Case Study

A 35-year-old man presents with a blood pressure of

150/95 mm Hg. He has been generally healthy, is
sedentary, drinks several cocktails per day, and does
not smoke cigarettes. He has a family history of
hypertension, and his father died of a myocardial
infarction心肌梗死 at age 55.
Physical examination is remarkable only for
moderate obesity. Total cholesterol is 220, and high-
density lipoprotein (HDL) cholesterol level is
40 mg/dL. Fasting glucose is 105 mg/dL. Chest x-ray
is normal. Electrocardiogram shows left ventricular
enlargement.

How would you treat this patient?

TC <200 mg/dL， HDL-C >40 mg/dL,

LDL--C <120 mg/dL, TG<150 mg/dL,
Fasting glucose <100 mg/dL,
空腹血糖障碍Impaired fasting glucose，IFG:100-125mg/dL.
 Pharmacology

Antihypertensive drugs

Queen. Liu, MD, Prof.

[email protected]
Department of pharmacology,
HaiNan Medical University
Lecture Plan

*Describe basic pharmacology of

the antihypertensive drugs.
*Introduce the major drugs such as :
*;
*
• *Describe the clinic pharmacology of these drugs.
• *Brief summary
Study guideline

1.Mechanisms for normal blood pressure regulation

including an understanding of major determinants of
blood pressure.
2. Baroreceptor related to regulating blood pressure.
与调节血压有关的压力感受器

3. Classification of antihypertensive agents .

4. The mechanisms of different antihypertensive
drugs.
5. Pharmacological actions，adverse effects and
precautions of each typical drug.
Section 1
Introduction
1. What is hypertension？
Hypertension is defined as an arterial pressure greater than or
equal to 140/90mmHg (BP≥140/90mmHg ) for an extended
period of time.
Morbidity: 15%-20%
2. Diagnosis

A warning BP are ≥120/80 called

sign but below 140/90 Pre-hypertension

Danger sBp ≥140 Hypertension

Zone DBP ≥90 Either of
them
3. Classification Of Hypertension

② Secondary Hypertension: High blood pressure

that is caused by another medical condition or
medication.
 TAB. Classification of hypertension
on the basis of blood pressure.

* From the Joint National Committee on prevention, detection, evaluation, and

treatment of high blood pressure. JAMA 2003;289:2560.
Primary (essential ) hypertension
Nearly 90% of patients have no specific cause.
Elevated blood pressure is usually caused by several
abnormalities such as genetic inheritance, psychological
stress, dietary factors.
Treatment: such hypertension can be controlled by some
combination of antihypertensive drugs and changes in
daily habits.
 Secondary hypertension

10%-15% of patients has a specific cause, such as

primary
aldosteronism or tumors of the adrenal
glands ( ).
Treatment: Treat the primary disease first
4. Overview of the situation in China

• At present, there are with

cardiovascular disease in China
suffer hypertension
die from stroke
• The condition itself usually . You
can have it for years During this
time, though, HBP can
5. Etiology of Hypertension

* more than 90% of patients with no identifiable cause.

* A family history .
* The prevalence of hypertension increases with age,
but decreases with education and income level.
* Non-Hispanic blacks > non-Hispanic whites and
Hispanic whites.
* Persons with diabetes, obesity, or disability status.

* environmental factors, such as a stressful lifestyle,

high dietary intake of sodium, and smoking~
 6. Normal Regulation of Blood Pressure

Arterial Cardiac Peripheral

blood = output X vascular
pressure (CO) resistance(PVR)

Heart rate Filling pressure Arteriolar

tone
Contractility CO and PVR are
controlled mainly by two
overlapping control
Arterial blood mechanisms: the
pressure is directly Blood Venous baroreflexes and the
proportional to CO renin–angiotensin–aldost
and PVR. volume tone erone system.
A. Postural Baroreflex

Fig. Baroreceptor reflex arc. IC, inferior colliculus; CP, cerebellar peduncle.
A fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the aortic
arch and carotid sinuses) to send fewer impulses to cardiovascular centers in the spinal
cord.
Mechanisms For Controlling Blood Pressure

