I. INTRODUCTION.
Pharmacology is the study of the properties of chemicals used as drugs for therapeutic purposes. It is divided into the study of pharmacokinetics and pharmacodynamics. Veterinary pharmacology focuses on drugs that are used in domestic animals. Pharmacokinetics is the study of drug absorption, distribution, biotransformation (metabolism), and excretion. Pharmacokinetic processes affect the route of administration, doses, dose intervals, and toxicities of drugs given to animals. Pharmacodynamics is the study of cell/tissue responses and selective receptor effects. In this chapter, we introduce standard concepts of pharmacokinetics and pharmacodynamics and comment on the need to be aware of species variation when considering principles of veterinary pharmacology.
II. DRUG ABSORPTION AND DISPOSITION
A. General principles. An overview of the principles involved in a drug’s journey in the body beginning from its administration to the pharmacologic response.
How do drugs reach their site of action? It is apparent from Figure 1-1 that a drug usually crosses several biological membranes from its locus of administration to reach its site of action and thereby produce the drug response. The manner by which drugs cross membranes are fundamental processes, which govern their absorption, distribution, and excretion from the animal.
1. Passive diffusion. Cell membranes have a bimolecular lipoprotein layer, which may act as a barrier to drug transfer across the membrane. Cell membranes also contain pores. Thus, drugs cross membranes based on their ability to dissolve in the lipid portion of the membrane and on their molecular size, which regulates their filtration through the pores.
a. Weak acids and weak bases. The majority of drugs are either weak acids or weak bases. The degree to which these drugs are fat soluble (nonionized, the form which is able to cross membranes) is regulated by their pKa and the pH of the medium containing the drug. pKa = pH at which 50% of the drug is ionized and 50% is nonionized.
b. To calculate the percent ionized of a drug or to determine the concentration of a drug across a biological membrane using the Henderson–Hasselbalch equation one needs to know whether a drug is an acid or a base.
If the drug is a weak acid use:
If the drug is a weak base use:
c. In monogastric animals with a low stomach pH, weak acids such as aspirin (pKa = 3.5) tend to be better absorbed from the stomach than weak bases because of the acidic conditions. In ruminants, the pH varies with feeds and the pH is often not low.
d. Weak bases are poorly absorbed from the stomach since they exist mostly in the ionized state (low lipid solubility) because of the acidic conditions. Weak bases are better absorbed from the small intestine due to the higher environmental pH.
FIGURE 1-1. This diagram relates what may be expected to occur to a drug in the animal following its administration (IV, intravenous; IM, intramuscular; PO, per os or oral; IP, intraperitoneal; SC, subcutaneous; inhalation, dermal). (From Figure 1-1, NVMS Pharmacology.)
2. Filtration
a. Some low molecular weight chemicals, water, urea, and so forth, cross membranes better than predicted on the basis of their lipid solubility, suggesting that membranes possess pores/channels.
b. The glomerular filtration process in the kidney provides evidence for large pores, which permit the passage of large molecular weight substances but small enough to retain albumin (mw ~60,000).
3. Facilitated diffusion
a. No cellular energy is required and it does not operate against a concentration gradient.
b. Transfer of drug across the membrane involves attachment to a carrier (a macromolecular molecule).
c. Examples: Reabsorption of glucose by the kidney and absorption from the intestine of vitamin B12 with intrinsic factor.
d. This is not a major mechanism for drug transport.
4. Active transport
a. Requires cellular energy and operates against a concentration gradient.
b. Chemical structure is important in attaching to the carrier molecule.
c. Examples: Penicillins, cephalosporins, furosemide, thiazide diuretics, glucuronide conjugates, and sulfate conjugates are examples of acidic drugs that are actively secreted by the proximal renal tubule. Amiloride, procainamide, quaternary ammonium compounds, and cimetidine are examples of basic drugs that are actively secreted by the proximal renal tubule cells. Intestinal absorption of 5-fluorouracil, an anticancer drug, which is transported by the same system used to transport uracil.
5. Pinocytosis. This is a minor method for drug absorption, but it may be important in the absorption process for some polypeptides, bacterial toxins, antigens, and food proteins by the gut.
B. Routes of administration. All routes of administration except intravascular (see Figure 1-1) involve an absorption process in which the drug must cross one or more membranes before getting into the blood.
