnitude for different species. (B328.1.w1)
  • For most drugs, although there are differences in plasma protein binding between species, they can be classified regarding whether they show a low, moderate or high degree of binding. However for some drugs variation in binding between species is much more pronounced. (B330.18.w18)
  • There are more pronounced differences in binding for those drugs (such as many basic drugs) which are mainly bound to α1-acid glycoprotein (α1-AGP), an acute phase protein, rather than albumin. Differences are mainly due to variations in affinity and in capacity. (B330.18.w18)
  • There may be considerable inter-individual variation in binding within a species, particularly for drugs bound to α1-AGP rather than to albumin. (B330.18.w18)
  • Plasma protein binding is affected by age, sex, pregnancy and disease states (such as renal failure, liver disease and inflammatory diseases) of an individual. (B330.18.w18)
  • The presence of inflammation increases binding of drugs bound to α1-AGP. (B327.7.w7, B330.18.w18)
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Special Compartments

Blood-brain barrier
  • The blood-brain barrier consists of a continuous layer of epithelial cells joined to one another by tight junctions and makes the brain inaccessible to many drugs. (B327.7.w7, B333.1.w1)
  • During inflammation the integrity of the blood-brain barrier may be impaired, allowing drugs which would not normally be able to do so to pass into the brain. (B327.7.w7)
  • The blood-brain barrier is "leaky" in specific areas such as the chemoreceptor trigger zone. (B327.7.w7)
  • Highly lipid soluble drugs enter the CNS readily, limited only by cerebral blood flow. (B331.1.w1)
  • For polar drugs, the rate of diffusion is proportional to the lipid solubility of the non-ionized form of the drug. (B331.1.w1)

Trans-placental distribution

  • Drugs cross the placental barrier mainly by simple diffusion. (B331.1.w1)
    • Lipid soluble non-ionized drugs cross the placental barrier most readily. (B331.1.w1)
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Effects of Age on Drug Distribution

In neonates, compared with older animals (B330.16.w16):

  • Total body water is higher; extracellular water volume decreases after birth and intracellular water volume tends to increase;
  • Total adipose tissue is lower;
  • Skeletal mass is lower;
  • Cardiac output is lower;
  • Blood-brain barrier permeability is higher;
    • For some drugs penetration into the CNS may be higher; effectiveness of some drugs such as penicillins may be enhanced, while for other drugs elevated concentrations, for examples of anaesthetics and anticonvulsants, may lead to toxic effects on the CNS. (B330.16.w16)
  • Plasma protein (particularly albumin) concentration is lower;
    • Neonates of various species, including goats, sheep and cows as well as dogs, pigs and humans, show low serum binding of drugs such as salicylates and sulphonamides, which are normally highly bound to plasma proteins, and a larger volume of distribution.

(B330.16.w16)

These may all affect drug distribution. (B330.16.w16)

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Drug Elimination

Introduction to Drug Elimination 

Drug can be eliminated by two mechanisms, metabolism and excretion. Most drugs are eliminated by a combination of renal excretion and hepatic metabolism, with one or other mechanism usually predominating for any given drug. Metabolism in the liver appears to require lipid solubility. The kidneys eliminate polar drugs and many metabolites. (B270.3.w3, B330.15.w15, B333.1.w1)

In order for a drug to be eliminated it must travel in the blood to the organs of elimination. Therefore drugs which have a widespread extravascular distribution have a reduced rate of elimination. (B270.3.w3) 

Clearance of a drug from the plasma depends on the intrinsic capacity of the clearing organ (generally the liver (biotransformation) or the kidney (excretion)), flow of blood/plasma to the organ, and the degree of binding of the drug to plasma proteins. (B330.15.w15)

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Drug Metabolism (Biotransformation)

The liver is the main site of drug metabolism within the body. Here many drugs, particularly lipid-soluble weak organic acids and bases which are not readily excreted by glomerular filtration or tubular secretion, are metabolised by hepatic enzymes, often associated with cytochrome P-450, into compounds which are polar, less lipid-soluble and more readily excreted. (J234.7.w1, B270.3.w3, B328.2.w2, B331.1.w1, B333.1.w1)

  • Drug metabolism also occurs to varying degrees in tissues such as the kidney and lung, in blood plasma, and in the lumen of the gut. (B270.3.w3, B328.2.w2, B331.1.w1)
  • Drugs appear more likely to be metabolised in organs other than the liver if they are similar to endogenous compounds which normally are metabolised in those particular organs. (B328.2.w2)

The purpose of drug metabolism (biotransformation) is generally to make a compound more readily excreted. Products of drug metabolism are generally less lipid soluble and more polar, thus more likely to be partitioned into the bloodstream and presented to the kidneys for excretion and, being more polar, also more suitable for carrier-mediated excretion processes. (B270.3.w3, B328.2.w2) 

  • Normally the metabolites are inactive or less active than the parent compound, although there are exceptions. (B328.2.w2)
    • Some drugs are administered as a pro-drug which is metabolised in the body to a more active compound. (B328.2.w2)
    • Some drugs are metabolised to a more toxic compound. (B331.1.w1)

The rate of elimination by metabolism may be limited either by rate of presentation of the drug to the organs of metabolism or by the capacity of the enzymatic system involved in metabolism. (B270.3.w3)

For most drugs hepatic clearance is restricted to the proportion of the drug which is free in the plasma and changes in blood flow to the liver have only a minor influence on clearance. However enzyme induction may have a considerable influence on clearance.

