Organic Medicinal Chemistry Course Audit SY 2024-2025 PDF
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2025
RJAB, RPh
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Summary
This document is a study guide for a course in Organic Medicinal Chemistry. It covers the introduction, history, drug discovery, and drug-receptor interactions within the field. The document is well-organized to support understanding of important topics.
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Module 1 Organic Medicinal Chemistry Course Audit I Prepared by: RJAB, RPh TOPIC 1: INTRODUCTION A. FOUNDATIONS MEDICINAL CHEMISTRY Incorporation of ____________ and ____________ in the research for the discovery and design of new and better therapeutic chemicals and developm...
Module 1 Organic Medicinal Chemistry Course Audit I Prepared by: RJAB, RPh TOPIC 1: INTRODUCTION A. FOUNDATIONS MEDICINAL CHEMISTRY Incorporation of ____________ and ____________ in the research for the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines Role of medicinal chemist ○ Make new compounds ○ ________________________ ○ Alter structure for optimum effect and minimum side effects ○ Study ____________ profile DRUG Any substance intended for use in ____________, ____________, ____________, ____________ or ________________________ or to ____________________________________ of the body of man or other animals Classifications ○ Origin ____________: from plants and animals ____________: from pure synthesis or synthesis of naturally occurring compounds ____________: natural intermediate of some drugs could be used for the synthesis of a desired product ○ Medicinal use Chemotherapeutic: fight malignant cells/tissues and microorganisms Pharmacodynamic agents: act on various functions of the body ○ Type of Disease treated ____________: caused by microorganism may be person-to-person, or by outside agents ____________: disorders caused by genetic malfunction, environmental factors, stress or old age ____________ Alleviation of pain and symptoms Prevention of pregnancy Anesthesia LIGAND A chemical agent that binds to a receptors ○ ____________: ability to bind to a receptor ○ ____________: ability to exert a pharmacologic action RECEPTOR Where the ____________ binds PHARMACOPHORE The ____________ of the structure of the ligand that binds to a receptor ANALOGS Synthetic compounds developed from a ____________ NUCLEUS Section of the structure which is responsible for its ________________________ STRUCTURE-ACTIVITY RELATIONSHIP How a structure ____________ the effect of the drug Exhibited by compounds with similar structures to a pharmacologically active drug B. HISTORY PRIEST-MAGICIANS Beliefs of disease occurrence are based on ____________ or ____________ CHINESE Shen nung: Father of ____________ Medicine ○ Pen T’sao: Ch’ang Shang, Ma huang ○ Ephedrine: E. sinica, E. quisitina EGYPTIANS ____________ Medico-magical Ebers Papyrus by ____________: Acacia, Castor, Fennel, etc INDIANS ____________ fruit (Hydnocarpus wightiana, H. kurzii) – for leprosy (hydnocarpic acid) SOUTH AMERICAN INDIANS Cocaine, Psilocybe: hallucinogens Brazil: Ipecac root = ____________ for amebiasis PARACELSUS Father of Toxicology: Philippus Aureolus ____________ Bombastus von Hohenheim The difference of poison and a drug is the ____________ PEDANIUS DIOSCORIDES ________________________: Aloe, Belladonna, Ergot, Opium, Colchicum, Hyoscyamus CARL SCHEELE Lactic, citric, oxalic, etc. FRIEDRICH SERTURNER Isolated ____________ PIERRE JOSEPH PELLETIER AND JOSEPH CAVENTOU Emetine from ____________ Purified caffeine, quinine, colchicine Strychnine, brucine CARDIAC GLYCOSIDES William Withering: used ____________ for edema and heart failure Humolle and Quevenne: isolated ____________ Nativelle, Schmiedberg: other digitalis glycosides ____________: isolated Digoxin STATINS Akira Endo: ____________ from Penicillium citrinum (compactin/mevastatin) Merck: Lovastatin from another fungus Sanky: Pravachol/Pravastatin Brown and Goldstein: Nobel prize for ____________ metabolism ALBERT NIEMANN Isolated ____________ Isolated Physostigma from ____________ PAUL EHRLICH Father of ____________ Magic bullet (Compound 606, Arshpenamine, Salvarsan): for ____________ GERARD DOMAGK Red Dye or ____________ (2,4-diaminoazobenzene-4’-sulfonamide) First general/broad spectrum antibacterial PENICILLIN ____________: accidental discovery from Penicillium notatum Howard Florey and Ernst Chain: ____________ and ____________ CHLORPROMAZINE (THORAZINE) First ____________ First discovered from antihistamine ____________ Paul Charpentier: ____________ Simon Courvoisier: effects on animals Henri Laborit: effects on man Pierre Deniker and Jean Delay: clinical trials MEPROBAMATE ____________ Mephenesin to meprobamate First Mass marketed ____________ CHLORDIAZEPOXIDE (LIBRIUM) First ____________ Lowell Randall: Tested the ____________ compound synthesized by Leo Sternback DIAZEPAM (VALIUM) 5-10x more potent than ____________ but shorter half-life Synthesized through structural modification of ____________ INSULIN Banting and Best: isolation from ____________ Collip and MacLeod: pure form from ____________ COCAINE Albert Niemann: ____________ Richard Willstatter: ____________ Carl Coller: anesthetic Property “Coca Koller” 6-MERCAPTOPURINE First effective drug for ____________ George Hitchings and Gertrude Elion: Pioneers of ________________________ PLATINUM CHEMOTHERAPY ____________: first generation; gold standard ○ Alfred Werner: Elucidated the structure ○ Barnett Rosenberg: cisplatin effect on cell division ____________: less toxic 2nd generation C. DRUG DISCOVERY, DESIGN, AND DEVELOPMENT GOALS To combat drug resistance, tolerance, tachyphylaxis Improve treatment of existing disease For treatment of newly identified disease Production of safer drugs by reduction or removal of adverse effects NATURAL PRODUCT SCREENING All synthetic organic compounds available are tested in ____________ assays for a specific type of biologic activity Ex. ________________________ ○ Target receptor/enzyme active site → chemical structure database → HTS and/or virtual screening → assay (in vivo/vitro) → refine model RATIONAL DRUG DESIGN Focused approach on ________________________ of the receptors or ligands to design, identify, or create a lead Involves molecular modeling and ____________ DRUG METABOLISM STUDIES Conducted for clinical ____________ or drugs already in the market Metabolites are also isolated and assayed for ________________________ DDD PROCESS Reduction of an ____________ pharmacologic response; Obtain a better Pharmacokinetic response; alter drug ____________; secure a more plentiful, less costly supply ____________: identification of new or previously biologically active compounds/hits ____________: hits are converted to lead compounds by the modification of functional groups Toxicology and Clinical Development: render the modified lead into a drug candidate for clinical trials D. DRUG-RECEPTOR INTERACTION DESCRIPTION The drug must bind to the receptor in order to ____________ an effect Only one ligand can bind to the binding site of the receptor It is derived from and obeys the ________________________ ○ When a drug combines with a receptor, it does so at a rate which is dependent on the conc of the drug and the conc of the receptor Different interaction/bonds are involved in the drug-receptor complex formation ○ Most drug-receptor interactions are made via ________________________ – reversible ○ Irreversible drug-receptor interactions are not common and only occur via covalent bonds Usually undesirable Interventions are required to reverse the effects May sometimes be caused by carcinogenicity or mutagenicity Ex. ________________________ SELECTIVITY ________________________: many tertiary amine compounds have muscle relaxant activity Disproven by Lowei and Navrat: discovered ____________ Ing: one chemical group can produce 2 different biologic effects (tubocurarine vs. Acetylcholine) Woods: ____________ and PABA – contains acidic functional group and steric character LIGAND-RECEPTOR/ENZYME-SUBSTRATE HYPOTHESES Receptor Hypothesis ○ By ____________ = receptors, selective toxicity ○ Side chains on the surfaces of cells were complementary to the dyes Lock and Key Theory ○ Substrate and active site are completely ____________ in shape to the active site Induced Fit Theory ○ “________________________” ○ The substrate and active site are not completely complementary, but there is still some complementarity ○ The enzyme conforms to the ____________ of the substrate RECEPTOR OCCUPANCY MODEL ____________: amount of drug needed to produce an effect; relates to affinity ____________: strength of Drug-Receptor complex in evoking a response; relates to intrinsic activity Hypothesis of Clark ○ “________________________” ○ Max pharmacologic effect can be obtained if ALL receptors are occupied ○ Obeys ____________: when a drug combines with a receptor, it does so at a rate which is dependent on the conc of the drug and the conc of the receptor ○ Only applies to full ____________ Hypothesis of Ariens and Stephenson ○ Effectiveness of a drug lasts as long as the receptor is occupied ○ Intrinsic activity: ability of a ligand to activate the receptor; determines drug efficacy ○ Response = ________________________ Hypothesis of Paton ○ “____________” ○ The effectiveness of a drug does not depend on the actual occupation of the receptor but by obtaining proper ____________ ○ ____________: strength of attraction of the ligand to the receptor; determines drug potency Hypothesis by Baker ○ Active site-directed ________________________ ○ Formation of ____________ bond between ligand and receptor Easson-Stedman Hypothesis ○ There is selective reactivity of one ____________ with its receptor ○ ____________: A 3-point fit to the receptor makes one enantiomer more potent than the other E. BIOPHARMACEUTICAL PROPERTIES ON DRUG DESIGN DESCRIPTION Physicochemical properties: how ____________ groups in the molecule influence the molecule’s characteristics ________________________: study of the relationship between the physicochemical properties of a drug and the effects