Pharmaceutical and Medicinal Organic Chemistry PDF Past Paper

8/23/2021 OUR LADY OF FATIMA UNIVERSITY COLLEGE OF PHARMACY Checklist:...

8/23/2021 OUR LADY OF FATIMA UNIVERSITY COLLEGE OF PHARMACY Checklist: Read course and unit objectives. Pharmaceutical and Medicinal Read study guide prior to class attendance. Read required learning resources, refer to unit terminologies Organic Chemistry for jargons. PSMA 411 Proactively participate in discussions. Answer and submit unit course tasks. Learning Outcomes: Topic Outline: At the end of this unit, the students are expected to: I. History of Medicinal Chemistry Demonstrate knowledge on history of medicinal II. Drug Discovery and Drug Product Development chemistry and its importance to drug development. III. Phase I Metabolism IV. Phase II Metabolism Basic studies of chemistry and physics shifted from Greco-Roman to Arabian History: History: Alchemy Drugs of Antiquity Middles Ages Paracelsus glorified Sb as cure-all in the belief that chemical could cure diseases Shen Nung -Ch’ang shang, ma huang 19th Century: American Indians -Chaulmoogra fruit Age of Innovation and Chemistry From finding new medicaments from vast world of plants to Brazil Ma huang Chaulmoogra fruit finding the Active Ingredient that accounted for their -Ipecacuanha root pharmacologic properties South American Indians 1805 Friedrich Sertürner extracted morphine from poppy -Coca leaves 1810 Samuel Hahnemann on his unproven principle Greek Apothecary Ipecacuanha root Coca leaves “similia similibus curantur” -opium, squill, hyoscyamus, doctrine that any drug capable of producing detrimental symptoms in healthy individuals will relieve similar viper toxin, Cu, Zn ores, Fe symptoms occurring as an expression of disease. sulfate, Cadmium oxide 1  8/23/2021 19th Century: 20th Century: Age of Innovation and Chemistry Pharmaceutical Industry Rise of synthetic chemotherapeutic agents 1816 Pierre-Pelletier – isolated emetine from Ipecacuanha 1820 Purification of caffeine, quinine and colchicine 1929 Alexander Fleming – Penicillin discovery 1826 Mass production of Quinine Sulfate 1932 Gerhard Domagk – Prontosil / Sulfamidochrysoidine 1845 Adolph Kolbe – acetic acid synthesis 1940 Bacteriostatic action of Sulfonamide-like drugs 1878 British pharmacologist John – concept of biological receptor 1886 First alkaloid synthesis – coniine 1897 Paul Ehrlich – sidechain theory 1898 First mass production of synthetic drug – Aspirin Psychopharmacologic Agents and Era of Endocrine Therapy Brain Research and Steroid Discovery of Chlorpromazine -single most important 1904 Henry Dale – Oxytocin breakthrough in psychiatric 1914 Edward Kendall – Thyroxine treatment 1921 Frederick Banting and Charles Best – Insulin Chlorpromazine Iproniazid Discovery of Iproniazid 1930 Russell Marker – converted Diosgenin to Progesterone -antidepressant 1950 Carl Djerassi – Noerthindrone Imipramine Imipramine Fluoxetine 1956 John Rock – Progesterone + Noerthindrone -first dibenzazepine 1980 Mifepristone – abortion pill Fluoxetine 1994 Mifepristone + Misoprostol – morning-after pill -first commercially successful SSRI Anesthetics and Analgesics Hypnotics and Anticonvulsants Horace Wells Laudanum -dentist who administered Nitrous - Induces sleep oxide during tooth extraction Bromides, chloral hydrate, Crawford Long paraldehyde, urethane and sulfenal Phenobarbital -used ether as an anesthetic agent 1864 – Adolph Von Beyer – William Morton synthesized 5,5-diethylbarbituric acid -gave the first successful public Bayer Pharm’l Company demonstration of surgical anesthesia - Introduced Phenobarbital (Luminal) Phenytoin (1846) Hydantoins Chloroform - Developed due to modification of -used as anesthetic agent at St. the barbituric acid molecule Bartholomew’s Hospital 2  8/23/2021 Drugs Affecting Renal and Local Anesthetics Cardiovascular Function 1860 – Albert Niemann isolated cocaine 1775 William Withering discovered Digitalis purpurea was Carl Koller beneficial to those suffering from abnormal