organic medicinal

• Organic Medicinal Chemistry


  The practice of medicinal chemistry devoted to the discovery and development of new drugs
• Metabolism


  The biotransformation of drugs in the body
• Metabolism


  • Important in the elimination of drugs from the body
  • Converts drugs to hydrophilic, inactive and nontoxic
  • Liver is the primary organ
• Phase I (Functionalization)


  • Introduce a polar functional group (OH, COOH, NH2, SH) by direct introduction or modifying/unmasking existing functionalities
  • Produce a handle on the molecule for Phase II
  • Reactions: Oxidation, Reduction, Hydrolysis
• Oxidation


  • Most common phase I reaction
  • Undergone by Olefins, Alcohols, Aldehydes & Aromatic moieties
• Oxidation


  • Phenylbutazone – aromatic hydroxylation → oxybutazone

  
• Reduction


  • Carbonyl compounds → Alcohol derivatives
  • Nitro and Azo compounds → Amine derivatives

  
• Reduction


  • Chloral hydrate → Trichloroethanol
  • Prednisone – Ketone reduction → Prednisolone

  
• Hydrolysis


  • Commonly undergone by lactams, esters and amides
• Hydrolysis


  • Aspirin → Salicylic acid + Acetic acid
• Phase II (Conjugation)


  • Attach small, ionizable, endogenous compounds to the functional handles
  • Purpose: Form excretable & inactive metabolites, Terminate/Attenuate activity, Detoxify
• Glucuronidation


  • Coenzyme: Uridine-5'-diphospho-α-D-glucuronic acid (UDPGA)
  • Transferase enzyme: Glucuronyltransferase
  • Most common because readily available supply of D-glucuronic acid, numerous functional groups can combine with glucuronic acid, the glucuronyl moiety produces hydrophilic product, not yet developed in neonates

  
• Sulfation


  • Coenzyme: 3-phosphoadenosine-5-phosphosulfate (PAPS)
  • Transferase enzyme: Sulfotransferase
  • Yields water soluble and inactive conjugates
  • Conjugate endogenous compounds such as steroids, heparin, chondroitin, catecholamines, thyroxine
  • In neonates, sulfation is the major process

  
• Glycine & Glutamine Conjugation


  • Conjugate Carboxylic acid, particularly aromatic acids & arylalkyl acid
  • Glycine – common to mammals
  • Glutamine – humans & other primates
  • Minor pathway

  
• Glycine & Glutamine Conjugation


  • Benzoic acid → Hippuric acid- The first mammalian metabolite discovered from glycine conjugation

  
• Glutathione


  • For detoxifying chemically reactive Electrophilic compounds
  • Glutathione is composed of 3 amino acids: Cysteine (-SH) is responsible for detoxification, Glycine, Glutamine

  
• Acetylation


  • For termination of activity & detoxification
  • Important route of primary amino groups
  • Acetyl group supplier: Acetyl-CoA
  • Transferase enzyme: N-acetyltransferase
  • Undergone by sulfonamides
  • Acetylation polymorphism – variation in acetylating activity

  
• Methylation


  • Coenzyme: S-Adenosylmethionine (SAM)
  • Transferase enzyme: Methyl transferase
  • Minor pathway that leads to non-polar & inactivated compounds

  
• Methylation


  • Biosynthesis of epinephrine, melatonin
  • Inactivation of norepinephrine, dopamine, serotonin, histamine
• First-Pass Metabolism / Pre-systemic metabolism


  When orally administered drugs are extensively metabolized before reaching the systemic circulation
• Drugs with extensive first pass effect

  • Isoproterenol
  • Lidocaine
  • Morphine
  • Meperidine
  • Nitroglycerin
  • Pentazocine
  • Propoxyphene
  • Propranolol
  • Salicylamide

  
• Enzyme Inhibitors


  • Sodium valproate
  • Griseofulvin
  • Isoniazid
  • Phenobarbital (Barbiturates)
  • Cimetidine
  • Phenytoin
  • Ketoconazole
  • Phenylbutazone
  • Fluconazole
  • Rifampicin
  • Alcohol (Acute)
  • Sulfonylurea
  • Ciprofloxacin
  • Carbamazepine
  • Erythromycin
  • Alcohol (chronic)
  • Sulfonamide
  • Meprobamate
  • Chloramphenicol
  • Omeprazole
  • St. John's wort
  • Metronidazole
  • Valencia oranges
  • Grape fruit

