Mekanisme kerja Digoxin

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Mekanisme

Mekanisme Kerja Kerja Digoxin pada Digoxin pada Miokardiak Miokardiak I.

I. DeskripsiDeskripsi

Digoxin adalah salah satu glikosida jantung (digitalis), yaitu suatu kelompok senyawa Digoxin adalah salah satu glikosida jantung (digitalis), yaitu suatu kelompok senyawa yang mempunyai efek khusus pada miokardium. Digoxin diekstraksi dari daun

yang mempunyai efek khusus pada miokardium. Digoxin diekstraksi dari daun Digitalis lanata Digitalis lanata11.. Digoxin merupakan kristal putih tidak berbau. Digoxin memiliki cincin aglycone, yang Digoxin merupakan kristal putih tidak berbau. Digoxin memiliki cincin aglycone, yang merupakan tempat aktivitas farmakologik Senyawa ini praktis tidak larut dalam air dan dalam merupakan tempat aktivitas farmakologik Senyawa ini praktis tidak larut dalam air dan dalam eter, sediki

eter, sedikit larut dalam alkohol t larut dalam alkohol dan dalam dan dalam kloroform dan skloroform dan sangat larut dalam angat larut dalam piridin. Digoxinpiridin. Digoxin dikenal sebagai racun namun pada akhirnya dapat digunakan sebagai obat gagal jantung dikenal sebagai racun namun pada akhirnya dapat digunakan sebagai obat gagal jantung kongestif khususnya pada kasus fibrikasi atrial

kongestif khususnya pada kasus fibrikasi atrial22..

II.

II. FarmakokinetikaFarmakokinetika Absorpsi

Absorpsi dilakukan melalui difusi pasif pada usus halus bagian atas, makanan dapatdilakukan melalui difusi pasif pada usus halus bagian atas, makanan dapat menyebabkan absorpsi mengalami penundaan (delay), tetapi tidak mempengaruhi jumlah yang menyebabkan absorpsi mengalami penundaan (delay), tetapi tidak mempengaruhi jumlah yang diabsorpsi.

diabsorpsi. Distribusi:Distribusi: Disebar ke hampir semua jaringan, termasuk ke eritrosit, otot skelet danDisebar ke hampir semua jaringan, termasuk ke eritrosit, otot skelet dan jantung. Pada keadaan seimbang, kadar dalam jaringan jantung 15-30 kali lebih tinggi daripada jantung. Pada keadaan seimbang, kadar dalam jaringan jantung 15-30 kali lebih tinggi daripada kadar dalam plasma, sementara kadar dalam otot setengah kadar dalam jantung. Efek maksimal kadar dalam plasma, sementara kadar dalam otot setengah kadar dalam jantung. Efek maksimal baru timbul 1 jam atau lebih setelah kadar maksimal di jantung tercapai. Ikatan dengan protein baru timbul 1 jam atau lebih setelah kadar maksimal di jantung tercapai. Ikatan dengan protein

(protein binding) : 25%-30%.

(protein binding) : 25%-30%. MetabolismeMetabolisme dilakukan melalui sequential sugar hydrolysis dalamdilakukan melalui sequential sugar hydrolysis dalam lambung atau melalui reduksi cincin lakton oleh bakteri di intestinal , metabolisme diturunkan lambung atau melalui reduksi cincin lakton oleh bakteri di intestinal , metabolisme diturunkan dengan adanya gagal jantung kongestif.

dengan adanya gagal jantung kongestif. Ekskresi dan Bioaviabilitas :Ekskresi dan Bioaviabilitas : dieliminasi di ginjal,dieliminasi di ginjal, Waktu paruh eliminasi digoksin rata-rata adalah 1,6 hari

Waktu paruh eliminasi digoksin rata-rata adalah 1,6 hari88. Bioaviabilitas 60-80% dari oral. Urin. Bioaviabilitas 60-80% dari oral. Urin (50% hingga 70% dalam bentuk obat yang tidak berubah ).

(50% hingga 70% dalam bentuk obat yang tidak berubah ). Dosis :Dosis : kisaran efektif antara 1-2,5kisaran efektif antara 1-2,5 ng/ml, Gagal jantung kongestif : 0,5 -0,8 ng/ml , aritmia : 0,8-2 ng/ml, dewasa : < 0,5 ng/ml, ng/ml, Gagal jantung kongestif : 0,5 -0,8 ng/ml , aritmia : 0,8-2 ng/ml, dewasa : < 0,5 ng/ml, toksik jika diatas 2,5 ng/ml

toksik jika diatas 2,5 ng/ml33..

III.

