How Synthetic Drugs Work : Insights Into Molecular Pharmacology of Classic and New Pharmaceuticals

How Synthetic Drugs Work: Insights into Molecular Pharmacology of Classic and New Pharmaceuticals provides comprehensive, structured access to robust information on molecular pharmacology for clinicians, research scientists and advanced health care students. The book covers the foundations of molecular pharmacology and the main drug classes, including detailed information on their mechanisms of action and the application of molecular pharmacology in drug development. This book is an ideal reference for graduate students and researchers in pharmacology, however, researchers in corporate settings will also benefit from the book's structured and detailed coverage of mechanisms of action of synthetic drugs. Presents the mechanism of action of most recent synthetic drugs available Includes newly reported action mechanisms of conventional drugs Contains colored illustrations of the pathway through which the drug exerts therapeutic action How Synthetic Drugs Work Copyright Contents List of contributors 1 Introduction to molecular pharmacology: basic concepts Pharmacology Drugs Brief history of pharmacology Routes of drug administration Enteral routes Parenteral routes of drug administration Local routes of drug administration Pharmacokinetics Passive diffusion Filtration Specialized transport Carrier transport Active transport Facilitated diffusion Pinocytosis Absorption Factors affecting absorption of drugs Physical factors Blood perfusion to the site of administration Surface area available for absorption Retention time at the surface area Drug distribution Volume of distribution Water compartments in the body Plasma compartment Extracellular fluid Total body water Other sites Apparent volume of distribution Plasma protein binding of the drugs Drug metabolism Kinetics of metabolism Phase I reactions Phase II reactions Drug excretion Pharmacodynamics: drug receptor interactions or mechanism of drug effects Principles of drug action Stimulation Depression Irritation Replacement Cytotoxic action Mechanism of drug actions Physical action Chemical action Through enzymes Through receptors Some important definitions75 Agonists Inverse agonist Antagonist Partial agonist Ligand Nature of receptors Transducer mechanisms G protein–coupled receptors Receptors with intrinsic ion channels Rho/Rho kinase The mitogen activated protein kinases Enzymatic receptors Rat Sarcoma (RAS)/Rapidly Accelerated Fibrosarcoma (RAF) pathway Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway Nuclear receptors Reference 10 Mechanism of action of antipsychotics and antimanics Introduction Psychological disorders at a glance Behaviors represented by a psychological disorder Definition of physiological disorders Common symptoms of psychological disorders Physical symptoms of psychological disorders Some serious symptoms that might indicate a life-threatening condition Causes psychological disorders Risk factors for psychological disorders Treatment of psychological disorders Common treatments for psychological disorders Ways to improve your psychological disorders Potential complications of psychological disorders Etiology of schizophrenia Genetic factors Neurotransmitters Pregnancy and birth complications Season of birth Cannabis use Genetic factors for psychological diseases Genetics of schizophrenia Familial clustering Genetic changes NRG1 Dysbindin (DTNBP1) G72(DAOA)/G30 Disrupted in schizophrenia 1 (DISC1) COMT Brain-derived neurotrophic factor Meta-analysis of genome-wide association study data and the major histocompatibility complex Locus Significance of non-MHC loci Conclusion Environmental factors Pollution Introduction Toxicology of pollution Environmental damages Pathophysiology of psychotic disease Psychoses Schizophrenia—split mind Chlorpromazine Trifluoperazine Fluphenazine Pimozide Mesoridazine Haloperidol Droperidol Penfluridole Benperidol Benzhexol Mechanism of action of antipsychotics Lithium Mechanisms of action of lithium Assume Unclear Electrolytes, membrane transport, membrane potential Monoaminergic signaling Second messenger system Transcription factors Regulation of intracellular calcium Glycogen synthase kinase Carbamazepine Valproic acid Mechanism Olanzapine Risperidone Thioridazine Triflupromazine Clozapine Loxapine Quetiapine Risperidone Olanzapine Aripiprazole Zotepine Paliperidone Lithium carbonate Carbamazepine Sodium valproate Lamotrigine References 11 Mechanism of action of antidepressants Introduction Pathophysiology of major depression Monoamines and other