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Antihypertensive Drugs

DR. Dr Umi Kalssum Mkes

Hypertension is defined as systolic blood pressure


(SBP) of 140 mmHg or greater, diastolic blood
pressure (DBP) of 90 mmHg or greater, VI I JNC, (The
Seventh Report of the Joint National Committee on
Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
(JNC 7)

Drugs Used in Hypertension


Objectives:
Untuk meninjau etiologi hipertensi
Untuk membahas penentu utama tekanan darah
Untuk memahami strategi terapi yang digunakan dalam
pengobatan tekanan darah tinggi
Untuk menggambarkan kelompok utama obat yang digunakan
dalam pengobatan tekanan darah tinggi.
To review the etiology of hypertension
To discuss the major determinants of blood pressure
To understand the therapeutic strategies used in the
treatment of high blood pressure
To describe the major classes of drugs used in the
treatment of high blood pressure.

Hypertensive Crisis
BP = 210/150
Drugs that may be used:
Sodium Nitroprusside
Dilates arterial and venous smooth muscle

Diazoxide
vasodilator

Labetolol
- and -blocker
Drug of choice

1999 WHO Guidelines :


Definitions and Classifications of BP Levels
SBP
Category*
(mm Hg)
Optimal
< 120
Normal
< 130
High-normal
130-139
Grade 1 hypertension (mild)
140-159
Borderline subgroup
140-149
Grade 2 hypertension (moderate) 160-179
Grade 3 hypertension (severe)
> 180

DBP
(mm Hg)
< 80
< 85
85-89
90-99
90-94
100-109
> 110

What Determines Arterial


Pressure?
Heart
Rate

Arterial Pressure

~~

Isi sekuncup

Cardiac Output

Contractility

Peripheral
Resistance
Visk darah

Resist p.d

Faktor yang menentukan


Cardiac Output
1) Heart Rate

Chronotropy

2) Contractility

Inotropy

3) Venous Return =

Preload

4) Total Peripheral Resistance =


Afterload

Penyakit yang dihubungkan


dengan Hypertensi
Heart Left Ventricular
Gangrene of the
Failure Hypertrophy Myocardial
Lower Extremities
Infarction
Hypertensive
Encephalopathy

Aortic
Aneurym

HYPERTENSION

Blindness

Coronary
Heart Disease

Cerebral
Chronic
Preeclampsi/ Hemorrhage
Kidney Stroke
Eclampsia
Failure
9

Types of hypertension
Essential hypertension
90%
Tidak diketahui penyebabnya

Secondary hypertension
Disebabkan oleh penyakit tertentu

10

Causes of Secondary Hypertension

Renal
Parenchymal
Vascular
Others

Endocrine
Neurogenic
Miscellaneous Unknown

11

Hypertension: Predisposing factors

Age > 60 years


Sex (men and postmenopausal women)
Family history of cardiovascular disease
Smoking
High cholesterol diet
Co-existing disorders such as diabetes,
obesity and hyperlipidaemia
High intake of alcohol
Sedentary life style
12

Life style modifications


Lose weight, if overweight
Limit alcohol intake
Increase physical activity
Reduce salt intake
Stop smoking
Limit intake of foods rich in
fats and cholesterol
13

Approaches For High


Blood Pressure Treatment
Non-Pharmacological:
Obesity, diet, stressful
lifestyle, cigarette
smoking, exercise
Pharmacological therapy:
Antihypertensive Drugs
14

TUJUAN TERAPI
MENGHILANGKAN GEJALA
MEMPERPANJANG HIDUP
MENCEGAH KOMPLIKASI

15

Antihypertensive Drugs
The Problem:
Sustained diastolic pressure can lead
to CHF, infarction, end-organ damage

Possible Solutions:
Mild Htn can be treated with a single
drug
Severe Htn treated with several
drugs, choice of which depends on
patient needs
16

Some Examples of
Antihypertensive Drugs
Beta Blockers
Atenolol, Metoprolol , Acebutolol

