OBAT OBAT ANTIHIPERTENSI

AVP

VASO KONSTRIKSI

Na RETENTION

MESANGIAL
CONTRACTION

CNS DYPSOGENIA

ANGIOTENSIN II

ACE INHIBITOR

VESSEL
HYPERTROPHY

ALDOSTERON

E4FFERENT
CONTRACTION
ANGIOTENSIN II RE
SEPTOR ANTAGONIS

MYOCARDIAL
HYPERTROPHY

NE RELEASE

OBAT OBAT ANTI HYPERTENSI

APA HYPERTENSI
BAGAIMANA PENGATURAN TEKANAN DARAH
KENAPA HIPERTENSI HARUS DIOBATI
KAPAN HIPERTENSI DIOBATI
BAGAIMANA PENGOBATAN HIPERTENSI
HIPERTENSI : TEKANAN DARAH
SISTOLE / DIASTOLE > 145/90

HIPERTENSI 95% ESSENTIAL PENYEBAB

TIDAK DIKETAHUI

AKTIVITAS SIMPATIS
PADA OATAK, JANTUNG
PEMBULUH DARAH
GINJAL

KELENJAR SUPRARENAL
CORTEK DAN MEDULA
FAKTOR GINJAL

BARORESEPTOR

SODIUM ELEKTROLI

TAHANAN PERIPER
CARDIAC OUTPUT
ANTI DIURETIK
HORMON

VOLUME DARAH

FAKTOR JANTUNG

PEMBULIUH DARAH

VISCOSITAS DARAH

GENETIK

OBESITAS

FOOD HABIT

HIPERTENSI

?
RENIN

?
SYMPATHIC DRIVE

HIPERTENSI

TIDAK LANGSUNG

LANGSUNG

ATHEROMA

LOAD
JANTUNG
HIPERTROPI

PEMBULUH DARAH
PROLIFERASI

PAYAH JANTUNG

ATHEROSKLEROSIS

TUJUAN TERAPI
MENGHILANGKAN GEJALA
MEMPERPANJANG HIDUP
MENCEGAH KOMPLIKASI
MATA

GINJAL

JANTUNG

OTAK

TERAPI HIPERTENSI
FAKTOR FAKTOR RESIKO
OBESITAS
MEROKOK
ENDOKRIN PIL KB
GAYA HIDUP STRESS
RENO VASCULER
KELEBIHAN GARAM
NOPRMAL 25-50 MMOL
1 GRAM = 17 MMOL
200 - 250 MMOL
12-15 GRAM NaCl/ HARI

OBAT UNTUK HIPERTENSI

OBAT DI CNS
TRANGUILIZER
NEURON SIMPATIS SENTRAL
OBAT DI SARAF SIMPATIS TEPI
GANGLION
UJUNG SARAF
RESEPTOR ADRENERGIK
OBAT LANGSUNG DI PEMB. DARAH
OBAT PADA GINJAL DIURETIK
OBAT PADA SYSTEM RAA
ANGIOTENSIN PATHWAYS
RESEPTOR ANGIOTENSIN II

OBAT ANTI HIPERTENSI

SITE OF ACTION

OBAT

MEKANISME KERJA

CEREBRAL CORTEX

SEDATIVE
TRANGUILIZER

GABA

MIBRAIN

RESERPIN
METHYLDOPA
B BLOKER
CLONIDIN

PENGOSONGAN NE
NT PALSU
?
ALPHA 2 HAMBAT
RELEASE

GANGLION OTONOM

HEXAMETHONIUM
PEMPIDINE

AMBAT TRANSMISI
SIMPATIS @ PARA S.

SITE OF ACTION

OBAT

MEKANISME. KERJA

ADRENERGIC AXON

RESERPIN
BRTYLIUM
BETHANIDINE
DEBRISOQUIN
GUANETHIDINE

DEPLESI NA
BLOK RELEASE
ADRE NEURON BLOCKER
ADRE. NEURON BLOKER
DEPLESI NA DAN ADRE
NEURON BLOKER
FALS NERO TRANSM
MAO INHIBTOR DAN
ADRE. NEURON BLOKER

