Organic Medicinal Chemistry.pdf

Organic Medicinal Chemistry De La Salle Medical and Health Sciences Institute College of Pharmacy | Manor Review Center Course Outline...

Organic Medicinal Chemistry De La Salle Medical and Health Sciences Institute College of Pharmacy | Manor Review Center Course Outline Cardiovascular Drugs...................................................... 12 Phases of Metabolism......................................................... 2 I. Carbonic Anhydrase Inhibitor.......................... 12 I. Phase I / Functionalization................................. 2 II. Thiazides.............................................................. 12 II. Phase II / Conjugation......................................... 2 III. Loop Diuretics..................................................... 12 IV. K – Sparing Diuretics......................................... 12 Local Anti-infectives............................................................ 3 V. Osmotic Diuretic................................................. 12 I. Alcohols and Related Compounds..................... 3 VI. Calcium Channel Blockers................................. 12 II. Phenol and its Derivatives.................................. 4 VII. ACE Inhibitors...................................................... 12 III. Cationic surfactant............................................... 4 VIII. Direct Vasodilators............................................ 13 IV. Dyes........................................................................ 4 IX. Antianginals......................................................... 13 Preservatives........................................................................ 4 X. Antiarrhythmics................................................... 14 I. Characteristics....................................................... 4 Chemotherapeutic............................................................. 14 II. Compounds............................................................ 4 I. Antibacterial....................................................... 14 Common Heterocycles Found within Drug Molecules.... 5 II. Aminoglycosides................................................. 16 CNS Drugs............................................................................ 6 III. Tetracyclines....................................................... 16 I. Anxiolytic and Sedative Hypnotics................... 6 IV. Macrolides........................................................... 17 II. Antipsychotic Drugs.............................................. 7 V. Lincosamides....................................................... 17 III. Antidepressant...................................................... 7 VI. Polypeptides....................................................... 17 IV. Opioid Analgesics................................................ 7 VII. Unclassified Antibiotics...................................... 17 V. Anesthetics............................................................. 8 Organic Medicinal Chemistry Cholinergic Drugs................................................................ 8 The practice of medicinal chemistry devoted to the discovery and development of new drugs I. Cholinergic Agonist.............................................. 8 Two main consideration in drug Discover o Drug Adrenergic Drugs................................................................ 9 o Receptor I. Adrenergic Agonist.............................................. 9 Drug – Receptor Interaction II. Adrenergic Antagonist...................................... 