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Chapter 4

Chapter 4. Circulatory System Agents. Section 1. β -Adrenergic Block Agents ( 肾上腺能 β - 受体 阻滞 剂 ). Propranolol Hydrochloride ( 盐酸普萘洛尔 ). 1. 3. 1-Isopropylamino -3- (1-naphthyloxy)- 2- propanol hydrochloride. 2. Structure Activity Relation (SAR). Section 2. Calcium Channel Blockers.

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Chapter 4

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  1. Chapter 4 Circulatory System Agents

  2. Section 1 β-Adrenergic Block Agents(肾上腺能β-受体阻滞剂)

  3. Propranolol Hydrochloride(盐酸普萘洛尔) 1 3 • 1-Isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride 2

  4. Structure Activity Relation (SAR)

  5. Section 2 Calcium Channel Blockers

  6. Ion channel • concept： • classification：

  7. Nifedipine (硝苯地平) • IUPAC name: 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate • Other name: 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester 6 1 2 Adalat / Procardia (心痛定) 5 3 4 INN:International Non-proprietary Names

  8. Other 1,4-dihydropyridine agents Nicardipine Nifedipine Nimodipine Nitrendipine Amlodipine Nisoldipine

  9. SAR ofNifedipine

  10. Section 3 Sodium and Potassium Channels Blockers

  11. Mexiletine Hydrochloride(盐酸美西律) • 1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride 1 2 3 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride

  12. Amiodarone Hydrochloride(盐酸胺碘酮) 3 • (2-Butyl-3-benzofuranyl)[4-(2-(diethyl- amino) ethoxy)-3,5-diiodophenyl] methanone hydrochloride 2 1 1 1 4 2

  13. Angiotensin(血管紧张素)Converting Enzyme Inhibitors (ACEI)&Angiotensin Ⅱ Receptor Antagonists(拮抗剂) Section 4

  14. Captopril (卡托普利) • 1-[（2S）-3-Mercapto(巯基)-2-methyl-1- oxopropyl）]-L-proline(脯氨酸) 3 2 1

  15. Its analogue Captopril OH Enalapril Act as prodrug Converted to activation by hydrolysis of its ethyl ester to form the diacid enalaprilat. A non-thiol-containing ACE inhibitor No thiol group, devoid of the side effects of rash and loss of taste sense with Captopril.

  16. Angiotensin(血管紧张素)ⅡReceptor Antagonists(拮抗剂)

  17. Losartan (氯沙坦) 3 • 2-Butyl-4-chloro-1-[[2’-(1H-tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol 4 2 5 1 4 2′ 1′ 1

  18. Section 5 NO Donor Drugs

  19. The Nobel Assembly at the Karolinska Institute in Stockholm, Sweden, has awarded the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott,Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system". The Nobel Prize in Physiology or Medicine 1998

  20. Mechanism of action • NO formed in smooth muscle from nitrovasodilators (硝基血管扩张剂)or from endothelial cell (EDRF) activates guanylate cyclase(鸟苷酸环化酶,GC*). • GC* activates cGMP-dependent protein kinases(激酶)that phosphorylatemyosin light-chain kinase (MLCK,肌凝蛋白),cause its inactivation and subsequent muscle relaxation.

  21. Section 6 Cardiac Agents(强心剂)

  22. Digoxin (地高辛) OH Steroid structure

  23. Section 7 Lipid Regulators

  24. Lovastatin (洛伐他汀) • 2-methylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester 8a 8 1 7 3 5

  25. Analogues of -statin H Pravastatin Mevastatin Lovastatin CH3 Fluvastatin Simvastatin

  26. Section 8 Antithrombotic Drugs (抗血栓药)

  27. Classification Aspirin Antiplatelet drug Clopidogrel According to mechanism Warfarin Sodium Anticoagulant Dicoumarol(双香豆素) Urokinase Thrombolytic Streptokinase

  28. Aspirin • More than 100 years for antipyretic analgesic(解热止痛剂). • In 1954, discovered that it can extend bleeding time. • In 1971, found its mechanism by inhibiting the synthesis of PG. Thromboxane A2 Arachidonic acid(花生四烯酸) Endoperoxide (EP) epoxidase inhibit inhibit Aspirin Clopidogrel

  29. WarfarinSodium • 4-Hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one sodium salt. • 3-(α-acetonylbenzyl)-4-hydroxycoumarin(羟基香豆素)sodium salt 1 2 3 4

  30. Warfarin interacts with many commonly-used drugs, and the metabolism of warfarin varies greatly between patients. • Antibiotics, alcohol, herbs and some food have been reported to interact with warfarin. • Vitamin K.

