chapter 11 antihypertensive agents chapter 11 antihypertensive agents weiping zhang, md. phd....

Chapter 11Chapter 11 Antihypertensive AgentsAntihypertensive Agents

Weiping Zhang, MD. PhD. Associate professor

Dept. Pharmacology, Medical School, Zhejiang University

[email protected]

2013.5

OverviewOverviewhypertension & regulation of blood pressurehypertension & regulation of blood pressure

I. I. Basic pharmacology of antihypertensive agentsBasic pharmacology of antihypertensive agents 1. Drugs that alter sodium & water balance;1. Drugs that alter sodium & water balance; 2. Drugs that alter sympathetic nervous system function;2. Drugs that alter sympathetic nervous system function; 3. Vasodilators;3. Vasodilators; 4. Agents that block RAAS;4. Agents that block RAAS;

II. Clinical pharmacology of antihypertensive II. Clinical pharmacology of antihypertensive agentsagents

Antihypertensive AgentsAntihypertensive Agents

0

10

20

30

40

50

60

<120 120-139

140-159

160-179

180+0

10

20

30

40

50

60

<75 75-84

85-94

95-104

105+

Ag

e-a

dju

ste

d a

nn

ual

incid

en

ce o

f C

HD

per

1000

Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baseline

Systolic blood pressure (mmHg)

Blood Pressure and Risk for Blood Pressure and Risk for Coronary Heart Disease in MenCoronary Heart Disease in Men

Diastolic blood pressure (mmHg)

Age 65-94Age 65-94

Age 35-64Age 35-64

Age 65-94Age 65-94

Age 35-64Age 35-64

Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.

CategorySystolic (mm Hg)

Diastolic (mm Hg)

Normal < 120 < 80

Prehypertension 120 – 139 < 80 – 89

Hypertension (Stage I)

140 – 159 90 – 99

Hypertension (Stage II)

160 100

JNC – 7 Definitions (2003)JNC – 7 Definitions (2003)

Twice as likelyTwice as likelyto progress toto progress tohypertensionhypertension

JNC － 8Expected Release Date: Fall 2011, spring 2012, still coming now

Causes of death in patients with HTNCauses of death in patients with HTN

MI or CHF50%

Stroke33%

Kidney Failure

15%

Other2%

MI or CHFStrokeKidney FailureOther

The goal of treatment:

• Lower the blood pressure;

• Protect the target organ;

• Reduce the morbidity and mortality rates;

• Best therapy and minimal risk;

Normal regulation of blood pressureNormal regulation of blood pressure

Arterial bloodArterial blood pressurepressure

Cardiac Cardiac outputoutput

Peripheral Peripheral Vascular resistanceVascular resistance

Venous Venous tonetone

Blood Blood volumevolume

Filling Filling pressurepressure

ContractilityContractilityHeart Heart raterate

arteriolararteriolartonetone

Baroreceptors and sympathetic nervous systemBaroreceptors and sympathetic nervous system Renin-angiotention-aldosterol system (RAAS)Renin-angiotention-aldosterol system (RAAS)

Hypertension & regulation of blood pressureHypertension & regulation of blood pressure

BP CO PVR


Anatomic sites of blood pressure control

Baroreflexes (mediated by autonomic nerves)

Humoral mechanisms (include: RAAS system and local release of hormones from vascular endothelium, such as, NO, endothelin 1)


Sense the stretch of the vessel walls• from a reclining to an upright posture;• reduction of peripheral vacular resistance;• Reduction in intravascular volume;-

A. Postural baroreflex: responsible for rapid , moment to moment adjustments in blood pressure.


B. Renin-Angiotensin-Adolsteron (RAAS)

This is responsible for long-term blood pressure control.

Redistribution of renal blood flow

Angiotensin II

I.I. Basic pharmacology Basic pharmacology of antihypertension of antihypertension agentsagents

1. Diuretics:1. Diuretics: depleting the sodium and reducing blood volume and perhaps by other mechanisms.

2. Sympathoplegic agents:2. Sympathoplegic agents: reducing peripheral vascular reducing peripheral vascular resistance, inhibiting cardic output, increasing venous resistance, inhibiting cardic output, increasing venous pooling.pooling.