Diuretics
Hydrochlorothiazide, spironolactone

ACE Inhibitors
Captopril

Calcium Channel Blockers


Nifedipine, Amlodipin , Nifedipin , verapamil

Centrally-Acting Drugs
Clonidine , Methyldopa

Vasodilators
Hydralazine , Minoxidil
17

Beta blockers
Example: Atenolol
Block 1 receptors on the heart
Block 2 receptors on kidney and inhibit release of renin
Decrease rate and force of contraction and thus reduce
cardiac output
Drugs of choice in patients with co-existent coronary
heart disease
Kelemahan
Adverse effects: lethargy, impotency, bradycardia
Not safe in patients with co-existing asthma and diabetes
Have an adverse effect on the lipid profile

18

-adrenoceptor blocker

(propranolol, atenolol, metoprelol)


-blockers and/or diuretics are currently
recommended as first-line drug therapy for
hypertension.
Their main effect is CO, also they inhibit
the release of renin from the kidneys.
Side effects: CNS (fatigue-lethargyinsomnia) - sexual dysfunction - rebound
hypertension

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Rebound Phenomena
Penghentian mendadak beta blocker
memicu timbulnya myocardial
infarction
Kontra Indikasi :
Asthma
Peripheral Vascular Disease
Relative contraindication

Heart failure
Bradycardia / Heart block
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Adverse Drug Reactions

fatigue
Lethargy
Impotence
Bradycardia
Bronchospasm

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Vasodilators
How do they work?
Mechanism 1:
ACE converts Angiotensin I to
Angiotensin II
Angio II has effects as shown
ACE inhibitors decrease A II

Angiotensin I

ACE

End Results:
Decrease fluid retention,
afterload

Examples:
Enalapril, Captapril

Angiotensin II
Sympathetic
Output
Constrict
Vascular Smooth
Muscle

Bradykinin
Na+/H20
Retention

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Renin/Angiotensin/AldosteroneSystem

afterload
Cardiac
Performance
23

DirectSmoothMuscleRelaxants(Nitrovasodilators)

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Other Vasodilators:
Mechanism 2:
Direct smooth muscle relaxants
Nitrates
Venous dilators
Reduce preload
Eg: sodium nitropruside

Calcium channel blockers


Amlodipine, felodipene

25

Diuretics
Bottom line: they decrease fluid volumes
Ada 4:
Carbonic anhydrase inhibitors
Loop diuretics
Thiazide diuretics
K+-sparing

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Diuretics
Example: Hydrochlorothiazide
Act by decreasing blood volume and cardiac output
Decrease peripheral resistance during chronic therapy
Drugs of choice in elderly hypertensives
KELEMAHAN :
Hypokalaemia
Hyponatraemia
Hyperlipidaemia
Hyperuricaemia (hence contraindicated in gout)
Hyperglycaemia (hence not safe in diabetes)
Not safe in renal and hepatic insufficiency

27

Therapeutic Agents that Alter Cardiac


Contractility (Inotropy)
- Agonists
- Antagonists
Cardiac Glycosides
Calcium Channel Blockers
Phosphodiesterase Inhibitors (?)
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Renin, Angiotensin,
Aldosterone System(RAAS)

()
()
()
()
()

Renal Perfusion
RAAS
TPR (A-II: direct & indirect)
Na+/H20 retention (Aldosterone)
Blood Volume

29

Calcium Channel Blockers:


Phenylalkylamine: Verapamil
Benzothiazipine: Diltiazem
Dihydropyridines: Nifedipine, et al.

