Antihypertensive Drugs

DR. Dr Umi Kalssum Mkes

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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)
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 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.
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 Hypertensive Crisis
• BP = 210/150
• Drugs that may be used:
• Sodium Nitroprusside
– Dilates arterial and venous smooth muscle
• Diazoxide
– vasodilator
• Labetolol
– - and β-blocker
– Drug of choice

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 1999 WHO Guidelines :
Definitions and Classifications of BP Levels

SBP DBP
Category* (mm Hg) (mm Hg)
Optimal < 120 < 80
Normal < 130 < 85
High-normal 130-139 85-89
Grade 1 hypertension (mild) 140-159 90-99
Borderline subgroup 140-149 90-94
Grade 2 hypertension (moderate) 160-179 100-109
Grade 3 hypertension (severe) > 180 > 110

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 What Determines Arterial
Pressure?

Heart Isi sekuncup

Rate

Arterial Pressure ~~ Cardiac Output X

Peripheral
Resistance

Contractility
Visk darah
Resist p.d

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Faktor yang menentukan
Cardiac Output
1) Heart Rate = Chronotropy

2) Contractility = Inotropy

3) Venous Return = Preload

4) Total Peripheral Resistance =

Afterload 8
 Penyakit yang dihubungkan
dengan Hypertensi
Heart Left Ventricular
Gangrene of the
Failure Hypertrophy Myocardial
Lower Extremities
Infarction
Aortic Hypertensive
Aneurym Encephalopathy
HYPERTENSION
Coronary
Blindness Heart Disease

Chronic Cerebral
Stroke Preeclampsi/ Hemorrhage
Kidney
Eclampsia
Failure

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 Types of hypertension
• Essential hypertension
– 90%
– Tidak diketahui penyebabnya

• Secondary hypertension
– Disebabkan oleh penyakit tertentu

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Causes of Secondary Hypertension
• Renal
– Parenchymal
– Vascular
– Others
• Endocrine
• Neurogenic
• Miscellaneous Unknown

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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

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 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
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 Approaches For High Blood
Pressure Treatment
• Non-Pharmacological:
– Obesity, diet, stressful
lifestyle, cigarette smoking,
exercise
• Pharmacological therapy:
Antihypertensive Drugs

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TUJUAN TERAPI

• MENGHILANGKAN GEJALA

• MEMPERPANJANG HIDUP

• MENCEGAH KOMPLIKASI

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 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

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 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

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 Beta blockers
Example: Atenolol
• Block b1 receptors on the heart
• Block b2 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
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 b-adrenoceptor blocker
(propranolol, atenolol, metoprelol)
• b-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-lethargy-insomnia)
- 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 I
Angiotensin II
– Angio II has effects as shown
– ACE inhibitors decrease A II ACE
• End Results:
– Decrease fluid retention, Angiotensin II
afterload
• Examples: ↑ Sympathetic
Output
– Enalapril, Captapril ↑ Bradykinin
Constrict
Vascular Smooth
Muscle ↑ Na+/H20
Retention 22
Renin/Angiotensin/Aldosterone System

 afterload

Cardiac
Performance
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Direct Smooth Muscle Relaxants (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

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 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)

• b - Agonists
• b - 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

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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 :

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 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 33
edema
 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
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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,
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hypotension, angioedema
 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 36
Peripheral 1-receptor antagonists
(Prazocin - Terazocin)
• Competitive blockers of 1-adrenoceptors
• They decrease TPR BP
• They are used in combination with b-blockers
or diuretics for additive effects
• Side effects: Reflex tachycardia - postural
hypotension
• Penggunaan b-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 Electrolyte imbalance, Hypersensitivity, Anuri
(e.g. Hydrochloro- total and LDL cholesterol
thiazide) levels, HDL cholesterol
levels, glucose levels,
uric acid levels
b-blockers Impotence, Bradycardia, Hypersensitivity,
(e.g. Atenolol) Fatigue Bradycardia,
Conduction
disturbances,
Diabetes,
Asthma, Severe
cardiacfailure

