Basic Veterinary Pharmacology PDF

BASIC VETERINARY PHARMACOLOGY Kay Abawag needed for understanding how drugs work at INTRODUCTION TO the organ and tissue levels. Paradoxically, PHARMACOLOGY...

BASIC VETERINARY PHARMACOLOGY Kay Abawag needed for understanding how drugs work at INTRODUCTION TO the organ and tissue levels. Paradoxically, PHARMACOLOGY real advances in basic pharmacology during this time were accompanied by an outburst History of Pharmacology of unscientific claims by manufacturers and Prehistoric people undoubtedly recognized marketers of worthless “patent medicines.” the beneficial or toxic effects of many plant Not until the concepts of rational therapeutics, and animal materials. Early written records especially that of the controlled clinical trial, list remedies of many types, including a few were reintroduced into medicine—only about that are still recognized as useful drugs 60 years ago—did it become possible to today. Most, however, were worthless or adequately evaluate therapeutic claims. actually harmful. In the last 1500 years, sporadic attempts were made to introduce Around the 1940s and 1950s, a major rational methods into medicine, but none expansion of research efforts in all areas of was successful owing to the dominance of biology began. As new concepts and new systems of thought (“schools”) that purported techniques were introduced, information to explain all of biology and disease without accumulated about drug action and the the need for experimentation and biologic substrate of that action, the drug observation. These schools promulgated receptor. During the last 60 years, many bizarre notions such as the idea that disease fundamentally new drug groups and new was caused by excesses of bile or blood in members of old groups were introduced. The the body, that wounds could be healed by last four decades have seen an even more applying a salve to the weapon that caused rapid growth of information and the wound, and so on. understanding of the molecular basis for drug action. The molecular mechanisms of The Materia Medica action of many drugs have now been Around the end of the 17th century, reliance identified, and numerous receptors have on observation and experimentation began been isolated, structurally characterized, and to replace theorizing in physiology and cloned. In fact, the use of receptor clinical medicine. As the value of these identification methods (described in Chapter methods in the study of disease became 2) has led to the discovery of many orphan clear, physicians in Great Britain and on the receptors—receptors for which no ligand has Continent began to apply them to the effects been discovered and whose function can of traditional drugs used in their own only be guessed. Studies of the local practices. Thus, materia medica—the molecular environment of receptors have science of drug preparation and the medical shown that receptors and effectors do not uses of drugs—began to develop as the function in isolation; they are strongly precursor to pharmacology. However, any influenced by other receptors and by real understanding of the mechanisms of companion regulatory proteins. action of drugs was prevented by the absence of methods for purifying active Targeting RNAs agents from the crude materials that were Pharmacogenomics—the relation of the available and—even more—by the lack of individual’s genetic makeup to his or her methods for testing hypotheses about the response to specific drugs—is becoming an nature of drug actions. important part of therapeutics. Decoding of the genomes of many species—from In the 18th & 19th Century bacteria to humans—has led to the In the late 18th and early 19th centuries, recognition of unsuspected relationships François Magendie and his student Claude between receptor families and the ways that Bernard began to develop the methods of receptor proteins have evolved. Discovery experimental physiology and pharmacology. that small segments of RNA can interfere Advances in chemistry and the further with protein synthesis with extreme development of physiology in the 18th, 19th, selectivity has led to investigation of small and early 20th centuries laid the foundation interfering RNAs (siRNAs) and micro-RNAs 1 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag (miRNAs) as therapeutic agents. Similarly, Pharmacology : Study of the properties of short nucleotide chains called antisense drugs and their effects on living organisms. oligonucleotides (ANOs), synthesized to be complementary to natural RNA or DNA, can Paracelsus (Philippus Aureolus interfere with the readout of genes and the Theophastus Bombastus von transcription of RNA. These intracellular Honhenheim) targets may provide the next major wave of advances in therapeutics - Grandfather of Pharmacology - said that drugs can be poisons; what Downside of Drug Therapy differentiates a poison from a remedy is the dose. Unfortunately, the medication-consuming public is still exposed to vast amounts of inaccurate or unscientific information Drug: Any chemical agent other than food regarding the pharmacologic effects of that affects the structure and function of chemicals. This has resulted in the irrational living organisms. use of innumerable expensive, ineffective, and sometimes harmful remedies and the growth of a huge “alternative health care” Four Divisions of Pharmacology industry. Furthermore, manipulation of the 1. Pharmacodynamics - study of how drugs legislative process in the United States has produce effects on living organisms. Studies allowed many substances promoted for the mechanism health—but not promoted specifically as “drugs”—to avoid meeting the Food and Drug Administration (FDA) standards described in the second part of this chapter. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of critical thinking about public health issues have led to rejection of medical science by a segment of the public and to a common tendency to assume that all adverse drug effects are the result of malpractice. A subdivision of Pharmacodynamics is Pharmacokinetics - studies the movement of drugs in the body, including the process of Rule of Thumb in Pharmacology absorption, distribution, localization in tissues, General principles that the student should biotransformation and excretion. remember are (1) that all substances can under certain circumstances be toxic; (2) that the chemicals in botanicals (herbs and plant extracts, “nutraceuticals”) are no different from chemicals in manufactured drugs except for the much greater proportion of impurities in botanicals; and (3) that all dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies. 2. Pharmacotherapeutics - useful application That is, there should be no artificial of drugs in the diagnosis, prevention and separation between scientific medicine and treatment of diseases and in the alteration of “alternative” or “complementary” medicine. normal body functions. Ideally, all nutritional and botanical substances should be tested by the same 3. Toxicology - the study of harmful effects types of randomized controlled trials (RCTs) of drugs, and the conditions under which as synthetic compounds. these harmful effects occur. 2 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag 4. Pharmacy - the art and science of developing, preparing, compounding, and dispensing of drugs. Includes:  Pharmacognosy - the study of sources of drugs  Posology - the study of drug dosages.  Metrology - deals with weights and measure of drugs Pharmacology based on specific purpose 1. Molecular Pharmacology - study of basic mechanisms of drug action on biological systems, aims to determine and interpret the relationship between biologic activity and the structure of molecules or group of molecules. 