3. Direct vasodilators:3. Direct vasodilators: relaxing vacular smooth muscle, relaxing vacular smooth muscle, dilaing resistance vessels and/or increasing capacitance.dilaing resistance vessels and/or increasing capacitance.

4. Agents that block RAAS:4. Agents that block RAAS: reduce peripheral vacular reduce peripheral vacular resistance and blood volume.resistance and blood volume.

I. Basic pharmacology of antihypertension agentsI. Basic pharmacology of antihypertension agents

Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure.

1) Pharmacological roles (1) Diurectic action: In the early stage: reducing blood volume and cardiac

output; In the late stage: reduce peripheral vascular resistance (by

reducing the Na+; reduce Na+-Ca2+ exchange in vascular smooth muscle cells (Ca2+i , peripheral resistance )

1. Diuretics1. Diuretics （利尿药）

Low blood [Na+][Na+]i ↓ ↓

Ca2+

Sodium channel

Na+

Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure.

1) Pharmacological roles

(2) Non diurectic action: • Direct vasodilating, e.g. Indapamide, a non-thiazide

sullfonamide diuretic with both diuretic and vasodilator activity;

• Amiloride inhibits smooth muscle responses to contractile stimuli.

1. Diuretics1. Diuretics （利尿药）

Selection of diuretcs

Nephron, a functional unit of kidney

Normally used in severe hypertension, in renal insufficiency and in cardiac failure or cirrhosis.

Normally used in mild or moderate hypertension with normal renal and cardiac function.

Useful to avoid excessive potassium depletion.

1. Diuretics1. Diuretics

Be careful increase blood pressure

Dosing considerations (thiazide vs. Furosemide)

100 - 200 mg thiazide diuretics are more natriurectic but the same effect of anti-hypertension is the same as 25 – 50 mg thiazide diuretcs.

A threshold amount of body sodium depletion may be sufficient for anti-hypertensive efficacy.

The blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.

2) Clinical application: diuretics alone for mild or moderate essential hypertension. Combine with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents.


Adverse effects of diuretcs（略）

• Hypokalemia: K+ depletion (except for potassium – sparing diuretcs); hypokalemia may be hazardous in persons taking digitalis, who have chronic arrhythmias, acute myocardial infarction or left ventricular dysfunction.

Restriction of dietary Na+ intake will minimize K+ loss.

• Mg2+ depletion;

• Impair glucose tolerance, induce hyperglycemia;

• Increase serum lipid concentrations, induce hyperlipidemia;

• Hyperuricemia, precipitate gout;


2. Sympathoplegic agents2. Sympathoplegic agents

Sedation, mental depression, sleep disturbance, dry mouth, analgesia

Inhibition of parasympathetic regulation, profound sympathetic blockade

Similar like surgical sympathectomy

More selective action

1) Centrally acting sympathoplegic drugs1) Centrally acting sympathoplegic drugs （略）（略）

Methyldopa: metabolize to -methyldopamine and - methylnorepinephrine;

Its antihypertensive action appears to be due to stimulation of central adrenoceptors by methylnorepinephrine or methldopamine.


Clonidine: After intravenous injection, it produces a brief rise in blood pressure (direct stimulation of adrenoceptors in arterioles) and flowed by a more prolonged hypotension (stimulation of adrenoceptors in medulla).

Clonidine lowers heart rate and cardiac output more than methyldopa.

Pharmacological roles: -methylnorepinephrine and clonidine both bind more tightly to 2 than to 1 adrenoceptors. • They bind to presynaptic 2 adrenoceptor to reduce catercholamine release• Bind to postsynaptic 2 adrenoceptor to inhibit activity of appropriate neurons.• Clonidine also binds to nonadrenoceptor site, the imidazoline receptor,

Guanabenz and guanfacine: stimulat adrenoceptor

1) Centrally acting sympathoplegic drugs 1) Centrally acting sympathoplegic drugs （略）（略） 2. Sympathoplegic agents2. Sympathoplegic agents

Clinical uses

Hypertension: mild to moderate hypertension that has not responded adequately to treatment with diuretics alone.

minimal changes in renal blood flow and glomerular filtration

inhibit gastrointestinal secretion and mobility Toxicity

Central and atropine-like side effects

Long-term uses:

water and sodium retention

rebound phenomenon

1) Centrally acting sympathoplegic drugs 1) Centrally acting sympathoplegic drugs （略）（略）


2) Ganglion blocking agents2) Ganglion blocking agents


2) Ganglion blocking agents2) Ganglion blocking agents


X

X

X

X

The ganglion blocking agents block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. So the toxicities are intolerable.

