Chemistry of NSAIDs, DMARDS and Opioids.docx

Chemistry of NSAIDs, DMARDS and Opioids NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) are a drug class FDA-approved for use as antipyretic (reduce fever), anti-inflammatory, and analgesic agents. These effects make NSAIDs useful for the treatment of muscle pain, dysmenorrhea, arthrit...

Chemistry of NSAIDs, DMARDS and Opioids NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) are a drug class FDA-approved for use as antipyretic (reduce fever), anti-inflammatory, and analgesic agents. These effects make NSAIDs useful for the treatment of muscle pain, dysmenorrhea, arthritic conditions, pyrexia, gout, migraines, and used as opioid-sparing agents in certain acute trauma cases. NSAIDs are typically divided into groups based on their chemical structure and selectivity. Based on the selectivity, there are two types of NSAIDs. Non-selective NSAIDs which inhibits both COX-1 and COX-2 enzymes COX-2 selective inhibitors TYPES OF NSAIDS Non-selective NSAIDs Cyclooxygenase-2 (COX-2) selective Diclofenac Diflunisal Etodolac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Mefenamic acid Meloxicam Nabumetone Naproxen Oxaprozin Piroxicam Sulindac Tolmetin Etoricoxib Valdecoxib Rofecoxib Celecoxib NSAIDs BRAND/GENERIC Aspirin (Ascriptin, Bufferin, Ecotrin) Diflunisal (Dolobid®) Choline magnesium trislaicylate (Trilsate®) Diclofenac (Cambia®, Voltaren®, Zipsor®, Zorvolex®) Diclofenac sodium + Misoprostol (Arthrotec®) Celecoxib (Celebrex®) Etodolac (Lodine®) Fenoprofen (Nalfon® Flubiprofen (Ansaid®) Ibuprofen (Motrin, Advil, Caldolor, Neoprofen®) Indomethacin (Indocin®)​ Ketoprofen (Orudis®) Ketorolac Tromethamine (Acular®, Acuvail®, Toradol®, Sprix®, Toradol-IV®)​ Meclofenamate (Meclomen®) Mefenamic acid (Ponstel®) Meloxicam (Mobic®) Nabumetone (Relafen®) Naproxen (Naprosyn®, Aleve®) Oxaprozin (Daypro®) Piroxicam (Feldene®) Salsalate (Disalcid®) Sulindac (Clinoril®) Tolmetin (Tolectin®) Cyclooxygenases (COXs) The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX). There are two COX isoenzymes, COX-1 and COX-2 that are involved in the conversion of arachidonic acid into key biological mediators, prostaglandins, prostaglandins, and prostacyclins. COX-1 is constitutively expressed in the body, and plays a role in maintaining gastrointestinal mucosa lining, kidney function, and platelet aggregation. COX-2 is not constitutively expressed in the body, and instead it inducibly expressed during an inflammatory response. Non-selective NSAIDs inhibit both COX-1 and COX-2, and reduce inflammation, inhibit platelet aggregation (aspirin) and increase the risk of gastrointestinal ulcer. However, COX-2 selective NSAIDs only target COX-2 and therefore have a different side effect profile. Importantly, COX-1 is the prime mediator for ensuring gastric mucosal integrity and COX-2 is mainly involved in inflammation. COX-2 selective NSAIDs provide anti-inflammatory relief without compromising the gastric mucosa NON-SELECTIVE NSAIDs Aspirin Aspirin, an acidic salicylate, covalently modifies COX-1 and COX-2 isozymes by acetylating the OH group of active site Ser-530 residue in COX-1 and Ser-516 of COX-2. Acetylation of Ser-530 totally blocks the accessibility of substrate arachidonic acid from entering into the active site. Salicylates being acidic, are readily absorbed from the stomach and small intestine. Their absorption depends strongly on the pH of the environment and therefore, co-administration of an antacid or other buffering agents hinder the absorption, bioavailability and onset of action of NSAIDs. Salicylic acid undergoes extensive phase II metabolism and excreted via kidney as the water soluble glycine conjugates ACETAMINOPHEN Acetaminophen (paracetamol, N-acetyl-p-aminophenol, APAP) Synthesized by the acetylation of p-aminophenol is a weak acid( pKa =9.7). It is used as a nonprescription antipyretic/analgetic under variety of trade names (Tylenol, Patrol and tempera), but it has NO anti-inflammatory activity. It is available in various formulations including suppositories, tablets, capsules, granules, and solutions. It is water insoluble and therefore, liquid formulations are prepared with solvents such as propylene glycol. Doses greater than 2.6g/day are not recommended for long-term use because of hepatotoxicity. ASSESSMENT: (1) At physiological pH, explain if acetaminophen (pKa,9.7) exists predominately in the ionized or unionized form and also (2) explain the predominate form of aspirin (pKa, 3-5) at physiological pH. METABOLISM OF ACETAMINOPHEN Acetaminophen undergoes rapid first-pass metabolism in the GI tract primarily by conjugation reactions, with the O-sulfate being the primary metabolite in children and O-glucuronide in adults. A minor, but significant, product of acetaminophen is the N-hydroxyamide produced by CYP2E1/3A4. CYP2E1/3A4 is induced by the ingestion of alcohol, accounting for the increase in acetaminophen toxicity. The N-hydroxyamide is then converted to reactive toxic metabolite, an N-acetyl-p-benzoquinone imine (NAPQI). Overdoses of acetaminophen leads to acute liver failure. Various sulfhydryl-containing compounds are useful as antidotes to acetaminophen overdoses. The most useful antidotes is N-acetylcysteine, which serves as a substitute for the depleted glutathione and also enhances non-toxic sulfate conjugation DICLOFENAC It is introduced in the US in 1989 and ranks among the top prescription drugs in US. It possesses structural characteristics of both arylalkanoic acid and the anthranilic acid classes on anti-inflammatory drugs. Displays anti-inflammatory, analgesic and anti-pyretic properties. It is a unique NSAID in that it possesses three possible mechanism of actions: Inhibition of arachidonic acid (AA)/Cox system resulting in decreased production of prostaglandins and thromboxanes Inhibition of lipoxygenase pathway resulting in decreased production of leukotrienes Inhibition of AA release and stimulation of its reuptake, resulting in a reduction of AA availability Diclofenac is rapidly and completely (100%) absorbed on oral administration. Only 50 to 60% of oral dose is bioavailable due to hepatic metabolism. METABOLISM OF DICLOFENAC Structure-activity relationship: It is not extensively studied. It appears that the function of the 2 O-chloro-groups is to force the amino-phenyl ring out of the plane of the phenylacetic acid portion. causing a twisting effect. This twisting effect appears to be important in the binding of NSAIDs to the active site of COX. Metabolism Aromatic hydroxylation of diclofenac results in 4 metabolites. The major metabolite resulting via CYP3A4 is the 4’-hydroxy derivative accounts for the 20 to 30% of the dose excreted. Although it is much less active than parent compound, it still exhibits significant biological activity The other metabolites 5’-hydroxy, 3’-hydroxy, and 4’,5’-dihydroxy metabolites are formed via CYP2C9 account for 10-20% of the dose excreted. The remaining drug is excreted in the form of sulfate conjugates. INDOMETHACIN Indomethacin-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) is a antiinflammatory, antipyretic and analgesic NSAID. The aqueous solutions of indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group. The conformation of indomethacin has a crucial role in its antiinflammatory actions. The acetic acid side-chain is flexible and can assume a large number of different conformations. The preferred and low-energy conformation of the N-p-chlorobenzoyl group is one in which the chlorophenyl ring is oriented away from the 2-methyl group (or cis to the methoxyphenyl ring of the indole nucleus). Indomethacin is converted to inactive metabolites. Approximately 50% of a single dose is 5-O-demethylated by CYP2C9 and 10% is conjugated with glucuronic acid. Non-hepatic enzyme systems hydrolyze indomethacin to N-deacylated metabolites SELECTIVE COX-2 INHIBITORS (COXIBS) Celecoxib (Celebrex) It is the first selective COX-2 inhibitor drug introduced into the market in 1998 for use in the treatment of rheumatoid arthritis, osteoarthritis, and acute pain. It belongs to the class of organic compounds containing known as phenylpyrazoles. Celecoxib is a 1,5-diarylpyrazole drug that is well absorbed and undergoes rapid oxidative metabolism to form hydroxycelecoxib via CYP2C9 to give its inactive metabolites. Because active isomer of Warfarin is primarily degraded by CYP2C9, a potential for drug interaction exist between celecoxib and warfarin. Rheumatoid Arthritis/ Autoimmune Disease TNF alpha biologic Adalimumab (Humira®) Infliximab (Remicade®) Infliximab – dyyb (Inflectra®) Certolizumab (Cimzia®) ►Etanercept (Enbrel®) Golimumab (Simponi®)  Non-TNF Baricitinib (Olumiant®) Tofacitinib (Xeljanz®) Tocilizumab (Actemra®) Rituximab (Rituxan®) Anakinra (Kineret®) Abatacept (Orencia®) Sarilumab (Kevzara®) Upadacitinub (Rinvoq®) Canakinumab (Ilaris®) Secukinumab (Cosentyx®) Belimumab (Benlysta®) ►Hydroxychloroquine (Plaquenil ®) Leflunomide (Arava®) ► Methotrexate (Trexall®, Otrexup®, Rasuvo®, Xatmep®) Sulfasalazine (Azulfidine®) 6-mercatopurine Azathioprine ► Top 300 Drug Rheumatoid arthritis-Steroids Detailed Chemistry Discussion with Anti-Gout Drugs **Hydrocortisone Cortisone ►Methylprednisolone (Medrol®)  ►Prednisone (Deltasone®) ►Prednisolone ***Triamcinolone Betamethasone ►Dexamethasone ►Top 300 Drug List for Arthritis ** Top 300 =Topical formulation ***Top 300 Drug List for topical skin disorders /nasal allergic rhinitis STEOID-GLUCOCORTICOIDS Steroid skeleton is Cyclopentanoperhydrophenanthrene! Cortisol (hydrocortisone) Natural glucocorticoid in the body Glucocorticoids and mineralcorticoids mimic hormones produced by the adrenal cortex HYDROXYCHLOROQUINE Class: A conventional synthetic DMARD (csDMARD) Synthetic DMARDs can be taken orally Hydroxychloroquine sulfate = oral tablet formulation 4-Aminoquinoline chemical class Metabolism: N-Dealkylation (tertiary amine) followed by oxidative deamination of the resulting primary amine to the carboxylic acid derivative. Toxicity: Corneal &renal toxicity and may also cause CNS, neuromuscular, GI & hematologic side effects. METHOTREXATE (MTX) Class: A conventional synthetic DMARD (csDMARD) Antimetabolite/ pyrimidine synthesis & metabolism inhibitor Oral formulation is methotrexate sodium Chemical class: a pteridine derivative Active urinary excretion by organic anion transporters, OATs. -NSAIDs-Life threatening interaction with those that inhibit OAT excretion -MTX Patients should not take NSAIDs ETANERCEPT Class: Biologic DMARD (bDMARD) Tumor necrosis factor (TNF) –blocking agent Given by IV infusion or subcutaneously Chemically produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell line. First biotechnology-derived drug for reduction of signs & symptoms of moderate to severe active rheumatoid arthritis in patients who have not adequately responded to one or more of the synthetic DMARDs. OPIOIDS – BRAND/GENERIC Buprenorphine (Burenex®, Belbuca®, Buprenex®, Butrans®, Probuphine® Implant Kit) Codeine (Tylenol with Codeine®) Fentanyl (Duragesic®, Sublimaze, Ionsys®) *Hydrocodone (Norco®, Lorcet®,Lortab®, Vicodin®, Zohydro ER®, Hysingla ER®) Hydromorphone (Dilaudid®, Exalgo) Methadone (Dolophine®, Methadose®) Meperidine (Demerol®) Morphine (MS Contin®, Avinza®, Kadian®) Oxycodone (Oxycontin®) Oxymorphone (Opana®) Tapentadol (Nucynta®) Tramadol (Ultram®) *NOTE products with Hydrocodone + Acetaminophen NARCOTIC ANALGESICS Narcotic analgesics are a class of medicines that are potent analgesics used for relieving from moderate to severe acute or chronic pain Narcotics are mainly centrally acting analgesics (brain and spinal cord) but also used for treating diarrhea (Lomotil) and severe cough (codeine) They bind to opioid receptors (mu, kappa and delta) that control pain, and pleasurable and addictive behavior. The main receptor to which opioids bind is mu receptors OPIOIDS Opium is one of the oldest herbal medicines isolated from opium poppy, papavar somniferum Opium contains over 40 different alkaloids with most alkaloids represented in the following five structures: Morphine (8%-17%) Codeine (0.7%-5%) Thebaine (0.1%-2.5%) Papaverine (0.5%-1.5%) Noscapine Morphine was isolated from opium in 1806 by a German pharmacist Friedrich Seturner He named the compound morphine after Greek god of dreams “Morpheus” MORPHINE Morphine is the prototype receptor mu agonist The structure of morphine includes A rigid pentacyclic structure consisting of five rings A,B,C,D, and E Aromatic A ring attached with 4th position of piperidine D ring Two hydroxyl functional groups C3-phenolic (hydroxyl group) C6-allylic (hydroxyl group) An ether linkage between C4 & C5 Unsaturation between C7 & C8 Basic tertiary amine function at 17 Five centers of chirality (C5, C6, C9, C13, and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic Physiochemical Properties Amphoteric Substance Amine pKa 8-10 Phenolic hydroxyl pKa 11 Receptor binding Cationic