DRUGS USED IN THE

TREATMENT OF
HYPERTENSION
IKE HUSEN
Depart. Of Pharmacology & Therapy
Faculty Of Medicine -Padjadjaran University
ANTIHYPERTENSIVE
DRUGS
 Principles of blood pressure regulation:
1. Blood pressure is regulated by the
following :
a. cardiac output
b. Peripheral vascular resistance
c.Volume of intravascular fluid
(controlled at the kidney)
2. Baroreflexes adjust moment-to- moment
blood pressure: Carotid baroreceptors
3. Reduction in renal perfusion pressure
 Major Factors Influencing Blood Pressure

ARTERIAL BLOOD  CARDIAC  PERIPHERAL

PRESSURE OUTPUT RESISTANCE

Arteriolar volume

Blood
Heart Filling Volume
rate Pressure
Contractility Venous
Tone
ANTIHYPERTENSIVE DRUGS

1. DIURETICS
2. SYMPATHOLYTIC DRUGS
3. VASODILATORS
4. ACE INHIBITORS AND
ANGIOTENSIN II RECEPTOR
ANTAGONISTS
5. CALSIUM CHANNEL BLOCKERS
1. DIURETICS

 Mechanisms of ACTION &

hemodynamic EFFECT :
- Depleting Na+ lead to BV  & CO, PR
may .
- 6-8 weeks : CO normal ; PR 
Figure 3.Actions of thiazide Diuretics
Thiazide
diuretics
Sodium, water
retention

Blood Volume

Peripheral Cardiac Output

resistance

Decrease in
Blood pressure
PHARMACOLOGICAL EFFECT Diuretics:
 Natriuretic (especially loop D.)
 K+ excretion (esp. acetazolamide; except
K+-Sparing D.)
 Ca++ excretion (esp. loop D. ; except
Thiazide D.)
 Water excretion (esp. loop D.)
INDICATION :
 THIAZIDE DIURETICS : Mild or moderate
essential HT with normal renal & cardiac
function.
 LOOP DIURETICS :
a. Severe HT when multiple drugs with
sodium-retaining properties are used, in
combination therapy.
b. Sodium retention : GFR < 30ml/mnt,
cardiac failure, cirrhosis
 POTASSIUM-SPARING DIURETICS :
a. >< excessive potassium depletion
b. Natriuretic effects of other diuretics 
TOXICITY/ADVERSE REACTION :
 Hypokalemia (except for potassium-sparing
D.), precaution :
 a. Persons taking digitalis
 b. Chronic arrhythmias

 c. AMI

 Hypomagnesia
 Metabolic effect (especially at dose):
a.Glucose intolerance
b.Serum lipid 
c.Uric acid , precipitate gout
2. SYMPATHOLYTIC DRUGS
2A.  BLOCKERS

 DRUGS:Prazosin, terazosin, doxazosin

1 blocking agent: relaxation of arterial &
venous smooth muscle PR and
arterial BP 
CO, RBF, GFR  min. (tachycardia and
increased renin release don not occur)
 PHARMACOKINETICS & DOSAGE:

Plasma concentration prazosin in patient CHD

owing primarily to reduced 1st pass metabolism

T 1/2 DOSAGE
Prazosin 3-4 h Dosis initial 1mg 3X sehari (*)
Dosis dapat ditingkatkan 20-30mg/h

Terazosin 12 h Umumnya: sehari sekali (5-20 mg/h)

Doxazosin 22 h Sehari sekali, dosis initial 1mg/h (*)

Dosis dapat ditingkatkan sampai 4mg/h
atau lebih (prn)
(prn): prorenata = bila perlu
(*); untuk mencegah hipotensi postural, sinkop
SIDE EFFECT & TOXICITY

 1 blockers causes postural hypotension,

and syncope after the 1st dose (1st pass
effect) the 1st dose should be small
and should be administered at bedtime
 Other toxicities (rare): dizziness,
headache, palpitations, lethargy
INDICATION :

 Mild to moderate HT.