Trimethaphan: pool the blood in capacitance vessels, the blood pressure due to the posture.

Adverse of trimethaphan:• sympathoplegia: excessive orthostatic hypotension, sexual dysfunction;• parasympathoplegia: constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth.

2) Ganglion blocking agents2) Ganglion blocking agents （略）（略）


3) Adrenergic neuron-blocking agents3) Adrenergic neuron-blocking agents


3) Adrenergic neuron-blocking agents 3) Adrenergic neuron-blocking agents （略）（略）

Guanethidine: very efficacy but also toxicities like “pharmacologic sympathectomy”, including postural hypotension, diarrhea and impaired ejaculation.

Guanadrel, bethanidine, debrisoquin are similar to guanethidine.

Mechanism of guanethidine action: inhibit the release of NE from sympathetic nerve endings. EARLY reduce cardiac output due to bradycardia and relaxation of capacitance vessels. Chronic therapy: decrease the peripheral vascular resistance.

Na+ and water retention may be marked during guanethidine therapy.


Reserpine: block the ability of aminergic transmitter vesicles to take up and store biogenic amines. Depletion of peripheral amines and central component.

Toxicity: Cerebral amine depletion cause sedation, lassitude, nightmare, mental depression and PD symptoms. Gastrointestinal tract amine depletion cause diarrhea, gastrointestinal cramps and increases gastric acid secretion.

3) Adrenergic neuron-blocking agents 3) Adrenergic neuron-blocking agents （略）（略） 2. Sympathoplegic agents2. Sympathoplegic agents

4) Adrenoceptor antagonists4) Adrenoceptor antagonists

receptor: receptor:

11 receptor: receptor:


Receptor:Receptor:




VasocontrictionVasocontriction

Inhibit NE release Inhibit NE release

Strengthen HR and constrictionStrengthen HR and constriction

Bronchial spasmBronchial spasm


Receptor blockers: PropranololReceptor blockers: Propranolol

(1) (1) Mechanism & Sites of Action: nonselective –block in brain, kidney and heart etc.



(2) (2) Clinical usesClinical uses

A. Hypertension: all kinds of hypertensionA. Hypertension: all kinds of hypertension

more effective in young patients than elderlymore effective in young patients than elderly

useful in treating coexisting conditions such as useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine infarction, angina pectoris, glaucoma and migraine headacheheadache

B. Other uses: angina pectoris; arrhythmiasB. Other uses: angina pectoris; arrhythmias

4) Adrenooceptor antagonists4) Adrenooceptor antagonists



(3) (3) Side effects

A. Bradycardia or cardiac conduction disease (over inhibition);

B. Asthma (Why);

C. Peripheral vascular insufficiency

D. Diabetes

E. Withdrawal syndrome after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;



Other Other Receptor blockers: Receptor blockers:

(1) Metoprolol: has cardioselectivity, equal potent with propranolol in blocking 1 receptors but 50- to 100-fold less potent than propranolol in blocking 2-receptors.

(2) Nadolol and carteolol, nonselective -receptor antagonists and atenolol, a 1-selective blocker are metabolized and are excreted in the urine.

Betaxolol and bisoprolol, 1-selective blockers are primarily metabolized in the liver but have long half lives.

Patients with reduced renal function or hepatic function should be careful.




(3) Pindolol, Acebutolol, & Penbutolol : partial agonists, ie, -blockers with intrinsic sympathomimetic activity.

(4) Esmolol: a 1-selective blocker with very short half life time (~9 min). Rapidly metabolized via hydrolysis by red blood cell esterases.

Normally esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia.



(1)Mechanism & Sites of Action: • Reduce arterial pressure by dilating both resistance

and capacitance vessels.