Physiologically, in both
normal and hypertensive
individuals, BP is
maintained by moment-
to-moment regulation of
CO and PVR, exerted at
3 anatomic sites (Fig):
arterioles, postcapillary
venules (capacitance
vessels), and heart.
A 4th anatomic control
site, the kidney,
contributes to
maintenance of BP by
regulating the volume of
Fig. Anatomic sites of blood pressure control. intravascular fluid.
B. Renal Response to Decreased Blood Pressure
β1 on the
heart 
CO
Sympathetic
activity Increased
α1  venous return
on smooth
Decrease in muscle Peripheral
BP resistance
β1 on
Increase
Renal blood kidney 
in BP
FLow
Angiotensin II
renin
Glomerular
filltration rate Aldosterone

Blood
Sodium, water retention volume
Fig. Response of the autonomic nervous system and the renin–angiotensin–aldosterone
system to a decrease in BP.
Section 2
antihypertensive drugs
Basic antihypertensive drugs :
1.Diuretics

Diuretics also called water or fluid pills, because it helps the

body remove excess sodium and water, which help control BP.
It is more effective if the cause of hypertension is due to fluid
built up in the body.
1.Diuretics

A. Thiazide diuretics
B. Loop diuretics

C. Potassium-sparing diuretics

* Routine serum electrolyte monitoring should be done

for all patients receiving diuretics.

A complete discussion of the actions, therapeutic uses,

pharmacokinetics, and adverse effects of diuretics can
be found in another Chapter .
1.Diuretics
A. Thiazide diuretics

Thiazide diuretics, such as hydrochlorothiazide [hye-droe-

klor-oh-THYE-a-zide] and chlorthalidone [klor-THAL-ih-done].

Thiazides are useful in combination therapy with a

variety of other antihypertensive agents.
Fig. Compensatory responses to vasodilators;
basis for combination therapy with β blockers
and diuretics.①Effect blocked by
diuretics. ②Effect blocked by β blockers.
A. Thiazide diuretics
①lower BP initially by
increasing sodium and water
excretion. This causes a
decrease in extracellular
volume, resulting in a
decrease in CO and renal
blood flow (Fig.).
②With long-term treatment,
plasma volume approaches a
normal value, but a
hypotensive effect persists
that is related to a decrease
in peripheral resistance. Fig. Actions of thiazide diuretics.
1.Diuretics
B. Loop diuretics
* Loop diuretics cause decreased renal vascular resistance
and increased renal blood flow.
* unlike thiazides, loop diuretics increase the Ca2+
content of urine, whereas thiazide diuretics decrease it.

C. Potassium-sparing diuretics

* Potassium-sparing diuretics are sometimes used in

combination with loop diuretics and thiazides to reduce
the amount of potassium loss induced by these diuretics.
2.Adrenergic receptor blockers
*.β-Blockers

β-Blockers are a treatment option for hypertensive

patients with concomitant heart disease or heart failure.
Some compelling indication for the use of beta-blockers in
hypertensive patients are childbearing women, increased
sympathetic drive, and intolerance to ACE inhibitors & ARBs.
 β1 on the CO
heart 
Peripheral
β-Blockers resistance

renin Angiotensin II

β1 on Aldosterone Decrease
kidney 
in BP

Sodium, Blood
water retention volume

Fig. Actions of β-adrenoceptor–blocking agents.

*.β-Blockers

* Therapeutic uses

The primary therapeutic benefits of β-blockers are seen

in hypertensive patients with concomitant heart disease,
such as supraventricular tachyarrhythmia (for example,
atrial fibrillation), previous myocardial infarction, angina
pectoris, and chronic heart failure.
*.β-Blockers
* Pharmacokinetics
The β-blockers are orally active for the treatment of
hypertension.
Propranolol undergoes extensive and highly variable
first-pass metabolism.
first-pass metabolism
* is a phenomenon of drug metabolism whereby the concentration of
a drug is greatly reduced before it reaches the systemic circulation.
* It is the fraction of drug lost during the process of absorption which
is generally related to the liver and gut wall.
*.β-Blockers
* Adverse effects

[1] Common effects:

[2] Alterations in serum lipid patterns

[3] Drug withdrawal:

Abrupt withdrawal may induce angina,
myocardial infarction, and even sudden
death in patients with ischemic heart
disease. Therefore, these drugs must be
tapered over a few weeks .

