3. ANATOMI JANTUNG
TAMPAK BAGIAN DALAM
Ruang jantung terdiri dari dua atrium
dan dua ventrikel yang fungsinya
untuk mengembalikan darah yang
tidak teroksigenasi kembali ke paru-
paru dan memompa darah yang
mengandung oksigen ke seluruh
tubuh
Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
4. Atrium kanan • Menerima darah vena dari SVC, IVC, sinus koroner, vena jantung anterior
• Pemisahan area yang halus dan kasar oleh crista terminalis
• Fossa ovalis pada septum interatrial
Ventrikel kanan • Katup trikuspid: anterior, posterior, dan septum
• Katup paru: tiga cusps semilunar
• Dilapisi oleh trabeculae carneae
• Band moderator menyampaikan cabang bundel kanan ke otot ventrikel
Atrium kiri • Menerima darah beroksigen dari empat vena paru
• Dinding lebih kecil tapi lebih tebal dari atrium kanan
Ventrikel kiri • 3 × dinding lebih tebal dari ventrikel kanan (ketebalan normal 6-10 mm)
• Dilapisi oleh trabeculae carneae
• Katup mitral: cusps anterior dan posterior
• Katup aorta: cusps posterior anterior, kanan dan kiri
ANATOMI RUANG JANTUNG
Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
5. Koroner
arteri
kanan
• Berasal dari sinus aorta anterior,
berjalan di sepanjang alur
atrioventrikular (AV)
• Cabang-cabang utama: nodus
sinoatrial, posterior descending,
AV nodal, marginal
Koroner
arteri kiri
• Berasal dari sinus aorta
posterior kiri
• Cabang utama: left anterior
descending, sirkumfleksa kiri
Vena
koroner
• Vena jantung yang besar,
sedang, kecil dan miring
mengalir ke koroner sinus
kemudian ke atrium kanan
SIRKULASI KORONER DALAM DETAK JANTUNG
Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
6. KONDUKSI SISTEM JANTUNG
Simpul sinoatrial (SA) ('alat pacu jantung') terletak di persimpangan
vena cava superior dan atrium kanan. Di sinilah siklus listrik dimulai.
1. Node SA memulai kontraksi dengan mendepolarisasi kedua atria,
menyebabkan mereka berkontraksi dan memompa darah ke ventrikel.
2. Potensi aksi atrium mengaktifkan simpul AV yang terletak di septum
interatrial tepat di atas pembukaan sinus koroner.
3. Node AV memperkenalkan penundaan 0,1 detik sebelum mengirimkan
impuls ke bundel milik-Nya. Penundaan ini memungkinkan ventrikel
terisi.
4. Depolarisasi kemudian menyebar melalui bundel-Nya (yang kemudian
terbagi menjadi kiridan cabang bundel kanan) dan serat Purkinje untuk
mencapai otot ventrikel.
5. Ini mengaktifkan ventrikel dan menyebabkan mereka berkontraksi. Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
7. Sementara sistem konduktif jantung memiliki alat pacu jantung intrinsik, namun sistem saraf otonom
penting dalam laju pembentukan impuls, konduksi dan kekuatan kontraksi
Pasokan saraf jantung berasal dari saraf vagus (cardioinhibitor parasimpatisethic) dan ganglia simpatis C1-
T5 (akselerator cardio) melalui superfisial dan dalam pleksus jantung
Banyak obat yang digunakan dalam kardiologi menargetkan reseptor yang ditunjukkan pada Tabel 1.1 (mis.
Beta-blocker).
PERSYARAFAN JANTUNG
Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
8. SIKLUS JANTUNG PADA DENYUT NADI
Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
12. Beta receptors exist in three distinct forms:
1) Beta-1 (B1) : Located primarily in the heart mediate cardiac activity.
2) Beta-2 (B2) : Located in many organ systems control various aspects
of metabolic activity and induce smooth muscle relaxation.
3) Beta-3 (B3) : Induce the breakdown of fat cells and are less clinically
relevant at present.