• Without affects on NE release (2 function)

• blood pressure is reduced more in the upright than in the supine position.

• Retention of salt and water occurs.• The drugs are more effective when used in

combination with other agents, such as a -blocker and a diuretic, than when used alone.

pinacidil, urapidil, and cromakalim.Prazosin & Other 1 Blockers



2. Drugs that alter sympathetic nervous system function2. Drugs that alter sympathetic nervous system function 4) Adrenooceptor antagonists4) Adrenooceptor antagonists

Prazosin & Other 1 Blockers

(2) Pharmacokinetics & Dosage:

Although long-term treatment with these -blockers causes

relatively little postural hypotension, it appears first-dose

phenomenon- precipitous drop in standing blood pressure

develops in a number of patients shortly after the first dose is

absorbed.

pinacidil, urapidil, and cromakalim.

(1) Pharmacological effects(1) Pharmacological effects

Relaxing Relaxing arterialarterial and and venousvenous smooth muscles smooth muscles

Decreasing peripheral resistanceDecreasing peripheral resistance

Nonselective Nonselective receptor blocker receptor blocker: activation of : activation of baroreflex and RAA system;baroreflex and RAA system;

Selective Selective 11 receptor blocker receptor blocker: activation of baroreflex : activation of baroreflex and RAA system at the beginning. and RAA system at the beginning.

(2) Clinical usage

Hypertension with benign prostatic hyperplasia





(2) Adverse effects :

• Infrequent and mild

• First dose phenomenon (postural hypotension)

• Water and sodium retention risk for heart failure

• Dizziness, palpitations, headache, and lassitude.

pinacidil, urapidil, and cromakalim.

and and 1 1 Receptor blockersReceptor blockers

Labetalol Labetalol 拉贝洛尔拉贝洛尔

Carvedilol Carvedilol 卡维地洛卡维地洛

Amosulalol Amosulalol 氨磺洛尔氨磺洛尔

Blocker effect:>1>>2


LabetalolLabetalol is formulated as a racemic mixture of four isomers

(S,S)- and (R,S)-isomers—are inactive

(S,R)- is a potent - blocker (1)

(R,R)- is a potent - blocker (3)

Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output.

Treating the hypertension of pheochromocytoma and hypertensive emergencies.





CarvedilolCarvedilol S(-), S(+), R(-), R(+)

•S(–) isomer is a nonselective -receptor blocker

•Both S(–) and R(+) isomers have approximately equal -receptor blocking potency.



NebivololNebivolol

D –Nebivolol 1 blocker

L-Nevivolol causes vasoliating not mediated by blocked.

Has active metabolites


Mild decrease of blood pressureMild decrease of blood pressure Minimal changes in cardiac output and heart rateMinimal changes in cardiac output and heart rate Used for all kinds of hypertension, including Used for all kinds of hypertension, including

hypertensive emergencyhypertensive emergency

Less adverse effects: dose-fixedLess adverse effects: dose-fixed


3. Vasodilators3. Vasodilators

(1)Mechanism & Sites of Action

• Hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension

• Parenteral vasodilators, nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies;

• Calcium channel blockers, which are used in both

(2) Hydralazine （略）

• Dilates arterioles but not veins. • A hydrazine derivative, dilates arterioles but not veins.• Disadvantage: tachyphylaxis to hypertensive effects developed rapidly.• Combination therapy are now suggested. Especially in severe hypertension.

Pharmacokinetics & Dosage• bioavailability is low (averaging 25%) because of the first pass metabolism and variable among individuals. The half-life of hydralazine ranges from 2 to 4 hours.


(2) Hydralazine （略）

Adverse effects

• Common: headache, nausea, anorexia, palpitations, sweating, and flushing.

• In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias.

• High dose or in patients with slow acetylate: arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus.

• Infrequency but severe: Peripheral neuropathy and drug fever


(3) Minoxidil: a potassium channel opener （略）• Dilates arterioles but not veins.• Can be used in patients with renal failure and severe hypertension, who do not respond well to hydralazine.

Pharmacokinetics & Dosage• Minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with –blocker and a loop diuretic.