2. Veterinary Pharmacology - concerned with drugs and how they are used in diagnosis and treatment of animal diseases, and in the intentional alteration of animal physiology. 3. Clinical Pharmacology - concerned with the rational development, effective use, and the proper evalation of drugs for the diagnosis, prevention and cure of the diseases. Terms  Chemotherapy - branch of pharmacology dealing with drugs that selectively inhibit or destroy specific agents of diseases such as bacteria, fungi, viruses and other parasites. Also refers to the use of drugs in the treatment of neoplastic diseases.  Selective toxicity - property of a drug that makes it poisonous to one form of organism but not to another. This property enables drugs to kill parasitic organisms without affecting the patient.  Dose- The quantity of medication to be administered at one time.  Dosage - refers to the determination and regulation of doses.  Potency - a measure of the dose that is required to produce a desirable effect.  Drug family - composed of drugs that have the same MOA (e.g. norephinephrine and epinephrine)  Nutraceutical - Nutrients used as drug. 3 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag ethanol), or gaseous (eg, nitrous oxide). GENERAL PRINCIPLES OF These factors often determine the best PHARMACOLOGY: The Physical And route of administration. Chemical Properties Of Drugs  The various classes of organic compounds— carbohydrates, proteins, The Nature of Drugs lipids, and smaller molecules—are all  Drug may be defined as any substance represented in pharmacology. As noted that brings about a change in biologic above, oligonucleotides, in the form of function through its chemical actions. small segments of RNA, have entered  In most cases, the drug molecule interacts clinical trials and are on the threshold of as an agonist (activator) or antagonist introduction into therapeutics. (inhibitor) with a specific target molecule  A number of useful or dangerous drugs that plays a regulatory role in the biologic are inorganic elements, eg, lithium, iron, system. This target molecule is called a and heavy metals. receptor.  Many organic drugs are weak acids or  In a very small number of cases, drugs bases. This fact has important implications known as chemical antagonists may for the way they are handled by the body, interact directly with other drugs, whereas because pH differences in the various a few drugs (osmotic agents) interact compartments of the body may alter the almost exclusively with water molecules. degree of ionization of weak acids and  Drugs may be synthesized within the body bases (eg, hormones) or may be chemicals not synthesized in the body (ie, xenobiotics). Drug Size  Poisons are drugs that have almost  The molecular size of drugs varies from exclusively harmful effects. However, very small (lithium ion, molecular weight Paracelsus (1493–1541) famously stated [MW] 7) to very large (eg, alteplase [t-PA], that “the dose makes the poison,”meaning a protein of MW 59,050). that any substance can be harmful if  However, most drugs have molecular taken in the wrong dosage. weights between 100 and 1000. The lower  Toxins are usually defined as poisons of limit of this narrow range is probably set by biologic origin, i.e, synthesized by plants or the requirements for specificity of action. animals, in contrast to inorganic poisons  To have a good “fit” to only one type of such as lead and arsenic. receptor, a drug molecule must be sufficiently unique in shape, charge, and The Physical Nature of Drug other properties to prevent its binding to  To interact chemically with its receptor, a other receptors. drug molecule must have the appropriate  To achieve such selective binding, it size, electrical charge, shape, and atomic appears that a molecule should in most composition. cases be at least 100 MW units in size.  Furthermore, a drug is often administered at a location distant from its intended site Drug Reactivy and Drug Bonds (Chemical of action, eg, a pill given orally to relieve a Properties) headache. Therefore, a useful drug must  Drugs interact with receptors by means of have the necessary properties to be chemical forces or bonds. These are of transported from its site of administration three major types: covalent, electrostatic, to its site of action. and hydrophobic.  Finally, a practical drug should be  Covalent bonds are very strong and in inactivated or excreted from the body at a many cases not reversible under reasonable rate so that its actions will be biologic conditions. Thus, the covalent of appropriate duration. bond formed between the acetyl group of  Drugs may be solid at room temperature acetylsalicylic acid (aspirin) and (eg, aspirin, atropine), liquid (eg, nicotine, cyclooxygenase, its enzyme target in 4 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag platelets, is not readily broken. The platelet Drug affinity aggregation–blocking effect of aspirin lasts  For example, carvedilol, a drug that long after free acetylsalicylic acid has interacts with adrenoceptors, has a single disappeared from the bloodstream (about chiral center and thus two enantiomers 15 minutes) and is reversed only by the (Table 1–1). One of these enantiomers, synthesis of new enzyme in new platelets, the (S)(–) isomer, is a potent β-receptor a process that takes several days. blocker. The (R)(+) isomer is 100-fold weaker at the β receptor. Importance of understanding the bonds:  However, the isomers are approximately  Electrostatic bonding is much more equipotent as α-receptor blockers. common than covalent bonding in drug- Ketamine is an intravenous anesthetic. receptor interactions.  The (+) enantiomer is a more potent  Electrostatic bonds vary from relatively anesthetic and is less toxic than the (–) strong linkages between permanently enantiomer. Unfortunately, the drug is still charged ionic molecules to weaker used as the racemic mixture. hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena.  Electrostatic bonds are weaker than covalent bonds.  Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets.”  The specific nature of a particular drug- DOSE-RESPONSE RELATIONSHIP receptor bond is of less practical importance than the fact that drugs that The Receptor bind through weak bonds to their receptors  Therapeutic and toxic effects of drugs are generally more selective than drugs result from their interactions with that bind by means of very strong bonds. molecules in the patient.  This is because weak bonds require a very  Most drugs act by associating with specific precise fit of the drug to its receptor if an macromolecules in ways that alter the interaction is to occur. Only a few receptor macromolecules’ biochemical or types are likely to provide such a precise biophysical activities. fit for a particular drug structure.  This idea, more than a century old, is  Thus, if we wished to design a highly embodied in the term receptor: the selective short-acting drug for a particular component of a cell or organism that receptor, we would avoid highly reactive interacts with a drug and initiates the chain molecules that form covalent bonds and of events leading to the drug’s observed instead choose a molecule that forms effects. weaker bonds.  