Pembekalan UKAI

Clinical Sciences
Juli 2022
HYPERTENSION
Klasifikasi Tekanan Darah
Kontraindikasi Antihipertensi
Efek Samping Antihipertensi
Tata Laksana
Hipertensi
Tanpa
Komplikasi
Pengobatan Hipertensi dengan Penyakit Arteri Koroner
Pengobatan Hipertensi dengan PGK
Pengobatan Hipertensi pada Gagal Jantung dengan Penurunan Fraksi
Ejeksi
Pengobatan Hipertensi dengan Fibrilasi Atrial
 Hipertensi dalam Kehamilan

• Definisi hipertensi dalam kehamilan

didasarkan pada pengukuran tekanan darah di
klinik, dimana TDS >140 mmHg dan/atau TDD
>90 mmHg.
• Klasifikasi hipertensi dalam kehamilan
berdasarkan derajat tekanan darah yaitu:
1) Ringan : TD 140-159/90-109mmHg
2) Berat : TD >160/110mmHg
 Klasifikasi Hipertensi Dalam Kehamilan
• Pre-existing hypertension (hipertensi kronik): Onset dimulai sebelum
kehamilan atau sebelum minggu ke-20 kehamilan, dan biasanya menetap
selama lebih dari 6 minggu pasca persalinan dan dapat disertai
proteinuria.
• Hipertensi gestasional : Terjadi setelah minggu ke-20 kehamilan dan
biasanya membaik dalam 6 minggu pasca persalinan.
• Hipertensi kronik plus superimposed hipertensi gestasional dengan
proteinuria
• Pre-eklampsia : Hipertensi gestasional dengan proteinuria bermakna (>0,3
g/24 jam atau >30 mg/mmol ACR).
• Hipertensi antenatal yang tidak terklasifikasi: Istilah ini dipakai jika TD
pertama kali diukur setelah 20 minggu kehamilan dan tidak jelas apakah
hipertensi kronik atau bukan. Evaluasi 6 minggu pasca persalinan
diperlukan untuk membedakan apakah hipertensi kronik atau gestasional
 Tata
Laksana
Hipertensi
dalam
Kehamilan
Sindrom Koroner Akut
• Acute coronary syndrome (ACS) refers to a
spectrum of clinical presentations ranging from
those for ST-segment elevation myocardial
infarction (STEMI) to presentations found in non–
ST-segment elevation myocardial infarction
(NSTEMI) or in unstable angina.
• In terms of pathology, ACS is almost always
associated with rupture of an atherosclerotic
plaque and partial or complete thrombosis of the
infarct-related artery.
Terapi Awal
Terapi Jangka Panjang NSTEMI
Terapi jangka panjang NSTEMI
Pemberian Fibrinolitik pada STEMI
Rekomendasi
Terapi
Fibrinolitik
STEMI
Dislipidemia
• Kolesterol total digunakan untuk estimasi risiko kardiovaskular.
• Kolesterol LDL adalah parameter lipid primer untuk analisis penapisan,
diagnosis, dan pengobatan dislipidemia.
• Kolesterol HDL digunakan sebagai parameter tambahan untuk estimasi
risiko kardiovaskular.
• Kolesterol non-HDL yang didapat dari pengurangan nilai kolesterol HDL
terhadap kolesterol total merupakan target terapi sekunder bagi pasien
dengan risiko kardiovaskular tinggi dan sangat tinggi yang mempunyai
konsentrasi trigliserida tinggi dan konsentrasi kolesterol LDL telah
mencapai target terapi.
• Dalam keadaan di mana konsentrasi TG ˃500 mg/dL, TG menjadi target
terapi primer (tanpa mempedulikan pencapaian target kolesterol LDL)
guna mencegah kejadian pankreatitis
• Trigliserida (TG) diperhitungkan karena menambah risiko kardiovaskular
yang disebabkan oleh kolesterol LDL dan mempengaruhi pilihan terapi
Kategori Risiko Kardiovaskular
Target Terapi untuk Kolesterol LDL
Strategi Intervensi Penurunan Kolesterol LDL
• Terapi obat dimulai ketika konsentrasi LDL terukur di atas
target terapi. Pengecualian diberlakukan bagi mereka dengan
risiko kardiovaskular rendah di mana terapi dimulai ketika
konsentrasi kolesterol LDL ≥190 mg/dL dan bagi mereka
dengan infark miokard akut di mana terapi dimulai tanpa
mempertimbangkan konsentrasi kolesterol LDL.
• Statin merupakan pilihan pertama untuk menurunkan
konsentrasi kolesterol LDL berdasarkan studi yang ada.
Terdapat beda potensi berbagai statin dalam menurunkan
konsentrasi kolesterol LDL.
• Atorvastatin dan rosuvastatin termasuk statin intensitas
tinggi. Pada dosis tinggi, atorvastatin dan rosuvastatin
berpotensi menurunkan konsentrasi LDL ˃50% .
• Saat ini terdapat pilihan antara statin monoterapi dan
kombinasi statin dengan non-statin (ezetimibe, inhibitor
PCSK9, bile acid sequestrant) untuk mereduksi konsentrasi
kolesterol LDL menuju target terapi
• Dengan pilihan terapi yang ada, target terapi untuk pasien dengan risiko
kardiovaskular tinggi dan sangat tinggi secara berurutan adalah ˂100 mg/dL
dan ˂70 mg/dL, yang diharapkan dapat dicapai tanpa memandang konsentrasi
kolesterol LDL sebelum terapi.
• Statin merupakan terapi pilihan bagi pasien dengan risiko kardiovaskular
tinggi dan sangat tinggi yang mempunyai konsentrasi kolesterol LDL sebelum
terapi berurutan 100-200 mg/dL dan 70-135 mg/dL. Reduksi konsentrasi
kolesterol LDL sebesar minimum 50% diprediksi dapat dicapai dengan terapi
statin intensitas tinggi sehingga target terapi dapat dicapai.
• Pada keadaan target terapi tidak tercapai dengan terapi statin,
direkomendasikan untuk menambahkan ezetimibe pada statin. Kombinasi
statin dengan ezetimibe meningkatkan efektivitas terapi statin monoterapi
sebesar 23-24% dan meningkatkan jumlah pasien yang mencapai target terapi.
• Pasien risiko sangat tinggi (ASCVD/atherosclerotic vascular disease dan
diabetes) dengan konsentrasi kolesterol LDL ˃140 mg/dL direkomendasikan
untuk diterapi dengan kombinasi statin dan inhibitor PCSK9.
• Efek luaran kardiovaskular dari kombinasi statin dan bile acid sequestrant
belum diketahui. Kombinasi ini hendaknya dipertimbangkan bagi pasien yang,
karena suatu alasan, tidak dapat diterapi dengan ezetimibe atau dengan
inhibitor PCSK9.
 Intensitas berbagai jenis dan dosis statin
terhadap penurunan konsentrasi kolesterol LDL
Panduan Terapi Penurunan Kolesterol LDL bagi
Pasien Risiko Kardiovaskular Sangat Tinggi
• Belum ada studi luaran klinis yang dapat
dipakai menunjang rekomendasi terapi
tunggal non-statin (ezetimibe, inhibitor PCSK9,
bile acid sequestrant) untuk menurunkan
risiko kardiovaskular. Terapi tunggal non-statin
dapat dipertimbangkan bagi mereka yang
tidak dapat mentoleransi statin sama sekali.
 Strategi Intervensi Kolesterol Non-HDL
• Target terapi kolesterol non-HDL dicapai dengan menurunkan konsentrasi
TG.
• Hipertrigliseridemia ringan hingga sedang: konsentrasi 150- 880 mg/dL.
Konsentrasi ˃880 mg/dL didefinisikan sebagai HTG berat.
• Terapi penurunan konsentrasi TG ditujukan hanya pada pasien dengan
risiko kardiovaskular tinggi dan sangat tinggi yang konsentrasi kolesterol
LDL-nya telah mencapai target dengan terapi statin sementara konsentrasi
TG-nya masih di atas 200 mg/dL.
• Konsentrasi kolesterol non-HDL ≥30 mg/dL di atas target terapi kolesterol
LDL dipakai sebagai nilai ambang memulai terapi penurunan TG. Target
terapi kolesterol non-HDL adalah 30 mg/dL di bawah target terapi
kolesterol LDL.
• Pasien yang mempunyai konsentrasi TG puasa ˃500 mg/dL perlu segera
mendapat terapi penurun TG tanpa memandang konsentrasi kolesterol
LDL untuk mencegah pankreatitis akut
• Mengingat statin mempunyai efek bermakna terhadap luaran
kardiovaskular pada pasien risiko tinggi dan sangat tinggi maka obat
ini pilihan pertama baik untuk mereduksi risiko kardiovaskular
maupun menurunkan TG pada HTG yang moderat.
• Statin mampu menurunkan konsentrasi TG sampai 30%.
