DRUG AFFECTING CARDIOVASCULAR FUNCTION

Peter Kabo

 Drug Affecting Cardiovascular Function

o Anti hypertensive agents
o Drugs used for the treatment of myocardial ischemia (anti angina agents)
o Pharmacological treatment of heart failure
o Ant arrhythmic drugs

 Physiology & pathophysiology of the cardiovascular system

o Hypertensions
o Coronary Artery Disease
o Heart failure
o Arrhythmia

Jantung Pembuluh darah

Sistem konduksi Tunika Antima
- Automatisasi - Vasoaktif sub
Miokard Tunika Media
- Kontraktilitas (Hukim Straling) - Elastisitas
Katup
- Ao,pul. Mitral. Trikomidal
Artery Coroner
- Lumen
- Driving Pressure

- Conservative
Parasimpati Acetyl cholin
s - Reservation

- Fight Adrenaline/nor
Sympathies - Flight reaction adrenaline
Respon Efektor terhadap perangsangan SSO

Organ Resptor Respon Respon

Perangsang Perangsang
Adrenergik Kolinergik
Jantung
Nodus SA β1 Nadi ↑ Nadi ↓
AV
Atrium/ Ventrikel otot β1 Kontraktilitas ↑ Kontraktilitas ↓
Sist – konduksi β1 Konduksi ↑ Kondulsi ↓ ↓
β1
Arteri & Vena
α1 & α2 Konstriksi ?
Paru-paru β2 Dilatasi
Otot bronkus + trankea
Kelenjar bronkus
Sel mast β2 Relaksasi Konstriksi
Sekresi ↑ ↑
Sal cerna Sekresi ↓ / ↑
Otot pls lambung & α2/β2 Mediator inflam ↓
usus β2
Otot Sfingter Relaksasi Kontraksi
Kelenjar α1 & α2 Relaksasi
β2 Kontraksi Relaksasi
Ginjal α1 Sekresi ↓ Sekresi ↑ ↑
Sekresi renin α2
↓ -
Kandung kemih α1 ↑
Otot detrusor β1
Trigon & Sfingter Relaksasi Kontraksi
β2 Kontraksi Relaksasi
Uterus α1
Kontraksi (hamil) Bervariasi
Prostat α1 Relaksasi
Mata β2 Kontraksi
Hati α1 Midriasis Miosis
α1 Glikogenolisis & -
Pankreas α1, β 2 glikoneogenesis
Sel β Sekresi insulin ↓
α2 Sekresi insulin ↓
Sel lemak β2
Kelenjar liur Lipolisis ↑ ↑
β3 Sekresi ↑ Sekresi ↑
α1
Transmisi Adrenergik
Fenilalanin
↓ Hidroksiterase
Tirosin
↓ Hidroksilase
Dopa
↓ Dekarboksilase
Dopamin
↓ β Hidroksilase
Noradrenalin
↓ Metiltrasferase
Adrenalin
↓ ↓ Comt
↓ Normetanefrin
Metanefrin
3 – metoksi 4 –hidroksi femilglikol asam 3, 4 – dihidroksi mandelat

Denervasi kurase
Reseptor Langley (1878)
Nikotin respon

Agonis Obat yang menimbulkan respon

Antagoni Obat yang menghambat respon

s yang ditimbulkan Agonis

Muskarinik
Asetilkolin
(M)
Nikotinik
(N)

Noradreanalin α
Adrenalin
Isoprenalin β
Anti Hypertensive Agents

- Heart rate x Peripheral

- Stroke volume reisstance
- ( Contractility x
- Venosum return )
- (Arteriole tone & elasticity

Cardiac Blood
output pressure

Diuretics

Sympatholytic drugs

Vasodilators

Ca++ Channels Blocker

Angiotensin Cooverting Enzyme Inhibitors (ACE-I)