III. Mekanisme AksiMekanisme Aksi Digoxin pada prinsi

Digoxin pada prinsipnya bekerja dengan cara mpnya bekerja dengan cara menghambat pompa enghambat pompa Na/K ATP-ase yangNa/K ATP-ase yang bekerja dengan meningkatkan pertukaran natrium-kalsium intraselular sehingga meningkatkan bekerja dengan meningkatkan pertukaran natrium-kalsium intraselular sehingga meningkatkan

kadar kalsium intraseluler dan meningkatkan kontraktilitas

kadar kalsium intraseluler dan meningkatkan kontraktilitas44. Digoxin secara spesifik berikatan. Digoxin secara spesifik berikatan dengan subunit- dari pompa Na

dengan subunit- dari pompa Na ++ / / K K ++ ATPase yang terletak di otot jantung (miokardia),ATPase yang terletak di otot jantung (miokardia), adanya ikatan ini meneyebabkan tidak berfungsinya pompa Na

adanya ikatan ini meneyebabkan tidak berfungsinya pompa Na++/K /K ++ ATPaseATPase33. Gambar 1.. Gambar 1. Menujukan mekanisme kerja Na/K ATPase. Hal ini kemudian mengaktifkan Na/Ca exchanger Menujukan mekanisme kerja Na/K ATPase. Hal ini kemudian mengaktifkan Na/Ca exchanger yang menyebabkan peningkatan konsentrasi ion natrium intraseluler, yang kemudian yang menyebabkan peningkatan konsentrasi ion natrium intraseluler, yang kemudian menyebabkan kenaikan tingkat ion kalsium. Mekanisme inhibisi transport enzim ini juga menyebabkan kenaikan tingkat ion kalsium. Mekanisme inhibisi transport enzim ini juga menghasilkan hilangnya K

menghasilkan hilangnya K ++ dari sel miokardiumdari sel miokardium44.. Gambar 2. Menunjukan mekanisme aksi dariGambar 2. Menunjukan mekanisme aksi dari digoxin.

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Gambar 1. Mekanisme Kerja Na/K ATPase

Gambar 2. Mekanisme Aksi Digoxin

Kerja dari otot jantung dipengaruhi oleh beberapa ion yaitu ion Na, K dan Ca. Ion Na terutama bertanggung jawab untuk memelihara tekanan osmosis agar tetap seimbang dalam jaringan,yaitu menjaga kepekaan sel-sel otot jantung terhadap rangsang yang mempengaruhi

kontraktilitas dan ritmisitas. Kelebihan ion Na ekstraseluler akan menimbulkan efek keracunan yang menyebabkan jantung berhenti berdenyut. Ion K berperan dalam iritabilitas, kelebihan ion K ekstraseluler akan mengganggu keseimbangan potensial membrane, bila konsentrasi ion K ekstraseluler berlebih maka akan menyebabkan berkurangnya kuat kontraksi dan jantung akan berhenti berdenyut pada keadaan diastole.Ion Ca mempengaruhi kuat kontraksi jantung karena ion Ca berperan dalam mekanisme sliding filament pada proses kontraksi5. Ion Ca ini akan berikatan dengan troponin agar otot dapat berkontraksi.

Adanya kelebihan konsentrasiion Ca akan menghasilkan potensial aksi yang mengubah permeabilitas retikulum sarkoplasma sehingga mengekresikan ion Ca yang akan menyebabkan

meningkatnya kuat kontraksi jantung melalui mekanisme sliding filament , jika konsentrasi ion ini terlalu banyak maka jantung akan terus berkontraksi dan tidak dapat berelaksasi sehingga akhirnya jantung akan berhenti berdenyut pada keadaan systole yang disebut kalsium rigor 5. Kalsium mempotensiasi efek toksin digoxin karena ada Na/ Ca exchanger yang kerjanya bergantung pada gradien natrium untuk memompa keluar kalsium, digoxin mengurangi gradien

konsentrasi natrium sehingga konsentrasi kalsium intrasel meningkat yang disebakan oleh menurunnya efflux Ca, hal ini mengarah pada meningkatnya konsentrasi kalsium dalam sel miokardiak dan pacemaker sehingga jantung mengalami kontraksi5. Gambar 3. Menjelaskan hubungan ion Ca dan kontraksi miokardium.

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Gambar 3. Hubungan ion Ca dan kontraksi otot.