METHYL DOPA
PARGYLIN
ALPHA ADRENOCEPTOR PHENTOLAMIN
PENOXY BENZAMINE
LABETOLOL
PRAZOSIN
INDORAMIN

BLOKE ALPHA RESEPTOR

BLOK ALPHA ADRE RECP
ALPHA DAN BETA BLOK
BLOK ALPHA RECEPTOR
ALPHA ADRE. BLOKER

SITE OF ACTION

OBAT

MEKANISME KERJA

B ADRENORECEPTOR

PROPANOLOL
OXPRENOLOL
ALPRENOLOL
PINDOLOL
TIMOLOL
SOTALOL

CO MENURUN,
BARORESPTOR,
ADAPTASI PANJANG,
PENURUNAN PLASMA
RENIN, PLASMA
VOLUME MENURUN

ATENOLOL
METOPROLOL
ACEBUTOLOL

CARDIOSELEKTIF
BETA BLOKER, EFEK
MINIMAL PADA BETA-2

THIAZIDE
DIAZOXIDE
HYDRALAZINE
MINOXIDIL
SOD. NITRO PRUSIDE
VERAPRAMIL
DILTIAZEM

MENURUNKAN Na K
UNKNOWN

OTOT POLOS VASKULER

CA ANTAGONIS

SITE OF ACTION

OBAT

MEKANISME KERJA

AIR DAN Na EXTRASEL THIAZIDE

DEPLESI VOLUME
FUROSEMIDE
GARAM Na
ALSDOTERON ANTAGONIS
SPIRONOLACTONE
TRIAMTEREN
RENIN ANGIOTENSIN SYSTEM
BETA BLOKER
CAPTOPRIL
SARALARASIN
LOSARTAN
VALSARTAN

HAMBAT RENIN RELEASE

BLOK ENZIM YG MERUBAH ANG I - ANG II
BLOK ANG. RECEPTOR

DIURETIC
THIAZIDE
CHLORTHALIDONE
INDAPAMIDE
LOOP DIURETIC
BUMETAMIDE
ETHACRINIC ACID
UROSEMIDE
POTASIUM SPARER
AMILORIDE
SPIRONOLACTONE
TRIAMTERENE
VASODILATOR
DIRECT
HIDRALAZINE
MINOXIDIL
CALCIUM CHANNEL
DYHYDROPYRIDINE
AMLODIPINE
FELODIPINE
ISRADIPINE
NICARDIPINE
NIFEDIPINE
NISOLDIPINE
DILTIAZEM
VRAPRAMIL

ADRENERGIC INHIBITOR
PHERIPERAL INH
BETA BLOKER
GUANADREL
ACEBUTOLOL
GUANETHIDINE
ATENOLOL
RESERPINE
BETAXOLOL
CENTRAL ALPHA AGONIS
BISOPROLOL
CLONIDINE
CARTEOLOL
GUANABENZ
METOPROLOL
GUANFACINE
NADOLOL
METHYLDOPA
PENBUTOLOL
ALPHA 1 BLOKER
PINDOLOL
DOXAZOSIN
PROPANOLOL
PRAZOSIN
TIMOLOL
TERAZOSIN
ALPHA AND BETA BLOCKER
CARVEDILOL
LABETOLOL
VASO DILATOR
ANGIOTENSIN CONVERTING
ENZYME INHIBITOR
BENAZEPRIL
CAPTOPRIL
ENALAPRIL
FOSINOPRIL
LISINOPRIL
MOEXIPRIL
QUINAPRIL
PERINDOPRIL
RAMIPRIL
TRANDOLAPRIL

ANGIOTENSIN II
RECEP. BLOKER
CANDERSARTAN
EPROSARTAN
IRBESARTAN
LOSARTAN
TELMISARTAN
VALSARTAN

DISLIPIDEMIA

OBESITY AND DM, HIPERTENSI

OBESITY + ANDROGEN

DMII
NIDDM

PERIPERAL
INSULIN
RESISANCE

LIPOLYSIS
INCREASE ABD
RELEASE OF
DOMINAL FAT
FREE FATTY ACID

INCREASE
PANCREATIC
INSULIN SECRE

DECREASE
HEPATIC INSULIN
EXTRACTION

HYPERINSULINEMIA

INCREASED
SYMPATHETIC
ACTIVITY

SODIUM
RETENTION

ATENUATED
VASODILATATION

HYPERTENSION

VASCULAR
HYPERTROPHY

Na K ATPase
(co Transport)

CELL Na

Na Fluxes
K fluxes
Ca Binding

Ca ATPase
(others)

Depolarization

CELL Ca

CONTRACTILITY

Na retention
Na H antiport
(Na Li coutertransport

CELL pH

GROWTH

HYPOTHESIS ABNORMAL IONIC FLUXES AND CONTRACTILITY

FUNGSI SEL ENDOTHEL

TARGET FUNGSI
LUMEN

MEKANISME KERJA CELLULER

VASOKONSTRIKSI
ENDOTHELIN
ANGIOTENSIN II
THROMBOXANE A2
PROSTAGLANDINE H2
GROWTH
STIMULATION
PLATELET GROWTH DF
FIBROBLAST GF
INSULIN LIKE GF
ENDOTHELIN
ANGIOTENSIN II
INFLAMATION PROINFLAMATORY
ADHESION MOLECULE
(ELAM, VCAM, ICAM)
HOMEOSTASIS PROTROMBOTIC
PLASMINOGEN ACTIVATOR
INHIBITOR

VASO DILATASI
NITRIC 0XIDE
BRADIKININ
HYPERPOLARIZING F.
INHIBITION
NITRIC 0XIDE
PROSTAGLANDIN I 2
TRANSFORMING GF
ANTI INFLAMATORY