Receptors largely determine the  A few substances that are almost quantitative relations between dose or completely inert in the chemical sense concentration of drug and pharmacologic nevertheless have significant effects. pharmacologic effects. For example,  The receptor’s affinity for binding a xenon, an “inert” gas, has anesthetic drug determines the concentration of effects at elevated pressures. drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce. 5 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  Receptors are responsible for selectivity of receptors, so-called because their natural drug action. ligands are presently unknown; these may  The molecular size, shape, and prove to be useful targets for future drug electrical charge of a drug determine development. whether—and with what affinity—it  The best-characterized drug receptors are will bind to a particular receptor regulatory proteins, which mediate the among the vast array of chemically actions of endogenous chemical signals different binding sites available in a such as neurotransmitters, autacoids, and cell, tissue, or patient. hormones. This class of receptors  Accordingly, changes in the chemical mediates the effects of many of the most structure of a drug can dramatically useful therapeutic agents. (The molecular increase or decrease a new drug’s structures and biochemical mechanisms of these regulatory receptors are described in a later affinities for different classes of section entitled Signaling Mechanisms & Drug receptors, with esulting alterations in Action.) therapeutic and toxic effects.  Enzymes may be inhibited (or, less  Receptors mediate the actions of commonly, activated) by binding a drug. pharmacologic agonists and antagonists. Examples include dihydrofolate reductase, Some drugs and many natural ligands, the receptor for the antineoplastic drug such as hormones and neurotransmitters, methotrexate; 3-hydroxy-3-methylglutaryl– regulate the function of receptor coenzyme A (HMG-CoA) reductase the macromolecules as agonists; this means receptor for statins; and various protein that they activate the receptor to signal as and lipid kinases. a direct result of binding to it. Some  Transport proteins can be useful drug agonists activate a single kind of receptor targets. Examples include Na+/K+-ATPase, to produce all their biologic functions, the membrane receptor for cardioactive whereas others selectively promote one digitalis glycosides; norepinephrine and receptor function more than another. serotonin transporter proteins that are  Other drugs act as pharmacologic membrane receptors for antidepressant antagonists; that is, they bind to receptors drugs; and dopamine transporters that are but do not activate generation of a signal; membrane receptors for cocaine and a consequently, they interfere with the ability number of other psychostimulants. of an agonist to activate the receptor.  Structural proteins are also important drug Some of the most useful drugs in clinical targets, such as tubulin, the receptor for medicine are pharmacologic antagonists. the anti-inflammatory agent colchicine. Still other drugs bind to a different site on the receptor than that bound by endogenous ligands; such drugs can Receptor on Dose-Response Relationship produce useful and quite different clinical 1) receptors as determinants of the effects by acting as so-called allosteric quantitative relation between the modulators of the receptor. concentration of a drug and the pharmacologic response, Macromolecular Nature of Drug 2) receptors as regulatory proteins and Receptors components of chemical signaling  Advances in molecular biology and mechanisms that provide targets for genome sequencing made it possible to important drugs, and identify receptors by predicted structural 3) receptors as key determinants of the homology to other (previously known) therapeutic and toxic effects of drugs in receptors. patients.  This effort revealed that many known drugs bind to a larger diversity of receptors 1. Median Effective Dose or ED50 than previously anticipated and motivated > dose required to produce the effect in efforts to develop increasingly selective 50% of the population drugs. It also identified a number of orphan 6 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag 2. ED99  This hyperbolic relation resembles the > dose of the drug sufficient to be mass action law that describes the effective in almost all of the individual association between two molecules of a person. given affinity.  This resemblance suggests that drug agonists act by binding to (“occupying”) a 3. Lethal dose or LD50 distinct class of biologic molecules with a > dose required to produce the death of characteristic affinity for the drug. 50% of the population Radioactive receptor ligands have been used to confirm this occupancy 4. Therapeutic index assumption in many drug-receptor systems. > Expresses simultaneously the efficiency and toxicity of the drug  In these systems, drug bound to receptors (B) relates to the concentration > LD50/ED50 of free (unbound) drug (C) as depicted in > A measure of drug safety Figure 2–1B and as described by an > A drug with higher therapeutic index is analogous equation: safer than with lower therapeutic index.  in which Bmax indicates the total concentration of receptor sites (ie, sites bound to the drug at infinitely high concentrations of free drug) and Kd (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed.  This constant characterizes the receptor’s affinity for binding the drug in a reciprocal fashion: If the Kd is low, binding affinity is high, and vice versa. The EC50 and Kd may be identical but need not be, as discussed below. Dose response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the The Dose-Response Curve dose or concentration(abscissa),  This relation between drug concentration transforming the hyperbolic curve. and effect is traditionally described by a hyperbolic curve according to the following equation:  where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect.  7 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag Receptor-Effector Coupling and Spare  For example, the same maximal inotropic Receptor response of heart muscle to  When an agonist occupies a receptor, catecholamines can be elicited even when conformational changes occur in the 90% of β adrenoceptors to which they bind receptor protein that represent the are occupied by a quasi-irreversible fundamental basis of receptor activation antagonist. Accordingly, myocardial cells and the first of often many steps required are said to contain a large proportion of to produce a pharmacologic response. The spare β adrenoceptors overall transduction process that links drug  In other cases, “spareness” of receptors occupancy of receptors and appears to be temporal. For example, β- pharmacologic response is called coupling. adrenoceptor activation by an agonist  Many factors can contribute to nonlinear promotes binding of guanosine occupancy-response coupling, and often triphosphate (GTP) to a trimeric G protein, these factors are only partially understood. producing an activated signaling intermediate whose lifetime may greatly  A useful concept for thinking about this is outlast the agonist-receptor interaction. that of receptor reserve or spare receptors. Receptors are said to be “spare” for a  Here, maximal response is elicited by given pharmacologic response if it is activation of relatively few receptors possible to elicit a maximal biologic because the response initiated by an response at a concentration of agonist that individual ligand receptor-binding event does not result in occupancy of all of the persists longer than the binding event itself. available receptors.  