Biopharmaceutics PDF RJAV 2022

MODULE 4 PHARM 4 BIOPHARMACEUTICS BIOPHARMACEUTICS Biopharmaceutics involves factors that influence: Bio life Pharmaceutics General area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms. Examines the interrelationship of the physical...

MODULE 4 PHARM 4 BIOPHARMACEUTICS BIOPHARMACEUTICS Biopharmaceutics involves factors that influence: Bio life Pharmaceutics General area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms. Examines the interrelationship of the physical/ chemical properties of the drug, the dosage form (drug product) in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption. 1. 2. 3. 4. 5. ↓ 6. INTRODUCTION DRUGS These are substances intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease. Drugs are given in a variety of dosage forms or drug products such as solids (tablets, capsules), semisolid, liquids, suspensions, emulsion, etc., for systemic or local activity. Drug product can be considered to be drug delivery systems that release and deliver drug to the site of action that they produce the desired therapeutic effect and are also designed The design of the drug product. Stability of the drug within the drug product. The manufacture of the drug product. The release of the drug from the product. The rate of dissolution/ release of the drug at the absorption site. Delivery of drug to the site of action which may involve targeting a localized area for action or systemic absorption of drug. PHARMACODYNAMICS Refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor. What the drug does to the body Toxicokinetic Application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies and in validating dose-related exposure in animals. convenience and safety. Clinical Toxicology The study of adverse effects of drugs and toxic substances (poisons) in the body. Drug Product Performance The release of drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity. The release of the drug substance from the drug product leading to bioavailability of the drug substance and eventually leading to one or more pharmacologic effect. PHARMACOKINETICS Is the science of the kinetics of drug absorption, distribution and elimination (metabolism and excretion) PRINCIPLES OF PHARMACODYNAMICS BIOAVAILABILITY Pharmacodynamics Study of the biochemical and physiologic effects of drugs in biological systems, Study of the mechanism by which these effects are produced Refers to the measurement of the rate and extent of active drug that reaches the systemic circulation. means access to the bloodstream Sequence of events A. PHARMACODYNAMICS: MECHANISM OF DRUG ACTION Absorption Drug release and Dissolution Drug in systemic circulation 1. Receptor-mediated Receptor cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells Drug in tissues 2. Non-Receptor-mediated Examples: Direct chemical interaction acid neutralizers (antacids), chelating agents (drugs that coat and coat bind to heavy metals that are present in excessive amount in the body) Colligative mechanism (dependent on the particles of the drug in solution)/ mass effect osmotic diuretics Counterfeit incorporation purine-pyrimidine analogues Elimination Excretion and Metabolism Pharmacologic clinical effect Critical Manufacturing Variables The most important steps in manufacturing process. RECEPTOR LOCATIONS Biopharmaceutical Consideration in Drug Product Design Items Therapeutic Objectives Drug (API) Route of Administration Drug Dosage and dosage regimen Type of Drug product Method of Manufacture Module 4 Cell membrane Cytoplasm Nucleus Considerations Drug is intended for rapid relief of symptoms, slow extended action given per day (weeks or longer), or chronic; is the drug for local action or systemic action Physical chemical properties of API, including solubility, polymorphic form, particle size Oral, topical, Parenteral, transdermal, inhalation, etc. Large or small drug dose, frequency of doses, patient acceptance of drug product, patient compliance Orally disintegrating tablets, immediate release tablets, transdermal, parenteral, implant, etc. Variables in manufacturing process, including weighing, blending, release testing, sterility Biopharmaceutics Page 1 of 8 RJAV 2022 Voltage-gated Na+ channel blocked by Class I antiarrhythmics, local anesthetic, tetrodotoxin, saxitoxin Voltage-gated K+ channel blocked by Class III antiarrhythmics such as Amiodarone and Sotalol Voltage-gated Ca2+ channels blocked by CCBs such as Verapamil, Diltiazem, Amlodipine. Cell membrane GPCRs Ion Channels Kinases Catalytic receptors Enzymes Transporters Structural protein and other molecules Cytoplasm and Nucleus Structural protein and other molecules Thyroid hormone receptor Steroid receptors b. Ligand-gated *Gating mechanism is controlled by a certain binding site, particularly a ligand may be able to interact. So, if a ligand interacts at the binding site, it will cause a change in configuration of the gate causing the gate to open and that will now allow the movement of certain molecules or ions RECEPTORS 1. GPCR (G protein-coupled receptor) Nicotinic receptor (Na+) Channel) blocked by neuromuscular blockers derived from tubocurarine GABAA receptors (Cl- channel) stimulated by BZDs, Barbs 7-transmembrane spanning receptor Metabotropic effects due to metabolites (or 2nd messengers) Involved in signal transduction Most common receptor 3. Kinases and Catalytic Receptors * The cell membrane and the GPCR consist of molecule that reverses the transmembrane spanning receptor. Now intracellularly, this receptor is associated with the G-Protein it is called G-Protein because this protein is intimately link to GDP. When a Drug or a Ligand bind to receptor the GDP is replaced by GTP and once this happens it will lead to production of 2nd messengers. If on the other hand the G-protein is not activated meaning the GDP is not replaced by GTP then what we expect would be a decrease in the 2nd messengers. This process where a drug binding to receptor that is found at the cell membrane which leads to stimulation of intracellular protein like the Gprotein is what we refer to as a Signal transduction process. *Are characterized by receptors that exist as monomers. What happens with the monomers is that when the ligand interacts with the monomers, they dimerize and this dimerization of receptors will lead to the activation of the receptors. There are several types of Kinases and Catalytic Receptors, and this type will depend on whether the kinase is an integral component or part of the entire receptor molecule or is a separate molecule from the receptor molecule. Types of GPCR: Gs Activation of AC (Adenylyl cyclase) Increase in cAMP Ex: Beta-receptors *It will activate the enzyme called Adenylyl cyclase this enzyme coverts ATP to the active cAMP intracellularly. cAMP inside the cell is metabolized by the enzyme Phosphodiesterase III which converts it to the inactive AMP. Gi Inhibition of AC (Adenylyl cyclase) 4. Enzymes Ex: alpha 2 presynaptic receptors ACE (Angiotensin Converting Enzyme) or Kininase II Gq Activates PLC (Phospholipase C) responsible for converting Angiotensin I to the more active Angiotensin II (responsible for vasoconstricting effect and drug such as: Captopril, Enalapril, Lisinopril can