VPha 1-3 PDF - Veterinary Basic Pharmacology

VPha 101 Veterinary Basic Pharmacology Shiela R. Rabe, DVM College of Veterinary Medicine Visayas State University Pharmacology- Definitions šThe study of the uses, effects and mode of action of drugs šThe study of the properties of chemicals used as drugs for therapeutic purposes Ph...

VPha 101 Veterinary Basic Pharmacology Shiela R. Rabe, DVM College of Veterinary Medicine Visayas State University Pharmacology- Definitions šThe study of the uses, effects and mode of action of drugs šThe study of the properties of chemicals used as drugs for therapeutic purposes Pharmacology- Definitions šThe science that broadly deals with the physical and chemical properties, actions, absorption and fate of chemical substances termed drugs that modify biological function. šThe discipline touches most areas of human and veterinary medicine and closely interfaces with pharmaceutical science and toxicology Pharmacology- History šPen Tsao- earliest recorded compilation of drugs which consisted of list of herbal remedies compiled in the reign of Chinese Emperor Shennung in 2700 B.C. Pharmacology- History šPapyri of ancient Egypt – records classic examples of medicinal use of chemicals, herbs and other natural substances Pharmacology- History šKahun papyrus- written about 2000 B.C. šLists prescriptions for treating uterine disease in women and specifically addresses veterinary medical concerns. Pharmacology- History šEbers papyrus, written in 1150 B.C. is the collection of folklore covering 15 centuries of history. šComposed of over 800 prescriptions for slaves, plasters, pills, suppositories and other dosage forms used to treat specific ailments. Pharmacology- History šMaterial medica- a compilation of therapeutic substances and their uses šCompiled in 77 A.D. by Aristotles student Dioscorides while serving as a surgeon in Nero’s Roman Legion travelling throughout Mediterranean. Pharmacology- History šGalen- wrote the authoritative material medica based on Dioscorides work which was used for 1,400 years. Pharmacology- History šPublius Vegetius- veterinary compilation for farm animal treatments was compiled in the 5th century in Byzantium Pharmacology- History šParacelsus (1492-1541) – A swiss physician, introduced the clinical uses of laudanum (opium) and a number of tinctures (extracts) of various plants. Pharmacology- History šLaudanum is a tincture of opium containing approximately 10% powdered opium by weight (the equivalent of 1% morphine). šLaudanum is prepared by dissolving extracts from the opium poppy (Papaver somniferum Linnaeus) in alcohol (ethanol). Pharmacology- History šPhilippus Aureolus Theophrastus Bombastus von Hohenheim (Paracelsus) Remembered for using drugs for specific and directed purposes, and for his famous dictum “ All substance are poisons; there is one which is not a poison. The proper dose separates a poison from a remedy.” “Father of toxicology” Pharmacology- History šPharmacopeia – official compilations of medicinal substances, their preparation, use, and dosages, started to appear in Europe šProvides unifying framework upon which the pharmaceutical sciences emerged. Pharmacology- History šDispensatorium- first printed pharmacopeia published by Valerius Cordus in 1547 in Nuremberg, Germany. šEdinburgh pharmacopoeia (1689) šUnited States pharmacopeia(1820) šBritish pharmacopeia (1864) Pharmacology- History š16th and 17th century - great explorations and beginning of medical experimentation. š1656- Sir Christopher Wren made the first intravenous (IV) injection of opium in dog Images downloaded from: https://www.britannica.com/science/opium  Pharmacology- History š1656- The bark of cinchona tree (Cinchona officinalis) was brought by Jesuits from South America for treatment of Malaria. Quinine-active ingredient of C.officinalis -inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum Image retrieved from: https://www.bbc.com/travel/article/20200527-the-tree-that-changed-the-world-map Pharmacology- History š1783- English physician William Withering reported the use of extracts from the foxglove plant to treat patients with “dropsy” which is a form of edema most likely cause by congestive heart failure. Image source: https://sugarcreekgardens.com/product/digitalis-pink-panther-foxglove/ Pharmacology- History šEarly 1800’s- the French physiologist- pharmacologist Magendie, working with pharmacist Pelletier studied the effects of IV injections of ipecac, morphine, strychnine and other substances in animals Pharmacology- History šEarly 1800’s- the French physiologist- pharmacologist Magendie, working with pharmacist Pelletier studied the effects of IV injections of ipecac, morphine, strychnine and other substances in animals - chemicals can be absorbed into the vascular system to exert a systemic effect. Pharmacology- History šMagendie, also published a formulary that survived through eight editions from 1821-1836 Pharmacology- History š1813- Spanish physician Orfila published the results of many experiments in a book entitled Toxicologic Generale šMid 1800’s- Claude Bernard showed that the active ingredient of foxglove botanical preparations was digitalis and that its action was on the heart. Pharmacology- History š Mid 18th century- biochemist Rudolph Buchheim in the Baltic city of Dorpat established the first true experimental laboratory dedicated to pharmacology š Published some 118 contributions on a variety of drugs and their actions. š Textbook Beitrage zur Arzneimittellehre, which classified drugs based on their pharmacologic action in living tissues. Pharmacology- History šBiochemist Rudolph Buchheim š-Deleted traditional remedies if he could not demonstrate their action in his laboratory Pharmacology- History šThe beginning of evidenced-based pharmacology which requires chemical to be termed a drug only if a specific action on living tissues has been demonstrated. Pharmacology- History š1872- Oswald Schmiedeberg, a student of Rudolph Buchheim became a Professor of Pharmacology at the University of Strasbourg. Pharmacology- History š1872- Oswald Schmiedeberg, š-took upon himself the goal of making pharmacology an independent scientific discipline based upon precise experimental methodology that ultimately displaced material medica school curriculums in Europe (end of 19th century and America (early 20th century) Oswald Schmiedeberg š Studied the correlation between the chemical structure of substances and their effectiveness as narcotics. š Published some 200 publications as well as an authoritative textbooks in 1883 that went through seven editions (classified drugs by their action and separated experimental pharmacology from therapeutics). Oswald Schmiedeberg šfounded and edited the first pharmacology journal “Archiv fur experimentelle Pathologie und Pharmakologie “ in 1975, which in 2007 published volume 375 as Naunym- Schmiedeberg’s Archives of Pharmacology Oswald Schmiedeberg šOswald Schmiedeberg,- his 150 students spread discipline of pharmacology throughout Europe and America. šSometime referred as “Father of Modern Pharmacology) Dr. John Abel šfirst fulltime professor in pharmacology at the University of Michigan šConsidered by some as “Father of American Pharmacology” Dr. John Abel- šFounded the “Journal of Biological Chemistry and Journal of Pharmacology and Experimental Therapeutics at Johns Hopkins Medical School Dr. John Abel šInstrumental in founding the American Society of Pharmacology and Experimental Therapeutics in 1908. Veterinary Pharmacology- History šDevelopment paralleled that of human pharma. š5000 B.C. –Indian military hospital for horses šExtensive medical education at the Hindu university at Takkasila Veterinary Pharmacology- History šFormal discipline has its origin in establishment of veterinary colleges and hospitals in France, Austria, Germany and Netherlands 1760’s in response to epidemics that decimated animal populations in W. Europe. š1791-Royal College of Vet. Surgeons was established in London š1823-Royal (Dick) School of Veterinary Studies in Edinburgh Veterinary Pharmacology- History šVeterinary colleges in USA, 1852-Philadelphia, 1854-Boston š1800’s- Iowa, Ohio, Ontario, Pennsylvania and New York Veterinary Pharmacology- History š American Academy of Veterinary Pharmacology and Therapeutics (AAVPT)-1977 š European Association for Veterinary Pharmacology and Toxicology (EAVPT)- 1978 š British Association for Veterinary Clinical Pharmacology (BAVCP) š Journal of Veterinary Pharmacology (JVPT-1978) Andrew Yoxall REGULATION of VET.PHARMA. šRegulatory bodies-safe, effective, pure drugs š1820- United States Pharmacopeia (USP) – a private, non-profit organization endeavors to establish standards for strength, quality, purity, packaging, and labelling for all manufacturers of USA pharmaceuticals š1990-standardization of USP -Dr. Lloyd Davis REGULATION of