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Calcium Channel Blockers

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Love - Hate Triangle :

32

Calcium channel blockers


Example: Amlodipine
Block entry of calcium through calcium channels
Cause vasodilation and reduce peripheral
resistance
Drugs of choice in elderly hypertensives and
those with co-existing asthma
Neutral effect on glucose and lipid levels
Drawbacks
Adverse effects: Flushing, headache, Pedal
edema
33

ACE inhibitors
Example: Lisinopril, Enalapril
Inhibit ACE and formation of
angiotensin II and block its effects
Drugs of choice in co-existent diabetes
mellitus
Drawbacks
Adverse effect: dry cough,
hypotension, angioedema
34

Angiotensin II receptor blockers


Example: Losartan
Block the angiotensin II receptor
and inhibit effects of angiotensin II
Drugs of choice in patients with
co-existing diabetes mellitus
Drawbacks
Adverse effect: dry cough,
hypotension, angioedema
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Alpha blockers
Example: Doxazosin
Block -1 receptors and cause vasodilation
Reduce peripheral resistance and venous
return
Exert beneficial effects on lipids and insulin
sensitivity
Drugs of choice in patients with co-existing
hyperlipidaemia, diabetes mellitus and BPH
Drawbacks
Adverse effects: Postural hypotension
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Peripheral 1-receptor antagonists


(Prazocin - Terazocin)
Competitive blockers of 1-adrenoceptors
They decrease TPR BP
They are used in combination with blockers or diuretics for additive effects
Side effects: Reflex tachycardia - postural
hypotension
Penggunaan -blocker diperlukan
mengurangi efek jangka pendek reflex
tachycardia
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Antihypertensive therapy:
Side-effects and Contraindications
Class of drugs

Main side-effects

Contraindications/
Special Precautions

Diuretics
(e.g. Hydrochlorothiazide)

-blockers
(e.g. Atenolol)

Electrolyte imbalance,
Hypersensitivity, Anuri
total and LDL cholesterol
levels, HDL cholesterol
levels, glucose levels,
uric acid levels
Impotence, Bradycardia,
Fatigue

Hypersensitivity,
Bradycardia,
Conduction
disturbances,
Diabetes,
Asthma, Severe
cardiacfailure
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Antihypertensive therapy: Side-effects and Contraindications


Class of drug
Calcium channel blockers
(e.g. Amlodipine,
Diltiazem)

Main side-effects
Pedal edema, Headache

Contraindications
Non-dihydropyridine
CCBs (e.g diltiazem)
Hypersensitivity,
Bradycardia, Conduction
disturbances,
Congestive heart failure
Left ventriculardysfunction.
Dihydropyridine- Hypersensitivity

-blockers

Postural hypotension

Hypersensitivity

ACE-inhibitors
(e.g. Lisinopril)

Cough, Hypertension,
Pregnancy,

Hypersensitivity,

Angioneurotic edema

Bilateral renal artery stenosis

Headache, Dizziness
Bilateral renal artery stenosis

Hypersensitivity, Pregnancy,

(e.g. Doxazosin)

Angiotensin-II receptor
blockers (e.g. Losartan)

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Keuntungan Terapi Kombinasi


Better blood pressure control
Lesser incidence of individual
drugs side-effects
Neutralisation of side-effects
Increased patient compliance
Lesser cost of therapy

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Fixed-dose combinations as recommended by


JNC-VI (1997) guidelines and 1999 WHOguidelines
Calcium channel blocker and -blocker
(e.g. Amlodipine and Atenolol)
Calcium channel blocker and ACEinhibitor (e.g. Amlodipine and Lisinopril)
ACE-inhibitor and Diuretic (e.g. Lisinopril
and Hydrochlorothiazide)
-blocker and Diuretic (e.g. Atenolol and
Hydrochlorothiazide)
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Drugs in special conditions


Condition
Pregnancy

Coronary heart
disease
Congestive heart
failure

Preferred Drugs
Nifedipine, labetalol,
hydralazine, betablockers, methyldopa,
prazosin
Beta-blockers, ACE
inhibitors, Calcium
channel blockers

ACE inhibitors,
beta-blockers
1999 WHO-ISH guidelines

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Atrioventricular and Semilunar Valves

43

Valves
SEMILUNAR VALVES
Ventricle contracts: open
Ventricle relaxes: closed

Cardiac Cycle
Systole: contraction.
Diastole: relaxation.

