Integrated Pharmaceutical Sciences 1: Organic Medicinal Chemistry Lecture Notes PDF

Integrated Pharmaceutical Sciences 1: Organic Medicinal Chemistry David Charles B. Alejandro, PharmD, MSPh, RPh Organic Medicinal Chemistry Discovery and Development of Novel Natural and Synthetic Organic Compounds Understanding the effects of the physiochemical properties of the org...

Integrated Pharmaceutical Sciences 1: Organic Medicinal Chemistry David Charles B. Alejandro, PharmD, MSPh, RPh Organic Medicinal Chemistry Discovery and Development of Novel Natural and Synthetic Organic Compounds Understanding the effects of the physiochemical properties of the organic compounds and their effects to drug therapy Drugs and the Discovery Process Natural products fermentation broths plant extracts animal fluids (e.g., snake venoms) Synthetic Medicinal Chemicals Project medicinal chemistry derived Combinatorial chemistry derived Drug Discovery MORPHINE Alkaloid derived from an organic acid extracted from poppy juice Friedrich Wilhelm Sertürner in 1815 MORPHINE DERIVATIVES PENICILLIN Discovered in 1928 by Alexander Fleming: a mold on his culture plates was apparently responsible for the bacterial lysis he observed In 1939, Howard Flory, Ernst Chain, and Norman Heatley began work to isolate and purify the active compound from the fungus Their successful isolation allowed clinical tests of the antibiotic PENICILLIN ASPIRIN Analgesic Antipyretic Anti-inflammatory Anticoagulant Hippocrates: powder made from the bark and leaves of the willow tree to help heal headaches, pains and fevers ASPIRIN SUBSTITUTES SULFADRUGS Drugs and the Discovery Process Biologicals Natural products (Isolation) Recombinant products Chimeric or novel recombinant products Drugs and the Discovery Process Most new drugs or drug products are discovered or developed through the following approaches: Identification or elucidation of a new drug target Rational design of a new molecule Screening for biologic activity of large numbers of natural products Chemical modification of a known active molecule, resulting in a me-too analog PRECLINICAL SAFETY & TOXICITY TESTING DISCOVERY VS. DEVELOPMENT Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization and also includes In Vivo proof of concept in animals and concomitant demonstration of a therapeutic index Development begins when the decision is made to put a molecule into phase I clinical trials SERENDIPITY AND DRUG DISCOVERY Often molecules are discovered/synthesized for one indication and then turn out to be useful for others Tamoxifen (birth control and cancer) Viagra (hypertension and erectile dysfunction) Salvarsan (Sleeping sickness and syphilis) Interferon- (hairy cell leukemia and Hepatitis C) THE BIOTECHNOLOGY OF RECOMBINANT DNA Since its inception in the mid-1970s, recombinant DNA (rDNA) via genetic engineering technology has driven much of the fundamental research and practical development of novel drug molecules and proteins. Isolates genetic material from any source RECOMBINANT PRODUCTS HUMAN INSULIN first pharmacologically active biological macromolecule to be produced through genetic engineering. Historically, insulin was isolated from bovine or porcine sources. Now available as Humulin (E.coli) and Novolin (S.cerevisiae) RECOMBINANT PRODUCTS GLUCAGON biosynthesized in the pancreas as a high–molecular-weight protein from which the active macromolecule is released by proteolytic cleavage Bovine and porcine glucagons, which possess structures identical with human glucagon, have been in use for years RECOMBINANT PRODUCTS GLUCAGON The rDNA drug has the benefit that there is no chance of acquiring bovine spongiform encephalopathy from glucagon therapy. Also known as mad cow disease RECOMBINANT PRODUCTS GROWTH HORMONE hGH is a protein that is essential for normal growth and development in humans. Used as a drug since the 1950s, and it has been extremely successful in the treatment of classic growth hormone deficiency, chronic renal insufficiency, Turner syndrome, failure to lactate in women, and Prader-Willi syndrome Synthesized from E.coli RECOMBINANT PRODUCTS FOLLICLE-STIMULATING HORMONE traditional source for isolation of FSH was postmenopausal urine, which provided a preparation that was less than 5% pure and was significantly contaminated by LH. The recombinant human FSH (rhFSH) is produced in a mammalian cell line, the CHO. RECOMBINANT PRODUCTS THYROTROPIN ALPHA TSH binds to TSH receptors on normal thyroid epithelial cells or on well-differentiated cancerous thyroid tissue to stimulate iodine uptake into the gland, organification of iodine, and secretion of thyroglobulin, T3, and