Antihypertensive Drugs-Cardiovascular Pharmacology抗高血压,心血管药理学
antihypertensive drugs抗高血压药精讲
Indapamide Increase in renal Na+ excretion →diuresis Dilate the vascular smooth muscle. Have no effect on the serum lipids.
Section one：introduction
• What is hypertension？ • Hypertension is defined as an arterial pressure greater than or equal to 140/90mmHg for an extended period of time. • BP≥140/90 mmHg • Morbidity:15%-20%
The mechanism for reduction of BP
1.Early：↑Na+ and H2O excretion， ↓extracellular volume and blood volume， ↓cardiac output 2.Long：↓Na+ of vessel wall， ↓Na+-Ca2+ exchange, ↓intracellular Ca2+ ↓sensitivity of VSM to vasoconstrictors (NE) 3.Dilate VSM directly
prevention measures
One is to feel comfortable, to avoid sadness. It will cause hypertension. Second, life regularly. A regular life, the prevention of hypertension is very important. Third, reasonable diet and avoid obesity. Fourth, to actively participate in sports. In addition, according to the characteristics of their hobby. We can Often listen to beautiful music.
心血管药物
第十二章心血管药物Cardiovascular drugs1心血管药物Cardiovascular drugs•第一节抗高血压药Antihypertensive drugs •第二节强心药Cardiotonic agents•第三节抗心率失常药Antiarrhythmic drugs •第四节抗心绞痛药Antianginal drugs•第五节血脂调节药Plasma Lipids Regulators2第一节抗高血压药Antihypertensive drugs34各种抗高血压药物作用靶点脑神经节心输出量增加肾脏血管收缩血流量增加高血压外周阻力增加肾素-血管紧张素-醛固酮 系统 甲基多巴 盐酸可乐定神经阻断剂利血平血管扩张剂ACE 抑制剂血管紧张素Ⅱ受体拮抗剂利尿剂增大血容积β-受体阻断剂肾素醛固酮Antihypertensive drugsI.中枢降压药II.作用于神经末梢的降压药III.神经节阻断剂IV.血管扩张降压药V.作用于肾素-血管紧张素-醛固酮系统药物VI.钙离子拮抗剂56I 、中枢降压药莫索尼定 Moxonidine IR 1 (+)NNCl CH 3ONHH 3CH N N可乐定 Clonidine IR 1 (+) : 降压 α2 (+) : 副作用NHH N NCl Cl （中枢镇静）中枢α2受体激动剂中枢咪唑啉受体激动剂非肾上腺素能咪唑啉受体激动剂(第二代中枢降压药)7II. 作用于神经末梢的降压药利舍平Reserpine212019181716151413121110987654321N H N CH 3OHHHOCH 3CH 3OOCOOCOCH 3OCH 3OCH 3第一个从植物提取出有效的抗高血压药物萝芙木8III. 神经节阻断剂美卡拉明mecamylamine 潘必定Pempidine对于一般性高血压已很少使用乙酰胆碱N 胆碱受体无神经节乙酰胆碱N 胆碱受体去甲肾上腺素乙酰胆碱乙酰胆碱肾上腺素能受体M 胆碱受体N 胆碱受体效应器骨骼肌神经节神经节自主神经运动神经CNS9Ⅳ、血管扩张降压药NN H N HN CN CH 3CH 3CH 3CH 3激活ATP 敏感的钾通道,直接松弛血管平滑肌Act on potassium channels that sensitive with ATP吡那地尔双肼曲嗪 Dihydralazine肼曲嗪 HydralazineN N NHNH 2N NNHNH 2NHNH 2N NNHNHCOOC 2H 5NN NHN CCH 3肼屈嗪氰胍类苯并肽嗪类V.