Menambahkan fibrat pada statin dapat dipertimbangkan ketika
statin tidak dapat menurunkan konsentrasi TG, sehingga konsentrasi
kolesterol non-HDL masih ≥30 mg/dL di atas target kolesterol LDL.
• Fenofibrat lebih terpilih daripada gemfibrozil mengingat risiko
miopati 15 kali lebih tinggi jika digunakan gemfibrozil daripada
fenofibrate. Dianjurkan untuk memantau kejadian miopati yang
diakibatkan oleh kombinasi statin dan fibrat.
• Keuntungan klinis terapi poly-unsaturated fatti acid /PUFA omega 3
(EPA dan DHA) masih belum jelas. Sebuah studi meta-analisa
menunjukkan efek netral asam lemak omega 3 terhadap luaran
kardiovaskular. Sebelum tersedia data baru, PUFA omega 3
dianjurkan diberikan bersama diet, statin, dan fibrat pada pasien
dengan konsentrasi TG ˃500mg/dL.
 Statin (Inhibitor HMG-coA Reductase)
• Statin adalah obat penurun lipid pertama yang harus digunakan untuk menurunkan
kolesterol LDL. Dalam keadaan tidak toleran terhadap statin, direkomendasikan
pemakaian ezetimibe, inhibitor PCSK9, atau bile acid sequestrant monoterapi.
• Selain berfungsi untuk menurunkan kolesterol LDL, statin juga mempunyai efek
meningkatkan kolesterol HDL dan menurunkan TG.
• Statin hendaknya digunakan sampai dosis maksimal yang direkomendasikan atau yang
maksimal dapat ditoleransi untuk mencapai target kolesterol LDL. Pada pasien dengan
risiko tinggi dan sangat tinggi, sebaiknya terapi statin dilanjutkan walau target terapi
sudah tercapai selama tidak ada indikasi kontra ataupun efek samping yang berat.
• Khusus untuk simvastatin, penggunaan dosis maksimum (80 mg) meningkatkan miopati
atau jejas otot yang bermakna, terutama jika digunakan selama 12 bulan berturutan.
• Miopati, sebuah terminologi umum untuk penyakit otot, terjadi pada 5% pasien
pengguna statin dan kejadiannya tidak berbeda dengan pengguna plasebo dalam
penelitian klinis acak. Miopati dapat berupa mialgia, miositis, atau rabdomiolisis.
• Miopati juga berhubungan dengan konsumsi atau obat yang spesifik seperti fibrat
(terutama gemfibrozil), eritromisin, klaritromisin, antibiotika makrolid, antifungal,
amiodaron, verapamil, siklosporin, jus anggur (sekitar 1 Liter perhari), dan minum
alkohol berlebihan.
 Inhibitor Absorpsi Kolesterol
• Ezetimibe merupakan obat penurun lipid pertama yang
menghambat ambilan kolesterol dari diet dan kolesterol
empedu tanpa mempengaruhi absorpsi nutrisi yang larut
dalam lemak.
• Dosis ezetimibe yang direkomendasikan adalah 10 mg/hari
dan harus digunakan bersama statin.
• Pada keadaan tidak toleran terhadap statin, ezetimibe
dapat dipergunakan secara tunggal.
• Tidak diperlukan penyesuaian dosis bagi pasien dengan
gangguan hati ringan atau insufisiensi ginjal berat.
• Berdasarkan bukti klinis yang ada, ezetimibe yang
dikombinasikan dengan statin direkomendasikan sebagai
obat penurun kolesterol LDL ketika target tidak tercapai
dengan statin dosis maksimal yang dapat ditoleransi
 Inhibitor PCSK9
(proprotein convertase subtilisin/kexin type 9 )
• Inhibitor PCSK9 merupakan obat penurun kolesterol LDL
terbaru yang menyebabkan degradasi reseptor LDL
memunculkan cara baru dalam mengontrol kolesterol LDL.
• Saat ini, ada 3 inhibitor PCSK9 yang telah dievaluasi
terhadap luaran kardiovaskular yaitu alirocumab,
bococicumab, dan evolocumab.
• Pada pasien dengan ASCVD kronik, terapi statin
dikombinasikan inhibitor PCSK9 meningkatkan regresi plak
aterosklerosis dan menurunkan kejadian kardiovaskular.
• Keamanan jangka panjang inhibitor PCSK9 belum diketahui.
Bukti yang ada saat ini menunjukkan inhibitor PCSK9 pada
umumnya ditoleransi dengan baik, dengan reaksi di tempat
penyuntikan dilaporkan terjadi pada sekitar 5% pasien.
Tidak dilaporkan peningkatan kreatinin kinase, mialgia, dan
keluhan otot lainnya.
 Terapi penurun Lipid pada Komorbiditas Tertentu
• Terapi statin tunggal atau kombinasi dengan ezetimibe atau inhibitor PCSK9
pada pasien dengan penyakit kardiovaskular juga ditujukan untuk prevensi
primer stroke.
• Terapi statin pada pasien dengan riwayat stroke iskemik (nonkardioembolik)
atau TIA ditujukan untuk menurunkan risiko stroke berulang (prevensi
sekunder stroke).
• pemberian statin atau statin/ezetimibe untuk menurunkan kejadian
aterosklerotik mayor bagi pasien gagal ginjal kronik (termasuk yang menjalani
transplantasi ginjal) kecuali jika pasien tersebut menjalani dialisis. Dosis
berbagai obat penurun lipid perlu disesuaikan dengan beratnya gagal ginjal
kronik kecuali atorvastatin, fluvastatin, bile acid sequestrant, dan ezetimibe.
• Strategi pengobatan pasien sindrom metabolik dan DM tipe 2 mengikuti tata
laksana dislipidemia bagi pasien risiko tinggi dan sangat tinggi.
• Statin dosis tinggi direkomendasikan diberikan pada hari 1 – 4 perawatan
sindrom koroner akut tanpa memandang konsentrasi kolesterol LDL awal. Jika
target konsentrasi kolesterol LDL tidak dapat dicapai dengan statin,
pertimbangkan menambahkan ezetimibe pada statin.
 Bile Acid Sequestrant
• Terdapat 3 jenis bile acid sequestrant yaitu kolestiramin,
kolesevelam, dan kolestipol.
• Bile acid sequestrant mengikat asam empedu (bukan
kolesterol) di usus sehingga menghambat sirkulasi
enterohepatik dari asam empedu dan meningkatkan
perubahan kolesterol menjadi asam empedu di hati.
• Dosis harian kolestiramin, kolestipol, dan kolesevelam
berturutan adalah 4-24 gram, 5-30 gram, dan 3,8- 4,5 gram.
Penggunaan dosis tinggi (24 g kolestiramin atau 20 g of
kolestipol) menurunkan konsentrasi kolesterol LDL sebesar 18-
25%.
• Bile acid sequestrant tidak mempunyai efek terhadap
kolesterol HDL sementara konsentrasi TG dapat meningkat
• Kombinasi statin/bile acid sequestrant direkomendasikan bagi
pasien yang, karena suatu alasan, tidak dapat diterapi dengan
kombinasi statin dengan ezetimibe atau inhibitor PCSK9.
• Efek sampingnya terutama berkenaan dengan sistem pencernaan
seperti rasa kenyang, terbentuknya gas, dan konstipasi.
• Bile acid sequestrant berinteraksi dengan obat lain seperti digoksin,
warfarin, tiroksin, atau tiazid, sehingga obat-obatan tersebut
hendaknya diminum 1 jam sebelum atau 4 jam sesudah bile acid
sequestrant.
• Absorpsi vitamin K dihambat oleh bile acid sequestrant dengan
akibat mudah terjadi perdarahan dan sensitisasi terhadap terapi
warfarin. Kolesevelam lebih sedikit berinteraksi dengan obat lain
sehingga dapat diberikan bersamaan dengan statin dan obat lain
ISCHEMIC STROKE
Hesty Utami, M.Clin.Pharm.,PhD.,Apt
 Definition
Strokes involves abrupt onset of focal neurologic deficit that lasts at
least 24 hours and is presumed to be of vascular origin.
Stroke can be either ischemic or hemorrhagic.
Ischemic strokes (87% of all strokes) are due either to local thrombus
formation or emboli occluding a cerebral artery. Cerebral
atherosclerosis is a cause in most cases, but 30% are of unknown
etiology.
Sudden loss of blood circulation to an area of the brain →
corresponding loss of neurologic function.
Hemorrhagic strokes (13% of strokes) include subarachnoid
hemorrhage, intracerebral hemorrhage and subdural hematoma
Transient ischemic attacks (TIAs): focal ischemic neurologic deficits
lasting less than 24 hours and usually less than 30 minutes.
 Treatment