Fig.Some adverse effects of β-blockers.

3.Calcium channel blockers

CCB blocks calcium entry; thus hearts' contraction is

not as forceful, relaxes blood vessels, reduce heart rate,
and lower blood pressure.
The British Hypertension Society recommended first-line therapy in patients over 55
should be a calcium channel blocker or a thiazide-type diuretic
 * Classes of CCB
The CCB are divided into 3
chemical classes:
[1].diphenylalkylamines: Verapamil
[ver-AP-a-mil]

[2] Benzothiazepines: Diltiazem [dil-

TYE-a-zem]
[3] Dihydropyridines: This class of
calcium channel blockers includes
nifedipine [nye-FED-i-peen] (the
prototype), amlodipine [am-LOE-di-peen],
felodipine [fe-LOE-di-peen], isradipine
[is-RADi-peen], nicardipine [nye-KAR-
di-peen], and nisoldipine [nye-ZOLdi-
peen].
* Actions of CCB

The intracellular concentration of calcium plays an important role in

maintaining the tone of smooth muscle and in the contraction of the
myocardium.
CCB causes vascular smooth muscle to relax, dilating
mainly arterioles.
CCB do not dilate veins.
* Therapeutic uses of CCB

* In the management of hypertension, CCBs may be used

as an initial therapy or as add-on therapy.
* They are useful in the treatment of hypertensive patients
who also have asthma, diabetes, and/or peripheral
vascular disease, because unlike β-blockers, they do not
have the potential to adversely affect these conditions.

* All CCBs are useful in the treatment of angina.

* In addition, diltiazem and verapamil are used in the

treatment of atrial fibrillation.
* Pharmacokinetics of CCB

Most of these agents have short half-lives (3 to 8 hours)

following an oral dose. Sustained-release preparations
are available and permit once-daily dosing. Amlodipine
has a very long half-life and does not require a
sustained-release formulation.
* Adverse effects of CCB

Verapamil Diltiazem Nifedipine

Headache,flushing, Headache,flushing, Headache,flushing,
hypotension hypotension hypotension
Peripheral edema Peripheral edema Peripheral edema
(ankle edema) (ankle edema) (ankle edema)
Cardiac depression, Cardiac depression, Tachycardia as a reflux
A-V block, bradycardia A-V block,
bradycardia
Constipation

Flushing Dizziness Headache Hypotension Peripheral Edema

Fig. Some common adverse effects of CCB.
4.Inhibitors of RAAS
* ACE inhibitors(ACEI)
such as enalapril [e-NAL-ah-pril] and lisinopril [lye-SIN-
oh-pril], are recommended as first-line treatment of
hypertension in patients with a variety of compelling
indications, including high coronary disease risk or
history of diabetes, stroke, heart failure, myocardial
infarction, or chronic kidney disease.
* ACE inhibitors(ACEI)

Advantages of ACE I – It improves glucose tolerance

and insulin resistance. It possess protecting against
renal glomerular especially in diabetes mellitus.
Do not adversely affect quality of life.
Angiotensinogen ACE Angiotensin II
(α2-globulin in Renin Angiotensin I
blood) (inactive) × × ARBs
×
ACE I
Renin Aldosterone
Inhibitors R-㊀

×
Aldosterone
Output of Vasodilation production
sympathetic of vascular
nervous system smooth muscle
Retention of
sodium and
water

* . Actions of ACEI Decreased BP

Fig. Effects of various drug classes on the renin–angiotensin–aldosterone system.
Blue = drug target enzymes; red = drug class.
* ACE inhibitors(ACEI)
* Therapeutic uses
(1) patients with DN(diabetic nephropathy).
Like the ARBs, ACEI slow the progression of diabetic nephropathy and decrease
albuminuria and, thus, have a compelling indication for use in DN .

(2) ACEI are a standard in the care of a patient following

a myocardial infarction.

