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
PRESSURE
PERIPHERAL
RESISTANCE
CARDIAC
OUTPUT
Heart
rate
Contractility
Filling
Pressure
Blood
Volume
Venous
Tone
Arteriolar volume
~
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
Decrease in
Blood pressure
Thiazide
diuretics
Cardiac Output
Blood Volume
Sodium, water
retention
Peripheral
resistance
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. o BLOCKERS

DRUGS:Prazosin, terazosin, doxazosin
o
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 1
st
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
o
1
blockers causes postural hypotension,
and syncope after the 1
st
dose (1
st
pass
effect) the 1
st
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.
Figure 4. Actions of |-adrenoceptor blocking
agents (|- BLOCKERS)

Activation of B1
adrenoceptors
on heart
Cardiac
output
Peripheral
resistance
Angiotensin II
Renin
Decrease in
Blood pressure
Aldosteron
Sodium, water
retention
Blood volume
|-Adrenoceptor
blockers
2B. | Blockers
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 o-blocking effect:
labetalol & carvedilol
PHARMACOKINETICS & DOSAGE:
Propranolol:
Oral doses >> IV doses (1
st
-pass hepatic
metabolic). T 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 (o
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 : 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
action
Strong
action
AV Conduction
Nifedipine
Verapamil
Diltiazem
Decreased
Little effect
Increased
Frequency of adverse effects
Verapamil
Dilitiazem
Nifedipine
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 (AT
1
) Receptor
Blocking Agents
- Losartan
- Valsartan

B2. Analog and competitive Inhibitor of
Angiotensin II : Saralasin
Fig. Page 16
Kininogen
Bradykinin
Vasodilation
VR+
BP +
inactive
Angiotensin I
Angiotensi II
Vasoconstriction Aldosteron |
VR| Na+, water retention|
BP |
*
*
**
Hypertrophi &
Remodeling cor & vasc.
*Site of ACE blockade (ACE inhibitor)
**Site of receptor blockade (angiotensin-
Receptor blocking agent
Figure. 6: Effects of ACE inhibitors
Angiotensinogen
(o
2
globulin in blood)
Angiotensin I
(inactive)
Renin
(from kidney)
Decreased
angiotensin II
ACE
-
ACE Inhibitors
Output of sympathetic
nervous system
Vasodilation of
vascular smooth
muscle
Retention of sodium
and water
Levels of bradykinin
Decreased
aldosterone
production
Decreased
blood
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: 2
nd
and 3
rd
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 (AT
1
) 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