Adverse effects• Tachycardia, palpitations, angina, and edema are observed when doses of -blockers and diuretics are inadequate. • Headache, sweating, and hirsutism, which is particularly bothersome in women,


(4) Sodium Nitroprusside: （略）• Dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return.• Powerful parenterally administered vasodilator• The mechanism: produce NO and stimulate guanylyl cyclase (GC), thus increase cGMP, which relaxes vascular smooth muscle.• Used in patients with hypertensive emergencies or severe heart failure.• In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, while cardiac output does not change or decreases slightly. • In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.


(4) Sodium Nitroprusside: （略）

Pharmacokinetics & Dosage• Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation.• The drug should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording.• Sodium nitroprusside in aqueous solution is sensitive to light

Adverse effects• the most serious toxicity is related to accumulation of cyanide.• Thiocyanate may also accumulate, particularly in patients with renal insufficiency.• Rarely, delayed hypothyroidism occurs.• Methemoglobinemia


(5) Diazoxide: （略）

Pharmacokinetics & Dosage• Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity.• Its half-life is approximately 24 hours, but blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4–12 hours.• The hypotensive effects of diazoxide are also greater if patients are pretreated with -blockers to prevent the reflex tachycardia and associated increase in cardiac output.

Adverse effects• excessive hypotension;• inhibits insulin release;


(6) Fenoldopam: an agonist of dopamine D1 receptors, resulting indilation of peripheral arteries and natriuresis. （略）

Pharmacokinetics & Dosage• Its half-life is 10 minutes. The drug is administered by continuous intravenous infusion. • the major toxicities are reflex tachycardia, headache, and flushing.• increases intraocular pressure and should be avoided in patients with glaucoma.


verapamiverapamill

diltiazemdiltiazem

nifedipinenifedipine

RestingResting (closed) (closed) Activated Activated (open)(open)

InactivatedInactivated (closed) (closed)

(7) Calcium Channel Blockers

Channel state


more selective as vasodilators


(7) Calcium Channel Blockers

VenousNitrates

MixedCalcium Antagonists-adrenergic Blockers

ACEINitroprusside

ArterialMinoxidil

Hydralazine

VenousVenousVasodilatorVasodilator

ArterialArterialVasodilatorVasodilator

Classification of VasodilatorsClassification of Vasodilators

• Approximately 20% of patients with essential hypertension have inappropriately low and 20% have inappropriately high plasma renin activity.

• Blood pressure of patients with high-renin hypertension responds well to -adrenoceptor blockers and to angiotensin inhibitors

Mechanism & Sites of Action

The stimulation of renin action:

• Reduced renal arterial pressure;

• Sympathetic neural stimulation;

• Reduced sodium delivery or increased sodium concentration at the distal renal tubule

4. Agents that block RAASs4. Agents that block RAASs

Angiotensinogen

Angiotensin I (AI)Renin

Angiotensin II (AII)

ACE

AT1 receptor AT2 receptor

The renin-angiotensin-aldosterone system (RAAS)

Angiotensinogen

A IRenin

A II

ACE

• Hypertrophy/proliferation• Vasoconstriction• Sympathetic stimulation• Aldosterone release• Vasopressin (AVP, 抗利尿激素， KANG LI NIAO JI SU）


RAAS

Aldosterone1. Sodium retention

Fluid retention Potentiate hypertension

2. Potassium & magnesium wasting Arrhythmogenic

3. Profibrogenic effect Myocardial fibrosis, thrombogenesis, vascular

inflammation, endothelial dysfunction

Bradykinin

Stimulation of endothelial NO formation Vasodilatation

Stimulation of prostaglandin formation Increase in vascular permeability Inhibition of sodium and water

reabsorption (collecting tubules)Contraction of visceral smooth muscleRole in nociception

Angiotensinogen

A IRenin

A II


ACE

Inactive Peptides

Bradykinin

ACEIsVasodilatation Vascular perm Prostaglandins Inhibits Na/H20

reabsorption

• Hypertrophy/proliferation• Vasoconstriction• Sympathetic stimulation• Aldosterone release• Vasopressin

X

X ACEI

the ACE inhibitors, Captopril, Enalapril, Lisinopril, benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril

Pharmacokinetics & Dosage

• The half-life of enalaprilat is about 11 hours.