neurotransmitters hypotheses Neurotrophic hypotheses Stress-responsive/HPA axis hypotheses Dysbiosis/gut/brain axis hypotheses Glutamate hypotheses Assimilation of hypotheses on depression pathophysiology Fundamental pharmacology of antidepressants Selective serotonin reuptake inhibitors Serotonin-norepinephrine reuptake inhibitors Selective serotonin-norepinephrine reuptake inhibitors Tricyclic antidepressants 5-Hydroxytryptamine receptor modulators Monoamine oxidase inhibitors Glutamate signaling antagonist Adverse effect and interaction of antidepressant drugs Conclusion References 12 Mechanism on the action of drugs for heart failure Introduction Classification of heart failure Etiology Pathophysiology Changes in hemodynamics Changes of neurohormones Changes in the cell Management of heart failure Diuretics Vasodilators Digoxin Positive ionotropic Atrioventricular node inhibition Angiotensin-converting enzyme inhibitors Angiotensin-II blockers (AT1 antagonists) Beta-blockers Calcium channel blockers Newer agents Conclusion References 13 Mechanism of action of antiarrhythmic drugs Introduction Signs and symptoms of cardiac arrhythmia General approach Palpitations Syncope and presyncope Sudden cardiac arrest and aborted sudden cardiac death Physical findings Genetics of cardiac arrhythmias The QT-opathies Long-QT syndrome Clinical description and manifestations Genetic basis Phenotypic correlates for the three canonical long-QT syndrome genotypes Short-QT syndrome Clinical description and manifestations Genetic basis Genotype–phenotype correlates Drug-induced torsade de pointes Clinical description and manifestations IKr channel blockers and therefore the “repolarization reserve” The other channelopathies Catecholaminergic polymorphic ventricular tachycardia Clinical description and manifestations Brugada syndrome Clinical description and manifestations Genetic basis Phenotypic correlates of SCN5A-mediated Brugada syndrome (BrS1) Sick sinus syndrome Clinical description and manifestations Genetic basis Principles of electrophysiology Descriptive physiology Mechanisms of cardiac arrhythmias Alterations in impulse initiation: automaticity Triggered automaticity and afterdepolarizations Abnormal impulse conduction: reentry Types of cardiac arrhythmias Bradycardia Sinoatrial node dysfunction Atrioventricular conduction block Supraventricular tachyarrhythmia Atrial premature complexes Junctional premature complexes Sinus tachycardia Atrial fibrillation Atrial flutter Atrial tachycardias Multifocal atrial tachycardia Focal atrial tachycardias Atrioventricular nodal tachycardias Atrioventricular nodal reentrant tachycardia Atrioventricular junctional tachycardias Tachycardias associated with accessory atrioventricular pathways Ventricular tachyarrhythmia Premature ventricular complexes Ventricular tachycardia Nonsustained ventricular tachycardia Sustained ventricular tachycardia Torsades de pointes Ventricular flutter Long-QT syndrome Antiarrhythmic drugs Classification of antiarrhythmic drugs Class I antiarrhythmic drugs General aspects of class I drugs Sodium channel binding and dissociation properties Use-dependent blockage Specific class IA drugs Molecular mechanisms and pharmacological effects Specific class IB drugs Molecular mechanisms and pharmacological effects Specific class IC drugs Molecular mechanisms and pharmacological effects Class II antiarrhythmic drugs General aspects β-Blockers commonly used for treating arrhythmias Class III antiarrhythmic drugs General aspects Specific class III drugs Amiodarone and dronedarone Molecular mechanisms and pharmacological effects Ibutilide and dofetilide Molecular mechanisms and pharmacological effects Sotalol Molecular mechanisms and pharmacological effects Class IV antiarrhythmic drugs General aspects Molecular mechanisms and pharmacological effects Other antiarrhythmic drugs Adenosine Molecular mechanisms and pharmacological effects Magnesium Vernakalant New developments in antiarrhythmic therapy Conclusion References 14 Insights into the mode of action of antianginal and vasodilating agents Pathophysiology associated with angina pectoris USFDA classification of antianginal drugs Mechanism of action of nitrates Mechanism of action of beta-blockers Mechanism of action of calcium channel blocker Mechanism of action of potassium channel opener Other drugs Dipyridamole Trimetazidine Ranolazine Fasudil Ivabradine Conclusion References 15 Mechanism of action of drugs used in hypertension Etiology of hypertension Normal regulation of blood pressure Control of renin secretion Renin and prorenin receptor Classification of