10 Structural Class / Barbiturates and Chemical Class Benzodiazepines Autacoids............................................................................ 10 Anxiolytic, Sedative and I. Divisions................................................................ 10 Hypnotics GABA II. Chemical Classes of H1 Blockers..................... 10 Penicillin III. H2 Antagonist..................................................... 10 Tetracyclines Three-Dimensional Morphine IV. Proton Pump Inhibitors....................................... 11 Shape of the Molecule µ receptor V. Hypoglycemic Agents........................................ 11 Type of Chemical Heparin (base) + Protamine Binding Involved (acid) à Neutralization 🐨 Earl John Timothy N. Malimban, RPh (2021) 1  Structural – Activity Relationship (SAR) 1. Oxidation o Relates the structure of the drug to the Most common and important in drug mechanism of action metabolism Mixed function oxidase system Isosteres Made up of several components o Compounds or groups of atoms having the same Cytochrome p450 number and arrangement of electrons o Responsible of attaching oxygen to the § [Example] R – OH (Alc) and R – SH (Thiols) substrate o Isoforms Metabolism § CYP3A4 – Most dominant o Aka Biotransformation § CYP206 – Antidepressants o Converts drugs into polar and water-soluble metabolites 2. Reduction o Metabolism also leads to compounds à Carbonyl compounds (C = O) pharmacologically inactive (nontoxic) o Alcohol derivatives Nitro (NO2) and Azo (N = N) compounds Prodrugs o Amino derivatives o Compounds that are inactive in the native form but are metabolized to the active agent B. Hydrolysis o [Example] + “-at” activated Adds water to esters and amides and their isosteres § Enalapril à Enalaprilat (Ester is more readily Susceptibility: absorbed orally) o (Most) Esters > thioester > carbonates > amides § Chloramphenicol à Chloramphenicol > carbamates > ureides (Least) palmitate Aspirin (ASA) à Salicylic acid + acetic acid ú Chloramphenicol – water soluble enough Procainamide (slower) and Procaine (faster) à contact with taste receptor on the o 4 – aminobenzoic acid tongue à producing unpalatable bitterness (addition of palmitic acid to mask taste) II. Phase II / Conjugation o Prodrug – masking the bitterness Attachment of small polar and endogenous molecules o Ester - ­ absorption, mask the taste such as glucuronic acid and etc. to the Phase I o Metabolism also leads to compounds that are metabolites said to be toxic § Acetaminophen à NAPQI (N – acetyl para A. Glucuronidation benzo quinone imine – Toxic!) The most common conjugation pathway Glucuronides are highly hydrophilic and water soluble First Pass Effect Enzyme o Most drugs absorbed from the GIT à Portal vein o UDP – Glucuronosyl transferase à Liver à Enzymes à Inactive Metabolites o Underdeveloped in neonates o Metabolism prior to systemic absorption Chloramphenicol à Gray – baby syndrome Cofactor Phases of Metabolism o UDP – Glucuronic acid I. Phase I / Functionalization B. Sulfation Introduction of polar functional groups Phenolic group requirement o [Example] OH, COOH, NH2, SH Reversible reaction due to sulfatases Achieve by the following mechanisms (2) Phenolic – O – glucuronidation competes favorably o Direct Introduction of Polar Groups with sulfation o Unmasking or Modifying Existing Functionalities Enzyme o Sulfotransferase A. Redox Cofactor Hydroxylation o PAPS Epoxidation o 3 – Phosphodenosyl – 5’ – Phosphosulfate Reduction of Ketones, Aldehydes, and Acids Examples o MATA – Ph Reduction of Nitro, Azo, and Azido Groups 🐨 Earl John Timothy N. Malimban, RPh (2021) 2 C. Amino Acid Conjugation