T4. The drug is used as a tool for radioiodine imaging in the diagnosis of thyroid cancer. RECOMBINANT PRODUCTS Cytokines HEMATOPOIETIC GROWTH FACTORS Pluripotent cells from bone marrow Two distinct lineage: Lymphoid Myeloid Products Erythropoietin Alfa Anemia in chronic renal failure Anemia in zidovudine treated HIV Cancer patients taking chemotherapy Significant increase in hematocrit Products Filgrastim (G-SF) Neutrophil proliferation and differentiation Enhances phagocytic activity For neutropenia accompanied by high fevers in cancer patients Reduces time of recovery and duration of fever in patients with myelogenous leukemia Products Sargramostim (GM-CSF) produced by T lymphocytes, endothelial fibroblasts, and macrophages dose-related increase in the peripheral white blood cell count. used to reconstitute the myeloid tissue after autologous bone marrow transplant and following chemotherapy in acute myelogenous leukemia Products Becaplermin recombinant human platelet–derived growth factor (rhPDGF-BB). released from cells that are involved in the healing process RECOMBINANT PRODUCTS INTERFERONS Response to viral infection Mechanism: Recruitment of Natural Killer (NK) cells Induce a state of viral resistance RECOMBINANT PRODUCTS INTERFERONS Classes of interferons (IFN): RECOMBINANT PRODUCTS INTERLEUKINS Promote the development and differentiation of T and B lymphocytes, and hematopoietic cells Aldesleukin Denileukin Diftitox Oprelvekin Tumor Necrosis Factor Enzymes Clotting Factors Anticoagulants Other Enzymes IMMUNOBIOLOGICALS Vaccines A suspension of live or inactivated microorganisms or fractions thereof, administered to induce immunity and prevent infectious disease or its sequelae. Toxoid A modified bacterial toxin that has been made nontoxic but retains the ability to stimulate the formation of antitoxin. Monoclonal Antibody (mAb) antibodies that are made by identical immune cells that are all clones of a unique parent cell Used as test kits mAb therapy Drug Design Strategies Identify Targets DRUG INACTIVATION VIA ORAL ADMIN ADDITION OF FUNCTIONAL GROUPS ADDITION OF FUNCTIONAL GROUPS HO O Succinate ester OH Cl H H N Cl O O Cl H H O N Esterase OH Cl H O O2N OH H Chloramphenicol O2N  HYDROPHOBIC ESTER ADDITION fatty ester N N O (CH2)8CH3 O H N CF3 S  Azathioprine for 6-mercaptopurine O2N N SH N S N N N Me N N N H N N H 6-Mercaptopurine Azathioprine (suppresses immune response) Slow conversion to 6-mercaptopurine Short lifetime - eliminated too quickly Longer lifetime SYNTHESIS INTERMEDIATES ENHANCEMENT OF ABSORPTION PROTEIN BINDING Affinity to plasma protein Bound drugs – prolonged DOA Drug accumulation Generally reversible May lead to Drug-drug interactions TISSUE DEPOTS Where drugs get lost 20-50% body weight is neutral fat Prone to decrease bioavailability of lipophilic drugs Ex Thiopental DRUG METABOLISM Biotransformation Main idea: To prepare xenobiotics for excretion Less active Less lipophilic Less toxic More water soluble First-pass effect  Lidocaine Tocainide Half-life 2 hours 15 hours First pass Yes No effect Oral Admin No Yes NON-TOXIC TO TOXIC Acid-base properties BRONSTEAD-LOWRY THEORY Acid: Proton donor Base: Proton acceptor Conjugate acid: base that gain proton Conjugate base: acid that lost proton GENERAL FORMULA Ka Review Henderson-Hasselbalch equation It is important to recognize that a pKa for a base is in reality the pKa of the conjugate acid (acid donor or protonated form, BH) of the base Acid Strength A general rule for determining whether a chemical is strong or weak acid or base is pKa 2: strong acid; conjugate base has no meaningful basic properties in water pKa 4 to 6: weak acid; weak conjugate base pKa 8 to 10: very weak acid; conjugate base getting stronger pKa 12: essentially no acidic properties in water; strong conjugate base PERCENT IONIZATION HA Acid BH+ Acid PARTITION COEFFICIENT An assumption is made that the ionic form is water-soluble and will remain in the water phase of an octanol/water system. STEARIC FEATURES OF DRUGS: AFFINITY Drug-receptor binding can be influenced by stereoisomerism Optical isomers: Enantiomers and diastereomers Geometric Isomers: EZ isomers or cis and trans Conformational Isomers: nonidentical spatial arrangement of atoms in a molecule STEARIC FEATURES OF DRUGS  DRUG METABOLISM GENERAL PATHWAYS Phase I ( functionalization) Phase II (conjugation) Phase I CYP Mediated Non CYP Dependent CYP450 Mixed function oxidases Monooxygenases CYP450 OH CYP450 Reaction Sequence DRUG DRUG CYP450 Fe3+ CYP450 CYP450 Fe3+ Fe3+ DRUG DRUG NADPH + H+ OH CYP450 e- reductase CYP450 Fe3+ CYP450 NADPH + H+ Fe2+ DRUG DRUG : O.. H+ e- H2O CYP450 CYP450 