VET.PHARMA. š1927 - Congress established Food Drug and Insecticide Administration, now Food and Drug Administration - 1938 pivotal Federal Food, Drug and Cosmetic Act was passed giving FDA the authority to regulate animal drugs by requiring evidence of product safety before distribution Questions ? VPha 101 Veterinary Basic Pharmacology SRRabe What is pharmacology? šDerived from the Greek words šPharmacon = DRUG šLogos = STUDY šThe science and study of drugs and their interaction with living organisms 2 What is pharmacology? šIncludes all the scientific knowledge of drugs šConcerned with physiological actions of drugs šAbsorption, action and fate in the body šTherapeutic uses šPoisonous effects due to overdosage 3 Pharmacology- Drug Source šDrug source may come from living or non-living organisms. Bacteria- penicillin Plants- atropine Animals-insulin Minerals-Fe, Na, K What is a drug? šFrom the French word “Drouge” which means DRY HERB 5  What is a drug? (Broad definition) šChemical substance that affects living protoplasm and does not act as a food; or šAny chemical agent other than food that affects the structure and functions of living organisms8 šUsed in the cure, treatment or prevention of disease and to alleviate suffering and pain 6  What is a drug? šEveryday we are exposed to drugs (if we consider drugs as plainly chemical agents) having interaction with living organisms š Germicidal substances in bath soaps and shampoos š Mosquito repellant š Talcum powder š Chemical food preservatives š Fluoride in toothpastes š Fertilizers in plants 7 How about food? Vitamin A in a carrot is considered a food, but If used to correct vitamin A deficiency, then it is a DRUG! 8 What is a drug? (Legal definition) šAny substance, food or non-food that is used to treat, cure, mitigate or prevent disease, or šAny non-food substance that is intended to affect the structure of function of the individual 9  What is a drug? (Legal definition) šFOOD: an article used for food or drink for human and animals, including articles that provide taste, aroma or nutritive value šCup of coffee/ tea? šPurified caffeine or theophylline? 10  Nutraceutical šNutrient substances that may cure or prevent the occurrence of disease š Examples šMinerals: Calcium šVitamins: β- carotene, lycopene, thiamine šChondroitin sulfate šGlucosamine 11 šFibers (simple- stomached animals) Distinct divisions of pharmacology šPharmacotherapeutics šPharmacodynamics šPharmacokinetics šToxicology šPharmacy šPharmacognosy šPosology 12 šMetrology  Branches of Pharmacology Pharmacology Pharmacotherapeutics Toxicology Pharmacokinetics Pharmacodynamics Absorption Systemic Effect Metabolism Cellular Effect Distribution Excretion Pharmacotherapeutics/ therapeutics šStudies the useful application of drugs in the šDiagnosis, prevention and treatment of diseases šPurposeful alteration of normal body functions šExamples šAnesthesia šEstrus synchronization in farm animals 14  Pharmacokinetics vs Pharmacodynamics Pharmacokinetics – Absorption, Distribution, Metabolism, Excretion Pharmacodynamics –Drug Receptor Interaction (Cellular and Systemic Effect) Pharmacodynamics šScience and study of how drugs produce effects on living organisms šThis includes time, intensity of therapeutic and adverse effects 16 Pharmacokinetics Study of the processes and factors determining the amount of drugs at the sites of action at various times between application of drugs on or in the body and their elimination from the body of a living organism. 17 Pharmacology - Branches Pharmacokinetics - What does the body do to the drug? Pharmacodynamics - What does the drug do to the body? Pharmacodynamics and Pharmacokinetics Relationship Prescribed Drug site Drug dosing of action effects regimen Compliance Drug receptor status Dosing and Genetic factors Medication errors Drug interactions Absorption Tolerance Tissue and body fluid mass and volume Drug interactions Source: Concepts in Clinical Pharmacokinetics (http://www.ashp.org/DocLibrary/Bookstore/P241 Elimination 8-Chapter1.aspx) Drug metabolism 19  Parenteral administration Rectal administration Stomach Intravenous Intramuscular/ subcutaneous Absorption Bloodstream n Absorptio Intestines Plasma- free drug Site of Tissues action Metabolites Protein- bound drug Distribution Liver Biotransformation Kidneys (Urine) Lungs Feces Mammary glands Sweat glands Salivary glands Excretion Excretion 20 Source: Pettes and Wannamaker. 2000  Toxicology šStudy of the harmful effects of drugs and the conditions under which these harmful effects occur šStudied by toxicologists: poisoning šSymptoms šDiagnosis šTreatment šIdentification of poisons 21 Toxicology šFields šChemical: chemical properties šClinical šDiagnosis šPrevention and treatment šForensic: solving crimes šLegal: promulgation of laws on safety of chemical substances 22 Pharmacy š Art and science of š Developing; š Preparing; š Compounding; and š Dispensing of drugs http://islandfamilypharmacy.com/ 23 Pharmacy šIncludes šPharmacognosy: sources šPosology: drug dosage šMetrology: weights and measures of drugs http://www.iitbhu.ac.in/phe/pharmacognosy.html 24 Categories in pharmacology šMolecular pharmacology šStudy of basic mechanisms of drug action on biological systems šAims to determine and interpret the relationship between biologic activity and the structure of molecules or group of molecules 25 Categories in pharmacology šClinical pharmacology šConcerned with rational development, effective use and the proper evaluation of drugs for the diagnosis, prevention and treatment of diseases šVeterinary pharmacology šDrugs used in the diagnosis and treatment of animal diseases šMedical (human) pharmacology 26 What is Veterinary PHARMACOLOGY? šCovers all aspects of using chemicals and biological substances to treat diseases of animals. šA discipline often simply divided into basic and clinical pharmacology. šCan be appropriately called as comparative pharmacology. QUESTIONS? 28 Vpha 101 Veterinary Basic Pharmacology Drugs Sources, categories, schedules, extra-label use, nomenclature, action Sources of drugs n Natural n Semi-synthetic n Biosynthetic n Synthetic Natural sources n Animal n Insulin n Vaccines n Vitamins n Plant n Aspirin n Digoxin n Morphine n Mineral n Microbiological Semi-synthetic drugs n Hybrid between natural and synthetic sources n Drugs that can be taken in naturally but can be chemically processed to produce a different drug n New drug is usually more potent n Example: Heroin, antibiotic (penicillin) Synthetic drugs n Produced from chemical reactions in the laboratory n Chemical structure is identical to naturally- occurring substances Biosynthetic drugs n Genetically engineered drugs n Example: DNA engineered insulin-diabetes type 2 Interferon-⍺-2a-hairy leukemia Drug categories n Prescription drugs n Need medical supervision n Relatively unsafe n Dispensed only by an order of registered practitioner n Examples: antibiotics, antidepressants n Sometimes referred as “legend” drug  Drug categories n Non-prescription or Over-the-counter (OTC) drugs n Considered relatively safe n Can be sold without physician's prescription n Examples: vitamins, antacids, paracetamol etc n Drugs that do not have potential for toxicity n Do not require administration in a special way Drug categories n Controlled Substances n Potential for abuse or dependence by people Controlled substances n Schedule I n The drug or other substance has a high potential for abuse n High potential to create severe psychological and/or physical dependence n The drug or other substance has no currently accepted medical use in treatment in the Philippines n There is a lack of accepted safety for use of the drug or other substance under medical supervision n Examples n Heroin n Lysergic acid diethylamide (LSD) n Marijuana n Methaqualone Controlled substances n Schedule II n The drug or other substance has a high potential for abuse n The drug or other substance has a currently accepted medical use in treatment in the Philippines or a currently accepted medical use with severe restrictions n Abuse of the drug or other substance may lead to severe psychological or physical dependence n Examples: n Morphine n Phencyclidine (PCP) n Cocaine n Methadone n Methamphetamine Controlled substances n Schedule III n The drug or other substance has less potential for abuse than the drugs or other substances in schedules I and II n The drug or other substance has a currently accepted medical use in treatment in the Philippines n Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence. n Examples n Anabolic steroids n Codeine and hydrocodone with aspirin or Tylenol®, and some barbiturates Controlled substances n Schedule IV n The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III n The drug or other substance has a currently accepted medical use in treatment in the Philippines n Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III. n Examples: n Barbital n Diazepam  Controlled substances n Schedule V n The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule IV n The drug or other substance has a currently accepted medical use in treatment in the Philippines n Abuse of the drug or other substances may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule IV n Example: Cough medicines with codeine Extra-label Use of Drugs n Using a drug in a way not specified by the label n Veterinarian should discuss with the client for extra-label use of drugs (veterinarian-client- patient relationship) Drug nomenclature n Chemical name n Proprietary/ trade/ brand name n Non-proprietary/ generic name Drug nomenclature: Chemical name n Based on the chemical constitution of a drug n Indicates the precise arrangement of atoms and atomic groups in the molecule n Too complex and difficult to be used in prescription Drug nomenclature: Proprietary name n Selected and registered by the pharmaceutical company n The name becomes the property of the pharmaceutical company n Non-proprietary drug may be marketed under many proprietary names by different firms Drug nomenclature: Non-proprietary/ generic name n Used uniformly all over the world by an international agreement through World Health Organization (WHO) n Called official when included in official books such as Indian, British, United States or International pharmacopeias Questions?  Drug Receptor Interaction Drug action is specific n Drugs bind to certain molecules when they enter the body n May or may not produce an effect n There is also nonspecific interaction n When drug molecules bind to plasma proteins (albumin): no perceptible drug effect  Drug action is specific. n Free (unbound) drug molecules are distributed to their site of action and bind with drug receptors n Results in specific drug effect (perceptible) Drug Specificity of a drug is determined by: nMolecule shape of a drug that complements with the molecular structure of the receptor Drug receptors n Molecules to which the drug has specific affinity in order to create a specific effect n Composition of receptors n Ligand-binding site n Effector site n Made of n Proteins: most important class n Lipids n carbohydrates Drug receptors n Sometimes refer to any target molecule with which the drug molecule combines resulting in an effect n Examples n Local anesthetics- voltage-gated sodium channel n Sulfonamide – folic acid synthesis enzyme Drug targets n Receptors n Enzymes n Carriers n Ion channels Receptors can accommodate an agonist or antagonist n Agonist n A drug acting on specific receptors n Mimics the effects of endogenous compounds n Antagonist n Drug that binds specifically with receptors and thus, blocks the action of the agonists An exception to the rule! n Not all drugs require receptors to produce an effect. n Examples: n Antacids n Chelators n Osmotic agents Drug activity: Molecular level n vs drug action? n Physiological effects n DRUG-RECEPTOR COMPLEX n Drug molecule interacts with a drug receptor n Different from either n Free drug n Unoccupied receptor Drug activity Drug Drug- + Receptor Receptor Complex Stimulus EFFECT  Affinity and intrinsic activity n Basic requirements for drug activity n Affinity n Tendency for a drug to bind with a specific receptor n First of the two requirements Affinity Affinity andand intrinsic intrinsic activity activity n Intrinsic activity n Also called efficacy n The inherent capacity of the drug to produce an effect n The capacity to activate the receptor All possible molecular types of molecular bond may be involved in drug- receptor binding. n Covalent bond n Two atoms share a pair of electron n High binding energy n Irreversible n Can be separated n At very high temperature n With intervention of catalytic enzyme n Ionic bond n From electrostatic attraction between opposite charge ions n Force of attraction between ions diminishes inversely with the square of the distance between them n Hydrogen bond (H bond) n Arises from the ability of a proton (H+) to accept electron pair n One from the donor and the other from another donor n Weaker than covalent bond n Several H bonds makes the interaction more stable n Intermolecular forces n Van der Waals forces n Very weak bonds are formed between dipoles or induced dipoles, often between similar atoms n Carbon atoms are usually involved in drug- receptor complex  Intrinsic activity is dependent on affinity, but affinity can exist independent of intrinsic activity. Silent receptors and silent interactions n Non- specific receptors n No resulting drug effect  Are there any clinical use for drugs with affinity but without intrinsic activity? nAs a blocker (antagonist)! n To reduce the normal functions normally dependent on the activity of the agonist. The effect of an endogenous neurotransmitter or hormone is decreased when an antagonist drug blocks its receptors. Competitive antagonism n When agonist and antagonist compete for the same binding site in the receptor. Non- competitive antagonism n There is no competition n Antagonist binds at other site that is related to the agonist’s binding site n Results in conformational defect (allosteric change) in the agonist’s binding site Questions??? Vpha 101 Elementary Pharmacology Principles of Drug Structure – Activity Relationship  How does the chemical structure of a drug influence its pharmacological effects? Recording drum ileum Experimental Set-up Recording drum ileum Experimental Set-up Recording drum ileum Experimental Set-up Recording drum ileum Experimental Set-up Recording drum ileum Experimental Set-up What happened? As the structure of the agonist histamine was modified, its effect on the isolated ileum changes… The only difference between histamine and 3-β-aminoethyl pyrazole: N position Example of a blocker/ competitive antagonist: 3-β-aminoethyl pyrazole alone: no contraction 3-β-aminoethyl pyrazole + histamine: reduced degree of contraction Example of a blocker/ competitive antagonist: Therefore, 3-β-aminoethyl pyrazole acts as a blocker or competitive antagonist to histamine… - there is affinity of the 1st analogue but no intrinsic activity… Difference between histamine and second analogue: 2nd analogue alone: Does not produce an effect 2nd analogue + histamine: no alteration of the degree of contraction This example indicates Therefore, there is no that the 2nd analogue interaction between 2nd has no affinity and analogue and histamine. intrinsic activity! n Important information about the specific receptor can be obtained by n Analyzing the structure n Evaluating the activity of a series of substances structurally related to its specific agonists n This is the principle of structure activity relationship (SAR) studies Structure-Activity Relationship n can help identify a species of receptors that mediate a set of pharmacological response n Make it possible to develop a drug with n Higher therapeutic ration n Less toxic effects n More selective to cells than its parent compound n An indirect way of gaining information about drug receptors Methods of Studying Drug-Binding Properties of Receptor n Direct methods n Isolation of receptors (extremely difficult and not always practical) n Biochemical and physical means: n Electron spin resonance n Fluorescence n High resolution electron microscopy n Nuclear magnetic resonance n X-ray crystallography Methods of Studying Drug-Binding Properties of Receptor n Indirect methods n Study on the influence of the chemical structure of a drug on its activity Basic Procedure in SAR Study } Biological response to a prototype (parent drug) is specified } Chemical structure of parent drug is sequentially modified } Derivatives are tested one by one if they can induce the same effect } Structurally related compounds with the parent drug are listed } Called congeneric series } Response of each member is compared with the parent drug Relationship between structural modification and the corresponding degree and nature of pharmacological response gives info on receptors The acetylcholine (C7H16NO2) congeneric series: An example The acetylcholine (C7H16NO2) congeneric series: An example n Congeneric series is tested for pharmacological effect on clam heart n Response of clam’s heart to acetylcholine (parent compound) is set to 100% The acetylcholine (C7H16NO2) congeneric series: An example n Ether oxygen is replaced with methylene: group n Response: 8.3% The acetylcholine (C7H16NO2) congeneric series: An example n Carbonyl oxygen is removed n Response: 1.5% The acetylcholine (C7H16NO2) congeneric series: An example n Carbonyl oxygen is moved to the left and closer to the quarternary nitrogen n Response: 0.16 to 0.62% The acetylcholine (C7H16NO2) congeneric series: An example n Both ether and carbonyl oxygens are removed n Response: ~ 1.5% (almost same