Irrespective of the biochemical basis of  Experimentally, spare receptors may be receptor reserve, the sensitivity of a cell or demonstrated by using irreversible tissue to a particular concentration of antagonists to prevent binding of agonist agonist depends not only on the affinity of to a proportion of available receptors and the receptor for binding the agonist showing that high concentrations of (characterized by the Kd) but also on the agonist can still produce an undiminished degree of spareness—the total number of maximal response (Figure 2–2). receptors present compared with the number actually needed to elicit a maximal biologic response. The Spare Receptors  The concept of spare receptors is very useful clinically because it allows one to think precisely about the effects of drug dosage without having to consider (or even fully understand) biochemical details of the signaling response.  The Kd of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist regardless of the receptor concentration: Antagonist  Antagonist drugs are further divided into two classes depending on whether or not they act competitively or noncompetitively relative to an agonist present at the same time. 8 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  In the presence of a fixed concentration of of the neurotransmitter norepinephrine, agonist, increasing concentrations of a resting heart rate is decreased. However, competitive antagonist progressively inhibit the increase in the release of the agonist response; high antagonist norepinephrine and epinephrine that concentrations prevent the response occurs with exercise, postural changes, or almost completely. Conversely, sufficiently emotional stress may suffice to overcome high concentrations of agonist can this competitive antagonism. Accordingly, surmount the effect of a given the same dose of propranolol may have concentration of the antagonist; that is, the little effect under these conditions, thereby Emax for the agonist remains the same for altering therapeutic response. Conversely, any fixed concentration of antagonist the same dose of propranolol that is useful for treatment of hypertension in one patient may be excessive and toxic to The Schlid Equation another, based on differences between the  The concentration (C′) of an agonist patients in the amount of endogenous required to produce a given effect in the norepinephrine and epinephrine that they presence of a fixed concentration ([I]) of produce. competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of Continuation of antagonist the antagonist. The ratio of these two  The actions of a noncompetitive agonist concentrations (called the dose antagonist are different because, once a ratio) is related to the dissociation constant receptor is bound by such a drug, agonists (Ki) of the antagonist by the Schild cannot surmount the inhibitory effect equation: irrespective of their concentration. In many cases, noncompetitive antagonists bind to the receptor in an irreversible or nearly irreversible fashion, sometimes by forming a covalent bond with the receptor. Partial Agonist  The use of the equation:  Based on the maximal pharmacologic 1. The degree of inhibition produced by a response that occurs when all receptors competitive antagonist depends on the are occupied, agonists can be divided into concentration of antagonist. The two classes: partial agonists produce a competitive β-adrenoceptor antagonist lower response, at full receptor occupancy, propranolol provides a useful example. than do full agonists. Patients receiving a fixed dose of this drug  Partial agonists produce concentration- exhibit a wide range of plasma effect curves that resemble those concentrations, owing to differences observed with full agonists in the presence among individuals in the clearance of of an antagonist that irreversibly blocks propranolol. As a result, inhibitory effects some of the receptor sites (compare on physiologic responses to Figures 2–2 [curve D] and 2–4B). norepinephrine and epinephrine  It is important to emphasize that the failure (endogenous adrenergic receptor agonists) of partial agonists to produce a maximal may vary widely, and the dose of response is not due to decreased affinity propranolol must be adjusted accordingly. for binding to receptors. 2. Clinical response to a competitive  A partial agonist’s inability to cause a antagonist also depends on the maximal pharmacologic response, even concentration of agonist that is competing when present at high concentrations that for binding to receptors. Again, propranolol effectively saturate binding to all receptors, provides a useful example: When this drug is indicated by the fact that partial agonists is administered at moderate doses competitively inhibit the responses sufficient to block the effect of basal levels produced by full agonists (Figure 2–4). 9 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag whether the latter is elevated by endogenous synthesis (eg, a tumor of the adrenal cortex) or as a result of glucocorticoid therapy.  In general, use of a drug as a physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist. Thus, for example, to treat bradycardia caused by increased release of acetylcholine from vagus nerve endings, the physician could use isoproterenol, a β- adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. However, use of this physiologic antagonist would be less rational—and potentially more dangerous—than use of a receptor- specific antagonist such as atropine (a competitive antagonist of acetylcholine receptors that slow heart rate as the direct targets of acetylcholine released from vagus nerve endings). PHARMACODYNAMICS: Drug Other Mechanisms of Drug Antagonism Mechanism & Interaction  Not all mechanisms of antagonism involve interactions of drugs or endogenous Types of Drug Interaction ligands at a single type of receptor, and some types of antagonism do not involve a receptor at all.  For example, protamine, a protein that is positively charged at physiologic pH, can be used clinically to counteract the effects of heparin, an anticoagulant that is negatively charged.  In this case, one drug acts as a chemical antagonist of the other simply by ionic binding that makes the other drug unavailable for interactions with proteins involved in blood clotting.  Another type of antagonism is physiologic antagonism between endogenous regulatory pathways mediated by different receptors. For example, several catabolic actions of the glucocorticoid hormones 1. Transmembrane ligand-gated ion lead to increased blood sugar, an effect channels: that is physiologically opposed by insulin.  The extracellular portion of ligand-gated  Although glucocorticoids and insulin act on ion channels contains the drug-binding quite distinct receptor-effector systems, site. This site regulates the opening of the clinician must sometimes administer the pore through which ions can flow insulin to oppose the hyperglycemic across cell membranes (Figure 2.2A). effects of a glucocorticoid hormone, 10 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  The channel is usually closed until the that cause further actions within the receptor is activated by an agonist, cell. These responses usually last which opens the channel for a few several seconds to minutes. milliseconds. Depending on the ion  Often, the activated effectors produce conducted through these channels, "second messenger" molecules that these receptors mediate diverse further activate other effectors in the cell, functions, including neurotransmission causing a signal cascade effect. and muscle contraction.  A common effector, activated by G. and  For example, stimulation of the nicotinic inhibited by G1, is adenylyl cyclase, receptor by acetylcholine opens a which produces the second messenger channel that allows sodium influx and cyclic adenosine monophosphate potassium outflux across the cell (cAMP). membranes of neurons or muscle cells.  