observed after administration via dosage forms or drug delivery systems ____________: LADME = what the body does to the drug ____________: what the drug does to the body = response ACID-BASE, POLARITY Acid and basic functional groups = ____________ ○ Hydrophilic, lipophobic, water soluble = ionized Neutral functional groups = ____________ ○ Lipophilic, hydrophobic, lipid-soluble = Unionized Example ○ Methylprednisolone (PO) – slightly water soluble ○ + acetate (topical) – ____________ ○ + Na succinate (oral, IV, IM) – water soluble ACIDIC MEDIUM BASIC MEDIUM ACIDIC DRUG BASIC DRUG *LUNA - Lipophilic, Unionized, Nonpolar, Absorbed *HIPE - Hydrophilic, Ionized, Polar, Excreted Ionization constant (Ka) ○ Negative log of Ka = pKa ○ Indicate relative strength of an acid or base ○ Dec pKa = inc Ka = inc acidity = dec basicity Salt Formation ○ ____________ reaction between a base and acid; forms water and a salt ○ Salt form of a drug is preferred = ____________ All salts are strong electrolytes EXCEPT Hg and Cd halides, Pb acetate Inorganic salt: drug + inorganic acid/base Organic salt: ________________________ SOLUBILITY ____________ ○ Max amount of solute that can be dissolved in a solvent at equilibrium ○ Saturation level – solvent cannot dissolve the solute anymore ____________ ○ Process by which a substance forms a solution in a solvent ________________________ ○ SA: how much exposed area of a drug molecule can interact with solvent ○ Inc surface area = dec particle size ________________________ ○ The ____________ of a drug with the particle surface area (S), the thickness of the unstirred solvent layer on the particle surface (h), diffusion coefficient of the drug (D), and the concentration gradient, that is, the difference in the concentration of drug solution at the particle surface (Cs) and the bulk solution (C). ○ Formula: dt/dC = rate of dissolution (change in concentration of the solute over time) D = diffusion coefficient of the solute in the solvent A = surface area of the solute exposed to the solvent Cs = saturation concentration of the solute in the solvent (solubility) C = concentration of the solute in the solvent at time ttt h = thickness of the boundary layer around the solute particle (diffusion layer thickness) ____________ ○ Maintain the physicochemical, therapeutic and microbial properties during the time of storage and usage by the patient Log of the Partition coefficient (Log P) ○ Calculate and predict ____________ and ____________ of functional groups or compounds ○ Ratio of drug conc in ____________ to that in water ○ Formula: High logP = nonpolar/lipophilic Small logP = polar/Hydrophilic POLYMORPHISM Ability of a compound to exist in ________________________ Theobroma cacao ○ α – 22 °C ○ β – 34.5 °C ○ β’ – 28 °C ○ γ – 18 °C STEREOCHEMISTRY ____________ differ in their pharmacokinetic and pharmacodynamic properties ____________: have different potencies, receptor fit, biological activity, transport and metabolism ○ R-thalidomide (____________) vs. S-thalidomide (____________) ○ Levorphanol (analgesic vs Dextrorphan (Antitussive) ____________ ○ Ephedrine vs Pseudoephedrine ○ Z-triprolidine (inactive) vs E-triprolidine (active) Geometric isomers (cis-trans, E-Z): have different physical and pharmacological activity ○ Do not fit to the same receptor equally ○ ________________________ GIT PHYSIOLOGY Parts ○ ____________ (Body and Pylorus): ____________ ○ ________________________ (Duodenum, Jejunum, Ileum + villi, microvilli): ____________ Intestinal Digestion ○ Final preparation for ____________ ○ ____________ of large molecules ○ Conversion to an ____________ solution or emulsion Absorption ○ ____________: rate and extent of disappearance of drug from the site of administration ○ ____________: rate and extent of drug entry into the systemic circulation ○ Factors Surface area: ↑surface area, ↑ absorption Degree of perfusion: ↑ perfusion, ↑ absorption Dose size administered: ↑ dose size, ↑ absorption pH of absorbing environment Gastric Emptying Time (GET) ________________________ ________________________ Stability Problems ○ ____________ into active form ○ Interaction to form a large, poorly or ____________ complex Other challenges ○ There is difference in physiological availability and clinical response due to various membranes to cross and there is also interaction with inter/intracellular fluids before reaching the site of action ○ ____________: rate limiting step for solid dosage forms ○ ____________: rate limiting step for absorption ○ Avoid oral dosage forms in patients who cannot swallow and for acid-labile drugs BIOPHARMACEUTICAL DRUG CLASSIFICATION Class 1 ○ ____________ solubility, ____________ permeability ○ Metoprolol, APAP, Valproic Acid, Verapamil ○ Diltiazem, Propranolol, Theophylline Class 2 ○ ____________ solubility, ____________ permeability ○ Griseofulvin, Digoxin, Diazepam, Nifedipine ○ Carbamazepine, Danazol, Glibenclamide, Ketoconazole, Phenytoin, Troglitazone Class 3 ○ ____________ solubility, ____________ permeability ○ Acyclovir, Chloramphenicol ○ Atenolol, Captopril, Cimetidine, Metformin, Neomycin, Ranitidine Class 4 ○ ____________ solubility, ____________ permeability ○ Furosemide, Paclitaxel ○ Coenzyme A, Cyclosporin, Ellagic Acid, Ritonavir, Saquinavir PRODRUGS ____________ derivatives of drug molecules that undergo an enzymatic/chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacologic effect Optimize ADME or improve oral BA Types ○ ____________: biologically active with inc water/lipid solubility ○ ____________: biotransformed in a rapid and predictable manner into nontoxic moieties ○ ____________: active drug + carrier group that can be removed enzymatically ○ Mutual prodrugs: two synergistic drugs attached to each other ○ ____________: inert molecules obtained by chemical modification Without a carrier; bioactivated via redox Examples ○ Chloramphenicol palmitate – ____________ ○ Olsalazine – ____________ ○ Enalapril – ________________________ ○ Levodopa – ____________ ○ Azathioprine – ____________ ○ Heroin - ____________ TOPIC 2: METABOLISM A. DEFINITION “biotransformation” (formerly detoxification) ○ Liver: ____________ ○ GIT: ____________ ○ Blood: esterases (cholinesterase, pseudocholinesterase) ○ Blood: ____________ ○ Lungs, Placenta, Aqueous humor of eyes Chemical alteration and structural modification to render the drug ____________, ____________ and r____________ GOAL: ____________ molecule (inc absorption & distribution) → ____________ (inc excretion) ○ If drug is not ____________ → accumulation → inc. duration of action/t½ → TOXICITY Factors: hereditary/genetics; ____________ (age, sex), environment; ____________ (route, dose, frequency, tissue distribution, protein binding), Drug interactions B. DRUG INTERACTION Metabolism-based: competition for the ____________ Mechanism-based: ____________ effects after producing an active inhibitor C. PRESYSTEMIC METABOLISM Aka ________________________ drug is deactivated due to enzymes in the ____________ drugs absorbed into ____________ system, leading to decreased bioavailability Lidocaine Morphine Pentazocine Propranolol D. TYPES OF METABOLISM BASED ON END PRODUCTS BIOACTIVATION to Active Metabolites ○ ____________ – inactive parent compounds that are biotransformed to biologically active metabolites Clopidogrel, allopurinol Phenacetin is de-ethylated to Paracetamol ____________ → prednisolone ○ Enalapril is hydrolyzed to enalaprilat All ACE inhibitors are prodrugs EXCEPT ________________________ All ACE inhibitors are P.O ________________________ DETOXIFICATION to inactive metabolites ○ Pharmacologic activity is not ____________ ○ ____________ is hydrolyzed by esterases to p-aminobenzoic acid and Diethylethanolamine ○ Phenol + Phenol Phosphokinase + PAPS = phenyl hydrogen sulfate BIOACTIVATION to a molecule with different activity ○ Iproniazid (antidepressant) N-dealkylation to Isoniazid (____________) BIOACTIVATION to toxic metabolites ○ Pesticide ____________ is oxidized to the toxic Malaoxon (sulfur is oxidized to oxygen) ○ ____________ is oxidized to N-acetyl-p-benzoquinone imine (CYP1A2), which binds to liver cells, causing hepatotoxicity Toxic dose: ____________ Antidote: Glutathione (glutamylcysteinylglycine) Also affect melanin production in high doses ____________ production is affected by melatonin FDA approved for adjunct treatment in ____________ chemotherapy DOC: N-acetylcysteine (____________) METABOLISM to active metabolites ○ Retains ____________ activity despite metabolism ○ Ex. ____________ undergoes demethylation to a more potent analgesic, morphine ○ ____________ hydroxylation to temazepam (short duration) then demethylation to oxazepam (short duration) ○ Diazepam (active) → N-desmethyldiazepam/nordiazepam (active) → ____________ (active) ○ Inactivation is via ____________ E. PHASES OF METABOLISM PHASE I: FUNCTIONALIZATION Also known as “____________ Reaction” Introduces a ____________ functional group (OH, COOH, NH2, SH) by: ○ Direct introduction ○ Modifying / unmasking existing functionalities Converts a parent drug to polar ____________ metabolites Produce a handle on the molecule for Phase II metabolism Reactions: ____________________________________ OXIDATION Most common ________________________ Undergone by olefins, alcohols, aldehydes, and aromatic moieties Example: Phenylbutazone –(aromatic hydroxylation)→ Oxybutazone REDUCTION Carbonyl Compounds → OH derivatives Nitro and Azo Compounds → Amine derivatives Examples: Chloral Hydrate → Trichloroethanol Prednisone –(____________ reduction)→ Prednisone HYDROLYSIS Commonly undergone by lactams, esters, and amides Example: Aspirin → ____________ + ____________ PHASE II: CONJUGATION Also known as “____________” Converts a parent drug to polar ____________ metabolites ○ Allows the attachment of small, polar, and ionizable endogenous compounds ○ ____________ or ____________ of a biologic activity ○ Serves to protect the body against ____________ reactive compounds or metabolites (detoxify) Enzymatic synthesis whereby a functional group is masked by the addition of a new group which increases the ____________ of a drug Reactions: Glucuronidation, Sulfation, Glutathione, Glycine and Glutamine Conjugation, Acetylation, Methylation GLUCURONIDE CONJUGATION Most common ____________ reaction Requires ____________ (from the oxidation of glucose) Glucose-1-P + UTP → UDP Glucose → [UDPG-DH, 2 NAD] → UDP-Glucuronate ○ O-glucuronidation: APAP ○ Acylglucuronidation: Ibuprofen ○ N-glucuronidation: p-aminosalicylic acid Enzyme: ________________________ Activated cofactor: uridine-5’-diphospho-a-D-glucuronic acid Not yet developed in ____________ Less expressed in > nicotinic and inc duration No changes on ________________________ B-methyl + carbamate = (selectivity + stability) = Bethanechol Drugs containing the chiral center are used as ____________ mixtures. PHYSICOCHEMICAL AND PHARMACOKINETIC PROPERTIES ____________ and ____________ ammonium salts are all water soluble. Quaternary ammonium chlorides are poorly absorbed via the oral route because of the quaternary nature of the compound. Ester, lactone, and carbamates are relatively stable in aqueous media, but are still prone to metabolism via ____________ CLINICAL APPLICATION Methacholine (Provocholine): Diagnostic for ____________ ____________ (Miostat): treatment for glaucoma and induction of ____________ (eye drops) Bethanechol (Duvoid, Urecholine): treatment of urinary retention and abdominal distention (oral) ____________ (Isopto Carpine, Pilopine HS, Salagen): Treatment of open-angle glaucoma and xerostomiam Sjogren syndrome (eye drops, oral) Cevimeline (Evoxac): ____________, Sjogren syndrome (oral) C. INDIRECT AGONISTS: ACETYLCHOLINESTERASE INHIBITORS MOA: ____________ is an enzyme, which is capable of binding ACh and chemicals of a similar structure. Acetylated AChE is considered to be “____________” Hydrolytic deacylation rapidly ____________ the active AChE. ____________: acylate the enzyme followed by diacylation ____________: phosphorylate AChE then slowly dephosphorylate = high potential toxicity CLASS Amino alcohol: ____________ ____________: Neostigmine, Physostigmine Organophosphates: Echothiophate, ____________, Insecticides (Malathion, Parathion), Nerve gases (Sarin, Soman, Tabun) PHYSICOCHEMICAL AND PHARMACOKINETIC PROPERTIES Quaternary amines: locally, via ____________, limited ____________ BA Tertiary amines: well absorbed, systemic use, enter CNS, ________________________ METABOLISM ____________: undergoes carbamate hydrolysis with AChE Tacrine, donepezil, galantamine: substrate of CYP = inactive/less active products ○ 1-hydroxytacrine: has some ____________ SIDE EFFECTS ____________ ecothiopate: burning, lacrimation, blurred vision, lens opacity Edrophonium, neostigmine, pyridostigmine: affect the ____________, respiratory, gastrointestinal, ____________, or musculoskeletal systems CLINICAL APPLICATION Echothiopate iodide: treatment of ________________________ (eye solution) Edrophonium Chloride: diagnosis of ________________________; very short duration Neostigmine methylsulfate (SC, IM, note well absorbed), Pyridostigmine bromide: control of myasthenia gravis Rivastigmine tartrate, donepezil, tacrine, galantamine: control mild to moderate ________________________ D. MUSCARINIC ANTAGONISTS – ANTICHOLINERGICS Antagonists at muscarinic sites at ____________ mAChR in the cholinergic nervous system Common in ____________ family Atropa belladonna (atropine), Hyoscyamus niger (Hyoscyamine), Datura stramonium MOA: Antagonists at ____________ sites at postganglionic mAChR Competitive ____________ antagonists of mAChR with affinity, but without intrinsic activity SAR: Amino alcohol Esters/Tropane: Atropine (Racemic hyoscyamine), ____________ (hyoscine + epoxide ring in tropane ring)/Hyoscine, Ipratropium (Isopropyl), Tiotropium R1: second aryl group or a ____________ group. The size of substituents on either ring is limited suggesting steric hindrance during binding to the mAChR. Hydrophobic binding appears to be outside of the ACh binding region. R2: tertiary hydroxyl or a ____________ group; increase the potency by participating in a hydrogen bond interaction at the receptor. X: ester/ether bond ____________ amine (2nd/3rd): involved in binding to the muscarinic receptor with small alkyl substituents PHARMACOKINETIC / PHARMACODYNAMIC Effective both ____________ Quaternary ammoniums taken orally are not well ____________; affects locally on respiratory/GIT; can be formulated into ________________________ Tertiary amines are absorbed following oral administration and cross the blood–brain barrier; can also be ____________ transdermally METABOLISM Hydrolysis to ____________ agents N-dealkylation to some active agents Fesoterodine is activated via ____________, while active metabolites of the other anticholinergics are formed following CYP450 oxidation. Affected by ____________ SIDE EFFECTS Systemic route: blurred vision, ____________, xerostomia, constipation, dyspepsia, difficulty in urination C/I: closed angle ____________, benign prostatic ____________ CLINICAL USES ____________, oxybutynin, tolterodine, solifenacin, darifenacin: treatment of overactive bladder Tiotropium, ____________, aclidinium, umeclidinium: Long-acting antimuscarinic agent for long term maintenance of bronchospasms ____________: Preop agent to reduce salivary, tracheobronchial, pharyngeal secretions Trihexyphenidyl, benztropine: adjunct in treatment of ____________; control of extrapyramidal symptoms Transdermal ____________: prevention of motion sickness E. NICOTINIC ANTAGONIST – NEUROMUSCULAR BLOCKING AGENTS MOA: Competitive antagonists of ____________ Either ____________ (succinylcholine) or ____________ ____________ NM blocking agent produces an initial muscle excitation followed by prolonged blocking action as a result of resistance to AChE ____________ NM blocking agents are competitive antagonists at the α-subunits preventing ACh from binding to nAChR preventing depolarization of the NM end plate SIDE EFFECTS ____________, bronchospasm, cardiac disturbances Depolarizing agents: initial muscle fasciculation before ____________ Release of ____________ = cutaneous (flushing, erythema, pruritus), pulmonary (bronchospasm, wheezing), ____________ (hypotension) effects SAR ____________ NM: flexible structure connecting the two quaternary heads ____________ NM: more rigid structure with the quaternary and protonated heads being part of bulky groups. PHARMACOKINETIC / PHARMACODYNAMICS Not absorbed ____________; well distributed ff. ____________ Polar = does not enter the ____________ Duration of action is limited by haptic hydrolysis of the esters; metabolites show partial activity METABOLISM Prone to ____________ Atracurium is also degraded via a Hofmann elimination which occurs in the plasma and as a result, the drug’s ____________ effects are independent of renal elimination and can be used in patients with ____________ renal function CLINICAL APPLICATIONS Adjunct to general ____________ Produce skeletal muscle relaxation that facilitates operative procedures such as abdominal surgery and ____________ the depth requirement for general anesthetics, thus decreasing the overall risk of a surgical procedure and shortens the ____________ recovery time. Used in the correction of ____________ and the ____________ of fractures Short-acting NM blocking agents, such as ____________, are routinely used to assist in tracheal intubation. F. NICOTINIC AGONIST - VARENICLINE MOA: Partial ____________ (efficacy relative to ACh of 13%) at nAChRs with selectivity for the α4β2 subtype as well as weak partial agonist on α3β4, α3β2, and α6-containing nAChR subunits. Full ____________ on the α7-nAChR subunit. May be involved in the mechanism of action of ____________ as a ____________ cessation aid PHARMACOKINETIC / PHARMACODYNAMICS Maximal plasma concentration is reached within 3 to 4 hours after oral administration. A steady-state concentration is reached within 4 days. ____________ has a half-life of 24 hours. ____________ bioavailability is not affected by ____________ or time of administration. The drug exhibits low ____________ binding (∼20%). Renal excretion occurs with 81% to 92% of the drug being excreted unchanged. CLINICAL APPLICATION for ____________ cessation, as an alternative to ____________ and ____________ patches SIDE EFFECTS weight gain, change in taste and ____________, mouth dryness, ____________, headache, irritability, heartburn, vertigo, nausea, diarrhea, and tachycardia. ALERT on depression, ____________, and suicidal thoughts and ____________. TOPIC 4: ADRENERGIC AGENTS A. ENDOGENOUS ADRENERGICS A1: postsynaptic, Gq; vascular smooth muscle, CNS; ____________ PLC = inc. IP3 and DAG A2: presynaptic, Gi; inhibits adenylyl cyclase = dec. intracellular cAMP = inhibits NE release from ____________ terminal Beta receptors: postsynaptic, Gs; activates adenylyl cyclase = inc. cAMP B1: ____________ = increased chronotropy and inotropy B2: lungs, uterus, vascular smooth muscle, ____________ muscle; relaxation, dilation of ____________ NOREPINEPHRINE Adrenergic ____________ produced and released from ____________ terminals Fraction of NE not binding to pre-and postsynaptic receptors is returned to presynaptic terminals via an ________________________ EPINEPHRINE ____________ A neurohormone produced in and secreted by the ____________ B. ADRENERGIC AGONISTS MOA: ____________: binds directly to the same receptors and communicates the same chemical/physiological message as NE; can be selective ____________: (nonselective) agonist is denied access to receptors, but augments NE’s action in adrenergic synapses by: ○ (1) stimulating its release from presynaptic terminals, ○ (2) blocking uptake-1 ○ (3) inhibiting its metabolism. Mixed: both ____________ and ____________ action C. BETA-2 AGONISTS METABOLISM Resistant to ____________ (no catechol nucleus) and ____________ (slow to no dealkylation) ____________: O-dealkylation ____________: benzylic hydroxylation Glucuronidation or sulfonation occurs before ____________ CLINICAL APPLICATIONS: SABA ○ ____________ in acute bronchospasm (asthma, COPD, emphysema) ○ ____________: oral/inj; others are inhalational only ○ Bronchodilation begins within ____________ and lasts for about 4-8 hours LABA ○ Controls