Goals of treatment:

❑Reduce ongoing neurologic injury and decrease mortality

& long-term disability
❑Prevent complications secondary to immobility and
neurologic dysfunction
❑Prevent stroke recurrence
 Pharmacologic
therapy

Anti- Anticoagul Seizure Cerebral Blood

Fibrinolitic edema Blood
platelet ation control pressure
control glucose
control control
 Treatment: fibrinolitic therapy

Fibrinolytics restore cerebral blood flow → lead to improvement or

resolution of neurologic deficits.
The only fibrinolytic agents showing benefit in acute ischemic stroke
patients is alteplase (tissue plasminogen activator (rt-PA)
Adverse effects: intra/extracranial hemorrhage, angioedema or allergic
reactions
Streptokinase may benefit patient with acute myocardial infarct →
increase risk of intracranial hemorrhage and death in ischemic stroke.
Alteplase is given within 4.5 hours after symptom onset. Dose: 0.9
mg/kg (max 90 mg) infused IV over 1 hr with 10% given a initial bolus
over 1 minute
Avoid anticoagulant and antiplatelet therapy for 24 hours.
Monitor closely: elevated BP, response, hemorrhage
Inclusion criteria Exclusion criteria
✓ Age ≥ 18 years • Evidence of intracranial hemorrhage
✓ Clinical diagnosis of • Only minor or rapidly improving stroke symptoms
ischemic stroke causing a • High clinical suspicion of subarachnoid hemorrhage even
measurable neurologic with normal CT scan
deficit • Active internal bleeding (genitourinary/gastrointestinal
✓ Time of symptom onset well bleeding within 21 days)
established to be < 4.5 hr • Receiving heparin within 48 hr and elevated aPTT
before treatment would • Recent use of anticoagulant (eg warfarin) & elevated PT
begin (>15 second)/INR (> 1.7)
• Major surgery or serious trauma within 14 days
• SBP>185 mmHg or DBP>110 mmHg at time of treatment
• Recent acute myocardial infarction within 3 months
• Intracranial surgery, serious head trauma or previous stroke
within 3 months
• Platelet count <100,000/µL
• Witnessed seizure at stroke onset
• History of intracranial hemorrhage, aneurysm,
arteriovenous malformation (AVM)
Additional exclusion criteria for alteplase if used within 3-4.5 hours

✓ Age > 80 years

✓ Current treatment with anticoagulation
✓ NIH stroke scale > 25 (severe stroke)
✓ History of both stroke and diabetes
 Treatment: antiplatelet agent

❑ Aspirin 160-325 mg/day started between 24-48 hour after

completion of alteplase → reduces long-term disability and death.
❑ Antiplatelet agents can be used in secondary prevention of
noncardioembolic stroke. The options:
✓ Aspirin 50-325 mg daily
✓ Clopidogrel 75 mg daily
✓ Aspirin 25 mg + extended-release dipyridamole 200 mg twice daily
 Treatment: anticoagulation

❖ Currently, data are inadequate to support the routine use of heparin

or other anticoagulants in the acute management of ischemic stroke
❖ Patients with embolic stroke with other indication for
anticoagulation (e.g atrial fibrillation) → may receive therapy
nonemergently as secondary prevention → the potential benefit
should be weighed against the risk of hemorrhage
❖ Immobilized stroke patients incresed risk of deep venous
thrombosis → recommended to use low molecular weight heparin
or low dose unfractionated heparin (eg enoxaparin SC)
 Treatment: blood pressure control

❑ Elevated BP should remain untreated in the acute period (first 7 days) after
ischemic stroke → avoid decreasing cerebral blood flow & worsening
symptoms
❑ For patients who are not candidates for fibrinolytric → moderate
hypertension is allowed. BP should be lowered if > 220/120 mmHg
❑ If there is evidence of aortic dissection, acute myocardial infarction,
pulmonary edema, or hypertensive encephalopathy → emergent BP
reduction.
❑ If BP is treated in the acute phase → short-acting parenteral agents (eg
labetalol, nicardipine, nitroprusside) are preferred. The goal is lowering BP
by 15% during the first 24 hr after stroke onset. Care must be taken not to
lower BP aggresively → worsen perfusion in the penumbra.
❑ Patients with elevated BP & are eligible for alteplase → BP carefully lowered
to <185/110 mmHg before starting alteplase
 Treatment : blood glucose control

❑ Persistent hyperglycemia during the first 24 hr of acute ischemic stroke

worse outcomes. Treat hyperglycemia (Fasting BGL >140 mg/dL or random
glucose consistently > 180 mg/dL to achieve blood glucose level/BGL 140-
180 mg/dL
❑ Persistent hyperglycemic patients receive standardized intravenous insulin
protocol to improve blood glucose control for at least the first 24 to 48 h of
hospitalization.
❑ They should then be transitioned to a subcutaneous insulin regimen that
includes basal long-acting insulin along with correction rapid-acting
insulin for glucose that is out of range.
❑ Caution and close glucose monitoring are necessary, especially for patients
prone to hypoglycemia, such as those with type 1 diabetes mellitus or hepatic
or renal impairment, or those on complicated feeding regimens.
❑ Hypoglycemia (BGL < 60 mg/dL) should be treated
 Treatment: seizure control

Seizures occur in 2-23% of patients within the first days after ischemic
stroke →usually focal but may be generalized
Primary prophylaxis for poststroke seizure is not indicated
Secondary prevention of subsequent seizures with standard
antiepileptic therapy is recommended.
Benzodiazepines (typically diazepam and lorazepam) are the first line
drugs for ongoing seizures. → should be augmented by longer-acting
anticonvulsants (eg phenytoin, phenobarbital)
 Treatment: cerebral edema control

Signicant cerebral edema after ischemic stroke is rare (10-20%).

Maximum severiy of edema is typically reached 72-96 hrs after stroke
onset.
Mannitol & other therapies to reduce intracranial pressure may be
used in emergency situation → yet their usefulness in swelling
secondary to ischemic stroke is unknown.
No evidence exists supporting the use of corticosteroids to decrease
cerebral edema in acute ischemic stroke
 Non-pharmacologic therapy:
mechanical thrombectomy

❖ Mechanical clot disruption is an alternative for patients in whom

fibrinolysis is ineffective or contraindicated.
❖ The guideline recommends thrombectomy in eligible patients 6-16
hours after a stroke.
 Monitoring

Neurologic function (motoric, verbal)

Vital signs (BP, heart rate, temperature)
Electrolytes abnormalities
Rhythm abnormalities → ECG
Bleeding signs → complete blood count including INR if on
anticoagulant
Liver function (ALT, AST, bilirubin)
Renal function (ureum, creatinine)
 Prevention
Primary
➢ Antiplatelet (recommended only in
patients with at least 6-10% risk of
cardiovascular events over 10 yr
➢ Statins
➢ Smoking cessation
➢ Life style interventions (low fat low salt
diet, exercise, weight loss)
Secondary
❖ Anti-hypertensives
❖ Diabetes control
❖ Intense statin therapy (reduce LDL at
least 50%
❖ Antiplatelet for non-cardioemboli
cause (aspilet 50-325 mg daily or
clopidogrel 75 mg/day or aspilet 20
mg + dipyridamole ER 200 mg
twice/day)
❖ Anticoagulant for cardioemboli cause
(warfarin as first line or dabigatran
150 mg twice/day)
❖ Smoking cessation
❖ Life style interventions
 Definition & Stages
According to National Kidney Foundation/Kidney dialysis
Outcome and Quality Initiative (NKF/KDOQI), chronic Kidney
disease (CKD) is defined as:
1. Kidney damage for ≥ 3 months, as defined by structural or
functional abnormalities of the kidney, with or without
decreased glomerular filtration rate (GFR), manifest by either:
• Pathophysiological abnormalities
• Markers of kidney damage including abnormalities in the composition of
the blood or urine, or abnormalities in imaging test
OR
2. GFR < 60 ml/min/1.73 m2 for ≥ 3 months, with or without
kidney damage.
Symptoms are generally absent in
CKD stages 1-2, dan may be
minimal during stages 3-4.