  • For some drugs, including lidocaine and propanolol, hepatic clearance is dependant mainly on blood flow to the liver, is not restricted to the free fraction of drug in the plasma and is less influenced by changes in enzyme activity. (B330.15.w15)

The reactions involved in drug metabolism or biotransformation can be grouped into Phase 1 and Phase 2 biotransformation reactions. (B270.3.w3, B328.2.w2, J234.7.w1)

Phase I reactions: These are oxidative, reductive and hydrolytic, and result in the unmasking or introduction into the molecule of polar groups such as -OH, -SH, -COOH or -NH2. (B270.3.w3, B328.2.w2, J234.7.w1)

  • Phase I reactions generally result in loss of pharmacological activity of a drug. (B331.1.w1)
  • Phase I reactions are responsible also for conversion of inactive pro drug compounds to active compounds. (B328.2.w2, B331.1.w1)
  • Products of Phase I reactions may be excreted in urine or subject to Phase II reactions. (B331.1.w1)

Phase II reactions: These involve conjugation with endogenous substances such as glucuronic acid, acetate, sulphate, glutathione or various amino acids, resulting in a substance which is highly polar, water soluble and in most cases pharmacologically inert. (B270.3.w3, B328.2.w2, J234.7.w1, B331.1.w1)

  • Some Phase II reactions result in production of an active compound, such as the glucuronide conjugate of morphine (a more potent analgesic than its parent compound). (B331.1.w1)
  • Conjugates of high molecular weight excreted in bile may be enzymatically cleaved by intestinal microflora and the released parent drug reabsorbed into the systemic circulation (enterohepatic recirculation) which may cause a delay in drug elimination and prolonged drug effect. (B331.1.w1)

The major catalyst of drug biotransformation reactions is the cytochrome P450 monooxygenase enzyme family. (B331.1.w1)

Some metabolic transformations are mediated by GIT microflora. this may occur not only following oral administration but also after passive diffusion of circulating drug into the GIT lumen. (B270.3.w3)

There are clear changes in drug metabolism when individuals of ruminant species start ruminating (i.e. become ruminants): there are increases of 50% in cytochrome P-450 and NADPH-dependent reductases, a three-times increase in analine hydroxylase and also increases in ethoxycoumarin O-deethylase, UDP glucuronic acid transferase and glutathione S-transferase. (B270.3.w3)

  • Several drugs stimulate (induce) the hepatic microsomal enzyme system, increasing the concentration of enzyme proteins (a process known as enzyme induction). This can considerably increase the metabolism of other drugs. (B270.3.w3)
    • This involves increased synthesis of cytochrome P450 protein. (B331.1.w1)
    • Some drugs induce both their own metabolism and that of other compounds. (B331.1.w1)
    • Inducers generally affect a specific cytochrome P450 family. (B331.1.w1)
    • Many cytochrome P450 inducers also induce various enzymes involved in phase II biotransformation reactions. (B331.1.w1)
  • Inhibition of drug metabolism may occur due to competition between two drugs for the active site of the same enzyme involved in biotransformation. (B331.1.w1)
    • The rate of metabolism of whichever drug has a lower binding affinity for the enzyme will be reduced. (B331.1.w1)
  • Depletion of necessary cofactors may cause inhibition. (B331.1.w1)
  • Inhibited metabolism of a drug can delay elimination and may also increase the importance of metabolites formed by other, normally minor, metabolic pathways. (B270.3.w3)
    • This may be important if the metabolite of the normally-minor pathway has toxic potential. (B270.3.w3)

Decreased binding of extensively (>80%) bound drugs can increase their availability for metabolism. (B270.3.w3)

Factors which may affect drug metabolism include (B328.2.w2):

  • Species, strain and breed (strain and breed differences shown most clearly for laboratory animals);
  • Age (drug elimination may be reduced in both neonates and the elderly);
  • Sex (shown clearly in rats);
  • Chronic administration;
  • Presence of other foreign compounds;
  • Drug administration route;
  • Dose;
  • Diet (a diet low in protein (quality or quantity) depresses drug biotransformation which a protein-rich diet may increase drug biotransformation);
  • Stress;
  • Presence of disease;
  • Temperature;
  • Season and time of day;
  • Excretion route;
  • Gut flora;
  • Altitude.

(B328.2.w2)

Induction of drug metabolism:

Following exposure of an individual to various compounds known as inducers, including administered drugs and compounds in the environment, an increase may occur in the activity of hepatic enzymes which metabolise drugs. The increased activity is due to an increased concentration of the enzymes with an associated increase in smooth endoplasmic reticulum and often also liver weight. (B328.2.w2)

  • Such inducers may cause increased metabolism not only of that compound but also of other exogenous and endogenous compounds, which may not be related to the inducer either chemically or pharmacologically. (B328.2.w2)
  • Broad spectrum inducers such as phenobarbitone stimulate an increase in biotransformation of a large number of compounds which are metabolised by oxidation, reduction or glucuronide conjugation. (B328.2.w2)
  • Narrow spectrum inducers such as carcinogenic polycyclic hydrocarbons stimulate only a few metabolic pathways. (B328.2.w2)

Factors affecting the magnitude of induction include:

  • Age of the individual: a lower dose of phenobarbitone is required to produce induction in neonates than in adults; (B328.2.w2)
  • Dose: many compounds are only effective inducers at near toxic doses; (B328.2.w2)
  • Duration of exposure: several days of exposure may be required for effective induction. (B328.2.w2)

Inhibition of drug metabolism:

Inhibition of biotransforming enzymes may lead to delayed drug elimination and therefore unexpectedly long duration of action following a single administration of a drug, or possible cumulative effects with repeated dosage. (B328.2.w2)

  • Some drugs inhibit the drug metabolising enzymes. (B328.2.w2)
  • Inhibition of non-microsomal enzymes may occur in the liver or elsewhere in the body, for example inhibition of butyrylcholinesterase and acetylcholinesterase in blood and tissues by irreversible binding to organophosphorus compounds decreases the ability of the animal to metabolise drugs normally biotransformed by blood butyrylcholinesterase. (B328.2.w2)