O2 Fe2+ Fe2+ DRUG DRUG O21- O2 CYP450 CYP Isozomes: CYP 1A2 Induced by Benzo alpha pyrene, cruciferous veggies and omeprazole CYP2C9, 2C19, 2D6 Subject to genetic polymorphism CYP 3A4 Most dominant CYP Inhibited by grapefruit juice Aromatic Hydroxylation Aromatic Hydroxylation Major route of metabolism for phenyl containing compounds Mostly occurs at the para position Proceeds most readily in activated rings Electron-withdrawing groups are resistant to hydroxylation Aromatic Hydroxylation Aromatic Hydroxylation Oxidation of Olefins Oxidation of Benzylic Carbon Oxidation of Allylic Carbon Oxidation at alpha-Carbon to Carbonyls and Imines Oxidation at Aliphatic and Alicyclic Carbon Oxidation at Aliphatic and Alicyclic Carbon Oxidation of Carbon-Heteroatoms Systems Oxidation of C-N sytem 1. Aliphatic (primary, secondary, and tertiary) and alicyclic (secondary and tertiary) amines 2. Aromatic and heterocyclic nitrogen compounds 3. Amides -Carried out by CYP and amine oxidases Oxidation of C-N sytem Oxidation of C-N sytem Oxidation of C-O systems Oxidation of C-S systems Oxidation of C-S systems Oxidation of C-S systems Oxidation of ROH and R=O If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Oxidation of ROH and R=O Reduction Reductive processes play an important role in the metabolism of many compounds containing carbonyl, nitro, and azo groups Reduction Reductive processes play an important role in the metabolism of many compounds containing carbonyl, nitro, and azo groups Hydrolysis Esters and amides are common substrates Phase II: Glucuronic acid Conjugation Most common conjugative pathway in drug metabolism because: Readily available supply of glucose Many functional groups can combine with glucuronic acid UDP-glucoronyltransferase is the most dominant transferase Oxygen-Glucuronides Nitrogen/Sulfur-Glucuronides Carbon-Glucuronides Sulfate Conjugation Sulfate Conjugation Conjugation reactions with glycine, glutamine and amino acids GSH or Mercapturic Acid Conjugates GSH or Mercapturic Acid Conjugates Acetylation Methylation Factors Affecting Metabolism Age Strain Differences Hereditary or Genetic Factors Sex Differences Enzyme inhibition/induction ANS DRUGS ANS Divisions of the ANS Parasympathetic Autonomic Nervous System (PANS) Sympathetic Autonomic Nervous System (SANS) Drugs affecting Adrenergic neurotransmission Mechanism Tyrosine hydroxylase inhibition Metyrosine DOPA-decarboxylase Carbidopa inhibition Dopamine-β-hydroxylase Disulfiram inhibition MAO inhibition pargyline, tranylcypromine, selegiline Storage Reserpine Release Bretylium Drugs affecting Adrenergic neurotransmission Metyrosine (-Methyl-L-tyrosine, Demser) used principally for the preoperative management of pheochromocytoma α-methyl-m-tyrosine Used in shock Drugs affecting Adrenergic neurotransmission Reserpine (an NT Depleter) indole alkaloid obtained from the root of Rauwolfia serpentine depletes the vesicle storage of NE in sympathetic neurons in PNS, CNS, and E in the adrenal medulla Blocks VMAT Drugs affecting Adrenergic neurotransmission Guanethidine (Ismelin) and guanadrel (Hylorel) There they bind to the storage vesicles and stabilize the neuronal storage vesicle membranes, making them less responsive to nerve impulses Adrenergic drugs CATHECHOLAMINE SYNTHESIS Direct-Acting Sympathomimetics STRUCTURE–ACTIVITY RELATIONSHIPS Optical Isomerism Separation of Aromatic Ring and Amino Group R1, Substitution on the Amino Nitrogen R2, Substitution on the Alpha Carbon OH substitution on the Beta Carbon Substitution on the Aromatic Ring R1, Substitution on the Amino Nitrogen R2, Substitution on the -Carbon (Carbon-2) Slows down MOA Small alkyl groups: increases resistance and lipophilicity Enhanced oral effectiveness Increase CNS activity Methyl or ethyl substitution: Decreases agonist activity Affects Selectivity to β2 Methyl group enhances OH substitution on the - carbon (carbon-1) Decreases CNS activity – Lowers lipid solubility Enhances agonistic activity for both alpha and beta receptors Substitution on the Aromatic Ring. Maximal activity depends on the presence 3’ and 4’ OH groups Replacement of the m-OH group to m-CH2OH group improves oral bioav and β2 selectivity Modification of the cathechol ring improves α1 selectivity as the both OH groups are selective only for α2 Absence of the resorcinol ring protects from COMT increasing oral bioave. Resorcinol Endogenous Catecholamines Dopamine Norepinephrine Epinephrine Imidazolines and -Adrenergic Agonists Can be selective or non-selective Open imidazoline rings are highly active Agonist activity is enhanced when there is a halogen and a small alkyl group in the ortho