when only the carbonyl oxygen is absent) n Potency lower than 1.5% n Reduction in the number of methylene groups n Chain length is increased beyond 5 methyl groups n Potency lost: Two methyls are removed n No change in potency: removal of one methyl attached to nitrogen n Activity terminates n Nitrogen is replaced by carbon so that the cationic charge is eliminated  What do all these observations mean? n The ester structure is required for a full biologic effect. n The carbonyl oxygen participates in a hydrogen bond formation with, an amino acid residue in a receptor, most probably serine or tyrosine n A 5-member chain is optimal for biological effect. Chains longer or shorter than 5 carbons have reduced activity n The receptor has anchor points for at least 2 methyl groups, and an ionic site for an electrostatic attraction with the cationic nitrogen Drug Family n Consists of drugs that act on specific receptors in certain effector systems n Produce the same effect but of different magnitude n !!!Not all drugs having affinity to the same receptors belong to the same drug family n They produce different response n Agonist and antagonist Determining the family to which a new drug belong is an important prerequisite to SAR study… Naming of Drug Family n Families of agonist n Families of antagonist n By typical name of n By the typical names of members of the group the members and their n Atropine-like agents corresponding agonist n By their chemical names n Antihistamine n Salicylates n Anticholinergics n A drug may have an affinity to more than 1 kind of receptor n Not all receptors of 1 kind are completely identical n Drugs having similar indication or use may not necessarily constitute a drug family n Atropine, attapulgite and loperamide Simultaneous Action of Two Drugs Simultaneous Action of Two Drugs Antagonism Competitive and Non-competitive Molecular, Physiological and Chemical (Pharmaceutical) Synergism Additive Potentiation Reasons for combining drugs — To optimize the beneficial effects of each drug being used — Combination to antibacterial agents — To reduce the toxic or adverse effect of one or both drugs — Use of pre-anesthetic agents to reduce dose and toxic reactions of anesthetics — To terminate the action of one drug when it is no longer needed — Use of antidote against sedatives Interaction between drugs — Drugs when administered together may interact — Main reason for combining is to make use of the good interaction — ! Bad interactions may result in: — Antagonism, levels: — Molecular (receptor level) — Pharmaceutical (Chemical) — Physiological — Toxicity Physiological interactions — Occurs when two drugs act on different receptors have combined effects manifested in the same (synergistic or additive) or opposite (antagonistic) way on the same effector organ Types of physiological interactions — Additivity — Antagonism — Synergism — Potentiation Interactions are categorized based on their chemical or biological mechanisms: — Chemical interaction(s) between administered chemicals — Modifications in absorption, metabolism, storage or excretion of one chemical by the other — Reactions at binding sites and receptors — Due to physiological changes caused by other chemicals  Molecular antagonism — Noncompetitive antagonism Response — Antagonist drug does not act agonist directly on the agonist-binding site in the receptor agonist + antagonist — There is conformational change of the agonist-binding site→ — No direct competition between the agonist and antagonist Log dose — Therefore, increasing the dose of the agonist will not improve the response  Molecular antagonism — Competitive antagonism Response — Antagonist competes with the agonist for the same binding site in the receptors agonist agonist + — Antagonist + receptor = reduced antagonist affinity of the agonist to the receptors — Receptors are blocked, but not changed — ! Number of functional receptors Log dose remains unchanged — Maximum response can still be achieved (compared to noncompetitive) by increasing the dose of the agonist Physiological interaction: Additivity — The most common type of drug interaction — The effect of the drug combination is equal to the sum of the effects of individual drugs — EAB =EA + EB (1+1=2) Physiological interaction: Additivity — Examples: — Toxicity of a combination of two organophosphate insecticides= sum of the toxicity of both — Organophosphate insecticides interfere with nerve conduction — Hepatotoxicity of a combination of an insecticide formulation containing chlorinated insecticides and halogenated solvents= sum of the hepatoxicity of both Additive Interactions 1. ACE Inhibitors + Spironolactone Hyperkalemia 2. NSAIDS + glucocorticoids Increased rick of gastric bleeding Physiological interaction: Synergism — Drug interaction in which the effect of a drug combination is greater than the separate effects of the individual drug — Occurs when both drugs are agonist — EAB =EA + EB (1+1=>2) Physiological interaction: Potentiation — Applies to that special case of synergism when one of the 2 drugs has zero intrinsic activity — The one with zero activity intrinsic activity is considered the potentiator — More appropriate if a drug lacking an effect on its own increases the effect of a second active drug — EAB =EA + EB (1+0=2) Chemical interaction — Occurs when a drug interferes chemically with another drug or poison — Examples — Neutralization between acids and bases — Penicillin (acid) + gentamicin (base) — Chelation of heavy metals — Chelation of calcium by tetracycline — Absorption of one drug by another — Drugs administered together with kaolin or attapulgite are being adsorbed Questions? Graded and Quantal ¡ Not measured in a continuous scale (compared to graded dose-response) ¡ Also called all-or-none response: individual unit of biological system responds to a drug dose either maximally or not at all 2 ¡ Used to establish the useful drug effect and the toxic drug effect curves ¡ Frequency in which a dose of a drug produces a stated fixed pharmacological response in a population 3 ¡ Graph shows the frequency with which dose produces the all-or-none response ¡ Done by administering drugs in increasing dose to groups of animals § Percentage of those who responded is recorded 4 ¡ Quantal response to be observed is defined § Example: Death as quantal response to drug toxicity ¡ Number of test animals of the same strain, sex, age and approximate weight; bred under the same condition is determined 5 ¡ Each animal is given a gradually increasing doses of the drug until death occurs ¡ Drug administration is stopped when death is observed 6 ¡ Smallest dose at which death occurs for each animal (threshold dose) is recorded § Not all animals die at the same threshold dose ¡ The number of animals that die for a particular dose range and plot in increasing threshold doses are counted 7 8  Drug A 100 sleep death Percent 50 Responding 0 ED50 LD50 Drug B dose 100 sleep death Percent 50 Responding 0 ED50 LD50 dose 9 10 ¡ The ratio used to evaluate the safety of the drug: LD50 TI = ED50 Where TI= therapeutic index LD50= dose necessary to kill 50% of the population (lethal dose) ED50= dose that results in the desired effect in 50% of the population (effective dose) ? Which drug is safer? - high or low TI? 11  Drug A 100 sleep death Percent 50 Responding 0 ED50 LD50 Drug B dose 100 sleep death Percent 50 Responding 0 ED50 LD50 dose 12  The therapeutic index The higher the TI the better the drug. TI’s vary from 1.0 (some cancer drugs) to >1000 (penicillin) Drugs acting on the same receptor or enzyme system often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide) 13 ¡ More conservative measure of a drug’s safety than TI ¡ Percent by which the ED99 must be increased before an LD1 is reached LD1 - ED99 SSM = x100 ED99 14 ¡ 10 mg/kg of a drug is effective in 99% of the animal population ¡ 100 mg/kg will cause toxicity in 1% of the same population 100 - 10 SSM = x100 10 ¡ Therefore, the dose effective in 99% of the population should be increased by 900% to produce toxicity in 1% of the population 15 ¡ Drug dose-response curves § very useful in preclinical and clinical tests of the safety and efficacy of drugs before these are marketed § can be constructed for any effect produced by chemicals 16 ¡ Provide the following information: § Potency § Maximal efficacy § Steepness or slope of the curve § Variability of a point in a curve 17 ¡ Refers to the range of concentrations over which an agonist produces increasing responses. ¡ The distance between the vertical axis and the foot of the curve ¡ Highly potent drugs produce effects at lower concentrations ¡ The more potent drug is not necessarily more effective 18  100 Drug A Drug B Response 50 Level 0 dose 19 ¡ Obtained when any increase in the dosages will not cause any further increase in the responses. ¡ May be achieved even if not all receptors are occupied ¡ The receptors that remain unbound after the maximal efficacy is attained are called spare receptors 20 ¡ An increase in the dosage yields a corresponding increase in the response. § steep curve ▪ small increase in the dose is needed to produce the effect § flat curve ▪ a larger concentration is necessary to obtain a corresponding increase in the responses ¡ In drugs that produce flatter curves, a larger concentration of drugs dose is necessary. 