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Pharmacology for cardiovascular system. . Antihypertensive Drugs. xiangnan_zhang@zju.edu.cn. Contents:. Overview Classification of antihypertensive drugs Antihypertensive drugs Clinical pharmacology of antihypertensive drugs. 1. Overview. - PowerPoint PPT Presentation

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  • Antihypertensive DrugsPharmacology for cardiovascular systemxiangnan_zhang@zju.edu.cn

  • Contents:OverviewClassification of antihypertensive drugsAntihypertensive drugsClinical pharmacology of antihypertensive drugs

  • 1. Overview

  • Age-adjusted annual incidence of CHD per 1000Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baselineSystolic blood pressure (mmHg)Blood Pressure and Risk for Coronary Heart Disease in MenDiastolic blood pressure (mmHg)Age 65-94Age 35-64Age 65-94Age 35-64Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.

  • High Risk Factors of Hypertension:Stressful life-styleHigh dietary intake of sodiumObesity and hyperlipidemiaSmokingHereditary factorsEtiology of HypertensionSecondary hypertension(10~15%)Essential hypertension(85~90%)

  • IIIIII 1~2 3

  • The end organ damage of hypertension: Kidney: renal failure Heart: coronary disease, cardiac failure Brain: stroke

  • The goal of treatment: Lower the blood pressure Protect the target organ Reduce the morbidity and mortality rates Best therapy and minimal risk

    1. Overview

  • 1. OverviewMajor factors influencing blood pressureArterial blood pressureCardiac outputPeripheral resistanceVenous toneBlood volumeFilling pressureContractility

    Heart ratearteriolarvolumeBaroreceptors and sympathetic nervous system RAAS

  • 2. Classifications of hypertensive DrugsDiureticsCalcium channel blockersRenin-angiotensin system inhibitors ACEIs ARBs Renin inhibitors

  • Sympathetic inhibitors Centrally acting adrenergic drugs Ganglion blockers Noradrenergic nerve ending blockers Adrenoreceptor blockers receptor blockers receptor blockers and receptor blockersVasodilators

  • 3. Antihypertensive Drugs3.1 DiureticsA ActionsReduce plasma volume(cardiac output )Reduce Na+-Ca2+ exchange in vascular smooth muscle cell (peripheral resistance )

  • NaHCO3 NaClH2ONa+ K+ Cl-Na+ Cl-K+

  • 3.1 DiureticsB Therapeutic uses:Hypertension - Single drug or combined with others - Particularly useful in the treatment of elderly patients, pure systolic hypertension, hypertension with heart failure3. Antihypertensive Drugs

  • Diuretics

  • 3. Antihypertensive Drugs3.1 DiureticsC Adverse effects: plasma level of renin hypokalemia () hyperuricemia () hyperglycemia () hyperlipidemia ()

  • 3. Antihypertensive Drugs3.2 Calcium channel blockers (CCBs)Nifedipine A ActionsRelaxs vascular smooth muscle B Therapeutic uses:Mild to severe hypertension (usually combined with blockers )

  • 3. Antihypertensive DrugsnifedipineC Adverse effects Peripheral edema Reflex sympathetic activation Renin activity

  • Other calcium channel blockers: Verapamil Diltiazem Nimodipine Amlodipine Felodipine

    3. Antihypertensive Drugs

  • Generations of calcium channel blockers

    First generation: verapamil(), nifedipine(), diltiazem(). Second generation: . nimoldipine(), felodipine(). Third generation: , t. pranidipine(), amlodipine().

  • 3. Antihypertensive Drugs3.3 Renin- angiotensin system inhibitors

    ACEIs ARBs Renin inhibitors

  • AT1Angiotensin converting enzyme, ACE

  • GFRProteinuriaAldosterone releaseGlomerular sclerosisAngII Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunctionLV hypertrophyFibrosisRemodellingApoptosisDEATH*Preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate AngII AT1 receptor

  • Constricts vessels, increases peripheral resistance and returned blood volume.Increases sympathetic tension, promotes release of sympathetic transmitter.Stimulates release of aldosterone.Induces expression of c-fosc-mycc-jun rapidly.Actions of angiotensin II

  • Angiotensin converting enzyme inhibitors(ACEIs)

  • 3. Antihypertensive Drugs3.3 Renin- angiotensin system inhibitorsACEIsA ActionsInhibit the production of Ang II (dilate vessels, decrease sympathetic activity, inhibit release of aldosterone, anti-hypertrophy)Inhibit the degradation of bradykinin

  • Angiotensin IIAngiotensin IACECirculation and local tissuesACEIACECirculation and local tissues()B 2 receptorACEI()BrandykininInactive peptideVasodilationAnti-proliferation, anti-hypertrophyActions of ACEIs

  • 3. Antihypertensive DrugsACEIsB Therapeutic usesAntihypertension - without reflexly increasing the activity of sympathetic system - effective in the treatment of CHF, diabetes and ischemic heart disease.

