Pharmacology for cardiovascular system

Part 3

Antihypertensive Drugs
Weiping Zhang, MD. PhD. Associate professor
Dept. Pharmacology, Medical School, Zhejiang University
weiping601@zju.edu.cn

2010.6.21
 Antihypertensive Drugs
Overview
I. Basic pharmacology of antihypertensive drugs
1. Drugs that alter sodium & water balance;
2. Drugs that alter sympathetic nervous system function;
3. Vasodilators;
4. Agents that block RAAS;
II. Clinical pharmacology of antihypertensive
agents
 Blood Pressure and Risk for
Coronary Heart Disease in Men
incidence of CHD per 1000

60 60
Age-adjusted annual

50 50

40 40
Age 65-94 Age 65-94

30 30

20 20
Age 35-64
10 10 Age 35-64

0 0
<120 120- 140- 160- 180+ <75 75- 85- 95- 105+
139 159 179 84 94 104
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease
(CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
 JNC – 7 Definitions (2003)
Systolic Diastolic
Category
(mm Hg) (mm Hg)
Twice as likely
Normal < 120 < 80 to progress to
hypertension
Prehypertension 120 – 139 < 80 – 89

Hypertension
140 – 159 90 – 99
(Stage I)
Hypertension
 160  100
(Stage II)
JNC－8
Expected Availability for Public Review and Comment: Spring 2011
Expected Release Date: Fall 2011
Causes of death in patients with HTN
Kidney Other MI or CHF
Failure 2% Stroke
15% Kidney Failure
Other

MI or CHF
50%

Stroke
33%
The goal of treatment:

• Lower the blood pressure;

• Protect the target organ;
• Reduce the morbidity and mortality rates;
• Best therapy and minimal risk;
 Hypertension & regulation of blood pressure
Normal regulation of blood pressure
BP CO PVR
Arterial blood
pressure  Cardiac
output  Peripheral
Vascular resistance
arteriolar
tone

Blood
volume
Heart Contractility Filling
rate pressure
Venous
tone
Baroreceptors and sympathetic nervous system
Renin-angiotention-aldosterol system (RAAS)
Hypertension & regulation of blood pressure

Baroreflexes (mediated by
autonomic nerves)

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

Anatomic sites of blood pressure control

Hypertension & regulation of blood pressure
A. Postural baroreflex: responsible for rapid , moment to moment
adjustments in blood pressure.

Sense the stretch of the vessel walls

• from a reclining to an upright posture;
• reduction of peripheral vacular resistance;
• Reduction in intravascular volume;
-
Hypertension & regulation of blood pressure
B. Renin-Angiotensin-Adolsteron (RAAS)
Angiotensin II

Redistribution of renal blood flow

This is responsible for

long-term blood pressure
control.
I. Basic pharmacology
of antihypertension
drugs
I. Basic pharmacology of antihypertension agents

1. Diuretics: depleting the sodium and reducing blood volume

and perhaps by other mechanisms.

2. Sympathoplegic agents: reducing peripheral vascular

resistance, inhibiting cardic output, increasing venous
pooling.

3. Direct vasodilators: relaxing vacular smooth muscle,

dilaing resistance vessels and/or increasing capacitance.
4. Agents that block RAAS: reduce peripheral vacular
resistance and blood volume.
1. Diuretics（利尿药）
 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  )
(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. Diuretics
Selection of diuretcs

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.

Be careful increase blood pressure Nephron, a functional unit of kidney

1. Diuretics
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.

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.
1. Diuretics
Adverse effects of diuretcs

• 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 agents

Sedation, mental depression, sleep

disturbance, dry mouth, analgesia

More selective action

Inhibition of parasympathetic
regulation, profound
sympathetic blockade Similar like surgical sympathectomy

The antihypertensive effect of these agents used alone may be limited by retention of
Na+ by the kidney and expansion of blood volume. So sympathoplegic
antihypertensive drugs are most effective when used concomitantly with a diuretc.
2. Sympathoplegic agents

1) Centrally acting sympathoplegic drugs

2) Ganglion blocking agents
3) Adrenergic neuron-blocking agents
4) Adrenoceptor antagonists （常用抗高血压药）
2. Sympathoplegic agents

1) Centrally acting sympathoplegic drugs

Methyldopa（甲基多巴）: metabolize to -
methyldopamine and - methylnorepinephrine;

Its antihypertensive action appears to be due to

stimulation of central  adrenoceptors by 
methylnorepinephrine or  methldopamine.
2. Sympathoplegic agents
1) Centrally acting sympathoplegic drugs
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

