HYPOLIPIDEMIC AGENTS

Free cholesterol Apolipoprotein Phospholipid

TG
esterified
cholesterol
 PENYAKIT JANTUNG KORONER (PJK)
PENYEBAB SEKITAR SETENGAH DARI
KEMATIAN DI AS.
INSIDENSI PJK DIHUBUNGKAN PADA
PENINGKATAN KADAR KOLESTEROL
TOTAL, LDL & TRIASILGLISEROL
SERTA RENDAHNYA HDL
 KOMPOSISI
Liporotein Kilomikron (%) VLDL (%) LDL (%) HDL (%)

Trigliserida 80-90 45-65 4-8 2-7

Kolesterol 2-4 16-22 45-50 15-20

ester

Fosfolipid 3-6 15-20 18-24 26-32

Protein 1-2 6-10 18-22 45-55

KARAKTERISTIK HIPERLIPIDEMIA GENETIK YG
UTAMA
TIPE I TIPE II TIPE II TIPE III TIPE IV TIPE V
A B
HIPERTRIG
HIPERKILO HIPERLIPID DISBETALIP
HIPERKOLE HIPERTRIG LISERIDEMI
MIKRONEM EMIA OPROTEINE
STEROLEMI LISERIDEMI A
IA KOMBINASI MIA
A FAMILIAL A FAMILIAL CAMPURAN
FAMILIAL FAMILIAL FAMILIAL
FAMILIAL
PENINGKAT VLDL &
AN KILOMIKR VLDL &
LIPOPROTE
LDL IDL VLDL KILOMIKR
ON LDL
IN ON
TERAPI DIET DIET DIET DIET DIET DIET
RENDAH NIACIN NIACIN / NIACIN /
LEMAK KOLESTIRAM KOLESTIRAM & FENOFIBRAT FENOFIBRAT
TDK ADA IN & IN & FENOFI E E / STATIN
TX OBAT YG NIACIN NIACIN BRATE /
EFEKTIF /STATIN /STATIN STATIN
 Treatment goals
Strategy Target Concen-
tration of LDL
Primary prevention
Men < 35 years and premenopaused women < 190 mg/dl
Men > 35 years and women > 45 years < 160 mg/dl
with < 2 other CV risk factor
Adults with > 2 other CV risk factor < 130 mg/dl
Adults with diabetes mellitus or a strongly < 100 mg/dl
family history of early CV disease
Secondary prevention < 100 mg/dl
 Treatment goals
Therapy : 1. Secondary cause (hypothyroidism,
DM)
2. Dietary modification 3-6 months
3. Hypolipidemic agents
Choice :
Hypercholesterolemia : Bile acid sequestrants-
niacin-statins-gemfibrozil
Hypertriglyceridemia : Gemfibrozil-niacin-statins
 TUJUAN TERAPI
MENCEGAH PENYAKIT ATEROSKLEROTIK
MENCEGAH INFARK ULANG
OBAT HIPOLIPIDEMIK
RESIN ( SEKUESTRAN/TERIKAT ASAM EMPEDU)
DERIVAT ASAM FIBRAT
STATINS (HMG-CoA reductase inhibitors
Asam Nikotinat / NIASIN
PROBUCOL
PENGHAMBAT ABSORPSI KOLESTEROL INTESTINAL
SEKUESTRAN/TERIKAT ASAM EMPEDU
(RESINS)
Penghambat
absorpsi lemak
Paling aman
karena tdk
diabsorpsi saluran
cerna
Aman digunakan
pd anak
MEKANISME AKSI
 Results
Cholesterol content dlm hati

HMG-CoA reductase inhibition


Cholesterol synthesis
LDL receptors

Net results :
- LDL catabolism in liver plasma cholesterol
- Compensatory increases in cholesterol and TG
synthesis
Results

Lipid Research Clinic Primary Prevention

Trial (1984) cholestyramine monotherapy : 12%
reduction of LDL and 19% reduction in CAD.
However, total mortality was unchanged.
 S.E.
Constipation, flatulence, nausea, vomiting, poor
palatability
SGOT , AP , hyperchloremic acidosis,
hypoprothrombinemia
Impair absorption of drugs: tetrasiklin, digoxin,
furosemide, gemfibrozil, niacin, thiazides, warfarin,
NSAIDs, aspirin, vitamins A,D,E,K etc. give other
drugs 1 h before or 4 hs after resins. Resins
administration with meals.
 Indication

Hyperlipoproteinemia (type II)

Homozygous familial hypercholesterolemia
Hypertriglyceridemia
Probably safe for pregnant and lactating
women, children (but pay attention to fat
sol. vitamins availability)
Reduce pruritus in partial biliary
obstruction.
 DERIVAT ASAM FIBRAT
FENOFIBRATE & GEMFIBROZIL
MENURUNKAN KADAR TRIASILGLISEROL
SERUM & MENINGKATKAN HDL
FENOFIBRATE EFEKTIF DIBANDINGKAN
GEMFIBROZIL DALAM PENURUNAN KADAR
KOLESTEROL PLASMA & TG
 Kinetics
Oral
TX TIPE III, IV & V yang tdk berespon terhadap diet /
obat lain
Highly bound to protein (90-95%) : ALBUMIN
Enterohepatic circulation
Elimination : kidney
* Fenofibrate : prodrug => ASAM FENOFIBRAT
* Gemfibrozil : homolog of clofibrate
22% reduction in death from CHD or non fatal MCI
1st line treatment of hypertriglyceridemia
2nd line treatment other hyperlipidemias
S.E.
GI tract
Rash, alopecia
Myositis = peradangan otot volunter
(bezafibrate)
Interaksi obat : Antikoagulan (Coumarin)

