16

(Drug treatment in hypertension)

. .

140/90 mmHg

, sympathoplegic agents,

vasodilators, angiotensin converting enzyme inhibitors

angiotensin receptor blockers, endothelin receptor
antagonists

1.

2.

3. ,
,
,

4.

1.
2.

16.1
16.2
1

2 Sympathoplegic agents
2.1 central sympatholytic agents
2

2.2 Ganglionic blocking agents

2.3 Peripheral adrenergic neurone antagonists
2.4 adrenoceptor antagonists
3 Direct vasodilator
4 Ca

2+

channel blockers

5 Angiotensin converting enzyme inhibitors

6


Drug treatment in hypertension

140/90 mmHg
, ,

primary hypertension essential hypertension

10-15%
secondary hypertension
renal artery constriction, pheochromocytoma,
Cushings disease, aldosteronism, thyroid diseases


, ,

angiotensinogen
gene

The Sixth Report of the Joint National Committee on

Prevention, detection, Evaluation and Treatment of High Blood

Pressure (JNC VI) 1997
16. 1

 16.1: Classification of Blood Pressure for adult age 18

and older
Category

Systolic

Optimal

<120

And

<80

Normal

<130

And

<85

140-159

Or

90-99

160-179

Or

100-109

180

Or

110

High-normal
Hypertension
Stage I

HG)

(mm

130-139

Stage II

Diastolic (mm
Hg)

Or

85-89

Stage III
* systolic diastolic categories
categories
1.

hydraulic equation

(cardiac output, CO)

(peripheral vascular resistance, PVR)

BP = CO

BP

arterial

blood

pressure,

CO=

cardiac

output,

PVR=peripheral vascular resistance

16. 1
4
( 16.1)

1. arterioles resistance
2. postcappilary venule capacitance vessels
3. heart pump output

4. kidney volume of intravascular fluid

baroreceptor reflex, renin angiotensin

system (RAS) vascular endothelium

 vascular resistance nitric oxide,

endothelin-1

baroreceptor reflex renal

blood volume pressure control system

stroke,

16. 2

1. (Diuretic)

2. Sympathoplegic agents

sympathetic

system
sympathetic reflex 3
2.1 Central sympatholytic agents
2.2 Ganglionic blocking agents

2.3 Peripheral adrenergic neurone antagonists

2.4 adrenoceptor antagonists

3 Direct vasodilators

resistance
4 Ca

2+

channel blockers

5. Agents that block the production of angiotensin PVR,

blood volume

6. serotonin antagonists, angiotensin receptor blockers,

endothelin receptor antagonists, imidazoline receptor agonist

 16.2

1 (Diuretic)

blood volume cardiac output

thiazide
Na
+

10-15 mmHg

thiazide, loop diuretic, potassium sparing diuretic
thiazide

loop diuretic

potassium sparing diuretic

digoxin
K

+

10



indapamide

2. Sympathoplegic agents

sympathetic nervous

system

sympathetic system compensatory response
Na -H2O retention
+

diuretic -blocker

sympathetic reflex arc

2.1Centrally acting sympathoplegic drugs ( 2-agonist)

methyldopa, clonidine

2-adrenergic receptor

presynaptic vasopressor center brain stem

norepinephrine sympathetic outflow

vasopressor centers

, ,
postural hypotension

11

Methyldopa (L--methyl-3,4-dihydroxyphenylalanine)

analog L-dopa -

methyldopamine -methylnorepinephrine

-methylnorepinephrine 2-adrenergic

receptor norepinephrine

peripheral vascular resistance

renal vascular resistance

methyldopa
cardiovascular reflex postural hypotension
volume depleted

12


bioavailability ( 25 %) first pass

metabolism gastrointestinal mucosa prodrug

metabolized active form

amino acid transporter

pump active transport
aromatic amino acid

4-6 active metabolite -

methylnorepinephrine 24


active metabolite metabolite

2 2 3

1-2 g/d

sedation
, ,

libido dopaminergic mechanism

hypothalamus hyperprolactinemia
galactorrhea

13

 impaired
mental concentration, mental lassitude

, mental depression, vertigo

hepatitis, hemolytic anemia, drug fever

Clonidine (2-imidazoline derivative)

partial agonist 2 adrenergic receptor

medulla norepinephrine
circulating catecholamine
sympathetic tone parasympathetic tone

cardiac output heart rate

peripheral vascular resistance (

sympathetic activity ) renal vascular

resistance maintenance renal blood flow

methyldopa
postural hypotension

14

 nonadrenergic receptor
imidazoline receptor

clonidine

Methyldopa Clonidine

clonidine heart rate cardiac

output methyldopa

bioavailability 75% 8-12

50
%

dose-response

curve
2
0.2-1.2 mg/d

(transdermal therapeutic systems, TTS)