antihypertensive drugs Diuretics Sympatholytic agents Ca2+ channel blockers Angiotensin-converting enzyme inhibitors AngII receptor antagonist Direct renin inhibitor Vasodilators D1 receptor agonist Conclusion References 16 Mechanism of action of diuretic and anti-diuretic drugs Introduction Brief anatomy and physiology of the nephron Classification of diuretics (according to site of their action) Normal physiology of different parts of nephron and related diuretics Glomerulus and Bowman’s capsule Diuretic acting on glomerulus Adenosine receptor antagonist: caffeine, theophylline, theobromine Mechanism of action Proximal convoluted tubule Drugs acting on proximal convoluted tubule Carbonic anhydrase inhibitors: acetazolamide, dorzolamide, ethoxzolamide, methazolamide, etc Mechanism of action Sodium-glucose cotransporter 2 inhibitors: dapagliflozin, canagliflozin, empagliflozin, etc Mechanism of action Loop of Henle Diuretics acting on thick ascending limb Loop diuretics: furosemide, torsemide, bumetanide and ethacrynic acid, etc Mechanism of action Mechanism of hypocalcaemia and hypomagnesemia Mechanism of hypokalemia and metabolic alkalosis Distal convoluted tubule Diuretics acting on distal convoluted tubule Thiazide diuretics: chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone Mechanism of action Mechanism of no hypocalcemia Collecting tubule system Diuretics acting on tubule system Aldosterone receptor antagonist or mineralocorticoid receptor antagonist (K+ sparing diuretics): spironolactone, eplerenone Mechanism of action Inhibitors of renal epithelial Na+ channel (K+ sparing diuretics): triamterene, amiloride Mechanism of action Antidiuretic hormone receptor (vasopressin) antagonist: tolvaptan, conivaptan Mechanism of action Nonspecific cation channel inhibitor: natriuretic peptides: (1) atria natriuretic peptide, (2) brain natriuretic peptide, (... Mechanism of action Others Osmotic diuretics: mannitol, urea, isosorbide, glycerol Mechanism of action Conclusion References Further reading 17 Mechanism of action of drugs used in gastrointestinal diseases Overview Introduction Neuronal and hormonal control over gastrointestinal tract Gastrointestinal acid regulation Peripheral regulation of acid Gastrin Acetylcholine Histamine Peptic ulcer Potential causes of peptic ulcer Drugs used for neutralizing and inhibiting acid release Antacids Classification Antacid side effects Contraindication Histamine receptor antagonist H+/K+ ATPase inhibitor/ Proton pump inhibitor (PPIs): Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Esomeprazole Mec... Antiemetics and emetics Vomiting Mechanism of evacuation Stimulants for vomiting Classification of antiemetics 5-Hydroxytryptamine 3 receptor antagonist D2 receptors antagonists/neuroleptics Prokinetic drugs Antihistamines and anticholinergic Antihistamines Anticholinergics Mechanism of action Cannabinoids Glucocorticoids Vitamin B6 Emetics Ipecacuanha Apomorphine Laxatives, purgatives, and cathartics Classification (laxatives, purgatives, and cathartics) Antidiarrheal agents Oral rehydration supplements References 18 Mechanisms of action of antibacterial agents (AMA) Introduction Classification of β-lactams Cell wall biosynthesis inhibitors7–9 Carbapenems Cephalosporins Protein synthesis inhibitors that bind the 30S subunit Protein synthesis inhibitors that bind the 50S and 30S ribosomal subunits Membrane function inhibitors Inhibitors of nucleic acid synthesis ATP synthase inhibitors Conclusion References 19 Mechanism of action of antifungal agents Introduction Pathophysiology fungal diseases Mechanism of antifungal agents Black fungus and COVID-19 Source Reasons for sudden development Symptoms Treatments Conclusion References Further reading 2 Mechanism of action of cholinergic drugs Introduction Chemistry of autonomic neurotransmitters Biochemistry of acetylcholine Signal transduction mechanisms involved in drug response Nicotinic receptor Muscarinic receptors Inhibition of adenylyl cyclase Cholinergic agonists Anticholinesterases Anticholinergic drugs Conclusion References Further reading 20 Insights into the mechanism of action of antiviral drugs Introduction Virus life cycle and pathogenesis Classification of drugs based on viral targets Pathophysiology of viruses Human immunodeficiency virus Antihuman immunodeficiency virus drugs Nucleoside reverse transcriptase inhibitors Zidovudine Stavudine Lamivudine (3TC) and emtricitabine (FTC) Abacavir Nucleotide reverse transcriptase inhibitors Tenofovir Protease inhibitors Ritonavir Saquinavir Indinavir Nelfinavir Lopinavir Atazanavir Fosamprenavir Tipranavir