 In combination with propranolol or a
diuretic for additive effect.
2B.  Blockers
Figure 4. Actions of -adrenoceptor blocking
agents (- BLOCKERS)
Activation of B1 Cardiac
adrenoceptors
on heart
output

Peripheral
-Adrenoceptor resistance
Decrease in
blockers Blood pressure

Renin Angiotensin II

Aldosteron

Sodium, water Blood volume

retention
DRUGS:

 Non selective: propranolol, nadolol,

carteolol
 1 blockers (cardioselective): atenolol,
metoprolol (relative), betaxolol, bisoprolol
 Partial agonist (-blockers with ISA):
pindolol, acebutolol (cardioselective),
penbutolol.
 -blockers with -blocking effect:
labetalol & carvedilol
PHARMACOKINETICS & DOSAGE:
Propranolol:
 Oral doses >> IV doses (1st-pass hepatic
metabolic). T ½ 3-6 h.
 Dose started 80mg/d in divided doses.
Effective antihypertensive dosage 80-
480mg/d, once or twice daily.
 Measures of resting bradycardia and
reduction in HR during exercise may be
used as guides in regulating dosage.
INDICATION:

- HT with SV tachyarrhythmia, previous

MI, A. pectoris, glaucoma, migraine
headache.
- It more effective : young patient > elderly.
2C. CENTRALLY ACTING
ADRENERGIC DRUGS

a. Clonidine (2 ) : Mild to moderate

HT (not responded to diuretic alone).
 Half of drugs: eliminated unchanged
in the urine patient with renal
insuff. DO 
 Toxicity: dry mouth and sedation
(frequent and may be severe)
 CI: risk of mental depression
b. Methyldopa : PR  BP 
 Do :1-2 g/d orally in divided/single
doses
 Renal insuff. : reduced drug clearance

 Distribution: CNS (+)

 Toxicity: sedation, drowsiness;

depression, Vertigo, lactation (included

in men)
3. VASODILATORS

Vasodilator:
A. Hidralazine & minoxidil (p.o):
long term outpatient Th/
B. P.e : nitroprusside & diazoxide
Hypertensive Emergencies.
C. Calcium channel blockers
 Figure 5
MEKANISME KERJA

Arteriole relax Renin C

Vasc. Resistance & BP Na+ & water retention

 blockers

Baroreflex:
Ino & chronotropic (+)
Oxygen consumption 

Risk: A.pectoris, Mi, Cardiac failure (in predisposed individuals

3A1. Hydralazine

Dilates arteries and arteriole (not veins)

 PR and reflex  HR & CO.

 Pharmacokinetics :
Bioavailability  (25%)
Metabolism : rapid & slow acetylators
Toxicity: headache, anorexia,
palpitations, Sweating and flushing
Usage: Th/ moderately severe HT
It is almost always as combination
with a -blockers and diuretics
(see figure 5: slide 22)
3A2. Minoxidil

 Dilates arterioles (not venules)

 Indication: severe to malignant HT that is
refractory to other drugs (p.o)
3B. HYPERTENSI EMERGENCY
 Diastolic BP > 150 mmHg
(uncomplicated p.) or >130 mmHg with
complications :
- Encephalopathy
- Cerebral hemorrhage
- Left ventricular failure
- Aortic stenosis
 Goal Th/ : rapidly reduce blood pressure
3B1. Sodium Nitroprusside (IV)

 Vasodilator (V&A) reflex tachycardia


VR  decomp. (-) CO(slight)
or  change

decomp. (+) CO 
PHARMACOKINETICS:

T ½ : in minutes continuous infusion.

(<1 hour)
Nitroprusside cyanide (*) thiocyanate
(toxic) (nontoxic)
thiosulfate

urine
(*) : rhodenase (mithoch. Enzyme)
SIDE EFFECT/TOXICITY:
 Metabolite: may produce cyanide, but cyani-
de toxicity is rare. Th/: thiosulphat and rho-
danase to produce thiocyanate (less toxic and
eliminated by kidneys).
 Per oral: hydrolyzed to cyanide (!!!)
 Toxicity related to accumulation of cyanide :-
- Metabolic acidosis
- Arrhythmias
- Excessive hypotension
- Death.
3B2. Diazoxide

 Direct-acting arteriolar vasodilator.

 Vascular effect  hydralazine.
 For coronary insuff. patients : diazoxide IV
 +  blocker (>< reflex activation of the heart).
 USAGE: Th/ HT emergency, especially:
- Malignant HT
- HT encephalopathy
- Eclampsia
 TOXICITY: Excessive hypotension
3C. Calcium Channel Blockers