21 ¡ Depends on the range of: § Responses for a particular drug dose § Doses that produce a particular responses ¡ Indicates the reliability of the drug in use 22 ¡ Idiosyncracy § apply to reactions that are qualitatively different from the effects obtained in the majority of the patients. § usually caused by genetic differences in metabolism of the drug (e.g. enzyme deficiencies) ¡ Hyporeactive § describes a lowered intensity of response to the drug ¡ Hyperreactive § describes an increased intensity of response to an ordinary dose of drug. 23 ¡ Tolerance § Refers to the decreased responsiveness with continued or chronic drug administration. § There is a need for increasing the amount of drug to obtain the same therapeutic effect. ¡ Tachyphylaxis § Implies rapid development of tolerance § Responsiveness diminishes rapidly after drug administration. ¡ Hypersensitivity (drug allergy) § a response that results from a previous sensitizing exposure and is mediated by an immunologic mechanism. 24 ¡ Anaphylaxis § Acute, systemic life-threatening reactions characterized by ▪ Bronchospasm ▪ Angioedema ▪ Urticaria ▪ Erythema ▪ Pruritus ▪ Cardiac arrhythmias ▪ Vomiting ▪ Colic ▪ Hyperperistalsis 25 Serum sickness § Systemic reaction manifested by ▪ Lymphadenopathy ▪ Neuropathy ▪ Vasculitis ▪ Nephritis ▪ Arthritis ▪ Urticaria ▪ Fever (onset is usually delayed until 10-20 days after receiving the drug; a type III hypersensitivity) 26 ¡ Contact dermatitis § Type IV hypersensitivity initiated by local exposure to drugs that act as hapten § Delayed reaction may develop at the site of drug application 27 Questions? 28 VPha 101 Veterinary Basic Pharmacology Graded and Quantal ¡ Describe a graded dose-response relationship ¡ Identify factors that affect the final amount of drug molecules that may directly interact with receptors ¡ Determine the problems and limitations in studying graded-dose response relationship ¡ Intensity of drug effect (response) on an animal is generally proportional to the dose of the drug § Dose increases, more drug molecules are distributed into the receptors § More receptors occupied, greater the intensity of response Keywords: Drug effect intensity, drug dose, receptors occupied ¡ Ileum + histamine = contraction ¡ Ileum, no histamine = no contraction § Therefore, no drug = no response ¡ ? Histamine added drop-by-drop? § First few drops: no contraction § Contraction is only possible when enough drug has been added § Threshold dose: lowest concentration of histamine that will result in contraction ¡ ? Histamine added drop-by-drop? § Force of contraction increases with further addition of histamine § When force of contraction reaches the maximum, no further increase in the force of contraction can be produced § If histamine concentration is reduced gradually, there is progressive decrease in the rate of contraction The rate of change in the intensity of the response (contraction) is proportional to the rate of change in drug concentration (dose). http://www.uwsp.edu/geo/faculty/ozsvath/images/dose-response.htm ¡ Magnitude of response directly proportional the number of drug-receptor complexes formed § More complexes formed- greater response § Less complexes formed- lesser response ¡ May not be observed at all times ¡ Physicochemical properties of the drug § Rate of dissolution § Lipid solubility § Molecular size § Plasma protein affinity ¡ Blood flow through the site of absorption § Less blood flow, less drug absorbed ¡ Extent and rate of distribution ¡ Non-specific binding of drug with tissue and plasma proteins ¡ Biotransformation of drug in tissues and plasma ¡ Excretion of drug before it reaches biophase ¡ Formed after the formation of drug-receptor complex ¡ Formation is affected by § The type and condition of effector system § Initial drug effect on the effector system § Local and systemic contra-regulation of the response ▪ Presence of other physiological processes ▪ Presence of antagonists ¡ Purely theoretical magnitude ¡ Simply an aspect of agonist- receptor interaction ¡ Magnitude of stimulus is directly proportional to the number of receptors occupied by the agonist ¡ Stimulus formation → DRUG RESPONSE ¡ Studying of drug effect in an intact animal is complicated § There are many variables to be eliminated  Rate of Absorption Affinity Physicochemical Intrinsic drug activity properties Stimulus formation Blood flow through Type and condition of absorption site effector system Effect Initial effect on the Blood effector system Physiological antagonism Drug Extent and absorption rate Tissue and plasma binding Biophase Subsequent drug Receptor liberation from reservoirs Questions??? Module 3: Pharmacokinetics Lesson 1: Drug Administration and Absorption Learning Outcomes: — Identify the different routes of administration, its advantage and disadvantages — Determine which route is the most practical in a given situation — Describe the mechanism of drug absorption Drug administration and absorption Routes of administration Alimentary or Enteral Parenteral (Subcutaneous, Intramuscular, Intravenous, Intradermal, Intraperitoneal, Epidural, Intraocular) Topical Inhalation Absorption Physiological Disposition of the Drugs — Refers to the movement and changes that undergoes within a body, from the time of its administration up top the time of elimination from the body — Includes — Absorption Allow the administered drug to reach its site of action to produce its effect — Distribution — Biotransformation Terminate the action of drug; drug effect may persist even drug action is terminated — Excretion  Parenteral Physical Disposition of Drugs administration Rectal administration Stomach Intravenous Intramuscular/ subcutaneous Absorption Bloodstream Absorption Intestines Plasma- free drug Site of Tissues action Metabolites Protein- bound drug Distribution Liver Biotransformation Kidneys (Urine) Lungs Feces Mammary glands Sweat glands Salivary glands Excretion Excretion Source: Pettes and Wannamaker. 2000 Drug absorption — Refers to the passage of drugs or other substances from the site of administration into the blood circulation — Drug crosses the cell (biological) membrane (semi- permeable) in order to reach the site of action Drug absorption — Means by which drug molecules cross the cell membrane — Diffusion — Passive: Requires concentration gradient — Facilitated — Active transport — Pinocytosis Drug absorption — Influenced by — Formulation — Physicochemical — Solid properties — Liquid — Water- or lipid- soluble — Colloid — Hydrophilic- IM — Gas — Lipophilic- Per os — Route of administration — pH (drug and environment) Drug absorption and physicochemical properties of drugs — Lipid solubility — Expressed in terms of partition coefficient; the ratio of drug solubility in oil to its solubility in water — Water-soluble drugs penetrate through aqueous channels — Lipid-soluble drugs cross membranes easier than the water-soluble ones — The higher the lipid solubility, the faster is the absorption rate Drug absorption and physicochemical properties of drugs — Degree of ionization in a given pH — Uncharged ones readily cross the membranes — pH of the drug — Absorption depends on the pH of the medium Drug absorption and drug formulation — Solid drug formulation needs to be absorbed through the gastrointestinal tract to reach the circulation — Injectable drugs have better absorption Drug absorption and routes of administration — General Principles — Drugs dissolve in body fluid (water). — Drugs enter the circulatory system as fluid enters the circulatory system. — Drugs must enter the circulatory system before they can be distributed to sites of action. — Drugs for enteric effects are an obvious exception. — Therefore, drugs are not IN the body until they are IN the bloodstream. Drug absorption and routes of administration — Parenteral route- other than the gastrointestinal tract Intravenous (IV) Intra-muscular (IM) Subcutaneous (SC) Intra-synovial Intra-peritoneal (IP) Intra-scleral Intra-thecal Intra-arterial Intranasal Intra-dermal Sub-conjunctival Intratracheal Drug absorption and routes of administration — Alimentary/ Enteral route - through the digestive tract — Oral- oldest route — Rectal — Miscellaneous routes — Inhalation — Topical Parenteral routes — Introduction into the bloodstream is equal to the actual rate of absorption — Drug concentration is