Drugs Affecting the Cardiovascular System

Ion Channels Blockers Antihypertension Drugs The Treatment of Congestive Heart FailureAntiarrhythmic DrugsAntianginal DrugsAntihyperlipidemic Drugs and Anti-artherosclerosis Drugs

Antihypertensive Drugs

OVERVIEW

Hypertension is defined as a sustained diastolic blood pressure greater than 90 mmHg (mercury) accompanied by an elevated systolic blood pressure(>140 mmHg). Hypertension results from increased peripheral vascular smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system. Elevated blood pressure is an extremely common disorder, affecting approximately 10-15% of the population. Although many of these individuals have no symptoms, chronic hypertension-either systolic or diastolic can lead to congestive heart failure, myocardial infarction, renal damage, and cerebrovascular accidents. The incidence of morbidity and mortality significantly decreases when hypertension is diagnosed early and is properly treated.

• ETIOLOGY OF HYPERTENSION

• Essential/primary hypertension: more than 90% of patients have essential hypertension, a disorder of unknown origin affecting the blood pressure-regulating mechanism.

• A family history of hypertension in creases the likelihood that an individual will develop hypertensive disease.

• Essential hypertension occurs more often among middle-aged males than among middle-aged females.

• Environmental factors such as a stressful lifestyle, high dietary intake of sodium, obesity, and smoking all further predispose an individual to the occurrence of hypertension.

• ETIOLOGY OF HYPERTENSION

Secondary hypertension: occurs in 5-10% of patients. The cause is usually one of the following:

• Renal disease which activates the Renin-Angiotensin-Aldosterone System (RAAS)

• Endocrine disease, steroid-secreting turmour of the adrenal cortex, adrenaline-secreting tumour of the adrenal medulla.

• Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima. Arterial blood pressure is directly proportional to the product of the blood volume, cardiac output and the peripheral vascular resistance. In both normal and hypertensive individuals, blood volume cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: the baroreflexes mediated by the sympathetic nervous system, and the renin-angiotensin-aldosterone system (RAAS). Most antihypertensive drugs lower blood pressure by reducing cardiac output and /or decreasing peripheral resistance.

MECHANISMS FOR CONTROLLING BLOOD PRESSURE

Classification of Antihypertension ：

I. Sympatholytic drugs

II. Vasodilators

III. Inhibitors of RAS

IV. Diuretics

Classification I ：Sympatholytic drugs (drugs that alter sympathetic nervous system function)

Classification I ： Sympatholytic drugs (drugs that alter sympathetic nervous system function)

1.central antihypertensive drugs Clonidine 可乐定 , Methyldopa 甲基多巴

2.ganglion-blocking agents( ganglionic blocking drugs) Mecamylamine 美加明

3.adrenergic neuron blocking agents( antipostganglionic sympathetic neurons)

reserpine 利血平 , guanethidine 胍乙啶

4.adrenoceptor antagonists (adrenergic receptor blocking agents)

①β-adrenoceptor-blocking agents

propranolol 普萘洛尔，②α-adrenoceptor-blocking agents

prazosin 哌唑嗪③αand β-blockers

labetalol 拉贝洛尔

Classification II ： Vasodilators

1. direct vasodilators• hydralazine 肼苯哒嗪• sodium nitroprusside 硝普钠2. calcium channel blockers( calcium antagonists)• nifedipine 硝苯地平• nitrendipine 尼群地平3. potassium channel openers• minoxide 米诺地尔（长压定）• diazoxide 二氮嗪• pinacidil 吡那地尔

Classification III ： Inhibitors of RAS

1.angiotensin converting enzyme inhibitors. ACEI• captopril 卡托普利• enalapril 依那普利2.angiotensin receptor-blocking agents• losartan 氯沙坦• valsartan 缬沙坦3. renin inhibitors: Enalkiren( 依那吉仑 ) , Remikiren( 瑞米吉仑 )

Classification VI ： Diuretics

hydrochlorothiazide 氢氯噻嗪indapamide 吲达帕胺

Classification I. Sympatholytic drugs

Normal regulation of blood pressure in CNS:

Vasomotor centers

Center nervous system controls peripheral sympathetic activity in brain stem

• Inhibiting neurons:α2 receptor resulting in blood pressure lowering bradycardia vasodilatation• Exciting neurons: β receptors resulting in blood pressure enhancing tachycardia

Subtype 1. Central antihypertensive drugs

• Clonidine 可乐定 and Methyldopa 甲基多巴 may stimulate inhibiting neurons of central adrenoceptors-α2 receptor, resulting in vasodilation, blood pressure lowers.