fluid -First to use cocaine for topical buildup anesthesia in ophthalmological 1841 E. Humolle and T. Quevenne isolated digitoxin surgery 1973 Akira Endo – discovered the first anticholesterol drug Richard Willstater -determined the structure of cocaine 1978 Merck – discovered Lovastatin and atropine 1929 Sydney Smith isolated digoxin Benzocaine, procaine, tetracaine and lidocaine -structural analogs of cocaine Anticancer Agents Pop Quiz Sulfur mustard and nitrogen mustard 1. What is the most widely used cardiac glycoside? DIGOXIN -used for leukemia therapy 2. Who is the dentist who administered Nitrous oxide during tooth 6-mercaptopurine extraction? -first effective leukemia, discovered by George 3. Root found in Brazil that is used for the treatment of dysentery? Hitchings and Gertrude Elion IPECACUANHA 1893 -Cisplatin gold standard 1963 -Paclitaxel discovered by Moeroe Wall and Masukh Wani A scientific discipline at the intersection Quantitative Structure-Activity Organic of chemistry and pharmacy involved with Relationships (QSAR) Pharmaceutical designing, synthesizing and developing Chemistry pharmaceutical drugs. is a strategy of the essential importance for chemistry and It also includes the study of existing pharmacy, based on the idea that when we change a drugs, their biological properties, and structure of a molecule then also the activity or property of the substance will be modified. their Quantitative Structure-Activity Relationships (QSAR). Medicinal Involves the identification, synthesis and development of new chemical entities Chemistry suitable for therapeutic use. Pharmaceutical Focused on quality aspects of medicines and aims to assure fitness for the Chemistry purpose of medicinal products 3  8/23/2021 Drug Development Process Drug Development Process 1. Discovery Phase – includes synthesis, isolation, fermentation, Ways of Discovering a Lead Compound screening, SAR studies i. Choosing a disease 1. Screening of natural products ii. Choosing a drug target 2. Medical Folklore 2. Choosing a drug target Depend on finding the drug first 3. Screening synthetic banks Discovery of the chemical messenger 4. Combinatorial synthesis 3. Identifying a bioassay 5. Computer-aided design In vivo – including a clinical condition and treated with the test drug 6. Serendipity and prepared mind In vitro – drug activity is tested on isolated tissues or cells 7. Use of NMR 4. Finding a lead compound compound showing a desired pharmacological property which can be used 8. Existing Drugs to initiate a medicinal chemistry project Drug Development Process 5. Isolate and purify the lead compound. 6. Determine the structure – NMR, IR, spectroscopy, X-ray crystallography, LC-MS 7. Identify the structure-activity relationship – in vitro 8. Identify the pharmacophore 9. Improve target interaction and pharmacokinetic properties 10. Study drug metabolism and test for toxicity 11. Design a manufacturing process Drug Development Process Drug Development Process Preclinical Studies Preclinical Studies Pharmacology the science of the properties of the drugs and its a sponsor evaluates the drug's toxic and pharmacologic effects effects in the body through in vitro and in vivo laboratory animal testing. Genotoxicity screening is performed, as well as investigations on Pharmacodynamics the study of the interaction of drugs with cells drug absorption and metabolism, the toxicity of the drug's Pharmacokinetics the handling of a drug within the body, it includes metabolites, and the speed with which the drug and its the ADME processes metabolites are excreted from the body. Toxicity Testing in vitro and in vivo testing , determination of LD 50 the FDA will generally ask, at a minimum, that sponsors: Pharmaceutics the general area of study concerned with the  develop a pharmacological profile of the drug; formulation, manufacturing, stability and  determine the acute toxicity of the drug in at least two effectiveness of a pharmaceutical dosage form species of animals  conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies. 4  8/23/2021 Drug Development Process Drug Development Process File IND Application Clinical Trials Filed before drug may be given to human (clinical trials) Phase Number of Length Purpose % special consideration is given on Orphan drugs (treatment Patients Successfully IND) completing orphan drug is used to treat orphan disease, or disease I 20-100 Several months Mainly safety 67 that affects fewer than 200,000 people in the US II Up to several Several month Some short- 45 Submitted to FDA  Review by FDA for 30 days hundred to 2 years term safety but mainly effectiveness III Several 1-4 years Safety, 5-10 hundred to effectiveness, several dosage thousand Drug Development Process Drug Development Process New Drug Application Postmarketing Surveillance Submission of New Drug Application (NDA) Phase 4 NDA is submitted for review and approval after the post-marketing studies and manufacturing scale-up completion of the clinical trials and requirements have activities take place been met. Modification on drug formulation as obtained from Give permission to market drug product manufacturing scale-up and validation process may be done ANDA – Abbreviated NDA (Generic drug) Pop Quiz Metabolism / Biotransformation plays a central role in the The following are submitted during what point in the drug elimination of drugs and other Inactive development process? foreign compounds 1. IND (xenobiotics) from the body 2. NDA an essential tool for 3. ANDA pharmacists in their role of Active Pare Prodrugs selecting and monitoring appropriate drug therapy for nt Detoxification their patients drug Occur at some point between Non toxic absorption into the circulation and its renal elimination Toxic 5  8/23/2021 Metabolism / Biotransformation Liver – main site of metabolism and detoxification of endo/exogenous compounds – Rich in almost all of drug-metabolizing enzymes PO drugs – pass thru the liver before being further distributed in body compartments First-Pass Effect – Metabolism before reaching systemic circulation – Limit the BA of orally administered drugs Extrahepatic Metabolism – Intestine, kidney, lungs, adrenal glands, placenta, brain, skin – Substrate specific Metabolism / Biotransformation Phase I Reactions Phase I Reactions Phase II Reactions Functionalization phase – polar functional groups are introduced into the molecule or unmasked by: Goals Goals Oxidation, Reduction and Hydrolysis – Produce a more water- – Attach polar, ionizable soluble compound endogenous compounds ⚫ by direct introduction of the Example: aromatic and aliphatic hydroxylation Glucuronidation functional group – Produce a molecule that can undergo subsequent Sulfation ⚫ by modifying or "unmasking" Examples: phase II reactions Glycine conjugation existing functionalities ⚫ reduction of ketones and aldehydes to – Terminate or attenuate alcohols biological activity ⚫ oxidation of alcohols to acids Methylation ⚫ hydrolysis of ester and amides to yield Alkylation COOH, NH2 and OH groups; reduction of – Protect body against azo and nitro compounds to give NH2 chemically reactive moieties; oxidative N-, O- And S- compounds dealkylation to give NH2. OH and SH GSH conjugation groups). Reactions Under Phase I Reactions Under Phase I Oxidation Microsomes Most are mediated by microsomes. form in vitro after cell homogenization Although oxidation would seem to and fractionation of ER Flavoprotein Cytochrome P450 imply the addition of oxygen, that is – Rough microsomes are primarily One mole of this enzyme Name based on light abs at not always the case. associated with protein synthesis contains one mole each of flavin 450nm when complexed with Oxidation may refer to the change in – Smooth microsomes contain a mononucleotide (FMN) and CO oxidation state of the substrate. class of oxidative enzymes called flavin adenine dinucleotide Hemoprotein containing an iron MFOs (FAD) atom which can alternate Two types of oxidation reactions: – Oxygen is incorporated into