Handbook of Veterinary Pharmacology is a clear and concise guide to pharmacology concepts and commonly used veterinary drugs. Providing a succinct overview of veterinary pharmacology, this book presents information in a user-friendly outline format to allow quick access to practical drug information. With chapters covering the basic principles, specific drugs, interactions, and legal considerations, Handbook of Veterinary Pharmacology offers up-to-date information on basic and clinical veterinary pharmacology.
As an aid to student comprehension, simple line drawings depict the mechanisms of action and study questions with explanations are included at the end of each chapter. Appendices on withdrawal times for drugs in production animals and drug dosages in domestic species are a valuable tool, allowing quick decisions on drug therapy. Handbook of Veterinary Pharmacology is an indispensable text for veterinary students and practitioners.
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Principles of Drug Absorption, Drug Disposition, and Drug Action
Richard J. Martin and Walter H. Hsu
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.