ANTITHROMBOTIC
PROSTACYCLIN
TISSUE PLASMINOGEN
ACTIVATOR

SYMPATIS

INTRAMURAL

NPY
NA
ATP

SENSORY - MOTOR

PARA SIMPATIS

PEPTIDA
ATP

SP
ATP
CGRP

P2X

P2Y

CGRP

VIP

VIP

ADVENTITIA

+
MEDIA

VP

AT II

ATP ACH 5HT SP

EDRF

EDRF

PG

SP 5HT M P2Y
S
P

ENDOTHELIUM

SHEAR STRESS

BLOOD PRESSURE
MEDIAL SMC
MIGRATION

ENDOTHELIAL CHANGES

LEUCOCYTE
ADHERNCE
PENETRATION

MACROPHAGE
ACCULMULATION

PERMEABILITY

CONSTRICTING
AND RELAXING
FACTORS

LIPO PROTEIN
PLASMA COMPN.

SMC PROLIFERATION
AND ACCUMULATION

NORMO LIPIDEMIA

HYPERLIPIDEMIA

INTIMAL TICKENING
FIBROUS PALQUE

INTIMAL
SMC

MATRIX

ATHEROSCLEROTIC
PLAQUE

BETA ADRENO RECEPTOR

BLOCKING AGENTS

NONSELECTIVE

SELECTIVE

WITH ALPHA BLOCKING

LABETOLOL

ISA NADOLOL
PROPANOLOL
TIMOLOL

ISA +
PINDOLOL
CARTEOLOL
PENBUTOLOL

ISA -

ISA +

ATENOLOL ACEBUTOLOL
ESMOLOL
PRACTOLOL
METOPROLOL
BISOPROLOL
BETAXOLOL

Hypertension

High bp assoc with decr LE, stroke, CAD, and

other end-organ diseases (e.g., retinopathy,
renal failure).
Problem: Risk is graded.
Lowering the bp is indicated in patients if the
diastole bp> 90 mm Hg and systole bp> 160
mm Hg.
Other risk factors for vascular disease may
be synergistic: smoking, obesity,
hyperlipidemia, DM and ventricular
hypertrophy.
In cases of mild hypertension, weight loss,
decr alcohol and salt may be sufficient, but
In more severe cases, drug treatment is
indicated.

Drugs used for Hypertension

-adrenergic receptor antagonists

Thiazide diuretics
ACE inhibitors
Ca2+ antagonists
1-adrenergic receptor antagonists?
Centrally acting drugs: 2-adrenergic
receptor agonists?
Moderate hypertention usually requires
just one drug, but becoming incr more
evident that >2 drugs will do the job
better.

Thiazide Diuretics

One of 2 1st-line of defense in treating

hypertension
Mechanism of decr arterial bp not known.
Initially, decr in blood vol, venous return,
and cardiac output decrbp.
Gradually, the cardiac output returns to
normal, but the hypotensive effect remains
because the peripheral resistance has, in
the meantime, decreased.
Diuretics have no direct effects on the
vascular smooth muscle.
Rather, the small, but persistent decr in
body Na+decr in H2O decrbp.

Thiazide Diuretics (contd)

One possible mech: decreased smooth

muscle Na+ 2 decr in [Ca2+]cyto so that
the muscle becomes less responsive.
These drugs may cause hypokalemia,
DM, gout.
Side-effects: impotence, libido loss.
These drugs have a flat-dose response
curve: **What does this mean, both
response-wise and clinically? (possible
exam question)

-Adrenoreceptor Antagonists

One of 2 1st-line of defense in treating

hypertension.
Decrbp by decr cardiac output (CO).
With contd treatment, the CO returns to normal,
but the bp remains low (not known how)
because the peripheral vasc resistance is
reset at a lower level.
Centrally acting mechanism? Not likely because
some of these drugs do not cross the BBB.
Block of 1-adrenoreceptors in renal JG cells that
secrete renin may be involved.
Adverse side-effects: cold hands, fatigue,
asthma provocation, HF, or conductance block,
incr serum TGs, and decr HDL levels.
All of these drugs decrbp, but at least some of
these side-effects can be averted
(cardioselectivehydrophillic drugs (w/o liver
metabolism or BBB penetration) (e.g., atenolol).

Vasodilator Drugs ACE Inhibitors

Recall angiotensin II strong circulating

vasoconstrictor. So, inhibiting its synthesis in
hypertensive patients decr in peripheral
resistance and bp.
ACEIs dont impair CV reflexes and share few
of the side-effects with diuretics and blockers.
Side-effects: incrbradykinin dry cough (ACE
also metabolizes bradykinin);
More serious side effects: angioedema,
proteinurea, neutropenia.
1st dose may cause a very steep fall in bp
(e.g., in patients on diuretics bec. they are
Na+-depleted)

May cause renal failure in patients

with bilateral renal artery stenosis:
- Angiotensin II required to constrict
postglomerular arterioles and
maintain adequate GF.
- Inhibition of angiotensin II formation
does not seriously impair secretion
and excessive K+ retention occurs only
with K+ supplements or K-sparing
diuretics (recall that aldosteroneincr
Na+reabsorption and K+ excretion).