7

sedation
(local skin reactions)

15

sedation

mental depression
depression

tricyclic antidepressants (TCA)

1 mg/d
(life-threatening hypertensive

crisis) sympathetic nervous activity

nervousness, tachycardia, headache,
sweating

guanabenz, guanfacine

clonidine

guanabenz cholesterol triglycerides

HDL-C guanfacine
16-23
1
2.2 Ganglionic blocking agents
competitive nicotinic

cholinergic receptor

post ganglionic neurons

parasympathetic sympathetic ganglia

16

 nicotinic acetylcholine channel

prototype trimethaphan


mecamylamine

sympathoplegia excessive

orthostatic hypotension, sexual dysfunction parasympathoplegia

constipation, urinary retention, precipitation of glaucoma,

blurred vision, dry mouth

2.3 Peripheral adrenergic neuron blocking agents

norepinephrine postganglionic sympathetic neurons

guanethidine, reserpine, pargyline

Guanethidine

severe hypertension

toxicity

sympathetic postural hypotension,

diarrhea, impaired ejaculation

17

 basic nitrogen

norepinephrine

sympathetic nerve ending

sympathoplegia ( 16.3)

bioavailability (5-50%)

50%


1-2

10 mg/d

postural hypotension, hypotension

, delay ejaculation, diarrhea (

parasympathetic system )
Drug interaction

amine

phenylpropanolamine

hypertension guanethidine
uptake vesicle

18

 16.3
gaunethidine
Gaunethidine (G) transported sympathetic

nerve membrane norepinephrine (NE)

G transmitter vesicle

transmitter vesicle ( NE) NE

NE nerve ending

G
NE G

local anesthetic sympathetic nerve terminal

membrane electrical activity NE

G cocaine, amphetamine, TCA,

phenothiazine, phenoxybenzamine

19

Reserpine

alkaloids indian plant (Rauwolfia

serpentina)

aminergic transmitter vesicle

biogenic amines
uptake
norepinephrine, dopamine serotonin

central peripheral neurons chromaffin granule

adrenal medulla vesicle

irreversible ( 16.4)

peripheral amine

20

 postural hypotension

central acting sympatholytic drugs

(methyldopa, clonidine) sedation, mental

depression, parkinsonism symptoms ( amine )

cardiac

output peripheral vascular resistance vagal

tone heart rate
gastric secretion

, metabolized

irreversible adrenergic vesicle


1

1 mg ( 0.25 mg)

sedation, lassitude, nightmare, severe

mental depression, sleep disturbance, nasal congestion (

cholinergic system) mild diarrhea,
gastrointestinal cramps, gastric secretion
21

 extrapyramidal effect
parkinson dopamine corpus
striatum

2.4 adrenoceptor antagonists

catecholamine alpha beta

adrenoceptors -blocker, -blocker ,-blocker

2.4.1 -blocker

competitively catecholamine

cardiac receptor (1-receptor) non-cardiac receptor

(2-receptor) heart rate, venous return, cardiac output,

cardiac work -blocker plasma

renin norepinephrine pressor response

catecholamine

-blocker
1. selective 1-adrenergic blocking agents (Cardioselective)
acebutolol, atenolol, betaxolol, bisoprolol, metoprolol

22


1-adrenergic receptor
,
cardioselective
2.