 ACTION :
- Inhibit Ca++ influx into vasc. smooth muscle
cells  tones & vasc. resistance   BP 
(vasodilators)
- Intrinsic natriuretic effect
- Useful in HT with asthma, diabetes, angina
and peripheral vascular disease
DRUGS :
A. Dihydropyridine family:
- Nifedipine - Isradipine
- Nicardipine - Nisoldipine
- Amlodipine - Felodipine
- Nimodipine (esp. cerebral vasodilator)
Pharmacological effect :
- Selective vasodilators
- Cardiac depressant <<< verap./diltiaz.
- Reflex sympathetic activation: slight
tachycardia and slight increases CO
B. Verapamil
 It has the greatest effect on the heart:
 Slows cardiac cond.  HR , balanced by
reflex activation, NET EFFECT : moderate
cardiac suppression (HR&CO )
 Contraindicated in patient with preexisting
depressed cardiac function or AV conduct.
abnormalities !!!
 Weak vasodilator
C. Diltiazem

 It reduces HR (lesser than verapamil),

BP .
SIDE EFFECT AND TOXICITY :
Excessive inhibition of Ca++ influx  serious
cardiac depression :
- Cardiac arrest - Bradycardia
- AV block - CHF

SIDE EFFECT :
- Flushing - Headache
- Hypotention - Peripheral edema
- Constipation - Fatigue
Dilation of Coronary Vessels
Nifedipine
Verapamil
Dilitiazem
Weak Strong
action action
AV Conduction
Nifedipine Little effect

Verapamil

Diltiazem
Decreased Increased
Frequency of adverse effects
Nifedipine
Verapamil
Dilitiazem
Infrequent Frequent
4. INHIBITORS OF ANGIOTENSIN

A. ACE-IBHIBITOR
- Captopril - Fesinopril
- Enalapril - Moexipril
- Lisinopril - Quinopril
- Benazepril - Ramipril (long
acting)
B. ANGIOTENSIN RECEPTOR-
BLOCKING AGENTS
B1. Angiotensin Type 1 (AT1) Receptor
Blocking Agents
- Losartan
- Valsartan

B2. Analog and competitive Inhibitor of

Angiotensin II : Saralasin
 Fig. Page 16
Kininogen Angiotensin I
*
*
Bradykinin inactive Angiotensi II

Vasodilation Vasoconstriction Aldosteron 

VR VR Na+, water retention

**

BP 
BP 
*Site of ACE blockade (ACE inhibitor)
Hypertrophi &
**Site of receptor blockade (angiotensin-
Remodeling cor & vasc.
Receptor blocking agent
 Figure. 6: Effects of ACE inhibitors

Angiotensinogen Output of sympathetic

(2globulin in blood) nervous system

Vasodilation of
Renin vascular smooth
muscle
(from kidney)
Decreased
Angiotensin I ACE Decreased aldosterone
(inactive) angiotensin II production
-
Retention of sodium Decreased
ACE Inhibitors and water
blood
Levels of bradykinin
pressure
4A. ACE INHIBITOR

Pharmacological effect:
Captopril:
- VR BP
- Aldosteron secretion  Na+ & water
retention  & K+ retention 
- Bradikinin  vasodilation
- Vasodilator preload  CO
Enalapril: bradykinin  
Pharmacokinetics & dosage:

 Bioavailability captopril p.o: 70% after fasting,

p.c.: 30-40%, the antihypertensive action un-
affected. Lisinopril is slowly absorbed.
 Distribution: captopril: most body tissues,
except CNS
 Do. : - captopril: 25mg, 2-3 times daily,
enalapril: 10-20mg once or twice daily, lisinopril:
10-80mg once daily.
 All of ACE inhib. except fosinopril & moexipril
are eliminated primarily by kidney.
Toxicity/side effect:

 - Severe hypotension after initial dose (in

hypovolemic due to diuretics, salt restric-
tion, or GI fluid loss)
 - ARF (particularly in renal stenosis)
 - Hyperkalemia
 - Dry cough
 - Angioedema
 - Altered sense of taste
 - Allergic skin rashes, Drug fever
 Contraindication: 2nd and 3rd trimesters
of pregnancy
 Drug interaction:
- Potassium supp./pot.-sparing diuretics
hyperkalemia
- NAIDS may impair the hypotensive
effect by blocking bradykinin
USAGE:

 - Mild-moderate hypertension
 - Hypertension who were refractory to
standard multidrug antihypertensive
regimens
 - Hypertension with chronic congestive
heart failure
4B1. Angiotensin Type 1 (AT1) Receptor
Blocking Agents (Losartan and
valsartan).
 Effect on bradykinin metabolism (selective
blockers)
 Losartan: uricosuric effect

4B2. Analog and competitive Inhibitor of

Angiotensin II : Saralasin
 Antagonist and also weak agonist AT II
the effect: unpredictable