Vasodilator Drugs
Angiotensin Receptor Antagonists

Losartan (e.g.) lowers bp by blocking

angiotensin (AT1) receptors.

Similar properties to the ACEIs, but

do not cause cough, because they do
not prevent bradykinin metabolism.

Vasodilator Drugs
Ca-Channel Blockers (Ca antagonists)

Vascular SM tone determined by [Ca2+]cyto.

Increased by 1-adrenoceptor activation
(recall incr sympathetic tone?) that triggers
Ca2+ release from the SR via ins-1,4,5-P 3 (IP3)
signaling.
Also, receptor-operated cation channels
depolariationCa2+ channels (L-type VG
Ca2+ channels) more Ca2+ enters cell.
Nifedipine, amlopidine bind Ca2+ channels,
block Ca2+ entry relaxation of arterial SM
decr peripheral resistance and decrbp.
Efficacy similar to that of the thiazides, blockers, and ACEIs
Side-effects: excessive vasodilation
dizziness, headaches, hypotension, flushing,
ankle edema.

Vasodilator Drugs
1-Adrenoreceptor Antagonists

Prazosin<doxazosin (longer-acting).
Selectively block vascular 1adrenoceptors vasodilation.
Unlike non-selective -blockers,
these drugs not likely to cause tach,
but may cause postural hypotension.
May be severe after 1st dose.

Vasodilator Drugs
Hydrazine

Used in combination with a -blocker

and diuretic.
Side-effects: reflex tach, which may
angina, headaches, fluid retention

(2 hyperaldosteronism).

In slow acetylators, hydrazine may

produce lupus syndrome fever,
arthralgia, malaise, and hepatitis.

Vasodilator Drugs
Minoxidil

Potent vasodilator that severe fluid

retention and edema.
But, when given with a -blocker and loop
diuretic, it is effective in severe hypertension
resistant to other drug combinations.
Relaxes vascular SM cells by opening ATPsensitive K+ channels hyperpolarization and
closing VG-Ca2+ channels.
[These K+ channels are normally kept closed
by ATPintracell, which is antagonised by minoxidil

Centrally-Acting Drugs

Methyldopa in adrenergic nerve

endings to -methylNE, which
stimulates 2-adrenoceptors in the
medulla and decr sympathetic outflow.
Side-effect: drowsiness, hemoytic
anemia.
Clonidine rebound hypertension if
suddenly withdrawn.

Acute Severe
Hypertension

Hydralazine in hypertension assoc

with eclampsia of pregnancy.
Nitroprusside in malignant
hypertension with encephalopathy.

Kidneys

Aldosteronestim Na+reabsorption in the

distal tubule and incr K+ and H+ secretion.
Cytoplasmic receptors.
Induces synthesis of the Na+/K+-ATPase in
the basolateral membrane and Na +
channels in the luminal membrane.
Cell surface aldosterone receptors may
mediate a more rapid incr in Na + channel
permeability.

Kidneys (contd)

Diuretics increase the Na+ load in the distal

tubules and incr K+ secretion and excretion
(except for the K+-sparing agents).
This effect is greater if [aldosterone]plasma are
high (e.g., vigourous diuretic therapy has
depleted the body of Na+ stores.)
Vasopressin (ADH) released from the Post Pit.
Incr the number of H2O channels in the
collecting ducts passive reabsorption of H2O.
In cranial diabetes insipidus, absence of ADH
large vols of hypotonic urine: treated with
vasopressin (or desmopressin, a longer acting
analogue)

Diuretics Drugs Acting on the

Kidneys

Purpose: to incr the excretion of NaCl and

H2O, normally controlled by aldosterone
and vasopressin, respectively.
Most work by decr the reabsorption of
electrolytes by the tubules.
Accompanied by an incr in H O excretion
2
so that osmotic balance is maintained.
[recall that diuretics are used to decr
edema in CHF]. But also used in some
renal diseases and hepatic cirrhosis.
Some diuretics, espthiazides, widely used
in treating hypertension, but their longterm hypotension action is not only
related to their diuretic properties.

Thiazides

Developed from carbonic anhydrase

inhibitors.
However, the diuretic effect of these drugs is
not related to their actions on this enzyme.
Relatively safe, orally active, but relatively
weak diuretics
Widely used for treatment for mild HF and
hypertension (also decr incidence of stroke).
Many different thiazides exist, differing
significantly only in their duration of action.
Bendoflumethiazide is widely used.

Thiazides - Mechanism

Act mainly on the distal segments of

tubules, where they inhibit
NaClreabsorption by binding to the
symporter responsible for the
electroneutralcotransport of Na+/Cl-.
incr excretion of Na+, Cl-, and H2O.
The increased Na+ in the distal tubule
stim Na+ exchange with K+ and H+,
increasing their excretion and
hypokalema and metabolic acidosis.