General symptoms associated with

stages 1-4: edema, cold
intolerance, shortness of breath,
fatigue, depression, muscle pain,
palpitations and sexual
dysfunction
CKD: Management of
Complications
 Complications: Pathophysiology

• Progression of CKD to ESRD occurs over years to decades

• However, the complications of marked reductions in kidney function are
fairly uniform irrespective of the underlying etiology.
• Accumulation of several toxins particularly uremic toxins ultimately results
in altered organ and immune function and leads to a number of secondary
complications: fluid & electrolyte abnormalities, anemia of CKD,
metabolic acidosis, cardiovascular diseases, secondary
hyperparathyroidism and renal osteodystrophy.
 Treatment Focus:

1. Delaying or halting the CKD progression

2. Diagnosing and treating the CKD manifestations
3. Timely planning for long-term renal replacement therapy (RRT)
 Treatment Focus #1: Delaying/halting CKD progression

• Treatment of the underlying condition if possible

• Blood pressure control
• Treatment of hyperlipidemia
• Glycemic control
• Avoidance of nephrotoxin (e.g., non-steroidal anti-inflammatory
drugs/NSAIDs, aminoglycosides, IV radiocontrast etc)
 Treatment of Hyperlipidemia
• The prevalence of hyperlipidemia increased as renal function declines
• The use of statin is recommended in adults > 50 and older with stage 1-5
CKD not on dialysis
 Treatment Focus #2: Diagnosing and treating the CKD
manifestations
• Anemia
• Electrolyte abnormalities (e.g., hyperkalemia)
• Metabolic and bone disorders (e.g., hyperphosphatemia, hypocalcemia,
hyperparathyroidism)
• Metabolic acidosis
• Volume overload
• Uremia
• Cardiovascular risk
 Management of Anemia
With erythropoietic-stimulating agent (ESA e.g., epoetin alfa, dabepoietin
alfa) → Target of Hb level 10-12 g/dL → normalization of HB level
associated with increased risk of adverse outcomes.
Before starting ESA → check iron stores → target iron saturation 30-50%
and ferritin 200-500 ng/mL.
Initiate ESA in CKD patients with Hb between 9-10 g/dL
Iron deficiency is the primary cause of resistance to treatment of anemia
iron → supplementation is required by most CKD patients. Iron status
should be reassessed every month during initial ESA and every 3 months
for those on a stable ESA regimen.
Hb should be monitored at least monthly or more frequently after
initiation of ESA and dose change until Hb is stable.
ESAs are well tolerated → hypertension is the most common adverse
event
Algoritma Terapi ESA
 Management of Bone & Mineral Disorder (MBD)
• CKD-MBD are common and include abnormalities in parathyroid hormone
(PTH), calcium-phosphorus,, vitamin D, bone turnover, soft tissue
calcifications.
• Calcium-phosphorus balance is mediated through a complex interplay of
hormones and their effects on bones (e.g., PTH), gastrointestinal tract,
kidneys.
• As kidney disease progresses → renal activation of vit D is impaired →
reduces gut absorption of calcium → hypocalcemia stimulates secretion of
PTH
• As renal function declines → serum calcium balance can be maintained
only at the expense of increased of bone resorption → renal
osteodystrophy
• Secondary hyperparathyroidism is associated with increased morbidity
and mortality in hemodialysis patients
 CKD-MBD: phosphate-binding agents/phosphate binders

• Phosphate binders decrease phosphorus absorption from the gut and are
first line agents for controlling both serum phosphorus and calcium level.
• Elemental calcium from calcium-containing binders should not exceed
1500 mg/day and the total daily intake from all sources should not exceed
2000 mg/day.
• Combination of calcium and non-calcium containing phosphate binders
(e.g., sevelamer HCl, lanthanum carbonate) may be necessary to avoid
hypercalcemia.
• Adverse effects of all phosphate binders are limited to GI effects
(constipation, diarrhoea,nausea, vomiting, abdominal pain)
• Aluminium (CNS toxicity and worsening of anemia) & magnesium binders
(hypermagnesemia, hyperkalemia) are not recommended for regular use
in CKD
 CKD-MBD: Vit D therapy
• Reasonable control of calcium and phosphorus must be achieved before
initiation and during continued vit D therapy
• Calcitriol (1,25-dihydroxyvitamin D3) directly suppresses PTH synthesis
and secretions and upregulates vitamin D receptors.
• The newer vit D analogues paricalcitol and doxercalciferol may be
associated with less hypercalcemia and hyperphosphatemia..
Vitamin D Agents
 Other CKD Manifestations

• Volume overload → treat with loop diuretics or dialysis

• Uremia → dialysis
• Metabolic acidosis → bicarbonate supplementation (e.g., sodium
bicarbonate)
• Hypocalcemia: Treat with calcium supplements with or without calcitriol
• Hyperkalemia: diuretic, potassium binder
 Cardiovascular risk
Guidelines issued in December 2013 by the Kidney Disease: Improving Global
Outcomes (KDIGO) workgroup recommend wider statin use among patients with CKD.
Specific recommendations include the following [77, 78] :
• Adults aged ≥50 years with GFR < 60 mL/min/1.73 m 2 who are not being treated
with long-term dialysis or kidney transplantation should be treated with a statin or
a statin plus ezetimibe
• Adults aged 18-49 years with GFR < 60 mL/min/1.73 m 2 who are not being treated
with dialysis or kidney transplantation should be treated with statins if they have
coronary disease, diabetes, prior ischemic stroke, or an estimated 10-year
incidence of coronary death or nonfatal myocardial infarction exceeding 10%
• Adults aged 50 years or older with CKD and GFR of 60 mL/min/1.73 m2 or higher
should be treated with a statin
• Adult kidney transplant patients should be treated with a statin because of an
increased risk for coronary events
• Treatment with statins or statin/ezetimibe should not be initiated in adults with
dialysis-dependent CKD (increase risk of coronary artery calcification) , but
patients already being treated with a statin at the time of dialysis should continue
Treatment Focus #3: Renal Replacement Therapy/ RRT (Hemodialysis,
Peritoneal Dialysis, Renal Transplant)
Indications for RRT:
• Severe metabolic acidosis
• Uremia
• Refractory Hyperkalemia
• Pericarditis
• Encephalopathy
• Uncontrollable volume overload
• Failure to thrive and malnutrition
• Peripheral neuropathy
• Uncontrollable gastrointestinal symptoms
• In asymptomatic adult patients → GFR 5-9 ml/min/1.73 m2 irrespective of
the casue of CKD or the presence/absence of other comorbidities.
Seorang ibu hamil mengalami hipertensi dengan tekanan darah
160/90 mmHg. Apa terapi hipertensi yang tepat?
A. Kaptopril
B. Nifedipn
C. Losartan
D. Propanolol
E. Furosemid
Wanita (62 tahun) didiagnosis gagal jantung selama 1 tahun dan
hipertensi selama 10 tahun. Kondisi ini tidak terkontrol sehingga
dibutuhkan tambahan terapi kombinasi. Apa obat yang
dikontraindikasikan pada pasien tersebut?
A. Metoprolol
B. Furosemid
C. Verapamil
D. Lisinopril
E. Valsartan
Seorang pasien didiagnosis hipertensi dan dokter berencana
memberikan kaptopril. Informasi apa yang harus disampaikan
apoteker terkait pemberian obat tersebut?
A. Diminum 30 menit sebelum makan
B. Diminum segera setelah makan
C. Diminum saat makan
D. Diminum 30 menit setelah makan
E. Diminum kapan saja
Pria (45 tahun) sudah 1 minggu mengkonsumsi obat
antihipertensi. Pasien tersebut mengeluhkan bagian
payudaranya membesar. Apa obat antihipertensi yang
menyebabkan kelhan tersebut?
A. Furosemid
B. Spironolakton
C. Kaptopril
D. Bisoprolol
E. Propanolol
Nyonya A (56 tahun, BB 78 kg, TB 165 cm) datang ke poli penyakit dalam dengan
keluhan pusing, lemas, mual, tidak nafsu makan, volum urin berkurang. Riwayat
penyakit: hipertensi, hiperkolesterolemia dan DM tipe 2. Pasien juga didiagnosis
penyakit ginjal kronik

Pengobatan yang sedang digunakan: verapamil 180 mg 1x/hari, gliklazid 80 mg

2x/hari, atorvastatin 40 mg 1x/hari. Pemeriksaan tekanan darah: 166/110 mm/Hg

Hasil pemeriksaan laboratorium menunjukkan hasil: kreatinin 6.8 mg/dL (0.7-1.3

mg/dL)

Berapakah klirens kreatinin pasien tersebut?

A. 56.20 ml/menit
B. 37.79 ml/menit
C. 12.25 ml/menit
D. 11.38 ml/menit
E. 7.09 ml/menit
Nyonya A (56 tahun, BB 78 kg, TB 165 cm) datang ke poli penyakit dalam dengan
keluhan pusing, lemas, mual, tidak nafsu makan, volum urin berkurang. Riwayat
penyakit: hipertensi, hiperkolesterolemia dan DM tipe 2, penyakit ginjal kronik.
• Hb 9.6 g/dL (11-18)
• kreatinin 6.8 mg/dL (0.7-1.3 mg/dL)
• Ureum 90 mg/dL (20-40 mg/dL)
• Natrium 138 mmol/L (135-150 mmol/L)
• Kalium 6.1 mmol/L (3.5-5 mmol/L)
• Fosfat 8.7 mg/dL (2.5-4.9)
• Kalsium 10.3 mg/dL (8.-10.2)
Apakah terapi untuk menurunkan kadar fosfat Nyonya A?

