The Role of Medicines in the Therapy of

CARDIOVASCULAR DISEASES

Ngatidjan, MD., M.Sc., Sp.FK.

Department of Pharmacology and Toxicology

Faculty of Medicine GMU
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Drugs for Cardiovascular Diseases
Diuretics
Sympatholytics
centrally acting sympatholytics, and adrenoceptor
blockers. Neuron and ganglion blockers are not used.

RAA system inhibitors

beta blockers, ACEI, AT-blockers, diuretics.

Calcium antagonists
Direct acting vasodilators
Cardiotonics and Cardiodepressants
Thrombolytics
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and antithrombus
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 Drugs for hypertension

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The principle usage of antihypertensives

* Low dose of less adverse effects (toxic)

drugs less toxic drugs to be chosen

* Low dose of combined drugs increase safety

to increase drug effect combine drugs
do not increase the dose of a drug
combined low dose drugs
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Chose of Drugs for Hypertension

1st Diuretics
2nd Sympatholytics
centrally acting sympatholytics and adrenoceptor
blockers. (neuron and ganglion blockers are not recommended)

3rd RAA system inhibitors

beta blockers, ACEI, AT-blockers, diuretics.

4th Calcium antagonists

5th Direct acting vasodilators
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 DIURETICS

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 DIURETICS
(especially thiazide)

inhibition of tubular Na+ reabsorption

intracellular Na+

intracellular Ca2+

after load vasodilatation preload

blood pressure

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heart workload
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 DIURETICS
(especially furosemide and thiazide)

inhibition of tubular Na+ reabsorption

diuresis
(Na+ and water loss)

Na+ and K+ loss

hypokalemia

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the risk of cardiac arrhythmia
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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
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is used in chronic heart
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 Sympatholytics

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Sympatholytics
Centrally acting sympatholytics
clonidine, methyldopa

Neuron blockers
reserpin now is not recommended anymore

Adrenoseptor blockers (a- and b-blockers)

propranolol (b), prazosin (a)

Sympathetic ganglion blockers

trimetafan is not for routine drug for CV diseases
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 Ganglion blockers

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 CLONIDINE
CLONIDINE

stimulates presynaptic a2-adrenoceptors (in the brain)

neurotransmitter NA release
(sympathetic drives)

sympathetic tone

heart contraction (strength and rate) and vasodilatation

blood pressure
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methyldopa noradrenergic nerve ending

TYROSINE .

TYROSINE
tyrosine hydroxylase
DOPA METHYLDOPA
dopadecarboxylase
DOPAMINE a-methyldopamine

Vesicle
DOPAMINE a-methyldopamine
b-hydroxylase

noradrenaline a-methylnoradrenaline
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 METHYLDOPA

inhibit noradrenalin syntehtic (CNS)

neurotransmission
(sympathetic drives)

sympathetic tone

heart contraction and vasodilatation

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blood pressure
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Methyldopa and Clonidine
* Increase RBF

good for elderly hypertensive patients

* May cause depression

contraindicated for depression patients

The two drugs are for hypertension

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ADRENOCEPTOR BLOCKERS

a-blockers
a1-blockers (prazosin, terrazosin)
a1 and a2-blockers (nonselctive) : phentolamine
(is never used in the drug therapy)

b-blockers
b1-nonselective (noncardioselective)
b1-selective (cardioselective
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a-blockers
* a1-blockers (prazosin, terrazosin)
cause vasodilatation
decrease of blood pressure (hypotension)
homeostatic tachycardia

* a1 and a2-blockers (nonselective) phentolamine

cause vasodilatation

decrease of blood pressure hypotension

severe homeostatic
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tachycardia unrecommended18
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a-blockers
* a1-selective
elicit tachycardia (homeostatic tachycardia)
do not use for patients with tachycardia

* a1-selective elicit orthostatic hypotension

do not combine with diuretics
orthostatic hypotension more prominents
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 b-BLOCKERS
b1-selective blockers (cardioselective)
acebutolol,
alprenolol,
atenolol,
metoprolol (low dose)

b1-nonselective blockers (noncardioselective)

propranolol
pindolol
oxprenolol, timolol
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 b-BLOCKERS
b1-partial agonist
acebutolol,
alprenolol,
oxprenolol,
pindolol

b1- ISA negative antagonist (full antagonist)

propranolol
atenolol
metoprolol, timolol
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b-blockers
* Cardioselectivity
may minimize its side effects (b2 blockade)
(bronchoconstriction, worsening of DM)