Competitive inhibition:

  • If two drugs which are biotransformed by the same metabolic pathway are administered concurrently, and there is also saturation of the metabolic pathway, there may be resultant inhibition of metabolism. (B328.2.w2)

Metabolism of drugs in the gastro-intestinal tract:

  • Microorganisms in the GIT may metabolise orally administered compounds and also drugs which enter the GIT by passive diffusion. The metabolic capacity of microorganisms in the GIT may be very large. (B328.2.w2)

Species-related differences in drug metabolism:

There are both quantitative and qualitative differences in drug metabolism between species. (B328.2.w2)

  • Variations in biotransformation (drug metabolism) frequently is the main determinant of variability in drug pharmacokinetics between species. (B330.15.w15)
  • There are considerable variations between species in their abilities to metabolise exogenous compounds such as drugs, generally depending on variations in hepatic enzyme systems. This includes differences in rate of drug biotransformation and metabolic pathways involved in biotransformation. Even within a taxonomic group considerable differences may be found. Caution must be applied when extrapolating from one species to another, even if the species are relatively closely related. (B328.2.w2, B330.15.w15, J289.10.w1, J234.7.w1)
    • There are variations between species in the concentrations of microsomal drug metabolising enzyme systems (cytochrome P-450, benzphetamine N-demethylase, aniline hydroxylase). (J289.10.w1)
    • The concentration of cytochrome P-450 and activities of benzphetamine N-demethylase and aniline hydroxylase are not directly proportional in all species; cattle have high levels of P-450 but low activity of benzphetamine N-demethylase. (J289.10.w1)
  • There are also species-related differences in metabolism of drugs by microorganisms in the gastro-intestinal tract, following oral administration or passive diffusion into the gastro-intestinal tract. (B328.2.w2)
In ruminants:
  • Ruminants possess only negligible amounts of plasma butyrylcholinesterase, which is present in larger quantities in dogs and horses. This affects dose requirements for succinylcholine in different species. (B328.2.w2)
  • Cattle: have lower activity levels than do rats of the hepatic enzymes N-demethylase, hydroxylase, sulfotransferase, acetyl transferase, glutathione transferase and UDP-glucuronyl transferase. (J234.7.w1)
  • Sheep: the activity levels of hepatic hydrolase, N-demethylase, O-deethylase and sulfotransferase are lower than in cattle. (J234.7.w1)

NOTE: Correct therapy, particularly therapy involving repeated doses, requires knowledge of the rate of metabolism of the drug in a particular species. (B328.2.w2)

  • Caution is vital when it is necessary to rely on occasional observations. (B330.15.w15)
  • For non-domesticated species, pharmacokinetic information is generally not available and extrapolation from related domestic species must be applied, but caution is advised. (J213.4.w1, V.w5)

Age-related differences in drug metabolism:

Neonates
  • Neonates may have reduced rates of drug metabolism (biotransformation) and may also have reduced rates of renal excretion, particularly active excretion. (B328.2.w2, B330.16.w16)
  • Neonatal ruminants require approximately one to three weeks to develop an adult level of biotransformation. (B330.16.w16)
    • The time taken varies with the metabolic pathway and drug studied. Mammals are generally deficient in the cytochrome P450-dependent mixed-function oxidase system and the glucuronide conjugating system at birth, while the acetylation system and sulphate and glycine conjugation may be well developed in neonates. (B330.16.w16)
  • The interval between doses may have to be extended in neonates to prevent toxicity. (B328.2.w2)
  • Drugs which require biotransformation prior to excretion in urine or bile may have a slower clearance and prolonged elimination half-life in calves. (J234.7.w1)
    • Phenylbutazone has a prolonged half-life in young calves, which may be due to decreased hepatic hydroxylation of the drug. (J234.7.w1)
  • There are age-related differences in the volume of distribution of many agents in cattle. (J234.7.w1)

Elderly individuals

  • In the elderly there are pharmacokinetic changes related to decrease in lean body mass, serum albumin and total body water and increased percentage body fat; these changes affect drug distribution. Clearance of many drugs is reduced in elderly individuals: renal function gradually declines and there is a variable reduction in the function of some drug metabolising enzymes. (B331.3.w3)
  • The elimination half-life is often increased due to a larger apparent volume of distribution of lipid soluble drugs and/or the effects of reduced renal elimination and/or drug biotransformation.  (B331.3.w3)
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Drug Excretion

Excretion of most drugs and their metabolites occurs mainly in urine. Some drugs are excreted mainly in bile. Salivary glands, sweat glands, mammary glands and lungs are the other non-renal sites of excretion. (B270.3.w3, B328.2.w2)

Excretion of a drug is usually a first-order process: the rate of drug removed is proportional to the amount of drug present (B270.3.w3, J234.7.w1). If the plasma concentration of the drug exceeds the capacity of a carrier-mediated transport mechanism then zero-order kinetics apply until the drug concentration decreases to the level at which the system is no longer saturated; the process then proceeds as first-order. (B270.3.w3, J234.7.w1)

  • Aspirin and phenylbutazone are both removed by zero-order reactions: a fixed amount of the drug is removed from the body per unit time, regardless of the concentration of the drug present in the body. (J234.7.w1)

Renal excretion 

Renal excretion is the principle process of elimination for drugs which are predominantly ionized at physiological pH and for compounds which have limited lipid solubility. Mechanisms which may be involved within the kidneys include (1) glomerular filtration of unbound molecules in plasma; (2) carrier-mediated excretion by the proximal tubular cells of certain polar organic compounds; and (3) in the distal portion of the nephron, pH-dependent passive re-absorption, by nonionic diffusion, of lipid-soluble substances (weak organic electrolytes). (B270.3.w3, B328.2.w2)