positions of the aromatic ring  Direct acting sympathomimetics Selective α1 agonists Phenylephrine Methoxamine and Midrodrine Non-selective α agonists Naphazoline (Privine) Tetrahydrozoline Xylometazoline Oxymetazoline  Direct acting sympathomimetics Selective α2 agonists (Centrally acting) Clonidine – Antihypertensive Methyldopa Guanfacine & Guanabenz Clonidine and Guanfacine –indicated for ADHD Tizanidine – Skeletal muscle relaxant Apraclonidine & Brimonidine – Open angel glaucoma  Direct acting sympathomimetics β1 selective agonist Dobutamine – (+) isomer is used for cardiogenic shock β non-selective agonist Isoproterenol – Formerly used for asthma but now used as an inotropic agent β3 selective agonist Mirabegron – For overactive urinary bladder Direct acting sympathomimetics β2 selective agonist For asthma Albuterol, pirbuterol, salmeterol, etc. Bronchodilation For tocolysis and management of fetal distress Isoxsuphrine, terbutaline, and ritodrine Beta-2 Agonists Indirect acting Sympathomimetics Acts by releasing endogenous NE from storage vesicles Presence of beta hydroxyl groups decreases effectivity while alpha methyl groups increases effectivity. Sympathomimetics with a Mixed Mechanism of Action ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS) Alpha-Blockers -anti-hypertensives -not structurally related to CA -more related to alpha-agonists ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS) ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS) Alpha-Blockers Selective alpha-2 blockers Yohimbine and Corynanthine (Stereoisomers) Yohimbine is more selective to alpha-2 while corynanthine is more selective to alpha-1 Mirtazapine Antidepressant via central alpha-2 blockade Beta-blockers Anti-hypertensives and first line treatment for glucouma Aryloxypropanolamines Dichloroisoproterenol (DCI) was the first compound reported but was not a full agonist Propranolol (Prototype standard) Beta-blockers SARs Beta-blockers Beta-blockers Non-selective Beta-blockers Propranolol Used for hypertension, cardiac arrhythmia, angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, migraine prophylaxis, and essential tremor Anti-anxiety Beta-BLOCKERS WITH Alpha1-ANTAGONIST ACTIVITY (THIRD GENERATION) Cholinergic Agents Drugs either enhance or reduce various components of the ANS and motor (efferent) nerves of the SNS. Stimulate or mimic the effects of Parasympathetic Response: Cholinergic stimulants Cholinergic agonists Cholinomimetics Parasympathomimetics PARASYMPATHOMIMETICS PARASYMPATHOMIMETICS Direct acting parasympathomimetic CHOLINE ESTERS AND CHOLINERGIC ALKALOIDS Acetylcholine Methacholine - acetyl-β-methylcholine Carbachol - Can also indirectly release Ach and to some extent inhibit AChE. Has no cardiovascular activity Pilocarpine – used for narrow angled glaucoma Bethanicol – used for urinary retention and abdominal distention after surgery Indirect-acting parasympathomimetics Reversible Irreversible Indirect-acting parasympathomimetics Cholinesterase inhibitors (Organophosphates) Isofluorphate & Echothiophate – previously for glaucoma Malathion and Parathion – from insecticides and used in warfare Schradan – from plant insecticides *Pralidoxime is used for organophosphate poisoning Classification  PARASYMPATHOLYTICS Antimuscarinics/ Anticholinergics SAR: 1. R1 and R2 should be carbocyclic or a heterocyclic rings for maximal antagonistic potency. 2. R3 may be a H/OH/C=ON or it can be a within one of the rings. Molecules with OH groups or CH2OH groups is more potent that a compound without. 3. X is most potent when it is an ester but not necessary. Can be an ether or even absent 4. Quaternary ammonium is the most potent but Tertiary ammoniums can also work. 5. Distance between the ring and the amine is not critical.  PARASYMPATHOLYTICS Atropine – prototype non-selective muscarinic blocker management of cholinergic poisoning management of sympathomimetic hearth block or bradycardia Toxicity A traditional mnemonic for atropine toxicity is “Dry as a bone, hot as a pistol, red as a beet, mad as a hatter.” This description reflects both predictable antimuscarinic effects and some unpredictable actions Mechanism of Action Anti-nicotinics/ Ganglionic blockers Emergency treatment for HTN Hexamethonium Mecamylamine Trimethaphan Neuromuscular-Blocking Drug Effects Neuromuscular-Blocking Drug Effects CHOLINESTERASE REGENERATORS Pralidoxime is the prototype cholinesterase regenerator. used to treat patients exposed to insecticides, such as parathion, or to nerve gases. CNS Drugs GENERAL OVERVIEW Anxiolytic, sedative, and hypnotic agents Antipsychotics Anti-Parkinsons Anti-Convulsants Drugs for Abuse Sedative-Hypnotics  Belong to a chemically heterogeneous class of drugs, almost all of which produce dose-dependent CNS depressant effects.  