BETA-RECEPTOR
14. Sistem saraf yang meregulasi jantung terletak di Pusat Kardiovaskuler di Medulla Oblongata.
Sumber input :
Cerebral Cortex
Sistem Limbic
Reseptor Sensorik
a) Propioceptors : Memonitor gerakan otot. Meningkatkan HR pada onset awal aktivitas fisik.
b) Chemoreceptors : Memonitor perubahan kimia dalam darah.
c) Baroreceptors : Memonitor adanya perubahan tekanan darah pada arteri dan vena.
Impuls pada pusat kardiovaskuler > Aktivasi saraf simpatik > Impuls pada cardiac accelerator nerve > Stimulasi rilis nor-
epinephrine > Berikatan dengan reseptor Beta-1 di otot jantung, efek :
Pada SA dan AV node fiber, NE meningkatkan kecepatan depolarisasi > HR meningkat
Pada Purkinje fiber, NE meningkatkan kadar Ca2+ di sitosol > Kontraktilitas atrium dan ventrikel meningkat > Volume darah yang
dipompa selama systole lebih besar. (Stroke Volume tidak mengalami penurunan meskipun peningkatan HR menurunkan waktu pre-
load).
Aktivasi saraf parasimpatik > Rilis Asetilkolin > Menurunkan kecepatan depolarisasi > HR menurun.
AUTONOMIC REGULATION OF HEART RATE
Gerrard J. Tortora. 14th edition. Principles of Anatomy and Physiology. Wiley. Pg 686-749
18. BETA-BLOCKER : FARMAKOKINETIK
Absorption
Sebagian besar obat dari
golongan beta blocker
diabsorpsi dengan baik
melalui pemakaian oral .
Kadar puncak dalam darah
tercapai dalam 1-3 jam setelah
pemakaian oral.
β antagonists didistribusikan secara cepat
dan mempunyai Vd yang besar.
Propranolol dan penbutolol bersifat
lipophilic dan dapat menembus blood-brain
barrier.
Sebagian besar β antagonists mempunyai
half-lives antara 3–10 jam.
Propranolol dan metoprolol secara besar
dimetabolisme di hepar, dengan sedikit
unchanged drug ditemukan dalam urine.
Eliminasi propranolol dapat menjadi lebih
panjang pada pasien dengan liver disease,
penurunan aliran darah ke hepar, atau
adanya inhibisi enzim hepar.
Propranolol mengalami first-
pass metabolism di hepar
secara besar-besaran; sehingga
bioavailabilitasnya relative
rendah.
Jumlah obat yang mencapai
sirkulasi sistemik meningkat
seiring dengan peningkatan
dosis, sehingga dapat
disimpulkan bahwa mekanisme
ekstraksi oleh hepar dapat
mengalami kejenuhan.
Distribution &
Clearance
Bioavailability
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
19. BETA-BLOCKER : FARMAKODINAMIK
Most of the effects
of these drugs are
due to occupation
and blockade of β
receptors.
However, some
actions may be due
to other effects,
including partial
agonist activity at β
receptors and local
anesthetic action,
which differ among
the β blockers.
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
20. Beta-blocking drugs given chronically lower blood pressure in patients with hypertension.
The mechanisms involved are not fully understood but probably include suppression of renin release and
effects in the CNS.
These drugs do not usually cause hypotension in healthy individuals with normal blood pressure. Beta-
receptor antagonists have prominent effects on the heart and are very valuable in the treatment of angina
and chronic heart failure and following myocardial infarction.
The negative ino-tropic and chronotropic effects reflect the role of adrenoceptors in regulating these
functions.
Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade
in the atrioventricular node.
In the vascular system, β-receptor blockade opposes β2-mediated vasodilation. This may acutely lead to a rise
in peripheral resistance from unopposed α-receptor–mediated effects as the sympathetic nervous system
discharges in response to lowered blood pressure due to the fall in cardiac output. Nonselective and β1-
blocking drugs antagonize the release of renin caused by the sympathetic nervous system.
