Transcript 幻灯片 1

Drugs Affecting the
Cardiovascular System
Ion Channels Blockers
Antihypertension Drugs
The Treatment of Congestive Heart Failure
Antiarrhythmic Drugs
Antianginal Drugs
Antihyperlipidemic 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 hypertensioneither 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 ReninAngiotensin-Aldosterone System (RAAS)
• Endocrine disease, steroid-secreting turmour
of the adrenal cortex, adrenaline-secreting
tumour of the adrenal medulla.
MECHANISMS FOR CONTROLLING BLOOD PRESSURE
• 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.
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
Subtype 1. Central antihypertensive 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
• 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
brain 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
peripheral 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: ①α-adrenergic blocker (phentolamine)
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
Drug 1. Reserpine利血平
Pharmacological action:
1. lower blood pressure, with long-term therapy with
reserpine
cardiac output↓
peripheral vascular resistance↓
heart rate↓
rennin secretion falls↓
salt and water are retained
2. sedative and neuroleptic （精神安定）effect
reserpine depletes catecholamine(儿茶酚胺) and 5hydroxytryptamine (5-HT)
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
Subtype 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
Drug1.β-adrenoceptor-blocking agents
1.Mechanism and sites of action
①blocking β-receptor in heart, decreasing cardiac output
②depressing secretion of rennin, inhibiting the renninangiotensin-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 norepinephrine
④in never center, affecting sympathetic regulation
⑤changing sensitivity of baroreceptor
⑥increasing 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, diarrhea
Contraindications:
• 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
Drug 3.α and β adrenoceptor -blocking agents
1.Mechanism:
•
Blocking α1 and β receptors
•
Blocking action of β R> blocking action of α1
R
2.Drugs:
•
labetalol 拉贝洛尔
Classification II. Vasodilators
Summary of the Action and Mechanism
1. Dilating directly arterioles but no veins, lowering blood
pressure, relaxing smooth muscle of arterioles.
2. Eliciting compensatory responses, mediated by
baroreceptors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.
Subtype1. direct vasodilators
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
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 vasodilators
②treating selectively angina or coronary spasm
③prolong effect, slow, persist, smoother, reflex sympathetic
activation with slight
④antiarteriosclerosis
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
ACEI and AT blocker
bradykinin
aldosterone
Subtype I. Angiotensin converting
enzyme inhibitors ACEI
Drugs: Captopril, 卡托普利
Mechanism of action:
1.inhibiting ACE
angiotensinⅠ------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)
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 AngⅡ, inhibiting remodeling of
myocadia and 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 b-blocker, an ACE
inhibitor, or a calcium channel blocker. If blood pressure
is inadequately controlled, a second drug is added. A bblocker 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