Pharmacology (Prelim) Reviewer PDF

PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 1 INTRODUCTION TO PHARMACOLOGY WHAT IS PHARMACOLOGY? Pharmacology can be defined as the study of substances...

PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 1 INTRODUCTION TO PHARMACOLOGY WHAT IS PHARMACOLOGY? Pharmacology can be defined as the study of substances that interact with living systems through chemical processes. These interactions usually occur by binding the substance to regulatory molecules and activating or inhibiting normal body processes. Another definition, Pharmacology is the science which involves all aspects of the FOUR DIVISIONS OF action of drugs on the living system. It is PHARMACOLOGY the study of the therapeutic value and/or 1. Pharmacodynamics is the study potential toxicity of chemical agents and of how drugs act on the body while biological systems. It targets every aspect the subdivision of of the mechanisms for the chemical pharmacodynamics, actions of both traditional and novel pharmacokinetics is the study of therapeutic agents. how the body acts on drugs. Pharmacodynamic and These substances may be chemicals pharmacokinetic aspects of the administered to achieve a beneficial action of chemical agents are therapeutic effect on some process within applicable to all related areas of the patient or for their toxic effects on study, including toxicology and regulatory processes in parasites infecting therapeutics. the patient. Such deliberate therapeutic applications may be considered the proper 2. Pharmacotherapeutics is a useful role of medical pharmacology, which is application of drugs in the often defined as the science of diagnosis, prevention and substances used to prevent, diagnose, treatment of diseases and in the and treat disease. Toxicology is the alteration of normal body functions. branch of pharmacology that deals with the undesirable effects of chemicals on 3. Toxicology the study of harmful living systems, from individual cells to effects of drugs, and the conditions humans to complex ecosystems (Figure under which these harmful effects 1–1) occur. Figure 1-1: Basic Principles 4. Pharmacy - the art and science of developing, preparing, compounding, and dispensing of drugs. Another definition, is the science that deals with the  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 2 preparation, formulation, experimental intervention in enzyme manufacture, standardization, activity and brain neurotransmitter levels preservation. and dispensing of and metabolism. drugs. The term pharmacy also indicates the place where drugs Endocrine pharmacology - is the study are dispensed or sold. of drugs that are either hormones or hormone derivatives, or drugs that may BRANCHES OF PHARMACOLOGY modify the sections of normally secreted Veterinary Pharmacology - concerned hormones. with drugs and how they are used in diagnosis and treatment of animal Clinical pharmacology - concerned with diseases, and in the intentional alteration the rational development, effective use, of animal physiology. and the proper evalation of drugs for the diagnosis, prevention and cure of the Neuropharmacology - is the study of diseases. neurophysiological or neurobiochemical functions of the nervous system including Chemotherapy - is a branch of the brain, spinal cord, and the nerves that pharmacology dealing with drugs that are modified by drug action. selectively inhibit or destroy specific agents of diseases such as bacteria, Cardiovascular pharmacology - fungi, viruses and other parasites. Also concerns the effects of drugs on the heart, refers to the use of drugs in the treatment the vascular system, and those parts of of neoplastic diseases. the nervous and endocrine systems that participate in regulating cardiovascular PHARMACOLOGY RELATED TERMS function. Pharmacotherapeutics is a useful application of drugs in the diagnosis, Molecular pharmacology - deals with the prevention and treatment of diseases and biochemical and biophysical in the alteration of normal body functions. characteristics of interactions between drug molecules and those of the cell. It is Pharmacometrics is the study of the molecular biology applied to techniques used in the measurement of pharmacology and toxicology. drug effects to the administered dose of drug. Biochemical pharmacology - is study of basic mechanisms of drug action on Pharmacogenetics is the study of biological systems, aims to determine and genetically determined variations in interpret the relationship between biologic animals that are revealed by the effect of activity and the structure of molecules or drugs. group of molecules. Pharmacogenomics This term describes Behavioral pharmacology - studies the the use of genetic information to guide the effects of drugs on behavior of organism. choice of drug therapy on an individual It includes topics such as the effects of basis. psychoactive drugs on the phenomena of learning, memory, wakefulness, sleep and Pharmacoepidemiology is the study of the behavioral consequences of drug effects at the population level. It is  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 3 concerned with the variability of drug agents to cure, ameliorate, or prevent effects between individuals in a population disease. and between populations. DRUG RELATED TERMS Pharmacoeconomics aims to quantify in Drug is any chemical agent except food economic terms the cost and benefit of that is used to promote or safeguard the drugs used therapeutically. health of human beings or animals. It is also defined as any substance or product Pharmacognosy is the study of the that is used or intended, to be used to source of drugs. It also deals with the modify or explore physiological systems or physical and chemical properties of drugs. pathological states for the benefit of the recipient. The word drug is derived from a Materia medica is an obsolete didactic French word 'Drogue' meaning a dry herb. subject that was concerned with pharmacy, posology, pharmacognosy and Over the counter drugs are those indications for therapeutic use of the drug. preparations that can be sold without any prescription because they can be Metrology is the study of weights and adequately labeled for layman use. measures as applied to the preparation and administration of drugs. Prescription drugs are drugs that can be used only on the order of a licensed Chronopharmacology is the study of veterinarian/physician/dentist/surgeon how the effects of drugs vary with based on a prescription. They are also biological timing and endogenous known as legend drugs. periodicities. Essential drugs are agents that satisfy Pharmacovigilance is the science and the healthcare needs of majority of the activities relating to the detection, population. They should therefore be assessment, understanding and available at all times in adequate amounts prevention of adverse effects or any other and in appropriate dosage form. drug-related problem. Pro-drugs are drugs that are inactive or Pharmacoepidemiology is the study of have a low order of activity in the form the use of and the effects of drugs in large administered and are metabolised to the numbers of people. active form in the body. Therapeutics focuses on the actions and effects of drugs and other chemical agents Hard drugs are drugs used for with physiological, biochemical, non-medical purposes that are liable to microbiological, immunological, or disable the individual seriously as a behavioral factors influencing disease. functioning member of the society by Each of these areas is closely interwoven inducing severe psychological and/or with the subject matter and experimental physical dependence. eg. Heroin Soft techniques of physiology, biochemistry, drugs are drugs used for non-medical cellular biology, microbiology, immunology, purposes that are less dependence genetics, and pathology. The ultimate goal producing. There may be psychological of Pharmacology is to design chemical dependence but not physical dependence,  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 4 except with heavy dose. eg. Dosage is the determination and Amphetamine. regulation of doses. Nootropic drugs are drugs that affect