Drug 1. Clonidine （可乐定）

又称氯压定， 2- imidazoline derivation

Pharmacokinetics:

• Lipid-soluble, rapid absorption by oral administration

• F, 75% t1/2 8~12 hours

• 30%~ 50% metabolisms in liver

• Others are eliminated unchanged in urine

Mechanism of action:1.stimulating postsynaptic α2 adrenoceptors in brai

n stem peripheral sympathetic activity↓ blood pressure↓ producing sedation

2.stimulating Ⅰ1-imidazoline 咪唑啉 receptor in rostral ventrolateral medulla oblongata (RVLM 延髓腹外侧核吻侧端 )peripheral sympathetic activity lowering

3.stimulating opium receptor

relieving abstinence syndrome 戒断症状

Pharmacodynamics:1. Relaxation of arterial vessels reduction in perip

heral vascular resistance blood pressure↓ lowers

2. Contracting force of cardiac muscule↓ reduction of cardiac output heart rate↓ decreases

3. Decreased renal vascular resistance and maintenance of renal blood flow

4. Inhibiting movement and secretion of gastrointestinal tract hypertensive patients with ulcer is the better

Adverse reaction:

1.dry mouth/ xerostomia (dry nasal mucosa, dry eyes), nausea, dizziness 头晕 , sedation 嗜睡 , parotid gland swelling and pain 腮腺肿痛 ,sleep disturbances with vivid dreams or nightmares 噩梦

2.water and sodium (Na+) retention

3.withdrawal syndrome 停药反应 headache apprehension( 恐惧忧虑 ), tremors( 震

颤 ),abdominal pain, sweating, tachycardia

treatment: α-adrenergic blocker (phentolamine)① ②continuative administration clonidine

Drug 2. Methyldopa

1.center antihypertension drug

2.treatment: mild to moderately severe hypertension with renal failure

3.reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output

4.no decreasing renal blood flow and glomerular filtration rate

Clinical uses:

1.moderate hypertensive disease

2.iv drop, therapy of hypertensive crisis 高血压危象

3.controlling abstinence syndrome of opium

Subtype 2. ganglion-blocking agents( ganglionic blocking drugs)

Drug: Mecamylamine 美加明

Subtype 3. Adrenergic neuronblocking agents

Pharmacological action:1. lower blood pressure, with long-term therapy with reserp

ine cardiac output↓ peripheral vascular resistance↓ heart rate↓ rennin secretion falls↓ salt and water are retained2. sedative and neuroleptic （精神安定） effect reserpine depletes catecholamine( 儿茶酚胺 ) and 5-hydr

oxytryptamine (5-HT)

Drug 1. Reserpine 利血平

Mechanism of action:

• Reserpine can remain bound to amine pump of vesicular membranes in central and peripheral adrenergic neurons for prolonged periods of time.

• The storage vesicles are destroyed as a result of their interaction with reserpine and nerve endings lose their ability to concentrate and store norepinephrine and dopamine.

• Catecholamines leak into the cytoplasm, where they are destroyed by intraneruronal monoamine oxidase (MAO), depressing the ability to uptake norepinephrine

• Reserpine -induced depletion of biogenic amines correlates with evidence of sympathetic dysfunction and antihypertensive effects.

• Recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug, so effect of reserpine is slow and persistent.

Clinical uses:• Mild hypertension• Cooperative administration

Adverse effects:

Sedation and inability to concentrate or perform complex tasks are the most common adverse effects.

More serious is the occasional psychotic depression.

Drug 2. Guanethidine 胍乙啶

Mechanism and sites of action:

• Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings.

• Guanethidine nerve concentration in transmitter vesicles replaces norepinephrine causes gradual depletion of norepinephrine stores in the nerve ending

①β-adrenoceptor-blocking agents

propranolol 普萘洛尔，②α-adrenoceptor-blocking agents

prazosin 哌唑嗪③αand β-blockers

labetalol 拉贝洛尔

Subtype 4. adrenoceptor antagonists (adrenergic receptor blocking agents)

Drug1.β-adrenoceptor-blocking agents1.Mechanism and sites of action①blocking β-receptor in heart, decreasing cardiac output②depressing secretion of rennin, inhibiting the rennin-angiot

ensin-aldosterone system, decreasing level of angiotersin in plasm

③β-blockers may also block β-receptor of presynaptic membrane in peripheral prejunctional to reduce sympathetic vasoconstrictor nerve activity

decreasing secretion of norepinephrine④in never center, affecting sympathetic regulation⑤changing sensitivity of baroreceptor⑥increasing synthesis of prostaglandin

Drugs

• 普萘洛尔 propranolol β1 β2

• 美托洛尔 metoprolol β1 intrinsic sympathetic mimetic activity

• 阿替洛尔 atenolol β1 intrinsic sympathetic mimetic activity

Clinical uses:• Moderate hypertension or severe

hypertension of therapeutic ineffective with other antihypertensive drugs.

