Drugs use in dislipidemia

Elly Nurus Sakinah

HMG Co A reduktase Inhibitor• competitive inhibitors of HMG-CoA

reductase lack of cholesterol in hepatocytes→ ↑ syntesis of LDL-receptors in liver → ↑ uptake of cholesterol in liver

• Indication hyperlipoproteinemia with ↑LDL• Contraindication: pregnancy, lactation, children (limited

experience)• Pleiotropic effects → improvement of endothelial

dysfunction

• Anti-platelet action

• Block proliferation of endothelial smooth muscle

Adverse effect

• ↑ aminotransferases

and creatine kinase (need to be monitored!)

• Myositis of skeletal

muscles (up to 0.5% of

patients) ↑ creatinine

kinase from muscle

• Simvastatin metabolized only by CYP3A4 –↑ risk of interactions

• inhibition of CYP3A4 (by e.g. ketoconazole, makrolids, metronidazole, cimetidin) → Accumulation and signs of toxicity

• TERATOGENIC

RESIN

• Colestipol [Colestid],

Cholestyramine [Questran])

and Colesevelam [Welchol]

• Synthetic resins that bind bile

acids in the intestinal lumen

decreased return of bile

acids to liver

• increased synthesis of BA from

cholesterol (activation of cholesterol 7-

α-hydroxylase)→ increased uptake of

LDL in liver (up-regulation of LDL-

receptor)→ mobilization of cholesterol

from tissues and removal from plasma

• Used also in bile duct-obstruction (to ↓ BA concentration and pruritus)

EFEK SAMPINGFrequent and complicate the therapy

(patient compliance): Constipation,

flatulence

• Drug-drug interactions - bind to

other drugs and fat-soluble

vitamins , (malabsorption of vit. A,D,E

K) Take other medications at least

1 hour before or 4 to 6 hours after

EZETIMIBE• Inhibits gut absorption of all sterols (phyto- and chole-sterol)

→ decreased load of cholesterol to liver ↑ reseptor LDL• Dose: 10 mg oral dose alone or in

combination with statins.• Combination with statin more effective• Adverse effects:

• Headache, GIT dyscomfort• Potencially cancerogenic• Cannot be combined with BA-binding resins

NIACIN MA: ↓TAG synthesis (by up to 60 %) – not fully understood• Inhibition of VLDL secretion from liver → ↓ VLDL and consequently LDL, ↓

HDL clearance PK: water soluble, metabolized in liver, excreted by kidneyAE: typically: rash phenomenon

• Skin flare (flashing) and pruritus – can disappear later (feeling hot – can be lessened by ASA)

• 1/5 of patients - hyperurikemia

!!! Registered only in combination with laropiprant (PGD2 rcp antagonist) that blocks the rash phenomenon!!!

FIBRATES: fenofibrate, ciprofibrate, bezafibrate (gemfibrozil, clofibrate)

Mode of action: PPARα rcp agonists (Peroxisome Proliferator-Activator Receptor Alpha)

↓ VLDL production in liver and ↑ VLDL catabolism↑ HDL cholesterol

• ↑ expression and activity of lipoprotein lipase and ↑ β-oxidation of FA

• ↑ FA synthesis in liver (limits sythesis of TAG and VLDL)

• ↑ synthesis of apo A-I a A-II (cofactor of LCAT and component of HDL)

• ↓ synthesis of apo C-III rcp (inhibits lipoprotein lipase and uptake of TAG)

• Frequent combination with statins

Fibrat • Dose: oral dose 1 to 2 times per day gemfibrozil (600 mg) fenofibrate (67 mg),

• fenofibrate is more potent than gemfibrozil.• Statin-induced myopathy potentiated with gemfibrozil [avoid]. Fenofibrate is safer to use with statins

• AE:• nausea• Very rare - myopathy to rhabdomyolysis (most common with gemfibrozil, which is

not in use anymore), arrhythmia • Clofibrate – chronic toxicity (cholelithiasis, increased mortality)

Drug Classes used in Hyperlipidemia

Adult Treatment Guidelines (2001)

Treatment with drug combination

• When VLDL significance ↑ during Tx with resin• When LDL & VLDL ↑ initially• When LDL & VLDL ↑ with single dose• When HDL ↓

TERIMAKASIH

• Seorang laki-laki datang ke dokter dengan riwayat dyslipidemia. Saat ini pasien mengalami kenaikan kadar kolesterol total, LDL kolesterol dan kadar TG yang sangat tinggi. HDL Normal. Dokter akan memberika terapi untuk menurunkan TG dulu dengan monoterapi. Apakah terapi yang dipilih?

• Atorvastatine• Ezetimibe• Gemfibrozil• Niasin• Resin

• Seorang wanita datang ke dokter dengan riwayat dyslipidemia. Saat ini pasien mengalami kenaikan kadar kolesterol total, LDL kolesterol dan kadar TG. Pasien tersebut hamil 4 bulan. Apakah obat dyslipidemia yang harus dihindari?

• Fibrat• Niasin• Resin• Simvastatin• Ezetimibe

• Seorang wanita datang ke dokter dengan riwayat dyslipidemia. Saat ini pasien mengalami kenaikan kadar kolesterol total, LDL kolesterol dan kadar TG. Pasien tersebut hamil 4 bulan. Pasien tersebut diterapi dengan gemfibrozil. Bagaimanakan mekanisme kerja obat tersebut?

• Meningkatkan ekskresi garam empedu• Meningkatkan ekspresi reseptor LDL• Meningkatkan sekresi VLDL dari hepar• Meningkatkan aktivitas enzim LPL• Menurunkan uptake kolesterol dari makanan

• Seorang wanita datang ke dokter dengan riwayat dyslipidemia. Saat ini pasien mengalami kenaikan kadar kolesterol total, LDL kolesterol dan kadar TG. Pasien tersebut hamil 4 bulan. Pasien tersebut diterapi dengan gemfibrozil. Apakah efek samping dari obat tersebut?

• Konstipasi• Hiperurisemia• Kolelitiasis• Kerusakan hati• Aritmia

• Seorang laki-laki datang ke dokter dengan riwayat dyslipidemia. Saat ini pasien mengalami kenaikan kadar kolesterol total, LDL kolesterol dan kadar TG yang sangat tinggi. HDL Normal. Pasien memiliki riwayat hiperurisemia. Manakah obat berikut yang dapat mencetuskan serang gout pada pasien tsb?

• Ezetimibe• Colestipol• Gemfibrozil• Niacin• Simvastatin