the Posology is the study of drug dosages, intellect. These drugs are claimed to which varies with the species of animals, enhance learning, increase brain the intended effect of the drug and the resistance to stress including hypoxia and individual tolerance or susceptibility. stimulate brain metabolism especially in senile patients. eg. Piracetam Orphan Loading dose is one or a series of doses drugs are drugs or biological products that may be given at the onset of therapy useful for diagnosis/treatment/prevention with the aim of achieving the target of a rare disease condition for which there concentration rapidly. is no reasonable expectation that the cost of developing and marketing it will be Maintenance dose is a series of relatively recovered from the sales of that drug. Eg. small doses that follow the loading dose in Acetylcysteine. These drugs may be life order to maintain an effective saving for some patients, but are not concentration in the bio phase. commercially available. Potency is the measure of the dose that is Placebo is a vehicle for cure by required to produce a desirable effect. suggestion and is surprisingly often successful though only temporarily. It can Drug family composed of drugs that have be used as a control in scientific the same MOA (e.g. norepinephrine and evaluation of drugs and to benefit or epinephrine) please a patient not by pharmacological actions but by psychological means (Latin: Nutraceutical refers to nutrients used as Placebo - I shall be pleasing or drugs. acceptable). Placebo reactor is an individual who reports changes of physical SOURCES OF DRUGS and mental state after taking a Plant Sources pharmacologically inert substance. Many drugs available from plants are even today used in the treatment of pathological Selective toxicity - property of a drug that conditions. With the increasing tendency makes it poisonous to one form of for the use of alternative medicine, this organism but not to another. This property source has gained more importance in the enables drugs to kill parasitic organisms recent past. The pharmacological activities without affecting the patient. of plants are attributed to certain active principles in plants. It includes the DOSE RELATED TERMS following: Dose of the drug is an estimated amount Alkaloids of a drug that, when administered by a Glycosides particular route to a certain species, is Oils most likely to produce a certain intensity of Tannins response. It is the quantity of medication Saponins to be administered at one time. Resins Gums  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 5 types, including a few that are still Animal Sources recognized as useful drugs today. Most, The body fluids or glands of animals are however, were worthless or actually also natural drug sources. The drugs harmful. obtained from animal sources include: hormones, such as insulin In the last 1500 years, sporadic attempts oils and fats (usually fixed), such were made to introduce rational methods as cod-liver oil into medicine, but none was successful enzymes, which are produced by owing to the dominance of systems of living cells and act as catalysts, thought (“schools”) that purported to such as pancreatin and pepsin explain all of biology and disease without vaccines, which include the need for experimentation and suspensions of killed, modified, or observation. These schools promulgated attenuated microorganisms, or bizarre notions such as the idea that antigenic materials obtained from disease was caused by excesses of bile or these. blood in the body, that wounds could be healed by applying a salve to the weapon Synthetic Sources that caused the wound, and so on. A number of drugs synthesized in the laboratory are used most Around the end of the 17th century, commonly. Even natural products reliance on observation and such as hormones, antimicrobials experimentation began to replace etc. are also synthesized in the theorizing in physiology and clinical laboratory. medicine. As the value of these methods in the study of disease became clear, Microbial Sources physicians in Great Britain and on the Microbes provide an important source of European continent began to apply them drugs, especially antibiotics. All the to the effects of traditional drugs used in antibiotics used against a variety of their own practices. Thus, materia pathogens and also cancer are obtained medica—the science of drug preparation from fungi, bacteria or actinomycetes. and the medical uses of drugs—began to Some systemic drugs like ergot alkaloids develop as the precursor to pharmacology. (fungal source) are also obtained from However, any real understanding of the microbes. mechanisms of action of drugs was prevented by the absence of methods for Penicillin (Penicillium notatum) purifying active agents from the crude Streptomycin materials that were available and—even Tetracyclines more—by the lack of methods for testing Chloramphenicol (Streptomyces hypotheses about the nature of drug sp.) actions. HISTORY OF PHARMACOLOGY In the late 18th and early 19th Prehistoric people undoubtedly centuries, François Magendie and his recognized the beneficial or toxic effects of student Claude Bernard began to many plant and animal materials. Early develop the methods of experimental written records list remedies of many physiology and pharmacology. Advances in chemistry and the further development  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 6 of physiology in the 18th, 19th, and early Phase III trials test if a new 20th centuries laid the foundation needed treatment is better than a for understanding how drugs work at the standard treatment. organ and tissue levels. Phase IV trials find more information about long-term Paradoxically, real advances in basic benefits and side effects. pharmacology during this time were accompanied by an outburst of Around the 1940s and 1950s, a major unscientific claims by manufacturers and expansion of research efforts in all areas marketers of worthless “patent medicines.” of biology began. As new concepts and Not until the concepts of rational new techniques were introduced, therapeutics, especially that of the information accumulated about drug controlled clinical trial, were action and the biologic substrate of that reintroduced into medicine—only about 60 action, the drug receptor. years ago—did it become possible to During the last 60 years, many adequately evaluate therapeutic claims. fundamentally new drug groups and new members of old groups were introduced. The last four decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function can only be guessed. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation; they are strongly Three Stages of Controlled Clinical influenced by other receptors and by Trial companion regulatory proteins. 1. Laboratory trial Pharmacogenomics—the relation of the 2. Animal trial individual’s genetic makeup to his or her 3. Human/Clinical trial - involves response to specific drugs—is becoming phases. an important part of therapeutics. Phase I trials test if a new Decoding the genomes of many treatment is safe and look species—from bacteria to humans—has for the best way to give the led to the recognition of unsuspected treatment. relationships between receptor families Phase II trials test if one and the ways that receptor proteins have type of disease responds to evolved. the new treatment.  