Darunavir Integrase inhibitors Fusion peptide inhibitor Adhesion inhibitor CCR5 receptor inhibitor Herpesvirus Antiherpes drugs Acyclovir and valacyclovir Penciclovir and famciclovir Idoxuridine Trifluridine Foscarnet Docosanol Influenza virus Antiinfluenza drugs Baloxavir marboxil Oseltamivir and zanamivir Amantadine and rimantadine Hepatitis virus Antihepatitis B drugs Antihepatitis C drugs Varicella zoster virus Antivaricella zoster virus drugs Cytomegalovirus Anticytomegalovirus drugs Ganciclovir and valganciclovir Antirespiratory syncytial virus drugs Severe acute respiratory syndrome coronavirus 2 Anti-Covid drugs Conclusion References 21 Insight into the molecular mechanism of action of anticancer drugs Introduction Pathophysiology United States Food and Drug Administration Newer United States Food and Drug Administration–approved drugs Classification of anticancer drugs/therapies Mechanism of action Drugs acting on endothelium DNA Growth factors Combretastatin MOA Protein Monoclonal antibodies Bevacizumab Small molecules Drugs acting on extracellular matrix Matrix metalloproteinases Marimastat Drugs acting on Host Cell Drugs acting on immune system Drugs directed against tumor DNA DNA helix DNA-related proteins Specific genes Drugs targeted against tumor RNA Drugs directed against proteins in tumor cell Receptor in the tumor membrane Intracellular pathways in tumor cells Tubulin Conclusion References 22 An insight into the agents used for immunomodulation and their mechanism of action Introduction Immunomodulators Immunosuppressants Glucocorticoid Mechanism of action of classical immunomodulatory drugs Prednisone Hydrocortamate Calcineurin inhibitors Cyclosporine Tacrolimus Mammalian target of rapamycin inhibitors Sirolimus Everolimus Antimetabolite Leflunomide 6-Mercaptopurine pathology and treatment Alkalyting agent Steroid-free medications Oral signs and symptoms Cyclophosphamide Definition of biologics Biologics are divided into three groups based on their chemical composition Mechanism of action of newer immunomodulators Usage of biologics for clinical indications Tumor necrosis factor-alpha Inhibitor Categorization Etanercept Infliximab Interleukin-1 inhibitors Anakinra Daclizumab Polyclonal antibody Antithymocyte immunoglobulin (ATG) Monoclonal antibodies Alemtuzumab Vaccine Bacillus Calmette-Guérin Antihelminthics Albendazole Discussion Conclusion References 23 Mechanism of opioids action and their receptor-dependent signaling Introduction Opioid receptors Opioid ligands Molecular recognition of opioids Classic mechanism Ion channels Adenylate cyclase Mitogen-activated protein kinase signaling Tolerance Conclusion References 24 Application of molecular pharmacology in research techniques and drug development Introduction Molecular pharmacology methods and their application in drug discovery approaches Molecular approaches based on network Mechanism-based approach in drug discovery Molecular biology method in human disease and drug discovery Human disease networks and molecular pharmacology Molecular pharmacology in treatment response prediction Investigation of disease mechanisms by molecular pharmacology Gene regulation and disease state Molecular pharmacology approaches in drug discovery Drug–target networks and molecular pharmacology Predictions of drug–target interactions Investigations of drug adverse effects by molecular pharmacology approaches Drug repositioning and molecular pharmacology Predictions of drug combination and molecular pharmacology approaches Conclusion References 3 Mechanism of action of adrenergic drugs and recent updates Background The Nervous System Peripheral Nervous System Adrenergic Drugs Pharmacological Actions Adrenergic Nerve Receptors Molecular structure of G protein–coupled receptor G-proteins Difference between α and β receptors Conclusion References 4 Insight into the mechanism of steroidal and non-steroidal anti-inflammatory drugs Introduction to inflammation and its role Pathophysiology of inflammation and inflammatory pathway Inflammatory mediators Inflammatory diseases Rheumatoid arthritis (RA) Asthma Chronic obstructive pulmonary disease Inflammatory bowel disease (IBD) Multiple sclerosis Allergic rhinitis Inflammatory disease and their treatments Classification of non steroidal anti-inflammatory drugs and corticosteroids in broad category Classification of NSAIDs Nonselective COX inhibitor Preferential cyclooxygenase II inhibitor Selective COX-2 inhibitor Newly approved NSAID drugs as per United States Food and Drug Administration (USFDA) Classification of corticosteroids Glucocorticoids Mineralocorticoids