The effector phospholipase C, when This change in ionic concentrations activated by Gq, generates two second across the membrane generates an messengers: inositol1 ,4,5-trisphosphate action potential in a neuron and (IP3) and diacylglycerol (DAG). DAG contraction in skeletal and cardiac and cAMP activate specific protein muscle. kinases within the cell, leading to a  On the other hand, agonist stimulation of myriad of physiological effects. IP3 the A subtype of the y-aminobutyric acid increases intracellular calcium (GABA) receptor increases chloride concentration, which in turn activates influx, resulting in hyperpolarization of other protein kinases. neurons and less chance of generating an action potential. 3. Enzyme-linked receptors:  Drug-binding sites are also found on many voltage-gated ion channels where  This family of receptors undergoes they can regulate channel function. For conformational changes when activated example, local anesthetics bind to the by a ligand, resulting in increased voltage-gated sodium channel, inhibiting intracellular enzyme activity (Figure 2.4). sodium influx and decreasing neuronal  This response lasts for minutes to hours. conduction. The most common enzyme-linked receptors (for example, growth factors and insulin) possess tyrosine kinase 2. Transmembrane G protein-coupled activity. receptors:  When activated, the receptor  The extracellular portion of this phosphorylates tyrosine residues on receptor contains the ligand-binding site, itself and other specific proteins (Figure and the intracellular portion interacts 2.4). Phosphorylation can substantially (when activated) with a G protein. modify the structure of the target protein, There are many kinds of G proteins (for thereby acting as a molecular switch. example, G., G1, and Gq), but all For example, the phosphorylated insulin types are composed of three protein receptor in turn phosphorylates other subunits. proteins that now become active.  The a subunit binds guanosine  Thus, enzyme-linked receptors often triphosphate (GTP), and the ~ and y cause a signal cascade effect like that subunits anchor the G protein in the caused by G protein coupled receptors. cell membrane (Figure 2.3). Binding of an agonist to the receptor increases 4. Intracellular receptors: GTP binding to the a subunit, causing  The fourth family of receptors differs dissociation of the a-GTP complex from considerably from the other three in that the Itt complex. the receptor is entirely intracellular, and,  The a and Itt subunits are then free to therefore, the ligand (for example, interact with specific cellular effectors, steroid hormones) must have sufficient usually an enzyme or an ion channel, 11 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag lipid solubility to diffuse into the cell to interact with the receptor (Figure 2.5).  The primary targets of activated intracellular receptors are transcription factors in the cell nucleus that regulate gene expression. The activation or inactivation of transcription factors alters the transcription of DNA into RNA and subsequently translation of RNA into proteins.  The effect of drugs or endogenous ligands that activate intracellular receptors takes hours to days to occur. Other targets of intracellular ligands are structural proteins, enzymes, RNA, and ribosomes.  For example, tubulin is the target of antineoplastic agents such as paclitaxel, the enzyme dihydrofolate reductase is the target of antimicrobials such as trimethoprim, and the 50S subunit of the bacterial ribosome is the target of macrolide antibiotics such as erythromycin. ` 1. Signal amplification:  A characteristic of G protein-linked and enzyme-linked receptors is the ability to amplify signal intensity and duration via the signal cascade effect. Additionally, activated G proteins persist for a longer duration than does the original agonist- receptor complex.  The binding of albuterol, for example, may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Further prolongation and amplification of the initial signal are mediated by the interaction between G proteins and their respective intracellular targets.  Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response. Systems that exhibit this behavior are said to have spare receptors. 12 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  About 99% of insulin receptors are response as the point at which a "spare; providing an immense functional response occurs or not. reserve that ensures that adequate  For example, a quantal dose response amounts of glucose enter the cell. relationship can be determined in a  On the other hand, only about 5% to 1 population for the antihypertensive drug 0% of the total j3-adrenoceptors in the atenolol. A positive response is defined heart are spare. Therefore, little as a fall of at least 5 mm Hg in diastolic functional reserve exists in the failing blood pressure. heart, because most receptors must be  Quantal dose-response curves are occupied to obtain maximum contractility. useful for determining doses to which 2. Desensitization and down-regulation of most of the population responds. They receptors: have similar shapes as log dose-  Repeated or continuous administration response curves, and the ED50 is the of an agonist or antagonist often leads drug dose that causes a therapeutic to changes in the responsiveness of the response in half of the population. receptor. A. Therapeutic index  The receptor may become desensitized  The therapeutic index (TI) of a drug due to too much agonist stimulation is the ratio of the dose that (Figure 2.6), resulting in a diminished produces toxicity in half the response. This phenomenon, called population {TD50) to the dose that tachyphylaxis, is often due to produces a clinically desired or phosphorylation that renders receptors effective response (ED50) in half unresponsive to the agonist. the population:  In addition, receptors may be  Tl = TD50 I ED 50 internalized within the cell, making them  The Tl is a measure of a drug's unavailable for further agonist safety, because a larger value interaction (down-regulation). indicates a wide margin between  Some receptors, particularly ion doses that are effective and doses channels, require a finite time following that are toxic. stimulation before they can be activated again. During this recovery phase, unresponsive receptors are said to be "refractory.“  Repeated exposure of a receptor to an antagonist, on the other hand, results in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the number of receptors available. Up-regulation of receptors can make cells more sensitive to agonists and/or more resistant to effects of the antagonist.  Another important dose-response B. Clinical usefulness of the therapeutic relationship is that between the dose of Index the drug and the proportion of a  The Tl of a drug is determined using population of patients that responds to it. drug trials and accumulated clinical  These responses are known as quantal experience. These usually reveal a responses, because, for any individual, range of effective doses and a either the effect occurs or it does not. different (sometimes overlapping)  Graded responses can be transformed range of toxic doses. to quantal responses by designating a  Although high Tl values are required predetermined level of the graded for most drugs, some drugs with low 13 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag therapeutic indices are routinely used  Solubility in the ultra filtrate: Drugs with to treat serious diseases. hydrophilic character are most  In these cases, the risk of commonly excreted in urine, in their experiencing adverse effects is not as unaltered state, while fat soluble great as the risk of leaving the pharmacons may be subject to disease untreated. Figure 2.14 shows metabolism (to form water-soluble the responses to warfarin, an oral compounds before being excreted). anticoagulant with a low TI, and  Occasionally (e.g., quinolones and old penicillin, an antimicrobial drug with a acetyl sulphonamides) a metabolite is large Tl. less soluble than the parenteral pharmacon in the concentrate acid ultra filtrate from the proximal convoluted tubule. In this case, there is the risk of precipitation of the drug in the convoluted tubules preventing renal function. 