Local Anti-infectives The first mammalian drug metabolite isolated Antiseptics o Hippuric Acid o Living tissues o Product of conjugation of benzoic acid Disinfectant Enzyme o Inanimate objects o N – Acetyl transferase Cofactor I. Alcohols and Related Compounds o Glycine SAR o Glutamine o The antibacterial potencies of primary alcohols (vs. S. aureus) increase with molecular weight up D. Glutamine Conjugation to 8C Glutathione is a tripeptide o Glu – Cys – Val A. Alcohol USP The thiol group of Cys is responsible for scavenging Common names harmful electrophilic parent drugs and their o Spiritus vini rectificatus metabolites “Antioxidant property” o Wine spirit Enzyme o Grain alcohol o Glutathione – 5 – transferase Most widely abused of all recreational drugs Cofactor Metabolism o Glutathione Final Metabolite !"# %&'(%)*+&,!-& !"% %&'(%)*+&,!-& 𝐴𝑙𝑐𝑜ℎ𝑜𝑙 '⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯) 𝐴𝑙𝑑𝑒ℎ𝑦𝑑𝑒 '⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯) 𝐶𝑂𝑂𝐻 o Mercapturic acid 1. Denatured Alcohol E. Acetyl Conjugation Rendered unfit for use in intoxicating beverages Metabolism of N – containing drugs and compounds due to addition of benzene and methanol The function of acetylation is to deactivate the drug, (completely denatured) except for NAPA – N – acetylprocainamide (toxic) Enzyme 2. Rubbing Alcohol o NAT Rubefacient Astringent o N – acetyl transferase Refrigerant Cofactor Mild local anesthetic o Acetyl CoA Fast and Slow acetylators 3. Dehydrated Alcohol o fastEAST Absolute alcohol o sloWEST 99% ethanol by weight § may cause the accumulation of HIPS Used chemical reagent o H – Hydralazine o I – Isoniazid B. Isopropyl Alcohol o P – Procainamide Used to disinfect the skin and surgical instrument o S – Sulfonamide C. Ethylene Oxide F. Methyl Conjugation Used to sterilized temp – sensitive medical equipment Minor conjugation pathway and pharmaceuticals that cannot be autoclaved Biosynthesis of Epi and Melatonin and for the Gas sterilant – alkylation catabolism of catecholamine Enzyme D. Formaldehyde o Methyl Transferase (ie. COMT) Contains NLT 37% of formaldehyde with methanol Cofactor added to retard polymerization o SAM Previously used as disinfectant o S – adenosylmethionine MOA Demethylation o Alkylation o Removal or methyl group E. Glutaraldehyde Sterilizing solution for equipment and instruments that cannot be autoclaved 🐨 Earl John Timothy N. Malimban, RPh (2021) 3 II. Phenol and its Derivatives B. Basic Fuschin Phenol coefficient Ingredient of carbol – fuschin solution (Castellani’s o The ratio of a disinfectant to the dilution of phenol paint) required to kill a given strain of the bacterium Salmonella typhi under carefully controlled C. Methylene Blue condition over a given period In high concentration, used as antidote for cyanide poisoning A. Phenol MOA.&/'("&,& 0"1& Carbolic acid 𝐻𝑒𝑚𝑜𝑔𝑙𝑜𝑏𝑖𝑛 '⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯) 𝑚𝑒𝑡ℎ𝑒𝑚𝑜𝑔𝑙𝑜𝑏𝑖𝑛 (↑ 𝑎𝑓𝑓𝑖𝑛𝑖𝑡𝑦 𝑓𝑜𝑟 𝐶𝑁) The use as disinfectant and antiseptic is not largely In low concentration, used to treat drug – induced obsolete methemoglobinemia General protoplasmic poison Phenol containing 10% of water Preservatives o Liquefied phenol I. Characteristics B. Cresol Effective at low concentration vs. all possible Inexpensive antiseptic and disinfectant microorganism Nontoxic C. Thymol Compatible with other constituents Antifungal for Tinea infections Stable for the shelf-life of the preparation D. Eugenol Local anesthetic and antiseptic properties II. Compounds Use to relieve toothache A. Parabens Used for liquid dosage forms E. Resorcinol Preservative effects tend to increase