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Antihypertensive therapy: Side-effects and Contraindications
Class of drug Main side-effects Contraindications

Calcium channel blockers Pedal edema, Headache Non-dihydropyridine

(e.g. Amlodipine, CCBs (e.g diltiazem)–
Diltiazem) Hypersensitivity,
Bradycardia, Conduction
disturbances,
Congestive heart failure
Left ventriculardysfunction.
Dihydropyridine- Hypersensitivity

-blockers Postural hypotension Hypersensitivity

(e.g. Doxazosin)

ACE-inhibitors Cough, Hypertension, Hypersensitivity,

(e.g. Lisinopril) Pregnancy,

Angioneurotic edema Bilateral renal artery stenosis

Angiotensin-II receptor Headache, Dizziness Hypersensitivity, Pregnancy,

blockers (e.g. Losartan) Bilateral renal artery stenosis

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 Keuntungan Terapi
Kombinasi
• Better blood pressure control
• Lesser incidence of individual
drug’s 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 b-blocker

(e.g. Amlodipine and Atenolol)
• Calcium channel blocker and ACE-
inhibitor (e.g. Amlodipine and Lisinopril)
• ACE-inhibitor and Diuretic (e.g. Lisinopril
and Hydrochlorothiazide)
 b-blocker and Diuretic (e.g. Atenolol and
Hydrochlorothiazide)
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 Drugs in special conditions
Condition Preferred Drugs

• Pregnancy • Nifedipine, labetalol,

hydralazine, beta-
blockers, methyldopa,
prazosin
• Coronary heart
disease • Beta-blockers, ACE
inhibitors, Calcium
channel blockers
• Congestive heart
failure • ACE inhibitors,
beta-blockers

1999 WHO-ISH guidelines 42

Atrioventricular and Semilunar Valves

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 Valves
• SEMILUNAR VALVES
• Ventricle contracts: open
• Ventricle relaxes: closed

Cardiac Cycle
• Systole: contraction.
• Diastole: relaxation.

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 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 life-
threatening.
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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

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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

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 Mechanism of Action
• Increased free calcium in the cytoplasm of
vascular smooth muscle cells leads to
vasoconstriction.

• The calcium ion, after binding to calcium-

binding proteins, activates a myosin light-
chain kinase (MLCK), causing
phosphorylation of myosin filaments followed
by an interaction of these filaments with actin
filaments and finally cell contraction.

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• 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 49
calcium in response to cell depolarization.
 Renin-Angiotensin Aldosterone System

Non-ACE Pathways  Vasoconstriction

(e.g., chymase)  Cell growth
 Na/H2O retention
 Sympathetic activation
Angiotensinogen

renin Angiotensin I AT1

Angiotensin II
ACE
Aldosterone AT2

Cough,  Vasodilation
Inactive  Antiproliferation
Angioedema  Bradykinin Fragments (kinins)
Benefits?

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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, coronary disease)

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 HERDITY ENVIRONMENT

PREHYPERTENSION (AGE 0-30)

INCREASED CARDIAC OUTPUT

EARLY HYPERTENSION (AGE 20-40)

INCREASED PERIPHERAL RESISTANCE

ESTABLISHED HYPERTENSION (AGE 30-50)

ACCELERATED ATHEROSCLEROSIS
COMPLICATED HYPERTENSION (AGE 40-50)

CARDIAC AORTIC RENAL CEREBRAL

Enlargement Aneurysm, Arteriosclerosis, Thrombosis, hemorrhage,
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Failure, Infarction embolization Insufficiency embolization
55
Angiotensin Converting Enzyme Inhibitors (e.g., captopril)
Angiotensin-II type 1 (AT1) receptor blockers (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 -methyl-
nor epinephrine
• Sides effects include sedation, dry mouth
and bradycardia
• Rebound hypertension occurs following
abrupt withdrawal of these drugs. 57
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