CARDIOTONICS

CARDIODEPRESSANTS AND VASODILATORS

Ngatidjan

Department of Pharmacology and Therapy

FACULTY OF MEDICINE UNIVERSITAS GADJAH MADA
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Drugs Acting on Heart
1. Cardiostimulants
a. Digitalis (  cardiotonics)  strength rate
b. Sympathomimetics  strength rate
2. Cardiodepressants
a. Quinidin
b. Lidokain
c. b-blockers
d. Calcium Antagonists
2. Vasodilators
a. Vasodilators (hydralazin, minoxidil, prazosin, calsium antagonists)
b. Coronary vasodilators (nitrate and nitrite)
Drugs for Chronic Heart Failure

1. Digitalis (digoxin, digitoxin, cedilanide)

2. HCT or other diuretics (bumetanide, spironolactone)

3. ACE inhibitors and AT blockers (ARB)

(captopril, lisinopril, enalapril, valsartan, losartan)

4. Vasodilator (prazosin, terazosin, hydralazine)

5. Others (K+, vitamine-B, etc.)

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 CARDIOTONICS
(Digitalis and its congeners)

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Herb Digitalis purpura Digitalis lanata
glycoside ? lanatoside A lanatoside B lanatoside C
(natural)

hydrolysis

? Deslanatoside A Deslanatoside B Deslanatoside C

(cedilanid D)
hydrolysis

glycoside gitalin digitoxin gitoxin digoxin

(pure)

hydrolysis
aglycon gitaligenin digitoxigenin gitoxigenin digoxigenin
(pure)
 Digitalis (digoxin, digitoxin, gitoxin)
 strengthen of heart muscle contraction
(positive inotropic effect)

 decrease of the rate of heart contraction

(negative chronotropic effect)

heart contraction : efficient

Digitalis
- inhibits Na+K+-ATP-ase
 Na+ pump
(Na+K+Ca++ exchange)
 Ca++ intracellular
heart contraction
 heart contraction : efficient
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Digitalis (digoxin, digitoxin, lanatosid A, B
and cedilanid D)

- Clinical use

- chronic heart failure

(cardiac decompensation)
other drugs : diuretics, vasodilator ect.
Digitalis (digoxin, digitoxin, digoxigenin, lanatosid A, B
and cedilanid D)

 Digitalis alone is not effective :

(have to be combined with other drugs)

which decrease pvr (peripheral vascular resistant)

(prazosin, ACEI, AT-blockers)

Digitalis (digoxin, digitoxin, lanatosid A, B
and cedilanid D)

- Side effect :

- nausea, vomitus, diarrhoea

- cardiac arrhythmias

- heart block, extrasystole (ECG)

Pharmacokinetic of digoxin
 Bioavailability 75%
 Onset of action (iv route) 30 minutes.
 Peak effects (iv route) 1 – 5 hours.
 Half life 36 hours
 Elimination 90% renal excretion
proportional to GFR.
 Volume of distribution large ( 640 L / 70 kgBW)
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Chronic Heart Failure (CHF)
1. Digitalis (digoxin, digitoxin, cedilanide)

2. HCT or other diuretics (bumetanide, spironolactone)

3. ACE inhibitors and AT blockers (ARB)

(captopril, lisinopril, enalapril, valsartan, losartan)

4. Vasodilator (prazosin, terazosin, hydralazine)

5. Others (K+, vitamine-B, etc.)

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 DIURETICS
1. Potent diuretics
furosemida, bumetanide, piretanide and etacrynic acid
2. Moderate diuretics
chlorothiazide, HCT, chlorthalidone, clopamide, xipamide
and indapamide

3. Weak diuretics (not used in the therapy of hypertension)

manitol, carbonic anhydrase inhibitor and spironolactone
4. K+ sparing diuretics
antagonis aldosteron (spironolactone)

 (1) and (2) are most used in the therapy of HT

(4) is used in chronic heart failure
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Diuretics
 Thiazida diuretics duration of action (hours)
– chlorothiazide, 6 – 12
– hydrochlorothiazide, 16 – 24
– chlorthalidone 48 – 72
– indapamide 24

 Loop diuretics
– bumetanide, 4–5
– furosemide, 4–5
– torsemide, 6–8
– ethacinic acid 4–5

 Potasium sparing diuretics

– amiloride 6 – 24
– spironolactone 72 – 96
– triamterene
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– heart
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 CONTROVERSY ON DIURETICS

 Thiazide diuretics is the first line drug for HT (JNC-VII)

 may reduce cardiovascular morbidity & mortality
(b-blockers does not)

 Diuretics is not better than ACE-I, ARB or CCB

(calcium channel blockers) for first line drug for HT (AHA)
 previous research have to be corrected.