  31. Chapter 5 Digestive System Agents

  32. Classification Antiacids Anticholinergic agents(抗胆碱能药) Pirenzepine(哌仑西平) NaHCO3/MgO Antigastrin agents(抗胃泌素) Mechanism of action Proglumide(丙谷胺) Inhibit the different link of acid secretion H2-receptor antagonists Cimetidine(西咪替丁) Proton pump inhibitors Mucous membrane(黏膜) protective drugs Omeprazole(奥美拉唑) Prostaglandin E（前列腺素E）/Sucralfate（硫糖铝）/Alginic Acid（藻朊酸）

  33. Ranitidine Hydrochloride(盐酸雷尼替丁) • N-[2-[[[5-[(dimethylamino)methyl-2-furanyl] methyl]thio]ethyl]-N’- methyl-2-nitro-1,1-ethenediamine monohydrochloride • An aminoalkyl furan derivative with pKa values of 2.7 and 8.2. (side chain and dimethylamino)

  34. Proton pump (PP) inhibitors • A group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. • Significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. • The most potent inhibitors of acid secretion, and the most widely-selling drugs in the world. They are generally considered safe and effective. • Majority of these drugs are benzimidazole derivatives; however, new research indicates that imidazopyridine derivatives may be more effective.

  35. Omeprazole (奥美拉唑) • (R,S)-5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfinyl)benzimidazole • A white to off-white crystalline powder with very slight solubility in water 4 3 5 2 1

  36. Section 3 Prokinetics (促动力药)

  37. Concept and classification • Prokinetics • Classification Promote GI content to push forward, used in the treatment of GI dyskinesis(动力障碍)such as reflux esophagitis(返流食道炎), dyspepsia(消化不良), intestinal obstruction(肠梗阻), etc. D2 receptor antagonists Metoclopramide(甲氧氯普胺) Periphery D2 receptor antagonists Domperidone(多潘立酮) Cisapride(西沙必利) Acetylcholine agonists

  38. Common Prokinetics

  39. Cisapride (西沙必利) 3 and 4-C are both chiral C • 4-amino-5-chloro-N-((3S,4S)-1-[3-(4-fluoro phenoxy)propyl]-3-methoxypiperidin-4-yl)-2-methoxybenzamide 2 1 4 3 5 4 1 2 3 3 and 4-substituents on the same side of pyridine ring

  40. 2-cis isomers in clinic 4-isomers of Cisapride

  41. Domperidone (多潘立酮) 吗丁啉 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl] piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

  42. Section 4 Adjuvant for Hepatic and Biliary Diseases (肝胆疾病辅助治疗药物)

  43. Common drugs Glutamic Acid (谷氨酸) Glucurolactone (葡醛内酯) Lactulose (乳果糖) Silibinin (水飞蓟宾) Bifendate (联苯双酯)

  44. Chapter 6 Antipyretic Analgesics & Nonsteroidal Anti-inflammatory Agents

  45. Aspirin—Acetylsalicylic acid It is more potent, less irritating. Nomenclature: Acetylsalicylic acid; 2-Acetoxy benzoic acid; (Aspro, Empirin) White crystal or white crystalline power Hydrolyzed to form salicylic acid

  46. Paracetamol(对乙酰氨基酚) • N -(4-Hydroxyphenyl) acetamide; • Acetaminophen; • N-Acetal-p-aminophenol; • 4-Hydroxyacetanilide; • APAP • It is Aniline and p-Aminophenol derivative. • It isn’t anti-inflammatory, different with Aspirin. • Not to exceed the recommended dosages.

  47. Metabolic Pathway of Paracetamol children adults

  48. Aspirin Salicylic acid Paracetamol Antipyretic Analgesics

  49. Diclofenac Sodium(双氯芬酸钠) Sodium 2-[(2,6-dichloroanilino)phenyl]acetate • Indicated for short- and long-term treatment of RA, OA, and ankylosing spondylitis（强直性脊柱炎）. • Available as delayed-release tablets.

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