the occurrence and severity of ________________________ ○ Cotherapy with ____________: treatment for ____________ ○ Onset = 30 minutes; cannot be used to rescue patients from acute asthmatic attacks ○ ____________: partial B2 agonist with inc. activity due to their ability to sequester in bronchial membranes Pseudoirreversible hydrophobic bonding ○ ____________ (Foradil): full B2 agonist with 3x lower B2 selectivity Potent: allows lower dosing Racemic: R, R-(-) isomer is arformoterol; 2x more potent but similar dose ○ ____________ (Arcapta), Oladaterol (Neohaler): newer B2 agonist 24 hours duration: once a day dosing Long duration due to concentration in bronchial membranes (indacaterol) and inc. B2 affinity (oladaterol) D. B3 AGONIST – MIRABEGRON Treatment of ____________ Acts at B3 in detrusor = relax = inc. bladder capacity Amide hydrolysis and subsequent N-acetylation No ____________ and blurred vision Moderately inhibits ____________ E. ADRENERGIC ANTAGONIST – NONSELECTIVE ALPHA BLOCKER MOA: Block the action of released NE and circulating ____________ on postsynaptic a1- receptors PHENOXYBENZAMINE Only ____________ acting adrenergic antagonist. Spontaneously generates an ____________ aziridinium ion that is readily attacked by αreceptor nucleophiles Oral: benign NE/Epi-secreting tumor of the adrenal glands called pheochromocytoma. S/E: postural ____________, nasal congestion, and ____________ F. A-1 SELECTIVE ANTAGONISTS – QUINAZOLINES MOA: Block the α1A-receptors in the ____________ CLINICAL APPLICATIONS: Used orally in the treatment of ________________________ ○ Esp. Tamsulosin, silodosin Prazosin (Minipres): ____________ Terazosin (Hytrin), Doxazosin (Rapaflo): HTN, BPH G. MIXED ALPHA/BETA BLOCKER MOA: Beta 1 blockade = dec. ____________ Alpha 1 blockade = blocks vasoconstriction = dec. ____________ Beta 2 blockade = ____________ Meta-carboxamide = B2 agonism = less ____________ LABETALOL (NORMODYNE) Two of labetalol - 4 stereoisomers are active ○ R,R: potent, nonselective B-blockade with minimal alpha blockade ○ Epimerizing the CH3-substituted carbon to S provides selective α1- antagonism. ○ Orally active; resistant to phase 1; glucuronide conjugates precede excretion CARVEDILOL (COREG) Aryloxy propanolamine; racemic ○ R: ____________ a-blocker ○ S: B-blockade > a-blockade ○ No inactive isomer; has enhanced anti-HTN potency than ____________ Can be used in ____________ Carbazole moiety has ____________ effects Extensively metabolized and excreted (feces) as the glucuronide conjugate of Phase 1 metabolites ○ 4’-hydroxy metabolite is 13x more ____________ than the parent compound H. ARYLOXYPROPANOLAMINE ANTAGONISTS CLINICAL APPLICATIONS Nonselective: CI in ____________, ____________, ____________ ○ Those with sympathetic activity can have less bronchoconstriction but not safe for patients at risk of ____________ B1 selective: dec. risk of ____________ All aryloxypropanolamines (except carteo-/lavobuno-/metipranolol): oral anti HTN Betaxolol, timolol, carteolol, levobunolol, metipranolol: for glaucoma ○ Polar molecules = ____________ ○ Lipophilic = ________________________ I. PHENYLETHANOLAMINE B-BLOCKER – SOTALOL Lone para substituent = no ____________ selectivity Methylsulfonamide: no intrinsic activity, hydrophilic For ____________ Sotalol AF = for atrial arrhythmia Can induce ____________ (pro-AR) TOPIC 5: ANTI-INFECTIVE AGENTS ____________ – introduced phenol (carbolic acid) ____________ – Salvarsan (Compound 606); selective toxicity Atoxyl (Na Arsanilate and Arsphenamine) – for ____________ Germicides – anti-infective agents that are used locally ____________ – application of an agent to living tissue to prevent infection ____________ – destruction or marked reduction in the number or activity of microorganisms ____________ – chemical or physical treatment on inanimate surfaces ____________ – reduction of microbial load on inanimate surface to a level acceptable for public health purposes ____________ – kill or remove all types of microorganisms ____________ – kills non-sporulating microorganisms by hot water at 65 – 100°C ____________ – anti-infective agents used locally ○ -cidal – ____________ ○ -static – ____________ A. ALCOHOLS AND RELATED COMPOUNDS SAR ○ ↑ no. of C = ↑ antibacterial activity up to ____________ ○ > 9C = non-polar ↓ water solubility ↓ antibacterial activity ○ Branching ____________ antibacterial property (EXCEPT isopropyl alcohol – more potent, cheaper, less toxic; 60% EtOH = 40% Isopropyl OH) ○ Isomeric OH potency decreases in the order: Primary > Secondary > Tertiary MOA: ________________________ TYPES OF ALCOHOLS Absolute Alcohol → ____________ Dehydrated Alcohol → ____________, prepared by azeotropic distillation Diluted Alcohol → ____________ Denatured Alcohol → EtOH rendered unfit for use in intoxicating beverages; completely denatured alcohol contains methanol and benzene Completely Denatured Alcohol → Contains added wood alcohol and benzene unsuitable for internal or external use Specially Denatured Alcohol → Treated with substituents so that its use is permitted for specialized purposes (ex. Iodine in alcohol) A.1. ALCOHOL, USP Ethanol, grain alcohol, wine spirit, ____________, spiritus vini rectificatus Most widely abused of all recreational drugs Commercial ethanol (95%) is manufactured by: ○ ____________ of grains and other CHOs ○ ____________ acid catalyzed hydration of ethylene Metabolism: ____________ → Acetaldehyde → Acetate (Acetic Acid) OH Dehydrogenase: EtOH → ____________ RCHO ____________: Acetaldehyde → Acetate DRUGS THAT INTERFERE WITH ALCOHOL METABOLISM: 1. ____________ ○ Inhibits OH ____________ ○ Used as an antidote for ____________ poisoning 2. ____________ ○ Used as a deterrent for alcohol addiction ○ Inhibits RCHO ____________ ○ Accumulation of RCHO = extreme hangover-like symptoms (N&V, vasodilatory flushing) A.2. ISOPROPYL ALCOHOL ____________ Substitute for ethanol Prepared by sulfuric acid catalyzed hydration of propylene 50 – 95%: ____________ A.3. ETHYLENE ALCOHOL / ETHER ____________ MOA: Alkylation of bacterial protein by nucleophilic opening of oxide ring Used to sterilize (gas sterilant) temperature sensitive pharmaceutical and equipment that ________________________ Carboxide – 10% ethylene oxide + 90% CO2 A.4. FORMALDEHYDE Aka ____________, HCHO MOA: Direct and non-specific alkylation of nucleophilic functional groups of proteins Contains NLT 37% of Formaldehyde + Methanol (retards polymerization to formic acid and paraformaldehyde) Uses: ________________________ A.5. GLUTARALDEHYDE Aka ____________ (Cidex®) Sterilizing solution for equipment and instruments that cannot be autoclaved Used in medical missions in ____________ B. PHENOL AND ITS DERIVATIVES ________________________ – ratio of a dilution of a given test disinfectant to the solution of phenol that is required that is required to kill a strain of ____________ under carefully controlled time and temperature ↑ PC = ↑ antibacterial property ↑ bactericidal property = straight chain substitution with alkyl, aryl, and halogen in para position Activity: Straight chain alkyl > branched ____________: Denatures bacterial proteins ____________: Lysis of cell membranes Formula: B.1. PHENOL / CARBOLIC ACID ____________ Introduced as a surgical antiseptic by ________________________ Standard for ____________ SAR: Substitution at para position increases bacterial activity Activity: Straight chain alkyl > ____________ Exhibits germicidal activity (general protoplasmic poison), caustic, local anesthetic Liquefied Phenol – phenol with ____________ p-chlorophenol – used in combination with camphor in liquid petrolatum P-chloro-m-xylenol ○ Aka ________________________ ○ 2% (shampoo), for athlete’s foot and jock itch Hexachlorophene ○ Aka ____________ ○ Easily adsorbed onto skin and enters sebaceous glands (neurotoxicity) B.2. CRESOL / METHYLPHENOL Mixture of three ____________ methyl phenols Obtained from coal tar or petrolatum by alkaline extraction ____________ – preservative B.3. THYMOL / ISOPROPYL M-CRESOL Meta cresol From oil of ________________________ Mild fungicidal (Tinea) B.4. EUGENOL 4-allyl-2-methoxyphenol From ____________ Applied on cotton to relieve ____________ Ingredient in mouthwashes B.5. RESORCINOL M-dihydroxybenzene Weak antiseptic, ____________ ____________ – produces numbness when applied to the tongue; ingredient in lozenges 1-3% in solutions, 10-20% in ____________ and ____________ for the treatment of skin conditions C. OXIDIZING AGENTS MOA: Oxidation / Liberation of oxygen in the tissues (peroxides) and protein denaturation (permanganates) Poor ____________ to infected tissues and organic matter Effective against ____________ bacteria C.1. HYDROGEN PEROXIDE (H2O2) Active against ____________ bacteria and find use in the cleansing of contaminated wounds Effectiveness is somewhat limited by its poor tissue penetrability and ____________ action (rapid action, short duration) Stability is increased in ____________ ____________ – has Acetanilide to increase its stability by catalytically retarding its decomposition Vincent’s Stomatitis (Hairy Tongue) – due to continued use of H2O2 as ____________ Volume Specifications: mL of Oxygen measured at std temp and pressure C.2. CARBAMIDE PEROXIDE Stable complex of urea and ________________________ Releases hydrogen peroxide when mixed with ____________ C.3. HYDROUS BENZOYL PEROXIDE Vanoxide, Panoxyl ____________ Keratolytic and keratogenic agent MOA: Induced proliferation of epithelial cell leading to ____________ and ____________ Increases ____________ Most effective topical OTC agent for the control of ____________ D. HALOGEN CONTAINING COMPOUNDS D.1. IODINE (I2) ____________ germicide in use today ____________ color with Starch and Dextrin Na, K – iodine stabilizer MOA: Inactivation of proteins by: ○ Iodination of aromatic residues (phenylanalyl & tyrosyl) ○ Oxidation (Sulfhydryl groups) OFFICIAL IODINE PREPARATIONS IN THE USP Iodine Solution → ________________________ Strong Iodine Solution (Lugol’s) → ________________________ Iodine Tincture → ________________________ Strong Iodine Tincture → ________________________ INORGANIC IODIDE SALTS