A. Menambahkan kalsitriol
B. Menambahkan kalsium karbonat
C. Menambahkan natrium bikarbonat
D. Menambahkan aluminium hidroksida
E. Menambahkan kation resin pengganti
Nyonya A (56 tahun, BB 78 kg, TB 165 cm) datang ke poli penyakit dalam dengan
keluhan pusing, lemas, mual, tidak nafsu makan, volum urin berkurang. Riwayat
penyakit: hipertensi, hiperkolesterolemia dan DM tipe 2, penyakit ginjal kronik.
• Hb 9.6 g/dL (11-18)
• kreatinin 6.8 mg/dL (0.7-1.3 mg/dL)
• Ureum 90 mg/dL (20-40 mg/dL)
• Natrium 138 mmol/L (135-150 mmol/L)
• Kalium 6.1 mmol/L (3.5-5 mmol/L)
• Fosfat 8.7 mg/dL (2.5-4.9)
• Kalsium 10.3 mg/dL (8.-10.2)
Bagaimana mengatasi kondisi uremia yang dialami pasien?
A. Menaikkan dosis hidroklorotiazid
B. Menambahkan allopurinol
C. Melakukan dialisis
D. Menghentikan atorvastatin
E. Menambahkan pengikat fosfat
Nyonya A (56 tahun, BB 78 kg, TB 165 cm) datang ke poli penyakit dalam dengan
keluhan pusing, lemas, mual, tidak nafsu makan, volum urin berkurang. Riwayat
penyakit: hipertensi, hiperkolesterolemia dan DM tipe 2, penyakit ginjal kronik.
• Hb 9.6 g/dL (11-18)
• kreatinin 6.8 mg/dL (0.7-1.3 mg/dL)
• Ureum 90 mg/dL (20-40 mg/dL)
• Natrium 138 mmol/L (135-150 mmol/L)
• Kalium 6.1 mmol/L (3.5-5 mmol/L)
• Fosfat 8.7 mg/dL (2.5-4.9)
• Kalsium 10.3 mg/dL (8.-10.2)
Apakah rekomendasi Anda sebagai Apoteker untuk membantu mengatasi abnormalitas
kadar kalium pasien?

A. Menurunkan dosis furosemid

B. Menambahkan lanthanum karbonat
C. Menambahkan resin penukar kation
D. Menghentikan pemberian furosemid
E. Menambahkan diuretik spironoakton
Pasien dengan penyakit ginjal kronis (PGK) rentan mengalami anemia. Salah satu
pengobatan anemia pada pasien PGK adalah dengan pemberian erytropoietin
stimulating agent (ESA). Efektivitas ESA ditentukan kecukupan zat besi dalam tubuh
pasien. Jika pasien mempunyai feritin >600 ng/mL dan Hb 9.2 mg/dL, bagaimana tata
laksana pengobatan anemia selanjutnya?
A. Pemberian suplemen zat besi secara oral
B. Pemberian suplemen zat besi secara intravena
C. Pemberian Erythropoietin stimulating agent
D. Pemberian transfusi darah
E. Penundaan erythtopoietin stimulating agent
Paska kejadian stroke iskemik pasien terkadang mengalami disabilitas yang dapat
menyebabkan berkurangnya mobilitas pasien. Komplikasi karena mobilitas yang
berkurang adalah resiko terjadinya trombosis vena dalam (DVT). Apakah terapi
profilaksis untuk mencegah komplikasi tersebut pada pasien resiko tinggi mengalami
DVT?
A. Heparin
B. Klopidogrel
C. Aspilet
D. Alteplase
E. Streptokinase
Pasien pria (48 tahun) didiagnosis menderita angina pektoris
datang ke apotek dengan membawa resep:
R/ Isosorbid dinitrate tab 5 mg No XXX
s.t.d.d.I
Informasi apa yang harus diberikan oleh apoteker terkait cara
penggunaan obat?
A. Tablet langsung ditelan
B. Tablet dikunyah terlebih dahulu baru ditelan
C. Tablet dilarutkan dahulu
D. Tablet disisipkan di pipi
E. Tablet disisipkan di bawah lidah
Seorang pria yang didiagnosis angina dan infark miokard yang
mengalami kenaikan segmen ST. Pasien diberikan fondaparinux
sebagai antitrombotik. Apa yang harus dimonitor selama
penggunaan obat tersebut?
A. Tekanan darah
B. Saturasi oksigen
C. Perdarahan
D. Kecepatan pernafasan
E. Kreatinin
Pasien Wanita (48 tahun) mengalami mati rasa pada tangan dan
kaki kiri serta tidak dapat menggerakkan Sebagian badannya
sejak 2 jam yang lalu. Pasien didiagnosis stroke iskemik. Apa obat
yang paling sesuai?
A. Alteplase
B. Warfarin
C. Aspirin
D. Heparin
E. Rivaroksaban
Apakah obat antihipertensi yang memiliki efek samping
konstipasi?
A. Verapamil
B. Furosemid
C. Hidroklorotiazid
D. Amlodipin
E. Metildopa
Apakah obat antihipertensi yang dapat meningkatkan nilai
kolesterol total dan trigliserida?
A. Asebutolol
B. Bisoprolol
C. Prazosin
D. Nadolol
E. Labetalol
Seorang pasien mengkonsumsi spironolaktok. Efek samping yang
mungkin dialami adalah…
A. Renal arteri stenosis
B. Takiaritmia
C. Hiperkalemia
D. Hipokalemia
E. Hipotensi ortostatik
Pada suatu pagi, seorang pasien yg menderita hipertensi terjatuh
saat bangun tidur. Obat antihipertensi apa yang berpotensi
menyebabkan kejadian tersebut?
A. Nifedipin
B. Verapamil
C. Prazosin
D. Metildopa
E. Labetalol
Seorang pria (68 tahun) didiagnosis hyperplasia prostat jinak.
Pasien memiliki Riwayat hipertensi. Obat apa yg
direkomendasikan untuk mengatasi hyperplasia prostat dan
sebagai antihipertensu?
A. Furosemid
B. Tiazid
C. Propanolol
D. Terazosin
E. Amlodipin
Seorang Wanita hamil yang mengalami eclampsia dan kejang
dibawa ke UGD. Apa obat yang disarankan apoteker kepada
dokter UGD?
A. Fenitoin
B. Karbamazepin
C. Magnesium sulfat
D. Asam valproate
E. Diazepam
Seorang Wanita (29 tahun) sedang hamil dengan usia kandungan
28 minggu diperiksa oleh dokter di klinik dan diketahui tekanan
darahnya mencapai 158/100 mmHg. Pasien juga mengeluh
pusing. Untuk mengetahui pasien menderita preeklampsia atau
tidak, data laboratorium apa yang diperlukan untuk pemeriksaan
penunjang?
A. Serum kreatinin
B. Hitung darah lengkap
C. ALT/AST
D. Kadar feritin
E. Protein urin
Dokter memberikan warfarin kepada pasien. Pengujian
laboratorium apa yang perlu dimonitor?
A. SGOT
B. Kreatinin
C. Masa protrombin
D. INR
E. BUN
 TATA LAKSANA
• Terapi yang digunakan untuk pasien dipengaruhi oleh hasil evaluasi
riwayat kesehatan serta mental pasien.
• Untuk melakukan pengobatan pada pasien dengan gangguan depresi
mayor, ada 3 tahapan yang harus dipertimbangkan antara lain :
➢Fase akut: fase ini berlangsung 6 sampai 10 minggu. Pengobatan pada fase ini
bertujuan untuk mencapai masa remisi (tidak ada gejala).
➢Fase lanjutan: fase ini berlangsung selama 4 sampai 9 bulan setelah mencapai
remisi. Pengobatan pada fase ini bertujuan untuk menghilangkan gejala sisa
atau mencegah kekambuhan kembali.
➢ Fase pemeliharaan: fase ini berlangsung 12 sampai 36 bulan. Pengobatan
pada fase ini tujuannya untuk mencegah kekambuhan kembali.

Mayasari, 2013 ; Direktorat 2007

 Terapi Non Farmakologis

• Psikoterapi adalah terapi pengembangan yang digunakan untuk

menghilangkan atau mengurangi keluhan – keluhan serta mencegah
kambuhnya gangguan pola perilaku maladatif.
• Teknik psikoterapi tersusun seperti teori terapi tingkah laku, terapi
interpersonal, dan terapi untuk pemecahan sebuah masalah.