Thiazides Adverse Effects

Hypokalemia may ppt cardiac arrhythmias,

esp in patients on digitalis.
Can be prevented by giving K supplements,
or by combining therapy with K-sparing
drugs.
Hyperuricaemia. Uric acidblood are often
increased because thiazides are secreted by
the organic acid secretory system in the
tubules and compete for uric acid secretion.
This may ppt gout.
Glc tolerance may be impaired and thiazides
are contraindicated in patients with NIDD.
Lipids. Thiazidesincr [cholesterol]plasma at
least during the 1st 6 mos of administration,
but the signif of this is uncertain.

Loop Diuretics (LDs) (high

ceiling)
More effective than the thiazides.
[Very
Powerful]
Act more rapidly, but shorter duration of

action.
Ususallyfurosemide used orally to decr
peripheral and pulmonary edema in
moderate and severe HF.
Given i.v. for pulmonary edema resulting
from acute ventricular failure.
Effective in patients with decr renal
function (unlike the thiazides).

Loop Diuretics - Mechanism

Inhibit NaClreaborption in the thick ascending
loop of Henle.
This segment has a high binding capacity for
absorbing NaCldiuresis produced at this site is
much greater than at other sites.
Act on the luminal membrane where they inhibit
the cotransport of Na+/K+/2Cl-.
[Recall that the Na+ is actively transported out of
the cells into the interstitium by an Na +/K+ATPase-dependent pump at the basolateral
membrane].
Specificity of these drugs due to their high
concentration in the renal tubules.
However, at higher doses, these drugs may
induce changes in the electrolyte composition of
the endolymph and cause deafness.

Loop Diuretics Adverse

Effects

Hyponatraemia
Hypotension
Hypovolemia
Hypokalemia may be unimportant unless
there are additional risk factors for arrhythmia
(e.g., digoxin).
Can cause severe electrolyte imbalance and
dehydration.
Ca2+ and Mg2+ excretion often increased
->hypomagnesmia may occur.
Over-enthusiastic use (high doses, i.v.) can
cause deafness, which may not be reversible.

Loop Diuretics (contd)

Metalazone thiazide-related drug with

activity between that of the LDs and
thiazides.
Synergistic with furosemide in treating
resistant edema and serious renal failure.
Both thiazides and LDs incr K+ excretion.
So, K+ supplements may be required to
prevent hypokalemia.

K+-Sparing Diuretics (KSDs)

Weak when used alone.

Given to retain K+.
Often given with thiazides and LDs to prevent
hypokalemia.
Act on aldosterone-responsive segments of the distal
nephron, where K+ homeostasis is controlled.
Aldosteronestim Na+reabsorption negative in the
lumen, which drives K+ and H+ into the lumen (and
hence their excretion).
The KSDs decr Na+reabsorption by either antagonizing
aldosterone (spironolactone) or blocking Na+ channels
(amiloride, triamterene).
This causes the electrical across the tubular
epithelium to fall, decreasing the driving force for K+
secretion.
These drugs may cause severe hypokalemia, esp if
renal impairment exists.
Hypokalemia may also occur in the presence of ACEIs
(e.g., catopril), because these drugs decraldosterone
secretion (and therefore K+ excretion).

KSDs (contd) - Spironolactone

Competitively blocks the binding of

aldosterone to its cytoplasmic receptor
incr Na+ (Cl- and H2O) excretion and decr
the electrically coupled K+ secretion.
Weak diuretic (only ~2 % of the total
Na+reabsorption is under aldosterone
control).
Used mainly in liver disease with ascites,
Conns syndrome (1 hyperaldosteronism)
and severe heart failure.

KSDs (contd)
Amiloride and Triamterene

Decrease the luminal membrane

Na+ permeability in the distal
nephron by blocking Na+ channels
on a 1:1 basis.
This increases Na+ (Cl- and H2O)
excretion and decreases K+
excretion.

Carbonic Anhydrase Inhibitors

Weak diuretics and rarely used for this purpose.

Osmotic diuretics (e.g., mannitol) are filtered, but not
easily reabsorbed.
Excreted with an osmotic equivalent of H 2O and are
used in cerebral edema.
Depress bicarbonate reabsorption in the prox tubule by
inhibiting the catalysis of CO 2 hydration and
dehydration reactions.
Thus, the excretion of HCO 3-, Na+, and H2O are
increased.
The loss of HCO3- metabolic acidosis the effects of
the drug becomes self-limiting as the [HCO 3-]blood falls.
The incr Na+ delivery to the distal nephronincr K +
secretion.
Acetazolamide used to treat glaucoma to decr
intraocular P (decr the secretion of HCO 3- and assoc H2O
into the AH.