影响RAS系统的抗高血压药(重点)肾素－血管紧张素－醛固酮系统Renin-angiotensin-aldosterone system,RAS or RAAS10重点药物血管紧张素转化酶抑制剂ACEI卡托普利血管紧张素II受体拮抗剂氯沙坦11转化酶（ACE）1213血管紧张素转化酶（ACE ）功能•促进缓激肽降解•促进AngⅠ酶解为AngⅡ血管紧张素 II Ang. II血管紧张素原(Angiotensinogen)血管紧张素 I Ang. I肾素血管紧张素转化酶(ACE)缓激肽降解间接引起血压上升血管扩张缓激肽血管紧张素转化酶(ACE)肝脏分泌453个氨基酸十肽八肽1)血管紧张素转化酶抑制剂•根据ACE活性部位的化学结构设计出的ACE 抑制剂•–可以抑制AngⅡ的生成•–减少缓激肽的失活•–抗高血压药物• 合理药物设计的范例141) 血管紧张素转化酶抑制剂代表药：卡托普利⏹发现过程⏹结构命名⏹理化性质⏹合成路线⏹同类药物15中美上海施贵宝制药有限公16卡托普利的发现•1971年从巴西毒蛇的蛇毒•分离纯化出九肽替普罗肽•(Teprotide ，SQ 20881 ) •谷-色-脯-精-脯-谷-亮--脯-脯•可抑制ACE •替普罗肽口服无效N HN N NNN HOON H OONHOONH N HOOO OOHN H NH NH 2ONH 2受羧肽酶A研究启发1973底，羧肽酶抑制剂研究结果:•活性中心含有Zn2+,附近有一正电荷•将多肽链的C-端氨基酸水解切去17假想模型Binding model1819合成琥珀酰-L-脯氨酸•对ACE 有特异性抑制作用•作用很弱OCOOHCH 2OOH CH 2OOH OCH 2HSCHHSSuccinyl- L-Proline 1/500 as potent as SQ 20,881D-2-methyl1/300 as po20研究琥珀酰脯氨酸构效关系•合成其系列衍生物•高抑酶活性的都是模拟C 末端二肽结构•D-2-甲基琥珀酰-L-脯氨酸活性增强了15-20倍N OCOOHCH 2OOH N OCOOHCH 3CH 2OOH OCH 2HSOCH 2HSSuccinyl- L-Proline 1/500 as potent as SQ 20,881D-2-methylsuccinyl- L-Proline 1/300 as potent as SQ 20,88121进一步结构改造--巯基的引入•推断•–该酶有Zn 2+•–用对Zn 2+亲和力更大的基团取代羧基• 3-巯基丙酰基L-脯氨酸•–对ACE 的抑制活性又增大1000倍22得到卡托普利•D-3-巯基-2-甲基丙酰-L-脯氨酸（卡托普利）•活性超过替普罗肽NO OHOHSH3223卡托普利与ACE 相互作用HOTy rNH 2H 2NNH ArgOOGluOOGluOHSerNH N HisNNH HisZn2+HSN O HOOH CH 3S 1'S 2'羧基阳离子对结合酶起重要作用吡咯环与S2′结合2-甲基丙酰基与S1′结合。
心血管药理学CARDIOVASCULARPHARMACOL
适于中、高度高血压，很少单用 不良反应：严重时为心肌缺血、心衰，
长期用有水钠潴留，高剂量可引起全身 性红斑狼疮样综合征及类风湿性关节炎
硝普钠 （soudium nitoprusside）
压是某些疾病的一种表现。
1.原发性高血压病因学说 1）神经学说 2）肾素学说
2.根据舒张压高度和脑、心、肾等重要 器官损害的程度,可分为1、2、3期或轻、中 、重型高血压病。
3.应用降压药意义 降低血压缓解症状，使高血压并发症↓ ，延长寿命，提高生活质量。
23.1 抗高血压药的分类
四大类 : 1.交感神经阻滞药
重要的一类抗高血压药
[作用特点]
1. 阻滞Ca2+通道→[Ca2+]i↓→小A松弛→外 周阻力↓→ Bp↓，对多数V无明显影响。
2. 外周阻力↓ →反射性交感神经活性↑→心 率↑（维拉帕米不明显）。增强的交感神 经活性对心脏的兴奋作用可克服钙拮抗剂 减弱心肌收缩力的影响。
3. 降压时不降低心、脑、肾等器官的血流 量；肾血管阻力↓，肾小球滤过率↑，对伴 有糖尿病患者及实质性肾病者有利；
少 见。严重肾功能不全、孕妇、哺乳期妇女禁 用。
乌拉地尔（urapidil）
选择性阻断α1受体，也激动中枢的 5-HT1A受体，降低延髓心血管调节中枢的交 感反馈调节，而使外周阻力降低，血压下降
。
适用于各期高血压，子痫、高血压危象，也
适拉用贝于洛后尔负（荷la增be高ta的lo急l）性左心衰竭。
竞争性阻断α1和β受体。降压作用温 和，适用于治疗各型高血压。
antihypertensive drugs抗高血压药
Indapamide Increase in renal Na+ excretion →diuresis Dilate the vascular smooth muscle. Have no effect on the serum lipids.
The mechanism for reduction of BP of thiazide diuretics
பைடு நூலகம்
Thiazide diuretics
Long-term ↓ Na+ in vessel wall ↑ Na+-Ca2+ exchange initial ↓ sodium, water retention
↓ blood volume
↓ Ca+ in smooth musclecell ↓ peripheral resistance
↓ cardiac output
Decrease in BP
Clinical uses and evaluation
Low-dose of thiazide diuretic therapy is safe , effective and cheap for hypertension. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension , particularly elderly patients. Low doses of hydrochlorothiazide(25-50mg/d) exert as much antihypertensive effect as do higher doses.