with molecular Keratolytic agent and antiseptic weight Methyl parabens o Molds III. Cationic surfactant Propyl parabens A. Benzalkonium Chloride o Yeasts New Merthiolate Detergent, emulsifying, and wetting agent B. Others Used with sodium nitrate as preservative 1. Chlorobutanol Bacteriostatic agent B. Methylbenzethonium Chloride Used to control diaper rash in infants caused by 2. Benzyl alcohol Bacterium ammoniagenesis Phenyl methanol Preservative in vials of injectable drugs in C. Cetylpyridinium Chloride conc. Of 1% to 4% in water or saline solution General antiseptic FDA approved for the treatment of Gingivitis 3. Benzoic Acid Preservative in foods and pharmaceuticals at D. Chlorhexidine low pH Irrigation solution Mouthwash 4. Sorbic acid Chemically classed – Biguanides Effective antifungal preservative IV. Dyes A. Gentian Violet Common names o Crystal violet o Methyl violet o Methyl rosaniline chloride Available as vaginal suppositories for the treatment of yeast infections Available as topical solution for the treatment of Candida infection Other uses – Anthelminthic 🐨 Earl John Timothy N. Malimban, RPh (2021) 4  Common Heterocycles Found within Drug Molecules !"#$%&'() Piperazine Purine Pyrimidine !⎯⎯⎯⎯⎯⎯# Pyrrole Pyrrolidine Pyrazine Pyran Morpholine !"#$%&'() !⎯⎯⎯⎯⎯⎯# Indole Indoline !"#$%&'() !⎯⎯⎯⎯⎯⎯# Pyridine Piperidine !"#$%&'() !⎯⎯⎯⎯⎯⎯# Imidazole Imidazoline !"#$%&'() !⎯⎯⎯⎯⎯⎯# Benzene Derivatives Thiazole Thiazolidine *+(,"-'+, !⎯⎯⎯⎯⎯⎯# Phenol Aniline Toluene Quinoline Isoquinoline *+(,"-'+, Catechol Resorcinol Hydroquinone !⎯⎯⎯⎯⎯⎯# Oxazole Isoxazole Xylene Cresol Benzaldehyde Furan Quinazoline Thiophene Benzoic acid Salicylic acid Anisole Benzoxazole Tetrazole Benzimidazole 🐨 Earl John Timothy N. Malimban, RPh (2021) 5  B. Benzodiazepines 1. General Structure and SAR N – R at 1 o Essential for the activity C = O at 2 o Essential for the activity Fused triazole or imidazole at 1 and 2 o Increase potency o Alprazolam and Triazolam has triazole fused system o Imidazolam has imidazole fused system CNS Drugs Substitution at 3 o With OH § Polar and readily converted to I. Anxiolytic and Sedative Hypnotics glucuronide ¯ DOA A. Barbiturates o Without Hepatic oxidation to active 1. General Structure and SAR metabolite Nucleus § ­ DOA o 2, 4, 6 – trioxo hexa The Phenyl ring hydro pyrimidine o ­ Activity R1 o 2’ or 2’, 6’ substitution with electron o Alkyl withdrawing group (ENG) o ­ Lipophilicity – § ­ Lipophilicity Quick onset and o Electron withdrawing atom / group (?) short duration of action (DOA) pulls electron to that group OàS § ­ Potency o ­ Lipophilicity – Rapid Onset Substitution at 7 (X) with ENG Position 5 (C5) o ­ Potency / Activity o Substitution at position 5 with alkyl or Benzodiazepine Antagonist aromatic ring confers sedative hypnotics o Flumazenil and other action o Must have 2 substituents for it to work 2. Classification Based on DOA CNS drugs: Short o ­ Lipophilicity = ­ Potency o Midazolam MOA o Triazolam o Increases the duration of opening of the Intermediate (TOLA) chloride channel o Temazepam o Oxazepam 2. Classification based on the duration of action o Lorazepam Ultrashort o Alprazolam o Thiopental Note: All ends with Long Note o Thiamylal o Diazepam o Methohexital “barbital” Ends with o Chlordiazepoxide o Zepam Short “al” o Flurazepam o Pentobarbital o Zolam o Clorazepate o Zepoxide o Secobarbital o Prazepam o Zepate Intermediate o Quazepam o Amobarbital o Butabarbital Long o Phenobarbital o Mephobarbital o Methabarbital 🐨 Earl John Timothy N. Malimban, RPh (2021) 6 II. Antipsychotic Drugs III. Antidepressant A. Classification of