inhibit the activity of Angiotensin Converting Enzyme this class of drugs are called ACEi) acts in triglycerides (2nd messengers; primarily involved in smooth muscles activities, so they increase intracellular calcium level in smooth muscles and are involved in the phosphorylation and activation of the myosin light chain kinase) COX (Cyclooxygenase): inhibit by NSAIDS MAO: inhibited by MAO-Is Non-specific: Tranylcypromine, Isocarboxazid, Phenelzine MAOA: Moclobemide (RIMA) MAOB: Selegiline, Rasagiline, Safinamide Ex: alpha postsynaptic receptors 2. Ion channels 5. Transporters a. Voltage-gated *Cell membrane and examples of Ion channel at the end, you see a gating mechanism that prevents ions from moving in or out through the channel. A voltage-gated ion channel is primarily governed by a change in the membrane potential. So, at resting state we know that the inside of the membrane is more negative than the outside if there is a change however in the membrane potential such as the inside becomes less negative or even positive there will now be a change in configuration of the gate which prevents the movement of ions through the channel and may lead to opening of the gate. Module 4 Biopharmaceutics The characteristics of a transporter or carrier molecule, is that it brings ions into or out of the cell by changing its confirmation or configuration. In the case of Na+-K+ ATPase it brings out 3 Sodium ions as it brings in 2 Potassium ions, the movement of this carrier requires energy or ATP. Page 2 of 8 RJAV 2022 Examples: Na+-K+ ATPase: inhibited by Digitalis (Digoxin) Proton Pump (H+-K+ ATPase): inhibited by PPIs (Omeprazole) Types: GPCRs, Ion channels, Transporters, Enzymes, Structural proteins, nuclear receptors B. PHARMACODYNAMICS: CHARACTERISTIC OF DRUGRECEPTOR INTERACTION 6. Structural Proteins and other molecules Definitions: Affinity Ability to bind to a receptor or target protein Ligand-activity Intrinsic activity Ability to generate a series of biochemical events leading to an effect after receptor-binding Constitutional activity Ability to generate a series of biochemical events leading to receptor effects even in the absence of a ligand Receptor Binding Sites: Orthosteric site Primary binding site Allosteric site. Allosteric site Binding site of other molecules Can alter binding of endogenous ligand to the orthosteric site Microtubule consists of Dimers , these dimers can be added to the chain or they can be removed from the chain. So, when additional dimers are added in to the chain, we called it polymerization and there is lengthening of the microtubule, in contrast when dimers are removed from the chain, we called it depolymerization and there is shortening of the microtubule. Agonists, Inverse Agonists, Antagonists Microtubules: Cytoskeleton Organelle movement From mitotic spindles Agonists Stabilizes active receptor state Inverse Agonist Stabilizes inactive receptor site Inhibitors: Griseofulvin Colchicine Anti-mitotics Taxanes, Vincas, Estramustine, Epothilones (Ixabepilone) Antagonist Maintains equilibrium between the inactive and active receptor states Prevents binding of agonist 7. Nuclear Receptor are found initially at the Cytoplasm and when the ligand is bound to them, they form a complex and they are then translocated into the nucleus Allosteric modulators: Allosteric agonists Improve/ enhance binding of endogenous ligand to the orthosteric site Thyroid hormone receptors Steroid receptors MOA: Allosteric antagonists Reduce or prevent binding of endogenous ligand to the orthosteric site Agonists: Full agonists Produce the maximal clinical effects expected with receptor interaction Partial agonists Produce less than the maximal clinical effects expected with receptor interaction. Produce some of the anticipated effects with receptor interaction and inhibit other effects attributed to receptor interaction (Mixed agonist-antagonist activity) Summary: Two General MOAs: Receptor-mediated and non-receptormediated Antagonists: Clinical antagonist Drugs that produce clinical effects that are opposite of another drug or of the endogenous agonist Includes Antagonists and Inverse agonists Non-receptor-mediated: direct chemical interaction, colligative mechanism, counterfeit incorporation Receptor-mediated: Cell membrane, cytoplasmic, nuclear Module 4 Biopharmaceutics Page 3 of 8 RJAV 2022 Classification of Antagonists: a. Based on Mechanism of antagonist action Pharmacologic opposite effects produced by binding to the same receptor or receptor system Example: Stress or Anxiety Due to Epinephrine/ Adrenaline Increase HR by binding to 1 Tremors due to binding to 2 Treatment: Propranolol Decreases HR by binding to 1 Reduces tremors by binding to 2 Hill-Langmuir Equation Where: A: agonist or ligand R: receptor [A-R]: agonist-receptor complex K: equilibrium dissociation constant pAR: proportion of binding sites occupied by ligand at equilibrium Physiologic Produce opposite effects by binding to a different receptor Example: Anaphylactic shock Due to massive Histamine release Vasodilation/ Hypotension by binding to H1 receptors Bronchospasm by binding to H1 receptors Treatment: Epinephrine Vasoconstriction by binning to 1 receptors Bronchodilation by binding to 2 receptors Affinity b. Based on ability to surmount antagonist/ opposite effect Dose-Response Graphs Guide question: 1. Graded Dose-Response Graph YES (completely) Competitive antagonist NO (or incompletely) Non-competitive antagonist Plot of Response against Dose or Log Dose Example: Drug A decreases SBP from 160mmHg to 120mmHg at 10mg/day. Dug B is taken by the patient at 500mg dose causing the SBP to increase to 160mmHg. You advise to increase the dose of Drug A to 15mg/day which caused the SBP to drop again to 120mmHg. Did the increase in the dose of Drug A completely overcome the effect of Drug B? YES. So, Drug B is a competitive antagonist of Drug A Parameters: c. Based on reversibility of drug-receptor interaction -R] or D+R [D-R] Reversibility is dependent on the Type of bond/ Interaction formed between the Drug and Receptor Reversible: interaction involves IMFAs (intermolecular forces of attraction) H-bond, vDW forces of attraction, dipole interaction, London forces, etc. a. Efficacy: maximum achievable response Ceiling effect b. Ceiling Dose (DC): smallest dose that produces the maximum response c. Potency (P): dose producing 50% of the maximum response d. Mid-slope: degree of change in response with change in dose Irreversible: interaction involves a permanent bond Covalent bond Clinical clue: duration of action Duration of action < 24 hours likely reversible Propranolol lowering of HR <8 hours Duration of action > 24 hours likely irreversible Antiplatelet effect of aspirin lasting for about 7 days after stopping therapy 10 C. PHARMACODYNAMICS: DOSE RESPONSE RELATIONSHIP Relationship between concentration/ dose and effect Hill Equation: Where: E: Effect Emax: Maximum Effect [A]: concentration of the agonist [A]50: concentration of agonist producing half maximal effect nH: Hill coefficient (slope of a logarithmically transformed binding curve Module 4 Biopharmaceutics Page 4 of 8 RJAV 2022 Mid-slope Steep slope: small increase in dose leads to a large change in response Applications