Benzodiazepines  Barbiturates  Miscellaneous agents  Atypical Seative-hypnotics Benzodiazepines  Mechanism of action Benzodiazepines BZ receptors The BZ receptors form part of a GABAA receptor chloride ion channel macromolecular complex Benzodiazepines increase the frequency of GABA- mediated chloride ion channel opening Flumazenil reverses the CNS effects of benzodiazepines and is classified as an antagonist Certain β-carbolines have a high affinity for BZ receptors and can elicit anxiogenic and convulsant effects. These drugs are classified as inverse agonists Sedative-Hypnotics SAR Benzodiazepines Duration of Action Benzodiazepine Short Acting Midazolam and Triazolam Intermediate Acting Alprazolam, Lorazepam, Oxazepam, Temazepam and Estazolam Long Acting Chlorazepate, Chlordiazepoxide, Clonazepam, Clobazam, Flurazepam, Diazepam Benzodiazepines NON-BENZODIAZEPAM DESATIVE HYPNOTICS BARBITURATES Previously used as sedative hypnotics Has low margin of safety Used as pre-anesthetic, anti-epileptic and emergency treatment for convulsions BARBITURATES SAR BARBITURATES Barbiturates Duration of Benzodiazepine Action Ultra Short Thiamylal, Methohexital, and Acting Thiopental Short Acting Secobartital, Pentobarbital, and Hexobarbital Intermediate Butabarbital, Amobarbital, and Acting Vinbarbital Long Acting Phenobarbital  Mechanism of action Barbiturates Barbiturates depress neuronal activity in the midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA and glycine Binds to a different site on GABAa receptors Their actions are not antagonized by flumazenil. Barbiturates increase the duration of GABA-mediated chloride ion channel opening. They may also block the excitatory transmitter glutamic acid At high concentration they can also block sodium channels. Other Sedative Hypnotics Glutethimide – Previously used for insomnia Chloral hydrate – metabolized to trichloroethanol Other Sedative Hypnotics Antihistamines – Diphenhydramine, etc. Ramelteon – Melatonin Agonist ANTI-CONVULSANTS Ureides Phenobarbital, hydantoins, oxazolidinediones, and succinimides are all chemically classified as cyclic ureides ANTI-CONVULSANTS DRUGS ACTING ON VOLTAGE GATED CHANNELS: Phenytoin – Diphenylhydantoin Fosphenytoin – Phenytoin prodrug Na+ channel Blocker ANTI-CONVULSANTS DRUGS ACTING ON VOLTAGE GATED CHANNELS: Valproic Acid – Na+ Channel and T-type Ca++ channel blocker  ANTI-CONVULSANTS DRUGS ACTING ON VOLTAGE GATED CHANNELS: Carbamazepine (CBZ) – Na+ channel blocker Carbamazepine and its active analogs are dibenzazepine-5- carboxamides Also used for: Bipolar disorder Manic depression ANTI-CONVULSANTS DRUGS THAT ALTER NEUROTRANSMISSION AND ACTING ON NEUROTRANSMITTER RECEPTORS: Phenobarbital Tiagabine Primidone Perampanel Clonazepam Vigabatrin Chlorazepate Diazepam Levetiracetam ANTI-CONVULSANTS DRUGS WITH MIXED AND MISCELLANEOUS ACTIONS: Gabapentin – GABA analog that increases GABA release; blocks Ca++ channels Pregabalin Succinimides: Ethosuximide – inhibits GHB formation and blocks T-type Ca++ channels Topiramate – blocks Na+ channels and glutamate receptors - also potentiates GABA Lamotrigine – blocks Na+ channels and glutamate release Felbamate - blocks Na+ channels and NMDA ANTI-CONVULSANTS DRUGS WITH MIXED AND MISCELLANEOUS ACTIONS: Carbonic anhydrase Inhibitors: Acetazolamide – inhibits bicarbonate induced depolarization - Also used as a diuretic Magnesium Sulfate – For eclamptic convulsion  General Anesthetic Inhaled Gas (Nitrous Oxide) Volatile liquids (Halothane) Intravenous Benzodiazepine (Midazolam) Barbiturates (Thiopental) Dissociative (Ketamine) Opioids (Fentanyl) Miscellaneous (Etomidate, Propofol) General Anesthetics: Volatile Agents General Anesthetics: Volatile Agents  Local Anesthetics commonly used for minor surgical procedures often in combination with vasoconstrictors such as epinephrine. Esters Long acting (Tetracaine) Short acting (Procaine) Surface acting (benzocaine, cocaine) Amides Long acting (bupivacaine, ropivacaine) Medium acting (lidocaine) ANESTHETICS Local anesthetics (Benzoic Acid Derivatives) Can be C, O, N, or S with activity S>O>C>N. When X = N the local anesthetic is an amide which is resistant to hydrolysis and therefore has a longer duration of action. ANESTHETICS Local anesthetics (Isogramine Analogs) ANTIPSYCHOTICS Classification Classic (D2 Receptor affinity) Newer agents (Serotonin 2 receptor affinity) ANTIPSYCHOTICS Classic drugs(D2 receptor affinity) Phenothiazines chlorpromazine, thioridazine, fluphenazine Thioxanthenes