Nephron anatomy and

the site of action of
Diuretics

Proximal Convoluted
Tubule Cell
Note the
Action of
acetazolamide

Logical Combinations
Diuretic
CCB
blocker
Diuretic
-
-blocker

CCB
ACE inhibitor

*
-

*
-

ACE
inhibitor

blocker

-blocker

* Verapamil + beta-blocker = absolute contra-indication

Compelling and possible indications and contrindications for

the major classes of antihypertensive drugs

INDICATIONS

CONTRAINDICATIONS

CLASSS OF DRUG

COMPELLING

POSSIBLE

POSSIBLE

COMPELLING

-blockers

Prostatism

Dyslipidaemia

Postural Hypotension

Unrinary incontinence

Angiotensin converting enzyme (ACE) inhibitors

Heart failure
Left ventricular dysfunction

Chronic renal disease *

Type II diabetic nephropathy

Renal impairment *
Peripheral vascular disease

Pregnancy
Renovascular disease

Angiotensin II receptor antagonists

Cough induced by ACE inhibitor

Heart failure
Intolerance of other antihypertensive drugs

Peripheral vascular disease

Pregnancy
Renovascular disease

blockers

Myocardial infarction
Angina

Heart failure

Calcium antagonists (dihydropyridine)

Isolated systolic hypertension (ISH) in elderly patients

Angina
Elderly patients

Calcium antagonists (rate limiting)

Angina

Myocardial infarction

Thiazides

Elderly patients including ISH

Heart failure
Dyslipidaemia
Peripheral vascular disease

Asthma or COPD
Heart block

Combination with blockade

Heart block
Heart failure

Dyslipidaemia

Gout

* ACE inhibitors may be beneficial in chronic renal failure but should be used with caution. Close supervision and specialist advice are needed when there is established and
significant renal impairment
Caution with ACE inhibitors and angiotensin II receptor antagonists in peripheral vascular disease because of association
with renovascular disease.
If ACE inhibitor indicated
-blockers may worsen heart failure, but in specialist hands may be used to treat heart failure

ADRENERGIC
BLOCKER

J-G

RENIN SUBSTRAT
RENIN
ANGIOTENSIN I
CE INHIBITOR

RENIN INHIBITION

ANGIOTENSIN II
ANGIOTENSIN BLOCKER

VASOKON
STRICTION

FEED BACK

SYNTHESIS
ALDOSTERON
SODIUM RETENTION

BLOOD PRSSURE

MEKANISME TERAPI DIURETIK KRONIK DAN EFEK SAMPING

DIURETIC THERAPY
HYPOMAGNESEMIA

RENAL REABSORBTION
OF Na AND Mg
HYPONATREMIA

SALURESIS AND DIURESIS

PLASMA VOLUME

CARDIAC OUTPUT

RENAL BLOOD FLOW

POSTURAL
HYPOTENSION

PRA

GFR
PRERENAL
AZOTEMIA

ALDOSTERON
PROXIMAL
REABSORB

CL URIC ACID
HYPERURICEMIA

DISTAL Ca++
REABSORB

KALIURESIS

CL CALCIUM
HYPERCALCEMIA

HYPOKALEMIA
GLUCOSE
TOLERANCE

EFEK PRIMER DAN SECUNDER OBAT VASODILATOR

DIURETIC
VASODILATOR
VASODILATION

SODIUM
RETENTION

FLUID
VOLUME

PERIPERAL
RESISTANCE
ALDOSTERON
ARTERIAL
PRESSURE

ANGIOTENSIN
RENIN
RELEASE

VASOCONS
TRICTION

PERIPHERAL
RESISTANCE

NOREPINEPRIN
SYMPATHETIC
ACTIVITY
SYMPHATETIC
BLOCKER

HEART RATE
CONTRACTION
VENOUS COMPLIANCE

CARDIAC OUTPUT

MEKANISME GAGALNYA TERAPI DENGAN NON DIURETIC

NON DIURETIC
ANTI HYPERTENSIVE

BLOOD PRESSURE
RENAL SODIUM RETENTION
ALDOSTERONE
RENIN SCRETION
VASODILATOR

BLOOD PRESSURE
INCREASE FLUID VOLUME

TERAPI HIPERTENSI
MENEGAKKAN DIAGNOSE HIPERTENSI
MENCARI AKTOR RESIKO, OBESITAS, DM FAMILI,
MENCARI PENYEBAB HIPERTENSI
MEMAHAMI HEMODINAMIKA HIPERTENSI SEDANG
MEMULAI DENGAN PENGOATAN NON FARMAKOLOGI
PENGOBATAN DENGAN OBAT ANTI HIPERTENSI
PENGGUNAAN OBAT LINI PERTAMA
DENGAN MEMPERTIMANGKAN COST BENEFIT
EDUKASI PENGUNAAN OBAT, KOMPLIANCE, EFFEK SAMPING
MEMONITOR EFFICACY DAN EFEK SAMPING
PENGOBATAN JANGKA LAMA KONTROL RUTIN

PRINSIP PEMILIHAN OBAT ANTI HPERTENSI

TERAPI 1986-2000
DIURETIC
CALCIUM CHANNEL BLOCKER
ANGIOTENSIN CONVERTING ENZYME INHIBITOR
BETA BLOCKER
ALPHA BLOCKER
ANGIOTENSIN RESEPTOR ANTAGONIS (1997-2000)
OBAT SEHARUSNYA :
MENURUNKAN TEKANAN DARAH
MENURUNKAN RESIKO CARDIOVASCULER
TANPA MENURUNKAN QUALITAS HIDUP
MEMPERBAIKI KUALTAS HIDUP
EFEK LON ACTING SEHARI SATU TABLET
HARGA TERJANGKAU

BELUM ADA OBAT YENG MEMENUHI SEMUA

KRITERIA DIATAS SAMPAI SAAT KINI.