the MFO Requirements Electron donor NADPH – cytochrome P450 between ferrous (Fe+2) and ✔Reducing Agents reductase ferric (Fe+3) states drug molecule 1. NADPH (Nicotinamide Adenine Serves as terminal oxidase (e.g. hydroxylation) Dinucleotide Phosphate) – Oxidation causes the loss of part of 2. Molecular Oxygen the drug molecule Electron transporter ―One oxygen molecule appears Electron acceptor (e.g. oxidative deamination, in the product dealkylation) ―Other oxygen in the form of No substrate water specificity 6  8/23/2021 Human Liver P450 Cytochrome P450 cycle in drug oxidations enzymes CYP isoform Substrates 3A4 APAP, Erythromycin, Lidocaine, Lovastatin, Responsible for Miconazole, Quinidine, Verapamil metabolism of over 50% of prescription drugs metabolized by the liver 2D6 Clozapine, codeine, Desipramine, Dextromethorphan, Fluoxetine, Haloperidol, Oxycodone, Paroxetine, Propafenone 2C8 Taxol, Retinoic Acid Derivatives 2C9 Celecoxib, Diclofenac, Ibuprofen, Losartan, Phenytoin, Tolbutamide Aromatic ROS POP QUIZ Hydroxylation Name based on light abs at 450nm when complexed with CO refers to the mixed-function oxidation of aromatic Microsomes that are primarily associated with protein synthesis compounds (arenes) to their corresponding phenolic Most common Phase I metabolic pathway metabolites (arenols) proceed initially through an epoxide intermediate called an "arene oxide” which rearranges rapidly and spontaneously to the arenol NIH Shift leading to the formation of arenols May also acted upon by epoxide hydrases leading to the formation of trans-dihydrodiols Or be acted upon by sulfhydryl group in GSH to yield GSH adduct It is important to prevent the formation of ROS by arene oxides Aromatic Examples of drugs that undergo Hydroxylation Aromatic Hydroxylation in humans Major route of metabolism for phenyl- containing drugs -OH Hydroxylation occurs at the para position | Microsomal aromatic OH hydroxylation reactions appear to proceed most readily in activated (electron-rich) rings Drugs containing electron withdrawing groups Cl, - NR3, COOH, SO2NHR) 7  8/23/2021 Examples of drugs that undergo Compounds with two aromatic rings Aromatic Hydroxylation in humans If there are two or more phenyl rings, hydroxylation proceeds in the electron rich ring Clonidine (Catapres) – The deactivating groups (Cl, -NH = C) Probenecid (Benemid) – electron-withdrawing grps: sulfamido grp There are certain compounds which are resistant to aromatic hydroxylation despite of the aromatic rings DUE TO presence of multi electronegative chlorine atoms attached to the rings Eg. Polychlorinated biphenyls (PCBs) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Oxidation of Olefins Olefinic Epoxidation The metabolic oxidation of olefinic carbon—carbon double bonds leads to the corresponding epoxide (or oxirane). Carbamazepine (Tegretol) The epoxide is cleaved by epoxide hydrases to form trans-diols The epoxide is reasonably stable and can be measured There are inhibitors such as cyclohexene oxide and trichloropropene quantitatively in the plasma of patients receiving the parent Epoxides drug – more stable than the arene oxides formed from aromatic compounds – susceptible to enzymatic hydration by epoxide hydrase to form trans-l,2- dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds Toxicity of olefinic compounds may result Green Pigments from their metabolic conversion to Protriptyline (Vivactil) Cyproheptadine (Periactin) abnormal heme derivative chemically reactive epoxide N-alkylated protoporphyrins – Aflatoxin – Allylisopropyl acetamide – DES – Secobarbital – Stilbene – Fluoroxene – Vinyl chloride Oxidation at Benzylic Carbon Atoms Oxidation at Allylic Carbon Atoms Carbon atoms attached to aromatic Allylic hydroxylation generally does not lead to the generation of reactive rings (benzylic position) are susceptible intermediates to oxidation, forming the alcohol (or carbinol) metabolite. ALLYL structural formula : 1⁰ alcohol metabolites are often H2C=CH-CH2R Primary alcohol