1. Alimentary routes
a. Oral (per os, PO)
(1) Advantages
(a) Usually safest, convenient, economical, but some animals are difficult to administer this way.
(b) May require the drug to be mixed in the food to facilitate administration.
(c) Food may stimulate bile secretion, which will help dissolve lipophilic drugs to increase absorption.
(2) Disadvantages
(a) Acidic environment of stomach and digestive enzymes may destroy the drug.
(b) In ruminants the bacterial enzymes may inactivate the drug.
(c) Some drugs may irritate the GI mucosa.
(d) The presence of food may adversely alter absorption.
(e) Some drugs are extensively metabolized by the GI mucosa and the liver before they reach the systemic circulation (e.g., propranolol) and this is referred to as the first-pass effect.
(f) Antimicrobials may alter the digestive process in ruminants and other herbivores.
b. Rectal
(1) Advantages
(a) Can be used in the unconscious animal and in those vomiting.
(b) Absorption is slower compared to the intramuscular route.
(c) There are some drugs like diazepam and phenytoin that have an erratic oral absorption and are better given rectally.
(d) In dogs, influence of the first-pass effect is reduced because the rectal veins bypass the portal circulation and go to the caudal vena cava.
2. Parenteral routes (circumvents the GI tract)
a. Examples
(1) Intravenous (IV)
(2) Intramuscular (IM)
(3) Subcutaneous (SC)
(4) Intraperitoneal (IP)
(5) Spinal and subdural. Used for regional anesthesia.
b. Advantages
(1) Rapid onset (IV > IM > SC), may be useful in an unconscious or vomiting patient, absorption is more uniform and predictable.
(2) Absorption from IM and SC injection sites is mostly determined by the amount of blood flow to that site. The absorption of local anesthetics is often purposely slowed by coadministration with epinephrine, which decreases the blood flow to the injection site.
c. Disadvantages
(1) Asepsis is necessary.
(2) Cause pain.
(3) May penetrate a blood vessel during IM injection.
(4) The speed of onset is so rapid as with IV administration that cardiovascular responses may occur to drugs, which normally have minimal effects on this system.
(5) In food animals, discoloration of the meat or abscess formation may occur to IM injection and these may be expected to devalue the carcass.
3. Other routes
a. Dermal or topical
(1) Degree of absorption is dependent on the drug’s lipid solubility.
(2) Abraded or damaged skin may be expected to absorb more drug than intact skin.
(3) Animals with thin skin, like cats, may absorb drugs like corticosteroids readily if they are applied topically than animals with thicker skin.
(4) It is convenient and allows nonskilled operators to administer the drugs by pour-on methods. For example, topical application of anthelmintics that are lipophilic, like levamisole and macrocyclic lactones, is frequently performed in this manner.
b. Inhalation
(1) It is used for volatile or gas anesthetics. Example: isoflurane.
(2) Response is rapid because of the large surface area of the lungs and large blood flow to the lungs.
(3) It is reversible if the anesthetic is turned off and the animal ventilated.
C. Drug distribution
1. Distribution refers to the reversible transfer of drug from one site in the body to another site.
2. In much of the body, the junctions between the capillary endothelial cells are not tight thereby permitting free (unbound to plasma proteins) drug to rapidly reach equilibrium on both sides of the vessel wall.
3. Distribution of drugs into the central nervous system (CNS) and cerebrospinal fluid (CSF) is restricted due to the blood–brain barrier (BBB).
a. There are three processes that contribute to keeping drug concentration in the CNS low:
(1) In much of the CNS (except: area postrema, pineal body, posterior lobe of hypothalamus), the capillary endothelial junctions are tight and glial cells surround the precapillaries. This reduces the filtration process and requires that drugs diffuse across cell membranes to leave the vascular compartment and thereby enter the extracellular fluid or CSF. This ability to cross cell membranes is dependent upon the drug’s lipid solubility.
(2) Cerebrospinal fluid production within the ventricles circulates through the ventricles and over the surface of the brain and spinal cord to flow directly into the venous drainage system of the brain. This process continues to dilute out the drug’s concentration in the CSF.
(3) Active transport mechanisms are found for organic acids and bases in the choroid plexus, which transports drug from the CSF into the blood. P-glycoprotein is one transporter protein that is present in the endothelial cells of the choroid plexus (blood–brain barrier) that contributes to drug entry into and exit from the brain.