directly proportional to absorption rate from intramuscular (IM) and subcutaneous (SC) sites — The greater the dose administered, the slower is the rate of absorption — Blood flow and diffusion limit absorption — Other factors affecting drug absorption — Ionization — Lipid solubility — Molecular weight Parenteral routes: Disadvantages — Asepsis is very important — May cause pain — Blood vessels may be penetrated with IM injection — Speed on onset of action is rapid (IV administration) — Discoloration of meat or abscess formation which is not good for food animals Intramuscular (IM) route: Advantages — More consistent absorption compared to — Oral route — Subcutaneous route — Depot or sustained effect is possible — Practical route for patients that are — Unconscious — Vomiting — Fractious Intramuscular (IM) route: Advantages — Last resort for dehydrated patients — Most common route of drug administration in large animals Intramuscular (IM) route: Disadvantages — Difficult in small patients — There is pain at site of injection — Muscle damage is possible — Exact blood and tissue levels may not be obtained IM route: Processes involved Drug in suspension or lipid solution is dissolved in tissue fluid ↓ Drug in tissue fluid diffuses into capillaries ↓ Drug in capillaries is carried to circulatory system Note: Any of the mentioned processes can affect rate of absorption. Subcutaneous (SC) route — Advantages: — Vasoconstrictor can be given at the site of injection to prolong the action — Allows administration of large drug volumes — Disadvantages: — Variable rate of absorption — Less rate of absorption compared to IM Intravenous (IV) route: Advantages — Accurate and rapid accumulation of blood and tissue levels — Allows administration of — Large drug volumes — Irritant drugs — Drugs that causes pain at the site of injection (IM) Intravenous (IV) route: Disadvantages — Administration requirements — Specific formulations — Good techniques — Toxic reactions are usually acute — May result in the formation of perivascular and intravascular thrombosis Intradermal (ID) route — Drug is administered within the skin — Very small needle should be used — Usually for skin testing procedures — TB test — Allergy test Different angles used in parenteral injection Intraperitoneal (IP) route — Advantage: Large absorptive surface than IM or SC — Disadvantages: — Drugs or vehicles may cause peritonitis — May result in organ damage due to needle puncture — Drugs may be injected into internal organs — Comment: generally restricted to laboratory animals © 2018 Newcastle University Intrathecal route — Advantages: direct delivery to the site of action — Disadvantages: — Difficult dose calculation — CSF volume is not proportional to body weight — Infection may be introduced Intrathecal route Intra-articular route: Advantages — Direct delivery to the site of action — High concentrations is achieved in the joint Photo Courtesy of Dr. Ramney. 2011. http://www.doctorramey.com/joint-therapies/ Intra-articular route: Disadvantages — Joint space may be difficult to hit (species difference: joint space size varies) — Difficult to calculate dose — Joint space volume is affected by diseases — May result in irritation/damage of joint surfaces/ capsules — Infection may be introduce instead, especially if not performed aseptically Drugs administered per os (Riviere and Papich, 2009) Processes after oral administration Per os Disintegration Dissolution administration Drug must still be non-ionized for absorption across the lipid membranes of the mucosa Drug factors affecting absorption — Disintegration — Barrier diffusion — Excipients/ vehicles — Solubility — Compaction pressure — Transit time — Enteric coatings, capsules — Homogeneity — Dissolution — Particle size/ surface area — Binding/ complexation to inert filler ingredients — Local pH, buffers — Boundary layers Drugs administered per os — Absorption is more complicated compared to parenteral routes — Factors affecting rate of absorption — pH differences in GIT segments — Surface area for absorption — Gastrointestinal secretions (juices, enzymes, bile and mucus) — Blood flow (perfusion) — Microbial population present (capable of pre-systemic metabolism) — Presence of food in the stomach — Species difference (nature of epithelial membranes) — Gastric motility Drugs administered per os — Used in conjunction with other drug forms — Balling gun is used to administer drugs orally in large animals Oral administration: Advantages — Safest — Convenient and economical — Sterilization not needed — Different drug forms are available Oral administration: Disadvantages — Drugs may be destroyed by — Acidic environment by the stomach — Digestive enzymes — Bacterial enzymes (ruminants) — Degree of absorption and bioavailability is variable, due to — Physiology — Presence of food — Disease — Presence of first-pass effect Oral administration: Disadvantages — Efficiently metabolized drugs are eliminated by the liver before they reach the bloodstream (first-pass effect) — Drugs may affect the normal gut flora — Drugs may cause irritation Oral administration: Disadvantages — Presence of antimuscarinic and narcotic drugs — May causes delay in gastric emptying → delay in absorption rate → prolonged drug onset of action — Increased gut motility — Shortens transit time → decrease drug contact time → less absorption Oral administration: Species differences — Stomach- in most species (abomasum- ruminants, 3rd compartment- camelids) — pH is so extreme — Absorptive surface is flat — Site of mechanical preparation of drugs Oral administration: Species differences — Rumenoreticulum (compartments 1 and 2 for camelids) — Epithelium: stratified squamous epithelium — pH is influenced by diet — Bacterial flora is involved in metabolism — Large volume of fluid is present Oral administration: Species differences — Small intestine — Absorptive surface is large — pH is relatively normal — Colon/ rectum — Accessible — Absorptive surface is also large Location of processes involved in the absorption of orally administered drugs Primary Secondary Process location(s) location(s) Duodenum for Breaking up of tablets Stomach enteric coated forms Dissolution of drugs from Stomach Duodenum suspension Absorption of drugs in lipid Small intestine suspension by the lacteals (all segments) Absorption of drugs in Duodenum, Stomach, ileum, solution through the mucosa jejunum colon Topical application — Application of drugs to various body surfaces — Provide local rather than systemic effects — Degree of absorption is dependent on lipid solubility of the drug and biological differences in skin — Area to be administered should be clipped — Facilitate better absorption — Ease of application Topical application — Application frequency depends on — Disease or disorder — Drug — Type of formulation Topical application — Aside from the skin, drugs can be applied to the following — Eyes — Remove foreign objects — Treat infections — Ears — Soften earwax and facilitate its removal — Treatment — Superficial infections — Earmites  Topical application: Advantages — For systemic problems — Application is painless — Example: mass medication in cattle or pig — For skin problems — Reduces systemic effects — Enhances skin effects Degree of absorption is dependent on lipid solubility of the drug. Topical application: Disadvantages — Patients tend to groom themselves — Application: topical, absorption: oral! — May result in toxic skin reactions — Blood flow to the skin is variable thereby influencing the rate of absorption and drug activity Factors affecting drug absorption through topical application — Lipid solubility and molecular size — Skin hydration and abrasion — Area of application — Drug penetration varies between body regions — Scrotal>forehead>axilla=scalp>back=abdomen>palm and plantar (humans) — Thickness — Hair follicle density — Lipid composition — Blood flow — Ambient and patient temperature Inhalation — For administration of dry powders, so nebulized particles are delivered as fine droplets — Used for volatile or gaseous anesthetics with the use of gas anesthetic machine — Response is rapid due to — Large surface area of the lungs — Large blood flow to the lungs  Source: DVM 360. Inhalant therapy: Finding its place in small-animal practice. Retrieved from http://veterinarymedicine.dvm360.com/vetmed/ArticleStandard/Article/detail/608394 on 28 July 2014. Source: Agri-Pro Enterprises of Iowa, Inc. Air Muzzle© Restraint. Retrieved from http://www.agri- pro.com/products/index.cfm?air_muzzle_restraint&show=product&productI D=270979 on 28 July 2014. References: — The Merck Manual Online (www.merck.com) — Ahrens, F. A. 1996. Pharmacology. Williams and Wilkins, USA. — Wannamaker, B.P. and Pettes, C.L. Applied Pharmacology for the Veterinary Technicians. 