amine interaction with Asp Hydroxyl groups h-bonding interactions with His It is a prototype mu receptor agonist It is a base and readily forms water-soluble salts with most acids Morphine itself is poorly soluble in water, the sulfate salts is formed for oral, IV, and suppository use. Starting parenteral morphine dose in adults is 2.5mg to 5mg per 4 hours Naturally occurring active form of morphine is the levorotatory enantiomorph with stereochemistry 5®, 6(S), 9)R), 13(S) and 14(R), which is the most active isomeric form of opioid receptor The x-ray determined conformation is a “T” shape with the A, B, and E rings B/C cis conformation 10 times more potent than B/C trans Aromatic A ring attached with 4th position of piperidine (D) ring This 4-phenylpiperidine structure is considered pharmacophore for opioid analgesic activity Metabolism Morphine is metabolized into morphine-3-glucoronide (60%) and morphine-6-glucoroinde (8%) and to a lesser extent the N-demethylated metabolite (3%) via glucuronidation by phase II metabolism enzyme UDP-glucoronosyl trasferase-2B7 (UGT2B7) Morphine-6-glucoronide found to be more active than morphine Derivatives Morphine is a precursor for heroin, hydromorphone and oxymorphone Morphine present in the opium as a natural product is used for aynthesizing morphine analogs Heroin (diacetylmorphine) It was first commercally synthesized in 1898 by bayer company in germany as an alternate analgesic to morphine Heroin is the 3,6 diacetylated form of morphie With both OH groups protected as an ester heroin can pass throgh the BBB blood brain barrier quicker than morphine and lead to euphoric “rush” that ecomes addictive to addict, especially after IV injection Once heroin is in the brain, it is quickly metabolied to 3-acetylmorphine, which has low to zero activity at the mu receptor and 6-acetylmorphine, which is 2 to 3 time more potent at the receptor than morphine The 3-acetate ester of heroin is readly hydrolzed in the CNS to generate the analgescally active 6-monoacetyl morphine The 6-acetate is slower to cleave because of carbonyl carbon, but eventually succumb to hydrolysis to produce morphine Codeine SYTHESIS & METABOLISM Codeine is naturally present in opium but the amount present is too small to be of commercial importance. Consequently most commercial codeine is prepared from morphine by methylating the phenolic OH group It occurs as colorless crystals or as a which crystalline powder It is light sensitive. Codeine is a basic and readily forms salts with acids, with the most important eing the sulfate and phosphate The general pharmacological action of codeine is similar to morphine, but it does not posses the same analgesic potency The decreased potency also leads to a lower addiction potential in comparison to morphine About 5 % of codeine is metabolized to morphine via O-demethylation The enzyme responsible for the O-demethylation of codeine is cytochrome P450 CYP2D6 Hydromorphone & Hydrocodone Oxycodone Dextromethorphan Opioid Antagonists Opioid antagonists marketed to reverse the central actions of opioid agonists are Nalaxone hydrochloride and Naltrexone hydrochloride They are: Both weak bases Have requisite 14-beta-OH group and The 7,8 dihydro-6-one or 6-ene ring With a 4-carbon N-cyclopropylmethyl substituent, Naltrexone is 2X more potent than the allyl substituted Naloxone. Both of these antagonists can be used to rescue patients from life threatening opioid overdose NALOXONE is orally inactive due to rapid inactivating allylic oxidation and phase II conjugation in the GI tract and liver, and only used as an emergency opioid antidote Prepackaged Nasal Spray (generic naloxone, Narcan®, Kloxxado®), developed as a result of NIDA-funded research, is an FDA-approved prefilled, needle-free device that requires no assembly and is sprayed into one nostril while the person lays on their back. This device can also be easier for loved ones and bystanders without formal training to use. NALTREXONE has sufficient bioavaiability for oral administration NALTREXONE is available in an injectable form (Vivitrol) and oral dosage form, which enhances its utility in opioid addiction and alcoholism recovery. Injectable form (Vivitrol): for alcohol and opioid use disorders Available in oral pill form (ReVia and Depade) for alcohol use disorders