Glomerular filtration:

  • The amount of a drug that enters the glomerular filtrate depends on the concentration of the drug free in plasma, and the glomerular filtration rate. (B270.3.w3)
  • Extensive protein binding (>80%) hinders passage of the drug through the glomerular capillary membrane. (B270.3.w3)
  • The glomerular filtration rate is lowered by any substance which lowers arterial blood pressure or constricts renal arterioles. (B270.3.w3)
  • Compounds of very high molecular weight are not subject to glomerular filtration as they are too large to pass through the pores in the glomerulus. (B328.2.w2)
  • Following filtration, the extent to which a drug is excreted depends on the degree of reabsorption in the tubules. (B328.2.w2)

Active secretion:

  • Carrier-mediated active secretion requires energy expenditure for combination of a drug with a carrier which then moves across the cell and releases the drug in the tubule lumen. (B328.2.w2)
  • This is not prevented by plasma binding. (B328.2.w2)
  • This route has a maximal capacity. (B328.2.w2)
  • Active transport can be inhibited by some agents; this can be utilised to prolong the half life of certain drugs. (B328.2.w2)
  • Drugs excreted by active transport include salicylates as well as penicillin, frusemide, trimethoprim and a number of conjugates. (B328.2.w2)

Tubular re-absorption:

  • This is a simple diffusion process which occurs due to the concentration gradient between fluid in the nephron and blood plasma as water is reabsorbed. (B328.2.w2)
  • Re-absorption is high for drugs which are highly lipid-soluble; compounds with low lipid solubility are more likely to remain in the tubular fluid. (B328.2.w2)
  • Drugs which are highly ionized at the pH of tubular fluid will tend to remain in the fluid and be excreted in urine. (B328.2.w2)

Effects of species on renal excretion:

  • There are interspecies differences in kidney excretion of drugs, for example related to blood flow to the kidney and extent of plasma protein binding of drugs as well as reabsorption and active secretion in the renal tubules. (B330.15.w15)
  • The urine of herbivores is alkaline (pH 7.0 to 9.0) although that of suckling/milk-fed herbivores is acidic. (B270.3.w3)
    • Increased ionization, decreased re-absorption and increased excretion will occur for weak acids with a pKa between 3 and 7 in alkaline urine; excretion of basic drugs with pKa 7 to 11 will be increased by acidifying urine. (B328.2.w2)

Effects of age on renal excretion:

  • Renal function is not completely developed in neonates, which may result in decreased renal excretion of drugs. There are species differences in renal function maturity at birth, with a greater degree of maturity in ruminants than in most other species. The rate of postnatal development of renal function can vary considerably between species. (B330.16.w16)
  • In goats, renal function has been shown to develop in the first two weeks of life, with increasing glomerular filtration rate and increases of both clearance of p-aminohippurate (PAH) and renal extraction of PAH. (B329.5.w5)
  • Neonates may have reduced rates of renal excretion, particularly active excretion. (B328.2.w2)
  • Glomerular filtration develops rapidly in ruminants (1 to 3 days in cattle, goats and sheep) as does tubular secretion (1 to 3 days in cattle, 1 to 2 weeks in sheep and goats). (B330.16.w16)
  • Although renal function of calves is reported to be well-developed shortly after birth, there are differences in renal clearance of drugs between young calves and adult cattle, with development of renal function. Renal clearance of drugs which are excreted by glomerular filtration, and of those which are excreted mainly by renal tubular secretion, is reduced in calves compared to adults. (J234.7.w1)

Effects of disease on renal excretion:

  • In renal disease causing uraemia, binding of drugs to plasma albumin may be altered, leading to increased drug distribution, possibly greater pharmacological response (even toxicity) and decreased excretory capacity thus prolonged duration of action and possible accumulation from repeated dosing. (B328.2.w2)
  • Impaired renal excretion causes slower excretion of drugs in the urine, with resultant difficulty in treating urinary tract infections. (B328.2.w2)

Excretion in bile

  • Biliary excretion is a minor route of excretion for many compounds. (B328.2.w2)
  • This route is of more importance for some compounds and conjugates, particularly glucuronides; these may be excreted in bile at higher concentrations. (B328.2.w2)
  • Biliary excretion varies in its importance between species. (B270.3.w3, B328.2.w2)
    • The sheep is considered to be a moderate biliary excretor. (B328.2.w2)
  • Because compounds excreted in bile enter the small intestine they may, depending on their lipid solubility, be reabsorbed, in a process known as enterohepatic circulation. (B270.3.w3, B328.2.w2)
    • Drugs excreted in bile in polar form are generally excreted in the faeces. (B328.2.w2)
    • Conjugated drug or drug metabolites may be hydrolysed by gut flora to a lipid-soluble parent compound or metabolite, which may be excreted in faeces, further degraded and metabolised, or re-absorbed through the wall of the intestines. (B328.2.w2)
    • Enterohepatic circulation is important only if large amounts of the compound are excreted via bile. (B328.2.w2)

Other routes of excretion

MILK 

Drugs may be excreted in varying but significant amounts in milk of lactating animals. (B328.2.w2)