DIMULAI DENGAN MERUBAH GAYA/POLA HIDUP

TIDAK BERHASIL MENURUNKAN BP < 140/90
(TARGET BP LEBIH RENDAH PADA DM
HIPERTENSI TANPA KOMPLKASI DIMULAI DENGAN DIURETIC ATAU BETA BLOCKER
DM : ACE INHIBITOR, A II RECEPTOR ANTAGONIS
PAYAH JANTUNG: ACE INH. ALPHA BLOCKER, BETA BLCKER, DIURETIC
HT USIA TUA: DIURETIC, CALCIUM ANTAGONIS
HT AND MIOKARD INFARK : BETA BLOCKER NON ISA, ACE INHIBITOR
SEMUA DIMULAI DENGAN DOSIS RENDAH DILAKUKAN TIRASI DOSE RESPON
KALAU PERLU KOMBINASI DALAMDOSIS RENDAH.
TARGET BP TIDAK TERCAPAI
RESPON NEG, ADA SIDE EFFECT
GANTI OBAT DARI KELAS LAIN

RESPON TIDAK CUKUP

TAMBAHKAN OBAT DARI KELAS LAIN

TARGET BP TIDAK TERCAPAI

PENAMBAHAN OBAT KELAS LAIN TERUS DILAKUKAN
DIRUJUK KE SPESIALIST HIPERTENSI

KOMBINASI BAT INTI HIPERTENSI

DIURETIC DAN POTASIUM SPARER
SPIRONOLACTONE + HYDROCH;LOROTHIAZIDE
BETA BLCKER DAN DIURETIK
PROPANOLOL + HYDROCHLOROTHIAZIDE
ACE INHIBOTOR DAN DIURETIK
ENALAPRIL + HYDROCHLOROTHIAZIDE
ANGIOTENSIN II RECEPTOR ANTAGONIS DAN DIURETIK
LOSARTAN + HIDROCHLOROTHIAZIDE
CALCIUM CHANNEL BLOCKER DANACE INHIBITOR
DILTIAZEM + ENALAPRIL
KOMBONASI YANG LAIN
CLONIDINE + CHLORTHALIDONE
HYDRALAZINE + HYDROCHLOROTHIAZIDE
METHYLDOPA + HYDROCHLOROTHIAZIDE
RESERPIN + HIDRALAZINE + HYDROCHLOROTHIAZIDE
RESERPIN + HYDROCHLOROTHIAZIDE

KRISIS HIPERTENSI
HYPERTENSIVE MERGENCY

HYPERTENSIVE URGENCY

TD MENINGGI MEMBUTUHKAN
PENURUNAN SEGERA DENGAN
PEMBERIAN OBAT PARENTERAL
ANCAMAN KERUSAKAN ORGAN

TD MENINGGI TETAPI TANPA

KELUHAN ATAU ANCAMAN
KERUSAKAN ORGAN YANG
PROGRESSIVE, TD DITURUNKAN
PERLAHAN DALAM WAKTU JAM

PENYEBAB: CEREBRO VASCULER

GINJAL, ECLAMPSIA, BEAH
CATHECOLAMINE, RAMA KEPALA
LKA BAKAR, GANGUAN JANTUNG

PENYEBAB: TEKANAN DARAH

TIDAK DIOBATI ATAU TIDAK
TERKONROL

OBAT: FUROSEMIDE, NITROPRUSIDE

NITROGLYSERIN, NICARDIPINE,
HYDRALAZINE,ENALAPRILATE,
PENTHOLAMINE, LABETOLOL
DIBERIKAN SECARA PARENTERAL

CAPTOPRIL, CLONIDINE, LASIX,

LABETOLOL, NIFEDIPINE,
PROPANOLOL, DIBERIKAN
SECARA ORAL / SUB LINGUAL

CRITICAL DEGREE OF HYPERTENSION

LOCAL EFFECTS
PROSTAGLANDINE
FREE RADIALS

SYSTEMIC EFFECTS
RAA, CATHECOLAMIN
VASOPRESSIN

ENDOTHELIAL DAMAGE

PRESSURE NATRIURESIS

PLATELET DEPOSITION

HYPOVOLEMIA

MITOGENIC AND MIGRATION

FACTORS

FURTHER INCREASE
VASOPRESSOR

MYOINTIMAL PROLIFERATION
FURTHER RISE IN BLOOD PRESSURE
AND VASCULAR DAMAGE
TISSUE ISCHEMIA

OBAT MASA DEPAN :