Antidepressant 1. Secondary Amine Ends with “triptyline” EXCEPT Desipramine and Amoxapine o Desipramine o Nortriptyline o Protriptyline o Amoxapine 2. Tertiary Amine Ends with “pramine” EXCEPT Amitriptyline and Doxepin o Amitriptyline o Doxepin o Imipramine A. General Structure and SAR o Clomipramine The Tertiary Amine (at 10; N – R) o Trimipramine o Essential for antipsychotic activity Substitution at position X (at 2) with ENG IV. Opioid Analgesics o ­ Activity o ENG – Halogens good withdrawing It must have a N – containing side chain substituent on the ring N for antipsychotic activity The ring and side chain N must be separated by at least 3C I LOVE YOU for antipsychotic activity 2C is crazy for antihistaminic / anticholinergic B. Generations of Antipsychotics 1. 1st Generation Typical ADRs o Sedation o Extrapyramidal / EPS Phenothiazines A. Characteristics o Aliphatic § Promazine 1. Contains 5 fused rings o Piperazine 2. Pronounced T shape § Perazine 3. Basic due to Tertiary amines § Phenazine o Piperidine B. Pharmacophore § Ridazine Part of the drug responsible for the MOA Thioxanthenes 1. Phenol ring o Thixene 2. Aromatic ring Butyrophenones 3. Tertiary Amine o Peridol 2. 2nd Generation Atypical Very different classes Low to no EPS Example o Aripiprazole 🐨 Earl John Timothy N. Malimban, RPh (2021) 7 C. Opioid Design and SAR B. Local Anesthetics 1. Addition of methyl or ethyl at 3 of morphine ¯ Activity 2. Removal of alkene or 6 – hydroxyl group of morphine Retained 3. Removal of Ring E ¯ Activity 4. Removal of Ring D Retained Morphinans are more potent and longer acting than morphine o Levorphanol o Levallorphan 5. Removal of Rings C and D C. Others Retained Benzomorphans 1. Propofol o MetazocinE 2, 6 – diisopropylphenol o PentazocinE Non – polar o “Zocin” – Alpha 1 blockers Milk of Anesthesia 6. Removal of Rings B, C, and D 2. Ketamine Retained Amylcyclohexylamine 4 – phenylpiperidines IV More flexible molecules and more likely to Dissociative anesthesia (Problem) bind to the receptors Recreational drug o Fentanyl – prototype o Remifentanil – short duration of action Cholinergic Drugs o Other fentanils I. Cholinergic Agonist V. Anesthetics A. Direct Acting A. Inhalational Halogenated hydrocarbons 1. Acetylcholine SAR Halogenation confers volatability 1. Halothane Prototype drug Metabolized to trifluoroacetic acid 2. Enflurane, Isoflurane, Desflurane, Sevoflurane Metabolized to fluoride Quaternary N Portion, Ethylene bridge, and Ester 3. Methoxyflurane o All essential for activity Most potent inhalational anesthetic The overall size of the molecule cannot be 4. Nitrous Oxide (Laughing gas) altered Least potent and safest The methyl group of the Ester / Acetoxy portion cannot be extend Acetylcholine o Short duration o Easily hydrolyzed o Not used as a drug 🐨 Earl John Timothy N. Malimban, RPh (2021) 8  Adrenergic Drugs 2. Changes in DOA Add of CH3 I. Adrenergic Agonist o Methacholine Replace acetyl A. General Structure and SAR with carbamate o Carbachol Both o Bethanechol Pilocarpine 3. Pilocarpine Eyedrops for glaucoma 1. Important Parts Has imidazole ring Phenylethylamine Catechol B. Indirect Acting: AChE Inhibitors Substitution at R1 (after NH group) o Increasing the size of substituent 1. Carbamates o ­b Activity Physostigmine § (Tertbutyl (Terbutaline), +, ­b2 activity) o ¯a Activity o ¯ Degradation of MAO Carbamate Substitution at R2 (in between OH and NH) o Ethyl From Calabar bean (Physostigma § ­b Activity venenosum) § ­ CNS and oral activity Carbamate portion § ¯a Activity o Equivalent to ester of acetylcholine § ¯ Degradation of MAO Intermediate acting o Methyl § ­a Activity 2. Other Examples Aromatic substitution Amino – Alcohols (Short Acting) o 3’ OH group is important for a activity o Edrophonium o 4’ OH group is important for b activity Carbamates (Intermediate Acting) 3’ and 4’ di OH group is important for both a o Stigmines and b agonist activity o Neostigmine o Polar - ¯ oral activity, ¯ CNS activity o Pyridostigmine o Metabolized by COMT = ¯ DOA Organophosphates (Longest Acting) 2. 