Mayasari, 2013 ; Direktorat 2007

Terapi Farmakologi

Marwick K, 2013
Terapi Farmakologi

• Antidepresan Trisiklik
• Antidepresan Tetrasiklik
• Selective Serotonin Reuptake Inhibitor (SSRI)
• Serotonin /Norepinephrin Reuptake Inhibitor ( SNRI)
• Monoamin Oxidase Inhibitor
• Mekanisme obat obat anti depresi adalah :
• Menghambat reuptake aminergic neurotransmitter
• Menghambat penghancuran oleh enzim monoamine oxidase

Peningkatan jumlah aminergic transmitter pd sinaps neuron di SSP.

• Antidepresan Trisiklik (TCA)
Mekanisme kerjanya menghambat pengambilan kembali amin biogenik spt Epinefrin,
Serotonin dan dopamin didalam otak,
Tidak lagi digunakan sebagai obat lini pertama, karena efek sampingnya
Efek samping yang sering efek kolinergik seperti mulut kering, sembelit, penglihatan
kabur, pusing, takikardi, ingatan menurun, dan retensi urin.
Obat – obat yang termasuk
a.l : Amitripilin, Clomipramine, Doxepin, Imipramine, Desimipramine, Nortriptyline.

Kontraindikasi :
Miokard Infark, aritmia (terutama blok jantung), mania.
Penggunaan bersamaan dengan MAOI
• Antidepresan Tetrasiklik
Mekanisme kerjanya sebagai antagonis pada presinaptic α2 – adrenergic
autoreseptor dan heteroreseptor, sehingga meningkatkan aktivitas
nonadrenergik dan seratonergik.
Bermanfaat untuk pasien depresi dengan gangguan tidur dan kekurangan
berat badan.
Efek samping yang ditimbulkan berupa mulut kering, peningkatan berat
badan, dan konstipasi.
Obat – obat yang termasuk golongan Tetrasiklik
a.l : Maproptilin, Mianserin, Amoxapine
Selective Serotonin Reuptake Inhibitor (SSRI)
• Batas keamanan lebar
• Meningkatkan serotonin ekstraseluler
• Diterima sebagai obat lini pertama.
• Mekanisme kerjanya menghambat pengambilan serotonin yang telah
disekresikan dalam sinap (gap antar neuron)
• Obat antidepresan yang termasuk dalam golongan SSRI al :
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, dan
Sertraline.
Selective Serotonin Reuptake Inhibitor (SSRI)
• Fluoxetine merupakan antidepresan yang memiliki waktu paro yang
lebih panjang, sehingga fluoxetine dapat digunakan satu kali sehari.

• Efek samping yang ditimbulkan Antidepresan SSRI yaitu gejala

gastrointestinal (mual, muntah, dan diare), disfungsi sexsual pada pria
dan wanita, pusing, dan gangguan tidur
Serotonin / Norepinephrin Reuptake Inhibitor (SNRI)
• mekanisme kerjanya memblok monoamin dengan lebih selektif
Antidepresan golongan SNRI memiliki aksi ganda dan efikasi yang
lebih baik dibandingkan dengan SSRI dan TCA dalam mengatasi remisi
pada depresi berat.
• Obat yang termasuk golongan SNRI yaitu Venlafaxine dan Duloxetine.
• Merupakan second line jika pasien tidak respon dengan SSRI
• Efek samping
- Venlafaxine : mual, disfungsi sexual.
- Duloxetine : mual, mulut kering, konstipasi, dan insomnia.
Mono Amin Oxidase Inhibitor ( MAOI )
• Suatu enzim komplek yang terdistribusi didalam tubuh, yang digunakan dalam
dekomposisi amin biogenik (norepinefrin, epinefrin, dopamin, dan serotonin).
MAO bekerja memetabolisme NE dan serotonin untuk mengakhiri kerjanya dan
supaya mudah disekresikan. Dengan dihambatnya MAO, akan terjadi peningkatan
kadar NE dan serotonin di sinap, sehingga akan terjadi perangsangan SSP.
• Moclobomida merupakan suatu obat baru yang menginhibisi MAO – A secara
ireversibel, tetapi apabila pada keadaan overdosis selektivitasnya akan hilang.
Selegin secara selektif memblokir MAO – B
• Obat – obat yang tergolong dalam MAOI al : Moclobemide, Phenelzine,
Tranylcypromine, dan Selegiline.
• Efek samping : postural hipotensi, penambahan berat badan, gangguan sexual
 Initial Dose Final Dose Amnesia, Arrhythmia
Generic name Hypotensive potential Sedative potential Precautions Advantages
(mg) (mg) potential

Tricyclic Antidepressan (TCA)

Therapeutic window 80-
May be fatal in overdose,
Nortriptyline 10-25 25-100 Moderate Moderate Moderate 120 ng/ml
glaucoma, prostatic disease

May be increased suicidal

Amitriptiline 25 - 50 300 Moderate High High thinking, bone -

marrow suppresion
Selective Serotonin Reuptake Inhibitors (SSRIs)
Side effects not life-
Prolonged T ½, nausea tremor, threatening,
Fluoxetine 10 20-40 Low Low Low insomnia, drug interactions liquid
available

Few drug interactions,

FDA-approved for
Sertralin 25 100-200 Low Low Low Nausea, tremor, insomnia PD, OCD,
PTSD

Mild sedative effect,

Nausea, tremor,
Paroxetine 10 20-40 Low Low Low FDA- approved for PD,
drug
OCD, social phobia
interaction
s

Few drug interactions, T ½

Citalopram 10 20-40 Low Low Low Nausea, tremor, insomnia
longer than sertraline
 Selective Norepinephrine Reuptake Inhibitor (SNRI)
Mild hypertentive, Anxiolytic SSRI &
headache, nausea, SNRI, fewer drug
vomiting, do not interactions,
Venlafaxine 37.5 75-225 Low Low Low
stop abruptly, not extended release
for hypertentives prep, FDA- approved
fo GAD.
Anxiolitic, for

Dopaminergic, aphathetic

noradrenergic, depression, when

Bupropion 75 150-300 low low low TCA/SSRI fail,
agitation, insomnia,
seizures, dose should sustained release

be divided preparation
available
 Terapi fase akut biasanya berlangsung
selama 6-10 minggu
Follow Up dan
Pemantau Terapi fase lanjutan pada umumnya
berlangsung selama 6-9 bulan setelah
pasien dimulainya masa remisi
Depresi
Terapi fase pemeliharan dilakukan
selama 12-36 bulan untuk mengurangi
resiko terjadinya rekurensi hingga 2/3
 Jenis Obat Antidepresan, Dosis dan Efek Samping

Nama Obat Dosis Efek Samping

Harian
(mg)
SSRI
Escitalopram 20-60 semua SSRI bisa
Fluoksetin 10-40 menimbulkaninsomnia,
agitasi, sedasi, gangguan
Sertralin 50-150
saluran cerna dan disfungsi
Fluvoksamin 150-300 seksual
Trisiklik/Tetrasiklik
Amitriptilin 75-300 antikolinergik
Maprotilin 100-225
Imipramin 75-300
 Nama Obat Dosis Efek Samping
Harian (mg)
SNRI
Duloksetin 40-60 mengantuk, kenaikan BB,
Venlafaksin 150-375 hipertensi,gangguan saluran cerna
RIMA
150-300 pusing, sakit kepala, mual, berkeringat,
Moklobemid mulut kering, matakabur

NaSSA
Mirtazapin 15 - 45 somnolen, mual
SSRE
12.5 – 37.5 somnolen, mual, gangguan
Tianeptin kardiovaskular

Melatonin Agonis
Agomelatin 25 - 50 sakit kepala
Migraine
 Definition

The word migraine comes from the Greek “hemicrania”→

unilateral headache
According to the International Headache Society (IHS) →
migraine is an idiopathic recurring headache disorder
manifesting in attack lasting 4 to 72 hr
Some migraine sufferers also experience a variety of visual
sensations that precede or accompany the pain of
migraine attack →migraine with aura
 Classification

Migraine

Common Classical
Complicated
migraine migraine
migraine
(Without aura) (with aura)
 Pathophysiology