2. Sympathoplegic agents
1) Centrally acting sympathoplegic drugs

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
2. Sympathoplegic agents
2) Ganglion blocking agents
2. Sympathoplegic agents
2) Ganglion blocking agents

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. Sympathoplegic agents
3) Adrenergic neuron-blocking agents
2. Sympathoplegic agents
3) Adrenergic neuron-blocking agents

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.
2. Sympathoplegic agents
3) Adrenergic neuron-blocking agents

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.
2. Sympathoplegic agents
4) Adrenoceptor antagonists
 Receptor blockers: Propranolol
(1) Mechanism & Sites of Action: nonselective –block in brain,
kidney and heart etc.
2. Sympathoplegic agents
4) Adrenooceptor antagonists
 Receptor blockers: Propranolol

(2) Clinical uses

A. Hypertension: 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
B. Other uses: angina pectoris; arrhythmias
2. Sympathoplegic agents
4) Adrenooceptor antagonists
 Receptor blockers: Propranolol
(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;
2. Sympathoplegic agents
4) Adrenoceptor antagonists
Prazosin & Other 1 Blockers pinacidil, urapidil, and cromakalim.
(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.
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists
Prazosin & Other 1 Blockers
pinacidil, urapidil, and cromakalim.
(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.
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists
Prazosin & Other 1 Blockers

(1) Pharmacological effects

 Relaxing arterial and venous smooth muscles
 Decreasing peripheral resistance
 Nonselective  receptor blocker: activation of
baroreflex and RAA system;
 Selective 1 receptor blocker: activation of baroreflex
and RAA system at the beginning.
(2) Clinical usage
 Hypertension with benign prostatic hyperplasia
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists
Prazosin & Other 1 Blockers
pinacidil, urapidil, and cromakalim.

(2) Adverse effects :

• Infrequent and mild
• First dose phenomenon (postural hypotension)
• Water and sodium retention
• Dizziness, palpitations, headache, and lassitude.
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists
 and 1 Receptor blockers

Blocker effect:
Labetalol 拉贝洛尔 >1>>2

Carvedilol 卡维地洛

Amosulalol 氨磺洛尔
2. Sympathoplegic agents
4) Adrenooceptor antagonists

 and 1 Receptor blockers

Labetalol 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.
2. Sympathoplegic agents
4) Adrenooceptor antagonists
Other  Receptor blockers:
Carvedilol
 S(–) isomer is a nonselective -receptor blocker
 Both S(–) and R(+) isomers have approximately equal -receptor
blocking potency.

Nebivolol
 D –Nebivolol 1 blocker
 L-Nevivolol causes vasoliating not mediated by  blocked.
Has active metabolites
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists

 and 1 Receptor blockers

 Mild decrease of blood pressure

 Minimal changes in cardiac output and heart rate
 Used for all kinds of hypertension, including
hypertensive emergency
 Less adverse effects
2. Drugs that alter sympathetic nervous system function
4) Adrenooceptor antagonists
3. 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
3. Vasodilators
3. Vasodilators

(2) Hydralazine （肼曲嗪）

• 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.
3. Vasodilators

(2) Hydralazine

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. Vasodilators

(3) Minoxidil（米诺地尔）: a potassium channel opener

• 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,
3. Vasodilators

(4) Sodium Nitroprusside: （硝普钠）

• 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.
3. Vasodilators
(4) Sodium Nitroprusside:

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
3. Vasodilators

(5) Diazoxide: （二氮嗪）

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;
3. Vasodilators

(7) Calcium Channel Blockers（常用抗高血压药）

Verapamil, diltiazem, and the dihydropyridine family (amlodipine,

felodipine, isradipine, nicardipine, nifedipine, and nisoldipine)

Nifedipine and the other dihydropyridine agents are more selective as

vasodilators and have less cardiac depressant effect than verapamil
and diltiazem.

Diltiazem has intermediate actions.

Sustained-release calcium blockers or calcium blockers with long

half-lives provide smoother blood pressure control and are more
appropriate for treatment of chronic hypertension.
3. Vasodilators
(7) Calcium Channel Blockers
Classification of Vasodilators

Venous Venous
Nitrates
Vasodilator

Mixed
Calcium Antagonists
-adrenergic Blockers
ACEI
Nitroprusside

Arterial
Arterial
Minoxidil
Vasodilator
Hydralazine
4. Agents that block RAASs（常用抗高血压药）
• 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
The renin-angiotensin-aldosterone system
(RAAS)

Angiotensinogen
Renin
Angiotensin I (AI)
ACE
Angiotensin II (AII)