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 7 Discovery that small segments of RNA from chemicals in manufactured can interfere with protein synthesis with drugs except for the much greater extreme selectivity has led to investigation proportion of impurities in of small interfering RNAs (siRNAs) and botanicals; and micro-RNAs (miRNAs) as therapeutic 3. that all dietary supplements and all agents. Similarly, short nucleotide chains therapies promoted as called antisense oligonucleotides health-enhancing should meet the (ANOs), synthesized to be complementary same standards of efficacy and to natural RNA or DNA, can interfere with safety as conventional drugs and the readout of genes and the transcription medical therapies. of RNA. These intracellular targets may provide the next major wave of advances That is, there should be no artificial in therapeutics. separation between scientific medicine and “alternative” or “complementary” Unfortunately, the medication-consuming medicine. Ideally, all nutritional and public is still exposed to vast amounts of botanical substances should be tested by inaccurate or unscientific information the same types of randomized controlled regarding the pharmacologic effects of trials (RCTs) as synthetic compounds. chemicals. This has resulted in the irrational use of innumerable expensive, THE NATURE OF DRUGS ineffective, and sometimes harmful remedies and the growth of a huge In the most general sense, a drug may be “alternative health care” industry. defined as any substance that brings Furthermore, manipulation of the about a change in biologic function legislative process in the United States through its chemical actions. In most has allowed many substances promoted cases, the drug molecule interacts as an for health—but not promoted specifically agonist (activator) or antagonist as “drugs”—to avoid meeting the Food (inhibitor) with a specific target molecule and Drug Administration (FDA) that plays a regulatory role in the biologic standards. Conversely, lack of system. This target molecule is called a understanding of basic scientific principles receptor. In a very small number of in biology and statistics and the absence cases, drugs known as chemical of critical thinking about public health antagonists may interact directly with issues have led to rejection of medical other drugs, whereas a few drugs science by a segment of the public and to (osmotic agents) interact almost a common tendency to assume that all exclusively with water molecules. adverse drug effects are the result of malpractice. Drugs may be synthesized within the body (eg, hormones) or may be chemicals not General principles that the student should synthesized in the body (ie, xenobiotics). remember Poisons are drugs that have almost exclusively harmful effects. However, 1. that all substances can under Philippus Aureolus Theophrastus certain circumstances be toxic; Bombastus von Hohenheim or also 2. that the chemicals in botanicals known as Paracelsus (1493–1541) (herbs and plant extracts, famously stated that “the dose makes “nutraceuticals”) are no different the poison,” meaning that any substance  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 8 can be harmful if taken in the wrong and heavy metals. Many organic drugs are dosage. Toxins are usually defined as weak acids or bases. This fact has poisons of biologic origin, ie, synthesized important implications for the way they are by plants or animals, in contrast to handled by the body, because pH inorganic poisons such as lead and differences in the various compartments of arsenic. the body may alter the degree of ionization of weak acids and bases. THE PHYSICAL NATURE OF DRUG SIZE DRUGS The molecular size of drugs varies from very small (lithium ion, molecular weight To interact chemically with its receptor, a [MW] 7) to very large (eg, alteplase [t-PA], drug molecule must have the: a protein of MW 59,050). However, most drugs have molecular weights between appropriate size, electrical charge, 100 and 1000. shape, and atomic composition. a drug is often administered at a The lower limit of this narrow range is location distant from its intended probably set by the requirements for site of action, eg, a pill given orally specificity of action. To have a good “fit” to to relieve a headache. Therefore, a only one type of receptor, a drug molecule useful drug must have the must be sufficiently unique in shape, necessary properties to be charge, and other properties to prevent its transported from its site of binding to other receptors. To achieve administration to its site of action. such selective binding, it appears that a Finally, a practical drug should be molecule should in most cases be at least inactivated or excreted from the 100 MW units in size. The upper limit in body at a reasonable rate so that molecular weight is determined primarily its actions will be of appropriate by the requirement that drugs must be duration. able to move within the body (eg, from the site of administration to the site of action). Drugs may be solid at room temperature Drugs much larger than MW 1000 do not (eg, aspirin, atropine), liquid (eg, nicotine, diffuse readily between compartments of ethanol), or gaseous (eg, nitrous oxide). the body. Therefore, very large drugs These factors often determine the best (usually proteins) must often be route of administration. administered directly into the compartment The various classes of organic where they have their effect. In the case of compounds—carbohydrates, proteins, alteplase, a clot-dissolving enzyme, the lipids, and smaller molecules—are all drug is administered directly into the represented in pharmacology. As noted vascular compartment by intravenous or above, oligonucleotides, in the form of intra-arterial infusion. small segments of RNA, have entered clinical trials and are on the threshold of introduction into therapeutics. DRUG REACTIVITY AND DRUG RECEPTOR BONDS A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron,  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 9 Drugs interact with receptors by means of chemical forces or bonds. These are of The specific nature of a particular three major types: covalent, drug-receptor bond is of less practical electrostatic, and hydrophobic. importance than the fact that drugs that bind through weak bonds to their Covalent bonds are very strong receptors are generally more selective and in many cases not reversible than drugs that bind by means of very under biologic conditions. Thus, strong bonds. This is because weak the covalent bond formed between bonds require a very precise fit of the drug the acetyl group of acetylsalicylic to its receptor if an interaction is to occur. acid (aspirin) and cyclooxygenase, Only a few receptor types are likely to its enzyme target in platelets, is not provide such a precise fit for a particular readily broken. The platelet drug structure. Thus, if we wished to aggregation–blocking effect of design a highly selective short-acting drug aspirin lasts long after free for a particular receptor, we would avoid acetylsalicylic acid has highly reactive molecules that form disappeared from the blood-stream covalent bonds and instead choose a (about 15 minutes) and is reversed molecule that forms weaker bonds. only by the synthesis of new enzyme in new platelets, a process A few substances that are almost that takes several days. Other completely inert in the chemical sense examples of highly reactive, nevertheless have significant covalent bond-forming drugs pharmacologic effects. For example, include the DNA-alkylating agents xenon, an “inert” gas, has anesthetic used in cancer chemotherapy to effects at elevated pressures. disrupt cell division in the tumor. DRUG AFFINITY Electrostatic bonding is much more common than covalent For example, carvedilol, a drug that bonding in drug-receptor interacts with adrenoceptors, has a single interactions. Electrostatic bonds chiral center and thus two enantiomers vary from relatively strong linkages (Table 1-1). One of these enantiomers, the between permanently charged (S)(-) isomer, is a potent ẞ-receptor ionic molecules to weaker blocker. The (R)(+) isomer is 100-fold hydrogen bonds and very weak weaker at the ẞ receptor. However, the induced dipole interactions such as isomers are approximately equipotent as van der Waals forces and similar a-receptor blockers. Ketamine is an phenomena. Electrostatic bonds intravenous anesthetic. The (+) are weaker than covalent bonds. enantiomer is a more potent anesthetic Hydrophobic bonds are usually and is less toxic than the (-) enantiomer. quite weak and are probably Unfortunately, the drug is still used as the important in the interactions of racemic mixture. highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets.  