(3)regression of left ventricular hypertrophy, and

prevention of ventricular remodeling after a myocardial
infarction.
ACEI are first-line drugs for treating heart failure,
hypertensive patients with chronic kidney disease, and
patients at increased risk of coronary artery disease.
* ACE inhibitors(ACEI)
* Adverse effects

（1）Common side effects include

dry cough, rash, fever, altered taste,
hypotension (in hypovolemic states),
and hyperkalemia. even Angioedema.
(2)The dry cough, which occurs in up to 10%
of patients, is thought to be due to increased
levels of bradykinin and substance P in the
pulmonary tree and resolves within a few days of
discontinuation. The cough occurs more frequently in
women.
(3)Potassium levels must be monitored.
* Angiotensin II Receptor Blockers
Angiotensiogen
Renin The ARBs, such as losartan
Ang I [LOW-sar-tan] and
ACE irbesartan [ir-be-SARtan],
Ang II are alternatives to the ACEI.

These drugs block the AT1-R,

ARBS decreasing the activation of
AT1-R by Ang II.
AT1R AT2R

Adverse effects are similar to those of ACE I, although the

risks of cough and angioedema are significantly decreased.
Their pharmacologic effects are similar to those of ACEI
in that they produce arteriolar and venous dilation and
block aldosterone secretion, thus lowering blood pressure
and decreasing salt and water retention.
* Renin inhibitor

Renin inhibitors inhibit the enzyme renin, which results in

widening blood vessels, making it easier for the blood to flow,
which lowers blood pressure.
Tekturna (generic name: Aliskiren [a-LIS-ke-rin])
5. Vasodilators

Vasodilators are a class of drugs that dilate, relax or widen

blood vessels (mainly the arterioles) results from relaxation
of smooth muscle cells, which allows blood to flow more
easily that causes blood pressure to drop.
* Vasodilators Types
Vasodilators are used to treat or prevent hypertension,
heart failure, preeclampsia (high BP during pregnancy),
angina, and pulmonary hypertension.
子痫前期（妊娠期间血压高）、心绞痛和肺动脉高压
reduce arterial pressure by decreasing systemic
1. Arterial dilators vascular resistance.
hydralazine hydrochloride ( Apresoline)、 Minoxidil
( Loniten)
reduce venous pressure, which reduces preload on the
2. Venous dilators heart thereby decreasing CO.
nitroglycerin, isosorbidenmono-/dinitrate, and
sodium nitroprusside
3. Mixed dilators act on both arteries and veins, and therefore termed as
mixed or balanced dilators.
Nitroprusside, Pimobendan
Other hypotensors
1.Centrally-acting sympathoplegic drugs
*
* Peripheral Adrenergic Inhibitors
Peripheral-acting adrenergic antagonists reduce
resistance to blood flow in small arteries by inhibiting
the release of epinephrine and norepinephrine.
1. peripheral α-adrenergic blocker
α1-R blockers：
Prazosin [PRA-zoe-sin], doxazosin [dox-AH-zoe-sin],
and terazosin [ter-AH-zoe-sin]
* Reflex tachycardia and postural hypotension often occur at
the onset of treatment and with dose increases, requiring slow
titration of the drug in divided doses.
* Due to weaker outcome data and their side effect profile,
α-blockers are no longer recommended as initial treatment for
hypertension, but may be used for refractory cases.
2. α-/β-Adrenoceptor blocking agents

Labetalol [la-BAY-ta-lol]
used in the management of
gestational hypertension
and hypertensive
emergencies.妊娠高血压

carvedilol [kar-VE-di-lol]

used in the treatment of

heart failure.
*
* Centrally acting adrenergic drugs
A. Clonidine
Clonidine [KLON-i-deen] acts centrally as an α2 agonist to
produce inhibition of sympathetic vasomotor centers, decreasing
sympathetic outflow to the periphery, total peripheral resistance
and decreased BP.

* Clonidine is used primarily for the treatment of hypertension that

has not responded adequately to treatment with two or more drugs.

* treatment of hypertension complicated by renal disease.

* Rebound hypertension occurs following abrupt withdrawal of

clonidine.
*
* Centrally acting adrenergic drugs
B. Methyldopa
* Methyldopa [meth-ill-DOE-pa] is an α2 agonist

* converted to methylnorepinephrine centrally to

diminish adrenergic outflow from the CNS.