2. Urinary pH  Renal excretion of weak acidic or basic drugs is closely related to urinary pH. So, weak acids are eliminated better when the urine is alkaline, while the weak bases in acidic urine. When the elimination is reduced (due to unfavorable pH), it will activate the metabolic processes (to make substances more soluble), thereby increasing the rate of conjugated compounds. 3. Coupling of plasma proteins MAIN FACTORS INFLUENCING DRUG  Medicinal substances coupled to plasma EFFECT proteins cannot be metabolized until (fr. Dr. Romeo Teodor Cristina) they are severed from their links and transformed in free fraction. As a result, Factors that Influence Drug Metabolism their half-life is even longer as the 1. Physiological (pharmacokinetic) factors medicine is of a higher percentage of  Renal blood flow: Effective couplings. hemodynamic is essential for renal function, this function influences the rate 4. Enzymatic Induction of drug excretion the most, trough the  Enzymatic induction means the fact that glomerular ultra filtration is stimulation of the activity of liver dependent on the pressure of filtration. enzymes; under the action of  In the healthy animal, the kidney xenobiotics (non-biological) this includes receives about 25% of the cardiac drugs and pesticides, etc. output, converts about 1/5 of this in  These inductors speed up the glomerular ultra filtrate, then reabsorbs metabolism, by increasing the rate of about 99% of the filtrate. synthesis of the enzymes.  For a drug that is eliminated massively  So far, we know more than 200 by excretion, the rate of blood flow substances that are considered enzyme through the kidneys is an important inducers, having very different chemical determinant of its existence in the body, structures. A correlation cannot be (ex. digoxin and gentamicin). 14 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag established between the chemical > chloralhydrate, is very effective in structure and the inductive effect. horses, but it is hardly supported by  The most studied enzyme inducer, cows. phenobarbital, is considered to be the > apomorphine in dogs, produces prototype of this action, given that it vomiting constantly, whilst in pigs its boosts the metabolic activity for action is inconsistent. numerous medicinal substances. > vomitive drugs in omnivores and Through enzyme self inductance, some carnivores can become drugs after repeated administration can ruminatories in ruminants. stimulate their own metabolism.  Sensitivity depending on the species:  Most of the enzymes responsible for the  pigs and poultry to salt, biotransformation are in the liver,  large ruminants to mercury specifically in the endoplasmic reticulum (ER), in the microsomes.  cats to phenolic drugs.  doses in ruminants, increased by 20 - 40% compared to equines, (drugs 5. Enzyme inhibition stagnate and even suffer  There are some substances that inhibit decomposition in the fore stomach. the activity of hepatic microsomal Equines and some dog breeds are enzymes, for example: sensitive to injectable Ivomec, due piperonylbuthoxid, piperonyl-sulfoxide, to the permeability of the meningeal sesamex, cloramphenicol, ketoconazole, blood brain barrier common in some cimetidine etc. individuals. In the case of using  For example long-term administration of drugs that are common for human chlortione will lead to a marked inhibition and veterinary use, the doses for of microsomal rat liver enzymes. In animals are: addition to the possibility of Correspondence Animal-Human Dose decomposition which is general and (after Suciu, 1990) non-specific, there are a number of Species Increasing the dose from humans specific mechanisms for some pharmacons, within which a series of the Cow x 24 body’s own substances are involved. Horse x 16 Sheep x3 Animal Related Factors Goat x3 1. Species Pig x3  Among the species of animals, there are some examples of extreme resistance or Dog Equal to that of humans sensitivity to drugs. Species influence Cat 1/2 of the human dose the effect, the cause being mainly: genetic or morphopathological factors. There are species that react differently Anatomy of Digestive System to the same drug.  In ruminants, food passage rate is slow,  Examples: and the intestinal content is large, in > dogs react to morphine through comparison to the rate of absorption. hypnosis or vomiting, whilst  Therefore, there is much time > cats and large ruminants will react available for absorption, while the large to the same drug through over volume of intestinal contents dilutes the excitement / hyperactivity orally administered drug, thus slowing > in cows alcohol is well supported as the rate of absorption. One problem is a narcotic, whilst horses are related to the compartment into which sensitive, the orally administered drug enters, influenced by the work of the esophageal tray. 15 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  Drugs with weakly alkaline character 4. Gender tend to accumulate in weak acid 5. Gestation ruminal juice, which has a very large  Gestation involves contraindications (ex: volume in ruminant species. purgatives or corticosteroids, which can induce abortion). Teratogenic effects are 2. Individuality/breed investigated and taken into account in 3. Age the evaluation of each new drug (for veterinary use too). The elimination of  Very young and very old animals drugs by drinking milk is another generally require the administration of example for toxicity risk related to reduced doses due to the possibility of animal gender. organ dysfunctions. In old animals dysfunctions are mostly degenerative, at 6. Feeding the hepatic and renal level. 7. Health status  In young animals excretory and 8. Genetic factors metabolic functions are not yet  Some breeds may be sensitive to the developed (ex: chloramphenicol is toxic action of drugs. for piglets due to the absence of suitable  This can be explained by the absence of enzymatic equipment). some specific enzymes (ex: deficiency  Youngsters, infants, will receive reduced in glucose-6-phosphate dehydrogenase doses with 30-40% (small animals) or in some breeds is associated with even 50-70% (youngsters up to 1 year toxicity). old in large animals).  Such anomalies have led to the  There are situations when, in compared emergence of a new branch, to adults, youngsters are more resistant Pharmacogenetics. to therapeutic doses (ex: barbiturates in  When response to a drug is abnormal piglets). They will receive doses reduced qualitatively or quantitatively, by 20-40% because the activity of some idiosyncrasy intervenes. enzymatic systems may be reduced or even abolished.  Sometimes idiosyncrasy can be explained genetically. In the case of improved breeds, the effect of the drug may be altered due to sensitizing genetic factors Susceptibility:  Is the term used to describe an abnormal quantitative response and is demonstrated by the so called hyperactive (a patient particularly sensitive to the action of a drug).  