Examples: The macrocyclic lactones, ivermectin, and selamectin but less so with moxidectin, are excluded from the brain via P-glycoprotein. In some breeds of dog, particularly the Collies, P-glycoprotein is defective and ivermectin accumulates in the CNS, leading to toxicity.
Penicillin (a weak acid) concentrations in the CNS are kept low due to an active organic ion transporter system.
4. Plasma protein binding of drug can affect drug distribution since only the free (unbound) drug is able to freely cross cell membranes (see Figure 1-1, II A).
drug + protein (free) ⇋ Drug − protein (bound)
Acidic drugs are bound primary to albumin and basic drugs are bound primarily to α1-acid glycoprotein. Steroid hormones and thyroid hormones are bound by specific globulins, respectively, with high affinity.
a. Drug–protein binding reaction is reversible and obeys the laws of mass action.
b. Binding does not prevent a drug from reaching its site of action but retards/slows the rate at which it reaches a concentration sufficient to produce a pharmacologic effect.
c. Drug–protein binding limits glomerular filtration as an elimination process since bound drugs cannot be filtered. Example: sulfa drugs with a high degree of binding to protein are eliminated more slowly in urine than those sulfa drugs with a lower binding affinity for plasma proteins.
d. Binding to albumin does not totally prevent the elimination of drugs that are actively secreted by the kidney or metabolized by the liver, rather it slows the rates of metabolism and/or secretion. Binding lowers the free drug concentration but there is still release from the drug–protein complex for the metabolism or secretion.
e. Drug interactions may occur when two drugs are used that bind at the same site on the plasma proteins. Competition for the same site will increase the percent of drug in the free form, thereby increasing the pharmacologic/toxicological response by the displaced drug.
5. Drug redistribution can terminate the drug response.
a. The biologic response to a drug is usually terminated by metabolism/biotransformation and excretion.
b. Redistribution of a drug from its site of action to other tissues will lower its concentration at its site of action, thereby terminating the drug response.
c. Drugs exhibiting the redistribution phenomenon are highly lipid soluble. Thiopental is the classic example in dogs where redistribution from the brain to less vascular area of the body, including the muscle and fat, allows recovery. In sheep and goats, however, liver biotransformation takes place at such a high rate so that in these species it is metabolism, not redistribution that dominates the duration of anesthesia. Propofol is very lipophilic and is rapidly redistributed following IV injection so that in goats and dogs anesthesia is ultrashort. Interestingly, the redistribution process varies between breeds of dogs due to the different leanness of the different breed. Very lean breeds like Greyhounds with less fat for the lipophilic anesthetics to redistribute to, take longer to recover.
6. Drug distribution from dam to fetus.
a. Drug transfer across the placenta occurs primarily by simple diffusion.
b. Drugs cross the placenta best if they are lipid soluble (nonionized weak base or acid).
c. The fetus is exposed to some extent even to drugs with low lipid solubility when given to the dam.
d. General rule: Drugs with an effect on the maternal CNS have the physical– chemical characteristics to freely cross the placenta and affect the fetus. Examples: anesthetics, analgesics, sedatives, tranquilizers, and so forth.
D. Drug metabolism/biotransformation is the term used to describe the chemical alteration of drugs (xenobiotics) as well as normally found substances in the body.
1. Principles
a. Following filtration at the renal glomerulus most lipophilic drugs are reabsorbed from the filtrate.
b. Biotransformation of drugs to more water-soluble (polar) chemicals reduces their ability to be reabsorbed once filtered by the kidney. This enhances their excretion and reduces their volume of distribution.
c. The liver is the most important organ for biotransformation but the lung, kidney, and GI epithelium also play a role.
d. Drug biotransformation frequently reduces the biological activity of the drug/chemical/toxicant.
e. Drug metabolism/biotransformation is not synonymous with drug inactivation as the parent chemical may be transformed to a chemical with greater or significant biologic activity.
FIGURE 1-2. Phases of biotransformation. (From Figure 1-2, NVMS Pharmacology.)
Example:
| Acetylsalicylic acid | → | salicylate |
| Inactive (aspirin) | active anti-inflammatory | |
| febantel | → | fenbendazole/oxfendazole |
| Inactive | active anthelmintic | |
| Primidone | → | phenobarbital |
| Inactive | active anticonvulsant | |
| codeine | → | morphine |
| active analgesic | more active analgesic |
2. Enzymatic reactions in biotransformation usually occur in two phases (Figure 1-2):
a. Phase I biotransformation enzymes are found in the smooth endoplasmic reticulum of the hepatic cells (also referred to as the microsomal enzymes since they are found in the microsomal fraction following high-speed centrifugation).