Admixed to increase the solubility of I2 and to reduce its volatility Ex: I2 + NaI IODOPHORS Complexes of ____________ and ____________ surfactants Retained germicidal properties, reduced volatility, and removed irritant properties Ex: Povidone–Iodine: A ____________ with the non-ionic surfactant polymer, polyvinylpyrrolidone D.2. CHLORINE (Cl2) Used for ____________ of water supplies MOA: Chlorination of amide nitrogen atoms in proteins, oxidation of sulfhydryl groups ________________________ – Active germicidal species formed when Cl2 is dissolved in water ____________ – chlorine containing; used to disinfect drinking water ____________ – may be precipitated from solution by the AgNO3 reagent ____________ – a glyceryltriacetate solution is used as wound dressing Oxychlorosene Sodium – complex of sodium salt of dodecylbenzesulfonic acid and hypochlorous acid E. CATIONIC SURFACTANTS ____________ MOA: Surface active property: absorption into the cell wall = ________________________ (lysis) Quaternary ammonium compounds that ionize in water and exhibit surface active properties With polar head group and non-polar HC chain from micelles (CMC – right conc) Inactivated by soaps and other anionic detergents Adsorbed on ____________, talc, and ____________ to reduce action Tissue constituents, blood, serum, and pus tend to reduce effectiveness of these substances Solutions are intended for disinfecting ____________, gloves, etc. – NEVER reuse as it can harbor pathogens E.1. BENZALKONIUM CHLORIDE New generic name of Merthiolate®; Zephiran® ○ Old generic name of Merthiolate® is “____________” Detergent, emulsifier, wetting agent, antiseptic, preservative (+ Na nitrate) Used with ____________ as a preservative Germicidal surfactant which renders inactive in the presence of ____________ E.2. METHYLBENZETHONIUM CHLORIDE Diaparene® For ____________ rash E.3. CETYLPYRIDINIUM CHLORIDE Difflam® Used as a ____________ antiseptic Available Forms: ○ ____________ ○ ____________ FDA approved treatment for gingivitis E.4. CHLORHEXIDINE Bactidol®, Orahex®, GynePro® TAKE NOTE: Classified under ____________, not a cationic surfactant but they share many physical, chemical, and antimicrobial properties Used in oral surgery, mouthwash, and ____________ Not ____________ through skin or mucous membrane and does not cause systemic toxicity Best antiseptic based on antibacterial effect F. PRESERVATIVES Dosage forms and cosmetic preparations – added to prevent ____________ contamination Parenteral and ophthalmic preparations – maintain ____________ in the event of accidental contamination during use Ideal Preservative: ○ Effective at low concentrations ○ ____________ ○ Compatible with other constituents of the preparation ○ ____________________________________ F.1. PARABENS Esters of p-hydroxybenzoic acid that has ____________ properties Methylparaben ○ Methyl-p-hydroxybenzoate ○ Effective against ____________ Propylparaben ○ Propyl-p-hydroxybenzoate ○ Effective against ____________ ○ More oil soluble; preferred for oils and fats Butylparaben, Ethylparaben – preferred preservatives for drugs in ____________ or ____________ bases F.2. CHLOROBUTANOL ________________________ Bacteriostatic agent in pharmaceuticals for injection, ophthalmic use, and intranasal administration F.3. BENZYL ALCOHOL Aka phenylcarbinol, phenylmethanol From ____________ Commonly used as preservative in vials of injectable drugs in concentrations of 1-4% in water or saline S/E: Gasping Syndrome ○ ________________________ ○ Metabolic acidosis ○ ________________________ ○ Circulatory failure ○ Intracranial bleeding F.4. BENZOIC ACID Naturally from gum benzoin and in ____________ and ____________ balsams Effective as a preservative in food and pharmaceutical products at low pH F.5 OTHERS Sodium Propionate – has ____________ properties ____________ – antifungal preservative in preserved syrups, elixirs, ointments, and lotions containing components such as sugars G. DYES Cationic dyes are ____________ against Gm (+) and fungi but Gm (-) are generally resistant Forms colorless leucobase forms in alkaline conditions Positively charged (+) G.1. TRIPHENYLMETHANE DYES Gentian Violet ○ Aka ____________, Crystal Violet, p-rosanilline ○ Uses: Yeast infections (____________) – vaginal suppositories (1 – 3%) Cutaneous candidiasis – ____________ ____________ (Strongyloides, Oxyuriasis) Basic Fuchsin ○ Mixture of chlorides of rosanilline and p-rosanilline ○ Ingredient of ____________ (Castellani’s Paint) ○ Used topically for the treatment of fungal infections: ringworm and athlete’s foot G.2. THIAZINE DYES Methylene Blue ○ Antidote for ____________ poisoning ○ Antiseptic property in the treatment of ____________ and ____________ ○ S/E: Blue green color of st____________ool ○ High Conc: Promotes the conversion of Hgb to methemoglobin ○ Low Conc: Treat drug-induced ________________________ H. HEAVY METALS ____________ With ____________ properties 1% drops for ophthalmia neonatorum; new alt: ____________ Ag Sulfadiazine (____________) – burn ointment I. MERCURY COMPOUNDS / MERCURIALS MOA: Reacts with sulfhydryl (-SH) groups in enzymes and other proteins – reversible by thiol-containing compounds such as Cysteine and Dimercaprol (BAL) Mercurous Chloride (Hg2Cl2) – ____________ Mercuric Chloride (HgCl2) – ____________ Ammoniated Mercury – ____________; used for skin infections ____________ – was a very popular antiseptic for skin and ocular infections because it is non-irritating and nonstaining Thimerosal – preservative for vaccines, ____________, and immune sera; MOA: Reaction with -SH of CHON Chlormerodrin (Hg-197) – used for ____________ scanning of kidney and brain for suspected tumors TOPIC 6: ANTHELMINTICS ANTHELMINTICS Drugs that are capable of eliminating ________________________ A. NEMATODES Aka ____________ A.1. PIPERAZINE MOA: Block response of ____________ muscle to Ach = ____________ paralysis of helminth Treatment of pinworm, roundworm A.2. PYRANTEL PAMOATE MOA: Depolarizing Nm blocking agent → ____________ paralysis Should not be used with piperazine due to opposite effects Treatment of ____________, ____________ A.3. THIABENDAZOLE MOA: Inhibit helminth-specific enzyme fumarate reductase / antimitotic / antimicrotubular Broad spectrum anthelmintic S/E: Erythema multiforme / ____________ Tx for ____________ (Threadworm) A.4. MEBENDAZOLE ____________ MOA: Irreversibly blocks glucose uptake → depleted glucose / antimitotic / antimicrotubular Broad spectrum (____________________________________) A.5. ALBENDAZOLE MOA: ____________ / ____________ Broad spectrum A.6. IVERMECTIN From ________________________ MOA: Stimulation of ____________ receptors → blocked interneuron-motor neuron transmission Treatment of Onchocerciasis (River Blindness) by ____________ A.7. DIETHYLCARBAMAZINE (DEC) MOA: ____________ A highly water-soluble compound that is effective against filariasis, including ________________________ and ____________ B. TREMATODES Aka ____________ B.1. PRAZIQUANTEL MOA: Increases ____________ membrane permeability → resulting in the loss of extracellular Ca+2 = tetanic-like contractions DOC in the treatment of infections caused by ____________ (blood flukes) B.2. NIRIDAZOLE For ____________ B.3. OXAMNIQUINE MOA: Inhibits DNA, RNA, and CHON synthesis Treatment of ________________________ B.4. BITHIONOL DOC for liver fluke (________________________) and lung fluke (________________________) C. CESTODES Aka ____________ C.1. NICLOSAMIDE MOA: Inhibits ________________________ TOPIC 7: ANTIPROTOZOAL AGENTS ANTIPROTOZOAL AGENTS Protozoal Infections: Malaria, Amoebiasis, Giardiasis, Trichomoniasis, Toxoplasmosis, P carinii pneumonia A. ANTIMALARIALS Common Structural Feature: ____________ ring, or a quinoline with an additional benzene added (____________ ring) None EXCEPT the ____________ has a quinuclidine ring A.1. QUININE Cinchona Alkaloid Reserved for malarial strains resistant to other agents S/E: ____________, ____________ A.2. CHLOROQUINE 7-chloro-4-aminoquinoline DOC for erythrocytic falciparum – for ____________ and ____________ Acute P. vivax attach Anti-inflammatory (________________________) A.3. AMODIAQUINE 7-chloro-4-aminoquinoline Highly suppressive (P. vivax, P. falciparum) Curative (P. falciparum) – for ____________ A.4. PRIMAQUINE 8-aminoquinoline Only for ____________ stages of malaria Radical cure of P. vivax & ovale Gametocidal for all ____________ A.5. QUINACRINE ____________ Giardiasis, tapeworm, malaria, leishmaniasis CI: ____________ (↑ Toxicity) A.6. MEFLOQUINE ____________ Schizonticide For multi-drug resistant forms of Plasmodium falciparum DOC for ____________ A.7. CYCLOGUANIL Both ____________ and ____________ B. Amebicides that are effective against BOTH INTESTINAL AND EXTRAINTESTINAL FORMS of the disease: B.1. EMETINE AND DEHYDROEMETINE Alkaloids from ____________ MOA: Inhibit CHON synthesis by preventing protein elongation (protoplasmic poison) Also used for balantidial dysentery, fascioliasis, paragonimiasis Limited use due to ____________ effects (GI, CV, Nm) B.2. METRONIDAZOLE ____________, ____________ MOA: Covalent binding of reactive intermediate from the reduction of 5-nitro group to the DNA = ____________ Treatment of amoeba, giardiasis, trichomonas, and anaerobic bacterial infections S/E: ____________-like effect (if taken with alcohol) C. Amebicides that are effective only against INTESTINAL FORMS of the disease: C.1. 