Differentiate Potency and Efficacy Efficacy: A = C >> B Potency: A > B > C Non-competitive antagonism: Shift pf the graph down and to the right 2. Quantal Dose-Response Graph Plot of cumulative number of Responders against the Dose A more effective drug is NOT necessarily more potent A more potent drug is NOT necessarily more effective Differentiate Partial agonist from Full agonists Parameters: a. b. c. ED50: median effective dose TD50: median toxic dose Therapeutic index (I) = TD50/ED50 Therapeutic index: measure of the relative safety of drug PRINCIPLES OF PHARMACOKINETICS Pharmacokinetics What the body does to the drug study of the different process a drug undergoes as it reaches and leaves the biologic state Differentiate Competitive from Non-competitive antagonist A. PROCESSES Transport processes Liberation Absorption Distribution Competitive antagonism: Shift of the graph to right Metabolism Elimination Excretion Module 4 Biopharmaceutics Page 5 of 8 RJAV 2022 1. TRANSPORT PROCESSES ii. Facilitated diffusion ATP independent Movement along concentration gradient Mechanism of drug movement across the cell membrane Passive Transport c. Convective Transport Carrier-mediated Transport Key Properties: Pore size: 7-10 Angstroms, allow passage of drugs with MW < 400-600 Allows passage of ions with charge opposite of pore lining Movement along electrochemical gradient Convective Transport Ion Pair Transport d. Pinocytosis Pinocytosis Key Properties ATP-driven Transport of large lipids in micelle form a. Passive Transport involves movement across a bilipid barrier Dominant No need for ATP Movement along concentration gradient Slow 2. LIBERATION Release of drug from the drug product Drug must be in aqueous solution required for most transport processes (except pinocytosis) Liquid nonNoyes-Whitney: Where: D = Diffusion Coefficient A = Surface Area of Membrane h = Thickness (C1 C2) = Concentration gradient Diffusion Coefficient and lipophilicity Where: property of drug dependent on particle size Surface Area of Membrane the greater the surface area the faster the rate (Ling > Small Intestine > Stomach) Thickness inversely related dM/dt = rate of dissolution D = diffusion coefficient A = surface area of the particle C = concentration in the stagnant layer Cb = concentration in the bulk layer h = thickness of the stagnant layer Intermediate vs Modified-Release Dosage Forms Concentration gradient concentration from where the drug is coming from and the concentration where the drug is going to Increased Diffusion Coefficient: Smaller particle size Increases surface area contact with cell membrane Application: micronization to improve bioavailability of Rifampicin Greater lipophilicity Less degree of ionization or dissociation into charged molecules/ions Weakly acidic drug in an acidic environment (lower pH) Weakly basic drug in a less acidic (basic or higher pH) environment High lipid-water partition coefficient Experimental procedure: solubility in an octanol-water system Lipid-water partition coefficient: ratio of solubility in lipid (octanol) to solubility in water 3. ABSORPTION Pharmacokinetic: rate and extent of a drug entry into the systemic circulation Physiologic: rate and extent of disappearance of the drug from the site of administration or absorption Factors affecting absorption: b. Carrier-mediated Transports a. Dose size b. pH of the absorbing environment Acidic environment for weak acids, basic environment for c. Degree of perfusion of the absorbing environment = blood supply d. Surface area of the absorbing organ e. Gastric emptying time Common Properties of Carriers: 1. Specificity/ Selectivity: carrier recognizes only certain molecular configuration/ conformation L-DOPA vs Dopamine 2. Subject to competition/ inhibition/ antagonism: molecules with similar configuration/ confirmation will compete for the same carrier L-DOPA vs 3-O-methyl-DOPA Gastric Emptying Time 3. Saturability: limited number of carriers GET = 1/GER (reciprocal relationship of Time with rate) Increase GET = Decrease Rate of Absorption Stress, Vigorous exercise, Gastric ulcer, Lying on the left side, anti-motility drugs (anticholinergics, opioids) i. Active transport ATP dependent Movement against concentration gradient (at least one) Fast Module 4 Biopharmaceutics Page 6 of 8 RJAV 2022 Decrease GET = Increase Rate of Absorption Mild exercise, Extremes of food temperature, Gastrectomy, Duodenal ulcer, Lying on the right side, DM, promotility drugs (D2-antagonists) How it is done 90% Confidence Interval AUC = 80 125% Cmax = 30 125% Tmax = 80 125% Measuring Absorption Bioavailability: measure of rate and extent of drug entry into the systemic circulation Blood measurement Urine measurement Measurement of Blood Levels of Drugs at Timed Intervals Time 0 hr 0.5 hr 1.0 hr 2.0 hr 4. DISTRIBUTION Plasma Concentration 0.0 mg/L 0.8 mg/L 1.2 mg/L 2.5 mg/L Process of drug movement from the systemic circulation to the different body compartments (organs/ tissues) Objective: Most biological sites of action are outside the systemic circulation Distribution allows drug to reach the biological site of action Measurement of Cumulative Amount of Drugs or Metabolites Excreted at Timed Intervals Time 0 hr 0.5 hr 1.0 hr 2.0 hr Two Distribution Parameters Cumulative Amount 0.0 mg 18 mg 40 mg 80 mg a. Protein Binding Free Drug Bound Drug Blood proteins: Albumin: for weak acids 1 acid glycoprotein: for weak bases Globulin: for hormones Highly protein drugs: Diazepam, Digitoxin, Indomethacin, Tolbutamide, Warfarin, Midazolam Relevance Limit access to compartments Longer duration Drug Displacement (?) Amount time = Urine Concentration x Volume Cumulative Amount time = Amount time + Amount previous times Bioavailability blood measurement Log Plasma Drug Conc tmax b. Volume of Distribution Hypothetical volume of body fluid necessary to dissolve a given dose or amount of drug to a concentration equal to that of the plasma Vd = D / CO (D = dose size, CO = concentration at time 0) Vd = A / CP (A = amount of drug, CP = drug plasma conc) Relevance Estimating loading doses Loading Dose (DL) = Vd x C desired Predicting fluid compartment of distribution Log Cmax AUC time Fluid Compartment Total Body Water a. Intracellular Water b. Extracellular Water i. Interstitial Water ii. Intravascular Water Parameters: Cmax rate and extent Tmax rate AUC extent Absolute Bioavailability (Fabs) Drug A: Vd (70kg patient) = 5,000 liters Drug B: Vd (70kg patient) = 40 liters Drug C: Vd (70kg patient) = 30 liters Drug D: Vd (70kg patient) = 2 liters Relative Bioavailability (Frel) Drugs with high Vd Atropine Chloroquine Digoxin Fluoxetine Imipramine TCAs BBs Bioequivalence Measure of similarity in bioavailability of generic drug product to that of the innovator or reference drug product Measures: 90% confidence interval about the ratios of AUC, Cmax and Tmax: AUC ratio = AUC generic / AUC innovator Cmax ratio = Cmax generic / Cmax innovator Tmax ration = Tmax generic / Tmax innovator Acceptable 90% confidence interval: 80 125% (extended to 75 133% for Cmax) Minimum Number: 12 (immediate release), 20 (controlled release) Module 4 Biopharmaceutics % Body Weight 60% 40% 20% 15% 5% Volume in a 70kg patient 42 liters 28 liters 14 liters 10-11 liters 