Traditional hypothesis (vascular hypothesis) says that the

primary causes of migraine alterations in cranial vessel
diameter and blood flow
It was thought that focal neurologic symptoms preceding or
accompanying the headache were caused by vasoconstriction
and reduction in cerebral blood flow
Recent evidence suggests that the pain of migraine is generated
centrally and involved episodic dysfunction of neural structure
that control the circulation (the trigeminovascular system)
 Pathophysiology of migraine with aura
A migraine with aura is characterized by visual disturbances such as flashes of
light, zig-zagging patterns or even blind spots
The aura is due to changes that take place in the cortex of the brain
The nerve cells of the brain are always active and can be seen through
electroencephalogram (EEG). The EEG shows a depression (lowering) of nerve
cell activity below a spot on the cortex of the brain that has been stimulated
Surrounding the area of depressed activity is a zone in which nerve cells have
become hyperactive that may result in flashing lights or tingling in the face
and hand
When the activity of nerve cells is depressed → there is impairment of
function in the part of the body controlled by these cells i.e there may be a
loss of vision
The depression of nerve cell activity slowly spreads
beyond the initial spot of stimulation →account for the
gradual development of the aura
For example, the patient may first notice a black spot in
the field of vision which is often surrounded by flashing
lights or bright zig-zag lines. The size of the black spot
gradually enlarges over a period of minutes.
The combination of loss of vision (negative symptoms)
with flashing lights or zig-zag lines (positive symptoms)
is a typical features of migraine aura
The negative symptoms →due to depressed nerve
activity and the positive visual symptoms are due to the
zone of hyperactive nerve cells
 Clinical Presentations

o Head pain
• Head pain may be either unilateral or bilateral and the
pain need not recur on the same side if unilateral
• The quality of migraine head pain usually begins as a
dull ache that intensifies over a period of minutes or
hours to a throbbing headache which worsens with
each arterial pulse
• If untreated →the headache lasts from several hours to
as long as 3 days or until the patient goes to sleep. The
pain is usually intense enough to interfere with daily
activities
 Clinical Presentations……………

o Sensitivity to light (photophobia) and sound

(phonophobia)
o The nausea with or without vomiting. Vomiting is
occasionally followed by a gradual resolution of migraine
symptoms
o Visual disturbances are the most common feature of
migraine aura. They include scotoma (blind spot), zigzag
lines that gradually float across field of vision, flashes of
light and loss of vision.
Precipitating factors
 Treatment
Before starting treatment →it is essential to exclude other
causes of headache i,.e abnormal neurological examination
and drugs that can cause headache
The aims of drug use may encompass relief of headache &
associated symptoms and prevention of recurrent migraine

Treatment

Acute migraine/ Prevention/

Abortive Prophylactic
treatment treatment

Nondrug Drug Nondrug Drug

 Acute Migraine Treatment

• Non drug treatment includes rest or sleep in a dark and quiet

room, relaxation techniques ,i.e yoga, may be of benefit

Acute migraine
drug treatment

5-HT1 agonists
Analgesics Antiemetics Ergot alkaloids
(Triptans)
 Analgesics

Ensure analgesics are taken in sufficient dosage and early

in the attack before nausea and reduction of GI motility
may slow absorption and reduce efficacy
NSAIDs (i.e ibuprofen, naproxen) and paracetamol may be
beneficial
Avoid opioids (including combination of paracetamol or
aspirin with codeine or dextropropoxypene) → aggravate
GI symptoms, have a risk of dependence, little evidence
for effectiveness in acute migraine
 Antiemetics

Antiemetics alone may be effective in relieving the headache of

migraine and when combined with other treatment for
migraine → additional analgesic effect
They work by reducing nausea and vomiting, increased GI
motility and improve absorption of analgesics
Example : metoclopramide, domperidone, prochlorperazine
Metoclopramide or domperidone may be used orally at the
onset of symptoms and then every 6-8 hr if needed
When nausea and vomiting are prominent, metoclopramide
(IM/IV) or prochlorperazine (IM/IV/per rectal) may be used
 5-HT1 Agonists (Triptans)
Mode of action : constrict cranial vessels by acting selectively at 5-HT1B/1D
receptors , inhibit the abnormal activation of trigeminal nociceptors and
attenuate the release of neuropeptides with inflammatory and
vasoconstricting properties i.e substance P
Triptans relieve headache in 50-75% of people approximately 2-4 hrs after
oral administration.
Triptans are most effective to relieve headache if taken when the headache is
beginning to develop, and not earlier (e.g during aura) or later (when
headache more severe).
They also improve associated symptoms such as nausea, vomiting,
photophobia and phonophobia
These agents have the potential to cause coronary arterial vasoconstriction →
contraindicated in patients with uncontrolled hypertension, coronary artery
disease, transient ischaemic attack (TIA) and peripheral vascular disease
 Triptans…………..

They are well tolerated relative to other agents used for

abortive treatment →initial therapy for patients with
moderate to severe migraine
Example : sumatriptan, naratriptan, zolmitriptan
There is no evidence that any particular triptan is safer to
another although the response to each agent can vary
considerably between patients
 Ergot Alkaloids

❖ Mode of action : block inflammation of the trigeminal

neurovascular system by inhibiting the release of
neuropeptides, constrict arterial and venous vessel and
act as agonists at 5-HT1B/1D receptors
❖ Ergot alkaloids should be taken at the onset of a migraine
attack. If administration is delayed until the headache is
firmly established →rarely effective
❖ Example : ergotamine and dihydroergotamine
 Ergot Alkaloids

❖ Ergotamine is only available combined with caffeine to improve

intestinal ergotamine absorption and potentiate the pain relief
property of analgesics
❖ Ergotamine can be used orally or rectally while
dihydroergotamine is both given SC or IM due to poor oral
absorption
❖ Contraindications: coronary, cerebral or peripheral vascular
disease, uncontrolled hypertension, sepsis, hyperthroidism.
❖ The use of ergot alkaloids is limited by adverse effects (i.e
peripheral vasoconstriction, nausea, vomiting), lack of evidence
regarding effective doses and associated with high risk of
overuse syndrome and rebound headache
 Algorithm/drug choice for acute migraine

✓ First line drug for mild to moderate migraine is usually an

analgesic such as paracetamol or NSAIDs
✓ If analgesic use is consistently ineffective or if migraine is severe
→use migraine specific agents where the first line agents are
triptans and possibly ergot alkaloids.
✓ Alternative migraine-specific drugs may be tried over
subsequent episodes to identify the most effective agents for a
particular patient
✓ Consider adding an antiemetic agent for nausea and vomiting
and for those who do not respond to an analgesic alone
 Abortive Medication Stratification by Headache Severity

Moderate Severe Extremely Severe

NSAIDs Naratriptan DHE (IV)
Isometheptene Rizatriptan Opioids
Ergotamine Sumatriptan (SC,NS) Dopamine antagonists
Naratriptan Zolmitriptan
Rizatriptan Almotriptan
Sumatriptan Frovatriptan
Zolmitriptan Eletriptan
Almotriptan DHE (NS/IM)
Frovatriptan Ergotamine
Eletriptan Dopamine antagonists
Dopamine antagonists
DHE=Dihydroergotamine; NSAIDs=nonsteroidal anti-inflammatory drugs,
NS=intranasal
Prevention/prophylactic treatment
 The criteria for migraine prophylaxis :

1. Headaches that impact a patient’s life despite the use of

abortive treatment
2. Headaches occurring so frequently that abortive
medications are overused (2-3 attacks/month)
3. Disabling headaches that are unresponsive to abortive
treatment
4. Patients in whom abortive agents are contraindicated
5. Headaches that present a significant risk for future
morbidity or mortality →complicated migraine
 The benefit of prophylactic treatment
• Reduce the severity of ensuing headache
• Reduce the duration of headaches or headaches become
more responsive to abortive treatment

Prophylactic
treatment

Other agents :
Antidepressant Anticonvulsant
Β-blockers Methysergide,
i.E amitriptyline i.e Valproate,
verapamil
 Β-blockers

The proposed mechanism of actions may be related to

their high affinity for serotonin receptors
Β-blockers with no intrinsic sympathomimetic activity can
be effective in decreasing the frequency of migraine attack
Β-blockers used for migraine attack : propanolol, timolol,
atenolol and metoprolol
Therapeutic failure with one Β-blockers does not predict
response to another →consecutive trial of different drugs
might be appropriate
 Antidepressants
It may be the drug of choice for migraine patients with
coexisting depression
Amiptriptyline is the most widely used antidepressants
The mechanism of amitriptyline antimigraine effect is
independent of its antidepressant activity and may be
related to its ability to block the reuptake of serotonin
at central sites
Start with a low dosage at bedtime (10-25 mg) and
gradually increase at weekly intervals by 10-25 mg until
the maximum dose of 150 mg is reached
However, most patients achieve optimal benefit from
50-75 mg/day
Common side effects : sedation, orthostatic
hypotension, dry mouth, blurred vision, reflex
tachycardia, weight gain
 Anticonvulsant i.e valproate

There is consistent evidence for the effectiveness of

antiepileptic drug valproate in reducing migraine
frequency
The initial dosage is 250 mg orally twice a day → then
increase up to the usual effective dose (50-1500 mg/day)
Common adverse effects : nausea, alopecia, tremor and
weight gain
Its use in women of child-bearing potential is limited by
the risk of congenital malformation
 Algorithm for prophylaxis

✓ First line drugs are beta blockers and amitriptyline, valproate is

second line. Other drugs can be used but their use is limited by
weak evidence and/or serious adverse effects
✓ The choice of treatment involves balancing clinical response
and tolerability as well as considering coexisting diseases for
which the drug may also be of benefit (i.e beta blocker for
migraine patient with hypertension)
✓ Treatment for acute attacks will still be required as preventive
therapy only reduces frequency and severity of attack. In
addition, it also may take 1-3 mth for showing the full effect
 Algorithm for prophylaxis……..