* Partial agonist properties

may minimize cardiac arrest
(in non tachycardia patients)
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 RAA System Inhibitors
(b-blokers, ACE-inhibitor, 3. AT-blockers, and Spironolacton)

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Renin-Angiotensin-Aldosteron System

b-blockers Angiotensinogen
renin
Angiotensin I (inactive)
ACE
ACE-inhibitors Angiotensin II (active)
AT-blockers AT-blockers

Vasculer smooth muscle cortex adrenal

aldosteron secretion

vasoconstriction
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+ reabsorption
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Renin-Angiotensin-Aldosteron System Inhibitors

- b-blockers (acebutolol)
inhibit renin release

- ACE inhibitor (captopril, lisinopril, enalapril, quinapril etc)

inhibit the conversion of inactive angiotensin I

- AT-blockers (losartan, valsartan)

blockade angiotensin receptors

- Aldosteron antagonist (spironolacton) diuretics

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 CALCIUM ANTAGONISTS

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 Ca2+ Antagonists

inhibits Ca2+ influx (into cytoplasm)

Intracellular Ca2+

cell exitability

heart muscle, smooth muscle, etc.

(vasodilatation, heart contraction bronchodilatation,
constipation, meteorrhismus)
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CALCIUM ANTAGONISTS

Decrease BP (without homeostatic tachycardia)

May increase organ blood flow

May cause fatigue

Do not give to heart failure

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CALCIUM ANTAGONISTS

1. Nifedipin vascular effect > heart effect

(nicardipin, nimlodipin etc.)

2. Diltiazem

3. Verapamil heart effect > vascular effect

(galopamil, ketopamil etc.)
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 Direct acting VASODILATORS

1. Hydralazine

2. Minoxidil

3. Nitropruside
Other vasodilators
4. a1-blobkers (prazosin, terazosin)
5. Calcium
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antagonists (nifedipin etc.)
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 CARDIOTONICS
and
CARDIODEPRESANTS

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Drugs Acting on the
Heart
1. Cardiostimulants
a. Digitalis ( cardiotonics)
b. Sympathomimetics

2. Cardiodepressants
a. Quinidin
b. Lidokain
c. b-blockers
d. Calcium Antagonists
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Cardiotonics chronic congestive heart failure

- digitalis (Digitalis purpura or Digitalis lanata)

- digoxin

- digitoxin

- lanatoside A, B, C (cedilanid D)
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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
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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

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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 faillure

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

- Side effect :

- nausea, vomitus, diarrhoea

- cardiac arrhythmias

- heart block, extrasystole (ECG)

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Chronic Heart Failure
1. Digitalis (digoxin, digitoxin, cedilanide)

2. HCT or other diuretics (bumetanide, spironolactone)

3. ACE inhibitors and AT blockers

(captopril, lisinopril, enalapril, valsartan, losartan)

4. Vasodilator (prazosin, terazosin, hydralazine)

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

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VASODILATORS (prazosin, hydralazin, ACE-Inhib.)

vasodilator

vasodiatation of arteriolae, capiler and venulae

peripheral vascular resistance veneous return

cardiac work load

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 RAA-system inhibitors

1. ACE-inhibitor vasodilatation and diuresis

2. AT-blockers vasodilatation and diuresis

3. Spironolacton diuresis

b-blockers ? cardiac work load

decrease heart contraction may cause arrest

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NIFEDIPIN (and other Ca-antagonists) in heart failure

Nifedipin, nicardipin etc.

arteriolae, capiler and venulae vasodilatation

heart negative inotropic and chronotropic effects

peripheral vascular resistance veneous return

but heart contraction also dangerous
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 CARDIODEPRESSANTS

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

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

- Ca-antagonists
(verapamil, galopamil, deltiazem)
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 Classification
Ia : Quinidine, Procainamide, disopyramide
Na+ channel blockers,
effect 2 5 seconds,
may cause prolongation of QRS interval

Ib : Lidocaine, Mexiletine, Tocainide

200 800 mseconds,
do not cause Ngatidjan,
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Ic : Encainide, Flecainide, Propafenide
Na+ channel blocking effect (>10 seconds)
cause prolongation of PR and QRS interval

II : Esmolol (b-adrenoceptor antagonist)

200 800 mseconds,
do not cause prolongation of QRS interval

III :Action potential prolongation

(Quinidin like drugs : satolol, amiodarone, acecainide
prolongation of repolarisation phase)

IV : Calcium antagonists
(verpamil, galopamil,
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CALCIUM ANTAGONISTS