- Angiotensin II Receptor Antagonis

Diuretics

- Hydrochorothiazide (hct) 50 mg, 25 mg/ tab

Thiazides & related agents
Loop diuretics
- Chlothalidone (hygrodone 50 mg/ tab)
- Indapamide (Natrilix SR 1,5 mg/ tab)
- Furosemide (Lasix 20 mg/ amp, 40 mg/ tab)
- Bumetanide
 - Spironolactone (Aldactone 25 mg, 50 mg, 100 mg)
K ± sparing diuretics
- Amilorita
Pharmacological Effects

Diuresis CO

Na+ Excretion α1 receptor sensitivity BP

Uric acid excretion

K+ excretion (except spironolactone)

Therapeutic uses Diuretic Resistance

Oedema 1Bed Rest

Hypertension Increase dose
Administration of smaller doses more
Congestive Heart Failure
frequently
Combination theraphy

Adverse effect

Hypo kalemia

Hyper uricemia

Hyoerglycemia

Ototokicity (loop diuretics)

LDL, Trigliceride & HDL – cholesterol

Gynecomastica (Spironolactone) Hyper K+

(NSAID, β Blocker & ACE-I)

Sexual impotance
Sympatholytic agents (Anti Adrenergic)

Central acting agents (methyldopa, clonidine)

Adrenergic neuron blocking agents

β - adrenergic antagonists (β – blockers)

α - adrenergic antagonists (α – blockers)

Mixed α & β - adrenergic antagonists (Labetolol, Carvedilol)

α-methyldopa (Dopamet 250 mg/tab)

↓
α-methyl dopamine
↓
α-methyl Noradrenaline

Pharmacological Effects:

↓ Sympathetic tone
• ↓ Cardiac output

• ↓ Peripheral resistance

• ↓ Myocardial contractility

• ↓ Heart rate

• ↓ Renin secretion
α-Blockers
Prazosin (Minipress, 1 & 2 mg/tab)

Terazosin (Hytrin, 1 & 2 mg/tab)

Doxazosin (Cardura, 1 & 2 mg/tab)

Indication Adverse Effects

Hypertension First dose effect

Vasospastic disorders Postural hypotension

Pharmacological Effects

Vasodilatation

•↓ Arterial resistence

•↓ Venous capaetance

↓ Triglyceride

↓ LDL Cholesterol

↓ HDL Cholesterol

↓ Resistence in trigone muscle – BHP – of bladder and urethra

β-Blockers
Isprenalin Bisopropolol

Propanolol Timolol

Atenolol Pindolol

Metoprolol

Bio
Metabolisme t1/2
Kardioselektif ISA Availibilitas
lintas I (Hati) (jam)
Oral (%)

ACEBUTOLOL + + 30 - 50 + 3

METOPROLOL + - 40 - 50 + 3-6

ATENOLOL + - 40 - 60 - 6-8

BISOPROLOL +++ - 90 10% 11

PROPANOLOL - - 25 - 35 + 2-6

PINDOLOL - ++ 95 - 100 - 3-4

OKSPRENOLOL - + 25 - 50 + 2

SOTALOL - - 90 - 100 - 10 - 15

TIMOLOL - - 50 - 75 + 4-5

LABETOLOL
- + 25 + 5-8
(Alfa blocker)

CARVEDILOL
 Farmakodinamik indikasi Efek samping

Sistem (-) inotropik Takikardi Gagal jantung

kardiovaskula (-) kronotropik Takiaritmia Bradikardi
r
↓ resistensi Hipertensiangin
perifer a pektoris
(non-selektif) Infark miokard
Turunka
↓ sekresi renin n TD HOCM
↓ cardiak output Feokromasitom
a
↓ resistensi
perifer Tirotoksikosis
(pengguna Glaukoma
kronis)

Saluran nafas Bronkokonstriks Bronkospasm

i e

Efek ↓ Asam lemak Hipertrigliserid

metabolik ↓ Trigliserida Hipoglikemi
↓ HDL !! Putus obat
↓glikogenolisis

Reserpin
Penghambat saraf adrenergik
Mekanisme kerja
• Mengosongkan katekolamin di ujung saraf adrenergik
Farmakodinamik
• Cardiac output ↓
• Resistensi perifer ↓
Indikasi
• Hipertensi
Efek samping
 • Depresi psikotik
Calcium Channel Blockers (CCB)

