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OBAT-OBAT

KARDIOVASKULER
ARIFAH SRI WAHYUNI
081329008616
Hypertension: A Significant CV and
Renal Disease Risk Factor

CAD
CHF
Stroke LVH

Blood
Pressure 
Renal disease  Morbidity
 Disability
Peripheral vascular
disease

National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.
Regulation of Blood Pressure

• Main coordinating
center is in the
medulla oblongata
of the brain;
medullary
cardiovascular
control center
• Reflex control of
blood pressure
•Baroreceptor
reflex
Factors determining ABP :

Blood Pressure = Cardiac Output X Peripheral Resistance

(BP) (CO) (PR)


Flow Diameter of
arterioles

■ BP depends on:
1. Cardiac output  CO = SV X HR.
2. Peripheral resistance.
3. Blood volume.
Heart rate, stroke volume and cardiac output

The pulse rate is not the only way of measuring the heart.
Stroke volume is the amount of blood pumped
out of the left ventricle per beat.

Cardiac output is the amount of blood pumped


out of the left ventricle of the heart per minute.

Cardiac output can be calculated by multiplying the


stroke volume by the heart rate:
cardiac output = stroke volume × heart rate

What is the cardiac output of someone with a heart


rate of 60 bpm and stroke volume of 90 ml?

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Normal Blood Pressure Regulation

Blood Pressure = Cardiac output (CO) X


Resistance to passage of blood through
precapillary arterioles (PVR)
• Physiologically CO and PVR is maintained
minute to minute by – arterioles (1)
postcapillary venules (2) and Heart (3)
Kidney is the fourth site – volume of
intravascular fluid
• Baroreflex, humoral mechanism and renin-
angiotensin- aldosterone system regulates
the above 4 sites
• Local agents like Nitric oxide
• In hypertensives – Baroreflex and renal
blood-volume control system – set at
higher level

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Mechanisms Controlling CO and TPR

Diuretics Vasodilators

• Sympatholytic drugs

RAAS

9
DIURETIC
• Adalah obat-obat yang bekerja pada ginjal untuk
meningkatkan ekskresi air dan Na.

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Nephron  Tubular reabsorption
 Small molecules
 Water

 Glucose, amino acids,


sodium, chloride, calcium,
bicarbonate
 Tubular secretion
 Larger molecules
 Potassium,phosphate,
Hydrogen, Ammonium
DIURETIC

• Bagaimana meningkatkan ekskresi urine?


↑ Filtrasi Glomerular atau ↓ reabsorbsi Tubular

• Tujuan penggunaan diuretic


1. Menjaga jumlah volume urine yang dikeluarkan ( e.g.: renal
failure)
2. Untuk mengurangi edema (e.g.: heart failure, liver failure;
nephrotic syndrome)
3. Untuk mengontrol tekanan Darah .

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Klasifikasi Diuretics

• Diuretik penghambat transport dalam


Tubulus proksimal  Diuretic Osmotic,
penghambat karbonat anhydrase
• Diuretics Thiazides
• Loop diuretics
• Diuretic hemat kalium
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A. Diuretics Osmosis

Osmotic Diuretics (e.g.: Mannitol)


• Mekanisme aksi : merupakan senyawa hidrofilik yang mudah
disaring melalui glomerulus dengan sedikit penyerapan kembali,
dengan demikian meningkatkan keluaran urin melalui osmosis ..
• Pemberian: Diberikan secara i.v
• Adverse Reactions:
– dehidrasi
– Hypernatremia karena yang diekskresikan lebih banyak air daripada garam
elektrolit.

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Carbonic anhydrase inhibitors

Acetazolamide inhibits carbonic


anhydrase (CA) manly in proximal tubules.