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 10 INTRODUCTION TO DRUGS: PHYSICOCHEMICAL PROPERTIES OF DRUGS Understanding a drug's physicochemical properties, histology and the influence of the combination on how the drug perme- ates membranes helps to predict its transport into and through the body. Drugs that are administered for mucosal absorption at a site, whether buccal, sublingual, vaginal, rectal, nasal, or pulmonary, or given perorally for absorption across the intestinal mucosa, DRUG - BODY INTERACTIONS must pass through the various layers of the absorbing membrane. The drug must The interactions between a drug and the also interact with a mélange of body are conveniently divided into two paracellular and intracellular fluids, classes: biopolymers, lipids and proteins before The actions of the drug on the entering the circulation. Drug molecules body are termed that do not have the requisite pharmacodynamics. These physicochemical properties necessary for properties determine the group in active-site accessibility may have only which the drug is classified, and minimal or even no biological activity. A they play the major role in deciding mechanistic analysis of the correlation whether that group is appropriate between permeation and physicochemical therapy for a particular symptom or properties will assist in understanding the disease. factors that influence mucosal permeation The actions of the body on the drug are called pharmacokinetics Below are the physicochemical properties Pharmacokinetic processes govern of drugs: the absorption, distribution, and elimination of drugs and are of 1. Isosterism - Isosteres are great practical importance in the compounds that have an identical choice and administration of a number of atoms and molecules. particular drug for a particular Example N₂ and CO, N₂O and CO₂, patient. etc. This phenomenon is called Isosterism. 2. Bioisosterism - substituents or groups with chemical or physical similarities that produce similar biological properties. Can attenuate toxicity, modify activity of  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 11 lead, and/or alter pharmacokinetics aluminum), this complex may of lead. Example- -COOH become less soluble and harder for (Carboxylic acid) is replaced with – the body to absorb. This can CH2N4 Tetrazoles to improve reduce the drug's effectiveness. lipophilicity. hence diffusion slows down. For example - tetracycline with 3. Hydrogen Bonding - Hydrogen Calcium(milk) forms a complex, Bonding occurs between two decreasing the diffusion rate of atoms of different tetracycline. electronegativities like oxygen and hydrogen, fluorine and hydrogen, 5. Surface Activity - refers to a nitrogen and hydrogen. This drug's ability to interact with difference in electronegativity can surfaces or interfaces, often have an electrostatic attraction between two immiscible phases called a hydrogen bond. Hydrogen such as water and air, or water and Bonding can be of two types- oil. Drugs that exhibit surface Intermolecular – occurs activity are known as between two molecules. surface-active agents or Example- HF, H₂O. surfactants. These compounds can Intramolecular - occurs lower the surface tension between within the same molecule- phases, which can influence their C₇H₆O₃ (Salicylic Acid). solubility, absorption, and Hydrogen Bonding governs the formulation. water solubility, boiling point and melting point, drug-receptor 6. Protein Binding - refers to the interactions, the strength of the process by which drugs bind to acid and biological products, proteins in the blood, primarily spectroscopic properties, surface albumin, but also to other plasma tensions, and viscosity critical in proteins such as alpha-1-acid analysing the physicochemical glycoprotein and lipoproteins. properties. Protein binding affects the pharmacokinetics and 4. Chelation (Complexation) - pharmacodynamics of a drug, Chelation is a chemical process in influencing its distribution, activity, which a substance, called a and clearance from the body. chelating agent, binds to metal Bound drug - When a ions to form a stable, water-soluble drug binds to plasma complex. This process is used to proteins, it forms a remove heavy metals or excess reversible complex. This minerals from the body or to make bound portion is usually nutrients more bioavailable in inactive because it cannot certain applications. Chelation can cross cell membranes or affect the absorption of drugs, bind to receptors. particularly those that interact with Free drug - Only the metal ions. When a drug forms a unbound or "free" drug is chelate with metal ions (like pharmacologically active. It calcium, magnesium, iron, or can cross membranes, bind  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 12 to target receptors, and Particle size - Smaller exert therapeutic or toxic particles have a larger effects. surface area relative to volume, which can increase Different drugs have different solubility. affinities for plasma proteins. Crystal form - Different Drugs with a high affinity for polymorphs (crystalline proteins tend to bind strongly, forms) of a drug can have reducing the concentration of free different solubility profiles. drug in circulation. Conversely, Amorphous forms of drugs drugs with lower protein binding tend to be more soluble distribute more freely into tissues. than their crystalline This affects their activity and counterparts duration in the body. For example, warfarin is highly protein-bound 8. Partition Coefficient - The (about 99%), meaning only a small partition coefficient (denoted as P fraction is active in the or Log P) is a critical measure in bloodstream. chemistry and pharmacology that describes how a compound 7. Solubility - is the maximum distributes itself between two concentration of a drug that can immiscible phases, typically a lipid dissolve in a given solvent at a (organic) phase and an aqueous specific temperature and pressure. (water) phase. It helps to assess a It is typically expressed in units like drug's lipophilicity or hydrophilicity, mg/mL or g/L. There are different which in turn impacts the drug’s factors that affect solubility of a absorption, distribution, drug such as: metabolism, and excretion. Nature of a solvent - Polar drugs dissolve better in polar solvents (like water), and non-polar drugs dissolve better in non-polar solvents (like oils or lipids). Temperature - Increasing temperature usually increases the solubility of solids in liquids, although this is not always true for gasses. pH - The solubility of Log P is the logarithmic value of ionizable drugs depends on this ratio, which is often used to the pH of the solvent. For simplify the interpretation. A example, weak acids are positive Log P means the more soluble in basic compound is more lipophilic, while environments, while weak a negative Log P indicates greater bases are more soluble in hydrophilic it. For example, acidic environments.  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 13 Ibuprofen: Log P ≈ 3.5, indicating potential is considered one of the more lipophilicity, making it better most important physicochemical at crossing cell membranes but properties, especially in the case of less soluble in water. vitamin preparation, as it determines the action of the drug. 9. Dissociation Constant - (often Redox potential can be calculated referred to as pKa in the context of using the equation: E = E₀ + acids and bases) is a fundamental 0.0592/n log[conc. of parameter in chemistry and reductant/conc. of oxidant] pharmacology that describes the extent to which a compound 12. Stereochemistry - This branch of (usually an acid or base) chemistry deals with the spatial dissociates into its ions in solution. arrangement of atoms and It is crucial in determining how a molecules of a compound and their drug behaves in different positional impacts on the environments within the body, physicochemical properties. The particularly in relation to its isomeric compounds and any ionization, solubility, absorption, change in their structure can and distribution. impact the physicochemical activity of the drug. Stereochemistry has a significant contribution to drugs used in psychiatric medicines. These drugs use enantiomers. Hence, one enantiomer may be more effective in one perspective, like biological, while another targets the therapeutic