3’ OH and 5’ OH (Metaproterenol); 3’ CH2OH and o Isofluorophate 4’ OH (Albuterol) o Tabun, Sarin, Soman § Nerve gases Isofluorophate o Parathion and Malathion § Oxon o Ecothiophate § Medicinal Organophosphate ­b Activity 3. Scopolamine ¯ Metabolism by COMT = ­ DOA Tropane 🐨 Earl John Timothy N. Malimban, RPh (2021) 9 II. Adrenergic Antagonist II. Chemical Classes of H1 Blockers A. b Blockers X Chemical Class of b Blockers: o Basis for o Aryloxypropandamines classification o X = O, C, or N A. Under H1 Blockers Diphenhydramine 1. Ethanolamine Most sedating Substitution lowers the activity Diphenhydramine à Can be varied with Heteroaromatic Rings name of structure B. a Blockers 2. Ethylenediamine Meclizine 3. Piperazine Meclizine “-clizine” Motion sickness Chlorpheniramine 4. Alkylamine Chlorpheniramine “-pheniramine” 1. SAR The 4 – amino group on the QUINAZOLINE ring is essential for a blocking activity III. H2 Antagonist Cimetidine nd At the 2 position of the quinazoline ring any o Prototype heterocyclic moiety (piperazine or piperidine) Autacoids I. Divisions A. Derivatives A. H1 Blockers 1. Ranitidine Anti – allergic reaction Furan derivative 4 – 10x more potent than cimetidine 1. 1st Generation 2. Famotidine 2. 2nd Generation Thiazole derivative Less sedating 40 – 60x more potent than cimetidine B. H2 Blockers 3. Nizatidine Anti – ulcer Thiazole derivative “-tidine” 5 – 18x more potent than cimetidine 🐨 Earl John Timothy N. Malimban, RPh (2021) 10 IV. Proton Pump Inhibitors B. Sulfonylureas Substituted Benzimidazole aka Benzyl sulfonylurea All are prodrug which are converted to sulfenamide in acid media Omeprazole – Prototype drug 1. GS V. Hypoglycemic Agents Sulfonyl Urea Hypoglycemic Agents Insulins OHAs 2. 1st Generation Tolbutamide Insulins Chlorpropamide Rapid Short Intermediate Long Tolazamide Acting Acting Acting 3. 2nd Generation Oral Hypoglycemic Agents (OHAs) “Gly” Insulin Insulin a- Dipeptidyl “Gli” (?) Secretagogues Sensitizers Glucosidase – Inhibitors Peptidase C. Biguanides 4 Formed from two molecules of Guanidine linked Inhibitors together Insulin Sensitizers Biguanides Thiazolidinediones (TZDs) Insulin Secretagogues Sulfonylureas (1st and 2nd) Meglitinides D. Thiazolidinediones (TZDs) A. Insulins 1. Pharmacokinetic Classification Rapid Acting o Lispro o Aspart o Glulisine Short Acting o Regular insulin Intermediate Acting 1. Examples o NPH (Neutral Protamine Hagedorn) Liglitazone (Prototype) Insulin Troglitazone o Insulin Zn Suspension Pioglitazone Long Acting Rosiglitazone o Glargine o Detemir E. a - Glucosidase Inhibitors Acarbose Miglitol Voglibose F. Dipeptidyl – Peptidase – 4 Inhibitors Linagliptin Sitagliptin Saxagliptin 🐨 Earl John Timothy N. Malimban, RPh (2021) 11  Cardiovascular Drugs V. Osmotic Diuretic A. Mannitol I. Carbonic Anhydrase Inhibitor Intravenous A. Acetazolamide Consists of OH Thiadiazole Contains an unsubstituted sulfonamide VI. Calcium Channel Blockers Contraction Increase HR à Pump II. Thiazides Benzothiadiazines A. Dihydropyridine (DHP) Contains sulfonamide and halogen group Nifedipine Hydrogenation will increase potency of thiazides “-dipine” III. Loop Diuretics Furosemide o Has Furan