Such variations are frequently dependent on the atypical elimination rates. Time Administration & Pathology  A drug administered orally, is more rapidly and completely absorbed if the anterior digestive segment is empty, but often, it is irritating to the tissue.  The recognition of the existence of the circadian rhythm within physiological 16 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag functions has already found application Concomitant drug therapy in drug administration.  Concomitant use of several remedies  Generally, sick animals have a requires the introduction of several diminished drug detoxification capacity. variables in calculating doses, because of An increased or decreased rate of the potential interactions between intestinal passage will change: administered components and patient.  absorption period, and therefore,  Use of ”shot-gun” type products or  the proportion of the absorbed dose. polypharmacy (active substances Also: associated without a certain diagnosis) is a simple substitute to a certain, professional  hypoalbuminemia decreases the diagnosis, often with undesirable coupling rate. implications.  heart failure will be accompanied by liver and kidney failure. Amplified resistance  enteritis reduces intestinal transit time and therefore may reduce the  To reduce the incidence of toxicity, one or absorption of drugs. more drugs can be administered simultaneously.  peripheral circulation is inadequate in states of shock of any origin,  The final answer can be quantitative = with preventing absorption of s.c. injections. the amount of expected responses in the case of independent administration = medication summation Tolerance & Intolerance  If the answer is higher than what can be  Tolerance to a drug disappears with the explained by simple summation, We are discontinuation of the treatment (ex: dealing with the effect of potentiation or dogs may exhibit tolerance to the synergism. narcotic effect of barbiturates).  Resistance to drugs can occur for many Diminished response reasons:  In multidrug therapy it happens that the > when a drug is a specific antigen, observed response is less than the sum of and antibodies may be produced for components responses = antagonism it, inactivatingit; between the drugs used. >(metabolic) resistance of  sometimes the antagonism can be Trichostrongylus population to explained by the fact that a drug interferes therapeutic doses of or performs an action, opposite to the benzimidazoles. other.  Therapeutic indications: This  the antagonism is often dependent on a assessment is purely therapeutic and mechanism that involves pharmacological includes : or physiological incompatibility.  dosage adjustment based on the nature of the disease and Incompatibilities  depending on the causative agent (ex: therapy of acute fasciolosis  The associated components may be requiring higher doses of the same incompatible: drug as in the chronic form). A. physically or  often the use of high doses is B. chemically, when reacting with each similar to increasing the risk of other toxicity, to the benefit of receiving  Often, the need for administration tempts increased effects. the clinician to combine remedies. In the  certain antibiotics are so toxic that case that, the compatibility of the remedies their systemic administration is only is unknown, concomitant use is done case of emergency (ex: contraindicated. polymyxin). 17 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  Pharmacodynamic incompatibility is the been demonstrated by administering to use of adrenaline as a cardiac stimulant in animals of the same species, same the anesthetized animals with a drug that gender, weight and age of CNS, sensitizes the heart to adrenaline action depressants (hypnotic or narcotic), it (e.g. cyclopropane). was found that the intensity and duration of the effect was different. In most animals, narcotic sleep duration was Amplified toxicity average, but there were also identified  The toxicity of a drug can increase several limit situations (too long or too short times, depending on the situation. sleep).  Two drugs whose degradation pathways are the same, can enter in competition if, 2. Exogenous compounds the metabolic pathway has limited capacity. If one of them has a narrow therapeutic  Chemical substances from the range, toxicity is facilitated. environment, (ex. insecticides, dyes, feed additives, auto oxidant substances  Competition for coupling sites is another etc.), ingested by animals through food mechanism which may increase the risk of and water, or entering the body in other toxicity of drugs which engage massively ways, have a definite influence on the to proteins. processes of metabolism. Many of them  Drugs whose plasma half-life is much have the effect of enzyme induction, shorter than the biological half-life, so- especially after repeated contacts, when called: “hit-and-run” (achieve plasma they produce a higher rate of levels rapidly, but are eliminated as quickly) metabolism (2 to 10 times). causes increased responses to other drugs. 3. Stress factor  Adverse conditions: cold, humidity, Reduced Toxicity agglomeration, noise, increase the  A common example of low toxicity can be metabolic activity of microsomal the premedication with tranquilizers before enzymes, by stimulating the pituitary - the induction of anesthesia. adrenal reflex arch. Stress increases the  This simplifies the process of induction adrenal ascorbic acid, observed in and reduces the dose of barbiturate treatments with phenobarbital (enzyme required; therefore it is useful in reducing inducer). the risk of anesthesia.  Small amounts of radiation (ionizing, in  The antidote in poisonings exploits both particular) can act as stressors pharmacokinetic and pharmacodynamic increasing the activity of microsomal interactions (competitive antagonism) in enzyme systems. Radiation reduces the benefit of the patient. drug metabolization by their effect on NADPH formation (nicotinamide adenine dinucleotide phosphate oxidaze) and Exogenous Factors glucuronide conjugation. 1. Circadian rhythm  Chronopharmacology revealed differences in drug metabolism related to circadian rhythms in humans. It has been found that the most active metabolism is reported around 2 AM, and the lowest at about 2 PM. These metabolic phases have a maximum and a minimum specific value in animals too.  In the case of sleep, the effect of the drug is closely related to the type of nervous activity of the animal. This has 18 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag  The anatomical disposition and PHARMACOKINETICS (introduction) permeability of vascular endothelium (the Drug disposition is divided into four stages cell layer that separates intravascular from designated by the acronym ‘ADME’: extravascular compartments) varies from 1. Absorption from the site of administration one tissue to another. 2. Distribution within the body  Gaps between endothelial cells are packed with a loose matrix of proteins that 3. Metabolism act as filters, retaining large molecules and 4. Excretion letting smaller ones through.  