* mainly used for management of

hyperten_x0002_sion in pregnancy.
Section 3
*
* Hypertensive emergency

Hypertensive emergency is a rare but life-threatening

situation:

systolic greater than 180 mm Hg or diastolic

greater than 120 mm Hg)
A variety of medications are used, including calcium channel
blockers (nicardipine and clevidipine), nitric oxide vasodilators
(nitroprusside and nitroglycerin), adrenergic receptor antagonists
(phentolamine, esmolol, and labetalol), the vasodilator hydralazine,
and the dopamine agonist fenoldopam.
Treatment is directed by the type of target organ damage present
and/or comorbidities present.
*
* Resistant hypertension

blood pressure that remains elevated (above goal) despite

administration of an optimal three-drug regimen that includes
a diuretic.

The most common causes of resistant hypertension are

poor compliance, excessive ethanol intake, concomitant conditions
(diabetes, obesity, sleep apnea, hyperaldosteronism, high salt
intake, and/or metabolic syndrome), concomitant medications
(sympathomimetics, nonsteroidal anti-inflammatory drugs, or
antidepressant medications), insufficient dose and/or drugs, and
use of drugs with similar mechanisms of action.
*
* Combination therapy
may lower blood pressure more quickly with
minimal adverse effects.

Initiating therapy with two antihypertensive drugs

should be considered in patients with blood pressures
that are more than 20/10 mm Hg above the goal.

A variety of combination formulations of the various

pharmacologic classes are available to increase ease of
patient adherence to treatment regimens that require multiple
medications to achieve the blood pressure goal.
Fig. Treatment of hypertension in patients with concomitant diseases.
[Note: Angiotensin receptor blockers (ARBs) are an alternative to angiotensin-converting
enzyme (ACE) inhibitors.]
Section 4
2018 Hypertension Guideline
Tab. Classification of office blood pressure and
definitions of hypertension grade
Tab. Compelling and possible contraindications to
the use of specific antihypertensive drugs
Tab. ESC Classes of recommendations
 What is new and what has changed in
the 2018 ESC/ESH Arterial Hypertension Guidelines?
 What is new and what has changed in
the 2018 ESC/ESH Arterial Hypertension Guidelines?
1. A 45-year-old man was just started on therapy for
hypertension and developed a persistent, dry cough.
Which is most likely responsible for this side effect?

A. Enalapril.
B. Losartan.
C. Nifedipine.
D. Prazosin.
.
E. Propranolol.

A. The cough is most likely an adverse effect of the ACE inhibitor enalapril.
Losartan is an ARB that has the same beneficial effects as an ACE inhibitor
but is less likely to produce a cough. Nifedipine, prazosin, and propranolol
do not cause this side effect.
2 Which may cause reflex tachycardia and/or postural
hypotension on initial administration?

A. Atenolol.
B. Hydrochlorothiazide.
C. Metoprolol.
.
D. Prazosin.
E. Verapamil.

D. Prazosin produces first-dose hypotension, presumably by blocking

α1 receptors. This effect is minimized by initially giving the drug in
small, divided doses.
The other agents do not have this adverse effect.
 3. A 60-year-old white female has not reached her
blood pressure goal after 1 month of treatment with a
low dose of lisinopril. All of the following would be
appropriate next steps in the treatment of her
hypertension except:

A. Increase dose of lisinopril. .

B. Add a diuretic medication.
C. Add on a calcium channel blocker medication.
D. Add on an ARB medication.

D. Increasing the dose of lisinopril or add_x0002_ing a second medication from a

different class (such as a calcium channel blocker or diuretic) would be appropriate
steps to control the blood pressure. Adding an ARB as the second medication is not
recommended. ARBs have a similar mechanism of action to ACE inhibitors, and
combination therapy may increase the risk of adverse effects.
4.A patient returns to her health care provider for
routine monitoring 3 months after her hypertension
regimen was modified. Labs reveal elevated serum
potassium. Which is likely responsible for this
hyperkalemia?

A. Chlorthalidone. .
B. Clonidine.
C. Furosemide.
D. Losartan.
E. Nifedipine.

D. Losartan, an ARB, can cause an increase in serum potassium similar to ACE

inhibitors. Furosemide and chlorthalidone can cause a decrease in serum
potassium. Nifedipine and clonidine do not affect potassium levels.