Mekanisme kedua dari digoxin dihubungkan dengan saraf parasimpatik, adanya perubahan pada tekanan darah rata-rata dapat dikenali oleh baroreseptor yang akan meneruskan informasi itu ke pusat kardiovaskuler di batang otak yang mengendalikan keluaran sistim saraf otonom simpatik (SANS) dan parasimpatik (PANS). Suatu peningkatan pada tekanan darah rata-rata menimbulkan perangsangan baroreseptor, menghasilkan peningkatan aktifitas PANS, (menstimulasi vagal central ) memicu bradikardi dan mengurangi aktifitas SANS, yang pada gilirannya menurunkanh_{eart rate, daya kontraksi dan vasokontriksi}4,6_.

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Daftar Pustaka

1. A. Hollman. 1996. Digoxin comes from Digitalis lanata. B_ritish _{Medical Journal}312

(7035): 912. http://www.bmj.com/cgi/content/full/312/7035/912.

2. Damian, Dodo Saputra. 2009. F _{armakologi Obat Inotropik/ Vasopressor.} _F_akultas

Kedokteran Lambung Mangkurat : Banjarmasin. 3. AHFS Drug Information 2005

4. NN. A_{utonomic nervous system: p}h_{ysiology and p}h_{armacology. http://www.scribd.com,}

diakses 4Februari 2010.

5. Martini. 1998. F _{undamental of} A_{natomy and P}h_{ysiology, 4}t h _{edition. Prentice Hall}

International , Inc. New Jersey

6. DJ Goodman et al . 1975. Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation. Circulation 51_{: 251-256.}

http://www.circ.ahajournals.org/cgi/reprint/51/2/251.

7. Trevor P, Nora MV, Raymon LP, Davis C. US _{MLE step 1 p}h_{armacology notes. USA:}

Kaplan Inc; 2002.p.109-39.

8. Muchtar,A dan Z.S.Bustami. ³Obat gagal Jantung´ dalam Ganiswarna ( eds.). 2002.

F _{armakologi dan Terapi. Jakarta : Bagian} _F_armakologi _F_{akultas Kedokteran Universitas}

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MEKANISME KERJA DIGOXIN PADA MIOKARDIAK

Disusun untuk memenuhi tugas mata kuliah Toksikologi Lingkungan

Oleh:

Rani

25309037

Kesehatan dan Keselamatan Lingkungan

SEKOLAH PASCASARJANA PROGRAM STUDI TEKNIK LINGKUNGAN

FAKULTAS TEKNIK SIPIL DAN LINGKUNGAN

INSTITUT TEKNOLOGI BANDUNG

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bioavailability (BA) adalah persentase obat yang diresorpsi tubuh dari suatu dosis yang diberikan dan tersedia, untuk melakukan efek terapeutisnya.BA mencakup pula kecepatan obat muncul di sirkulasi darah.kl persentase pengikatan tergantung pada konsentrasi obat di dalam darah.

Utk memperbaiki atrial fibrilasi  aritmia jantung dg kontraksi miokardium atrium yg cepat dan tdk terkoordinasi

Utk memperbaiki flutter atrial  aritmia jantung dg kontraksi yg cepat 200-300 denyut/menit

Tachyarrhythmia (Fast Heart Rate)

View enlargement of illustration

Some fast heart rates are appropriate.For instance, if you are being chased, your body has a need for more oxygen; therefore, it is necessary for your heart rate to rise to meet this demand. This is called sinus tachycardia²a normal response and a normal rhythm. Other high heart rates occur because there is a problem with the heart or its conduction system (the part o f the heart that

generates electricity and allows the electricity to travel down the heart muscle, causing it to beat).

There are two types of fast heart rates, or tachyarrhythmias:

y Tachycardia - a rate higher than 100 beats per minute y Fibrillation - a rate higher than 350 beats per minute

Fast heart rates are also classified based on where in the heart they begin:

y The upper chambers - the atria y The lower chambers - the ventricles

Fast heart rates that occur in the upper chambers of the heart are called supraventricular tachycardias (SVTs) and include:

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y Atrial flutter

y Atrial fibrillation (AF)

y AV nodal reentrant tachycardia (AVNRT) y Wolf-Parkinson-White (WPW)

Those occurring in the lower chambers of the heart are:

y Ventricular tachycardia (VT) y Ventricular fibrillation (VF)

Atrial fibrillation is the most common serious arrhythmia worldwide, with an estimated 2. 5 million affected persons in North America and 4.5 million in Euro pe.1 Not all people with arrythmias require treatment. Supraventricular tachycardias, such as atrial fibrillation, and ventricular tachycardia are usually not medical emergencies, but require prompt medical attention. Ventricular fibrillation is fatal if not treated immediately.