AT1 receptor AT2 receptor

 RAAS
Angiotensinogen
Renin
AI
ACE
A II

AT1 receptor AT2 receptor

• Hypertrophy/proliferation
• Vasoconstriction
• Sympathetic stimulation
• Aldosterone release
• Vasopressin (AVP, 抗利尿激素，KANG LI NIAO JI SU）
 Aldosterone
1. 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 muscle
 Role in nociception
 Vasodilatation
Vascular perm ACEIs
Prostaglandins
Inhibits Na/H20 Angiotensinogen
reabsorption Renin
Bradykinin x
ACE
ACEI
AI

x
Inactive
Peptides
A II

AT1 receptor AT2 receptor

• Hypertrophy/proliferation

x
• Vasoconstriction
• Sympathetic stimulation
• Aldosterone release
• Vasopressin
 4. Agents that block RAASs

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;
4. Agents that block RAASs

(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 Efferent
arteriole arteriole
normal

NSAIDS,
low
volume or
poor renal
perfusion

ACEI/
ARB
 RAAS
Angiotensinogen
Renin t-PA
ACE AI Cathepsin G
CAGE Tonin
Cathepsin G A II
Chymase

AT1 receptor AT2 receptor

• Hypertrophy/proliferation
• Vasoconstriction
• Sympathetic stimulation
• Aldosterone release
• Vasopressin
• Antiproliferation
• Antifibrotic effects
• NO Release
• Differentiation
• Vasodilation
 Vasodilatation
RAAS
Vascular perm
Prostaglandins
Inhibits Na/H20 Angiotensinogen
reabsorption t-PA
Renin
Cathepsin G
Bradykinin
X
ACE AI
Tonin
Degradation CAGE
X
products Cathepsin G
A II
Chymase

AT1 receptor AT2 receptor

• Hypertrophy/proliferation • Antiproliferation
• Vasoconstriction • Antifibrotic
X
• Sympathetic stimulation • X
NO Release
• Aldosterone release • Differentiation
• Vasopressin • Vasodilation
 Vasodilatation
RAAS ARB
x
Vascular perm
Prostaglandins
Inhibits Na/H20
reabsorption
Angiotensinogen
Renin
t-PA
Bradykinin AI Cathepsin G
ACE Tonin
CAGE
Degradation Cathepsin G A II
products Chymase

ARB

x
AT1 receptor
• Hypertrophy/proliferation •
AT2 receptor
Antiproliferation

x
• Vasoconstriction
• Sympathetic stimulation
• Aldosterone release
•
•
•
Antifibrotic
NO Release
Differentiation
• Vasopressin • Vasodilation
4. Agents that block RAASs

(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.
5. Clinical Pharmacology of Antihypertensive Agents

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;
Algorithm for treatment of hypertension
Lifestyle modifications to manage hypertension
3. Clinical Pharmacology of Antihypertensive Agents
1) Monotherapy Vs. Polypharmacy in Hypertension

Prescribe according to the severity degree of

hypertension
(1) Mild: diuretics,  blockers, ACEI, ARB, calcium
channel blockers, 1 blockers, single drug.

(2) Moderate: combined with two above drugs

(3) Severe: adding centrally acting drugs or

vasodilators to the two combined drugs
 3. Clinical Pharmacology of Antihypertensive Agents
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

3. Clinical Pharmacology of Antihypertensive Agents
1) Monotherapy Vs. Polypharmacy in Hypertension

Hypertension with other diseases:

3. Clinical Pharmacology of Antihypertensive Agents
2) Outpatient Therapy of 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,
A or B + C or D
• an ACE inhibitor plus a thiazide,
• An angiotensin receptor blocker plus a diuretic,
• a calcium channel blocker plus an ACE inhibitor
3. Clinical Pharmacology of Antihypertensive Agents
3) Hypertension emergency

 Vasodilators (nitroprusside sodium,

diazoxide)
 Labetalol
 Loop diuretics
Future treatment options
 Blood pressure vaccinations
CYT006-AngQb
 Tissot AC, Maurer P, Nussberger J et al. (2008). Effect
of immunisation against angiotensin II with CYT006-
AngQb on ambulatory blood pressure: a double-blind,
randomised, placebo-controlled phase IIa study. Lancet
371 (9615): 821–7.
 Samuelsson O, Herlitz H (2008). Vaccination against
high blood pressure: a new strategy. Lancet 371 (9615):
788–9.
 Nov 2008, two new phase II studies are recruiting
patients to evaluate safety and efficacy of this vaccine
Life long treatment
 References
 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), 2009.
 Goodman & Gilman’s the pharmacological basis of
therapeutics (10th), 2002.