effects or 10. Ionization - It is the acquisition of pharmacokinetics. negative or positive charges by an Example- (S) α-methyldopa is atom or molecules by gaining or hypersensitive, whereas (R) losing electrons and chemical α-methyldopa is inactive. changes. This is dependent on the pKa value and pH of the drug. Conclusion Ionisation plays a vital role in the The physicochemical properties of drugs physicochemical property of depend upon various factors like pH, solubility of the drug, which helps temperature, pressure, and receptors in drug-receptor interaction. iterating. These factors help in the measurements of constants like partition 11. Redox potential - Redox, also coefficients, dissociation constants, pKa known as the oxidation-reduction value, etc., which constitute the chemical potential, is the quantitative properties like micelle formation, redox expression that defines the potential, and complexation that forms the capability of a compound that has chemical part of the physicochemical to gain or lose electrons. Redox properties of the drug. Others like stereochemistry and isosteric take care of  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 14 the physical properties of the drug. Hence, can dramatically increase or the physical and chemical components decrease a new drug's affinities for combine to form the physicochemical different classes of receptors, with properties of drug molecules or resulting alterations in therapeutic compounds. and toxic effects. 3. Receptors mediate the actions of DOSE-RESPONSE pharmacologic agonists and antagonists. Some drugs and RELATIONSHIP: GRADED AND many natural ligands, such as QUANTAL hormones and neurotransmitters, RECEPTOR regulate the function of receptor Therapeutic and toxic effects of drugs macromolecules as agonists; this result from their interactions with means that they activate the molecules in the patient. Most drugs act receptor to signal as a direct result by associating with specific of binding to it. Some agonists macromolecules in ways that alter the activate a single kind of receptor to macromolecules' biochemical or produce all their biologic functions, biophysical activities. This idea, more than whereas others selectively a century old, is embodied in the term promote one receptor function receptor: the component of a cell or more than another. organism that interacts with a drug and 4. Other drugs act as pharmacologic initiates the chain of events leading to the antagonists; that is, they bind to drug's observed effects. receptors but do not activate generation of a signal; 1. Receptors largely determine the consequently, they interfere with quantitative relations between the ability of an agonist to activate dose or concentration of drug and the receptor. Some of the most pharmacologic effects. The useful drugs in clinical medicine receptor's affinity for binding a drug are pharmacologic antagonists. determines the concentration of Still other drugs bind to a different drug required to form a significant site on the receptor than that number of drug-receptor bound by endogenous ligands; complexes, and the total number of such drugs can produce useful and receptors may limit the maximal quite different clinical effects by effect a drug may produce. acting as so-called allosteric 2. Receptors are responsible for modulators of the receptor. selectivity of drug action.The molecular size, shape, and MACROMOLECULAR NATURE OF electrical charge of a drug RECEPTORS determine whether-and with what affinity it will bind to a particular Advances in molecular biology and receptor among the vast array of genome sequencing made it possible to chemically different binding sites identify receptors by predicted structural available in a cell, tissue, or homology to other (previously known) patient. Accordingly, changes in receptors. This effort revealed that many the chemical structure of a drug known drugs bind to a larger diversity of  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 15 receptors than previously anticipated and RECEPTOR ON DOSE-RESPONSE motivated efforts to develop increasingly RELATIONSHIP selective drugs. It also identified a number of orphan receptors, so-called because 1. Receptors as determinants of the their natural ligands are presently quantitative relation between the unknown; these may prove to be useful concentration of a drug and the targets for future drug development. pharmacologic response 2. Receptors as regulatory proteins The best-characterized drug receptors are and components of chemical regulatory proteins, which mediate the signaling mechanisms that provide actions of endogenous chemical signals targets for important drugs, and such as neurotransmitters, autacoids, and 3. receptors as key determinants of hormones. This class of receptors the therapeutic and toxic effects of mediates the effects of many of the most drugs in patients. useful therapeutic agents. The molecular structures and biochemical mechanisms of A. Median Effective Dose or ED50 these regulatory receptors are described - dose required to produce in a later section entitled Signalling the effect in 50% of the Mechanisms & Drug Action. population B. ED99 Enzymes may be inhibited (or, less - dose of the drug sufficient commonly, activated) by binding a drug. to be effective in almost all Examples include dihydrofolate reductase, of the individual person. the receptor for the antineoplastic drug C. Lethal dose or LD50 methotrexate; - dose required to produce 3-hydroxy-3-methylglutaryl-coenzyme A the death of 50% of the (HMG-CoA) reductase the receptor for population statins; and various protein and lipid D. Therapeutic index kinases. - Expresses simultaneously the efficiency and toxicity of Transport proteins can be useful drug the drug targets. Examples include - LD50/ED50 Na+/K+-ATPase, the membrane receptor - A measure of drug safety for cardioactive digitalis glycosides; - A drug with higher norepinephrine and serotonin transporter therapeutic index is safer proteins that are membrane receptors for than with lower therapeutic antidepressant drugs; and dopamine index. transporters that are membrane receptors for cocaine and a number of other psychostimulants. Structural proteins are also important drug targets, such as tubulin, the receptor for the antiinflammatory agent colchicine.  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 16 used to confirm this occupancy assumption in many drug-receptor systems. In these systems, drug bound to receptors (B) relates to the concentration of free (unbound) drug (C) as depicted in Figure 2-1B and as described by an analogous equation: DOSE-RESPONSE CURVE This relation between drug concentration and effect is traditionally described by a hyperbolic curve according to the following equation: 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 where E is the effect observed at fashion: If the Kd is low, binding affinity is concentration C, Emax is the maximal high, and vice versa. The EC50 and Kd response that can be produced by the may be identical but need not be, as drug, and EC50 is the concentration of discussed below. Dose Response data drug that produces 50% of maximal effect. are often presented as a plot of the the drug effec effect (ordinate) against the This hyperbolic relation resembles the logarithm of the dose or mass action law that describes the concentration(abscissa), transforming the association between two molecules of a hyperbolic curve. given affinity. This resemblance suggests that drug agonists act by binding to ("occupying") a ( distinct class of biologic molecules with a characteristic affinity for the drug. Radioactive receptor ligands have been  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 17 (Katzung, Chapter 2, page 22) RECEPTOR-EFFECTOR COUPLING AND SPARE RECEPTOR When an agonist occupies a receptor, conformational changes occur in the receptor protein that represent the fundamental basis of receptor activation and the first of often many steps required to produce a pharmacologic response. The overall transduction process that links drug occupancy of receptors and pharmacologic response is called coupling. Many factors can contribute