Lithogenicity index shg mudah

terbentuk batu empedu (LITIASIS)
 Indication
Hypertriglyceridemia
FA : - TG (25-60%)
- Cholesterol (5-25%)
- HDL (10-20%)
- LDL (10-20%) or (5-20%)

Hypercholesterolemia (type II b) DM, nephrotic

syndrome
Dysbetalipoproteinemia (type III)
Contraindication
Pregnancy, lactation
Liver, kidney diseases
Anticoagulants
 STATINS
(HMG-CoA reductase inhibitors

Penghambat sintesis kolesterol

Statins (lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, cerivastatin)
Competitive inhibitors of HMG-CoA reductase
cholesterol synthesis (modest)
LDL receptors
 FARMAKODINAMIK
Menghambat sintesis kolesterol dlm hati
Menghambat enzim HMG-CoA reductase
Penurunan sintesis kolesterol ini
Terjadi peningkatan sintesis reseptor LDL
LDL, VLDL dan IDL jg menurun
sedangkan HDL meningkat
45 study (Scandinavian Simvastatin Survival
Study Group, 1994)
Total cholesterol 25%
LDL 35%
TG 10%
HDL 8%

42% reduction in mortality from CHD

30% reduction in mortality from all causes
Kinetics

Oral : absorption varies, 12% (atorvastatin),

> 90% (fluvastatin)
All except cerivastatin undergo extensive first
pass metab. target : liver
Lovastatin & simvastatin : prodrug
 ATORVASTA FLUVASTAT LOVASTATI PROVASTAT ROSUVAST SIMVASTAT
KARAKTERI
TIN IN N IN ATIN IN
STIK
REDUKSI
LDL SERUM
YG 50 24 34 34 50 41
DIHASILKAN
(%)
REDUKSI TG
SERUM YG
29 10 16 24 18 18
DIHASILKAN
(%)
PENINGKATA
N HDL
SERUM YG 6 8 9 12 8 12
DIHASILKAN
(%)
T PLASMA
14 1-2 2 1-2 19 1-2
(JAM)
PENETRASI
TIDAK TIDAK YA TIDAK TIDAK YA
SSP
EKSKRESI
DOSIS YG
DIABSORPSI 2 <6 10 20 10 13
OLEH GINJAL
(%)
Indications
Hypercholesterolemia (heterozygous
familial hypercholesterolemia / type II
hyperlipoproteine-mia and polygenic
forms)
Statin kecuali ATORVASTATIN DAN
ROSUVASTATIN diberikan malam hari
 S.E.
Liver function , SGPT > 3x stop therapy
Liver function monitoring 4-6 weeks (11/2 years)
Myophaty, rhabdomyolisis CPK >10 x normal
X combination with cyclosporine, gemfibrozil, niacin,
erythromycin, imidazole antifungals
Skin rash, GI complaints
Contraindication
Premenopausal women
KEHAMILAN
MENYUSUI
ANAK DAN REMAJA
Asam Nikotinat / NIASIN
 Asam Nikotinat
Meningkatkan HDL (30-40%)
Efek hipolipidemik dosis lebih besar
dbandingkan efek sbg vitamin
Kinetics
Oral : rapid & complete
First-pass metabolism
t 1/2 : 45 min.
Distribution : all tissues
Excretion : kidney
Indications :
1st line agent for hypertriglyceridemia and
hypercholesterolemia kecuali tipe I
Type III, IV, & V hyperlipoproteinemia
 S.E.
Flushing, pruritus, dryness, hyperpig-
mentation
Liver dysfunction : AP , SGPT , SGOT
GI complaints
Atrial fibrillation, ventricular ectopy
Glucose intolerance, uric acid
Contraindications :
Peptic ulcer
 PROBUCOL

M.A. : LDL (not TG), antioxidant

HDL
Indication : type IIA hypercholesterolemia
Side effects : - GI complaints
- Odorous perspiration
- Blood abnormality
- Liver dysfunction
 PENGHAMBAT ABSORPSI
KOLESTEROL INTESTINAL
Ezetimibe (azetidione-based cholesterol
absorption inhibitor)

M.A. : block intertinal absorption of chol.

total cholesterol and LDL-C

Kinetics : glucorunidation in intestine

active metabolic bile
(enterohepatic circulation) t : 22
h
Studies :
10 mg daily LDL-C 19%
20 mg simvastatin + 10 mg ezetimibe LDL-
C 52%
~ 80 mg simvastatin
margin of safety
Indications :
Primary hypercholesterolemia
Homozygous familial hypercholesterolemia
S.E. :
- Not a substrate for cytochrome P450
- Reversibly impaired hepatic function
- Liver function test every 2-4 mo.
Others
Neomycin, activated charcoal, psyllium
hydrophilic mucilloid, -sitosterol, D-
thyroxin
THANK YOU