ENDOTHELIN RESEPTOR ANTGONIS
VASOPRESSIN RESEPTOR ANTAGONIS
ENDOTHELIAL PROTECTOR
TRANSCRIPTION MODULATING DRUGS
ANTISENSE GEN THERAPY
OBAT INI MASIH DALAM PENELITIAN FARAKOLOGI DAN
TRIAL KLINIK

Clinical pharmacology of hypertension

Hypertension in the elderly
Benefit from antihypertensive therapy is evident up to at least
80 years of age, but it is probably inappropriate to apply a strict
age limit when deciding on drug therapy.
Elderly individuals who have a good outlook for longevity should
have their blood pressure lowered if they are hypertensive.
The thresholds for treatment are diastolic pressure averaging
90mmHg or systolic pressure averaging 160mmHg
over 3 to 6 months observation (despite appropriate nondrug treatment).
A low dose of a thiazide is the clear drug of first choice, with
addition of another antihypertensive drug when necessary.

Isolated systolic hypertension

Isolated systolic hypertension (systolic pressure 160 mmHg,
diastolic pressure <90mmHg) is associated with an increased
cardiovascular disease risk, particularly in those aged over 60 years.
Systolic blood pressure averaging 160mmHg or higher over 3 to 6
months (despite appropriate non-drug treatment) should be
lowered in those over 60 years, even if diastolic hypertension is absent.
Treatment with a low dose of a thiazide, with addition of a betablocker when necessary is effective; a long-acting dihydropyridine
calcium-channel blocker is recommended when a thiazide is contraindicated or not tolerated.
Patients with severe postural hypotension should not receive blood
pressure lowering drugs.
Isolated systolic hypertension in younger patients is uncommon but
treatment may be indicated in those with a threshold systolic pressure of
160mmHg (or less if at increased risk of cardiovascular disease).

Hypertension in diabetes
For patients with diabetes, the aim should be to maintain systolic
pressure <130mmHg and diastolic pressure <80mmHg.
However, in some individuals, it may not be possible to achieve this
level of control despite appropriate therapy.
Low-dose thiazides, beta-blockers, ACE inhibitors (or angiotensin-II
receptor antagonists) and long-acting dihydropyridine calcium-channel
blockers are all beneficial. Most patients require a combination of
antihypertensive drugs.
Hypertension is common in type 2 (non-insulin-dependent) diabetes and
antihypertensive treatment prevents macrovascular and
microvascular complications.
In type 1 (insulin-dependent) diabetes, hypertension usually indicates
the presence of diabetic nephropathy. An ACE inhibitor (or an
angiotensin-II receptor antagonist) may have a specific role in the
management of diabetic nephropathy;
In patients with type 2 diabetes, an ACE inhibitor (or an angiotensin-II
receptor antagonist) can delay progression of microalbuminuria to
nephropathy.

Hypertension in renal disease

The threshold for antihypertensive treatment in patients with renal
impairment or persistent proteinuria is a systolic blood pressure
140mmHg or a diastolic blood pressure 90 mmHg.
Optimal blood pressure is a systolic blood pressure <130mmHg
and a diastolic pressure <80mmHg, or lower if proteinuria exceeds
1g in 24 hours. Thiazides may be ineffective and high doses of
loop diuretics may be required. Specific cautions apply to the use of
ACE inhibitors in renal impairment, but ACE inhibitors may be
effective. Dihydropyridine calcium-channel blockers may be added.
Hypertension in pregnancy
Methyldopa is safe in pregnancy.
Beta-blockers are effective and safe in the third trimester. Modifiedrelease preparations of nifedipine [unlicensed] are also used for
hypertension in pregnancy.
Intravenous administration of labetalol can be used to control
hypertensive crises; alternatively, hydralazine may be used by the
intravenous route.
Magnesium sulphate in pre-eclampsia and eclampsia

Accelerated or very severe hypertension

Accelerated (or malignant) hypertension or very severe hypertension
(e.g. diastolic blood pressure >140mmHg) requires urgent
treatment in hospital, but it is not an indication for parenteral
antihypertensive therapy.
Normally treatment should be by mouth with a beta-blocker
(atenolol or labetalol) or a long-acting calcium-channel blocker
(e.g. amlodipine or modified-release nifedipine).
Within the first 24 hours the diastolic blood pressure should be
reduced to 100110mmHg. Over the next 2 or 3 days blood pressure
should be normalised by using beta-blockers, calcium-channel
blockers, diuretics, vasodilators, or ACE inhibitors.
Very rapid reduction in blood pressure can reduce organ perfusion
leading to cerebral infarction and blindness, deterioration in
renal function, and myocardial ischaemia.
Parenteral antihypertensive drugs are rarely necessary;
sodium nitroprusside by infusion is the drug of choice on the rare
occasions when parenteral treatment is necessary.