to nonlinear occupancy-response coupling, and often these factors are only partially understood. A useful concept for thinking about this is that of receptor reserve or spare receptors. Receptors are said to be For example, the same maximal inotropic "spare" for a given pharmacologic response of heart muscle to response if it is possible to elicit a maximal catecholamines can be elicited even when biologic response at a concentration of 90% of ẞ adrenoceptors to which they agonist that does not result in occupancy bind are occupied by a quasi-irreversible of all of the available receptors. antagonist. Accordingly, myocardial cells Experimentally, spare receptors may be are said to contain a large proportion of demonstrated by using irreversible spare ẞ adrenoceptors. antagonists to prevent binding of agonists to a proportion of available receptors and In other cases, "spareness" of receptors showing that high concentrations of appears to be temporal. For example, B agonist agonists can still produce B-adrenoceptor activation by agonist undiminished maximal response (Figure promotes binding of guanosine 2-2). triphosphate (GTP) to a hist promotes protein, binding roducing an an activated signaling intermediate whose whose  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 18 lifetime may greatly outlast the - In the presence of a fixed agonist-receptor interaction. Here, concentration of agonist, maximal response is elicited by activation increasing concentrations of a of relatively few receptors because the competitive antagonist response initiated by an individual ligand progressively inhibit the agonist RECEPTOR binding event persists longer response; high antagonist than the binding event itself. Irrespective concentrations prevent the of the biochemical basis of receptor response almost completely. reserve, the sensitivity of a cell or tissue to Conversely, sufficiently high a particular concentration of agonist concentrations of agonist can depends not only on the affinity of the surmount the effect of a given receptor for binding the agonist concentration of the antagonist; (characterized by the Kd) but also on the that is, the Emax for the agonist degree of spareness-the total number of remains the same for any fixed receptors present compared with the concentration of antagonist. number actually needed to elicit a maximal biologic response. SCHLID EQUATION - The concentration (C) of an THE SPARE RECEPTORS agonist required to produce a The concept of spare receptors is very given effect in the presence of a useful clinically because it allows one to fixed concentration ([I]) of think precisely about the effects of drug competitive antagonist is greater dosage without having to consider (or than the agonist concentration (C) even fully understand) biochemical details required to produce the same of the signaling response. The Kd of the effect in the absence of the agonist-receptor interaction determines antagonist. The ratio of these two what fraction (B/Bmax) of total receptors agonist concentrations (called the will be occupied at a given free dose ratio) is related to the concentration (C) of agonist regardless of dissociation constant (Ki) of the the receptor concentration: antagonist by the Schild equation: THE USE OF THE EQUATION 1. The degree of inhibition produced ANTAGONISTS by a competitive antagonist - Antagonist drugs are further depends on the concentration of divided into two classes depending antagonist. The competitive on whether or not they act 3-adrenoceptor antagonist competitively or noncompetitively propranolol provides a useful relative to an agonist present at the example. Patients receiving a fixed same time. dose of this exhibit range of concentrations, owing to  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 19 differences among individuals in drug, agonists cannot surmount the clearance of propranolol. As a the inhibitory effect irrespective of result, inhibitory effects on their concentration. In many cases, physiologic responses to noncompetitive antagonists bind to norepinephrine and epinephrine the receptor in an irreversible or (endogenous adrenergic receptor nearly irreversible fashion, agonists) may vary widely, and the sometimes by forming a covalent dose must be adjusted accordingly. bond with the receptor. 2. Clinical response to a competitive PARTIAL ANTAGONISTS antagonist also depends on the - Based on the maximal concentration of agonist that is pharmacologic response that competing for binding to receptors. occurs when all receptors are Again, propranolol provides a occupied, agonists can be divided useful example: When this drug is into two classes: partial agonists administered at moderate doses produce a lower response, at full sufficient to block the effect of receptor occupancy, than do full basal levels of the agonists. Partial agonists produce neurotransmitter, norepinephrine, concentration-effect curves that resting heart rate is decreased. resemble those observed with full agonists in the presence of an However, the increase in the antagonist that irreversibly blocks release of norepinephrine and some of the receptor sites epinephrine that occurs with (compare Figures 2-2 [curve D] exercise, postural changes, or and 2-4B). It is important to emotional stress may suffice to emphasize that the failure of partial overcome this competitive agonists to produce a maximal antagonism. Accordingly, the same response is not due to decreased dose of propranolol may have little affinity for binding to receptors. effect under these conditions, Indeed, a partial agonist's inability thereby altering therapeutic to cause a maximal pharmacologic response. response, even when present at high concentrations that effectively Conversely, the same dose of saturate binding to all receptors, is propranolol that is useful for indicated by the fact that partial treatment of hypertension in one agonists competitively inhibit the patient may be excessive and toxic responses produced by full to another, based on differences agonists (Figure 2-4). between the patients in the amount of endogenous norepinephrine and epinephrine that they produce. ANTAGONISTS - The actions of a noncompetitive antagonist are different because, once a receptor is bound by such a  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 20 blood sugar, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of a glucocorticoid hormone, 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 ẞ-adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. However, use of this physiologic OTHER MECHANISMS OF DRUG antagonist would be less rational-and ANTAGONISM potentially more dangerous-than use of a Not all mechanisms of antagonism involve receptor-specific antagonist such as interactions of drugs or endogenous atropine (a competitive antagonist of ligands at a single type of receptor, and acetylcholine receptors that slow heart some types of antagonism do not involve rate as the direct targets of acetylcholine a receptor at all. For example, protamine, released from vagus nerve endings). a protein that is positively charged at physiologic pH, can be used clinically to counteract 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 lead to increased  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 21 CONT. OF DRUG opens a channel stim that allows sodium influx and potassium MECHANISM AND outflux across the cell membranes INTERACTION — of neurons or muscle cells. This change in ionic concentrations PHARMACODYNAMICS across the membrane generates an action potential in a neuron and TYPES OF DRUG contraction in skeletal and cardiac muscle. INTERACTION On the other hand, agonist stimulation of the A subtype of the y-aminobutyric acid (GABA) receptor increases chloride influx, resulting in hyperpolarization of neurons and less chance of generating an action potential. Drug-binding sites are also found on many voltage-gated ion channels where they can regulate channel function. For example, local anesthetics bind to the voltage-gated sodium channel, inhibiting sodium influx and decreasing neuronal conduction. 