Mechanism of action of corticosteroids and non steroidal anti-inflammatory drugs Molecular mechanism of action of each class of NSAIDs Nonselective COX inhibitors Pyrazolone derivative—oxyphenylbutazone, phenylbutazone Acetic acid derivative—indomethacin, nebumetone, ketorolac Salicylates—aspirin Fenamate—mephenemic acid Propionic acid derivative—ketoprofen, flurbiprofen, ibuprofen, naproxen Enolic acid derivative—piroxicam, tenoxicam Preferential COX II inhibitors—nimesulide, diclofenac, aceclofenac, meloxicam, etodolac Selective COX-2 inhibitors—celecoxib, etoricoxib, parecoxib Aniline derivatives (analgesics and antipyretics) Paracetamol, metamizole, propiphenazone, nefopam Anti-inflammatory mechanism of corticosteroids Contraindications of corticosteroids Contraindications of nonsteroidal anti-inflammatory drugs Conclusion References 5 Insight into the mechanism of action of anti-diabetic drugs Introduction Biochemical background of diabetes mellitus Classification of diabetes Type 1 diabetes mellitus Pathophysiology of type-1 diabetes Type 2 diabetes mellitus Pathophysiology of Type 2 diabetes Other specific types of diabetes14 Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes mellitus Etiology Genetic component Susceptibility loci Obesity and Physical Inactivity Insulin resistance Oxidative stress in diabetes mellitus Pathophysiology of oxidative stress in diabetes β-cell demise and dysfunction Sulfonylureas Effect of amaryl in adipose cells: regulation of key metabolic proteins/enzymes Biguanides Metformin Metformin and organic cation transporters KATP channel modulators (nonsulfonyl ureas): meglitinides Repaglinide α-Glucosidase inhibitors Dipeptidyl peptidase-4 inhibitors Mechanism of action Dipeptidyl peptidase-4 inhibition in the gut Thiazolidinediones Mechanism of action Bromocriptine Na+–Glucose transporter-2 inhibitors GLP-1 agonist Exenatide Liraglutide Albiglutide Other glucose-lowering agents Pramlintide: amylin analog References 6 Molecular mechanism of action of estrogens, progestins, and androgens Introduction Synthesis of endogenous estrogens, progesterone, and androgens Mechanism of action of endogenous steroid sex hormones (estrogens, progesterone, and androgens) Role of estrogen, progesterone, and androgen in diseases Hormonal imbalance in females Polycystic ovary syndrome Hormonal imbalance in males Cancer Synthetic estrogens, progestins, and androgens for treatment of hormone-related diseases Hormonal therapy Mechanism of action of synthetic estrogens Mechanism of action of progestins Mechanism of action of synthetic Androgens References 7 Mechanism of action of sedatives, hypnotics, and antianxiety drugs Introduction Generalized mode of action of anxiolytics, sedatives/hypnotics Anxiety and antianxiety medications Novel molecules with diverse pharmacological targets Systems containing monoamines Vilazodone AVN-101 Brexpiprazole Cyclobenzaprine VLD (TNX-102) Glutamate system Ketamine Xenon gas (NBTX-001) Endocannabinoid system Inhibitors of fatty acid amide hydrolase Additional targets for the eCB system GABA system Sedatives and hypnotics Benzodiazepines Additional agents Hypnotics are used to induce and maintain anesthesia Selection of a hypnotic agent Sedatives/anesthetics administered intravenously Closing remarks References 8 Mechanism of action of antiepileptic drugs Introduction Pathophysiology and pathogenesis of epilepsy Role of GABA Role of glutamate General treatment Phenobarbital mechanism of action Bromide (potassium bromide/sodium bromide) Phenytoin mechanism of action Benzodiazepines mechanism of action Carbamazepine mechanism of action Ethosuximide mechanism of action Valproic acid mechanism of action Gabapentin mechanism of action Newer antiepileptic drugs Mechanism of action of eslicarbazepine acetate Levetiracetam Brivaracetam Lacosamide Perampanel Cannabidiol Stiripentol Conclusion References 9 Mechanism of action of anti-Parkinson's drugs Introduction to Parkinson’s disease Parkinson’s disease symptoms, and its subtypes Epidemiology and risk factors for Parkinson’s disease Substantia nigra and its association with neuronal components Pathophysiology and pathoanatomy of Parkinson’s disease Anti-Parkinson’s disease drugs Levo-DOPA Dopamine agonists Catechol-o-methyltransferase Catechol-O-methyltransferase inhibitors and Parkinson’s disease Monoamine oxidase Monoamine oxidase-A and monoamine oxidase-B Inhibitors of monoamine oxidase-A and monoamine oxidase-B Monoamine oxidase-B inhibitor selegiline and Parkinson’s disease Monoamine oxidase-B inhibitor lazabemide in Parkinson’s disease Summary References Index