oxidized further to aldehydes and metabolite - carbinol carboxylic acids (CH2OH → CHO → COOH), and secondary alcohols are converted to ketone. Eg. Tolbutamide (Orinase) Quinidine Eg. Tolmetin (Tolectin) 8  8/23/2021 Oxidation at Carbon alpha to Imine Oxidation at Aliphatic Carbon Atoms Carbonyl and Imine ⚫ Common to Metabolic oxidation at the terminal carbon is referred to as ω oxidation benzodiazepines Oxidation of the penultimate carbon atom (i.e., next-to-the-last carbon) is called ⚫ Oxidized to 3- ω— I oxidation hydroxy metabolites Benzodiazepine ring ⚫ Diazepam(Valium) ⚫ 3-hydroxy diazepam (also called N- methyloxazepam) ⚫ Flurazepam (Dalmane) ⚫ Nimetazepam are Anticonvulsants Oxidation Involving Carbon-Hetero POP QUIZ Systems Hydroxylation of the alpha-carbon atom attached directly to the Naturally occurring carcinogenic agent heteroatom (N, O, S). Other name for alkene Hydroxylation or oxidation of the heteroatom These are metabolized olefinic carbon—carbon double bonds that – (N, S only, e.g.. N-hydroxylation. N-oxide formation. sulfoxide. leads to the corresponding epoxide and sulfone formation) Oxidation Involving Carbon-Nitrogen Systems N-demethylation and oxygen deamination N-hydroxylation of secondary amines p and N-hydroxylation N-hydroxylation Oxidation Involving Carbon-Oxygen Systems Oxidative O-dealkylation Oxidation Involving Carbon-Sulfur Systems S-dealkylation Desulfuration S-oxidation reactions Oxidation Involving Carbon-Nitrogen Oxidation Involving Carbon-Nitrogen Systems Systems Three basic classes of nitrogen-containing Drugs containing nitrogen compounds – natural products Dealkylation of secondary Oxidative N- dealkylation morphine, cocaine, nicotine) amines gives rise to the 1. Aliphatic (primary, secondary, and tertiary) Other drugs corresponding primary and alicyclic (secondary and tertiary) amines – phenothiazines. antihistamines, amine metabolite tricyclic antidepressants, beta- 2. Aromatic and heterocyclic nitrogen adrenergic agents, phenylethylamines, N-deisopropylation compounds benzodiazepines 3. Amides Susceptible to either a-carbon hydroxylation or N-oxidation Primary aliphatic amines are biotransformed by oxidative deamination (through the carbinolamine pathway) or by N-oxidation. Enzyme: MFO Endogenous primary amines (e.g Dopamine,norepinephrine,tryptamine, and serotonin) Enzyme: MAO 9  8/23/2021 N-demethylation and Oxidative Deamination N-hydroxylation of secondary amines generates the corresponding N-hydroxylamine metabolites In primary aliphatic amines, such as phentermine, chlorphentermine and amantadine, N-oxidation appears to be a major biotransformation pathway because a-carbon hydroxylation cannot occur. N-hydroxylation p and N-hydroxylation 1 amine 🡪 [hydroxylamine] 🡪 nitroso 🡪 nitro Phentermine 2 amine 🡪 [hydroxylamine] 🡪 nitrone 🡪 Primary aromatic amines are oxidized to hydroxylamines then further oxidized to nitroso (Chlorphentermine, Aniline) Oxidation Involving Carbon-Oxygen N-hydroxylation Systems Amides Three basic classes of Drugs containing N- alkyl substituents are also dealkylated through N- nitrogen-containing nitrogen dealkylation compounds – natural products Hydroxylation also happens to the alpha carbon of the amide morphine, cocaine, nicotine) or phosphamide. 1. Aliphatic (primary, Other drugs secondary, and tertiary) and – phenothiazines. alicyclic (secondary and antihistamines, tricyclic tertiary) amines antidepressants, beta- 2. Aromatic and heterocyclic adrenergic agents, nitrogen compounds phenylethylamines, 3. Amides benzodiazepines Susceptible to either a- carbon hydroxylation or N- oxidation 10  8/23/2021 Oxidative O- dealkylation It involves the oxidation of the alpha carbon Oxidation Involving Carbon-Sulfur Systems S-dealkylation It also involves the alpha carbon hydroxylation Methiural GLUCURONIDATION H CARBONYL MOIETY H Desulfuration Sulfoxidation Thiono C=S 🡪 Carbonyl S-oxidation – (s- to sulfoxides to sulfone) Thiopenthal 🡪 Pentobarbital P=S 🡪 P=O Parathion 🡪 Paraoxon Oxidation of