(完整版)药学英语专业词汇
（完整版）药学英语专业词汇一、药物分类及命名1. 抗生素（Antibiotics）青霉素（Penicillin）头孢菌素（Cephalosporins）大环内酯类（Macrolides）2. 抗病毒药物（Antiviral Drugs）抗流感病毒药物（Antiviral for Influenza）抗艾滋病病毒药物（Antiviral for HIV）3. 抗肿瘤药物（Anticancer Drugs）化疗药物（Chemotherapeutic Agents）靶向治疗药物（Targeted Therapy Drugs）4. 心血管系统药物（Cardiovascular Drugs）抗高血压药物（Antihypertensive Drugs）抗心绞痛药物（Antianginal Drugs）抗心律失常药物（Antiarrhythmic Drugs）5. 消化系统药物（Gastrointestinal Drugs）抗胃溃疡药物（Antigastric Ulcer Drugs）止泻药物（Antidiarrheal Drugs）泻药（Laxatives）6. 中枢神经系统药物（Central Nervous System Drugs）抗抑郁药物（Antidepressants）抗精神病药物（Antipsychotic Drugs）镇痛药物（Analgesics）二、药物剂型及给药途径1. 剂型（Dosage Forms）片剂（Tablets）胶囊（Capsules）注射剂（Injections）2. 给药途径（Routes of Administration）口服（Oral）肌内注射（Intramuscular）静脉注射（Intravenous）三、药物作用及不良反应1. 药物作用（Pharmacological Actions）抗菌作用（Antibacterial Action）抗病毒作用（Antiviral Action）镇痛作用（Analgesic Action）2. 不良反应（Adverse Reactions）过敏反应（Allergic Reactions）胃肠道反应（Gastrointestinal Reactions）肝脏毒性（Hepatotoxicity）四、药学专业英语词汇1. 药理学（Pharmacology）药物代谢（Drug Metabolism）药物动力学（Pharmacokinetics）药效学（Pharmacodynamics）2. 药剂学（Pharmaceutics）制剂工艺（Preparation Technology）药物稳定性（Drug Stability）药物质量控制（Drug Quality Control）3. 药物化学（Medicinal Chemistry）药物合成（Drug Synthesis）药物结构（Drug Structure）药物设计（Drug Design）本文档旨在帮助药学专业学生和从业者掌握药学英语专业词汇，提高专业英语水平，为学术交流和临床实践提供便利。
2013心血管药物药剂
N N+
N O
O
N-
O
CH3
吗多明 molsidomine 肝脏代谢氧化释出NO 无硝酸酯类的头痛、眩 晕等中枢神经副作用
2. 硝酸酯及亚硝酸酯类作用比较
药物
起效时间 作用时间
给药方式
min
min
亚硝酸异戊酯 吸入
0.5
1
硝酸甘油
舌下
2
30
丁四硝酯
口服
15
3×60
硝酸异山梨酯 口服
15
5×60
戊四硝酯
Antihyperlipoproteinemic drugs
抗心率失常药 Antiarrhythmic drugs
1. 作用 2. 分类 3. 发展 4. 构效关系
1. 心肌细胞膜电位与离子转运
+20 跨 0膜 电 -20 位 -40 mv
-60 -
-80 -
-100 -
1
去 0极
化
2
复 极
化3
β －受体拮抗剂
非选择性β受体拮抗剂 β1 受体拮抗剂 混合型α/β 受体拮抗剂
（2）.发展历史
OH
H
HO
N
CH3
CH3 HO
Isoproterenal
OH
H
N
CH3
CH3
Pronethalol
OH
H
Cl
N
CH3
CH3 Cl
Dichloroisoproterenal（DCI）
OH
O C H2
H
N
14
HO H
2
Ar
NHCH(CH3)2
3
R－绝对构型
抗高血压药 antihypertensive drugs[可修改版ppt]
![抗高血压药 antihypertensive drugs[可修改版ppt]](https://img.taocdn.com/s3/m/cb540345cc22bcd127ff0c8d.png)
1. 血管紧张素转化酶抑制药 2. 血管紧张素Ⅱ受体阻断药 3. 肾素抑制药：瑞米吉仑 remikiren
肾素—血管紧张素系统 （renin-angiotensin system, RAS）
血管紧张素原 angiotensinogen
肾素
血管紧张素I angiotensin I
50 0 1990
1995
心脑血管病 肿瘤 呼吸病 损伤/中毒 消化病 传染病
2000
2005(年)
高血压分类
根据病因分类:
➢ 原发性高血压：也称高血压病，占90% （原因尚不明确）
➢ 继发性高血压：即症状性高血压，占10% （继发于嗜铬细胞瘤、肾动脉狭窄、肾实 质性病变、妊娠等）
高血压发病的危险因素
抗高血压药 antihypertensive
drugs
血压水平的定义和分类
分类 正常血压 高血压前期 1期高血压（轻） 2期高血压（中） 3级高血压（重） 单纯收缩期高血压
收缩压（mmHg） 120
120～139 140～159 160～179
≥180 ≥140
舒张压（mmHg） 80
80～89 90～99 100～109
利血平，胍乙啶
肾上腺素受体阻滞药：普萘洛尔
ACE抑制药：卡托普利
肾素-血管紧张素 系统抑制药
AT1受体阻滞药：氯沙坦 肾素抑制药：依那克林 肾醛固酮受体阻滞药：依普利酮
抗高血压药物分类
利尿药
钙拮抗药
第一线抗高血压药物
β受体阻断药 ACE抑制药
常用抗 高血压药
血管紧张素Ⅱ受体阻断药
一、肾素-血管紧张素系统抑制药
萘普生埃索美拉唑镁缓释片说明书(英文)
_______________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VIMOVO safely and effectively. See full prescribing information for VIMOVO. VIMOVO ™ (naproxen and esomeprazole magnesium) DELAYED RELEASE TABLETS Initial US Approval: April 2010 -----------------------RECENT MAJOR CHANGES------------------------ WARNINGS AND PRECAUTIONS 05/2011 Hypomagnesemia (5.19) WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS See full prescribing information for complete boxed warning Cardiovascular Risk •Naproxen, a component of VIMOVO, may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (5.1) •VIMOVO is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) Gastrointestinal Risk•NSAIDs, including naproxen, a component of VIMOVO, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events. (5.4) -------------------------INDICATIONS AND USAGE------------------------- Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers (1) ------------------------DOSAGE AND ADMINISTRATION----------------One tablet twice daily. Use the lowest effective dose. Not recommended in moderate/severe renal insufficiency or in severe hepatic insufficiency. Consider dose reduction in mild/moderate hepatic insufficiency (2) ----------------------DOSAGE FORMS AND STRENGTHS----------------Delayed release tablets: 375 mg/20 mg or 500 mg/20 mg of naproxen and esomeprazole magnesium (3) ----------------------------CONTRAINDICATIONS------------------------- •Known hypersensitivity to any component of VIMOVO or substituted benzimidazoles (4) •History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4, 5.8, 5.9, 5.13) • Use during the peri-operative period in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • Late pregnancy (4, 5.10, 8.1) --------------------WARNINGS AND PRECAUTIONS---------------------- •Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk (5.1) •Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. VIMOVO should be used with caution in these patients (5.4, 8.5) •Treatment should be withdrawn when active and clinically significantbleeding from any source occurs (5.5)•Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinueuse immediately if abnormal liver enzymes persist or worsen (5.11, 8.6, 12.3)•New onset or worsening of pre-existing hypertension. Blood pressureshould be monitored closely during treatment