3-4 liters Total body water Total body water Intracellular Intravascular High Vd Low Vd Drugs with low Vd Chlorpramide Furosemide Tolbutamide Valproic acid Warfarin 5. METABOLISM Biotransformation: chemical change First Pass Effect/ First Pass Metabolism (FPE/FPM) Initial metabolism a drug undergoes before reaching the systemic circulation Outcomes: Goals: metabolites that are Less active/ inactive Less toxic/ Polar and easily excreted Page 7 of 8 RJAV 2022 Exceptions CYP3A4: indinavir, nelfinavir, ritonavir, saquinavir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil NonPhase of Drug Metabolism Genetic Polymorphism: Genetic differences in the expression of enzymes Phase I: Functionalization Phase Addition or unmasking of a functional group Reactions: Oxidation, Reduction, Hydrolysis Categories based on enzyme expression: a. EM (extensive metabolizers) produce normal/ adequate amount of enzymes Phase II: Conjugation or Synthetic Phase Addition of a polar conjugate Glucuronidation, Acetylation. Glycine conjugation, etc. b. UM (ultra-rapid metabolizers) produce more than the normal amount of enzymes c. PM (poor metabolizers) produce less than the normal amount of enzymes or Phase I: a. Oxidation (CYP-mediated) CYP 1A2 Common enzyme system subject to polymorphism CYP2D6 PM: increase risk of cardiotoxicity with thioridazine and antidepressants (poor Debrisoquin metabolism) NAT2 (N-acetyltransferase-2) PM: slow acetylators, have higher risk of side effects with substrates of acetylation (procainamide, hydralazine, Isoniazid) EM: rapid acetylators Substrate Theophylline, Caffeine, Duloxetine, Melatonin, Clozapine, Ramosetron Cyclophosphamide, Ifosfamide, Bupropion, Efavirenz Repaglinide, Montelukast, Pioglitazone Celecoxib, Phenytoin, 2nd Gen Sulfonylureas, Tolbutamide, SWarfarin Omeprazole, Lansoprazole, Rabeprazole, Diazepam, Voriconazole, S-Mephenytoin Desipramine, Dextromethorphan, Eliglustat, Nebivolol, Nortriptyline, Perphenazine, Tolterodine, Venlafaxine, Amitriptyline, Encainide, Imipramine, Metoprolol, Propafenone, Propranolol, Tramadol, Trimipramine Macrolides, Amiodarone, Cortisol, Diazepam, Grapefruit juice 2B6 2C8 2C9 2C19 2D6 3A4 b. Reduction Nitro-reduction: Chloramphenicol Carbonyl reduction: Naloxone, Methadone Azo reduction: Prontosil c. Hydrolysis Esters: Procaine, Aspirin, Enalapril (prodrug), Cocaine (metab = benzoic acid) Amides: Lidocaine, Indomethacin, Procainamide 6. EXCRETION Elimination Metabolism and Excretion Excretion: loss of the drug from the body Site: Kidneys (major), Biliary, Lungs, Sweat/Secretions, Mammary Prerequisite: Drugs must be polar or water soluble PK Parameters Biological half-life t ½ = 0.693/k Time it takes for the amount of drug in the body to be reduced to half its current amount Phase II: a. Glucuronidation Acetaminophen, Diazepam, Chloramphenicol, Digoxin, Morphine Enzyme: UDP-Glucuronosyl Transferase b. Acetylation Isoniazid, Hydralazine, Procainamide Enzyme: NAT1 and NAT2 c. Glycine conjugation Nicotinic acid d. Glutathione conjugation Ethacrynic acid e. Methylation Dopamine No. of t ½ elapsed 0 1xt½ 2xt½ 3xt½ 4xt½ 5xt½ % Remaining in the body 100 50 25 12.5 6.25 3.125 Predicts when a steady state level is achieved when drug doses are given at regular intervals No. of t ½ elapsed 0 1xt½ 2xt½ 3xt½ 4xt½ 5xt½ Enzyme inhibition-induction Enzyme inducers: Benzo[a]pyrene, Phenobarbital, Phenytoin, Rifampicin CYP1A2: broccoli, brussel sprouts, char-grilled meat (benzo[a]pyrene), omeprazole, tobacco CYP2C9: rifampin CYP2C19: rifampin CYP2D6: rifampin, dexamethasone rt, Carbamazepine, glucocorticoids % to reach steady state level 0 50 75 87.5 93.75 96.875 Clearance (CL) Volume of blood that is cleared of the drug per given time CL = k*Vd k = elimination rate constant CL = (0.693/t ½) * Vd Total Clearance (CLtotal) = CLrenal + CLliver + CLother sites Enzyme inhibitors: CYP1A2: fluvoxamine, ciprofloxacin CYP2C9: fluconazole, amiodarone CYP2C19: PPI except pantoprazole (for Clopidogrel activation) CYP2D6: fluoxetine, paroxetine, quinidine, duloxetine, terbinafine Module 4 Biopharmaceutics Page 8 of 8 RJAV 2022 MODULE 4 PHARMACOLOGY PHARMACOLOGY 1. ANATOMIC DIVISIONS OF THE NERVOUS SYSTEM Study of drugs Nervous System Drugs articles used in diagnosis, prevention, treatment, mitigation of diseases. Peripheral nervous system CLASSIFICATION OF DRUGS 1. Diagnostic agents drugs being given primarily to determine the cause of a disease or to confirm diagnosis Edrophonium (Tensilon®) diagnosis of Myasthenia gravis, differentiates myasthenic from cholinergic crisis (base on the Efferent division improvement or deterioration in the muscle strength when the drug is given) Myasthenic crisis insufficient dose of the drug we are given. Radiopharmaceuticals Technetium 99m sestamibi for Myocardial ischemia Insulin performance of Insulin Tolerance Test to determine reserves of growth hormone. Enteric 2. Replenishers given to supplement lacking endogenous substances Cyanocobalamin Mx of Pernicious Anemia (B12 deficiency); characterized by the presence of auto antibodies that is Autonomic system Somatic system Parasympathetic Sympathetic Efferent Neurons Motor leave the CNS for Insulin-requiring DM 3. Functional modifiers alter normal physiologic function processes. Analgesics alter pain perception Antipyretic alter effects of endogenous pyrogens BIGGEST CLASS OF DRUGS Afferent division Nervous System Central Nervous System Peripheral Nervous System Afferent Neurons Sensory enter the CNS directed against their own cells, these antibodies destroy an important cell which is responsible for producing a substance for Vitamin B12 absorption in the Ilium. Cyanocobalamin is given IM in as much as there is lack of the intrinsic factor in Pernicious Anemia that will allow the absorption of B12 in the GIT. Insulin Central nervous system Efferent Neurons 4. Chemotherapeutic agents Drugs used to treat or inhibit growth of cells or proliferation of nucleic acids that considered foreign to the body Anti-infectives (antibacterial, antiviral, antifungal, antiparasitic) Anti-neoplastic a. Somatic Nervous System Single neuron Carries impulses going to the organs that are voluntarily moving such as skeletal muscles b. Autonomic Nervous System 2-neuron set-up Carries impulses towards the organs that are independent or involuntarily moving such cardiac muscles, smooth muscles and exocrine glands BRANCHES OF PHARMACOLOGY Ganglion 1. Pharmacodynamics (PD) What the drug does to the body Study of the biochemical and physiologic effects of drugs in biological systems, and the mechanism by which these effects are produced Pre-ganglion Effector 2. Pharmacokinetics (PK) What the body does to the drug Study of processes a drug undergoes as it reaches and leaves the biological site of action CNS Ganglion collection of neuron cell bodies in the PNS 2. SYNAPTIC NEUROTRANSMISSION 3. Pharmacotherapeutics Study of rational use of drugs in the management of diseases Nervous system is not a continuous system Gaps are present between 2 neurons between a neuron and an effector (See Biopharmaceutics) AUTONOMIC PHARMACOLOGY Post-ganglion Parts of the Synapse - A. ANATOMY AND PHYSIOLOGY OF THE ANS 1. Anatomic Divisions of the Nervous System 1. Pre-synapse - Synthesis, storage and