thiothixene ANTIPSYCHOTICS Classic drugs(D2 receptor affinity) Electronegative atom at C2 is essential Side chain amine is unbranched N10-C11 Replacement with B gives a more active compound cis>trans Long-fatty acid chain at hydroxyls will prolong activity ANTIPSYCHOTICS Classic drugs(D2 receptor affinity) Butylrophenone Haloperidol ANTIPSYCHOTICS Newer agents (5HT2 receptor affinity) Second Generation (heterocyclic) Aripipazole, Clozapine Olanzapine Quetiapine Risperidone Ziprasidone ANTIDEPRESSANTS SSRI’s – First line treatment against depression Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline MAO Inhibitors – DOC for severe depression Phenelzine, Selegiline, Trancypromine TCA – inhibits NE and 5HT Reuptake Amitriptyline, Clomipramine, Imipramine Heterocyclic Antidepressants Amoxapine, Bupropion, Mirtazepine DRUGS FOR BIPOLAR DISORDER LITHIUM CARBONATE/ CITRATE Lithium is effective in treatment of the manic phase of bipolar disorder and continues to be used for acute-phase illness and for prevention of recurrent manic and depressive episodes. Replaces Na+ for action potentials Decreases NE receptor sensitivity Increases NE metabolism Used with Lamotrigine DRUGS FOR BIPOLAR DISORDER OTHER DRUGS INCLUDE: Valproic acid CBZ Oxcarbazepine Gabapentin Olanzapine and Quetiapine is used as monotheraphy PARKINSONISM ANTIPARKINSONISM Dopamine precursors (levodopa) Dopamine agonists (bromocriptine, pramipexole) MAOI (selegiline) COMT inhibitors (entacapone) Muscarinic antagonists (benztropine) CENTRALLY ACTING SYPATHOMIMETIC AGENTS Centrally acting phenylethylamines Psychotomimetic agents – contains methoxy methylenedioxy groups N-methylation increases CNS activity; larger groups diminish CNS stimulation but not its anorexiant effect CENTRALLY ACTING SYPATHOMIMETIC AGENTS Amphetamine, Methamphetamine, Dextroamfetamine, MDMA Lisdexamphetamine (prodrug) Fenfluramine and Dexfenfluramine Phenmetrazine and Phendimetrazine Phentermine and Sibutramine CENTRALLY ACTING SYPATHOMIMETIC AGENTS Drugs approved for ADHD Methylphenidate and Dexmethylphenidate – Releaser and blocks reuptake of CA Other drugs: Atomoxetine, Pemoline, Dextroamphetamine, Lisdexamfetamine METHYLXANTHINES DRUGS OF ABUSE 1. Canabinoids: Marijuana -Δ 1-Tetrahydrocannabinol or Δ 9-THC: active agent -Dronabinol and Tabinole – Approved for CINV and appetite stimulant 2. Hallucinogens/Psychedelic agents -Mescaline, Psilocbin & Psilocin, Dimethyltryptamine, LSD, MDMA DRUGS OF ABUSE 3. Phencyclidine/PCP aka. Angel Dust - Pharmacologically similar to ketamine 4. Nicotine 5. Gamma hydroxybutyrate 6. Narcotics: Heroin 7. Methamphetamine and Cocaine  Analgesic Agents and Drugs for Arthritic Conditions PHARMACOLOGIC TREATMENT OPTIONS OPIOID PEPTIDES Opioid receptors are thought to be activated by endogenous peptides under physiologic conditions. Endorphins have highest affinity for μ receptors Enkephalins for δ receptors Dynorphins for κ receptors. Can be displaced by Opioid Antagonists CHEMICAL CLASSIFICATION: PHENANTRENES Morphine – Prototype Narcotic Agents Hyrdomorphone Oxymorphone Apomorphine Codeine Hydrocodone Oxycodone Dihydrocodeine Tramadol Nalbuphine Buprenorphine Heroin CHEMICAL CLASSIFICATION: PHENANTRENES CHEMICAL CLASSIFICATION: PIPERADINE Meperidine – Used for lessening labor pains Diphenoxylate Loperamide Fentanyl Alfentanil Remifentanil Sufentanil CHEMICAL CLASSIFICATION: PHENYLHEPTYLAMINES Methadone – used as an analgesic and for opioid dependence. LAAM – Drug addiction withdrawal (Discontiued, 2003) Propoxyphene – Analgesic and antitussive (Discontinued, 2011) Noscapine - Antitussive  CHEMICAL CLASSIFICATION: MORPHINANS Antitussives Levophanol Butophanol Dextromethorphan Levallorphan CHEMICAL CLASSIFICATION: BENZOMORPHANS OPIOIDS Opioid Agonists Naloxone (short acting) Morphine (MS CONTIN) NARCAN Codeine (CODIPRONT) Naltrexone (longer acting) Heroin TREXAN Oxycodone (OXYCONTIN) Methadone (DOLOPHINE) Mixed Agonists-Antagonists Meperidine (DEMEROL) Nalbuphine (NUBAIN) Loperamide (IMODIUM) Butorphanol (STADOL) Fentanyl (DURAGESIC) Buprenorphine (SUBUTEX) Pentazocine (TALWIN) Opioid Antagonists NON-OPIOID ANALGESICS NSAID’s Salicylates Propionic Acids (Profens) Aryl and Heteroarylacetic Acids Anthranilates (Fenamates) Oxicams (“Enol Acids”) Phenylpyrazolones Anilides COX Enzyme Topography The COX-2 allosteric site is larger and more flexible than the COX-1 allosteric site. COX-2 selective inhibitors bind predominantly within the COX-2 allosteric site. They are denied access to the COX-1 allosteric site. SALICYLATES Potent anti-inflammatory activity Mainly COX-1 selective Irreversible inhibitor Is generally acidic Propionic Acid