Adverse reaction:• Postural hypotension, dizziness, nausea,

vomiting, diarrheaContraindications:• Severe diseases accompanied heart,

brain, kidney, arteriosclerosis, dysfunction of circulation

Drug 2. α1-adrenoceptor-blocking agents

1. Mechanism:

1). blocking selectively postsynaptic α1 receptors in arterioles and venules

2). dilating both resistance and capacitance vessels

2. Drugs:

1). prazosin 哌唑嗪 2). terazosin 特拉唑嗪 3). urapidil 乌拉地尔

1.Mechanism:

• Blocking α1 and β receptors

• Blocking action of β R> blocking action of α1 R

2.Drugs:• labetalol 拉贝洛尔

Drug 3.α and β adrenoceptor -blocking agents

Classification II. Vasodilators

Summary of the Action and Mechanism1. Dilating directly arterioles but no veins, lowering blood pr

essure, relaxing smooth muscle of arterioles.2. Eliciting compensatory responses, mediated by barorece

ptors 压力感受器 and the sympathetic nervous system, as well as rennin, angiotension and aldosterone opposing the antihypertensive effect of vasodilator such as ： tachycardia 心动过速 ; cardiac output↑; plasma rennin activity↑; retention of salt and fluid.

3. Vasodilators are used common by combination with other antihypertensive drugs that oppose the compensatory cardiovascular response.

Drugs:

1.hydralazine 肼屈嗪，肼苯哒嗪 Action: relaxing smooth muscle in arterioles

①via release of nitric oxide (NO) in vascular

②interfere with Ca2+ entering into cell

2.sodium nitroprusside 硝普钠 ①.treating hypertensive emergencies and severe cardiac

failure, crisis

②.dilating both arterial and venous vessels decreasing cardiac preload and afteroad

Subtype1. direct vasodilators

Subtype 2. Calcium channel blockers

Action:– Antianginal effects 抗心绞痛– Antiarrhythmic effects 抗心律失常– Dilating peripheral arterioles 扩张外周血管

Reducing blood pressure

Mechanism of action: inhibiting calcium influx into arterial smooth muscle cells

Drugs:1.Nifedipine 硝苯地平 ,Verapamil 维拉帕米 ,Diltiazem 地尔硫

卓2. Dihydropyridine family:• amlodipine, • felodipine, • isradipine, • nicardipine,• nifedipine,• misolipine,①more selective as vasodilators②treating selectively angina or coronary spasm③prolong effect, slow, persist, smoother, reflex sympathetic

activation with slight④antiarteriosclerosis

Subtype 3. potassium channel openers

Drugs: • minoxide 米诺地尔（长压定）• diazoxide 二氮嗪• pinacidil 吡那地尔

Classification III. Inhibitors of RAS

NO PGI2

bradykinin

aldosterone

ACEI and AT blocker

Subtype I. Angiotensin converting enzyme inhibitors ACEI

Mechanism of action:

1.inhibiting ACE

angiotensin ------Ⅰ angiotensin Ⅱ ↑

ACE ← (-) inhibitors

2.inhibiting RAS( rennin- angiotensin system) in local tissue

3.inhibiting the kalliurein-kini system( 激肽释放酶 - 激肽系统 )

Drugs: Captopril, 卡托普利

4.Accelerating release of prostacyclin(PGI2) ↓ vasodilatations ↓ decreased peripheral vascular resistance ↓ decreased blood pressure

5.accelerating release of nitric oxide (NO)

6.improving myocardial hypertrophy of left ventricle, inhibiting hyperplasia of vascular smooth muscles. decreasing formation of Ang , inhibiting remodeling of myocadia anⅡd vascular smooth muscles.

7.cleansing free radical( 自由基 ), protecting tissue ischemia and reperfusion injury

8.affecting metabolism

decreasing cholesterol and triglyceride

increasing HDL (high density lipoprotein)

Subtype II. Antagonist of Angiotensin II Receptor (Angiotensin II Receptor Blockers

Drugs: Losatan 氯沙坦； Valsartan 缬沙坦

Subtype III. renin inhibitors: Drugs: Enalkiren ( 依那吉仑 ) , Remikiren ( 瑞米吉仑 )

Classification VI ： Diuretics

• hydrochlorothiazide 氢氯噻嗪，

• indapamide 吲达帕胺

• TREANTMENT STRATEGIES Mild hypertension can often be controlled with a

single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a -blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A -blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step for those patients who still fail to respond.

Drugs Affecting the Cardiovascular System

Antihypertension Drugs

The Treatment of Congestive Heart Failure

Antiarrhythmic Drugs

Antianginal Drugs

Ion Channels Blockers

Antihyperlipidemic Drugs