  
• Enzyme Inducers


  • SICKFACES.COM
• Anti-infective Agents


  • Antisepsis – application of agent to living tissue to prevent infection
  • Decontamination – destruction or reduction in the number of microorganisms
  • Disinfection – chemical or physical tx on inanimate surfaces
  • Sanitization – reduction of microbial load on inanimate surface to a level acceptable for public health purposes
  • Sterilization – kill or remove all types of microorganisms
  • Pasteurization – kills nonsporulating microorganisms by hot water @ 65C-100C
  • Germicides – anti-infective agents used locally
  • Cidal – kill
  • Static – prevent growth
• Alcohols & Related Compounds


  • ↑ # of C - ↑ antibacterial activity up to C8 only
  • ↑ 9C – nonpolar ↓ water solubility, ↓ antibacterial activity
  • Branching decreases antibacterial property (except isopropyl alcohol = more potent, cheaper, less toxic; 60%EtOH = 40% Isopropyl Alcohol)
  • Isomeric alcohol potency decreases in the order: Primary > Secondary > Tertiary
• Alcohol, USP


  • ethanol, grain alcohol, wine spirit, cologne spirit, spiritus vini rectificatus
  • Manufactured by: Fermentation of grains and other CHOs, Hydration of ethene
  • Metabolism: Ethanol → Acetaldehyde → Acetic acid
  • Enzymes: alcohol dehydrogenase, aldehyde dehydrogenase
• Fomepizole


  • Inhibits alcohol dehydrogenase
  • Used as an antidote for methanol poisoning
• Disulfiram


  • Used as a deterrent for alcohol addiction
  • Inhibits aldehyde dehydrogenase
  • Accumulation of aldehyde = extreme hangover like symptoms (nausea, vomiting, vasodilatory flushing)
• Types of Alcohols


  • Absolute alcohol
  • Dehydrated alcohol
  • Diluted alcohol
  • Denatured alcohol
  • Completely denatured alcohol
  • Specially denatured alcohol
• Isopropyl alcohol


  • aka: 2-propanol
  • Substitute for ethanol
  • Prepared by sulphuric acid catalyzed hydration of propylene

  
• Ethylene alcohol


  • C2H4O
  • MOA: alkylation of bacterial protein by nucleophilic opening of oxide ring
  • Used to sterilize (gas sterilant) temperature sensitive pharmaceuticals and equipment that can't be autoclaved

  
• Formaldehyde


  • aka: Methanal, HCHO
  • MOA: direct and nonspecific alkylation of nucleophilic functional groups of proteins
  • Contains not less than 37% of formaldehyde
  • Uses: embalming fluid, disinfectant

  
• Glutaraldehyde


  • aka: Glutarol
  • Sterilizing solution for equipment and pharmaceuticals that cannot be autoclaved
  • Used in medical mission in remote areas
  • Cidex®

  
• Phenol, USP


  • aka: Carbolic acid, C6H5OH
  • Discovered by Joseph Lister
  • SAR: Substitution at para position increases bacterial activity, Activity: straight chain alkyl> branched
  • Germicidal standard: Phenol coefficient = Dilution of a disinfectant / Dilution of phenol that is required to kill a strain of Salmonella typhi

  
• Liquefied phenol


  Phenol with 10% water
• 1. chloro-m-xylenol


  • aka: PC-MX, Metasep
  • Antibacterial & antifungal

  
• Hexachlorophene


  • aka: pHisoHex
  • In soaps, lotions, shampoos
• Cresol


  • Methylphenol
  • From coal tar or petroleum by alkaline extraction
• Thymol


  • Isospropyl m-cresol
  • From oil of Thymus vulgaris (Thyme)
  • Antifungal property
• Eugenol


  • 4-allyl-2-methoxyphenol
  • From clove oil
  • Dental analgesic "toothache drops", used in mouthwashes