EFFECTS ON THE CARDIOVASCULAR SYSTEM
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
21. EFFECTS ON RESPIRATORY TRACT
Blockade of the β2 receptors in bronchial smooth muscle may
lead to an increase in airway resistance, particularly in patients
with asthma.
Beta1-receptor antagonists such as metoprolol and atenolol
may have some advantage over nonselective β antagonists
when blockade of β1 receptors in the heart is desired and β2-
receptor blockade is undesirable.
However, no currently available β1-selective antagonist is
sufficiently specific to completely avoid interactions with β2
adrenoceptors.
Consequently, these drugs should generally be avoided in
patients with asthma.
On the other hand, some patients with chronic obstructive
pulmonary disease (COPD) may tolerate β 1-selective blockers
and the benefits, for example in patients with concomitant
ischemic heart disease, may outweigh the risks.
EFFECTS ON THE EYE
Beta-blocking agents reduce intraocular
pressure, especially in glaucoma.
The mechanism usually reported is
decreased aqueous humor production.
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
22. Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis.
The effects on carbohydrate metabolism are less clear, though glycogenolysis in the human liver is at least partially inhibited after
β2-receptor blockade.
Glucagon is the primary hormone used to combat hypoglycemia; it is unclear to what extent β antagonists impair recovery from
hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients.
This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since
catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia.
Beta1-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia.
Beta-receptor antagonists are much safer in those type 2 diabetic patients who do not have hypoglycemic episodes.
The chronic use of β-adrenoceptor antagonists has been associated with increased plasma concentrations of very-lowdensity
lipoproteins (VLDL) and decreased concentrations of HDL cholesterol.
Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although low-density lipoprotein
(LDL) concentrations generally do not change, there is a variable decline in the HDL cholesterol/LDL cholesterol ratio that may
increase the risk of coronary artery disease.
These changes tend to occur with both selective and nonselective β blockers, though they may be less likely to occur with β
blockers possessing intrinsic sympathomimetic activity (partial agonists). The mechanisms by which β-receptor antagonists cause
these changes are not understood, though changes in sensitivity to insulin action may contribute.
METABOLIC AND ENDOCRINE EFFECTS
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
23. Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β
blockers.
This action is the result of typical local anesthetic blockade of sodium channels and can be demonstrated
experimentally in isolated neurons, heart muscle, and skeletal muscle membrane.
However, it is unlikely that this effect is important after systemic administration of these drugs, since the
concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident.
The membrane-stabilizing β blockers are not used topically on the eye, because local anesthesia of the
cornea, eliminating its protective reflexes, would be highly undesirable.
EFFECTS NOT RELATED TO BETA-BLOCKADE
Bertram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.
24. BETA-BLOCKER
Adverse Effects
Bradycardia and hypotension are two
adverse effects that may commonly occur.
Fatigue, dizziness, nausea, and constipation
are also widely reported. Some patients
report sexual dysfunction and erectile
dysfunction.
Less commonly, bronchospasm presents in
patients on beta-blockers. Asthmatic
patients are at a higher risk.
Patients with Raynaud syndrome are also at
risk of exacerbation.
Beta-blockers can induce both
hyperglycemia and mask the hemodynamic
signs, usually seen in a hypoglycemic patient,
such as tachycardia.
Some patients report insomnia, sleep
changes, and nightmares while using beta-
blockers. This effect is more pronounced
with beta-blockers that cross the blood-brain
barrier.
The patient's heart rate and
blood pressure require
monitoring while using beta-
blockers. When using sotalol,
the clinician must monitor the
QTc interval as sotalol has QT-
prolonging effects.
Patients who have either
acute or chronic bradycardia
and/or hypotension have
relatively contraindication to
beta-blocker usage.
Traditionally, beta-blockers
have been contraindicated in
asthmatic patients. However,
recommendations have
aligned for allowing cardio-
selective beta-blockers, also
known as beta-1 selective, in
asthmatics but not non-
selective beta-blockers.