Alcohols and Aldehydes Reactions Under Phase I 2. Reduction Primary alcohol ------------🡪 Aldehyde – addition of hydrogen or Carbonyl reduction gain of electrons – alcohol play an important role in nitro, and azo reduction the metabolism of many – amino derivative compounds containing N-oxides carbonyl, nitro, and azo – tertiary amine group Sulfoxides Hydroxyl and amino groups are susceptible to – sulfides conjugation Disulfide – -SH + -SH Miscellaneous Reductions Reduction of N-oxides to tertiary amine Reduction of sulfur-containing carbinolamine functional groups, such as the disulfide (2-hydroxymedazepam) and sulfoxide 11  8/23/2021 Reductions of Carbonyl Containing Reductions of Carbonyl Containing Compounds Compounds Ketones are resistant to oxidation are reduced to Acetohexamide secondary alcohol – not recommended in diabetic patients with renal failure, because of the possible accumulation of its active metabolite hydroxyhexamide Aldehydes are reduced to form primary alcohol The (R)( + ) enantiomer of the oral anticoagulant warfarin undergoes extensive reduction of its side chain keto group to generate the (R,S)( +) alcohol as the major plasma metabolite Enzyme : aldo-keto reductases Reduction of Nitro and Azo Compounds Reduction of Nitro Compounds Leads to primary amine metabolites Clonazepam and Nitrazepam – are metabolized to 7-amino metabolites E.g – Clonazepam – Nirazepam Dantrolene – Dantrolene – Metronidazole Azo Reductions Reactions Under Phase I Proceed via a hydrazo intermediate (-NH-NH-) that is 3. Hydrolysis cleaved reductively to yield Ester hydrolysis the corresponding aromatic – reaction of water with amines: substrate resulting in – mediated by nonspecific breaking scissile carbon- esterases found in the heteroatom bonds) liver, kidney, and Prontosil intestine and pseudocholinesterases The reaction is frequently present in plasma enzyme - mediated although serum pH may Amide hydrolysis cause reaction. – mediated by liver major biotransformation pathway for drugs containing microsomal amidases. an ester functionality. Esterases and deacylases 12  8/23/2021 Hydrolysis Ester derivatives POP QUIZ Phase II Metabolism This is the active metabolite of acetohexamide. endogenous compounds that undergo conjugation reactions Acetohexamide is contraindicated in what patients? 1. Bilirubin These are susceptible to either a-carbon hydroxylation or N- oxidation 2. Steroids 3. Catecholamines 4. Histamine mediated by more specific transferase enzymes. Conjugated Products relatively water soluble and readily excretable biologically inactive and nontoxic Reactions under Phase II Two steps in the formation of B-glucuronides 1. Glucuronidation Two steps in the formation of B -glucuronides the most common conjugative pathway in drug metabolism for 1.Involves synthesis of an activated several reasons: coenzyme readily available supply of D- uridine-5'-diphospho-a-D- glucuronic acid glucuronic acid (UDPGA) numerous functional groups that can combine enzymatically with 2. subsequent transfer of the glucuronic acid glucuronyl group from UDPGA to an the glucuronyl moiety, when appropriate substrate attached to xenobiotic substrates, catalyzed by microsomal greatly increases the water solubility of the conjugated product enzymes called In neonates and children, UDP-glucuronyltransferases glucuronidating processes are Found primarily in the liver often not developed but also occur in kidneys, fullyaccumulation of drug  intestine, skin, lungs, and toxicity brain. 