  • Drugs enter milk by passive diffusion through the mammary gland epithelium, which acts as a lipoidal membrane. (B331.1.w1, J289.1.w2)
  • Excretion of drugs in milk is important when an effect is required within the mammary gland following systemic administration. It is also important in milking animals for determination of milk withdrawal periods, which may have a significant economic influence. Excretion of drugs into milk has been studied most extensively for antibiotics. (B329.17.w17)
  • Factors which may affect excretion into milk include the active ingredient (the drug), the formulation of the drug (e.g. rapid-release versus sustained release preparations), dosage, duration of treatment, route of administration and variations in the individual animal, including disease states present. (B329.17.w17)
  • Active ingredient: 
    • Drugs pass from blood to milk mainly by non-ionic passive diffusion. Such diffusion is increased if the molecular weight of the drug is low, its lipid solubility high and the drug is non-ionized and unbound to plasma proteins. (B329.17.w17)
      • Only the lipid-soluble, non-ionized form of a drug diffuses into the milk. (J289.1.w2)
    • The ratio of drug in milk compared to serum is less than one for weak acids and greater than one for drugs that are weak bases.
    • Drugs with low lipid solubility show low mammary excretion. (B329.17.w17)
    • Nonelectrolytes such as ethanol and urea readily enter milk where they are found at the same concentration as in plasma. (B331.1.w1)
  • Formulation:
    • Drugs may continue to be detectable in milk for a longer time following administration of drug forms with a slower release rate. (B329.17.w17)
  • Dose:
    • A higher dose results in greater persistence of drug in milk as well as greater concentration. (B329.17.w17)
  • Duration of treatment:
    • Repeated parenteral administration does not affect mammary elimination of drugs if drug absorption and clearance are relatively rapid, but repeated administration of sustained release drugs may prolong the duration of elimination of the drug in milk. (B329.17.w17)
  • Administration route:
    • Bioavailability is affected by administration route; this affects the plasma concentration of the drug and thereby the concentration in milk. (B329.17.w17)
    • Intramammary administration greatly increases the maximum concentration of drug in milk and the percentage recovered in milk for most antibiotics (not for chloramphenicol) while the duration of elimination is similar to that seen following intramuscular administration for most antibiotics (shorter than following intramuscular administration for tetracycline). (B329.17.w17)
  • Milk yield
    • Following intramammary administration, faster elimination is seen with some drugs (penicillins, aminoglycosides) in individuals with high milk yield. (B329.17.w17)
  • Mastitis:
    • Rate of binding of drugs to milk proteins may be increased (from 10% in normal milk to 25% in mastitic milk for many antibiotics). (B329.17.w17)
    • The change of milk pH, from about 6.6 in normal milk to about 7.4 in mastitic milk, will reduce concentration of macrolide antibiotics due to ion trapping. (B329.17.w17)
    • Lower levels of weakly basic drugs will be found in mastitic than in normal milk, due to reduced ion trapping. (B333.1.w1)

SALIVA 

  • Drugs enter saliva by passive diffusion. (B328.2.w2, B331.1.w1)
    • Only a small fraction of drug elimination is by salivary excretion. (B328.2.w2)
    • Drug excreted in saliva may be reabsorbed in the gastro-intestinal tract. (B328.2.w2)

SWEAT

  • Drugs enter sweat by passive diffusion. (B328.2.w2, B331.1.w1)
    • Only a small fraction of drug elimination is by excretion in sweat. (B328.2.w2)
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Mathematics of Drug Elimination

In general, the duration of pharmacological activity of a drug is related to its plasma concentration (there are exceptions, for example with corticosteroids). (B328.2.w2)

  • The rate of elimination is usually an important determinant of the duration of pharmacological effect of a drug. (B270.3.w3)
  • The rate of elimination of a drug is determined mainly by the mechanisms of the elimination process and may be affected by: (B270.3.w3)
    • Extensive (>80%) plasma protein binding; (B270.3.w3)
    • Degree of perfusion of the main organ(s) of elimination; (B270.3.w3)
    • Activity of metabolising hormones; (B270.3.w3)
    • Efficiency of renal excretion. 

    (B270.3.w3)

There are differences between species in the rate of drug elimination.

  • For drugs which are eliminated mainly by renal excretion and in particular by filtration, half-life is generally longer in herbivores than in dogs, which is consistent with the lower glomerular filtration rate in herbivores. (B270.3.w3)
  • Herbivores, and particularly ruminants, generally show faster elimination of drugs which are eliminated by extensive hepatic metabolism. (B270.3.w3)

If a drug is absorbed more slowly than it is eliminated, then the rate of removal of the drug from the body is determined by absorption rather than by elimination. (B333.2.w2)

  • In the dog, cat and pig, absorption from the gastrointestinal tract is generally fast and relatively complete, while absorption is much more variable in equines and slow in ruminants. (B333.2.w2)

Plasma concentration of drugs typically decline by a first-order rate process: a constant fraction of the drug is eliminated per unit time. (B270.3.w3)

The elimination half-life is the time required for the body to eliminate one half of the remaining drug: t1/2 = 0.693/β, where β (or K), the overall elimination rate constant, is the negative value of the slope of the elimination (linear terminal) phase of the plot of the logarithm of concentration versus time. (B270.3.w3)

The elimination half-life, apparent volume of distribution and protein binding of a drug largely determine its duration of activity. (B328.2.w2)

A drug with a large elimination rate constant K (β) has a short elimination half-life. The elimination half-life may be determined simply by measuring the time required for a given plasma concentration of the drug to decrease by 50% during the linear phase of the drug concentration-time profile. (B270.3.w3) (i.e. once a steady state of distribution has been attained, when elimination, rather than drug redistribution, is the main factor influencing the rate of decline of drug concentration in the plasma). (B328.2.w2)

If drug elimination is zero-order then the half-life is longer for a larger dose and the drug has nonlinear, dose-dependent pharmacokinetics. this may occur if the rate of elimination is limited by the capacity of particular drug-metabolising enzyme systems. (B270.3.w3)

Body clearance, or total clearance represents the sum of clearances by the various eliminating organs. (B270.3.w3)