Derivatives (“Profens”) Alpha-methyl substituent increases COX inhibition and decreases toxicity Agents are NSAIDs with antipyretic and analgesic activity Generally selective for COX-1 but Naproxen has slight COX-2 selectivity ARYL AND HETEROARYLACETIC ACIDS ARYL AND HETEROARYLACETIC ACIDS INDENE AND INDOLE ACETIC ACIDS: Indomethacin COX-1 Selective Indicated for: RA, OA, ankylosing spondylitis, to suppress uterine contraction, and to promote closure of patent ductus artiosus Sulindac – MOA same as indomethacin. Prodrug Fx Etodolac ARYL AND HETEROARYLACETIC ACIDS PYRROLE ACETIC ACIDS: Tolmetin Non-selective COX inhibitor Short-acting Used for RA, OA and AS. Ketorolac Lacks benzylic methyl group Has longer half-life Analgesic and antipyretic action For post-op pain ANTHRANILATES Non-COX selective Mild analgesics and occasionally for inflammatory disease Diclofenac Used for RA, OA, AS and post- op pain Meclofenamate for joint, muscular pain, arthritis and dysmenorrhea Mefenamic Acid Mild analgesic for dysmenorrhea OXICAMS (ENOLIC ACIDS) 4- hydroxybenzothiazine heterocycle Acidity is due to 4-OH Less acidic compared to carboxylic acid NSAIDs Higher COX-2 selectivity than many other NSAIDs, particularly meloxicam. These agents have utility in treatment of RA and OA. PHENYLPYRAZOLONES Anti-inflammatory, but has some analgesic and antipyretic. Also has mild uricosuric activity. Phenylbutazone and oxyphenbutazone are used primarily in the treatment of rheumatoid arthritis and osteoarthritis. COX-2 SELECTIVE INHIBITORS All COX-2 inhibitors are diaryl-5-membered heterocycles Sulfonamide binds to a distinct hydrophilic region that is present on COX-2 but not COX-1. COX-2 SELECTIVE INHIBITORS The COX-2 inhibitors have analgesic, antipyretic and inflammatory activity comparable to NSAIDs and are used therapeutically in OA (all), RA (celecoxib and Valdecoxib), acute pain (Celecoxin, Rofecoxib) andprimary dysmenorrhea (all). Less GI irritation due to COX-2 selectivity Does not inhibit platelet aggregation CI: 3rd trimester of pregnancy since they promote closure of ductus arteriosus ANILIDES ANILIDES They are believed to act as scavengers of hydroperoxide radicals. Have no anti-inflammatory action. The lack of an acidic functionality and COX inhibitory activity in the anilides imparts several advantages to these agents including limited gastric irritation and ulceration, limited CV and respiratory effects and little effect on platelets (no increase in clotting). *Aniline causes Methemoglobinemia (MetHb) Autacoid Modifiers Histamine and Serotonin Drugs Histamine Formed from histidine via histidine decarboxylase Synthesized and stored in mast cells and basophiles Released in response to antigens and antibodies, bacterial products, xenobiotics, IgE-antigen complexes and other stimulus In gastric mucosa, it is released from enterochromaffin-like cells via gastrin and acetylcholine Histamine H1 Antagonists X = C, N or O (CH2)n is an alkyl chain usualy ethyl Diaryl (can be linked) substitution is needed for H1 receptor affinity Benzene in one of the aryl groups increases potency The tertiary amine can be a part of the hetero cycle The carbon chain is usually unbrancheds exepts for Promethazine Metabolism pathway First Generation Antihistamines Ethanolamines (Aminoalkyl ethers) Ethylenediamine Derivatives Piperazine Derivatives Propylamine Derivatives (Alkylamines) Phenothiazine Derivatives Ethanolamines Diphenhydramine was the prototype Other derivatives were para substitutions in One of the phenyl rings. Replacement of one of the phenyl rings of the diphenhydramine with a 2-pyridyl group, as in doxylamine and carbinoxamine, enhances antihistaminic activity The diaryl tertiary aminoalkyl ether structure also serves as a pharmacophore for muscarinic receptors Most sedating class Ethanolamines Carbinoxamine maleate Dimenhydrinate Diphenhydramine HCl Diphenylpyraline HCl Doxylamine Succinate Clemastine Fumarate Ethylenediamines N is the connecting atom and a two-carbon atom chain as the linking moiety between the key diaryl and tertiary amino moieties All compounds in this series are simple diarylethylenediamines except antazoline, in which the terminal amine and a portion of the carbon chain are included as part of an imidazoline ring system Ethylenediamines Phenbenzamine Pyrilamine maleate Methapyriline HCl Tripelennamine HCl/Citrate Thonyzylamine HCl Antazoline Phosphate Piperazines (Cyclizines) considered ethylenediamine derivatives or cyclic ethylenediamines (cyclizines) connecting moiety (X) is a CHN group carbon chain, terminal amine functionality, and the nitrogen atom of the connecting group are all part