-adrenergic

blocking

sympathomimatic activity (ISA)

agents

with

intrinsic

(Drugs with -agonist)

acebutolol, carteolol, penbutalol, pindolol (max ISA)

cardiac output, heart rate

total peripheral resistance

bradycardia
-blocker
peripheral vascular disease,
lipid disorders HDL
triglycerides

3. Non selective -adrenergic blocking agents

1 2-adrenergic receptors

carteolol, nodolol, propranolol, pindolol, timolol

4. ,-adrenergic blocking agents

labetalol non-selective -blocker

-adrenergic receptors

23

 -blocker

Propranolol
mild to moderate hypertension

severe hypertension propranolol reflex

tachycardia vasodilators

non-selective -blocker 1

2 adrenergic receptors

cardiac output
renin
catecholamine

mild to

moderate hypertension
postural hypotension

first pass metabolism

3-6 80-480 mg/d

2

-adrenergic receptor

,
, , peripheral vascular insufficiency

withdrawal syndrome nervousness,

24

tachycardia, blood pressure ( up-regulation

supersensitivity -adrenergic receptor)

plasma triglycerides, HDL

-blocker

diarrhea, constipation, nausea, vomiting, CNS effects night

mares, lassitude, mental depression, insomnia

1 -blocker

hypertension

2.4.2 -adrenergic blocker

prazosin, terazocin, doxazosin

selective 1-adrenergic receptor

arteriole venule

1-adrenergic receptor non- selective adrenergic receptor antagonist reflex

tachycardia

arterial blood pressure

diuretic

metabolism

lipid profiles

25

16.3

postural hypotension

(first dose phenomenon)

side effects
dizziness, palpitation, headache, lassitude
2.4.3 , -adrenergic blocker
labetalol, carvedilol

labetalol

racemic mixture 4 isomers 2

isomer (SS,RS isomers)

isomer SR potent

-adrenergic blocker isomer RR potent blocker selective 2-adrenergic receptor agonist

non-selective -adrenergic receptor antagonist
non-selective :-adrenergic receptors
antagonist 3:1

systemic vascular resistance (

- blocker) heart rate
cardiac output ( 2 adrenegic receptor)

pheochromocytoma hypertensive emergencies
26

 HDL-C orthostatic hypotension,

sexual dysfunction
Carvedilol

racemic mixture S (-) isomer

nonselective -blocker

S (-), R (+) isomer -adrenergic

receptor 7-10
6.25 mg/d
3. Direct Vasodilator

hydralazine, minoxidil

nitropusside, diazoxide, fonoldopam
hypertensive emergencies

vasodilator

systemic vascular resistance

arterial resistance arterial blood pressure
compensatory response

baroreceptor reflex, sympathetic nervous system,

renin angiotensin system (RAS) compensatory response

vasodilator

27


compensatory response 16.5

sympathetic reflex
orthostatic hypotension sexual dysfunction

16.5 compensatory response vasodilator; basic for

combination therapy with -blocker and diuretic
by diuretics

effect blocked

effect blocked by -blocker

Hydralazine

28

 severe
hypertension
sympatholytic drugs diuretic

sympathetic nervous system heart rate

contractility renin
fluid retention

vascular resistance coronary cerebral

renal circulation

postural hypotension

bioavailability ( 25%) first pass metabolism

metabolized
29

 metabolized (intervariable)
fast acetylator first metabolism bioavailability
16%

low acetylator

bioavailability

35 % fast acetylator

slow acetylator

2-4

12 vascular tissue
40-200 mg/d

1.

headache,

nausea,

tachycardia, dizziness, anorexia

flushing,

hypotension,

palpitating,

- angina ischemic arrhythmia

ischemic heart disease

reflex tachycardia sympathetic
2.
immunological reaction

drug-induced lupus syndrome

hydralazine serum sickness,

hemolytic anemia, vasculitis, rapidly progressive glomerulonephritis,
arthralgia, myalgia, skin rash