• Lisinopril has a half-life of 12 hours

• All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys;


(1) the Adverse effects of ACE inhibitors:

• Severe hypotension (esp. hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss).

• Acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney),

• Hyperkalemia

• Dry cough and angioedema.

• During the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death.

• Captopril may cause neutropenia or proteinuria.

• Minor toxic effects like altered sense of taste, allergic skin rashes, and drug fever


Afferent arteriole

Efferent arteriole

ACEI/ ARB

NSAIDS, low

volume or poor renal perfusion

normal

t-PA

Cathepsin G

Tonin

Angiotensinogen

A IRenin

A II

ACECAGECathepsin GChymase

• Antiproliferation• Antifibrotic effects• NO Release• Differentiation• Vasodilation



RAAS

Angiotensinogen

A IRenin

A II

• Antiproliferation• Antifibrotic• NO Release• Differentiation• Vasodilation



ACE

Degradation products

Bradykinin

RAAS

t-PA

Cathepsin G

Tonin

CAGECathepsin GChymase

Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20

reabsorption

X

X

X

ARB

(2) ARBs: Losartan and valsartan (first marketed). More recently, candesartan, eprosartan, irbesartan, telmisartan and olmesartan have been released.

• No effect on bradykinin metabolism

• More complete inhibition of angiotensin action compared with ACE inhibitors

• The adverse effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy.

• Cough and angioedema can occur but are much less common.


Goal blood pressure for patients:• Young and middle-age adults:

< 130 / 85 mmHg;

• With diabetes: < 130 / 85 mmHg;

• With renal disease:

< 130 / 85 mmHg;

• With renal disease and proteinuria: < 125 / 75 mmHg;

5. 5. Clinical Pharmacology of Antihypertensive Agents

Probably will change in JNC8

Algorithm for treatment of hypertension

Lifestyle modifications to manage hypertension

Prescribe according to the severity degree of Prescribe according to the severity degree of hypertensionhypertension

(1) Mild: diuretics, (1) Mild: diuretics, blockers, ACEI, ARB, calcium blockers, ACEI, ARB, calcium channel blockers, channel blockers, 11 blockers, single drug. blockers, single drug.

(2) Moderate: combined with two above drugs(2) Moderate: combined with two above drugs

(3) Severe: adding centrally acting drugs or (3) Severe: adding centrally acting drugs or vasodilators to the two combined drugsvasodilators to the two combined drugs


1) 1) Monotherapy Vs. Polypharmacy in Hypertension

• sodium restriction: A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day

• Weight reduction:;

• Regular exercise;

• Thiazide diuretics, -blockers, and ACE inhibitors have been shown to reduce morbidity and mortality.

Lifestyle modification + drug therapy


1) 1) Monotherapy Vs. Polypharmacy in Hypertension

Hypertension in different race:

• blacks respond better to diuretics and calcium channel blockers than to -blockers and ACE inhibitors.

• Chinese are more sensitive to the effects of -blockers and may require lower doses.

drug combinations :

• In the USA, fixed-dose drug combinations containing

• a -blocker plus a thiazide,

• an ACE inhibitor plus a thiazide,

• An angiotensin receptor blocker plus a diuretic,

• a calcium channel blocker plus an ACE inhibitor

3. 3. Clinical Pharmacology of Antihypertensive Agents 2) 2) Outpatient Therapy of Hypertension

A or B + C or D

3. 3. Clinical Pharmacology of Antihypertensive Agents 3) 3) Hypertension emergency

Vasodilators (nitroprusside Vasodilators (nitroprusside sodium, diazoxide)sodium, diazoxide)

LabetalolLabetalol Loop diureticsLoop diuretics

Life long treatment Life long treatment

ReferencesReferences

The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (The JNC7 report). JAMA, 2003, 289(19): 2560-2572.

Basic & Clinical Pharmacology (11th edition), 2010.

Goodman & Gilman’s the pharmacological basis of therapeutics (11th), 2006.

chapter 11 antihypertensive agents chapter 11 antihypertensive agents weiping zhang, md. phd....

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