44

Heart Disease
Arrhythmias = abnormal
heart rhythms.
Bradycardia = slower
Tachycardia = faster
(exercise!)
Flutter: extremely rapid
Fibrillation:
Contractions of different
groups of myocardial cells at
different times.
Ventricular fibrillation is lifethreatening.

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Drug -Drug Interactions


Primarily Pharmacodynamic
Hypotension when used with other hypotensive
agents
Bradycardia when used with other rate limiting
drugs such as verapamil or diltiazem
Cardiac failure when used with negatively inotropic
agents such as verapamil, diltiazem or
disopyramide
NSAIDs antagonise antihypertensive actions

46

Calcium Channel Blockers


DILTIAZEM, VERAPAMIL, AMLODIPINE
Prevent calcium influx into myocytes and smooth
muscle lining arteries and atrerioles by blocking
the voltage dependent L-Type calcium channel
Rate limiting CCBs like diltiazem and verapamil
also reduce heart rate
CCBs like nifedipine or amlodipine may produce
a reflex tachycardia

47

Mechanism of Action
Increased free calcium in the cytoplasm of
vascular smooth muscle cells leads to
vasoconstriction.
The calcium ion, after binding to calciumbinding proteins, activates a myosin lightchain kinase (MLCK), causing
phosphorylation of myosin filaments followed
by an interaction of these filaments with actin
filaments and finally cell contraction.
48

The calcium ion can enter the vascular smooth


muscle cell by two main channels.
The receptor-regulated channels cause, upon
activation with an agonist (eg, angiotensin II,
norepinephrine, endothelin), the formation of
inositol trisphosphate (IP3).
This intracellular messenger triggers the release
of calcium from the sarcoplasmic reticulum (SR).
The rapid calcium mobilization by this pathway
stimulates then sustains entry of calcium through
the channel.
Calcium antagonists block voltage-dependent
channels. These channels allow the entry of
calcium in response to cell depolarization.
49

Renin-Angiotensin Aldosterone System


Non-ACE Pathways

(e.g., chymase)

Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activatio

Angiotensinogen
renin

AT1

Angiotensin I
Angiotensin II
ACE

Cough,
Angioedema
Benefits?

Bradykinin

Aldosterone
Inactive
Fragments

AT2

Vasodilation
Antiproliferation
(kinins)
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Akibat apabila tek. Darah


tinggi tidak diobati
1) Increase morbidity and
mortality due to accelerated
atherosclerosis (sudden
death, aortic aneurysm,
stroke, renal insufficiency)
2) The higher the blood pressure
the higher the risk of
cardiovascular diseases (CHF,
53
coronary disease)

HERDITY

ENVIRONMENT

PREHYPERTENSION(AGE030)
INCREASEDCARDIACOUTPUT
EARLYHYPERTENSION(AGE2040)
INCREASEDPERIPHERALRESISTANCE
ESTABLISHEDHYPERTENSION(AGE3050)
ACCELERATEDATHEROSCLEROSIS
COMPLICATEDHYPERTENSION(AGE4050)
CARDIAC

AORTIC

Enlargement
Aneurysm,
Failure,Infarction embolization

RENAL

Arteriosclerosis,
Insufficiency

CEREBRAL

Thrombosis,hemorrhage,
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embolization

55

AngiotensinConvertingEnzymeInhibitors(e.g.,captopril)
AngiotensinIItype1(AT1)receptorblockers(e.g.,losartan)
captopril

losartan

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CNS 2-agonists
(Clonidine - methyldopa)

Stimulation of 2-receptors in the medulla


sympathetic outflow TPR BP
Generally used as second-line agents,
after diuretics, in the treatment of
hypertension
-methyldopa is converted to -methylnor epinephrine
Sides effects include sedation, dry mouth
and bradycardia
Rebound hypertension occurs following
abrupt withdrawal of these drugs.

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