The total body clearance of a drug is the quantity of blood that is cleared of the drug in a unit of time. This represents the body's intrinsic ability to remove a drug by renal excretion or liver biotransformation. (J234.7.w1)

  • Clearance is influenced by blood flow to the organs of drug elimination and by the concentration of drug present in the body. (J234.7.w1)
  • Clearance can be altered by changes in plasma protein binding of a drug, enzyme activity and secretory activity. (J234.7.w1)
  • Mathematically: ClB = F x (D/AUC) (B270.3.w3)
  • For drugs with a given clearance value, the smaller the apparent volume of distribution, the shorter the half-life. (B270.3.w3)
  • Total body clearance or plasma clearance Clp = k x 0.693 / Vd  (B330.15.w15)
  • Clearance of a given drug, over the range of concentrations encountered clinically, is generally constant (assuming first-order kinetics, i.e. a constant fraction of drug is eliminated per unit time). (B331.1.w1)
    • CL = rate of elimination / concentration. (B331.1.w1)
    • CL = Dose / AUC . (B331.1.w1)
  • For drugs exhibiting saturable (dose-dependent) elimination, clearance varies with the concentration of drug. Often this follows:
    • Total plasma clearance = vm / (Km + Cp) (B331.1.w1) [Km is the plasma concentration at which half the maximal elimination rate is reached (units mass/volume), vm is the maximal rate of elimination (units mass/time), Cp = concentration of drug in plasma]

Half-life and the elimination rate constant

The half-life of a drug is an important determinant of the duration of pharmacological effect of a drug and of the optimum dosage regimen for the drug. (J234.7.w1)

  • Half-life is the length of time required for measured drug concentration (usually concentration in serum or plasma) to decrease by one half. (J234.7.w1)
  • The elimination rate constant λ or ke and the half-life of a drug are related (J234.7.w1); the elimination constant K = 0.693 / t1/2  (B330.15.w15)
  • The unit of half-life (t1/2) is time; the unit of the elimination rate constant λ is inverse time. (J234.7.w1)
  • Apparent volume of distribution, total body clearance and the elimination rate constant are mathematically related: CL = λ x Vd (clearance equals elimination rate constant multiplied by the apparent volume of distribution). (J234.7.w1)
  • Half-life is affected by age, disease, drug interactions changes in pH and species differences. (J234.7.w1)

N.B. clearance reflects the action of the clearing organs while half-life is dependent on clearance and on the volume of distribution. (B330.15.w15)

  • For two drugs with a similar whole body clearance, the drug with a larger apparent volume of distribution will have a longer half life. (B330.15.w15)

Following injection intravenously of a single dose of a drug, a semilogarithmic graph (log concentration against time) gives a biphasic curve. There is an initial steep decline in concentration (α phase) mainly due to intravascular mixing and to distribution of the drug, by passive diffusion, into the body tissues and organs, with a lesser contribution by elimination. Once a distribution pseudoequilibrium is reached, the rate of decline of plasma concentration decreases (β phase) and is due mainly to elimination of the drug from the body. (B270.3.w3, B328.1.w1)

For a drug administered systemically, and if a one-compartment model can adequately approximate the pharmacokinetics of a drug, a few measurements and calculations can be used to adjust drug dosages for particular patients:

  • The elimination rate constant can be calculated: λ = (ln Cmax - ln Cmin) / t [ln is the natural logarithm, Cmax the measured peak serum concentration of drug, Cmin the measured trough concentration and t the time interval between these measurements; this assumes a one compartment open model]. (J234.7.w1)
  • An approximation of the apparent volume of distribution can be calculated: Vd = D/Cmax [D is the dose of drug administered]. (J234.7.w1)
  • Clearance can then be calculated from these two values (CL = λ x Vd). (J234.7.w1)

Steady state will be reached when the rate of drug administration (assuming total bioavailability) is equaled by the rate of drug elimination. (B331.1.w1)

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Dosage Calculations

The objective in a dosage regimen is to maintain the plasma concentration of the particular drug within the therapeutic (safe and effective) range. (J289.1.w3)

The dose (D) which must be administered in order to provide a required therapeutic concentration of drug in plasma (Cther) can be calculated if the apparent volume of distribution (Vd) is known :

  • D (mg/kg) =  Cther (mg/L) x (Vdarea /F) (L/kg) (this equation allows for the fact that if the drug is administered other than intravenously then the bioavailability (F), which may be less than 1.0, must be taken into account). (B270.3.w3)

The dosing rate = Cl x Css [Cl = clearance, Css = steady state concentration]. (B331.1.w1)

The dosing rate (dose per unit time) required to give an average steady state concentration Css can be calculated

The duration of a therapeutic concentration of a drug tCther is given by: tCther = [lnA0/Amin] x t1/2 (B270.3.w3) (where A0 is the dose administered and Amin is the minimally effective dose)

Note: "Dose regimen estimations cannot be made unless something is known about the drug's therapeutic window, volume of distribution, half-life, and bioavailability." (J215.11.w1)

Changing the dosing interval

Increasing the interval between doses is often desirable for practical purposes. 

  • Increasing the dose given may be used to extend the intervals between doses. (B328.1.w1)
  • Limits to this are:
    • Initial high concentrations may be toxic; (B328.1.w1)
    • Cost of treatment may become prohibitive. (B328.1.w1)
  • Increasing the interval between doses may be achieved by use of long-acting, slow-release preparations: (B328.1.w1)
    • These may not provide adequate concentrations; (B328.1.w1)
    • These may be used in combination with a more rapidly-released formulation. (B328.1.w1)
Effect of species:
  • It should be noted that there are marked differences between species in the dose rate and dose frequency required in order to obtain a particular response. Therefore usually it is not possible to extrapolate data between species. (B328.2.w2)
Effects of immaturity: 
  • In neonates, the dosing interval may need to be  increased in order to prevent possible accumulation of drug and toxic effects due to reduced drug elimination (see above). (B328.2.w2)

Scaling of doses

Scaling is used to adjust doses between animals and between species. A variety of methods of scaling may be used. The simplest method of scaling is by body weight, however although this is the simplest method to use, it is not always the most appropriate.