2nd Ed. W.B. Saunders Company, USA DRUG DISTRIBUTION VPha 101 Learning Outcomes: ¨ Describe the fate of drug molecules inside the animal’s body ¨ Define and describe the principles of translocation ¨ Describe the first pass effect mechanism ¨ Enumerate the factors that could affect the rate of drug distribution Distribution ¨ Reversible movement of a drug from the plasma to various fluid and tissues (site of action) ¨ Distribution may begin as soon as drug is absorbed Body fluid compartment Volume in a 10-kg Compartment % Body weight dog Blood/ plasma 4 0.4 L Interstitial 18 1.8 L Transcellular 2 0.2 L Intracellular 40 4.0 L 64 TOTAL 6.4 L (~ 80 in neonates) ¨ Rate and extent of distribution vary inside the body ¨ If physiochemical property of a drug is known, drug distribution can be predicted ¨ The concentration of a drug attained in various tissues is not necessarily correlated with the intensity of response to the drug. ¤ Examples n Digitalis: low concentration in the heart, primary action is in the heart n Lead poisoning n Low levels in the brain and skeletal muscles, but is greatly affected n Highest concentration: liver, kidneys and bones Regional blood flow in human and dog % Body Blood flow % Cardiac output Organ/ tissue weight (mL/100g/min Human Pig Adrenals 0.02 550.0 1.0 - Kidneys 0.4 450.0 24.0 23.1 Thyroid 0.04 400.0 2.0 - Liver Hepatic - 20.0 5.0 - Portal - 75.0 20.0 17.7 Heart 0.4 70.0 4.0 4.9 Brain 2.0 55.0 15.0 - Skin 7.0 5.0 5.0 3.8 Muscle 40.0 3.0 15.0 33.0 Connective tissues 7.0 1.0 1.0 0.0 Fat 15.0 1.0 2.0 - Rate of distribution ¨ Therefore, drugs are distributed more readily to organs with good blood supply than those with less ¤ Adipose tissue, less distribution of drugs due to less blood perfusion ¨ Blood flow through different organs varies as follows à kidney > liver> heart> brain > muscle > adipose Redistribution or sequestration ¨ Drug action is terminated before drugs are eliminated ¤ Example: n Anesthetic (thiopental)- after injection goes to the brain, thereby inducing anesthesia n Factors affecting accumulation of thiopental in the brain n High blood flow rate to the brain n High lipid content of the brain n Steep difference of drug concentration between plasma and the brain in the early stage of distribution ¨ Concentration of the brain equilibrates with its concentration in the plasma ¤ Amount that goes to the brain = amount that goes out of it ¨ Later, no drug goes to the brain ¤ Other amount has already been circulated to and taken by other tissues (esp. Adipose tissue) ¨ Concentration in the plasma becomes high ¨ Thiopental diffuses back to the plasma and redistributed ¨ Thiopental accumulates in the adipose tissues ¤ Drug does not return to circulation due to poor blood supply (trapped in body fat) ¤ Lowers level of anesthetic in the brain →patient recovers from anesthesia ¨ Patient recovers from anesthesia ¤ Even before biotransformation and excretion of thiopental will occur ¤ Therefore, termination is due to redistribution Thiopental: Ultra-short acting barbiturate Anesthetic through IV Minimum concentration for surgical anesthesia Fat compartment Blood Brain compartment Thiopental: Ultra-short acting barbiturate Anesthetic through IV Minimum concentration for surgical anesthesia Fat compartment Blood Brain compartment Thiopental: Ultra-short acting barbiturate Anesthetic through IV Minimum concentration for surgical anesthesia Fat compartment Blood Brain compartment Volume of distribution (Vd) ¨ Pharmacokinetic value that approximates the degree to which a drug is distributed throughout the body ¨ Assumption ¤ Drug concentration in the blood= drug concentration equally dispersed throughout the body ¤ ↑Volume of distribution of a drug, ↑ # of tissues penetrated, ↓drug concentration in the blood Physiochemical properties of drugs ¨ Lipid solubility ¨ pH ¨ Molecular size ¨ Ion trapping Lipid solubility ¨ More lipid soluble = increased rate of distribution ¤ Most of the biological barriers are made up of lipid- rich membranes Binding to tissue components or plasma proteins ¨ Tissues- major binding sites of most drugs ¤ Withdrawal period n Interval between the time of last drug administration and the time at which the level of drug becomes safe and acceptable n Considered especially in food producing animals Binding to tissue components or plasma proteins ¨ Plasma proteins ¤ Almost all, if not all, drugs bind to plasma proteins ¤ Silent receptors- Binding does not produce an effect (silent interaction) ¤ Albumin - mostly ¤ Binding n Different forms n Type depends on kind of drug n Percent binding= effectiveness of drug n High plasma protein binding- less effective ¨ Factors affecting the extent of drug binding to proteins ¤ Increase in concentration of drug in plasma, percent binding decreases ¤ If albumin concentration is reduced to below 2 mg/dL, there is decrease in percent binding ¨ Factors affecting the extent of drug binding to proteins ¤ Effect of pH, temperature and divalent cations are not significant in vivo ¤ Diseases influence plasma protein binding of drugs ¨ Factors affecting the extent of drug binding to proteins ¤ High lipid solubility increase the albumin binding of certain drugs n Drugs with high lipid solubility have greater percent plasma binding ¤ There is species variations in drug-albumin binding ¨ Factors affecting the extent of drug binding to proteins ¤ Competing molecules may produce important drug interactions of clinical importance ¤ Age of animal n Low plasma albumin concentration at birth (increases in 2-3 weeks and becomes equal to adult values) n Increases when the animal matures ¨ Protein-bound drugs ¤ Free from being biotransformed and excreted ¤ Serve as reservoir (binding is reversible) n Concentration of free drug is reduced, reservoir is utilized to supply the drug Distribution of drugs into selected specialized compartments ¨ Possible compartments where drugs can be distributed ¤ Milk ¤ Ruminal fluid ¤ Saliva ¤ Cerebrospinal fluid ¤ Fetuses ¤ Brain: consider blood-brain barrier ¨ Blood-brain barrier ¤ Continuous layer of tight junctions between capillary endothelial cells in the CNS ¤ A defensive complex comprising various physical features and chemical reactions having to do with the permeability of cells ¨ Blood-brain barrier ¤ Protects the brain from foreign proteins carried by the blood to enter the brain Many drugs are unable to cross the blood–brain barrier1 ¤ Do not perform pinocytosis ¨ Blood-brain barrier ¤ Drugs must be highly lipid-soluble in order to cross this barrier ¤ Latentiation n Pharmaceutical process that attaches lipophilic group to a drug with low lipid solubility to facilitate its passage through the barrier n Drug detaches from the lipophilic group when it reaches the brain ¤ Inflammation of the brain may facilitate passage of some drugs, such as penicillin ¨ Placenta ¤ Interfere with the gas exchange between maternal and fetal circulation ¤ Acts as fetal lung ¤ Acts as a partial barrier to allow development of a fetus which is immunologically different from the mother ¨ Placenta ¤ All drugs can cross the placenta and reach the fetus ¤ Rate of passage depends on the following n Physiochemical properties of the drug n Degree of ionization: not applicable in transplacental transfer n Charged molecules may penetrate easily depending on concentration gradient (maternal vs. fetal circulation) n Only free drugs can cross readily n May attach to proteins in the fetal blood and organs ¨ Sink effect ¤ Free drug concentration gradient between the mother and the fetus n There is a decrease in free drug concentration in the fetus due to drug binding to protein present in the fetal blood and organs Questions? Biotransformation  Learning Outcomes: — Describe what biotransformation is. — Describe and explain the process of biotransformation — Identify the enzymes that biotransform a drug. 2  Biotransformation — Drug metabolism — Biochemical processes that affect the pharmacological activity of drugs and other foreign substances — Activity of a biotransformed drug could be either — Increased — Reduced — Detoxification - Always — Unchanged results in the reduction of — Inactivated drug activity 3  Biotransformation — Rate vary among animal species — Responsible for most differences in response to drugs of various species — Ruminants versus non-ruminants — Schedule of eating (gastric emptying time) — pH fluctuations in the stomach — Anatomy and physiology of the stomach — Horse? 