(1) Oxidation is carried out by a family of isozymes termed cytochrome P450s.
(2) The enzyme system is also called a mixed function oxidase since one atom of oxygen is incorporated in the drug molecule and the other atom of oxygen combines with hydrogen to form water. Nicotinamide adenine dinucleotide phosphate (NADPH) provides the reducing equivalents. Examples of microsomal oxidation:
(a) Side chain and aromatic hydroxylation: pentobarbital, phenytoin, phenylbutazone, propranolol
(b) O-dealkylation: morphine, codeine, diazepam
(c) N-oxidation: acetaminophen, nicotine, phenylbutazone, pentobarbital
(d) S-oxidation: phenothiazines (acepromazine, chlorpromazine), cimetidine
(e) Deamination or N-dealkylation: lidocaine
(f) Desulfuration: thiopental
(3) Nonmicrosomal oxidation
A few chemicals are oxidized by cytosol or mitochondrial enzymes.
(a) Alcohol dehydrogenase and aldehyde dehydrogenase. Example: ethanol, acetaldehyde, ethylene glycol
(b) Monoamine oxidase. Example: epinephrine, norepinephrine, dopamine, serotonin
(c) Xanthine oxidase. Example: theophylline
(4) Oxidative metabolism. There are considerable differences among the species in the activity of the oxidative enzymes. Generally, the difference has been attributed to differences between the kinetic parameters (Michaelis constants and Max velocity) of the species enzymes. Oxidation is higher in horses than cattle, which in turn are higher than dogs. Oxidation is lowest in cats among domestic animals. The level of oxidative enzymes is lower in very young animals. The duration of pentobarbital anesthesia in horses is much shorter than in dogs. Young calves are much more sensitive to pentobarbital and lindane than adult cattle.
(5) Reduction biotransformation reactions are less frequent than oxidation-type reactions. Enzymes are located in both microsomal and nonmicrosomal fractions. Examples: chloramphenicol and naloxone.
(6) Hydrolysis reactions occur with either ester (esterases) or amide linked chemicals (amidases).
(a) Esterases occur primarily in nonmicrosomal systems and are found in the plasma, liver, and other tissues. Examples of drugs hydrolyzed: acetylcholine, succinylcholine, and procaine.
(b) Amidases are nonmicrosomal enzymes found primarily in the liver. Examples of drugs hydrolyzed: acetazolamide, lidocaine, procainamide, sulfacetamide, and sulfadimethoxine.
b. Phase II biotransformation (conjugation) may occur to a phase I metabolite or to a parent drug/chemical. This involves the coupling of an endogenous chemical (glucuronic acid, acetate, glutathione, glycine, sulfate, or methyl group to the drug). Enzyme systems are present in the microsomes, cytosol, and in the mitochondria.
(1) Products of phase II biotransformation have greater water solubility and are more readily excreted via the kidney.
(2) Examples of drugs undergoing phase II biotransformation (Table 1-1).
(3) Species variation in phase II metabolism. There are considerable species defects in certain conjugation reactions:
(a) In the cat, glucuronide synthesis where the target is −OH, −COOH, −NH2, =NH,−SH is only present at a low rate. Thus, cats often have longer plasma t½ for many drugs than other species.
(b) In the dog acetylation of aromatic-NH2 groups is absent and this affects the metabolism of sulfonamides and other drugs.
(c) In the pig sulfate conjugation of aromatic-OH, aromatic-NH2 groups are only present at a low extent.
(4) Enterohepatic recirculation
(a) Drugs biotransformed via the formation of a glucuronic acid metabolite may be eliminated via the bile.
(b) Glucuronide metabolites can be hydrolyzed by intestinal or bacterial β-glucuronidases, thereby releasing free drug, which can then be reabsorbed. This process can greatly increase a drug’s residence in the body. This is recognized for etorphine in horses and may give rise to relapse despite initial reversal with the antagonist diprenorphine.
(5) Biotransformation by GI microflora. In addition to the liver, metabolism of drugs can also take place in the rumen and GI tract by the microflora where hydrolytic activity and reductive activity may occur. Gut-active sulfonamides (phthalylsulfathiazole) require hydrolysis for the release of sulfathiazole for antimicrobial action. Cardiac glycosides are hydrolyzed in the rumen and become inactive, the chloramphenicol –NO2 group is reduced and the drug is inactivated.