of a piperazine moiety The X in this structure is usually H or Cl Piperazine Cyclizine HCl/ Lactate Chlorcyclizine HCl Meclizine HCl Hydroxyzine HCl Buclizine HCl PROPYLAMINES (MONOAMINOPROPYL/ALKYLAMINE DERIVATIVES) characterized structurally by an sp3 or sp2 carbon-connecting atom with a carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moieties Those propylamines with a saturated carbon-connecting moiety are commonly referred to as the pheniramines pheniramines consist of a phenyl and a 2-pyridyl aryl group and a terminal dimethylamino moiety PROPYLAMINES Pheniramine Maleate Brompheniramine Maleate Chlorpheniramine Maleate Pyrrobutamine Phosphate Triprolidine HCl Dimethindene Maleate Phenindamine Tartrate PHENOTHIAZINES Contain a two- or three-carbon, branched alkyl chain between the ring system and terminal nitrogen atom. Differs significantly from the phenothiazine antipsychotic series in which an unbranched propyl chain is required. The branched alkyl chain contains a chiral carbon, giving rise to optical isomerism Unlike the phenothiazine antipsychotics, the heterocyclic ring of the antihistamines is unsubstituted. PHENOTHIAZINES Promethazine 1. Anticholinergic, α1 antagonist (produce hypotension), 2. Dopamine antagonist - increases prolactin release, decreased corticotrophin and growth hormone release 3. Local anesthetic effect, 4. Antiarrhymthic action, 5. Used as a sedative and an antiemetic PHENOTHIAZINES Promethazine HCl Trimeprazine Tartrate Methdilazine Cyproheptadine HCl (Dibenzocycloheptene) Azatadine maleate (Dibenzocycloheptane) SECOND GENERATION ANTIHISTAMINES The second generation agents have reduced affinity for muscarinic, adrenergic or serotonergic receptors These compounds were developed as selective H1- receptor antagonists with relatively high potency. Most of these compounds also produce prolonged antihistaminic effects Piperidines Terfenadine Fexofenadine HCl Aztemizole Loratadine Levocarbastine (opthalmic) Piperazine: Cetirizine Cetirizine is the primary acid metabolite of hydroxyzine resulting from complete oxidation of the primary alcohol moiety Relatively polar = Does not cross BBB Can be given OD Pyrrolidine: Acrivastatine No significant anticholinergic activity at therapeutic concentrations Enhanced polarity limiting BBB penetration Dual Acting Antihistamines Compounds that block the release of histamine from mast cells (MCS) and antagonize the actions of histamine at H1-receptors. Compound introduced in this class over the past several years include azelastine, ketotifen and permirolast and others. These agents have utility as ocular antihistamines and for other indications: Mast Cell Stabilizers Inhibitors of mast cell degranulation and histamine release Cromolyn sodium and Nedocromyl - prophylaxis for asthma believed to inhibit calcium influx Lodoxamide tromethamide - prevents antigen-induced calcium influx into mast cells that causes histamine release. Used topically for inflammatory diseases of the eye. Mast Cell Stabilizers Inhibitors of mast cell degranulation and histamine release Lodoxamide tromethamide - prevents antigen-induced calcium influx into mast cells that causes histamine release. Used topically for inflammatory diseases of the eye. H2 Receptor Antagonists H2 antagonists can inhibit responses to gastric secretagogues Cimetidine Ranitidine Famotidine Nizatidine H2 Receptor Antagonists Commonly used for: GERD Peptic Ulcer Disease Nonulcer Dyspepsia Prevention of Bleeding from Stress-Related Gastritis Potential Drug Interactions Cimetidine interferes with several important hepatic cytochromeP450 drug metabolism pathways, including those catalyzed by: CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Serotonin Important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome Nature of Serotonin After synthesis it is either stored or rapidly inactivated (MAO) 90% is found in enterochromaffin cells Found in the blood (platelets) 5-HT1D/1B Agonists & Migraine Headache Two primary hypotheses: 1. Triptans, may activate 5-HT1D/1B receptors on to inhibit the release of vasodilating peptides 2. Vasoconstrictor actions of direct 5-HT agonists may prevent vasodilation and stretching of the pain endings. 5-HT1D/1B Agonists & Migraine Headache Sumatriptan and its congeners are currently first-line therapy for acute severe migraine attacks in most patients. Almotriptan Naratriptan Eletriptan Rizatriptan Frovatriptan Zolmitriptan Common Problems with Triptans Chest discomfort occurs in 1–5% of patients probably because of the ability of these drugs to cause coronary vasospasm. Duration of actions are shorter than the headache’s duration Expensive