with VIMOVO (5.2, 7.1, 7.4)•Congestive heart failure and edema. VIMOVO should be used with caution in patients with fluid retention or heart failure (5.3) •Renal papillary necrosis and other renal injury with long-term use. Use VIMOVO with caution in the elderly, those with impaired renal function, hypovolemia, salt depletion, heart failure, liver dysfunction, and those taking diuretics, or ACE-inhibitors. Not recommended for patients with moderate or severe renal impairment (2, 5.6, 5.7, 7.1, 7.4, 8.7) •Anaphylactoid reactions. Do not use VIMOVO in patients with the aspirin triad (5.8) • Serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and can occur without warning. Discontinue VIMOVO at first appearance of skin rash or any other sign of hypersensitivity (5.9) • Long-term proton pump inhibitor (PPI) therapy is associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine (5.16) • Symptomatic response to esomeprazole does not preclude the presence of gastric malignancy (5.4) • Atrophic gastritis has been noted on biopsy with long-term omeprazole therapy (5.4) • Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.19) ---------------------------------ADVERSE REACTIONS-------------- Most common adverse reactions in clinical trials (>5%): erosive gastritis, dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or /medwatch. ----------------------------DRUG INTERACTIONS----------- •Concomitant use of NSAIDs may reduce the antihypertensive effect of ACE Inhibitors, diuretics, and beta-blockers (7.1, 7.4, 7.9) • Concomitant use of NSAIDs increases lithium plasma levels (7.5) • Concomitant use of VIMOVO with methotrexate may increase the toxicity of methotrexate (7.6) • Concomitant use of VIMOVO and warfarin may result in increased risk of bleeding complications. Monitor for increases in INR and prothrombin time (7.7) • Esomeprazole inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, iron salts and digoxin) (7.11) ---------------------------USE IN SPECIFIC POPULATIONS------- • Pregnancy Category C: VIMOVO should not be used in late pregnancy (4, 5.10, 8.1) • Hepatic Insufficiency: VIMOVO is not recommended in patients with severe hepatic insufficiency (2, 4, 5.11, 8.6, 12.3) • Renal Insufficiency: VIMOVO is not recommended in patients with moderate or severe renal insufficiency (2, 5.6, 5.7, 8.7, 12.3) SEE 17 FOR PATIENT COUNSELING INFORMATION AND FDA APPROVED PATIENT LABELING OR MEDICATION GUIDE REVISED MAY 2011 FULL PRESCRIBING INFORMATION: CONTENTS* 5.5 Active Bleeding 5.6 Renal Effects Cardiovascular Risk 5.7 Advanced Renal Disease 1 INDICATIONS AND USAGE 5.8 Anaphylactoid Reactions 2 DOSAGE AND ADMINISTRATION 5.9 Skin Reactions 3 DOSAGE FORMS AND STRENGTHS 5.10 Pregnancy 4 CONTRAINDICATIONS 5.11 Hepatic Effects 5 WARNINGS AND PRECAUTIONS 5.12 Hematological Effects 5.1 Cardiovascular Thrombotic Events 5.13 Pre-existing Asthma 5.2 Hypertension 5.14 Concomitant NSAID Use 5.3 Congestive Heart Failure and Edema5.15 Corticosteroid Treatment5.17 Masking of Inflammation and Fever5.18 Laboratory Tests5.19 Hypomagnesemia6 ADVERSE REACTIONS6.1 Clinical Studies Experience6.2 Postmarketing experience7 DRUG INTERACTIONS7.1 ACE-inhibitors7.2 Aspirin7.3 Cholestyramine7.4 Diuretics7.5 Lithium7.6 Methotrexate7.7 Anticoagulants7.8 Selective Serotonin Reuptake Inhibitors (SSRIs)7.9 Other Information Concerning Drug Interactions7.10 Drug/Laboratory Test Interaction7.11 Interactions related to absorption7.12 Antiretroviral agents7.13 Effects on hepatic metabolism/cytochrome P-450 pathways7.14 Other pharmacokinetic-based interactions8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Insufficiency8.7 Renal Insufficiency10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed1FULL PRESCRIBING INFORMATION Cardiovascular RiskNon-Steroidal Anti-inflammatory Drugs (NSAIDs), a component of VIMOVO, may cause an increased riskof serious cardiovascular thrombotic events,myocardial infarction, and stroke, which can be fatal.This risk may increase with duration of use. Patientswith cardiovascular disease or risk factors forcardiovascular disease may be at greater risk [seeWarnings and Precautions (5.1)].VIMOVO is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypassgraft (CABG) surgery [see Contraindications (4), andWarnings and Precautions (5.1)].Gastrointestinal RiskNSAIDs, including naproxen, a component of VIMOVO, cause an increased risk of seriousgastrointestinal adverse events including bleeding,ulceration, and perforation of the stomach or intestines,which can be fatal. These events can occur at any timeduring use and without warning symptoms. Elderlypatients are at greater risk for serious gastrointestinalevents [see Warnings and Precautions (5.4)].INDICATIONS AND USAGEVIMOVO is a combination product that contains naproxenand esomeprazole. It is indicated for the relief of signs andsymptoms of osteoarthritis, rheumatoid arthritis andankylosing spondylitis and to decrease the risk of developinggastric ulcers in