13  8/23/2021 Types of Compounds forming Oxygen, Nitrogen, Sulfur and Carbon Glucuronic Acid Conjugation Glucuronide functional groups undergoing glucuronidation: Phenolic hydroxyls Oxygen Glucuronides Hydroxyl compounds Morphine, Acetaminophen, Hydroxyphenytoin Phenols: morphine, acetaminophen, p-hydroxyphenytoin Alcohols: Tricholoroethanol, chloramphenicol, propranolol Enols: 4-hydroxycoumarin N-Hydroxyamines: N-Hydroxydapsone N-Hydroxyamides: N-Hydroxy-2-acetylaminofluorene Carboxyl compounds Aryl acids: benzoic acid, salicylic acid Arylalkyl acids: naproxen, fenoprofen Glucuronic Acid Conjugation Glucuronic Acid Conjugation Alcoholic hydroxyls Enols: N-glucuronides Carboxyl-Containing Compounds Trichloroethanol 4-hydroxycoumarin Aryl acids: benzoic acid, salicylic acid glucuronide glucuronide glucuronide glucuronide Chloramphenicol N-Hydroxyamines: N-Hydroxydapsone glucuronide Arylalkyl acids: Propranolol Naproxen Fenoprofen glucuronide glucuronide glucuronide glucuronide Glucuronic Acid Conjugation POP QUIZ Sulfur Glucuronide Sulfhydryl groups: methimazole, propylthiouracil, diethyithiocarbamic acid What phase of metabolism makes the drug more water soluble? glucuronide These are sufficiently polar metabolites that are readily excretable in the urine and are devoid of pharmacological activity and toxicity. glucuronide Chloramphenicol in neonates can produce? Carbon Glucuronides 14  8/23/2021 Reactions under Phase II 2. Sulfation Drugs susceptible to sulfate formation Sulfate Conjugation leads to water-soluble and inactive Alcohols metabolite (e.g.. aliphatic C1 to C5 alcohols, endogenous compounds that underogo diethylene glycol Drugs containing phenolic moieties sulfate conjugation: Aromatic Amines steroids, heparin, chondroitin, catecholamines, and thyroxine (e.g.. aniline, 2-naphthylamine) SO3 Two Steps in formation of B-glucoronides 1.involves activation of inorganic sulfate to O-sulfate conjugates of some N- hydroxy compounds give rise to toxic SO3 the coenzyme metabolites (hepatotoxic and ―3'-phosphoadenosine- nephrotoxic) 5'.phosphosulfate (PAPS). Sulfate conjugation of N hydroxy metab 2. Subsequent transfer of the sulfate  0-sulafte esters (ultimate group from PAPS to the accepting substrate carcinogenic agent) is catalyzed by various soluble sulfotransferases present in the liver and SO3 other tissues (e.g.. kidneys, intestine). For many phenols, sulfoconjugation may represent only a minor pathway. Reactions under Phase II Competes with Glucuronidation of phenols Eg. acetaminophen 3. Conjugation With Glycine,Glutamine and Other Amino Acids glycine and glutamine are used by mammalian systems to conjugate carboxylic acids, particularly aromatic acids and arylalkyl acids Glycine - mammals In adults: Glutamine – human Major metabolite: O-glucuronide conjugate not converted to activated co- O-sulfate conjugate formed in small amounts enzymes. Instead, the carboxylic acid substrate is activated with adenosine triphosphate (ATP) and In infants and young children (ages 3 to 9 co-enzymeA (CoA) to form an acyl- years) CoA complex 0-sulfate conjugate is the main urinary Acylation of glycine or glutamine product by N-acyltransferase (mitochondria of liver and kidney cells) Reactions under Phase II Reactions under Phase II 5. Acetylation constitutes an important metabolic route for drugs containing primary Terminate pharmacological amino groups 4. GSH Conjugation activity and detoxification primary aromatic amines (ArNH2) important pathway for Many industrial chemicals, such few reports indicate that Sulfonamides (H2NC6H4SO2NHR). detoxifying chemically reactive as benzyl chloride , allyl chloride acetylated metabolites may be as hydrazines (—NHNH2) electrophilic compounds active (N-procainamide) or more (CH2 = CHCH2CI). and methyl Hydrazides (—CONHNH2) GSH protects vital cellular toxic (N-acetylisoniazid) than constituents against chemically iodide are known to be toxic and primary aliphatic amines reactive species by virtue of its carcinogenic parent compounds The amide derivatives formed from nucleophilic sulfhydryl (SH) The acetyl group used in N- group. The reactivity of these three acetylation of these amino halides toward GSH conjugation acetylation of xenobiotics is functionalities are generally inactive and The SH group reacts with supplied by acetyl-CoA. electron-deficient compounds to in mammalian systems is nontoxic. form S-substituted GSH adducts demonstrated by the formation of Transfer of the acetyl group from Aromatic compounds with a primary