Mostly sulfonamides B. Non – DHP o Ethacrynic acid (non-sulfonamide) Diltiazem o Furosemide Benzothiazepine o Torsemide IV. K – Sparing Diuretics A. Spironolactone VII. ACE Inhibitors “-pril” 1. Captopril Fast acting 🐨 Earl John Timothy N. Malimban, RPh (2021) 12  2. Enalapril IX. Antianginals Hydrolysis à Enalaprilic acid à Enalaprilat (Active) A. Nitroglycerin Vasodilatory effect Problem: Tolerance B. Isosorbide Dinitrate Tolerance capacity is lower VIII. Direct Vasodilators A. Hydralazine NH – NH2 (Hydrazo) C. Isosorbide Mononitrate Tolerance capacity is lower B. Sodium Nitroprusside Slow infusion rate Risky D. Dipyridamole Antiplatelet with ASA C. Minoxidil E. Clopidogrel Antiplatelet “Clo” – Thienopyridine D. Diazoxide 🐨 Earl John Timothy N. Malimban, RPh (2021) 13  A. Propranolol F. Amrinone Bipyridine “-inone” (+) Inotropes = ­ Contraction B. Amiodarone “iod” – Iodine Class 3 G. Digoxin Thyroid related ADRs Cardiac glycoside o Because it has iodine (+) Inotropic Maintenance for HF Acute o IV Dobutamine / Dopamine Chemotherapeutic I. Antibacterial A. b - Lactam Compounds X. Antiarrhythmics 1. Penicillin Derived from Cys and Val Classes of Antiarrhythmic Drugs Overall shape of molecule Class Drugs Mechanism of Action o Half open book IA Quinidine Lengthens refractory Beta lactam (cyclic amide) ring is attached to Procainamide period the thiazolidine Disopyramide Nucleus IB Lidocaine Shorten duration of o 6 – aminopenicillanic acid Phenytoin action potential GS and SAR Tocainide Mexiletine IC Encainide Slows conduction Flecainide Lorcainide Morocizine Propafenone II b - Adrenergic Slows AV conduction blockers (Propranolol) time, suppresses o Beta lactam automaticity § Essential III Amiodarone Prolongs o Bicyclic ring system (1 – 4) Bretyllium refractoriness § Essential Sotalol o Free carboxylate (3) IV Calcium channel Blocks slow inward § Essential for activity and allows blockers (Verapamil, Ca2+ channel Penicillin to be formulated as Na+, K+ Diltiazem) or Na+ salts o Cis stereochemistry (5 – 6) § Essential o Amide side chain § Essential o R § Point of variation o Sulfur atom § Not essential but always present 🐨 Earl John Timothy N. Malimban, RPh (2021) 14  MOA 3. Cephalosporins o Inhibits transpeptidase b - Lactam ring is attached to the Natural Penicillin dihydrothiazine ring o Penicillin G Nucleus § Benzylpenicillin o 7 – aminocephalosporanic acid § Acid labile – not given orally GS and SAR § Repository forms (IM) ú PenG Procaine ú PenG Benzathine o Penicillin V § Phenoxymethylpenicillin § Acid stable Antistaphylococcal Penicillin o Methicillin § 2, 6 – dimethoxyphenylpenicillin § Prototype drug o Nafcillin § 6 – (2 – ethoxy – 1 – naphthyl) o All are essential penicillin § b - Lactam ring o Isoxazoyl Penicillin § COOH (free carboxylated) § Oxacillin § Cis stereochemistry ú Prototype drug § Amide side chain § Cloxacillin § Bicyclic ring system § Dicloxacillin o 5th gen § Flucloxacillin § Ceftobiprole Aminopenicillin o “Am” in the name 4. Carbapenems o Ampicillin Differ from penicillin in the sulfur atom of the § Prototype thiazolidine ring has been externalized and o Amoxicillin replaced by carbon atom § Has better GI absorption than GS and SAR ampicillin o Bacampicillin o Hetacillin and Ciclacillin § Prodrug of Ampicillin Antipseudomonal penicillin o Carboxypenicillins § “Car” in the name § Ticarcillin § Carbenicillin o Ureidopenicillins Drugs under Carbapenem § Piperacillin o Thienamycin (Prototype drug) § Azlocillin § Streptomyces cattleya § Mezlocillin o Imipenem § Undergoes hydrolysis by 2. Beta Lactamase Inhibitors dihydropeptidase resulting to the