patients at risk of developing NSAID-associated gastric ulcers. VIMOVO is not recommended forinitial treatment of acute pain because the absorption ofnaproxen is delayed compared to absorption from othernaproxen-containing products. Controlled studies do notextend beyond 6 months.2 DOSAGE AND ADMINISTRATIONCarefully consider the potential benefits and risks ofVIMOVO and other treatment options before deciding to useVIMOVO. Use the lowest effective dose for the shortestduration consistent with individual patient treatment goals.VIMOVO does not allow for administration of a lower dailydose of esomeprazole. If a dose of esomeprazole lower thana total daily dose of 40 mg is more appropriate, a differenttreatment should be considered.Rheumatoid Arthritis, Osteoarthritis and AnkylosingSpondylitisThe dosage is one tablet twice daily of VIMOVO 375 mgnaproxen and 20 mg of esomeprazole or 500 mg naproxenand 20 mg of esomeprazole.The tablets are to be swallowed whole with liquid. Do notsplit, chew, crush or dissolve the tablet. VIMOVO is to betaken at least 30 minutes before meals.Geriatric PatientsStudies indicate that although total plasma concentration ofnaproxen is unchanged, the unbound plasma fraction ofnaproxen is increased in the elderly. Use caution when highdoses are required and some adjustment of dosage may berequired in elderly patients. As with other drugs used in theelderly use the lowest effective dose [see Use in SpecificPopulations (8.5) and Clinical Pharmacology (12.3)].Patients With Moderate to Severe Renal ImpairmentNaproxen-containing products are not recommended for usein patients with moderate to severe or severe renalimpairment (creatinine clearance <30 mL/min) [seeWarnings and Precautions (5.6, 5.7) and Use in SpecificPopulations (8.7)].Hepatic InsufficiencyMonitor patients with mild to moderate hepatic impairmentclosely and consider a possible dose reduction based on thenaproxen component of VIMOVO.VIMOVO is not recommended in patients with severehepatic impairment because esomeprazole doses should notexceed 20 mg daily in these patients [see Warnings andPrecautions (5.11), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].Pediatric PatientsThe safety and efficacy of VIMOVO in children youngerthan 18 years has not been established. VIMOVO istherefore not recommended for use in children.3 DOSAGE FORMS AND STRENGTHSOval, yellow, delayed release tablets for oral administrationcontaining either:• 375 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium trihydrate) tabletsprinted with 375/20 in black, or• 500 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium trihydrate) tabletsprinted with 500/20 in black.4 C ONTRAINDICATIONSVIMOVO is contraindicated in patients with knownhypersensitivity to naproxen, esomeprazole magnesium,substituted benzimidazoles, or to any of the excipients.VIMOVO is contraindicated in patients who haveexperienced asthma, urticaria, or allergic-type reactions aftertaking aspirin or other NSAIDs. Severe, rarely fatal,anaphylactic-like reactions to NSAIDs have been reported insuch patients [see Warnings and Precautions (5.8, 5.13)].Hypersensitivity reactions, eg, angioedema and anaphylacticreaction/shock, have been reported with esomeprazole use.VIMOVO is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft(CABG) surgery [see Warnings and Precautions (5.1)].VIMOVO is contraindicated in patients in the late stages ofpregnancy [see Warnings and Precautions (5.10) and Use inSpecific Populations (8.1)].5 WARNINGS AND PRECAUTIONS5.1 Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselectiveNSAIDs of up to three years duration have shown anincreased risk of serious cardiovascular (CV) thromboticevents, myocardial infarction, and stroke, which can be fatal.All NSAIDS, both COX-2 selective and nonselective, mayhave a similar risk. Patients with known CV disease or riskfactors for CV disease may be at greater risk. To minimizethe potential risk for an adverse CV event in patients treatedwith an NSAID, the lowest effective dose should be used forthe shortest duration possible. Physicians and patients shouldremain alert for the development of such events, even in theabsence of previous CV symptoms. Patients should beinformed about the signs and/or symptoms of serious CVevents and the steps to take if they occur.There is no consistent evidence that concurrent use of aspirinmitigates the increased risk of serious CV thrombotic eventsassociated with NSAID use.Two large, controlled, clinical trials of a COX-2 selectiveNSAID for the treatment of pain in the first 10–14 daysfollowing CABG surgery found an increased incidence ofmyocardial infarction and stroke [see Contraindications (4)].5.2 H ypertensionNSAIDs, including naproxen, a component of VIMOVO, canlead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to theincreased incidence of CV events. Patients taking thiazides orloop diuretics may have impaired response to these therapieswhen taking NSAIDs. NSAIDs should be used with cautionin patients with hypertension. Blood pressure (BP) should bemonitored closely during the initiation of NSAID treatmentand throughout the course of therapy [see Drug Interactions(7.1, 7.4)].5.3 Congestive Heart Failure and EdemaFluid retention, edema, and peripheral edema have beenobserved in some patients taking NSAIDs and should be usedwith caution in patients with fluid retention or heart failure.