Normal Rhythm

Every normal heart has a nor mal rhythm. That rhythm varies from person to person. In most healthy people, the heart at rest beats about 60 to 100 times per minute. A small bunch of heart cells called the sinoatrial node keeps t ime.

1

Fuster V, Ruden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation²executive summary: a report of the American College o f Cardiology/American Heart Association task force on practice guidelines and t he European Society of Cardiology Committee for practice guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With AtrialFibrillation). Circulation.

2006;114(7):700-752.

Some fast heart rates are appropriate.For instance, if you are being chased, your body has a need for more oxygen; therefore, it is necessary for your heart rate to rise to meet this demand. This is called sinus tachycardia²a normal response and a normal rhythm. Other high heart rates occur because there is a problem with the heart or its conduction system (the part o f the heart that

generates electricity and allows the electricity to travel down the heart muscle, causing it to beat).

There are two types of fast heart rates, or tachyarrhythmias:

y Tachycardia - a rate higher than 100 beats per minute y Fibrillation - a rate higher than 350 beats per minute

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y The upper chambers - the atria y The lower chambers - the ventricles

Fast heart rates that occur in the upper chambers of the heart are called supraventricular tachycardias (SVTs) and include:

y Atrial flutter

y Atrial fibrillation (AF)

y AV nodal reentrant tachycardia (AVNRT) y Wolf-Parkinson-White (WPW)

Those occurring in the lower chambers of the heart are:

y Ventricular tachycardia (VT) y Ventricular fibrillation (VF)

Atrial fibrillation is the most common serious arrhythmia worldwide, with an estimated 2. 5 million affected persons in North America and 4.5 million in Euro pe.1 Not all people with arrythmias require treatment. Supraventricular tachycardias, such as atrial fibrillation, and ventricular tachycardia are usually not medical emergencies, but require prompt medical attention. Ventricular fibrillation is fatal if not treated immediately.

Normal Rhythm

Every normal heart has a nor mal rhythm. That rhythm varies from person to person. In most healthy people, the heart at rest beats about 60 to 100 times per minute. A small bunch of heart cells called the sinoatrial node keeps t ime.

1

Fuster V, Ruden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation²executive summary: a report of the American College o f Cardiology/American Heart Association task force on practice guidelines and t he European Society of Cardiology Committee for practice guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With AtrialFibrillation). Circulation.

2006;114(7):700-752.

Gagal jantung kongestif adalah suatu keadaan dimana jantung tidak dapat memompa darah yang mencukupi untuk kebutuhan tubuh. Penyakit ini dapat

disebabkan oleh gangguan kemampuan otot jantung berkontraksi atau meningkatnya beban kerja dari jantung (Mycek et al _{., 2001).}

Digoxin Side Effects

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Please note - some side effects for Digoxin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to theFDA at

http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

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Side Effects of Digoxin - for the Consumer

Digoxin Immune Fab

All medicines may cause side effects, but many people have no, o r minor, side effects. No COMMON side effects have been reported with Digoxin ImmuneFab . Seek medical attention right away if any of these SEVERE side effects occur when using Digoxin ImmuneFab:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or to ngue); fast or irregular heartbeat; fever.

Digoxin

All medicines may cause side effects, but many people have no, o r minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Digoxin:

Diarrhea; nausea.

S_{eek medical attention right away if any of these}SE_VE_RE_{side effects occur when using Digoxin:}

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or to ngue); blurred vision, yellow vision, or other vision changes; confusion; fast, slow, or irregular heartbeat; hallucinations; mood or mental changes (eg, depression); severe or persistent nausea, vomiting, o r stomach pain; unusual bruising or bleeding; unusual tiredness or weakness.

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Digoxin Capsules

All medicines may cause side effects, but many people have no, o r minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Digoxin Capsules:

Diarrhea; nausea.

S_{eek medical attention right away if any of these}SE_VE_RE_{side effects occur when using Digoxin}

Capsules:

Digoxin Elixir

All medicines may cause side effects, but many people have no, o r minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Digoxin Elixir:

Diarrhea; nausea.

S_{eek medical attention right away if any of these}SE_VE_RE_{side effects occur when using Digoxin}E_lixir:

Top

Side Effects by Body System

G_eneral

Side effects generally have been dose-related and occurred more frequently when serum digoxin levels exceed 2.0 ng/mL. Cardiovascular (50%), gastrointestinal (25%), and CNS symptoms (25%) have been reported most often.

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Patients at increased risk include those with underlying renal, cardiopulmonary, or thyroid disease, electrolyte imbalances such as hypokalemia, hypomagnesemia, or hypercalcemia, and patients greater than 65 years of age.