Body weight:

  • This is the simplest approach to adjusting drug doses between animals. (B270.3.w3)
    • This approach will tend to underdose small individuals and overdose larger individuals, since smaller animals have a faster metabolic rate on a body weight basis. (B270.3.w3)
    • For most therapeutic agents the therapeutic margin is sufficiently large that this approach can be used safely and effectively. (B270.3.w3)

Body surface area: (B270.3.w3)

  • This is a more precise approach than that of body weight. In general the body surface area increases more gradually with increasing size than does the body weight (which is proportional to body volume). (B270.3.w3)
    • Within a species, body surface area nomograms can be used for effective scaling of drugs with a narrow therapeutic margin, such as some cancer chemotherapy drugs. (B270.3.w3)
    • In veterinary medicine, as opposed to human medicine, this approach is rarely used since body surface area nomograms are not available for most species. (B270.3.w3)

Allometric scaling:

  • Allometric scaling involves describing pharmacokinetic profiles for a number of species across a wide range of body weights. The pharmacokinetic parameters of the model are scaled using the equation: Y = aWb [Y is the pharmacokinetic parameter of interest, W is the body weight (in kg) log (a) is the intercept and log (b) is the slope of a plot of log (Y) versus log (W)]. (B270.3.w3)
  • Allometric scaling is based on the observation that metabolism and many other physiological functions are higher in small than in large species within a class (such as mammals). Per unit of body weight, organ weights, blood flow to organs, heart rate and cardiac output are larger in small than in larger species and these affect drug deposition and drug elimination. (B270.3.w3)
    • In general, scaling across species (or even within a species) by the allometric approach is likely to be appropriate (only) for drugs which: (B270.3.w3, J215.25A.w1)
      • a) have low protein binding; (B270.3.w3, J215.25A.w1) and
      • b) are eliminated primarily by renal mechanisms or by blood flow-limited hepatic (or other) metabolism, rather than by enzyme capacity-limited metabolism. (B270.3.w3, J215.25A.w1)
  • Allometric scaling may not be applicable for drugs with pharmacokinetics which are affected by factors such as protein binding of the drug, activity of hepatic enzymes, enterohepatic cycling and urine pH: factors which are not themselves allometrically scaled. (J215.25A.w1)

  • Allometric scaling cannot be applied across classes of animals, such as from mammals (Mammalia - Mammals (Class)) to reptiles (Reptilia - Reptiles (Class)). (J215.25A.w1)

Tolerance

Tolerance may develop to a variety of drugs including opioids. (B331.1.w1)
  • Mechanisms of tolerance:
    • Tolerance may occur due to induced synthesis of hepatic microsomal enzymes responsible for drug metabolism (pharmacokinetic tolerance). (B331.1.w1)
    • Tolerance may occur due to cellular adaptation (pharmacodynamic tolerance); this is the type of tolerance involved in development of tolerance to opioids. (B331.1.w1)
  • Effects of tolerance:
    • The practical effect of tolerance is that drug dosage needs to be increased to maintain a given therapeutic effect. (B331.1.w1)
      • There may be cross-tolerance to the effects of drugs which are pharmacologically related, particularly those which act at the same receptor site as one another. (B331.1.w1)
      • There may be a decrease in therapeutic index (due to tolerance to the required effect but not to toxic effects). (B331.1.w1)
      • In some cases there may be development of tolerance to side effects, thus an increase in therapeutic index. (B331.1.w1)

Withdrawal times

When medicating animals producing milk or meat for human consumption, it is very important to ensure that at the time of milking or slaughter residues of the drug given are undetectable, or below accepted limits set by regulatory bodies, in the milk or tissues respectively. 
  • For pharmaceutical products being used according to their licence, i.e. given to a species in which the product is licensed, at the indicated dose rate, required milk and meat withdrawal times are provided in the data sheet for the product. However if a pharmaceutical product is used "off label", i.e. at a dose rate above that stated on the data sheet, in a manner not stated on the data sheet, or in a species not stated on the data sheet, then it is necessary for the veterinarian to determine the length of time required after use of the product before milk is taken, or the animal slaughtered, for human consumption. (J15.25.w1)
  • In the UK, when medicines are used off-label or under the cascade system there is a minimum milk withdrawal period of seven days, although depending on the product a longer period may be required. (J15.25.w1)

Note: 

  • Withdrawal times may vary between different pharmaceutical formulations of a given drug, and depending on the route of administration. 
  • In Europe the prescription cascade must be followed when choosing a product for use in any individual animal. 

Rule of ten half lives:

  • "The rule of ten half-lives usually provides a conservative estimate that accounts for statistical variation within the population of animals treated." (J234.12.w1)
  • Drug concentrations should have declined by 99.9% after ten half-lives. For this to apply it is assumed that: (J234.12.w1)
    • metabolites of the drug, if present, are not excreted more slowly than the parent drug;
    • the half-life has been calculated according to the route by which the drug has actually been administered;
    • drug clearance mechanisms in the individual in question are functioning normally: usual withdrawal times may not apply if an individual has a problem such as liver or kidney failure which drastically affects drug clearance. 