— Risk of Ulceration, Bleeding, 5.4 G astrointestinalEffectsand PerforationNSAIDs, including naproxen, a component of VIMOVO, cancause serious gastrointestinal (GI) adverse events includinginflammation, bleeding, ulceration, and perforation of thestomach, small intestine, or large intestine, which can befatal. While VIMOVO has been shown to significantlydecrease the occurrence of gastric ulcers compared tonaproxen alone, ulceration and associated complications canstill occur.These serious adverse events can occur at any time, with orwithout warning symptoms, in patients treated with NSAIDs.Only one in five patients who develop a serious upper GIadverse event on NSAID therapy is symptomatic. Upper GIulcers, gross bleeding, or perforation caused by NSAIDsoccur in approximately 1% of patients treated for 3–6months, and in about 2–4% of patients treated for one year.These trends continue with longer duration of use, increasingthe likelihood of developing a serious GI event at some timeduring the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed.VIMOVO should be prescribed with caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk of developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants or antiplatelets (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.To minimize the potential risk for an adverse GI event in patients treated with an NSAID or NSAID-containing product, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding [see Drug Interactions (7.2, 7.8)]. Although these studies focused on upper gastrointestinal bleeding, bleeding at other sites cannot be ruled out.NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Gastrointestinal symptomatic response to therapy with VIMOVO does not preclude the presence of gastric malignancy.Atrophic gastritis has been noted occasionally in gastriccorpus biopsies from patients treated long-term withomeprazole, of which esomeprazole is an enantiomer and acomponent of VIMOVO.Bleeding5.5 A ctiveWhen active and clinically significant bleeding from anysource occurs in patients receiving VIMOVO, the treatmentshould be withdrawn.5.6 Renal EffectsLong-term administration of NSAIDs has resulted in renalpapillary necrosis and other renal injury. Renal toxicity hasalso been seen in patients in whom renal prostaglandins havea compensatory role in the maintenance of renal perfusion. Inthese patients, administration of an NSAID may cause adose-dependent reduction in prostaglandin formation and,secondarily, in renal blood flow, which may precipitate overtrenal decompensation. Patients at greatest risk of this reactionare those with impaired renal function, hypovolemia, heartfailure, liver dysfunction, salt depletion, those takingdiuretics and ACE inhibitors, and the elderly.Discontinuation of NSAID therapy is usually followed byrecovery to the pretreatment state.5.7 Advanced Renal DiseaseNo information is available from controlled clinical studiesregarding the use of VIMOVO in patients with advancedrenal disease. Therefore, treatment with VIMOVO is notrecommended in these patients with advanced renal disease.If VIMOVO therapy must be initiated, close monitoring ofthe patient’s renal function is advisable [see Dosage andAdministration (2), Use in Specific Populations (8.7) andClinical Pharmacology (12.3)].5.8 Anaphylactoid ReactionsAnaphylactoid reactions may occur in patients withoutknown prior exposure to either component of VIMOVO.NSAIDs should not be given to patients with the aspirin triad.This symptom complex typically occurs in asthmatic patientswho experience rhinitis with or without nasal polyps, or whoexhibit severe, potentially fatal bronchospasm after takingaspirin or other NSAIDs [see Contraindications (4)].Emergency help should be sought in cases where ananaphylactoid reaction occurs. Anaphylactoid reactions, likeanaphylaxis, may have a fatal outcome.5.9 Skin ReactionsNSAIDs can cause serious skin adverse events such asexfoliative dermatitis, Stevens-Johnson syndrome, and toxicepidermal necrolysis, which can be fatal. These seriousevents may occur without warning. Patients should beinformed about the signs and symptoms of serious skinmanifestations and use of the drug should be discontinued atthe first appearance of skin rash or any other sign ofhypersensitivity.5.10 P regnancyPregnancy Category CIn late pregnancy, as with other NSAIDs, naproxen, acomponent of VIMOVO, should be avoided because it maycause premature closure of the ductus arteriosus [seeContraindications (4), and Use in Specific Populations (8.1)].5.11 Hepatic