2. Transmembrane G 1. Transmembrane ligand-gated protein-coupled receptors: The ion channels: The extracellular extracellular portion of this receptor portion of ligand-gated ion contains the ligand-binding site, channels contains the drug-binding and the intracellular portion site. This site regulates the interacts (when activated) with a G opening of the pore through which protein. There are many kinds of G ions can flow across cell proteins (for example, G., G1, and membranes. The channel is Gq), but all types are composed of usually closed until the receptor is three protein subunits. The a activated by an agonist, which subunit binds guanosine opens the channel for a few triphosphate (GTP), and the ~ and milliseconds. Depending on the ion y subunits anchor the G protein in conducted through these channels, the cell membrane (Figure 2.3). these receptors mediate diverse Binding of an agonist to the functions, including receptor increases GTP binding to neurotransmission and muscle the a subunit, causing dissociation contraction. of the a-GTP complex from the Itt complex. The a and Itt subunits are For example, stimulation of the then free to interact with specific nicotinic receptor by acetylcholine cellular effectors, usually an  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 22 enzyme or an ion channel, that insulin receptor in turn cause further actions within the phosphorylates other proteins that cell. These responses usually last now become active. Thus, several seconds to minutes. Often, enzyme-linked receptors often the activated effectors produce cause a signal cascade effect like "second messenger" molecules that caused by G protein coupled that further activate other effectors receptors. in the cell, causing a signal cascade 4. Intracellular receptors: The fourth family of receptors differs A common effector, activated by G. considerably from the other three and inhibited by G1, is adenylyl in that the receptor is entirely cyclase, which produces the intracellular, and, therefore, the second messenger cyclic ligand (for example, steroid adenosine monophosphate hormones) must have sufficient (cAMP). The effector lipid solubility to diffuse into the cell phospholipase C, when activated to interact with the receptor (Figure by Gq, generates two second 2.5). The primary targets of messengers:inositol1,4,5-trisphosp activated intracellular receptors are hate (IP3) and diacylglycerol transcription factors in the cell (DAG). DAG and cAMP activate nucleus that regulate gene specific protein kinases within the expression. The activation or cell, leading to a myriad of inactivation of transcription factors physiological effects. IP3 increases alters the transcription of DNA into intracellular calcium concentration, RNA and subsequently translation which in turn activates other of RNA into proteins. The effect of protein kinases. drugs or endogenous ligands that activate intracellular receptors 3. Enzyme-linked receptors: This takes hours to days to occur. Other family of receptors undergoes targets of intracellular ligands are conformational changes when structural proteins, enzymes, RNA, activated by a ligand, resulting in and ribosomes. For example, increased intracellular enzyme tubulin is the target of activity (Figure 2.4). This response antineoplastic agents such as lasts for minutes to hours. The paclitaxel, the enzyme most common enzyme-linked dihydrofolate reductase is the receptors (for example, growth target of antimicrobials such as factors and insulin) possess trimethoprim, and the 50S subunit tyrosine kinase activity. When of the bacterial ribosome is the activated, the receptor target of macrolide antibiotics such phosphorylates tyrosine residues as erythromycin. on itself and other specific proteins (Figure 2.4). Phosphorylation can substantially modify the structure of the target protein, thereby acting as a molecular switch. For example, the phosphorylated PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 23 Signal amplification: A characteristic of G protein-linked and enzyme-linked ne-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  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 24 activated G proteins may last for following stimulation before they hundreds of milliseconds. Further can be activated again. During this prolongation and amplification of recovery phase, unresponsive the initial signal are mediated by receptors are said to be the interaction between G proteins "refractory." Repeated exposure of and their respective intracellular a receptor to an antagonist, on the targets. Because of this other hand, results in up-regulation amplification, only a fraction of the of receptors, in which receptor total receptors for a specific ligand reserves are inserted into the may need to be occupied to elicit a membrane, increasing the number maximal response. Systems that of receptors available. exhibit this behavior are said to Up-regulation of receptors can have spare receptors. About 99% make cells more sensitive to of insulin receptors are "spare; agonists and/or more resistant to providing an immense functional effects of the antagonist. reserve that ensures that adequate amounts of glucose enter the cell. Another important dose-response On the other hand, only about 5% relationship is that between the dose of to 10% of the total the drug and the proportion of a j3-adrenoceptors in the heart are population of patients that responds to it. spare. Therefore, little functional These responses a are known as quantal reserve exists in the failing heart, responses, because, for any individual, because most receptors must be either the effect occurs or it does not. occupied to obtain maximum Graded responses can be transformed to contractility. quantal responses by designating a predetermined level of the graded Desensitization and response as the point at which a response down-regulation of receptors: occurs or not. For example, a quantal Repeated or continuous dose response relationship can be administration of an agonist or determined in a population for the antagonist often leads to changes antihypertensive drug atenolol. A positive in the responsiveness of the response is defined as a fall of at least 5 receptor. The receptor may mm Hg in diastolic blood pressure. become desensitized due to too Quantal dose-response curves are useful much agonist stimulation (Figure for determining doses to which most of the 2.6), resulting in a diminished population responds. They have similar response. This phenomenon, shapes as log dose-response curves, and called tachyphylaxis, is often due the ED50 is the drug dose that causes a to phosphorylation that renders therapeutic response in half of the receptors unresponsive to the population. agonist. In addition, receptors may be internalized within the cell, A. Therapeutic index making them unavailable for - The therapeutic index (TI) of a further agonist interaction drug is the ratio of the dose that (down-regulation). Some produces toxicity in half the receptors, particularly ion population {TD50) to the dose that channels, require a finite time produces a clinically desired or  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 25 effective response (ED50) in half of experiencing adverse effects is the population: TI TD50/ED 50 not as great as the risk of leaving the disease untreated. Figure 2.14 The Tl is a measure of a drug's shows the responses to warfarin, safety, because a larger value an oral anticoagulant with a low TI, indicates a wide margin between and penicillin, an antimicrobial drug doses that are effective and doses with a large TI. that are toxic. B. Clinical usefulness of the MAIN FACTORS INFLUENCING therapeutic Index DRUG EFFECT - The Tl of a drug is determined using drug trials and accumulated clinical experience. These usually Factors that influence drug metabolism: reveal a range of effective doses and a different (sometimes 1. Physiological (pharmacokinetic) overlapping) range of toxic doses. factors Although high TI values are - Renal blood flow effective required for most drugs, some hemodynamic is essential for renal drugs with low therapeutic indices function, this function influences are routinely used to treat serious the rate of drug excretion the