release of neurotransmitters Metabolizing enzymes Auto receptors - Metabolizing enzymes Majority of receptors Metabolizing enzymes 2. Synaptic Neurotransmission 3. Synaptic Cleft 3. Subdivisions of Autonomic Nervous System 2. Post-synapse Module 4 Pharmacology Page 1 of 33 RJAV 2022 Steps Functional Difference Neurotransmitters carry information from the pre-synaptic sending neuron to the post-synaptic receiving cell. Synapses are usually formed between nerve terminals axon terminals on the sending neuron and the cell body or dendrites of the receiving neuron. A single axon can have multiple branches, allowing it to make synapses on various postsynaptic cells. Similarly, a single neuron can receive thousands of synaptic inputs from many different presynaptic sending neurons. Inside the axon terminal of a sending cell are many synaptic vesicles. These are membrane-bound spheres filled with neurotransmitter molecules. There is a small gap between the axon terminal of the presynaptic neuron and the membrane of the postsynaptic cell, and this gap is called the synaptic cleft. Pre-synaptic cell Heart Eyes Lungs Intestine Gall bladder Palms and Soles SANS Fight/ Flight Tachycardia Mydriasis Bronchodilation Ileus PANS Rest/ Digest Bradycardia Miosis Bronchoconstriction Bowel Movement Urinary Retention Urination Sweating Generalized B. SYMPATHETIC DRUGS Axon terminal Synaptic vehicle 1. Natural Catecholamines Neurotransmitter 2. Receptors Voltage-gated Ca2+ channel 3. Sympathomimetics Receptor for neurotransmitter (ligand-gated ion channel) Synaptic cleft 3. Sympatholytics 1. NATURAL CATECHOLAMINES Post-synaptic cell Endogenous self-made; they are being produced inside the body Norepinephrine, Epinephrine, Dopamine When an action potential, or nerve impulse, arrives at the axon terminal, it activates voltage-gated calcium channels in the cell membrane. Ca2+ which is present at a much higher concentration outside the neuron than inside, rushes into the cell. The Ca2+ allows synaptic vesicles to fuse with the axon terminal membrane, releasing neurotransmitter (Exocytosis) into the synaptic cleft. Action potential arrives Locations: a. Sympathetic post-ganglion 1. Action potential reaches axon terminal and depolarizes membrane 2. Voltage-gated Ca2+ channel is open and Ca2+ flows in 3. Ca2+ influx triggers synaptic vesicles to release neurotransmitter depolarization more likely to fire action potential particularly NE b. Adrenal medulla NE, Epi c. Brain NE, Dopamine Steps 4. Neurotransmitter binds to receptors on target cell (in this case, causing positive ions to flow in The molecules of neurotransmitter diffuse across the synaptic cleft and bind to receptor proteins on the postsynaptic cell. Activation of postsynaptic receptors leads to the opening or closing of ion channels in the cell membrane. This may be depolarizing make the inside of the cell more positive or hyperpolarizing make the inside of the cell more negative depending on the ions involved. Drugs 3. SUBDIVISIONS OF AUTONOMIC NERVOUS SYSTEM 3 Major Subdivisions: Enteric Nervous System Sympathetic Nervous System Parasympathetic Nervous System Anatomical Difference Sympathetic NS Parasympathetic NS Origin/ Roots of Fibers Thoraco-Lumbar NS Cranio-Sacral NS T1 T12 Cranial: 3,7,9,10 L1 L4 S2 S4 Length of Fibers Short: Pre-ganglionic neuron Long: Pre-ganglionic neuron Long: Post-ganglionic neuron Short: Post-ganglionic neuron Location of Ganglion Near the CNS Near the Effector organ Neurotransmitters Ach: Pre-ganglionic neuron Ach: Pre-ganglionic neuron & NE: Post-ganglionic neuron Post-ganglionic neuron Receptors Ganglia: Nicotinic Ganglia: Nicotinic Effector: , , Dopa Effector: Muscarinic, Nicotinic Module 4 Pharmacology Tyramine Ephedrine Amphetamine Angiotensin II -latrotoxin Guanethidine Guanadrel Bretylium Page 2 of 33 RJAV 2022 Termination Cell membranes Neuromuscular endplates 3) Skeletal muscles Increased inward conductance to K+ ions = Hypokalemia Contraction = Tremors Receptors: Target Adipocytes Response Lipolysis Dopaminergic Receptors: Dopaminergic1 Receptor (Gs-linked) Target Renal and Splanchnic Blood vessels Response Dopaminergic2 Receptor (Gi-linked) Target Response Peripheral (GI tract) Relaxation (ileus; no peristalsis) Perception and behavior Central (Brain) Modulation of motor activity The vesicular monoamine transporter (VMAT) is responsible for the transport of catecholamines to the storage vesicles, maintaining their cytosolic concentration low. After catecholamine release to the synaptic cleft, catecholamines are reuptaken to the presynaptic terminal by noradrenaline transporter (NET), and/or taken to extraneuronal cells by the extraneuronal transporters. The most important extraneuronal transporter for catecholamines is extraneuronal monoamine transporter (EMT). Catecholamines are metabolized by intracellular enzymes. Monoamine oxidase (MAO) is located in the outer membrane of mitochondria in neurons and in extraneuronal cells. Catechol-O-methyl transferase (COMT) is located at extraneuronal cells. Both enzymes (COMT and MAO) are the main responsible for the metabolism of catecholamines. The enzymatic process leads to the formation of several metabolites. To exert their actions, the catecholamines and other neurotransmitters in the synaptic cleft bind to different pre-and postsynaptic receptors. Such binding leads to alterations in the postsynaptic cell and activation of intracellular pathways through G proteins. In presynaptic neurons, catecholamines bind to autoreceptors and activate feed-back responses that change their own release. 2. RECEPTORS 3. SYMPATHOMIMETICS Adrenergic Agonists Mimicry Classifications Based on Chemistry Based on Mechanism of Action Catecholamines Catechol 3,4-dihydroxybenzene group High potency in activating and receptors Metabolized by MAO and COMT Do not penetrate the CNS Alpha ( Pilomotor smooth muscles (skin) Response Urinary Retention Contraction = mydriasis Contraction (piloerection) = goosebumps Alpha2 ( 2) Receptors Target Response Pre-synaptic alpha 2 (Gi-linked) from the vesicles) Central Sedation Peripheral blood vessels : 1) Receptors (Gs-linked) Target Heart (Cardiac myocytes) Kidneys Renal Juxtaglomerular Apparatus Direct-acting Indirect-acting Mixed-acting BASED ON CHEMISTRY Dopaminergic (D) Receptors Alpha1 ( 1) Receptors Target (Smooth muscle) Vascular smooth muscle Bladder, trigone & sphincter females Prostatic smooth muscles males Radial muscles (iris) Catecholamines Non-catecholamines Non-catecholamines No catechol Not metabolized by MAO and COMT Longer half-lives Administered orally Response (+) Inotropism Force of contraction (+) Chromotopism Heart rate (+) Dromotropism AV nodal conduction Renin secretion RAAS activation = Increased BP 2) Receptors (Gs-linked) Target Response Smooth muscles Bronchi Bronchodilation Uterus Relaxation (tocolysis) Blood vessels (skeletal muscles) Vasodilation Module 4 Pharmacology Page 3 of 33 RJAV 2022 BASED ON MOA - Direct-acting: Non-selective binds and activate more than 1 general type of adrenergic receptor Selective binds and activates 1 general type of adrenergic receptor 1 - - Anaphylaxis, anaphylactic shock, anaphylactoid reaction Cardiac stimulant Local vasoconstrictor (+ Lidocaine) Galucoma: Dipivefrin lower intraocular pressure Septic Shock - Cardiogenic shock (alternative) Acute Heart Failure 2 Norepinephrine: 1 Releasers Enhances exocytosis of NE 1 Dopamine: 1 1, D1 Toxic Effects: - - Tyramine Ephedrine Amphetamine Methamphetamine - Methylphenidate ADHD (1st line) Phenmetrazine Anorexiant Modafinil Narcolepsy - 1 1 Selective 1-selective Agonists Constrictor Agents: Phenylephrine Methoxamine Propyhexedrine Tetrahydrozoline Oxymetazoline Nafazoline Non-selective Agonists 1-selective Agonists 2-selective Agonists Toxic Effects: Local: Rhinitis medicamentosa or rebound congestion (do not use for more than 3 days) Systemic: Hypertension Urinary retention (Benign prostatic hyperplasia) Tolerance (do not use for more than 5days) Anti-hypertensive: Clonidine hypertensive crisis (rapid acting) alternative for ADHD Toxic effects: Clonidine withdrawalinduced HTN Methyldopa FDA approved for Pregnant women Toxic effects: Sedation, Hepatotoxicity, (+) Coombs test Guanfacine centrally acting Guanabenz centrally acting 4. SYMPATHOLYTICS Adrenergic Antagonists Relaxation (blocking alpha receptors) Cardiac depression (blocking beta receptors) Classifications Direct-Acting Alpha Blockers Beta Blockers PeripherallyActing Adrenergic Neuronal Blockers DIRECT-ACTING 1 1 2 2 Alpha Blockers Nonselective, Irreversible, Noncompetitive Nonselective, Reversible 2 Selective, Reversible Adrenergic Selective, Reversible 2 Phenoxybenzamine Anti-glaucoma Apraclonidine Brimonidine Isoproterenol Alternative during shock states Management of Acute Heart Failure Inotropic Dobutamine First line for cardiogenic shock Management of Acute Heart Failure Pharmacologic stress test (with dipyridamole) Bronchodilators SABAs (Salbutamol/Albuterol, Terbutaline, Pirbuterol, Metaproterenol) LABAs (Salmeterol, Formoterol, Bambuterol, Indacaterol) Phentolamine Clinical Uses: Pheochromocytoma (pre-surgical) a catecholamine secreting tumor of cells derived from the adrenal medulla used prior to surgical removal of tumor to prevent hypertensive crisis Carcinoid Tumor (5-HT blockade) abnormal high levels of serotonin Pheochromocytoma (during surgical) Raynaud Syndrome Accidental local infiltration of alpha agonists and sympathomimetic poisoning Yohimbine Prazosin Doxazosin Clinical Uses : Management of bronchial asthma and COPD (bronchodilators) Pharmacology Phenoxybenzamine Phentolamine Yohimbine Prazosin Doxazosin Terazosin Tamsulosin Alfuzosin Mastocytosis (H-blockade) too much masts cells that store histamine Tocolytics Ritodrine Isoxsuprine Terbutaline (off-label use) Module 4 Reuptake inhibitors Tricyclic antidepressants Centrally acting Cocaine Local Anesthetic Atomoxetine ADHD Sibutramine Obesity Mixed-acting Ephedrine For Narcolepsy Mephentermine and Metaraminol For Hypotension Phenylpropanolamine For Nasal congestion Clinical uses Nasal & Ophthalmic congestion Hypotension Local vasoconstrictions 2-selective Agonists Toxic effects : Tremors Hyperkalemia Fenoldopam (Corlopam ®) Used as an alternative for hypertensive crisis Indirect-acting Non-selective: Epinephrine: 1 D1-Selective Agonists Management of preterm labor (tocolytics) Adjunct in the management of hyperkalemia Page 4 of 33 Erectile Dysfunction Locally administered Erectile dysfunction HTN: Prazosin, Doxazosin, Terazosin Vasodilators RJAV 2022 Terazosin Tamsulosin Alfuzosin Selective Beta 1 antagonist Useful in hypertensive patients with impaired pulmonary function First line therapy for chronic stable angina Benign prostatic hyperplasia (BPH): Tamsulosin, Alfuzosin Used as an alternative to surgery Toxicities: Reflex Tachycardia Orthostatic Hypotension Nausea and Vomiting Acebutolol and Pindolol Beta blockers with ISA are effective in hypertensive patients with moderate bradycardia, because a further decrease in heart rate is less pronounced in these drugs. Not used for stable angina and arrhythmias due to their partial agonist effect Beta Blockers Effects: (-) Dromotropism = Lesser conduction velocity (-) Inotropism = Lesser force (-) Chronotropism = Lesser rate Classes: Based on Non-selective Nadolol selectivity Sotalol Timolol Propranolol Metoprolol 1-Selective or Cardioselective Acebutolol Celiprolol Betaxolol Atenolol Bisporolol Esmolol Based on their Beta blocker with Intrinsic Celiprolol miscellaneous Sympathomimetic Activity (ISA) Carteolol action Labetalol 1 Acebutolol 2 agonism effect Penbutolol Beta blocker with Membrane Pindolol Stabilizing Action ( MSA ) Propranolol they possess local Acebutolol anesthetic effect Labetalol not instilled in the eyes Metoprolol not prepared as ophthalmic drops due to inhibition of blinking reflex resulting to drying of the eyes leading to corneal injury Beta blocker with Alpha-1 Carvedilol blocking effect Labetalol Vasodilating effect Most cardio selective Beta Nebivolol blocker among Beta blockers it has a vasodilating effect due to increase of Nitric oxide Labetalol Alternative to methyldopa in the treatment of pregnancy-induced hypertension Used in hypertensive emergencies (it can rapidly lower blood pressure) Toxicities: Augmentation of hypoglycemia Bradycardia; AV Block Dyslipidemia Bronchoconstriction (Asthma) PERIPHERALLY-ACTING Adrenergic Neuronal Blockers Inhibits storage Reserpine regulators like serotonin and NE - Inhibits release bind to the receptor Bretylium Guanadrel Guanethedine Pharmacologic sympathectomy characterized by mark postural hypotension; impaired ejaculation C. PARASYMPATHETIC DRUGS 1. Acetylcholine 2. Cholinoreceptors 3. Parasympathomimetics 3. Parasympatholytics Indications: Cardiovascular diseases 1st line agent in the management of Hypertension in patients with history of post myocardial infarction Treatment of angina pectoris (CSAP) Management of congestive heart failure: Bisoprolol, Metoprololsuccinate, Carvedilol, Nebivolol Arrhythmia: Class II agents 1. ACETYLCHOLINE Locations: a. Vesicle b. Cholinergic Post gangllion c. Central Nervous System d. Skeletal Muscles e. Stomach Propranolol Useful in chronic management of Stable Angina 1st line agent in the management of hypertension in patients with a history of post myocardial infarction *protective effect on the myocardium; can protect a patient against a second heart attack (prophylaxis)reduces infarct size and hasten recovery Prophylaxis in acute migraine headache Management of sympathetic symptoms of Hyperthyroidism Protects against serious cardiac arrhythmias (due to thyroid storm) Management of Stage Fright Steps Nadolol and Timololmore potent than Propranolol Nadolol very long duration of action Timolol reduces the production of aqueous humor in the eye | topically used in the treatment of chronic openangle glaucoma (Timolol and Betaxolol) | decreases the secretion of aqueous humor by the ciliary body * note: Pilocarpine is still the DOC for emergency lowering of IOP (acute glaucoma) Module 4 Pharmacology Page 5 of 33 RJAV 2022 Choline is transported into the presynaptic nerve terminal by a sodiumdependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl-CoA (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltagesensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft This step can be blocked by botulinum t by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins. Alkaloids Non selective