In other organs (e.g. the liver and spleen), Drug molecules move around the body in endothelium is discontinuous, allowing free two ways: passage between cells. In the liver, hepatocytes form the barrier between A. bulk flow (i.e. in the bloodstream, intra- and extravascular compartments and lymphatics or cerebrospinal fluid) take on several endothelial cell functions. B. diffusion (i.e. molecule by molecule,  Fenestrated endothelium occurs in over short distances). endocrine glands, facilitating transfer to  The chemical nature of a drug makes no the bloodstream of hormones or other difference to its transfer by bulk flow. The molecules through pores in the cardiovascular system provides a rapid endothelium. Formation of fenestrated long-distance distribution system. endothelium is controlled by a specific  In contrast, diffusional characteristics differ endocrine gland-derived vascular markedly between different drugs. In endothelial growth factor (dubbed EG- particular, ability to cross hydrophobic VEGF). diffusion barriers is strongly influenced by  There are four main ways by which small lipid solubility. molecules cross cell membranes (Fig. 9.1):  Aqueous diffusion is part of the overall 1. by diffusing directly through the lipid; mechanism of drug transport, because it is 2. by combination with a solute carrier this process that delivers drug molecules (SLC) or other membrane transporter; to and from the non-aqueous barriers. 3. by diffusing through aqueous pores  The rate of diffusion of a substance formed by special membrane depends mainly on its molecular size, the glycoproteins (aquaporins) that traverse diffusion coefficient being inversely the lipid; proportional to the square root of molecular weight. 4. by pinocytosis.  Consequently, while large molecules  Of these routes, diffusion through lipid and diffuse more slowly than small ones, the carrier-mediated transport are particularly variation with molecular weight is modest. important in relation to pharmacokinetic mechanisms.  Diffusion through aquaporins is probably Transport of Molecules important in the transfer of gases such as  Cell membranes form the barriers between carbon dioxide, but the pores are too small aqueous compartments in the body. A in diameter (about 0.4 nm) to allow most single layer of membrane separates the drug molecules (which usually exceed 1 intracellular from the extracellular nm in diameter) to pass through. compartments.  Consequently, drug distribution is not  An epithelial barrier, such as the notably abnormal in patients with genetic gastrointestinal mucosa or renal tubule, diseases affecting aquaporins. consists of a layer of cells tightly  Pinocytosis involves invagination of part of connected to each other so that molecules the cell membrane and the trapping within must traverse at least two cell membranes the cell of a small vesicle containing (inner and outer) to pass from one side to extracellular constituents. The vesicle the other. contents can then be released within the 19 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag cell, or extruded from its other side. This the extent of renal elimination – can be mechanism is important for the transport of predicted from knowledge of its lipid some macromolecules (e.g. insulin, which solubility. crosses the blood–brain barrier by this process), but not for small molecules. Diffusion through lipid  Non-polar molecules (in which electrons are uniformly distributed) dissolve freely in membrane lipids, and consequently diffuse readily across cell membranes.  The number of molecules crossing the membrane per unit area in unit time is determined by the permeability coefficient, Ion Trapping P, and the concentration difference across  Ionization and membrane permeability the membrane. affect not only the rate at which drugs  Permeant molecules must be present permeate membranes but also the steady- within the membrane in sufficient numbers state distribution of drug molecules and must be mobile within the membrane between aqueous compartments. if rapid permeation is to occur.  Lipid-soluble molecules diffuse into cells  Thus, two physicochemical factors where they can be metabolized (e.g. by contribute to P, namely solubility in the esterases); this may liberate a functionally membrane (which can be expressed as a important charged (and hence impermeant) partition coefficient for the substance metabolite, which is consequently trapped distributed between the membrane phase within the cell. and the aqueous environment) and diffusivity, which is a measure of the mobility of molecules within the lipid and is expressed as a diffusion coefficient.  The diffusion coefficient varies only modestly between conventional drugs, as noted above, so the most important determinant of membrane permeability for conventional low molecular-weight drugs is the partition coefficient (Fig. 9.2).  Many pharmacokinetic characteristics of a drug – such as rate of absorption from the gut, penetration into different tissues and 20 DOCTOR OF VETERINARY MEDICINE | PRELIMS | 1ST SEMESTER | A.Y. 2024-2025  BASIC VETERINARY PHARMACOLOGY Kay Abawag Solute carrier  At therapeutic concentrations in plasma,  Two structurally related SLCs of many drugs exist mainly in bound form. importance in drug distribution are the  The fraction of drug that is unbound and organic cation transporters (OCTs) and pharmacologically active in plasma can be organic anion transporters (OATs). less than 1%, the remainder being  The carrier molecule consists of a associated with plasma protein. transmembrane protein that binds one or  Seemingly small differences in protein more molecules or ions, changes binding (e.g. 99.5% vs 99.0%) can have conformation and releases its cargo on the large effects on free drug concentration other side of the membrane. and drug effect. Such differences are  Such systems may operate purely common between human plasma and passively, without any energy source; in plasma from species used in preclinical this case, they merely facilitate the drug testing, and must be taken into process of transmembrane equilibration of account when estimating a suitable dose a single transported species in the for ‘first time in human’ studies during drug direction of its electrochemical gradient. development.  P-glycoproteins (P-gp; P for ‘permeability’),  The most important plasma protein in which belong to the ABC transporter relation to drug binding is albumin, which superfamily, are the second important binds many acidic drugs (e.g. warfarin, class of transporters, and are responsible non-steroidal anti-inflammatory drugs, for multidrug resistance in cancer cells, sulfonamides) and a smaller number of many of which express an ATP dependent basic drugs (e.g. tricyclic antidepressants pump with broad specificity called and chlorpromazine). multidrug resistance protein 1 (mdr1).  Other plasma proteins, including β-globulin  This is expressed in animals, fungi and and an acid glycoprotein that increases in bacteria and may have evolved as a inflammatory disease, have also been defence mechanism against toxins. implicated in the binding of certain basic drugs such as quinine. The amount of a  P-gps are present in renal tubular brush drug that is bound to protein depends on border membranes, in bile canaliculi, in three factors: astrocyte foot processes in brain microvessels, and in the gastrointestinal 1. the concentration of free drug tract. 2. its affinity for the binding sites  They play an important part in absorption, 3. the concentration of protein distribution and elimination of many drugs,  The usual concentration of albumin in and are often co-located with SLC drug plasma is approximately 0.6 mmol/L (4 carriers, so that a drug that has been g/100 mL). With two sites per albumin concentrated by, for example, an OAT molecule, the drug-binding capacity of transporter in the basolateral membrane of plasma albumin would therefore be about a renal tubular cell may then be pumped 1.2 mmol/L. out of the cell by a P-gp in the lumenal  For most drugs, the total plasma membrane. concentration required for a clinical effect  In addition to the processes so far is much less than 1.2 mmol/L, so with described, which govern the transport of usual therapeutic doses the binding sites drug molecules across the barriers are far from saturated, and the