EffectsBorderline elevations of one or more liver tests may occur inup to 15% of patients taking NSAIDs including naproxen, acomponent of VIMOVO. Hepatic abnormalities may be theresult of hypersensitivity rather than direct toxicity. Theselaboratory abnormalities may progress, may remainessentially unchanged, or may be transient with continuedtherapy. The SGPT (ALT) test is probably the most sensitiveindicator of liver dysfunction. Notable elevations of ALT orAST (approximately three or more times the upper limit ofnormal) have been reported in approximately 1% of patientsin clinical trials with NSAIDs. In addition, rare cases ofsevere hepatic reactions, including jaundice and fatalfulminant hepatitis, liver necrosis and hepatic failure, someof them with fatal outcomes, have been reported.A patient with symptoms and/or signs suggesting liverdysfunction, or in whom an abnormal liver test has occurred,should be evaluated for evidence of the development of moresevere hepatic reaction while on therapy with VIMOVO.If clinical signs and symptoms consistent with liver diseasedevelop, or if systemic manifestations occur (eg,eosinophilia, rash, etc.), VIMOVO should be discontinued.Chronic alcoholic liver disease and probably other diseaseswith decreased or abnormal plasma proteins (albumin) reducethe total plasma concentration of naproxen, but the plasmaconcentration of unbound naproxen is increased. Caution isadvised when high doses are required and some adjustmentof dosage may be required in these patients. It is prudent touse the lowest effective dose for the shortest possibleduration of adequate treatment.VIMOVO is not recommended in patients with severehepatic impairment because esomeprazole doses should notexceed 20 mg daily in these patients [see Dosage andAdministration (2), and Use in Specific Populations (8.6)].5.12 H ematological EffectsAnemia is sometimes seen in patients receiving NSAIDs.This may be due to fluid retention, occult or gross GI bloodloss, or an incompletely described effect upon erythropoiesis.Patients on long-term treatment with NSAIDs should havetheir hemoglobin or hematocrit checked if they exhibit anysigns or symptoms of anemia.NSAIDs inhibit platelet aggregation and have been shown toprolong bleeding time in some patients. Unlike aspirin, theireffect on platelet function is quantitatively less, of shorterduration, and reversible. Patients receiving VIMOVO whomay be adversely affected by alterations in platelet function,such as those with coagulation disorders or patients receivinganticoagulants or antiplatelets, should be carefully monitored. 5.13 Pre-existing AsthmaPatients with asthma may have aspirin-sensitive asthma. Theuse of aspirin in patients with aspirin-sensitive asthma hasbeen associated with severe bronchospasm, which can befatal. Since cross reactivity, including bronchospasm,between aspirin and other NSAIDs has been reported in suchaspirin-sensitive patients, VIMOVO should not beadministered to patients with this form of aspirin sensitivityand should be used with caution in patients with pre-existingasthma.5.14 Concomitant NSAID UseVIMOVO contains naproxen as one of its active ingredients.It should not be used with other naproxen-containingproducts since they all circulate in the plasma as thenaproxen anion.The concomitant use of VIMOVO with any dose of a non-aspirin NSAID should be avoided due to the potential forincreased risk of adverse reactions.5.15 C orticosteroid TreatmentVIMOVO cannot be expected to substitute for corticosteroidsor to treat corticosteroid insufficiency. Abruptdiscontinuation of corticosteroids may lead to diseaseexacerbation. Patients on prolonged corticosteroid therapyshould have their therapy tapered slowly if a decision is madeto discontinue corticosteroids and the patient should beobserved closely for any evidence of adverse effects,including adrenal insufficiency and exacerbation ofsymptoms of arthritis.5.165.17 5.185.19 Bone FractureSeveral studies and literature reports indicate that proton pump inhibitor (PPI) therapy is associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Those patients with the highest risk received high-dose or long-term PPI therapy (a year or longer). Patients should use the lowest effective dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. Adequate vitamin D and calcium intake is recommended. Masking of Inflammation and FeverThe pharmacological activity of VIMOVO in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.Laboratory TestsBecause serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, VIMOVO should be discontinued.Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically.HypomagnesemiaHypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [see Adverse Reactions (6.2)]。
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Since the product of heart rate and stroke volume equals cardiac output, an increase
in heart rate will increase arterial blood pressure, all other factors remaining equal.