MonitoringContraindications
Toxicity
The antidote for beta-blocker
overdose is glucagon. It is
especially useful in beta-
blocker-induced cardiotoxicity.
The second line of treatment is
cardiac pacing if glucagon fails.
Farzam, Khashayar. 2019. Beta Blockers. StatPearlsPublishing LLC.
25. WHAT WILL TODAY’S LESSON
LOOK LIKE?
WHAT WILL TODAY’S LESSON
SOUND LIKE?
36. SINTESIS NITRIT OKSIDA DI SEL ENDOTEL
Nitrat oksida diproduksi dari L-arginin dan oksigen
dalam suatu reaksi yang dikatalisis oleh enzim nitrat
oksida sintase (NOS). Ada tiga isoform NOS, endotel
(eNOS), neuronal (nNOS), dan indofible NOS
isoform (iNOS). Baik eNOS dan nNOS terdapat di
ventrikel kiri myocytes, sedangkan nNOS adalah
isoform konstitutif myokard yang bertanggung
jawab atas mediasi-NO inotropi dan relaksasi
miokard. antara eNOS dan nNOS dapat menjelaskan
efek beragamnya pada miokardium. NO
memberikan efek fisiologis dan farmakologis
utamanya, otot polos relaksasi, dengan
mengaktifkan jalur NO / cGMP.
37. Senyawa NO mengaktifkan guanylate cyclase. Aktivasi ini
meningkatkan kadar siklik guanosin 3 ', 5'-monofosfat (cGMP). cGMP
mengaktifkan protein kinase dan menyebabkan serangkaian reaksi
fosforilasi yang mengarah pada defosforilasi rantai cahaya miosin dari
serat otot polos. Akhirnya ada pelepasan ion kalsium yang
menyebabkan relaksasi otot polos dan vasodilatasi. Relaksasi pada
vena lebih besar daripada arteri
NO adalah molekul pembawa pesan fisiologi relaksan dari endotel sel
ke sel otot polos
NO menurunkan preload, menurunkan afterload, menurunkan kerja
jantung. Sehingga hasilnya keseimbangan O2 jantung (Suplai O2
meningkat, kebutuhan O2 menurun). Mencegah arteri koroner
spasme
EFEK NITRIT OKSIDA
Lullman, H, dkk. 2005. Color atlas of pharmacology ed 3. New York. Thieme
38. OBAT Farmakokinetik / Farmakodinamik
Nitrogliserin (NTG) Kemampuan penetrasi ke membran tinggi, stabilitas sangat rendah
• Ikatan obat protein : 60%
• Metabolisme : Hepar
• T1/2 : 1-4 menit
• Ekskresi : urin (metabolit inaktif)
• Target aksi: agonis atrial natriuretic peptide receptor 1
PROFIL SEDIAAN NITROGLISERIN
Bentuk sediaan Onset of action Durasi
Tab sublingual 1-3 menit 30-60 menit
Translingual spray 2 menit 30-60 menit
Sustained release 20-45 menit 4-8 jam
Topikal 15-60 menit 2-12 jam
Trasdermal 40-60 menit 18-24 jam
Intravena, drip segera 3-5 menit
Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information, Inc.;2018
39. OBAT Farmakokinetik / Farmakodinamik
Isosorbid dinitrat (ISDN) Kemampuan penetrasi ke membran baik, stabilitas lebih baik daripada NTG
Metabolisme : Hepar
T1/2 : parent drug 1-2 jam, metabolit aktif (5-mononitrate) 4 jam
Ekskresi : urin dan feses
Target aksi: agonis atrial natriuretic peptide receptor 1
Bentuk sediaan Onset of action Durasi
Tab sublingual 2-10 menit 1-2 jam
Tab chewable 3 menit 0,5-2 jam
Tab oral 45-60 menit 4-6 jam
Tab/caps SR
PROFIL SEDIAAN ISDN
Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information, Inc.;2018
40. OBAT Farmakokinetik / Farmakodinamik
Isosorbide Mononitrate
(ISMN)