• Nifedipin

• Amlodipin

Golongan Dihidropiridin • Felodipin

• Nikardipin

• Nimodipin

Benzoditiazepin • Ditiazem

Difenalkilamin • Verapamil

Relative Cardiovascular Effects

Supression of
Vasodilatas
i Contractilit Automaticit Conductio
y y n

Nifedipin
5 1 1 0
Diltiazem
3 2 5 4
Verapami
4 4 5 5
l
ANGIOTENSIN CONVERTING ENZYME (ACE) – INHIBITORS

+
NA Antigrowth
Pharmacodynamic
reabsorbsion

Bradikinin system Angiotensin system

Kinino gen Angitensinogen

Endothelium

Symathetic activity
Bradykinine Angiotensin I

Apoptosin
Prostaglandin NO ACE-I

ion
Inactive peptide Angiotensin
t rict II
ns
oco
s
Va
Va AT1
sGrowth
od
(cardiac remodeling
Vascular
ila hyperthrophy) AT2
ta
tio
n G
Vasodilatory
PLC

DAG IP3

Proteinkinase C

Contraction
Adverse effect Angiotensin receptor antagonists
AT1 - antagonists

Cough Losartan

Angioedema Valsartan

Hyper K++ Irbesartan

Prelipitating renal failure Candesartan

Applets anemia

Dygensia

PENGHAMBAT ACE & ANGIOTENSIN RECEPTOR ANTAGONIST

Sel juxtaglomerolus
Angitensoinogen
Renin

Bradikinin
AI
Non - ACE
ACE-I
AI ACE

Peptide maktif

Vasokinstriksi ↑ Aldosteron
Mekanisme Kerja ACE-I Efek samping:

↓ aktivitas system simaptis Batuk kering

↓ All Udem Angioneurotik

↓ Sekresi Aldosteron First dose hipotensi

↓ Atrial Natriuric Factor Hiper K++

↓ Prostaglandin

Angiotensin antagonis:

Losartan

Valsartan

Kegunaan: Preparat

Hipertensi ringan s/d sedang Captopril (Capoten) 25 mg/ tab

(+) gagal jantung Enalapril (Inoprilat) 5 mg/ tab

LVH Lisinopril (Zestril) 5 mg/ tab

DM Perindopril (Prexum) 4 mg/ tab

Ramipril (Triatec) 5 mg/ tab

ACE - Inhibitors

Sulfhydryl Containing • Captopril

• Zefenoprilat

Non- Sulfhydryl Containing • Enalaprilat • Benazeprilat

• Lisinopril • Cilaprilat
 • Perindoprilat • Delaprilat
• Quinaprilat • Spriraprilat
• Ramiprilat • Trandolaprilat

Phophoryl containing • Fosinoprilat

Pharmacokinetic • Lipid solubility

• Cone max
• T 1/2
• T max
• AUC

Pharmacological Treatment of Hypertension

Compelling indication & drug of choice (except contraindication)

Diabetes (+ protein urea)

• ACE-I
Heart Failure
• ACE-I, Diuretics
Isolated systolic HT
• Diuretics, CA++ antagonists
Myocardial Infraction
• β-blockers, ACE-I
Angina Pectoris
• β-blockers, CA++ antagonists
Dyslipidemia
• α-blockers
Hyperthyroidism
• β-blockers
Osteoporosis
• Thiazide
Essential tremor
• β-blockers (non-selective)
Benign Prostate hypertrophy
• α-blockers
Renal insuffciency
• ACE-I

VASODILATORS

Arterial (Hydrolazine, Minoxidile)

Arterial & Venous (Na+ - Nitroprusside)

NITRAT ORGANIK
ANGINA PECTORIS

Arnil nitrat
Nitro gliserin
(Gliseril trinitrat = GTN)
Isosorbid Di-Nitrat
• (ISDN)

Isosorbid 5 – Mononitrat
Penta Eritritol Tetranitrat
Eritritil Tetranitrat
Mekanisme kerja

in
res
T p
so
-H bi
n
Va
G P m
h o
ad ac AD Tr

Nitrat B2 M S P T V

Endotel

EDRF NO?)