Nifedipin
(afinity to vascular smooth muscle >)

Diltiazem
(afinity to vascular smooth muscle = cardiac muscle)

Verapamil
(afinity to cardiac Ngatidjan,
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muscle >)
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 b-BLOCKERS

Blokade cardiac b1-receptor

heart contraction

(strengthn + frequency)

Blokade renal b1-receptor renin secretion

insulin secretion

bronchoconstriction
Blokade b (b1 or b2)
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 b-BLOCKERS
1. Cardioselectivity
b1-nonselective (noncardioselective)
- propranolol
- pindolol
b1-selective (cardioselective)
- atenolol
- acebutolol
2. parsial agonist (ISA : intrinsic sympathomimetic activity)
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CORONARY VASODILATORS

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Angina pectoris
Manifestation of myocardial ischemia

caused by imbalance of

* myocardial oxygen demand

* and coronary blood supply

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relatively decrease of oxygen
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Angina pectoris

caused by

- coronary spasm

- occlusion of coronary blood vessel

(partially) thrombus

totally
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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 myocardian infarction)
4. Varian Prinzmetal angina pectoris
(coronary spasm)
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Therapy of ANGINA PECTORIS

- increase coronary blood flow

coronary vasodilators

- decrease myocardial oxygen demand

decrease heart contraction (b-blockers and Ca2+ antag.)

- antithrombus aspirin, heparin

(for unstable angina)
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drugs for ANGINA PECTORIS

- Nitrate dan nitrite

(amilnitrite, nitroglyserine, isosorbide dinitrate)

- Calcium antagonists
(verapamil, diltiazem, nifedipin)

- b-blockers (acebutolol, atenolol, propranolol)

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Nitrate and nitrite
- increase intracellular cAMP vasodilatation

- coronary vasodilatation
increase coronary blood supply

- dilatation of venule
. veneous return end diastolic pressure
. cardiac dilatation

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heart contraction O demand
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 NITRATE - NITRITE
nitrate - nitrite

vasodilatation vasodilataion
of coronary blood vessel of arteriole and venule

oxygen supply venous return

heart contraction

oxygen demand
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Nitrate - nitrite
- side effects
. Headache

. Flushing

. Orthostatic hypotension

. Tachycardia (reflectory)
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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

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 CALCIUM ANTAGONISTS

Calcium antagonists

heart contraction and vasodilatation

oxygen demand and blood supply

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

heart contraction

oxygen demand

angina
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 b-blockers (acebutolol, atenolol, dsb.)
b-blockers
- cardioselectivity (bronchial asthma, DM)

- ISA - positive (partial agonist) bradycardia

- triglyceride
- HDL atherosclerotic risk
LDL
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 ASA (acetyl salicylic acid)

low dose ASA

(an antithrombotic agent)

inhibits COX1 and COX2

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 COX1
(cyclooxygenase-1)

acetosal
COX1-thrombocyte COX1-endotel
- TX-A2 synthesis - prostacyclin synthesis
(stimulate thrombocyte aggregation)
inhibit thrombocyte aggregation
- COX1 can not be synthesized instantly
(antithrombotic properties)
- new COX-1 can be synthesized
low dose acetosal
effectively inhibit COX1 thrombocyte
low dose acetosal
ineffective in COX1 endothel inhibition
thrombocyte aggregation
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Acetosal (acetyl salicylic acid)

Side effects

1. Epigastric dyscomfort
(gastric irritation)

2. Gastrointestinal bleeding (melena)

3. Prolonged bleeding time

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 Acetosal (acetyl salicylic acid)

Side effects
1. Epigastric dyscomfort

(gastric iritation)

2. Gastrointestinal bleeding (melena)

3. Prolonged bleeding time

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 THROMBOLYTICS
(in acute heart infarction)

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 Thrombolytics (fibrinolytics)
* Streptokinase
- enzyme isolated from Streptococcus hemolytic
- bind to plasminogen plasmin fibrin degradation

* Urokinase
- enzyme similar to streptokinase from human urine

* Alteplase (tissue plasminogen activator : tPA)

- obtained from recombinant technology (tissue culture)

* Anistreplase
- p-anisoylated (human) lys-plasminogen streptokinase
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8/28/2017 Ngatidjan, OBAT CARDIVAS-1 (Rang, et al., 2003)
71
 e-aminocaproic acid
tranexamic acid
inhibit endogenous
plasminogen activator fibrin

plasminogen plasmin

febrin
fibrinolytics degradation
- streptokinase product
activate plasminogen

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 THANK YOU

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