CA
H2O + CO2 H2CO3 H2CO3– + H+
B. Penghambat karbonik anhidrase
• Carbonic Anhydrase Inhibitors
(Acetazolamide (Oral) ;
Dorsolamide (Ocular) ;
Brinzolamide (Ocular)
• Mekanisme aksi : Menurunkan
reabsorbsi bikarbonat pada tubulus
proksimal melalui inhibisi katalis
hidrasi CO2 dan reaksi dehidrasi.
Na+ yang meningkat akan dialirkan
nefron distal, meningkatkan
sekresi K
• ESO Acetazolamide: Sedasi,
Acidosis; Renal stone (Phosphate
and Calsium stone) ;
Hyperchloremia, hyponatremia dan
hypokalemia
Thiazide Diuretic
• (e.g.: Thiazides and Thiazide-
like (Indapamide; Metolazone)
• Mekanisme aksi : Menghambat
Na + melalui penghambatan Na+
/ Cl- cotransporter. Terjadi
peningkatan ekskresi Na+ / Cl-
yang disertai H2O, beban Na+
yang meningkat dalam tubulus
distal menstimulasi pertukaran
cotransporter
• ESO : hiponatremia,
hiperglikemia Bagaimana?
hypelipidemia dan
hyperurecemia
Mechanisms of Action: Loop diuretics
 Obat ini bekerja dengan
menghambat reabsorpsi NaCl
dalam ansa Henle ascending.
Karena kapasitas absorpsinya yang
besar, maka menyebabkan diuresis
yang lebih besar.
 Mekanisme Menghambat
kotransport Na+/K+/2Cl-
2. Side effects:. 3. Therapeutic Uses
a) Edema
Ototoxicity; Hypokalemic
metabolic alkalalosis; b) Acute renal failure
hypocalcemia (hypercalceuria)
and hypomagnesemia; c) Hyperkalemia
hypochloremia; Hypovolemia; d) Hypercalcemia
hyperuricemia (How?);
hypersensitivity reactions.
Potassium-Sparing Diuretics
e.g : amiloride, triamterene, and spironolactone.
Termasuk diureik lemah, aksinya pada saluran
pengumpulcollecting ducts.

Amiloride dan triamterene  mengeblok Channel Na +


sehingga mengurangi Na + yang masuk melalui membran
luminal dan mengurangi reabsorpsi NaCl.
Aldosterone antagonist (Spironolactone, eplerenone)
– Aldosterone induces the expression of Na/K- ATPase and
Na+ channel
– Spironolactone and eplerenone blocks aldoserone receptor
 reduces Na+ reabsorption and K+ secretion
21
Mechanisms of Action: Collecting tubule and potassium-
sparing diuretics
 Two cell types in collecting tubule
1. Principal cells – transport Na, K, water
2. Intercalated cells – secretion of H+ and
HCO3
3. Blocking Na+ movement in also prevents
K+ movement out
Peripheral a-1 Adrenergic Antagonists
Drugs: prazosin (Minipres); terazosin (Hytrin), doxazosin (Cardura®)
1. Site of Action- peripheral arterioles, smooth muscle
2. Mechanism of Action
α1 stimulation cause VC : Vasoconstriction in the skin & viscera cause
increase TVR causing increase BP So, hypertension may be treated by
blocking α1 . Competitive antagonist at a-1 receptors on vascular, smooth
muscle.
3. Effects on Cardiovascular System
Vasodilation, reduces peripheral resistance

Stimulate alpha1 receptors -> hypertension


Block alpha1 receptors -> hypotension

 only class of antihypertensive agents


that may have the combined effect of 
LDL-cholesterol,  (HDL)-cholesterol,
and improving insulin sensitivity
Peripheral a-1 Adrenergic Antagonists, cont.
4. Adverse effects
nausea; drowsiness; postural hypotenstion;

5. Contraindications : Hypersensitivity

6. Therapeutic Considerations
• no reflex tachycardia; small 1st dose;
• tidak mengganggu toleransi latihan
• dapat untuk pasien : diabetes, asthma, and/or
hypercholesterolemia
• mild to moderate hypertension
• Sering dikombinasi dengan diuretic,  antagonist

Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-4


mg thrice daily (Minipress/Prazopress)
Central Sympatholytics (a-2 Agonists)
Drugs: clonidine (Catapres), methyldopa (Aldomet)
1. Site of Action
• CNS medullary
• cardiovascular centers
clonidine; direct a-2 agonist
methyldopa: “false neurotrans.”
2. Mechanism of Action
CNS a-2 adrenergic stimulation
Peripheral sympathoinhibition
Decreased norepinephrine release
3. Effects on Cardiovascular System
Decreased NE-->vasodilation--> Decreased TPR
CRITICAL POINT!
Stimulation of a-2 receptors in the medulla decreases peripheral
sympathetic activity, reduces tone, vasodilation and decreases TPR.
Clonidine

• Stimulate central α2 –adrenoceptors


• Decreasing PVR
• Useful in hypertension complicated by renal disease
• Sedation & drying of the nasal mucosa
• Rebound hypertension
α-METHYL DOPA
• α2-agonist
• Valuable in treating hypertensive patients with
renal insufficiency
• In pregnant women
 Adrenergic Antagonists
Drugs: propranolol (Inderal); metoprolol (Lopressor)
atenolol (Tenormin); nadolol (Corgard);
pindolol (Visken)
1. Sites of Action
1 : eye, kidney, heart
2 : lung, vascular system,
metabolic system
 Adrenergic Antagonists, cont.
2. Mechanism of Action
competitive antagonist at - adrenergic receptors

β1 Reduce heart rate, blood pressure, myocardial


contractility, myocardial oxygen consumption

selective  blocker : atenolol, metoprolol

2 Menghambat relaksasi otot di sirkulasi


sistemik, paru dan GI system
Non selective  blocker : propranolol, carvidelol,
sotalol, Timolol
 Adrenergic Antagonists, cont.

3. Effects on Cardiovascular System

a. Cardiac--  HR,  SV  CO


b. Renal--  Renin   Angiotensin II   TPR

4. Adverse Effects
impotence; bradycardia;
fatigue; exercise intolerance;

5. Contraindications
asthma; diabetes; bradycardia;
hypersensitivity
VASODILATOR
Vasodilators
Drugs: hydralazine (Apresoline); minoxidil (Loniten);
nitroprusside (Nipride); diazoxide (Hyperstat I.V.);
fenoldopam (Corlopam)
1. Site of Action- vascular smooth muscle
2. Mechanism of action nitroprusside

NO
fenoldopam
DA


Na+ Ca++ K+ minoxidil
diazoxide
Ca++
hydralazine
Vasodilators, Cont
3. Effect on cardiovascular system vasodilation, decrease TPR
4. Adverse Effects
reflex tachycardia
Increase SymNS activity (hydralazine, minoxidil,diazoxide)
lupus (hydralazine) hypertrichosis (minoxidil)
cyanide toxicity (nitroprusside)
5. Therapeutic Considerations
nitroprusside- iv only
hydralazine- safe for pregnancy
diazoxide- emergency use for severe hypertension

Uses: 1) Moderate hypertension when 1st line fails – with beta-blockers and
diuretics 2) Hypertension in Pregnancy, Dose 25-50 mg OD
Minoxidil :
0 Orally not used any more
0 Topically as 2-5% lotion/gel and takes months to get effects
0 Mechanism in hair growth:
0 Enhanced microcirculation around hair follicles and also by direct
stimulation of follicles
0 Alteration of androgen effect of hair follicles
0 More often in alopecia to promote hair growth
Vasodilators
Hdralazine Minoxidil Diazoxide Na
nitropruside