G_{astrointestinal}

Gastrointestinal side effects reported in 25% of patients have included anorexia, nausea, vomiting, diarrhea, and general abdo minal pain. Rarely, intestinal ischemia or hemorrhagic necrosis, dysphagia, and esophageal dystonia have been reported.

Cases of severe abdominal pain and documented intestinal ischemia have been reported in

patients after hemodialysis. Contraction of intravascular volume combined with digo xin-induced splanchnic vasoconstriction may induce abdominal pain.

Cardiovascular

Cardiovascular side effects have been reported the most frequently. These have included premature ventricular depolarizations (50%), AV nodal arrhythmias (50%), AV conduction

disturbances (36%), wide complex tachycardia (less than 1%), paroxysmal atrial tachycardia with AV block, complete heart block, PR prolongation, and ST segment changes.

Ocular

Ocular side effects have included chromatopsia, snowy or blurry vision, photopsia, and

decreased visual acuity. Rarely, transient blindness has been rep orted. Decreased color vision has been reported.

The development of photopsia characterized by innumerable points of light in the per ipheral visual fields or a decrease in visual acuity has been associated with therapeutic serum digitalis concentrations in the elderly. Digitalis-induced visual disturbances other than c hromatopsia or disturbances of color vision may occur in elderly patients who have no ot her clinical

manifestations of digitalis intoxication.

Digoxin-mediated inhibition of sodium-potassium ATPase influences normal uptake o f

extracellular potassium by Muller's cells and other retinal neurons and may result in decreased color vision.

Nervous system

Nervous system side effects reported in 25% of patients have included headache, d izziness, and weakness. At least one case of trigeminal neuralgia has been reported.

A 51-year-old man with ischemic cardiomyopathy complicated by congestive heart failure developed right trigeminal neuralgia associated with hyperalgesia between at tacks. The pain resolved when digoxin was discontinued and reappeared upon rechallenge.

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P_sychiatric

Psychiatric side effects have included decreased co gnition, memory, disorientation, emotional lability, and depression.

A 74-year-old man with supraventricular tachycard ia developed altered cognition, memory, and depression with a serum digoxin level o f 0.9 ng/mL. Symptoms resolved when digoxin levels decreased to 0.5 ng/mL.

Endocrine

Endocrine side effects have included increased (significant) serum estrogen, decreased serum luteinizing hormone, decreased (significant) serum testosterone, and g ynecomastia.

A study of 38 patients (20 postmenopausal women) who had taken d igoxin for at least two years, revealed significantly decreased serum luteinizing hor mone and testosterone levels and

significantly increased serum estrogen levels relative to a control group of men and

postmenopausal women. The study did not control for underlying disease and it is possible that the sex hormone alterations were associated with the underlying diseases rather than use of digoxin.

Hypersensitivity

A 77-year-old man with congestive heart failure developed a psoriasiform rash associated with a positive macrophage inhibition factor test to digoxin. The rash resolved upon discontinuation of

the drug and reappeared on rechallenge.

Hypersensitivity reactions have been reported rarely. At least o ne case of psoriasiform rash has been reported.

Hematologic

Hematologic side effects have been reported rarely. These have included thrombocytopenia. A 60-year-old man with thyroid cancer and supraventricular tachycardia developed reversible thrombocytopenia during digoxin and heparin therapy. The thrombocytopenia resolved when digoxin alone was discontinued. The bone marrow examination and immunological studies were consistent with a digoxin-induced immune thrombocytopenia due to circulating immune

complexes.

Metabolic

Three patients with Type II diabetes who experienced greater antidiabetic control and significant reduction in requirements of hypoglycemic agents fo llowing discontinuation of digoxin has been reported. Rechallenge in one patient resulted in increased glucose levels and subsequent dosage increases of hypoglycemic agents.

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Metabolic side effects have included hypokalemia, hypomagnesemia, and hypercalcemia. Diabetes mellitus and glucose intolerance have been reported.

Dermatologic

Dermatologic side effects have been reported rarely. These have included maculopapular rash and other nonspecific skin reactions.

Other

Other side effects have been reported rarely. At least one case of diaphoresis and malaise has been reported. At least one case of digoxin cachexia, fatigue, weight loss, and decreased appetite

has been reported.

A 48-year-old man with rheumatic mitral valve d isease and atrial flutter/fibrillation developed profound diaphoresis and malaise associated with a serum digoxin level of 0.7 ng/mL. The

symptoms resolved when digoxin was discontinued, and reappeared on rechallenge.

Cachexia, fatigue, and documented weight loss have been reported in rare cases. Appetites and weights improved after discontinuation of digoxin