30

reflex tachycardia cardiac output

fluid retention

coronary artery disease myocardial infarction

- slow acetylator

bioavailability fast acetylator

hydralazine

hydralazine
hypertensive emergencies

(early pregnancy) DNA ( 16.2)
Minoxidil

severe hypertension

31

active metabolite minoxidil N-O-sulfate

active metabolite K channel
+

K
+

hyperpolarization

systemic hypotension renal blood

flow renin
sympathetic hydralazine
renal failure

metabolized conjugation
1


active metabolite

4
24

metabolite

5-10

mg/d 40 mg/d severe

hypertension 80 mg/d minoxidil

32

 hydralazine diuretic -blocker

fluid retention reflex tachycardia

3
1. fluid and salt retention

renin

thiazide diuretic
loop diuretic
2. hypertrichosis

, , ,

3. cardiovascular effects

heart rate, tachycardia, palpitation, myocardial O2

consumption

diuretic blocker

- topical
male-pattern baldness

Sodium nitroprusside



33

hypertensive emergencies
venous return peripheral vascular

resistance hypertensive emergency

severe congestive heart failure

complex of iron, cyanide group, nitroso

moiety metabolized red blood cell cyanide
metabolized thiocyanate

Sodium nitroprusside nitrovasodilator metabolized

smooth muscle cell active metabolite nitric oxide

guanylate cyclase cGMP

vasodilation

peripheral vascular resistance

venous return non-selective vasodilator

34

 renal blood flow

GFR renin vasodilator
heart rate
O2

infusion pump metabolized cyanide metabolized

thiocyanate

sensitive

Onset 30 peak effects 20

1-10 0.5
g/kg/min 10 g/kg/min

(excessive vasodilator)

cyanide

thiocyanate toxicity
cyanide severe lactic acidosis, arrhythmia

thiocyanate toxicity anorexia, nausea,

fatigue, disorientation, toxic psychosis, muscle spasm, convulsion

hypothyroidism, methemoglobinemia
35

1. cardiac preload/afterload hypertensive

emergency

2. cardiac output congestive heart failure

O2 myocardial
infarction

Diazoxide
long acting parentally arteriolar vasodilator

thiazide diuretic
hypertensive emergencies

K channel hyperpolarization
+

vascular smooth muscle

reflex sympathetic nervous system
Na
+

36

serum albumin vascular tissue

metabolized
24
5

4-12 50-150 mg/d

15-30 mg/min

-blocker hypotension

reflex tachycardia

Hyperglycemia

insulin K channel pancreatic cell

+

hypotension

reflex sympathetic response

tachycardia, myocardial ischemia, angina
cardiac failure
fenoldapam
(peripheral arteriolar

dilator) hypertensive emergencies postoperative

hypertension D1-dopamine receptor agonist

peripheral arteries

37

 metabolized conjugation
5
0.025-0.05 g/kg/min

reflex tachycardia, headache, flushing

4. Calcium channel blockers

Calcium channel blocker

Ca

2+

arteriolar smooth muscle peripheral vascular resistance

verapamil, diltiazem, dihydropyridine family

-nifedipine dihydropyridine group selective

vasodilator

verapamil peripheral vascular resistance

baroreceptor reflex
reflex tachycardia cardiac output

-Verapamil Ca

2+

channel

heart rate cardiac output

-Diltiazem
Ca

2+

channel

38

 : verapamil diltiazem

negative

chronotropic reflex tachycardia

dihydropyridine

Calcium channel blocker

, ( renin )

K , glucose, uric
+

acid, cholesterol
, ,

sustained release Calcium channel blocker

short acting chronic hypertension
prompt-acting Ca

2+

channel blocker

myocardial infarction
nifedipine

capsule

sublingual
10 mg
10
30-40

5. Angiotensin converting enzyme inhibitors (ACEI)

39

ACEI angiotensin II
aldosterone
left ventricular hypertrophy

heart rate

drug of choice

glucose, uric acid, lipid
profiles
gout hyperlipidemia
6.


serotonin antagonists ketanserin, ritanserin

angiotensin receptor blockers lorsatan, vorsatan

endothelin receptor antagonists
imidazoline receptor agonists
Serotonin antagonists

ketanserin ritanserin

Ketanserin

5HT1c, 5HT2 receptor

vascular 1-adrenergic receptor 5HT2
receptor

ketanserin

40

Ritanserin
5HT2 antagonist

vascular 1-adrenergic receptor

Angiotensin receptor blockers
losartan vorsatan

competitive antagonist angiotensin II

angiotensin type I (AT1) receptor

aldosterone bradykinin

metabolites 24

ACEI

angioedema
ACEI
Endothelin receptor antagonists

endothelin peptides vasoconstriction

endothelin isoform 3 ET-1,

ET-2, ET-3

ET-1 endothelial vascular smooth muscle cell

ET-2 ET-3

, ,
endothelin
41

inotropic chronotropic

potent coronary

vasoconstrictor renal vasoconstriction

glomerular filtration (GFR)

receptor subtype 2 ETA ETB

ETA receptor ET1

ETB receptor ET1

vascular endothelial cell PGI2

nitric oxides

antagonist ETA ETB receptor

BQ 123, FR 139317, 50 235, IRL 1038
Imidazoline receptor agonists
imidazoline (I)-receptor 1984

receptor
brain stem

2-receptor

imidazoline (Il)-receptor
H /Na exchanger
+

rilmenidine, moxonidine

42

 JNC VI

diuretic betablocker

16.2 antihypertensive drugs used in pragnancy
Suggested drugs
Central acting agonist
Beta-blocker