Adrenergic Neuron Blocker
Guanethidine Reserpine
Adrenoceptor Antagonists
Labetalol (alpha & beta) Prazosin (alpha) Terazosin (alpha)
Vasodilators
Diazoxide Hydralazine Minoxidil Nitroprusside sodium
Angiotensin Converting Enzyme Inhibitors (ACEI)
Benazepril Captopril Enalapril Fosinopril Quinapril Ramipril
Angiotensin Receptor Blocker
Saralasin Losartan Irbesartin
Peripheral resistance:
For a given cardiac output, blood pressure depends only on peripheral resistance. Some antihypertensive drugs act to reduce peripheral resistance.
Cardiovascular Pharmacology
Antihypertensive Drugs
Classification of Arterial Hypertension
Systolic hypertension
Systolic and Diastolic
hypertension
Renal Disease
Centrally Active
Clonidine Methyldopa Guanabenz Guanfacine
α2-Adrenergic Agonist
• clonidine • major action is in the brain (tends to
overrideaction in the periphery) – decrease sympathetic tone – sedative effect at higher doses
Control of Blood Pressure
Physiological Factors Influencing Arterial Pressure
Preload & Contractility
Peripheral resistance
Heart Rate
Preload & Contractility
Mechanism of Antihypertension
Reduce preload
Reduce contractility
Reduce peripheral resistance
Antihypertension
Reduce afterload
Decrease heart rate
The basic regulating mechanism of short period arterial blood pressure is baroreceptors. When the blood pressure is elevated, the baroreceptors is stimulated. It can inhibit vasoconstrictor center through oblongata solitary tract, and stimulate vagus nerve center. The results are that peripheral vasorelaxation, myocardial negative tension effect and negative rhythm effect.
Diuretics Centrally Active Adrenergic Neuron Blocker Adrenoceptor Antagonists Vasodilators Calcium Channel Blockers Angiotensin Converting Enzyme Inibitors Angiotensin Receptor Blocker
– Atrial fibrillation – Diabetic diarrhea – Reduction of allergen-induced inflammatory reactions in patients with extrinsic
α-methyldopa :
Enters the synthesis pathway at the DOPA step
The sympathetic nervous system maintains arterial blood pressure by several mechanisms:
Sympathetic maintains BP
Long-Term Regulation
Anti-Hypertensive Drug Classes
Unknown Etiology
◆ Toxemia of pregnancy ◆ Acute intermittant porphyria ◆ Essential Hypertension (> 90% of all cases of hypertension）
Essential Hypertension
Clonidine
Approved or severe pain in cancer patients
Clonidine
Unlabeled uses: – Alcohol withdrawal – Methadone/opiate detoxification – Smoking cessation facilitation
ß-Adrenergic Antagonists (Beta Blockers)
Acebutalol (Sectral) Atenolol (Tenormin) Betaxolol (Kertone) Bisoprolol (Zebeta) Carteolol (Cartrol) Metoprolol (Lopressor)
Neurogenic Disease
◆ Psychogenic ◆ Polyneuritis ◆ Elevated intracranial pressure ◆ Familial dysautonomia
Miscellaneous
◆ Increased intravascular volume ◆ Polyarteritis nodosa ◆ Hypercalcemia ◆ Aortic coarctation
Endocrine Diesease
◆ Adrenocortical hyperactivity (Cushing‘s disease, primary hyperaldosteronism) ◆ Oral contraceptives ◆ Pheochromcytoma ◆ Acromegaly ◆ Myxedema
Endocrine Disease
Miscellaneous
Etiology
Unknown Etiology
Neurogenic Disease
Renal Disease
◆ Renovascular stenosis or renal infarction ◆ Polycystic kidney disease ◆ Acute and chronic glomerulonephritis ◆ Chronic pyelonephritis ◆ Renin-producing tumors ◆ Other severe renal diseases
* Crosses membranes easily->α-CH3-DA-> αCH3-NE * Conversion occurs only in neurons and CNS
-Displaces NE from granules->NE metabolized by MAO -Higher affinity for presynaptic α2R -> ↓ NE release in vasomotor center -> ↓ TPR and ↓ BP -Is as potent as NE on periphal receptors
Penbutalol (Levatol) Pindolol (Visken) Propranolol (Inderal) Sotalol (Betapace) Timolol (Blocadren)
THANKS!
Calcium Channel Blockers
Dihydropyridines
Amlodipine Felodipine Nimodipine Isradipine Nicardipine Nifedipine
Non-Dihydropyridines
Bepridil Diltiazem Verapamil
As blood volume returning to the heart increases, preload increases and there is enhanced filling with ventricular dilation.