8-HYDROXYQUINOLINE MOA: Chelation of ____________ C.2. IODOQUINOL Derivative of 8-hydroxyquinoline For acute and chronic ________________________ C.3. DILOXANIDE Treatment of asymptomatic carriers of ____________ From ____________ of α-dichloroacetamides D. PNEUMOCYSTIS CARINII PNEUMONIA D.1. COTRIMOXAZOLE Sulfamethoxazole + Trimethoprim DOC for ____________ D.2. PENTAMIDINE ISETHIONATE Prophylaxis for ________________________ – rapidly distributed where it is stored D.3. ATOVAQUONE Analog of ubiquinone – component of ____________ ETC MOA: Interferes with the ETC as it is an antimetabolite for ubiquinone E. TRYPANOSOMIASIS E.1. BENZIMIDAZOLE Treatment of ________________________ E.2. SURAMIN Bisurea derivative containing 6 sulfonic acid groups Used as a long-term prophylactic agent for ____________ due to high CHON binding, effect can last up to 3 months E.3. MELARSOPROL DOC for later stages of both forms of ________________________ E.4. EFLORNITHINE MOA: Irreversible inactivation of ornithine decarboxylase Treatment of ________________________ ____________ E.5. NIFURTIMOX Treatment of Southern ________________________ (T. cruzi) F. TOXOPLASMOSIS F.1. SULFADIAZINE + PYRIMETHAMINE Most effective therapy for ____________ F.2. SODIUM STIBOGLUCONATE Aka Sodium Antimony Gluconate MOA: Inhibit ________________________ Treatment of ____________ TOPIC 8: ANTISCABIES & ANTIPEDICULAR AGENTS A. SCABICIDES Agents that control the mite, ________________________ A.1. BENZYL BENZOATE From Peru Balsam, also from ____________ + ____________ Topical scabicide Immediate relief from ____________ Colorless liquid ester with faint ____________ odor A.2. CROTAMITON Antipruritic (local anesthetic action) 10% lotion / cream for ____________ ____________, oily liquid B. PEDICULICIDES Used to eliminate ____________, ____________, and ____________ B.1. PERMETHRIN Exerts a ____________ action against lice, ticks, mites, and fleas MOA: Acts on nerve cell membranes → disrupt Na+ channel conductance = paralysis ____________ for the treatment of lice ____________ for the treatment of scabies S/E: Pruritus B.2. LINDANE Kwell®, Scaben®, Kwildane® 3-fold actions: ○ ____________ ○ ____________ ○ ____________ S/E: Neurotoxicity B.3. PYRETHRIN From chrysanthemum plants MOA: ____________ B.4. PIPERONYL BUTOXIDE Enhances the ____________ effects of ____________ TOPIC 9: ANTIBACTERIAL AGENTS Mechanisms of Antibacterial Action: ________________________ ________________________ ________________________ ________________________ ________________________ I. INHIBITION OF CELL WALL SYNTHESIS A. BETA LACTAM ANTIBIOTICS A.1. PENICILLINS History Discovered by ____________ Old: ________________________ New: ________________________ Isolated by Florey & Chain by freeze drying / lyophilization Properties Contains an unstable bicyclic system: ○ Beta-lactam and thiazolidine ring ○ Nucleus: 6-aminopenicillanic acid (APA) ○ AA Biosynthetic Precursors: Cys, Val ○ Shape: ____________ Structure-Activity Relationship (SAR) Addition of e- withdrawing group: ____________ Addition of bulky groups: ____________ Addition of amino group: ____________ Mechanism of Action (MOA): Irreversibly inhibits ____________ by covalently binding to the serine residue of the active site thus inhibiting ____________ synthesis NARROW SPECTRUM PENICILLINS / NATURAL PENICILLINS 1. Penicillin G (Benzyl Penicillin) ○ Given ____________ ○ Depot Forms: Benzathine Penicillin, Procaine Penicillin ○ DOC for ____________ 2. Penicillin V (Phenoxymethyl Penicillin) ○ Given ____________ PENICILLINASE-RESISTANT PENICILLINS / ANTISTAPHYLOCOCCAL PENICILLINS 1. Methicillin ○ 2,6-dimethoxyphenylpenicillin ○ ____________ ○ S/E: Interstitial nephritis ○ Emergence of ____________ 2. Nafcillin ○ 2-ethoxy-1-phenylpenicillin ○ Can be given to patients with ____________ 3. Oxacillin, Cloxacillin, Dicloxacillin ○ Isoxazolyl Penicillin – contains 3-phenyl and 5-methyl ○ Dicloxacillin – best ____________ BROAD SPECTRUM PENICILLINS / AMINOPENICILLINS 1. Ampicillin ○ Given IV; poor ____________ ○ Prodrugs: ____________ ____________ ____________ ○ Unasyn® – Ampicillin + Sulbactam ○ DOC for ________________________ 2. Amoxicillin ○ Given PO; more acid stable ○ Co-Amoxiclav® – Amoxicillin + Clavulanic Acid ○ Commonly used in ____________ infections EXTENDED SPECTRUM PENICILLINS / ANTIPSEUDOMONAL PENICILLINS 1. Carbenicillin, Ticarcillin ○ Carboxypenicillin ○ Carboxyl at the ____________ 2. Piperacillin, Azlocillin, Mezlocillin ○ Ureidopenicillins ○ Urea at the ____________ ○ ____________ – most potent A.2. CEPHALOSPORINS History Cephalosporin C – 1st cephalosporin Old: Cephalosporium acremonium New: Acremonium chrysogenum Properties Contains an unstable bicyclic system: ○ Beta-lactam and dihydrothiazine ○ Nucleus: ________________________ ○ AA Biosynthetic Precursors: Cys and Val ○ Better ____________ stability and ____________ to β-lactamase Mechanism of Action (MOA): Irreversibly inhibits ____________ by covalently binding to the serine residue of the active site thus inhibiting cell wall synthesis Generations of Cephalosporins: based on their bacterial spectrum of activity and β-lactamase resistance 1st Gen: All starts with “Ceph-“ except ____________, ____________ 2nd Gen: All starts with “Cef-“ nothing ends in -one or -ime except Cefuroxime, Loracarbef, Cefoperazone 3rd Gen: All starts with “Cef-“ and all ends in -one or -ime except ____________, Cefdinir, Ceftibuten, ____________ 4th Gen: Cefepime, Cefpirome 5th Gen: Ceftaroline fosamil, ____________ Clinical Uses ____________ – used for UTI in pregnant px ____________ – pre-surgical prophylaxis ____________ – New DOC: Typhoid Fever Antipseudomonal Cephs (Cefoperazone, Cefotaxime, Ceftazidime, Ceftriaxone, Moxalactam) – have useful antipseudomonal activity Side Effects Hypersensitivity Disulfiram-like reaction Hypoprothrombinemia N-methyl-5-thiotetrazole (MTT) Cephs: ○ Cefamandole ○ ____________ ○ Moxalactam ○ ____________ A.3. CARBAPENEMS Properties ○ Differ from penicillin in that the S atom has been replaced by a C atom ○ Broad spectrum of activity, including ____________ DRUGS: ○ THIENAMYCIN Isolated from ____________ Inactivated by renal dehydropeptidase-I ○ IMIPENEM N-formimidoyltheinamycin Cleaved by ____________ ____________ – Imipinem + Cilastatin ○ MEROPENEM 2nd generation ____________ Resistant to dehydropeptidases and β-lactamases ○ ERTAPENEM Benzoic acid contributes to high ____________ binding and prolongs the half-life of the drug A.4. MONOBACTAM Properties ○ Monocyclic β-lactams ○ Inactive against ____________ ○ Moderate activity against a narrow group of Gm (-) bacteria, including P. aeruginosa DRUGS: ○ AZTREONAM Isolated from ________________________ ____________ for pseudomonas This β-lactam is not fused to another ring, no cross sensitivity with penicillin B. CYCLOSERINE Sources: ○ ________________________ ○ ________________________ ○ ________________________ MOA: Prevents the formation of D-ala-D-ala (inhibits L-alanine racemase & D-ala-D- ala ligase) Use: 2nd line drug for ____________ C. FOSFOMYCIN Synthetic derivative of ____________ MOA: Inhibits UDP-N-acetyl glucosamine enolpyruvyl transferase Use: UTI caused by ____________ D. VANCOMYCIN A glycopeptide from ________________________ MOA: Inhibits ____________, inhibits synthesis of mucopeptide polymer DOC: MRSA (IV), C. difficile induced Pseudomembranous colitis (PO) S/E: Red Man Syndrome – Remedy: ________________________ E. BACITRACIN A polypeptide from ____________, isolated from a fracture fragment from ____________ MOA: Binds to the lipid carrier; alters cell membrane permeability Use: Bacitracin + Polymyxin B for the topical treatment of ________________________ N/E: Nephrotoxic, hematotoxic Action is enhanced by ____________ E. TEICOPLANIN A glycopeptide from Actinoplanes teichomyceticus MOA: Long alkyl chain anchors the antibiotic to the outer surface of the cell membrane Use: Treatment of Gm (+) infections II. INTERACTIONS WITH PLASMA MEMBRANE A. POLYMYXINS Cation polypeptides MOA: Bind to phospholipids on the cell membrane of Gm (-) bacteria S/E: Nephrotoxic, neurotoxic DRUGS: ○ POLYMYXIN B Source: ____________ Polymyxin B + Bacitracin – for ____________ infections Polymyxin B + Dexamethasone + Neomycin – for ____________ infections ○ COLISTIN / POLYMYXIN E Source: Aerobacillus colistinus For refractory ____________ and ____________ infections B. GRAMICIDIN A Source: ____________ Mechanism of Action (MOA): Acts as ____________ allowing the loss of K+ ions C. DAPTOMYCIN Cyclic lipopeptide from ____________ Use: Reserve agent for ____________ III. INHIBITION OF CHON SYNTHESIS A. AMINOGLYCOSIDES Properties ○ Amino sugars joined by a ____________ linkage ○ Derived from ____________ spp (-mycin) or ____________ spp (-micin) ○ Given IV EXCEPT ____________ ○ Aminoglycosides + Penicillins = Synergism ○ For the treatment of serious infections caused by ____________ Mechanism of Action (MOA): Binds to 30s ribosomal subunit to prevent the reading of the mRNA Side Effects: ○ Allergic reactions ○ Ototoxicity, nephrotoxicity ○ Neuromuscular paralysis ○ ____________ – Most ototoxic ○ ____________ – Most vestibulotoxic ○ ____________ – Most nephrotoxic DRUGS: ○ GENTAMICIN Source: Micromonospora purpurea ○ TOBRAMYCIN Source: ________________________ ○ AMIKACIN Semi-synthetically derived from ____________ First prepared in ____________ ○ NEOMYCIN Source: ________________________ ○ KANAMYCIN Source: ________________________ ○ STREPTOMYCIN Source: ________________________ 1st aminoglycoside discovered 1st effective agent used against tuberculosis B. TETRACYCLINES Properties ○ Consists of ____________ rings with a system of conjugated double bonds ○ Broadest spectrum of the antibiotics ○ Have activity against Gm (+) and Gm (-), spiro____________chetes, and atypical bacteria ○ ____________ – Streptomyces aureofaciens ○ DOC: Lyme disease, ____________ DRUGS R1 R2 R3 R4 H OH CH3 H Cl OH CH3 H H OH CH3 OH Cl OH H H H CH2 OH H CH3 H OH N(CH3)2 H H H Mechanism of Action (MOA): Binds to the ____________ subunit of ribosomes which prevents aminoacyl-RNA from binding to the mRNA ribosome complex CLASSES OF TETRACYCLINE Short Acting: ○ ____________ ○ ____________ Intermediate Acting: ○ ____________ ○ ____________ Long Acting: ○ ____________ ○ ____________ Very Long Acting: ____________ INTERACTIONS Products containing ____________ Dairy products and drugs containing divalent and trivalent metals ○ Decreased absorption of tetracycline due to chelation Penicillin – ____________ SIDE EFFECTS Photosensitivity ____________ Tooth discoloration and stunting of growth CI in ____________ and ____________ C. MACROLIDES Properties ○ Common chemical characteristics: 1-4 membrane lactone ring Ketone group ____________ linked amino sugar Mechanism of Action (MOA): Binds to the 50s ribosomal subunit, inhibiting translocation DRUGS: ○ ERYTHROMYCIN (ILOTYCIN) Source: ________________________, from ____________ Ester Salts: ____________ – lipid soluble, acid stable prodrug with better oral absorption; S/E: Cholestic jaundice ____________ – prodrug with more lipophilicity; longer DOA ____________ – water soluble salt of glucoheptanoic acid; for parenteral use ____________ – used for parenteral means Substitute for penicillin in allergic patients Motilin agonist DOC: ____________ ○ CLARITHROMYCIN Methylated Erythromycin More potent for ____________ More ____________ in gastric acid and has improved oral absorption Use: Treatment of ulcers caused by ____________ w/ Omeprazole / Lansoprazole ○ AZITHROMYCIN Has a 15 membered macrocycle with ____________ For non-gonococcal urethritis (____________, LRTI, PID, ____________, Legionnaire’s) 40-68h half-life; prolonged because of extensive tissue sequestration and binding (high volume of distribution) Food ____________ absorption Hydrate Forms: Dehydrate (Zithromax®) Monohydrate (Azyth®) ○ ROXITHROMYCIN Semisynthetic macrolide derived from ____________ (+ N-oxime side chain) D. LINCOSAMIDES Properties: ____________-containing antibiotics Mechanism of Action (MOA): Binds to 50s ribosomal subunit DRUGS: ○ LINCOMYCIN Source: ________________________ ○ CLINDAMYCIN 7-chloro-7-deoxy derivative of lincomycin Potent drug for ________________________ S/E: Clostridium difficile induced pseudomembranous colitis TX: ____________, ____________ E. CHLORAMPHENICOL Source: ________________________ Mechanism of Action (MOA): Binds to 50s ribosomal subunit, inhibiting peptidyl transferase DOC: ____________ – New: ____________ + Palmitic Acid = Chloramphenicol palmitate (reduced bitterness) S/E: ____________, ____________ Toxicophore: Nitro group F. STREPTOGRAMINS Mechanism of Action (MOA): Binds to different regions of the 50s subunit and form a complex with it DRUGS: ○ PRISTINAMYCIN Source: ________________________ ○ QUINUPRISTIN Derived from ____________ Mechanism of Action (MOA): Inhibits peptide chain ____________ ○ DALFOPRISTIN Derived from ____________ Mechanism of Action (MOA): Interferes with the transfer of the ____________ from one tRNA to the next G. LINEZOLID Classified under ____________, synthetic antibiotics Mechanism of Action (MOA): Binds to ____________ ribosomal subunit, preventing the formation of the 70s DOC: ____________ IV. INHIBITION OF DNA REPLICATION A. QUINOLONES Properties ○ Patterned after Nalidixic Acid (____________) – parent structure ○ Synthetic antibacterial agent Mechanism of Action (MOA): ○ Inhibition of DNA synthesis ○ Inhibits DNA gyrase (topoisomerase II) Topoisomerase II – responsible for introducing ____________ supercoils into the circular duplex DNA GENERATIONS OF QUINOLONES GENERATION DRUGS ACTIVITY 1st Gen Moderate Gm (-) activity 2nd Gen Improved activity against Gm (-), has activity against Gm (+) and atypical microorganisms 3rd Gen Retained Gm (-) activity, improved Gm (+) and atypical activity 4th Gen Retained Gm (-), Gm (+), and atypical activity, added activity against anaerobic microorganisms STRUCTURE ACTIVITY RELATIONSHIP Nucleus: 1,4 dihydro-4-oxo-3 pyridine carboxylic acid – essential for ____________ activity Pyridone system must be annulate with an aromatic ring = it should have an aromatic ring 1: ____________ substitution at the 1 position is essential for activity, with lower alkyl (methyl, ethyl, cyclopropyl) compounds generally having progressively greater potency 1: ____________ substitution at the 1 position is also consistent with antibacterial activity, with a 2,4 difluoro phenyl group providing optimal potency 2: Addition of groups greatly ____________ or ____________ activity 5, 6, 7 (especially), 8: May be substituted with ____________ 6: Addition of F increases antibacterial activity ○ ____________ – broad spectrum (+, -) 7: Addition of ____________ provides activity against P. aeruginosa 8: Addition of Halogen = photosensitivity ○ Lomefloxacin – ____________ ○ Sparfloxacin – ____________ Ring condensations at the 1,8-, 5,6-, 6,7-, and 7,8- positions also lead to active compounds (ex. Levofloxacin, Ofloxacin) INTERACTIONS Enzyme inhibitor Products containing ____________ and ____________ SIDE EFFECTS Photosensitivity GI irritation Rare: CNS Effects – attributed to the antagonism of ____________ receptors in the brain B. NITROFURANS Properties ○ Nitro heterocyclic compounds ○ Derivatives of 5-nitro-2-furaldehyde Mechanism of Action (MOA): Inhibits ________________________ Structure Activity Relationship (SAR): Nitro at 5th position = antibacterial activity DRUGS: ○ NITROFURANTOIN Used in ____________ Urinary antiseptic Brown / dark yellow ____________ ○ NITROFURAZONE Used topically in ____________ ○ FURAZOLIDONE Taken ____________ Used in bacterial or protozoal ____________ ○ METRONIDAZOLE Effective against trichomonas, ____________, giardia, anaerobic bacteria DOC: Clostridium difficile induced pseudomembranous colitis V. INHIBITION OF CELL METABOLISM A. SULFONAMIDES History Discovered by ____________ Studied a bright red dye, ____________, which was metabolized in vivo to sulfanilamide Mechanism of Action (MOA): Inhibits dihydropteroate synthetase, thus preventing folic acid synthesis Active Form: ____________ Structure Activity Relationship (SAR) Para-amino group (N4) is essential for activity and must be unsubstituted The ____________ ring and the sulfonamide FG are both required Both the sulfonamide and amino group must be directly attached to the aromatic ring The aromatic ring must be ________________________ The sulfonamide nitrogen must be ____________ or ____________ Side Effects: Crystalluria, hypersensitivity (SJS), hemolytic anemia in G6PD, nausea, kernicterus DRUGS: SULFASALAZINE ○ Prodrug of 5-aminosalicylic acid ○ Used in ____________ CO-TRIMOXAZOLE ○ Sulfamethoxazole + Trimethoprim ○ Synergistic ○ Use: 1st attack of ____________, DOC: P. carinii pneumonia CO-TRIMAZINE ○ ____________ + ____________ SULFADIAZINE + PYRIMETHAMINE ○ Used in ____________ SULFADOXINE + PYRIMETHAMINE ○ Used in ____________ SILVER SULFADIAZINE + MAFENIDE ○ Used in ____________ B. SULFONES Mechanism of Action (MOA): Inhibits dihydropteroate synthetase DRUG: ○ DAPSONE DOC: ____________ CI in G6PD deficiency May cause ____________ C. MISCELLANEOUS AGENTS DRUGS: METHENAMINE (UROTROPIN) ○ Urinary antiseptic used in ____________ ○ Formaldehyde release in low pH is required for antibacterial effect – given with ____________ agents (____________) to optimize the effect ○ Certain bacteria produce urease, causing resistance – give acetohydroxamic acid (____________), a urease inhibitor TOPIC 10: ANTIMYCOBACTERIAL DRUGS A. TUBERCULOSIS FIRST LINE DRUGS RIFAMPICIN ○ Rifampin, R ○ Source: ____________ ○ Mechanism of Action (MOA): Inhibits ____________ Nucleic acid synthesis inhibitor ○ Most active agent in clinical use ○ S/E / Interactions: ____________________________________ ISONIAZID ○ Aka Isonicotinic acid hydrazine (INH), H ○ Mechanism of Action (MOA): Inhibits the synthesis of mycolic acid ○ S/E: ________________________ – due to the competition of INH with pyridoxal PO4 for the enzyme apotrytophanase); TX: Vit B6 ____________ PYRAZINAMIDE ○ Pyrazinecarboxamine (PZA), Z ○ Mechanism of Action (MOA): ____________ ○ First line drug for short term treatment ○ Prodrug of pyrazinoic acid ○ S/E: ________________________ ETHAMBUTOL ○ Mechanism of Action (MOA): Inhibits ________________________ → inhibition of the formation of mycobacterial cell wall ○ S/E: ________________________ STREPTOMYCIN ○ ____________ antibiotic effective in the treatment of tuberculosis ○ S/E: ____________ SECOND LINE DRUGS CAPREOMYCIN ○ Source: ____________ ○ S/E: Ototoxicity, nephrotoxicity 4-AMINOSALICYLIC ACID ○ Aka Para-amino-salicylic acid (PAS) ○ Mechanism of Action (MOA): Inhibits dihydropteroate synthetase ○ One of the very first drugs for TB ○ S/E: ____________ ETHIONAMIDE ○ Analog of ____________ ○ For isoniazid-resistant TB ○ S/E: ________________________________________________ B. LEPROSY Clofazimine (Lamprene) ○ A phenazine red dye ○ MOA: bind to ____________ ○ Used in Dapsone resistant lepromatous leprosy ○ s/e: ________________________ Dapsone Rifampicin For tuberculoid leprosy (mild), dapsone + rifampicin is given. However, for lepromatous leprosy (severe), clofazimine is added to the regimen. TOPIC 11: ANTIFUNGAL DRUGS ANTIFUNGAL DRUGS General Mechanism of Action (MOA): Inhibition or ergosterol; synthesis injury to cell membrane ANTIFUNGALS For ________________________ ○ Griseofulvin, Nystatin, Topical Azoles, Terbinafine, Naftifine, Whitfield’s Ointment, Selenium sulfide For ________________________ ○ Ketoconazole, Fluconazole, Itraconazole For ________________________ ○ Amphotericin B, Itraconazole, Caspofungin, Voriconazole, Flucytosine TOPICAL AGENTS FOR DERMATOPHYTES ____________ – present in perspiration at low concentration (0.1%) ____________ – from destructive distillation of castor beans (Ricinus communis) ____________ – from caprylic acid (in coconut and palm oil) A. POLYENES Mechanism of Action (MOA): ○ Pore formation ○ Binds to ____________ = disrupts membrane function = cell death A.1. AMPHOTERICIN B Gold standard Source: ________________________ DOC for systemic mycoses S/E: Reversible azotemia – monitor ____________ A.2. NYSTATIN Source: ________________________ DOC for candida infections A.3. NATAMYCIN Source: ________________________ B. AZOLES Mechanism of Interaction (MOA): Inhibition of ____________ synthesis through the interaction with lanosterol 14α-demethylase to block demethylation of lanosterol to ergosterol in membranes Structure Activity Relationship (SAR) ○ Imidazole or 1,2,4-triazole ring bonded by a N-C linkage ○ 2 or 3 aromatic rings increases potency ○ Addition of halogen increase potency Groups of Azoles (Based on Structure): ○ Triazole: ____________ ____________ ____________ ____________ ○ Imidazole: ____________ ____________ ____________ ____________ ____________ B.1. KETOCONAZOLE Nizoral® ____________ Inhibits androgen and adrenal steroid synthesis – S/E: ____________ Needs acidic pH to be absorbed B.2. ITRACONAZOLE ____________ Alternative to Ketoconazole Not hepatotoxic, no adrenal suppression