✓ Use only 1 prophylactic agent at a time. Start at a low dose

and increase gradually up to the lowest effective dose. If
the drug is effective →continue for 4-6 mth and then to
assess if it is still required →gradually withdraw over 2-3
weeks
✓ Longterm prophylaxis may be necessary in some patients
but evidence of benefit is weak
 Case Study
L is a 35-year-old woman with a 10-year history of migraines. The frequency of
her migraines has increased from one to two–three attacks per month, and they
seem to be triggered by sleep deprivation and stress.. She has history of
intermittent asthma and takes salbutamol inhaler prn for treating asthma attack.
She presents to her GP with a 24-hour history of unilateral severe throbbing
headache which is associated with photophobia, nausea and vomiting (three
times in 24 hours). As discussed previously with her GP, her initial self-
management is aspirin (soluble) 900 mg and metoclopramide 10 mg orally with a
repeated dose of aspirin 600 mg every 4 hours. L has had no symptom relief from
the aspirin. L has been unable to attend work or care for her due to the severe
attacks .On examination she looks pale and tired. Blood pressure is 120/75
mmHg, heart rate regular at 70 beats per minute.
a. What is your recommendation for treating her acute migraine?
b. After managing the acute migraine, would you recommend
preventive/prophylactic drug therapy for her? If yes, what do you
recommend?
c. Mention two non-pharmacological approaches that you would discuss with
her to assist in managing her migraine?
Seorang pemuda mengkonsumsi kombinasi ergotamine dan
kafein untuk mengatasi migrain yang dideritanya. Apa tujuan
kombinasi obat tersebut?
A. Meningkatkan aktivitas ergotamine
B. Menurunkan aktivitas ergotamine
C. Menghilangkan efek samping
D. Menghilangkan withdrawal syndrome
E. Meningkatkan kepatuhan pasien
Contraceptives & Menstrual
Disorder
• The menstrual cycle is regulated by the complex interaction of hormones: luteinizing
hormone, follicle-stimulating hormone, and the female sex
hormones estrogen and progesterone.
• The menstrual cycle has three phases:
Follicular (before release of the egg)
Ovulatory (egg release)
Luteal (after egg release)
• The menstrual cycle begins with menstrual bleeding (menstruation), which marks the
first day of the follicular phase.
• When the follicular phase begins, levels of estrogen and progesterone are low. As a
result, the top layers of the thickened lining of the uterus (endometrium) break down
and are shed, and menstrual bleeding occurs. About this time, the follicle-stimulating
hormone level increases slightly, stimulating the development of several follicles in the
ovaries. Each follicle contains an egg. Later in this phase, as the follicle-stimulating
hormone level decreases, only one follicle continues to develop. This follicle
produces estrogen.
• The ovulatory phase begins with a surge in luteinizing hormone and follicle-
stimulating hormone levels. Luteinizing hormone stimulates egg release (ovulation),
which usually occurs 32 to 36 hours after the surge begins. The estrogen level peaks
during the surge, and the progesterone level starts to increase.
• During the luteal phase, luteinizing hormone and follicle-stimulating hormone levels
decrease. The ruptured follicle closes after releasing the egg and forms a corpus
luteum, which produces progesterone. During most of this phase, the estrogen level is
high. Progesterone and estrogen cause the lining of the uterus to thicken more, to
prepare for possible fertilization. If the egg is not fertilized, the corpus luteum
degenerates and no longer produces progesterone, the estrogen level decreases, the
top layers of the lining break down and are shed, and menstrual bleeding occurs (the
start of a new menstrual cycle).
• Oral contraceptive pills are either combined estrogen-progesterone(also called
combined oral contraceptive pill- COC) or progesterone-only pill (POP).
• The most commonly prescribed pill is the combined hormonal pill with estrogen
and progesterone.
• The main contraceptive efficacy of COCs is suppression of ovulation by inhibition
of gonadotropin-releasing hormone (GnRH) from the hypothalamus, as well as
inhibition of both luteinizing hormone (LH) and follicle-stimulating hormone
(FSH), and disruption of the mid-cycle LH surge. These effects are mediated by
both the progestin and estrogen component of the COC working synergistically, but
it is estrogen's ability to suppress FSH and thus prevent folliculogenesis that is
likely the most important mechanism.
• The usual estrogen component is combined with a different generation of progestin
components with varying degrees of androgenic and progestogenic potential. The
combination is prescribed based on desirable effects and risk of adverse events with
progestin component and dose of estrogen and progestin component.
✓ Estrogen component: Estradiol, Ethinylestradiol, or Estetrol
✓ First-generation progestin: Norethindrone acetate, Ethynodiol diacetate,
Lynestrenol, Norethynodrel
✓ Second generation progestin: Levonorgestrel,dl-Norgestrel
✓ Third generation progestin: Norgestimate, Gestodene, Desogestrel
✓ Unclassified progestin: Drospirenone, Cyproterone acetate
 Choice of Combined Oral Contraceptives
• Usually, Ethinyl estradiol dose is less than 50 mcg in this combination of
pills. The pills can be either monophasic (same dose of both components in
the active pills) or multiphasic (varying doses weekly of both or either
component in the active pills).
• Depending on withdrawal bleeding desired by the patient and clinically
recommended, it can be prescribed as a cyclic (monthly bleeding),
extended cyclic (every three months bleeding), or continuous dosing(no
bleeding).
• Cyclic formulations: The cyclic formulations have active hormone pills
for 21-24 days, followed by 7-4 days of hormone-free pills.
• Extended cycle formulations: extended cycle formulations have active
hormone pills every day for three months, followed by a placebo week.
• Continous use formulation: can be manipulated by using the only active
pills from monthly formulations for one year period, which will
functionally stop all menstrual bleeding. The most common complication
from the extended cycle is break-through bleeding. Any formulation of a
combined oral contraceptive pill can be used in this manner, but typically
the monophasic pills are the easiest to manipulate.
• Initiation: Combined oral contraceptive pills are to be taken daily at
approximately the same time each day. Avoid taking them greater
than 24 hours apart as this could affect efficacy.
• There are two methods of initiating COC for women per their
priority as follow:
1. First-day start: Pills are started on the first day of menses, and this
is considered the best strategy as it attains contraceptive efficacy faster
than other methods.
2. Quick start: Pills are started on any day medicine is given to
women. When patients initiate this method, they are not protected from
pregnancy in the first seven days, and an additional form of birth
control is recommended.
• Missed doses: If a patient misses a tablet, take the missed tablet as
soon as they remember and the next tablet at the usual time (taking
two pills in 1 day). If the patient misses two tablets in a row in the
first or second week, take two tablets the day the patient remembers
and two pills the next day, then resume 1 per day. Use additional
forms of contraception until the patient begins a new cycle
 Progesterone only Pill (POP)
• While multiple types of progestin pills are available, most
frequently formulations have drospirenone or
norethindrone.
• Drospirenone suppresses ovulation and also has anti-
mineralocorticoid activity.
• While norethindrone primarily acts by thickening cervical
mucus to inhibit sperm penetration, suppressing
ovulation, decreasing the mid-cycle LH and FSH peaks,
which slows the movement of the ovum through fallopian
tubes, and alters endometrium thickness.
• Some progestin compounds have more potent
antiandrogenic properties and, therefore more effective in
treating polycystic ovary syndrome, hirsutism, and acne.[
• Initiation: The pill must be taken at the same time each day to
maximize contraceptive efficacy. Use backup contraception if the
patient starts POPs more than five days from the onset of menses. It
can be started on any day of the menstrual cycle, but
recommendations exist to begin on the first day of menses. Use a
backup contraceptive (e.g., condoms) method for the first 48 hours
following initiation if POP is started within the first five days of
menses.
• Missed dose: Women who miss taking a norethindrone POP dose by
more than three hours or had vomiting or severe diarrhea within
three hours of taking a POP are advised to take the missed pill as
soon as they remember and the next tablet at the scheduled time.
Use of additional contraception (e.g., condoms) for 48 hours after
the late dose is also recommended.