Muscarinic-selective Arecholine Muscarine Pilocarpine Nicotine Lobeline Varenicline Nicotinic-selective Indications Betanechol Metacholine - Pilocarpine - Drugs: Acetylcholine Nicotine Lobeline Varenicline Hemicholinium block entry of choline Vesaminol inhibits storage of ACh into the vesicle Botulinum toxin inhibit exocytosis of Ach Anticholinesterases - Management of Urinary retention Post-operative abdominal distention and gastric atony Pulmonary challenge test (provocative test for bronchial hyperactivity) Reduces intraocular pressure in open angle and narrow angle glaucoma Binds preferentially at muscarinic receptors Produce miosis in ophthalmic surgery Smoking cessation - Irreversible Inhibitors Organophosphates 2. CHOLINOCEPTORS Echothiophate Malathion Parathion Nerve Gases: Sarin Tabbun Soman Muscarinic (M) Nicotinic (N) Muscarinic (M) Receptors: Muscarinic 1 (M1) Gq - linked Target Gastric gland INDIRECT ACTING Response HCl secretion Muscarinic 2 (M2) Gi - linked Target Heart (artria) Reversible Inhibitors Aminoalcohol Carbamates Endrophonium (Tensilon) Physostigmine/Eserine Neostigmine Pyridostigmine Ambenonium Demecarium Response contractility of the atria) Muscarinic 3 (M3) Gq - linked Target Exocrine Glands Smooth Muscles CNS-acting Tacrine Donepezil Galantamine Rivastigmine Response Secretion = Eccrine, Lacrimal, Salivary, Gastric acid Contraction = Miosis, Bronchospasm, Diarrhea, Urination Nicotinic Receptors: Nicotinic neural (Nn) Target Ganglion, CNS Indications Physostigmine Demecarium Echothiophate Edrophonium Dx. (Tensilon Test) Pyridostigmine Ambenonium Neostigmine Tacrine Donepezil Galantamine Rivastigmine Response Stimulation Epi release Nicotinic (Nm) Target Neuromuscular endplates Response Skeletal muscle contraction = Tremor 3. PARASYMPATHOMIMETICS Cholinergic Agonists Cholinomimetics Mimicry Indirect-Acting: Cholinesterase Inhibitors Direct receptor activation Inhibit metabolism of ACh Muscarinic-selective Module 4 Pharmacology - Myasthenia Gravis autoimmune disease (Progressive muscle, weakness, dropping of eyelids, Repiratory paralysis) - Primary: Atropine DIRECT-ACTING Choline esters Non selective Glaucoma GI and Urinary Tract Anatomy Adverse Effects: Diarrhea Urination Miosis Bradycardia, Bronchoconstriction Emesis Lacrimation Salivation, Sweating Treatment: Classifications: Direct-Acting - Acetylcholine Carbachol Metacholine Betanechol (Urecholine) Cholinesterase Reactivators Pralidoxime Diacetylmonoxime Page 6 of 33 RJAV 2022 4. PARASYMPATHOLTICS Neuromuscular Blockers: Classifications Depolarizing NMB Non-depolarizing NMB Succinylcholine Curare derivatives Cholinergic Antagonists - Classifications Antimuscarinics Antinicotinics Muscarinic blocker Nicotinic blocker - ANTIMUSCARINICS MOA: irreversibly activates Nm receptor A.k.a. Anticholinergics Atropine Other Anticholinergics Phase of effect : Initial = skeletal muscle contraction Final = relaxation paralysis Atropine Blocks M1: Inhibits gastric secretion Blocks M2: Tachycardia Blocks M3: Inhibits secretion Dry mouth Anhidrosis Cutaneous vasodilation Erythema Blocks M3: Smooth Muscles Mydriasis Cycloplegia Bronchodilation Ileus Urinary retention CNS Effects Acute Psychosis Confusion Agitation Disorientation CNS: Eyes Bronchi Gastric Gland GIT and Urinary Bladder Adverse effect : Respiratory Paralysis: (Tx. Endrophonium, Neostigmine) Malignant Hyperthermia: (Tx. Dantrolene) Myalgia, Myositis, Rhabdomyolysis Scopolamine Trihexyphenidyl Benztropine Biperiden Homatropine Anistropine Cyclopentolate Ipratropium Tiotropium Oxytropium Pirenzepine Telenzepine Methscopolamine Glycopyrrolate Hyoscine Dicycloverine Oxybutinin Scopolamine - Symptomatic Bradycardia Treatment of Cholinomimetic Poisoning Given with Diphenoxylate to minimize addiction with Diphenoxylate Management of Motion sickness Management of EPS and Parkinsonism - Mydriatic Cycloplegics - Bronchial and COPD - Management of hyperacidity - Management of hypermotility D/O and urinary incontinence MOA: blocks Nm receptor immediate paralysis At low doses : competitively block ACh at the nicotinic receptors, preventing depolarization of the muscle cell membranes and inhibit muscle contraction At high doses : Blocks the ion channels of the motor template, leading to further weakening of the neuromuscular transmission, thereby reducing the ability of cholinesterase inhibitors to reverse the actions of the nondepolarizing blockers Type I : Isoquinoline (-curium) Atracurium Tubocurarine Type II : Steroidal (-curonium) Pancuronium Rocuronium Adverse effects : Respiratory/diaphragmatic paralysis. (Tx : Neostigmine, Edrophonium) Tubocurarine anaphylactoid reaction (Tx. Epinephrine) DRUGS WITH IMPORTANT ACTIONS ON SMOOTH MUSCLE Other Anticholinergics Scopolamine, Trihexyphenidyl, Benztropine, Biperiden Homatropine, Anistropine, Cyclopentolate Ipratropium, Tiotropium, Oxytropium Pirenzepine, Telenzepine Methscopolamine, Glycopyrrolate, Hyoscine, Dicycloverine, Oxybutinin, Scopolamine Clinical Uses Atropine anti nicotinic agonist Useful when rapid endotracheal intubation is required during the induction of anesthesia Used during electroconvulsive shock treatment AUTACOIDS Localized hormones Site of release = near the site of action Produced by virtually all cells Vs. Endocrine Hormones - Systemic; produced by specific cells Histamine Serotonin Eicosanoids Bradykinin HISTAMINE Locations: Mast cells Basophils Stomach CNS Biosynthesis ANTINICOTINICS Muscle relaxant Ganglionic Blockers Neuromuscular Blockers Ganglionic Blockers are Nn blockers Hexamethonium Trimethaphan Mecamylamine - Module 4 Vasodilation and anticholinergic These agents are no longer clinically useful Pharmacology Neuromuscular Blockers are Nm blockers Skeletal muscle relaxants Used for spastic disorders Anesthetic adjuncts Mechanism of Release: Ca2+ dependent degranulation Vesicle Ca2+ independent degranulation Ca2+ dependent degranulation Induced by immunoglobulin E (IgE) fixation to mast cells Anaphylaxis Page 7 of 33 RJAV 2022 Ca2+ independent degranulation Induced by drugs Morphine Guanethedine Tubocurarine Amine Antibiotics Anaphylactoid reaction Piperidine Cyproheptadine also possesses antiserotonergic and anticholinergic activiies used in management of serotonin syndrome Piperazines Less sedating 2nd generation Less lipohilic Less sedating Mechanism of Action Binds histaminic receptors Cetirizine Levocetirizine Piperidines True, non-sedating HISTAMINIC RECEPTORS Histaminic-1 (H1) Vasodilation Bronchoconstriction Pain and itchiness Contraction of endothelial cells Wakefulness Histaminic-2 (H2) Increase gastric acid production Enhances degranulation of histamine Histaminic-3 (H3) Decrease histamine release Histaminic-4 (H4) Chemotaxis Loratadine Desloratadine Fexofenadine H2 antihistamines H2 blockers Cimetidine (least potent) Famotidine (most potent) Ranitidine Nizatidine Betahistine Agonists No longer used clinically Obsolete use : Pulmonary challenge test Test of gastric secretory function H1 agonist ; H3 antagonist Impromidine Use: Management of associated with vertigo (Endolymph: presence of fluid in the inner ear) Investigational Antagonists Functional: Epinephrine - - Drugs Histamine - Cimetidine (prototype) - Promote healing of gastric and duodenal ulcers