Calcium antagonist
diuretic
Direct vasodilator

comments
Methyldopa (c)

Atenolol, metoprolol (safe in late

pregnancy)

Potential synergism with

magnesium sulfate

Are recommended for chronic

hypertension

Hydralazine is the parenteral

drug of choice base on its long
history of safety and efficacy

* NHBPEP working group on high pressure in pregnancy

category C

43

 ACEI Angiotensin receptor blockers

(category D)

44

 16.3
mechani absorpti distributi metabol eliminat

sm
on
on
ism
ion

T1/2

Usual dosage

use

1. Sympathoplegic agents
Methyldopa Stimulat
(aldomet )

Crosses

2 -

the

receptor

Intestin
ally

85% in
urine

placenta, and
appear

liver

75-

Oral 1-1.5 g/d Moderate to

2-3 times/d

severe

min

IV 250-500

hypertension

6-20

0.1 mg bid

Mild to

80

mg q 6-8 h

in breast
milk
Clonidine

Stimulat

Onset

Vd 2.1

Hepatic 65% in

receptor

h,

highly

22% in

soluble,

(Catapress ) e

2 -

0.5-1

L/kg,

Tmax2-4 lipid

PB 2040%

urine,
feces

moderate
hypertension

Guanethidin Peripher

25-50 mg/d

e (Ismelin ) al

Moderate to
severe

adrenerg

hypertension

ic

blocker
Reserpine
(Resa )

Depleate Onset
d of

3-6 d,

Cross

sympath

duratio

appears

biogenic

wk, abs milk, PB

etic

amines

n 2-6
40%

liver

placenta, >96%
in Brest

30-60% 50-

in feces, 100

0.1-0.25 mg/d Mild to

moderate

10% in

hypertension

4-6 h <320 mg

Mild to

urine

96%

2. adrenergic receptor antagonists

Propranolol

Non-

onset

(inderal )

selective 1-2 h,
-

duratio

blocker

n6h

Vd 3.9

First

96% in

L/kg,

pass

urine

plaenta,

in liver

cross

effect

divided in 2-3 moderate

dose/d

hypertension
46

PB 93%

16.3 ()
mechani absorpti distributi metabol eliminati

sm
on
on
ism
on
Metoprolol
(Betaloc )

Cardiose Abs
lective

95%,

Duratio

PB 8%

receptor
Atenolol

1
adrenerg

in urine

3-4 h 100-450 mg

use
Mild to

in 2-3 divided moderate

hypertension

20 h

lete in

15%

Partial

hepatic

GI

40% in
urine,

50% in
feces

ic

Cardiose Well

6-9 h 50 mg OD,

>100 mg are
unlikely to
produce

Mild to

moderate
hypertension

benefit

receptor
Acebutalol

Usual dosage

dose

in liver

Cardiose Incomp PB 3-

(Tenormin ) lective

pass

3-10%

effect

adrenerg n 10ic

First

T1/2

PB 5-

Extensi

55% in

6-7 h 400-800

Mild to
47

(Sectral )

lective

abs

15%

1
adrenerg

ve first

feces,

pass

35% in

effect

mg/d

moderate
hypertension

urine

ic

receptor,
exhibit
ISA
Pindolol

(Visken )

Block

50-95% PB 50% 60-65% 35-50%

rapidly

in the

abs

liver

Bioavai PB 92-

Liver

both 1,
receptor,

in urine

2.5-4 5 mg bid
h

Mild to

moderate
hypertension

exhibit
ISA
Prazosin

Block

adrenerg 43-

(Minipress

1 -

lability

97%, Vd
0.5 L/kg

6-10%

in urine

2-4 h 1 mg/dose 23 times/d

Moderate to
severe

hypertension
48

ic

82%

receptor
16.3 ()
mechani absorpti distributi metabol eliminati

sm
on
on
ism
on
Terazosin

1 -

(Hytrin )

specific

rapid

PB 90-

Liver

95%

blocking

60% in

9.2-

feces,

12 h

40% in

agents

T1/2

Usual dosage
1 mg hs

use
Mild to
moderate

hypertension

urine

Dozaxosin

Completi

1 mg OD in

Mild to

(Cardura )

ve

the morning

moderate

inhibit at

or hs

hypertension

receptor
Labetarol

Block , Bioavai PB

First

receptors 25%

metabol unchang

(Normodyne 1, 2
)

lability

50%, Vd pass
3-16

<5% in
urine

2.5-8 200-400 mg
h

bid

Mild to severe

hypertension, IV
foe hypertensive
49

Carvedilol
(Coreg )