GS

GMP
GMP
Toleransi P
- SH
CGMP
CGMP

Relaksasi
Relaksasi

Farmakokinetik :
Reabsorbsi Hati
• SL • Metablolik
• Oral Sirkulasi Ginjal
• Topikal
• IV

Farmakodinamik :
 Relaksasi otot polos Pembuluh darah ↑ Supply

Koroner ↓ preload → ↓ Wall

+ stress
sistemik
Hipotensi
Skit kepala
Refleks Takikardi

Rebound fenomena
Kontraindikasi: Syok &Hipersensitif

Indikasi

Angina Pektoris
Miokard Infark
Gagal Jantung Kongestif

Cardiac Glicoside
William Withering (1789) Digitalis lanata (foxglove putih)
Digitalis purpura (foxglove ungu)

Farmakokinetik
Absorbsi (40 – 75%) • Kardenolit : Inti steroid → lipofilik
tergantung jenis • Inti lakton → hidrofilik
 • Metabolit → usus → (reabsorbsi) → sirkulasi & lerohepatis
Metabolisme : Hati
• (t 1/ 2 ↑)
Distribusi : Seluruh tubuh
terutama di jantung
Eliminasi : tanpa perubahan
melalui ginjal

Farmakokinetik

Dosis (beban digitalisasi • 0,75 – 1,5 mg (oral)

(loading dose) • 0,5 – 1,0 mg (I.V.)
Dosis pemeliharaan/ hari • 0,125 – 0,5 mg (oral)
(maintenance dose) • 0,25 mg (I.V.)
• 1,5 – 3 jam (oral)
Mula kerja
• 5 – 30 menit (I.V.)
• 4 – 6 jam (oral)
Efek maksimal
• 1,5 – 3 jam (I.V.)
Absorbsi intestinal • ± 75%
T½ • 1,6 hari
Kadar terapi • 0,5 – 2,0 mg/ml
Eliminasi • Ginjal

Sign & Symptoms of Cardiac Glycoside Toxicity

• Arterial + ventricular Ectopic

Cardiac
• SA & AV node conduction disturbances (bradyarrhytmias
Gastrointestinal • Anorexia, Nausea, vomiting, Abdominal pain
Visual • Blurred or yellowvision, halos
Psychiatric • Delirium, fatigue, confusion, abnormal dreams, dizziness

Drug interaction with Digoxin

drug Change in digoxin level
Cholestyramine
Kaolin – peptin
Sulfazolazi, Bram
Antacid, Albuterol,
↓
Tyroxim
Propafenone
Pecinidine
Amiodarone
Verapamil
Ditiazem ↑
Nifedipine
Captopril
cylcosporin
Pharmacodynamic

β-blockers, Verapamil, Ditiazem, • ↓ Cardiac contractile state

Flecainide, Disopyramide • ↓ SA – AV conduction
Kaluretic, diuretics, sympathomimetic drug • ↑ Automaticity

Management of Digoxin toxicity

Antidigoxin immunotherapy (fab fragments)

K+
Lidocamil/ Phenytoin

Farmakodinamik

Efek pada Jantung

• Menghambat NA+/K+ - ATP – ASE (+) inotropik Indikasi

Efek mekanik
Gagal Jantung
• ↑ Potensial aksi dini
• ↑ resistensi membrean diikuti Arterial Fibrilasi (Indikasi)
Efek listrik • ↓ Potensial aksi fase plateas Arterial Fluter (Indikasi)
• ↓ resistensi membran indikasi SVT
• ↑ tonus vagus

Efek pada organ lain

Semua organ eksitase termasuk otot polos & saraf

GIT
SSP
Ginekomastik (perangsangan estrogen)

Anti Arrhytmic drugs

Decreased phase 4 slope
• β blocker
Increase threshold
• NA+ channel blocker
• CA++ channel blocker