 Other clinical trials showed that :

 the used of ACEI, CCB, or ARB reduced cardiovascular events
 RAA System Inhibitors
(ACE-inhibitor, AT-blockers, Spironolacton and b-blockers)

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Renin-Angiotensin-Aldosteron System Inhibitors

- b-blockers (labetolol)
 inhibit renin release  but may cause worsening of heart failure

- ACE inhibitor (captopril, lisinopril, enalapril)  inhibits conversion AT

 vasodilatation  decrease PVR  decrease heart work load

- AT-blockers (ARB : angiotensin receptor blockers)

 losartan, valsartan, etc. blockade ATR
 vasodilatation  decrease PVR  decrease heart work load

- Aldosteron antagonist (spironolacton)  diuretics

 blocks aldosteron receptors at renal tubular cells.
 ACE-inhibitors

- captopril, - benazepril
- lisinopril, - cilazapril
- enalapril - quinapril
- alacepril - ramipril
- zofenopril - trandolapril
- spirapril - ect.
 Side effects

ACE inhibitors AT-blockers

- hypotension, -  up regulation
 rebound phenomenon

- dry cough - do not cause cough

 due to bradykinin
accumulation in
in bronchial mucosa
 dry cough

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RAA-system inhibitors and CHF

• 1. ACE-inhibitor vasodilatation and diuresis

• 2. AT-blockers vasodilatation and diuresis

• 3. Spironolacton diuresis

b-blockers ? heart work load

decrease heart
02/01/2012 contraction
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VASODILATORS (prazosin, hydralazin, ACE-Inhib.)

vasodilator

vasodiatation of arteriolae, capiler and venulae

peripheral vascular resistance veneous return

cardiac work load

VASODILATORS - nifedipin and Ca-antagonists

Nifedipin and other Ca-antagonists

arteriolae, capiler and venulae vasodiatatation

heart negative inotropic and chronotropic effects

peripheral vascular resistance veneous return

cardiac contraction  further decrease of h.c.
CORONARY VASODILATORS
Coronary vasodilators
 Increase cGMP (in the vascular smooth muscle cells)
 nitrates (isosorbide dinitrate etc.)

 Decrease Ca2+ (in the vascular smooth muscle cells)

 Ca-antagonist (nifedipine etc.)

 Stabilizing or preventing depolarization (in the

vascular smooth muscle cells)
 minoxidil, nicorandil
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Angina pectoris
is manifestation of myocardial ischemia

 caused by imbalance between myocardial

oxygen demand and coronary blood supply

 relatively decrease of oxygen supply

 if oxygen supply absolutely stop  infarct

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Angina pectoris
The cause of the symptom :
 coronary spasm

 occlusion of coronary blood vessel

 partially  thrombus or spasm  angina pectoris

 if totally  myocardial infarction

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Angina pectoris
1. Acute angina pectoris (exercise, spasm, emboli)
2. Stable angina pectoris
(exercise - atheroma  predictable)

3. Unstable angina pectoris

(resting  embolus  myocardial infarction)

4. Varian – Prinzmetal angina pectoris

(coronary spasm)
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DRUGS FOR ANGINA PECTORIS

 increase coronary blood flow

  coronary vasodilators

 decrease myocardial oxygen demand

 decrease heart contraction (b-blockers and Ca2+ antagonists)

 antithrombus  aspirin
 for unstable angina
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DRUGS ANGINA PECTORIS

 Nitrate dan nitrite

(amilnitrite, nitroglyserine, isosorbide dinitrate)

 Calcium antagonists
(verapamil, diltiazem, nifedipin)

 b-blockers (acebutolol, atenolol, propranolol)

Nitrate and nitrite
 increase intracellular cAMP vasodilatation

 coronary vasodilatation
increase coronary blood supply

 dilatation of venule
• veneous return  end diastolic pressure
• cardiac dilatation

 heart contraction  O2 demand

 NITRATE - NITRITE
nitrate - nitrite

vasodilatation vasodilataion
of coronary blood vessel of arteriole and venule

oxygen supply venous return

heart contraction

oxygen demand
angina
Nitrate - nitrite
- side effects
. Headache

. Flushing

. Orthostatic hypotension

. Tachycardia (reflectory)
worsening of the angina pectoris
Nitrate - nitrite
- To reduce side effects
. begin from small dose (MED)
. sitting position when taking the drugs
standing  postural hypotension  tachycardia

lying down  veneous return

 cardiac work load  worsening of angina

 CALCIUM ANTAGONISTS

Calcium antagonists

heart contraction and vasodilatation

oxygen demand and blood supply

angina
b-blockers (acebutolol, atenolol, dsb.)
b-blockers

heart contraction

oxygen demand

angina
CARDIODEPRESSANTS
Cardiodepresants
- Sodium channel blockers
(quinidine, procainamide, lidocaine, phenytoin, tocainide,
mexiletin)

- Sympatholytics (b-blockers)
(esmolol, propranolol)

- Ca-antagonists
(verapamil, galopamil, deltiazem)
Classification  antiarrhythmias
Ia : Quinidine, Procainamide, disopyramide

Ib : Lidocaine, Mexiletine, Tocainide

Ic : Encainide, Flecainide, Propafenide

II : Esmolol (b-adrenoceptor antagonist)

III :Action potential prolongation (quinidine)

IV : Calcium antagonists (verapamil)

THANK YOU