Nonselec rapid
tive

L/kg

ism

First

Primaril

effect

feces

Large

14%

pass

e in

and

receptor
Hydralazine
(Aprezoline
)

Direct

30-

or of

availabi

PB 85-

vasodilat 50%bio 90%

arterioles lity

pass

first

orally,

y in

unchang

emergencies
7-10
h

6.25 mg bid

Mild to

moderate
hypertension

2-8 h 10 mg 4
time/d

Moderate to
severe

hypetension

urine

acetylat
ed in
liver
Minoxidil

Directly

90%

(loniten )

relax

bioavail

arteriolar ability
smooth

Non PB

88%

12%

3.5-

via

excreted

4.2 h divided dose

glucoro unchang

10-40 mg 1-2 Severe

hypertension

nidation e in
50

muscle
urine
16.3 ()
mechani absorpti distributi metabol eliminati

sm
on
on
ism
on
Nitroprussid Vasodila -

Liver

IV 0.3-0.5

b7 continuous

tion on

(Nitropress

venous

kidney

arteriolar

se

and

rhodana

smooth

Usual dosage

thioc

e
)

and

Renal

T1/2

yanat mcq/kg/min

use
Hypertensive
crisis

2.7-7 IV infusion

system

muscle
Losartan

Angioten

Vd 34

14% is

(Cazaar )

sin II

L,highly

antagoni

plasma

receptor
st

bound

protein

3-8% in

1.5-2 50 mg OD

Mild to

metabol urine,

h, E-

moderate

CYP

: 3-4

ized by 60% in
450 to

feces

3174

hypertension

active
51

metabol
ized E3174
Valsartan

(Diovan )

Angioten

94-97%

receptor

Vd 17 L an

sin II

antagoni
st

PB,

Metabo 13 in
lized to urine

9h

80 mg/d

and 83%

Mild to moderate
hypertension

Have advantage

inactive feces

over lorsatan due

metabol

to minimal

ized

metabolism so
can use in mild
to moderate
hepatic

repairment
16.3 ()

mechani absorpti distributi metabol eliminati

T1/2

Usual dosage

use
52

sm
Eposartan

(teveten )

on

on

ism

Angioten

PB 308

receptor

PB 98% metabol

sin II

antagoni

L,

st

No

active
ized,

on
90% in
feces

5-9 h 400-800
mg/d

Mild to

moderate
hypertension

not

metabol
ize

* PB= protein binding, abs= absorption

53

54


1. , . 1.
2,

, , 2542.

2. . ACE inhibitor

. , 2541

3. . . 3,

, . 2539

4. Gilman AG, Goodman LS. Goodman and Gilmans the

pharmacology basis of therapeutic.

9 . McGraw-Hill. New York. 1996

ed

5. National High Blood Pressure. The sixth report of the joint

national committee on prevention,

detection, evaluation, and treatment of high blood pressure.

National Institute of Health.

1997.

6. Rang HP, Dale MM, eds. Pharmacology. Edinburg: Churchill

Livingstone, 2000

7. Katzung BG, ed. Basic and clinical Pharmacology, 8 ed.

th

New York: McGraw-Hill; 2001.

55



............1.
a. atenolol

............2. centrally acting sympathoplegic drugs

b. pindolol

............3.
c. captopril

............4. peripheral adrenergic neuron blocking agents

d. minoxidil

............5. cardioselective beta-blocker

e.

............6. beta-blocker with ISA

f.

............7. hypertrichosis

g.

nifedipine
clonidine

gaunethidine

............8.

h. methyldopa

............9.
i. furozemide

............10. severe hypertension

j. sodium nitroprusside

56


1. i, 2. f, 3. h, 4. g, 5. a,

6.

b 7. d 8. c, 9. e 10. j

57