catalyzed by a family of the corresponding mercapturic this cofactor to the accepting amino group such as: cytoplasmic enzymes known acid derivatives. amino substrate is carried out by as glutathione S-transferases Aniline (liver and kidney) Arene oxides and aliphatic soluble N-acetyltransferases p-aminobenzoic acid# GSH – tripeptide (y-glutamyl- epoxides (or oxiranes) represent a present in hepatic p-aminosalicylic acid cysteinylglycine) very important class of substrates reticuloendothelial cells procainamide(Pronestyl) that are conjugated and dapsone (Avlosulfon) detoxified by GSH. especially susceptible to N-acetylation. 15  8/23/2021 Acetylation Acetylation Polymorphism Rapid Acetylator Slow Acetylators Eskimos and Asians Egyptians and some Western more likely to show an European groups inadequate therapeutic more likely to develop adverse response to standard drug reactions doses Plasma halif-life plasma half-life (slow acetylators) is about 140 to 200 minutes (rapid acetylators) = ranges Greater Adverse effects: from 45 to 80 minutes peripheral neuritis and drug- more likely to develop induced systemic lupus isoniazid-associated hepatitis erythematosus syndrome) -to patients taking : hydralazine and procainamide Acetylation Reactions under Phase II 6. Methylation play an important role in the coenzyme involved: biosynthesis of many S-adenosylmethionine (SAM) endogenous compounds epinephrine and melatonin catalyzed by various cytoplasmic and microsomal and in the inactivation of Methyltrasferases numerous physiologically active catechol-O-methyltransferase biogenic amines (COMT) phenol-O-methyltransferase norepinephrine, dopamine, nonspecific N-methyltransferases serotonin, and histamine and S-methyltransferases Factors affecting Metabolism Age differences Species and strain differences Deficiency in enzymes metabolism of amphetamine occurs Leading to gray-baby syndrome by two main pathways: Neonatal hyperbilirubinemia human, rabbit,and guinea pig = oxidative deamination appears to Hereditary or genetic factors genetic be the predominant polymorphism Rat=aromatic hydroxylation Sex differences Enzyme differences Adult male rats metabolize faster Cats lack glucuronyltransferase Enzyme induction enzymes therefore through (phenobarbital induces sulfoconjugation glucuronyltransferases, cabbage, Pigs lack sulfoconjugation (no cauliflower and charcoal broiled sulfotransferase) foods Enzyme inhibition (chloramphenicol, isoniazid, disulfiram and GRAPEFRUIT) 16  8/23/2021 Diseases affecting Metabolism POP QUIZ Thyroid dysfunction This is used in humans to conjugate carboxylic acids. Hypothyroidism This play an important role in the biosynthesis of many endogenous inc t1/2 of Digoxin, Methimazole and B-blockers compounds such as epinephrine and melatonin. Biliary cirrhosis, alcoholic hepatitis, hemochromatosis, drug-induced Give 1 human race that are fast acetylators. hepatitis Significantly impair hepatic drug-metabolizing enzymes (microsomal oxidases) Chlordiazepoxide/Diazepam w/ increased t1/2 = may cause coma when given in normal doses Viral inf, CA, inflammation Impair drug metabolism by inactivationg P450s and enhancing their degradation Video Links: References: Organic Chemistry and Medicine Intro Lecture Wilson and Gisvold’s Textbook of Organic Medicinal and https://www.youtube.com/watch?v=ZjM-NO86JEE Pharmaceutical Chemistry pg. 3, 43, 88 Drug discovery and development process https://www.youtube.com/watch?v=3Gl0gAcW8rw Ansel’s Pharmaceutical Dosage Forms and Drug Delivery A guide to new medicines approval Systems https://www.youtube.com/watch?v=G4bxGG4PHbE Pharmacokinetics 4=Metabolism - https://www.youtube.com/watch?v=ztsBn8gsfHw CYP450 Enzyme Systems - https://www.youtube.com/watch?v=OhIopfQm9_w Phase II Metabolism - https://www.youtube.com/watch?v=iIWAUo05GFE Factors affecting drug metabolism including stereochemical aspects - https://www.youtube.com/watch?v=4RYGT5uBRTI OUR LADY OF FATIMA UNIVERSITY COLLEGE OF PHARMACY Thank you! Any questions? 17