Tidak difromulasi dalam tab sublingual karena polaritasnya tinggi dan absorbsinya
lambat
Metabolisme : Hepar
T1/2 : 4 jam
Ekskresi : urin dan feses
Target aksi: agonis atrial natriuretic peptide receptor 1
PROFIL SEDIAAN ISMN
Bentuk sediaan Onset of action Durasi
Tab oral 30-60 menit 4-6 jam
Tab ER - -
Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information, Inc.;2018
41. OBAT Farmakokinetik / Farmakodinamik
Nitropruside Stabilitas rendah
Metabolisme: Nitropruside dikonversi menjadi ion cyanide dalam darah, dekomposisi
prussic acid kaitannya dengan donor sulfur dikonversi menjadi thiocyanate (hepatic dan
renal)
T1/2 : parent drug < 10 menit, thiocyanate 2,7 – 7 hari
Ekskresi : urin (sebagai thiocyanate)
Target aksi: agonis atrial natriuretic peptide receptor 1
PROFIL SEDIAAN NITROPRUSIDE
Bentuk sediaan Onset of action Durasi
intravena < 2 menit 1-10 menit
Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information, Inc.;2018
42. OBAT Farmakokinetik / Farmakodinamik
Molsidomine Merupakan prekursor, long acting nitrate
Bentuk sediaan: oral, intravena
Metabolime: Hepatik menjadi linsidomine (metabolit aktif)
T1/2 : 1-2 jam
Eksresi: Urin
Target aksi: agonis guanilate cyclase soluble subunit alpha 2
PROFIL SEDIAAN MOLSIDOMINE
Wishart DS, dkk. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037.
44. Efek samping potensial sakit kepala karena dilatasi chepallic
vessel. Selain itu penggunaan nitrat jangka panjang terjadi
toleransi nitrat memicu disfungsi endotel
Interaksi obat :
Toksisitas obat golongan nitrat meningkat jika digunakan
bersama obat yang menghambat CYP3A4 contohnya: diklofenac,
sildenafil, dll
Penurunan efek obat golongan nitrat menurun jika digunakan
bersama obat yang menginduksi CYP3A4 contohnya:
carbamazepine, fenitoin, dll
EFEK SAMPING DAN INTERAKSI OBAT NITRAT
Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information, Inc.;2018
Opie, L.H, dkk. 2013. Drugs for the Heart ed8. Philadelphia. Elsevier
45. PENCEGAHAN TOLERANSI NITRAT DENGAN
CARA MENGATUR INTERVAL TERAPI ATAU
KOMBINASI DENGAN OBAT LAIN
Opie, L.H, dkk. 2013. Drugs for the Heart ed8. Philadelphia. Elsevier
46. DAFTAR PUSTAKA :
• Lullman, H, dkk. 2005. Color atlas of pharmacology ed 3. New York. Thieme
• Charles, dkk. Drug Infromation Handbook, 27 th ed. Hudson, Ohio, Wolters Kluwer Clinical Drug Information,
Inc.;2018
• Vaswani. A, dkk. 2016. Cardiology in Heartbeat. UK. Scion
• Ahmad. A, dkk. review Role of Nitric oxide in the Cardiovascular and Renal Systems. Int. J. Mol. Sci. 2018, 19,
2605; doi:10.3390/ijms19092605
• Wishart DS, dkk. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017
Nov 8. doi: 10.1093/nar/gkx1037.
• Opie, L.H, dkk. 2013. Drugs for the Heart ed8. Philadelphia. Elsevier
• Gerrard J. Tortora; Derrickson, Bryan. 14th edition. Principles of Anatomy and Physiology. Wiley. Pg 689-749.
• Farzam, Khashayar. 2019. Beta Blockers. StatPearlsPublishing LLC. PMID 30422501.
www.NCBI.nlm.nih.gov/books/NBK532906.
• Betram G. Katzung. 13th edition. Basic and Clinical Pharmacology. Mc Graw Hill.