TABLE 1-1. Drug Conjugation Reactions
| Conjugation Reaction | Drug Conjugated |
| Glucuronidation | Aspirin, morphine, sulfadimethoxine, digitoxin, steroids, thyroxine, phenobarbital, phenytoin, chloramphenicol, phenylbutazone |
| Acetylation | Sulfonamides, clonazepam, procainamide |
| Glutathione formation | Ethacrynic acid |
| Glycine formation | Salicylic acid, nicotinic acid |
| Sulfate formation | Catecholamines, acetaminophen |
| Methylation | Catecholamines, histamine |
FIGURE 1-3. Proximal renal tubule. Only drugs (D) which are free in the plasma are filtered. Once in the tubular lumen the drug may be passively reabsorbed. In the proximal renal tubule active transport mechanisms exist for secreting acid and base drugs (D) from the extracellular fluid into the renal tubule.
E. Drug excretion refers to the processes by which a drug/drug metabolite is eliminated from the body. The kidney is the primary organ for drug excretion.
1. Renal excretion. Primary mechanisms.
a. Glomerular filtration. All drugs (D, Figure 1-3) not bound to plasma proteins are filtered.
b. Active tubular secretion. In the proximal portion of the renal tubule active transport mechanisms exist for both acidic and basic drugs. Examples of drugs actively secreted into the tubule lumen are presented above. Competition among the acidic drugs or basic drugs can be expected to occur for the secretion process (Table 1-2).
c. Passive tubular reabsorption. The lipid nature of the cellular membrane lining the tubule dictates that only lipophilic drugs will be reabsorbed.
(1) Since most drugs are weak acids or bases the degree of ionized (water soluble, non-reabsorbable) or nonionized (lipid soluble, reabsorbable) form of the drug will vary with the pKa of the drug and the pH of the lumen urine.
(2) Urinary pH of carnivore animals is acidic (pH 5.5–7.0).
(3) Urinary pH range of herbivore animals is 7.0–8.0.
(4) Food will influence the urinary pH for both carnivores and herbivores.
(5) Excretion can be enhanced for drugs eliminated primarily by the kidney through altering the pH of the urine. For practical purposes this is limited to weak acidic or weak basic drugs with a pKa of 5–8.
(6) Quaternary drugs (R4–N+) are polar at all urine pH and can be expected to be eliminated rapidly, since they cannot be reabsorbed.
2. Other routes of excretion
a. Biliary secretion. Both the parent drug and glucuronide form of the drug may be eliminated via the bile.
(1) Glucuronide-drug conjugates eliminated via the bile may be hydrolyzed by β-glucuronidases from gut bacteria. The free drug then may be reabsorbed giving rise to “enterohepatic recycling.”
(2) Transport processes exist in the liver for actively transporting acidic, basic, and neutral drugs into the bile. Since these drugs may eventually be reabsorbed from the gut lumen, biliary elimination processes tend to be less important than are renal excretion processes.
(3) Role of P-glycoprotein in drug excretion. P-glycoprotein is a transmembrane efflux pump that has a role in the “first-pass clearance” of some oral drugs. P-glycoprotein is also found in the biliary and renal tubular epithelia and thus plays a role in the “secretion” of some but not all drugs into the gut and renal tubules. As stated earlier, this protein is also found in the BBB and its effect there is to “expel” the drug from the CNS. Substrates of P-glycoprotein include azole antifungal agents, corticosteroids, cyclosporine, digoxin, diltiazem, doxorubicin, opioids, macrocyclic lactones, macrolide antibiotics, quinidine, and vincristine/vinblastine.
b. Milk. While this is not a major route for drug excretion for the dam, it is important since the drugs given to the dam appear in the milk and produce residues requiring a withdrawal period if the milk is to be used for human consumption. Antimicrobial drugs given to the dam appear in concentrations sufficient to treat mastitis. Milk is acidic relative to plasma. Therefore, weak organic bases will diffuse from the plasma into the milk where they will become more ionized, thereby preventing passage back to the plasma. This is an example of ion trapping. Drugs which are basic (tylosin, erythromycin, and lincomycin) can be expected to be found in milk in higher concentrations than in the plasma.
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