  • 3. Antihypertensive DrugsACEIsC Adverse effects Hypotension ( first dose phenomenon ) Renal injury (renal artery sclerosis ) Dry cough and angioneuroedema (bradykinin accumulation) Hyperkalemia (aldosterone inhibition) Rashes and altered taste Fetotoxicity

  • 3. Antihypertensive DrugsACEIsD Contraindications Renal artery stenosis Pregnant and lactation women

  • 3. Antihypertensive DrugsARBsCompared with ACEIs:Block actions of angiotensin II directlyNo influence on bradykinin metabolismProtect renal functionUsed for mild to moderate hypertension Less adverse effects

  • 3. Antihypertensive DrugsRenin inhibitorsInhibit whole RAASInclude renin antibody, peptide and nonpeptide renin inhibitors (eg. remikiren)

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.1 Adrenoreceptor blockers receptor blockersA ActionsDecrease cardiac outputInhibit the release of renin from kidney (formation of angiotension and secretion of aldosterone )

  • 3. Antihypertensive Drugs receptor blockersA ActionsDecrease sympathetic outflow from CNS and release of noradrenalin from peripheral nerve endingsIncrease production of PGsIncrease sensitivity of baroreceptor

  • 3. Antihypertensive Drugs receptor blockersB Therapeutic usesHypertension: all kinds of hypertension - more effective in young patients than elderly - useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headache

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.1 Adrenoreceptor blockers 1 receptor blockersA ActionsRelax arterial and venous smooth muscle, decrease peripheral resistanceAlterations in serum lipid patterns

  • 3. Antihypertensive Drugs1 receptor blockersB Therapeutic usesHypertension: mild to moderate (single) and severe hypertension(combined with diuretics and blockers) minimal changes in cardiac output, renal blood flow renin release and glomerular filtration

  • 3. Antihypertensive Drugs1 receptor blockersC Adverse effects First dose phenomenon (postural hypotension) sodium retention

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.1 Adrenoreceptor blockers and 1 receptor blockersMild decrease of blood pressureMinimal changes in cardiac output and heart rateUsed for all kinds of hypertension, including hypertensive emergencyLess adverse effects

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.2 Centrally-acting drugs Clonidine ()A ActionsDiminishes central adrenergic outflow - activates 2 receptor in medulla - activates I1 receptor in medulla

  • 3. Antihypertensive DrugsClonidine B Therapeutic usesHypertension: mild to moderate - minimal changes in renal blood flow and glomerular filtration - inhibits gastrointestinal secretion and mobility

  • 3. Antihypertensive DrugsClonidineC Adverse effects Atropine-like effects Water and sodium retention (renal filtration ) Rebound phenomenon

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.2 Centrally-acting drugs I1 receptor agonists Rilmenidine Moxonidine

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.3 Ganglion blockers Trimetaphan() Mecamylamine

  • 3. Antihypertensive Drugs3.4 Sympathetic system inhibitors3.4.4 Noradrenergic nerve ending blockers Reserpine () Guanethidine ()

  • 3. Antihypertensive Drugs3.5 VasodilatorsHydralazine ()Dilates arteries and arteriolesDecreases peripheral resistanceReflexly elevates heart rate, cardiac output and renin release.Administrated with blockers and diuretics. Adverse effects due to vasodilation and lupus-like syndrome can occur.

  • 3. Antihypertensive Drugs3.5 VasodilatorsNitroprusside sodium ()Dilates small arteries and veins Used for treatment of emergency hypertension, hypertension with CHF, controlled hypotension and obstinate CHF Adverse effects due to hypotension in excess and sulfocyanate poisoning.

  • 3. Antihypertensive Drugs3.5 VasodilatorsPotassium channel openersIncluding minoxidil, nicorandil, diazoxide, etc.Dilates arteries (Ca influx )Reflexly elevates heart rate, cardiac output and renin release.Used for treatment of obstinate and severe hypertensionAdverse effects include sodium retention, palpitation, etc

  • 4.1 General information 4. Clinical pharmacology of Antihypertensive DrugThe diagnosis of hypertension should be established by find

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