most, diseases. In these cases, the risk trough the fact that glomerular ultra  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 26 filtration is dependent on the - Medicinal substances coupled to pressure of filtration. In the healthy plasma proteins cannot be animal, the kidney receives about metabolized until they are severed 25% of the cardiac output, from their links and transformed in converts about 1/5 of this in free fraction. As a result, their glomerular ultra filtrate, then half-life is even longer as the reabsorbs about 99% of the filtrate. medicine is of a higher percentage For a drug that is eliminated of couplings. massively by excretion, the rate of blood flow through the kidneys is 4. Enzymatic Induction an important determinant of its - Enzymatic induction means the existence in the body, (ex, digoxin stimulation of the activity of liver and gentamicin). enzymes; under the action of xenobiotics (non-biological) this - Solubility in the ultra filtrate. Drugs includes drugs and pesticides, etc. with hydrophilic character are most - These inductors speed up the commonly excreted in urine, in metabolism, by increasing the rate their unaltered state, while fat of synthesis of the enzymes. soluble pharmacons may be - So far, we know more than 200 subject to metabolism (to form substances that are considered water-soluble compounds before enzyme inducers, having very being excreted). Occasionally different chemical structures. A (e.g., quinolones and old acetyl correlation cannot be established sulphonamides) a metabolite is between the chemical structure less soluble than the parenteral and the inductive effect. pharmacon in the concentrate acid - The most studied enzyme inducer, ultra filtrate from the proximal phenobarbital, is considered to be convoluted tubule. In this case, the prototype of this action given there is the risk of precipitation of that it boosts the metabolic activity the drug in the convoluted tubules for numerous medicinal preventing renal function. substances. Through enzyme self inductance, some drugs after 2. Urinary pH repeated administration can - Renal excretion of weak acidic or stimulate their own metabolism. basic drugs is closely related to - Most of the enzymes responsible urinary pH. So, weak acids are for the biotransformation are in the eliminated better when the urine is liver, specifically in the alkaline, while the weak bases in endoplasmic reticulum (ER), in the acidic urine. When the elimination microsomes. is reduced (due to unfavorable pH), it will activate the metabolic 5. Enzyme inhibition processes (to make substances - There are some substances that more soluble), thereby increasing inhibit the activity of hepatic the rate of conjugated compounds. microsomal enzymes, for example: piperonylbuthoxid, 3. Coupling of plasma proteins piperonyl-sulfoxide, sesamex,  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 27 cloramphenicol, ketoconazole, SUSCEPTIBILITY cimetidine etc. - Is the term used to describe an - For example long-term abnormal quantitative response administration of chlortione will and is demonstrated by the so lead to a marked inhibition of called hyperactive (a patient microsomal rat liver enzymes. In particularly sensitive to the action addition to the possibility of of a drug). decomposition which is general - Such variations are frequently and non-specific, there are a dependent on the atypical number of specific mechanisms for elimination rates. some pharmacons, within which a series of the body's own SPECIES substances are involved. Among the species of animals, there are some examples of extreme resistance or ANIMAL RELATED FACTORS sensitivity to drugs. Species influence the Species effect, the cause being mainly: genetic or Individuality/breed morphopathological factors. There are Age species that react differently to the same Gender drug. Gestation Feeding Correspondence Animal - Human Dose Health status Species Increasing the Genetic factors dose from humans GENETIC FACTORS Cow × 24 - Some breeds may be sensitive to Horse × 16 the action of drugs. - This can be explained by the Sheep ×3 absence of some specific enzymes (ex: deficiency in Goat ×3 glucose-6-phosphate Pig ×3 dehydrogenase in some breeds is associated with toxicity). Dog Equal to humans - Such anomalies have led to the emergence of a new branch, Cat ½ the human dose Pharmacogenetics. - When response to a drug is abnormal qualitatively or Examples: quantitatively, idiosyncrasy dogs react to morphine through intervenes. hypnosis or vomiting, whilst cats - Sometimes idiosyncrasy can be and large ruminants will react to explained genetically. In the case the same drug through over of improved breeds, the effect of exciternent/hyperactivity the drug may be altered due to in cows alcohol is well supported sensitizing genetic factors as a narcotic, whilst horses are sensitive,  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 28 chloralhydrate, is very effective in weak acid ruminal juice, which has horses, but it is hardly supported a very large volume in ruminant by cows. species. apomorphine in dogs, produces vomiting constantly, whilst in pigs AGE its action is inconsistent. - Very young and very old animals vomitive drugs in omnivores and generally require the administration carnivores can become of reduced doses due to the ruminatories in ruminants. possibility of organ dysfunctions. In old animals dysfunctions are Sensitivity depending on the species: mostly degenerative, at the hepatic pigs and poultry to salt, and renal level. large ruminants to mercury - In young animals excretory and cats to phenolic drugs. metabolic functions are not yet doses in ruminants, increased by developed (ex: chloramphenicol is 20-40% compared to equines, toxic for piglets due to the absence (drugs stagnate and even suffer of suitable enzymatic equipment). decomposition in the fore stomach. - Youngsters, infants, will receive Equines and some dog breeds are reduced doses with 30-40% (small sensitive to injectable Ivomec, due animals) or even 50-70% to the permeability of the (youngsters up to 1 year old in meningeal blood brain barrier large animals). common in some individuals. In the - There are situations when, in case of using drugs that are compared to adults, youngsters common for human and veterinary are more resistant to therapeutic use, the doses for animals are: doses (ex: barbiturates in piglets). They will receive doses reduced by 20-40% because the activity of ANATOMY OF THE DIGESTIVE some enzymatic systems may be SYSTEM reduced or even abolished. - In ruminants, food passage rate is slow, and the intestinal content is large, in comparison to the rate of Doses by Age categories absorption. - Therefore, there is much time Species Category Expected available for absorption, while the dose large volume of intestinal contents Equines 3 - 15 yrs. 1 dose dilutes the orally administered drug, thus slowing the rate of 15 - 20 yrs. ¾ dose absorption. One problem is related to the compartment into which the 20 - 25 yrs. ½ dose orally administered drug enters, Foals 2 yrs. ½ dose influenced by the work of the esophageal tray. Foal 1 yr. 1/12 dose - Drugs with weakly alkaline character tend to accumulate in Foals 2 - 6 1/24 dose  PHARMACOLOGY REVIEWER K.D.D. (DVM 3 - 2024-2025) 29 - The recognition of the existence of months the circadian rhythm within 3 - 8 yrs. 1 dose physiological functions has already found application in drug 10 - 15 yrs. ¾ dose administration. Cattle 15 - 20 yrs. ½ dose - Generally, sick animals have a diminished drug detoxification Calves 4 - ⅛ dose capacity. An increased or 8 months decreased rate of intestinal passage will change the absorption Calves 1 - 1/16 dose 4 months period, therefore the proportion of the absorbed dose. Over 2 yrs. 1 dose Also: - hypoalbuminemia decreases the Sheep and 1 - 2 yrs. ½ dose coupling rate. goat Lambs and ¼ dose - heart failure will be accompanied kids 6 - 12 by liver and kidney failure. months - enteritis reduces intestinal transit time and therefore may reduce the Over 1 - 5 1 dose absorption of drugs. years - peripheral circulation is inadequate Swines 8 - 18 ½ dose in states of shock of any origin,