    (J234.12.w1)

  • Note: for most anaesthetic and anaesthetic adjunct drugs half-lives are generally short: minutes rather than hours. Therefore, if a period of 48 to 96 hours elapses after administration of these drugs before slaughter, most of the drug will have been cleared. (J234.12.w1)
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Definitions

Primary pharmacokinetic terms 
  • Cp = the concentration of drug in plasma at time t. (B270.3.w3)
  • AB(t) = the amount of drug in the body at time t. (B270.3.w3)
  • A, B and C are intercept terms, representing the plasma drug concentration at time 0, based respectively on the distribution, apparent elimination, and deep tissue elimination phases of the drug disposition curve. (B270.3.w3)
  • α β γ are hybrid rate constants related to the slopes of, respectively, the distribution, apparent elimination and deep tissue elimination phases of the drug disposition curve. β is the overall elimination rate constant, and is the negative value of the slope of the linear terminal phase of the plot of dug concentration C versus time. (B270.3.w3)
  • C0 = the initial concentration of the drug in plasma after intravenous injection of a single dose (C0 = A + B + C). (B270.3.w3)
  • λi = the general first-order rate constant for the i different exponential phases in a polyexponential predictive mathematical equation that describes the drug disposition curve. (B270.3.w3)
  • Ci = general coefficients for the i different exponential phases in a polyexponential predictive mathematical equation that describes the drug disposition curve. (B270.3.w3)
  • k12, k21 = first-order transfer rate constants for drug distribution between central and peripheral compartments of the two-compartment open model. (B270.3.w3)
  • kel = the first-order rate constant for elimination of a drug from the central compartment. (B270.3.w3)
  • t1/2 = the half-life of a drug based on first-order (exponential) elimination. (t1/2 = 0.693/β). (B270.3.w3)
  • e = base of the natural logarithm (ln). (B270.3.w3)
Volume terms
  • Vc = apparent volume of the central body compartment. (B270.3.w3)
  • Vdarea apparent volume of distribution based on the total area under the plasma drug concentration versus time curve (area method). (B270.3.w3) Vd area = (D x F) / AUC x β  (B270.3.w3)

    (AUC = area under conc./time curve from t=0 to t= infinity; F = the bioavailability for a drug administered by a given route; D = the dose administered; β = the slope of the terminal disappearance portion of the plasma concentration-time profile when plotted as a natural logarithm of concentration on the Y axis versus time on the X axis). (B270.3.w3)

  • Vdβ apparent volume of distribution obtained by neglecting the α (distribution) phase of drug disposition (extrapolation method). (B270.3.w3)
  • A less accurate but more straightforward calculation than Vdarea  (B270.3.w3) is: VdB = (D x F)/B (D is the administered dose, F is the bioavailability of the dose administered by that route, B (ml/L) is a value obtained by extrapolating the linear terminal phase of the drug disposition curve to its intercept on the ordinate (plasma drug concentration axis). 
  • VdSS steady-state volume of distribution of a drug (B270.3.w3) Vdss= (D x F x AUMC)/ AUC2 (B270.3.w3)
  • AUC = the total area under the plasma drug concentration versus time curve from t = 0 to t = infinity. (B270.3.w3)
  • AUMC = the total area under the plasma drug concentration multiplied by time versus time curve from t=0 to t = infinity, after administration of a single dose. 

Clearance and Elimination terms

  • ClB (mL/min)/kg = total body clearance of a drug. It is the sum of individual clearance processes for the drug. (B270.3.w3)
  • Clr = renal clearance: the volume of blood cleared of a drug by the kidneys in unit time. (B270.3.w3)
  • Clnr = nonrenal clearance; the volume of blood cleared of a drug other than by renal processes (mainly by metabolic processes) per unit time. (B270.3.w3)
  • fex = the fraction of the dose which is excreted unchanged in urine. (B270.3.w3)
  • First-order rate process: a constant fraction of the drug is eliminated per unit time (B270.3.w3)
  • Zero-order rate process: a constant amount of drug is eliminated per unit time. (B270.3.w3)
Dosage-associated terms
  • D = administered dose. (B270.3.w3)
  • DL = loading or priming dose. (B270.3.w3)
  • DM = maintenance dose. (B270.3.w3)
  • D/τ = maintenance dose (dosing) rate: the dose per unit time. (B270.3.w3)
  • τ = dosage interval (B270.3.w3)
  • F = the systemic availability of a drug: the fraction of the dose administered that enters the systemic circulation intact. (B270.3.w3)
  • fel = the fraction of the amount of drug in the body which is eliminated during a dosage interval . This represents the extent of fluctuation in steady-state concentrations of a drug which takes place during the interval between successive doses of the drug. (B270.3.w3)
  • Cther = the therapeutic range of drug concentration in plasma or serum. (B270.3.w3)
  • Css the steady state or plateau concentration of a drug achieved by continuous intravenous infusion of the drug; also used for the average steady-state concentration of a drug in plasma achieved by a given dosage regimen. (B270.3.w3)
  • Cmax = the maximum concentration of drug in plasma or serum achieved by a single dose of the drug. (B270.3.w3)
  • Css,max = the maximum concentration of drug in plasma or serum at steady state. (B270.3.w3)
  • Cmin = the minimum concentration of drug in plasma or serum achieved by a single dose of the drug. (B270.3.w3)
  • Css,min = the minimum concentration of drug in plasma or serum at steady state. (B270.3.w3)
  • TM = the interval required between maintenance doses (DM) to maintain the concentration within the therapeutic range. (B270.3.w3)
  • R0 = the intravenous infusion rate. (B270.3.w3)
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Authors & Referees

Authors Dr Debra Bourne MA VetMB PhD MRCVS (V.w5)
Referee A.B.Forbes BVM&S.,CBiol.,MIBiol.,DipEVPC.,MRCVS (V.w66); Quintin McKellar, BVMS, PhD, FRagS, MRCVS (V.w68)

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