Treatment of hypersecretory states (Zollinger-Ellison Syndrome) Adjuncts in the management of allergic reactions enzyme inhibitor Interactions = Toxicityantiandrogenic (gynecomastia, loss of libido, infertility) SEROTONIN Locations: Enterochromaffin cells Platelets Stomach CNS Biosynthesis Pharmacologic: Antihistamine Antihistamine H1 antihistamines anti-allergy Use: allergic reaction, asthma Do not give for bronchial asthma st 1 generation (classical) Ethanolamines Lipophilic (can cross most sedating the Blood brain most efficacious barriers or BBB) Powerful central Diphenhydramine anticholinergics management of Acute Dystonic Sedating agents Crisis Mechanism of Action Interacts with Serotonergic receptors SEROTONERGIC RECEPTORS 5-HT1A Decrease cAMP Pre-synaptic receptors (CNS) Autoregulation Inhibits further release of serotonin 5-HT1B/1D Vascular smooth muscles Not involved: blood vessels in the heart and in the skeletal muscles Vasoconstriction 5-HT2 Enhances phospholipase C activity Smooth muscles (bronchi, blood vessels, intestines) contarction Dimenhydrinate Carbinoxamine Doxylamine Sleeping Aid Ethylenediamine Tripelennamine Pyrilamine Cause moderate sedation Cause GI upset Piperazines Meclizine and Cyclizine for motion sickness 5-HT3 Inotropic receptors Hydroxyzine prodrug; active form of Cetirizine Alkylamines 5-HT4 Enhances cAMP Brompheniramine and Chlorpheniramine component of OTC cold medications Phenothiazine Promethazine preanesthetic agent Module 4 Pharmacology Page 8 of 33 RJAV 2022 Drugs Platelets Buspirone -triptans: Sumatriptan, Naratriptan, Zolmitriptan Cisapride, Tegaserod (Partial 5-HT4 agonists) Eyes Agonists Partial 5-HT1A agonist Anxiolytic Therapeutic effects: 2 weeks 5-HT1B/1D Agonists Inhibits vasodilation of cerebral blood vessels Inhibits inflammation of meninges Use: Anti-migraine Agents A/E: Increase in blood pressure Management of irritable bowel syndrome with predominant constipation - Misoprostol Epoprostenol Dinoprostone Alprostadil Prucalopride (Full 5-HT4 agonist) Latanoprost Cyproheptadine Antagonists Blocks 5-HT1 and 5-HT2 receptors Antihistaminic Anticholinergic Block 5-HT3 receptors Prevention/ Treatment of chemotherapyinduced nausea and vomiting - -setrons: Ondansetron Granisetron Palonosetron - - Inhibits aggregation = PGE1 Aggregation = TXA2 Reduction of IOP = PGF enhances outflow of aqueous humor Prostaglandin Analogs PGE1 analog ytoprotectant Treatment of NSAID-induced ulcer Abortifacient PGI2 analog Vasodilation Management of primary pulmonary hypertension PGE2 analog Cervical opening Induction of abortion PGE1 analog Vasodilation Treatment of erectile dysfunction PGF analog Lowers IOP Treatment of glaucoma DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM CENTRAL NERVOUS SYSTEM consisting of the brain and spinal cord It is referred to a the entire body and co-organs activity across the whole organism Brain control center of the body Blood Brain Barrier a tightly packed layer of cells that line the blood vessels in the brain & spinal cord Gatekeeping system that prevents entry of toxins and only allowing entry of nutrients In drugs, the BBB prevents entry of most drugs from the blood Neuron ERGOTS ALKALOID Claviceps purpurea (Ergoline) Strong structural similarity to DA, NE, and 5-HT Mehanism of Action Acts primarily on alpha-adrenergic receptorson uterine and vascular smooth muscle, increasing uterine tone and causing vasoconstriction Drugs: Also known as nerve cells, sends and receive signals from the brain Soma carries genetic and provides energy to drive activities Axons allow neurons to send electrical signals to other cells Dendrites receives signals Nerve cells pass messages one to another and it is achieved through chemical and electrical impulses EICOSANOIDS From metabolism of 20-carbon, unsaturated fatty acids (eicosanoids acids) Arachidonic acid Biosynthesis NEUROTRANSMITTERS Phospholipids Phospholipase A2 Arachidonic acid Lipoxygenase Leukotrienes Vascular smooth muscles Bronchi Uterus Stomach Module 4 Pharmacology Cyclooxygenase Prostanoids Actions Vasodilation = PGE2, PGF , PGI2 (prostacyclin) Vasoconstriction = TXA2 (thromboxane) Inflammation = PGI2 PGE2 , LTB4 Bronchodilation = PGE series Bronchoconstriction = PGF, LTC4, LTD4 Slow-reacting Substances of Anaphylaxis (SRSAs) Contraction of uterus and dysmenorrhea = PGE series, PGF Cytoprotection pepsinogen secretion = PGE series Endogenous chemicals responsible for the transmission of signals Excitatory NT fires action potential Inhibitory NT decrease the chances of neurons to fire action potential Both Excitatory & Inhibitory NT: Acetylcholine, Norepinephrine, Serotonin, Glutamate Inhibitory NT: Dopamine, GABA, Glycine, Opioids GABA Gamma Amino Butyric Acid Major inhibitory NT of the brain Binds either GABAA or GABAB receptors GABAA receptor (ionotropic) opens Cl- channels GABAB receptor (metabotropic) opens K+ channels or closes Ca2+channels Inhibitory effects Fast Inhibitroy Postsynaptic Potentials (IPSPs) are blocked by GABAA receptor antagonists Slow IPSPs are blocked by GABAB receptor antagonists Glutamate Excitatory amino acid (EAA) Stimulates EAA receptors (NMDAR & AMPAR) Page 9 of 33 RJAV 2022 Thought to be important in learning, memory and other brain functions Glutamine is imported to the glutamatergic neuron and converted to glutamate by the enzyme glutamase The glutamate is concentrated in the vesicular glutamate transporter Upon release unto the synapse, the glutamate can interact to its neurons in the post synaptic neuron such as NMDAR & AMPAR Binding to its receptors (NMDAR & AMPAR) stimulates the opening of Na & Ca2+ channels, causing cations influx producing depolarization in both synaptic neurons resulting to excitatory effects Some glutamate will enter the glutamate transporter and converted to glutamine by the enzyme glutamine synthetase The glutamine will be transported in the pre-synaptic neuron to be converted again as glutamate STATER PACK: Reuptake inhibitors Increase NT levels in the synapse MAO inhibitor Increase NT levels in the synapse Receptor blocker Decrease NT effects Na channel blocker Prevents depolarization causing inhibitory effect PYSCHOSIS Schizophrenia research suggests that a combination of physical, genetic, psychological, environmental factors can make a person more likely to develop this condition have been reported to cause the symptoms of schizophrenia Schizophrenia is a type of disorder characterized by several types of symptoms, including: Positive symptoms Hallucinations (auditory: most common type) Delusions (paranoia or grandeur delusions) Disorganized speech (random rumbling of words) Bizzare behavior Negative symptoms Alogia (inability to speak because of mental defect, mental confusion, or aphasia) Anhedonia (lack of interest pleasure) Avolition (lack of motivation) Asociality (isolate themselves) Flattening of affect (poor eye contact Dopamine An inhibitory NT due to activation of K+ channels or inactivation of Ca2+ channels D2 receptors is main subtype in the basal ganglia neurons Norepinephrine Excitatory effects are produced by activation of 1 and 1 receptors Inhibitory effects are caused by activation of 2 & 2 receptors Serotonin Serotonin can cause excitation or inhibition of CNS ne