Structurally related to the b - Lactam ring of formation of inactive metabolites Penicillin which is known to be nephrotoxic Do not have significant anti – bacterial activity § Combined with Cilastatin which inhibits dihydropeptidase o Meropenem § Second generation carbapenem o Ertapenem § Newer carbapenem § Invanz 🐨 Earl John Timothy N. Malimban, RPh (2021) 15  5. Monobactams 1. MYCIN Beta – lactam ring is not fused to another ring Derived from Streptomyces Aztreonam Streptomycin – prototype o Bactericidal o Chromobacterium violaceum 2. MICIN Moxalactam allergic (Cephalosphorin) Derived from Micromonospora o If allergic with just one Beta lactam Gentamicin compound, you’re allergic to all Beta lactam compounds (Cross allergic C. Adverse Effects reaction) 1. Ototoxicity KAN 2. Nephrotoxicity NTG 3. Vestibulatoxicity SG III. Tetracyclines Broadest spectrum antibiotics A. MOA Inhibits 30s ribosomal subunits B. Chemical Characteristics II. Aminoglycosides A. Chemical Characteristics 1. Derivative of Octahydro naphthacene Hydrocarbon system consisting of 4 1. All have at least one amino hexose annulated six-membered ring system Forms stable complexes with Divalent and 2. KATG trivalent cations 1, 3 – diaminocyclohexane ring o Complexation à Precipitation (won’t be Kanamycin absorbed) Amikacin Tobramycin Gentamicin 3. The highly polar structure of aminoglycosides prevents adequate absorption after oral administration C. Classification Based on DOA 1. Short acting Chlortetracycline Oxytetracycline 2. Intermediate acting Demeclocycline Methacycline 3. Long acting B. MOA Doxycycline Inhibits 30s ribosomal subunits o Only Tetracycline used for SIADH AT – 30 (TRENT – A) (syndrome of inappropriate ADH All must be given parenterally to achieve adequate secretion / Anti diuretic hormone serum levels EXCEPT Neomycin (extremely secretion) nephrotoxic) Minocycline 4. Very Long acting Tigecycline 🐨 Earl John Timothy N. Malimban, RPh (2021) 16 IV. Macrolides A. Drugs under Lincosamide 1. Clindamycin A. Chemical Characteristics Currently available in the market 1. Macrocytic lactone ring (12, 14, 16 atoms) Cyclic ester B. ADR 1. Pseudomembranous Colitis 2. Contains ketone Overgrowth of C. difficile Tx o Vancomycin 3. Contains glycosidically linked amino sugars o Metronidazole VI. Polypeptides A. Vancomycin From Streptomyces orientalis For MRSA For antibiotic colitis Slow IV infusion of systemic infection AE o Redman’s syndrome B. Bacitracin B. MOA Bacillus subtilis Inhibits 50s ribosomal subunits C. Polymyxin Erythromycin (prodrug) Bacillus polymyxa o Streptomyces erythreus From gram (+) organisms If allergic to b - Lactams: ALTERNATIVE D. Gramicidin C. Drugs under Macrolides Bacillus brevis 1. Erythromycin For gram (-) organisms Erythromycin base is inactivated by gastric acid à formulated as enteric coated tablets or capsule containing enteric coated pellets VII. Unclassified Antibiotics or esters of Erythromycin A. Chloramphenicol o Stearate From Strep. venezuelae o Ethyl succinate MOA o Estolate (cholestatic jaundice) o Inhibits 50s ribosomal subunits CELS 50 2. Clarithromycin o Chloramphenicol Semisynthetic derivative of erythromycin o Erythromycin (Macrolide) 6 – methyl ether of Erythromycin o Lincosamide o Streptogramins “Pristin” 3. Azithromycin DOC for typhoid fever Long elimination half-life (40 – 68 hours) AE o Gray baby syndrome V. Lincosamides o Aplastic anemia (Adult) Sulfur containing antibiotics isolated from Strep. lincolnensis B. Mupirocin Pseudomonas fluorescens Use o Impetigo o Eczema o Staph and Beta hemolytic Strep infection 🐨 Earl John Timothy N. Malimban, RPh (2021) 17