Needs ____________ to increase absorption B.3. FLUCONAZOLE Diflucan®, PO/IV Lipophilic – crosses ____________ DOC & Prophylaxis: Cryptococcal meningitis B.4. POSACONAZOLE Broad acting synthetic antifungal Structurally similar to ____________ S/E: GI disturbances, N&V, diarrhea, HA B.5. VORICONAZOLE Broad acting synthetic antifungal Structurally similar to ____________ DOC for invasive ____________ S/E: Visual and auditory hallucinations, hepatotoxicity C. ECHINOCANDINS Mechanism of Action (MOA): Inhibits synthesis of ____________, thus inhibiting fungal cell wall synthesis Potent against Aspergillus and most Candida species S/E: ____________ (Rapid infusion) Drugs: ○ ____________ ○ ____________ ○ ____________ OTHER ANTIFUNGALS FLUCYTOSINE ○ Mechanism of Action (MOA): Inhibits ________________________ by replacing uracil in nucleic acid synthesis (both DNA and RNA) ○ Nucleoside antifungal (pyrimidine antimetabolite) ○ ____________ ○ Used in combination with Amphotericin B in Cryptococcal meningitis GRISEOFULVIN ○ Source: ________________________ ○ Mechanism of Action (MOA): Interacts with the microtubule within the fungus and inhibits mitosis (____________) ○ Mitotic spindle / microtubule poison ○ DOC for refractory ringworm infections of the body, nails, hair, and feet Long duration of treatment (3-6 mos) ○ Poor bioavailability – solution: micronized, take with ____________ to increase absorption TOPIC 12: PARASYMPATHETIC SYSTEM junction PARASYMPATHETIC SYSTEM run Y Aka ____________ Cholinergic system NT: Acetylcholine (ACh) -G-protein-coupledLigand-gated Receptors: ____________ Muscarinic (M), ____________ Nicotinic (N) Metabolism: ____________ Acetylcholinesterase (AChE) BIOSYNTHESIS OF ACETYLCHOLINE 1. L-serine → Ethanolamine ○ Enzyme: ________________________ Serine decarboxylase 2. Ethanolamine → Choline ○ Enzyme: ________________________ Choline-N-methyl transferase 3. Choline → Acetylcholine ○ Enzyme: ________________________ choline-acetyl (ChAT) transferase METABOLISM OF ACETYLCHOLINE 1. ACh → Choline + Acetic Acid; Enzyme: AChE ○ Cholinergic Agonists ACh – prototype Problems: ____________ prone to hydrolysis ____________ Non-selective Requirements: Stability to stomach HCl and esterases 2. Selectivity for cholinergic receptors – SAR: ACh ○ A. Addition of Carbamate – less prone to susceptibility More stable ester, resulting to long-acting effect Used for ____________ glaucoma ○ B. Addition of Alkyl group – less prone to susceptibility and more selective to muscarinic than nicotinic More stable on muscarinic over nicotinic receptors Used for the diagnosis of ____________ asthma ○ Combination of A and B More selective on muscarinic over nicotinic receptors Used to stimulate ________________________ GIT and urinary bladder after surgery BIOSYNTHESIS OF NEUROTRANSMITTERS 1. Tyrosine → L-DOPA ○ Enzyme: ________________________ Tyrosine hydroxylase 2. L-DOPA → Dopamine ○ Enzyme: ________________________ Aromatic 1-Amino acid decarboxylase 3. Dopamine → Norepinephrine ○ Enzyme: ________________________ Dopamine B-hydroxylase 4. Norepinephrine → Epinephrine > adrenaline - ○ Enzyme: ________________________ Phenyl ethanolamine N-methyl transferase (PENMT) ○ ____________ Norepinephrine – DOC for septic shock ○ ____________ Epinephrine – DOC for anaphylactic shock ○ ____________ Dobutamine – DOC for cardiogenic shock METABOLISM OF NEUROTRANSMITTERS 1. Norepinephrine / Epinephrine vanillylmandelic Acid (VMA) ○ MAO and COMT → ________________________ 2. Dopamine ○ MAO and COMT → ________________________ Homovanillic Acid (HVA) STRUCTURE ACTIVITY RELATIONSHIP (SAR) 1. Parent Structure: β-phenyl ethylamine 2. 2 Carbon atoms separate the aromatic ring and the amino group 3. Optical Isomerism: 1R Configuration – more potent 4. Substitution on N: Increase in size and bulkiness ○ ________________________ Increased B agonist activity - ○ ________________________ Reduced Br > CF3 > Cl Substitution on 6, 8, and 9 = ____________ ↓ activity If ____________ Ring A is a heterocyclic ring = weaker activity and affinity compared to an aromatic ring ON RING B: Proton accepting group (carbonyl oxygen) at 2 position is necessary to interact with the receptor ____________ histidine + OH in 3 position – ____________ excretedFaster + Alkyl subs in 3 position – ____________ ↓ activity ON RING C: ____________ 5-phenyl ring ( – not required for binding to the receptor but contributes favorable steric or hydrophobic reactions to receptor binding Substitution at para – ____________ ↓ activity Substitution at meta – ________________________ not detrimental to agonist activity FUSED RINGS ON B: Annelating the 1,2- bond of ring B with an additional e- rich ring such as ____________ triazole or ____________ imidazole results in pharmacologically active BZP derivatives with high affinity to the receptor A.1. TRIAZOLOBENZODIAZEPINES BZD fused with triazolo ring ____________ short acting Ex: ____________, Triazolam ____________ Alprazolam A.2. IMIDAZOBENZODIAZEPINE BZD fused with ____________ imidazole ring Short acting Ex: ____________ Midazolam B. BARBITURATES Was used extensively Mechanism of Action (MOA): Increase the ____________ duration of ____________ GABA mediated chloride ion channel opening ↳ inhibitors effects in the CNS STRUCTURE ACTIVITY RELATIONSHIP Nucleus: 2,4,6-triohexahydropyrimidine (Barbituric acid) At 5, + Alkyl/aryl groups confer activity At 2, if S replaces O = thiobarbiturates: ○ ____________ Rapid CNS penetration ○ Short duration of action ○ More lipid soluble (very high lipid water partition coefficient ○ Ex: ____________ Thiopental S- Barbiturates : BarbiDuration moa = Benzfrequency Benzodiazepine - TOPIC 14: ANTIPSYCHOTICS A. TYPICAL ANTIPSYCHOTICS 1. Phenothiazines ○ ____________: Aliphatic Chlorpromazine, Promazine, Triflupromazine ○ ____________: Piperidine Thioridazine, Mesoridazine, Piperacetazine ○ ____________: Piperazine Fluphenazine, Perphenazine, Trifluoperazine ○ ____________: Butgrophenone Haloperidol, Droperidol 2. Thioxanthenes: Thiothixene, Chlorprothixene, Flupentixol PHENOTHIAZINES ____________, 6-6-6 system two benzenes are linked by S and N At 2, + EWG subs = ↑EN ↑ activity Position 10 and amino nitrogen must be separated by a 3-carbon chain 2 carbon chain (↑ antihistamine and anticholinergic effect) Ex: ____________ Promethazine Amine is always ____________ tertiary BUTYROPHENONES At C4, + tertiary amino group = essential for ____________ neuroleptic activity ○ Highest activity if cyclic form ____________, p-fluor aids activity (fluorobutyrophenones) Modification of the 3-carbon propyl chain ____________ decreases neuroleptic potency B. ATYPICAL ANTIPSYCHOTICS 1. Dibenzoazepine: ____________ Loxapine 2. Dibenzodiazepine: ____________ clozapine 3. Dibenzothiazepine: ____________ Quetiapine 4. Benzoxazole: ____________ Risperidone 5. Thienobenzodiazepine: ____________ olanzapine 6. Dihydroindolone: ____________ Ziprasidone 7. Dihydrocarbostyril: ____________ Aripiprazole 8. Benzamide: ____________ Amisulpride TOPIC 15: ANTIDIABETIC AGENTS INSULIN B- cells Produced by ____________ of the pancreas Promotes the absorption of glucose Hexamer – storage form ____________ Monomer ____________ – absorbed form; interacts with the insulin receptor CATEGORIES OF INSULIN 1. RAPID ACTING INSULIN Humalog ○ Insulin Lispro (____________) Lysine and proline exchanged at positions B28 and B29 Stabilized by cresol preservative into hexamers Novolog ○ Insulin Aspart (____________) Formed by replacement of proline at B28 with aspartic acid ○ Insulin Glulisine (____________) Apidra Glutamic acid replaces lysine at B29, and lysine replaces asparagine at B3 2. SHORT ACTING INSULIN ○ Regular Insulin · Soluble crystalline Zn insulin ____________ Only IV 3. INTERMEDIATE ACTING INSULIN ○ Neutral Protamine Hagedorn/ NPH/ Isophane Insulin ○ Suspension of insulin in a complex w/ Zn and protamine in PO43- buffer In insulin ○ Insulin ____________ ○ Mixture of crystallized and amorphous form of insulin in acetate buffer 4. LONG-ACTING INSULIN Lantus ○ Insulin Glargine (____________) Asparagine at A21 replaced with glycine Levemir ○ Insulin Detemir (____________) Terminal threonine is dropped and myristic acid is attached to the B29 lysine ○ Insulin Degludec (____________) Tresiba Threonine at B30 is removed and the lysine at B29 is conjugated to hexadecenoic acid TOPIC 16: ANTINEOPLASTIC AGENTS ANTINEOPLASTIC AGENTS Prevents, inhibits, or halts the development of a neoplasm or tumor Tumor / Neoplasm – collection of abnormally proliferating cells ○ ____________ Benign – does not invade surrounding tissues ○ ____________ Malignant – invade and metastasize to all parts of the body Solid Tumors: carcinoma ○ ____________ – epithelial cells ○ Sarcoma – connective tissues ○ ____________: Bone Osteosarcoma ○ Muscles: Leiomyosarcoma Hematologic Malignancies: ○ Lymphoma – lymphatic system ○ ____________ Leukemia – blood forming elements Etiology of Cancer: ○ Viruses ○ Environmental and occupational exposure Ionizing and UV rad Vinyl chloride, asbestos, benzene ○ Lifestyle factors ○ Medications ○ Genetic factors Warning Signs of Cancer: (ACS) ○ Change in bowel or bladder habits ○ ________________________ non-healing sore ○ Unusual bleeding / discharge ○ Thickening or lump in breast or elsewhere ○ Indigestion or difficulty swallowing ○ ________________________ Obvious change in a wart or mole ○ Nagging cough or hoarseness Screening: ○ Mammography ○ ________________________ Fecal - occult Blood test (FOBT) ○ Papanicolaou Test (Pap Smear) ○ ________________________ Digital Rectal Exam(DRE) Tumor Markers ○ Colorectal: Carcinoembryonic antigen (CEA) ○ Prostate: PSA / High acid phosphatase ○ Breast: ________________________ ER PR CA15-3 HER-2 , , , ○ Liver: Alpha-feto protein (AFP) ○ Ovarian: ____________ CA-125 Cell Cycle Non-Specific Agents – are not dependent on the cell being in a particular phase of the cell cycle for them to work; they affect cells in all phases of the cell cycle Cell Cycle Specific Agents – act on the cells in a specific phase PHASES OF CELL CYCLE ____________ Go/Resting Phase – cell is not committed to division ____________ 61 phase ?