Site of Arteriodilator Arteriodilator Arteriodilator Arterio &


action venodilator

Mechanism Direct Opening of Opening of Release of nitric


of action potassium channels potassium oxide (NO)
in smooth muscle channels NO→activation of
membranes by guanylyl cyclase
minoxidil sulfate →↑intracellular
( active metabolite ) cGMP

Route of Oral Oral Rapid Intravenous


admin. intravenous infusion
Continue Hdralazine Minoxidil Diazoxide Na
Vasodilators nitropruside

1.Moderate - 1.Moderate – 1.Hypertensive 1.Hpertensive


severe severe emergency emergency
hypertension. hypertension

Therapeutic In combination with diuretic & β-blockers


uses
2.Hypertensive 2.correction of 2.Treatment of 2.Severe heart
pregnant baldness hypoglycemia due to failure
woman insulinoma
Continue Hdralazine Minoxidil Diazoxide Na nitropruside
Vasodilators
Hypotension, reflex tachycardia, Severe
palpitation, angina, salt and water hypotension
Adverse effects retention ( edema)

Specific lupus Hypertrichosis. Inhibit insulin 1.Methemoglobin


adverse effects erythematosus release from β during infusion
like syndrome cells of the 2. Cyanide
pancreas toxicity
causing 3. Thiocyanate
hyperglycemia toxicity

Contraindicated Contraindicated
in females in diabetic
The Renin-Angiotensin-Aldosterone (RAA) System

Kidneys Adrenal cortex


Liver secretes secrete secretes
angiotensinogen renin aldosterone

Β-BLOCKER
Angiotensin
converting
Blood Renin enzyme SPIRONOLACTON

(ACE)
ACE I

Angiotensinogen Angiotensin I Angiotensin II Aldosterone


ARB

NA+ retention
Growth Vascular H2O retention
factor Sympathetic
smooth muscle K+ excretion
stimulation activation
constriction Mg+ excretion
ANTIHYPERTENSIVE DRUGS

DRUGS AFFECTING RAAS [renin angiotensin aldosterone system]-

 RENIN INHIBITOR: Beta blockers [Propranolol, Atenolol, etc]

 ACE INHIBITORS: Enalapril, Ramipril

 ANGIOTENSIN II RECEPTOR [AT 1-receptor] BLOCKERS: Eprosartan, Losartan

 ALDOSTERONE ANTAGONIST [ potassium sparing diuretic ]: Spironolactone


Sites of action of ACE inhibitors & Receptor blockers
Nama Obat ACE I Dosis
Captopril 12,5-25 mg 2-3
times/daily
enalapril, 5-20 mg OD
Ramipril Start with low dose; 2.5
to 10 mg daily
Lisinopril available as 1.25, 2.5, 5,
10 1nd 20 mg tab –
start with low dose
2-ANGIOTENSIN RECEPTOR –BLOCKING AGENTS

Mechanism of action :
Block AT 1 receptors.
Advantages over ACEI :
They have no effect on bradykinin system: No cough,wheezing
or angioedema.
Complete inhibition of angiotensin action compared with ACEI
Losartan is the specific AT1 blocker
CALCIUM CHANNEL BLOCKERS
Calcium Channel Blockers - Classification
 Inhibit calcium influx into arterial smooth muscles & cardiac muscles.
 Dihydropyridine group (amlodipine, nifedipine) are more selective as
arteriodilators ( decreasing afterload)
 Verapamil &Diltiazem are more selective as cardiac depressant (
decreasing C.O) .
CCB Site of Action

diltiazem & verapamil

nifedipine
(and other
dihydropyridines)
CCB Action

 diltiazem & verapamil


• decrease automaticity & conduction in SA & AV nodes
• decrease myocardial contractility
• decreased smooth muscle tone
• decreased PVR
 nifedipine
• decreased smooth muscle tone
• decreased PVR
Side Effects of CCBs

 Cardiovascular
• hypotension, palpitations & tachycardia

 Gastrointestinal
• constipation & nausea

 Other
• rash, flushing & peripheral edema