4  Biotransformation — Metabolites — Products of biotransformation — Almost always more polar than the parent compound — In general, less active than the parent compound Lethal synthesis: happens when the metabolites have greater activity than the parent compound 5  Liver- Important organ in biotransformation — Most important site — Only site for first-pass effect — First-pass effect — Also called first-pass metabolism or pre-systemic metabolism — Concentration of drug is reduced before going to the circulation 6  Liver- Important organ in biotransformation — Enzymes present in the liver is important for biotransformation — Microsomal enzyme (cytochrome P450 or cyt P450) — 12 families in mammalian species, 3 for drug biotransformation 7  Phases of biotransformation — Phase I — Involves metabolic transformation — Oxidation (Cy P450 Enzymes)- most important — Reduction — Hydrolysis — Hydration — Acetylation — Isomerization — Enzymes are found the endoplasmic reticulum — So with glucuronyl transferase for Phase II 8  Phases of biotransformation — Phase I — Functional group is attached to the drug molecule — Sulfhydryl (SH) — Hydroxyl (OH) — Amine (NH2) — Carboxyl (COOH) 9  Phases of biotransformation — Outcomes of the drug — Becomes water soluble — May be directly excreted — Activity — Increased — Reduced — Unchanged — Phase I products are the substrates for Phase II 10  Phases of biotransformation — Phase II — Involves synthetic reaction — Glucuronidation/glucosidation — Sulfation — Methylation — Acetylation — Amino acid conjugation — Glutathione conjugation — Fatty acid conjugation — Ornithine conjugation (birds) 11  Phases of biotransformation — Enzymes are found in the cytoplasm except for glucuronyl transferase — Conjugated drugs may become — Inactive — Even more water soluble 12 Phase 1 of Biotransformation Oxidation, reduction, or hydrolysis METABOLITES ↑ water solubility, maybe pharmacologically active, less active, or more active Phase 2 of Biotransformation Conjugation reaction Conjugated For excretion product: ↑ ↑ ↑ water solubility; ↓biologic activity  4 reactions in microsomal drug biotransformation — Oxidative reactions — Reductive reactions — Hydrolytic reactions — Conjugation reactions (Phase II or Synthetic reactions) — Functional groups involve in conjugation — Carboxyl, sulfhydryl, hydroxyl, amino groups 15  Glucuronidation — Also known as glucuronic acid conjugation — An important pathway in many species — Glucuronic acid — Conjugating substance — Derived from glucose — Glucuronyl transferase- conjugating enzyme FYI! Cats are deficient in glucuronyl transferase. Toxicity of 16 drugs needing this enzyme is high.  Sulfation — Also called as sulfate conjugation — Occurs with phenolic and alcoholic compounds to form sulfate esters or ethereal sulfates — Sulfate: Conjugating substance — Active form: 3’-phosphoadenosine-5’-phosphosulfate (PAPS) — Sulfokinase: conjugating enzyme FYI! 17 Pigs don’t have sulfate conjugation  Acetylation — Also known as acetyl conjugation — Acetylation of NH2 group is the only important reaction — Acetate: conjugating substance — Acetyl coenzyme A: active form — Acetyl transferase: conjugating enzyme 18  FYI! — Dogs cannot acetylate primary amines such as sulfonamide. — Dogs are prone to sulfonamide toxicity manifested as keratoconjunctivitis sicca. 19  Methylation — Synonym: methyl conjugation — Requires the presence of the active form of methyl: S-adenosyl-methionine — Enzyme: methyl transferase 20  Non-microsomal biotransformation — Biotransformation occurring in other tissues other than the hepatic microsomes — Extramicrosomal sites — Plasma — Neurons and neuromuscular junctions — Mitochondria — Intestinal microbial organisms 21  Non-microsomal biotransformation — Plasma: with the aid of enzymes — Cholinesterase against cholinesters and local anesthetics — Neurons and neuromuscular junctions — Acetylcholinesterase — Mitochondria — Monoamine oxidases (MAO) inactivating — Histamine — Serotonin — Catecholamines 22  Non-microsomal biotransformation — Gut: with the help of drug-metabolizing microorganisms — Glucuronidase — Anaerobic bacteria and lactobacilli- hydrolyze glucuronide conjugates — Results in reactivation of conjugated drugs — Glycosidases — Important in ruminants (herbivores) — Poisonous glycosides from plants are converted into cyanogenic factors 23  Non-microsomal biotransformation — Gut: with the help of drug-metabolizing microorganisms — Amidases: — For hydrolysis of amine drugs — Found in the liver — Procainamide and procaine — Reducing enzymes — For reduction of activity of chloramphenicol 24 Enterohepatic cycling — Happens when the glucuronide-conjugated (inactive) drugs excreted in the bile are acted upon by glucuronidases — Drug may be reactivated and reabsorbed — Prolong drug’s systemic effect 25  Factors affecting biotransformation by microsomal enzymes — Concurrent drug use — Age: Reduced metabolism due to less well- developed enzyme system — Young — Newborn — Aged 26  Factors affecting biotransformation by microsomal enzymes — Species — Difference can be — Quantitative: difference in the rate of biotransformation — Qualitative: difference in metabolic pathways — Presence or absence of enzymes — Cytochrome P-450 system is well-developed in terrestrial animals 27  Some examples of species difference Species Cat 1. Are more sensitive to drugs and chemicals, due to relatively slow rates of drug metabolism, unusual sensitivity of drug receptors and grooming habits 2. Deficient in glucuronide conjugation, hydroxylation reactions and dealkylation reactions 3. Glucuronide transferase activity is very slow 4. Can form glucuronide endogenous metabolites from - bilirubin, thyroxin and steroid hormones 28  Some examples of species difference Species Dogs Cannot acetylate primary amines such as sulfonamides Pigs Cannot carry out sulfate conjugations Primates Capable of producing phenylacetyl- glutamate Birds and reptiles Form ornithine conjugates Goldfish No glucuronide formation 29  Factors affecting biotransformation by microsomal enzymes — Disease and starvation — Liver problems — Congestive heart failure — Kidney problems — Gender: important in rats — Males metabolize drugs faster than females — Genetic differences 30  Microsomal enzyme induction — Enzymes are chronically exposed to enzyme inducers, such as — Anesthetics — Analgesics — Antihistamines — Environmental chemicals 31  Microsomal enzyme induction — Mechanism of induction — Increased rate of synthesis of enzyme, or decreased degradation or both — Observations associated with increased synthesis — Increase in weight and protein content of the liver — Increase in mRNA — Increased incorporation of amino acids from tRNA — Increased cytochrome P450 — Increased cytochrome P450 reductase — Increased number of SER 32  Microsomal enzyme induction — Consequences- important cause of some clinical drug interactions — Between phenobarbital and warfarin- fatal hemorrhages in humans — Phenobarbital and phenytoin-enhance endogenous cortisol metabolism= deficiency in steroid hormones — Phenobarbital and digoxin — Carbon tetrachloride (Rx=liver fluke in ruminants) + some plants- hepatic tissue damage 33  Microsomal enzyme induction — Clinical uses of enzyme induction — DDT and dieldrin residues in cattle = Phenobarbital — Hyperbilirubinemia in children= phenobarbital (increases synthesis of bilirubin glucuronyl transferase) 34  Microsomal enzyme inhibition — Due to inhibitor drugs — Example: Chloramphenicol — Result: patients become over-sensitive to drug leading to toxicity 35  Questions? 36 Drug Excretion  Learning Outcomes: — Define drug excretion. — Enumerate the routes of drug excretion. — Describe what half-life is. 2  Drug excretion — Process by which a drug or drug metabolite is eliminated from the body 3  Urine — Kidney- primary organ for drug excretion — Glomerular filtration — Filtration of drugs that are not bound to plasma proteins — Active tubular secretion — Proximal tubule — Competition between drugs for same carrier system may lead to adverse reactions or therapeutic advantage 4  Urine — Passive tubular reabsorption — Only lipid-soluble drugs are reabsorbed in this process — pH of the drug is important — Diet influences the urinary pH of carnivores and herbivores o Carnivores: urinary pH= 5.5- 7.0 o Herbivores: urinary pH= 7.0- 8.0 — pH of the urine can be altered to facilitate excretion of particular drugs 5  Bile and feces — Forms that can be eliminated — Parent drug — Glucuronide form (conjugated form) 6  Bile and feces — Systems involved — Active transport — Happens in the liver for transporting acidic, basic and neutral drugs into the bile — Biliary secretion is less effective (drug can be reabsorbed back) — Enterohepatic circulation — Increase drugs’ stay in the body — Product of metabolism can be reabsorbed back into the body 7  Milk — Not a significant route, but newborn may acquire the drug from the dam — Drug may affect newborn’s gut microflora 8  Saliva — Drugs reach the saliva from the blood through passive diffusion — Not a major route of excretion — Important in herbivores given with parenteral antimicrobials 9  Expired air — Very important route of excretion for volatile drugs — Inhaled anesthetics Tears and sweat — Minor routes of excretion 10  Questions? 11