Transcript of Hi Poli Pide Mik
OBAT HIPOLIPIDEMIKDepartment of Pharmacology
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology
Cholesterol
Department of Pharmacology
Structure of Lipoproteins
*
Lipoproteins are macromolecular aggregates of lipids and
apolipoproteins. Lipids can be divided into two main groups, simple
and complex. The two most important simple lipids are cholesterol
and fatty acids. Lipids become complex lipids when fatty acids
undergo esterification to produce esters.1-3
Simple lipids Cholesterol is a soft waxy substance present in all
cells of the body. Most tissues can produce cholesterol, but it is
synthesised primarily in the liver and small intestine.
Approximately 50% of the cholesterol requirement is synthesised,
whilst the rest is obtained from animal produce in the diet.
Cholesterol is important in the repair of cell membranes and in the
synthesis of steroid hormones, vitamin D and bile acids. Fatty
acids are the simplest form of lipid found in the body and are an
important energy source. They exist as saturated, monounsaturated
and polyunsaturated forms, distinguished by the number of bonds
between the hydrocarbon chain and carbon atoms. The most common
fatty acids in the body are stearic and palmitic (saturated), and
oleic (monounsaturated). Fatty acids exist freely in the plasma
mostly bound to albumin, but are stored in adipose tissue as
triglycerides.1-3
Complex lipids Triglycerides are mainly stored in adipose tissue
and are the main lipid currency of the body. Phospholipids are
glycerol esters containing two fatty acids. They have a
water-soluble and a lipid-soluble surface and are an important
component of the cell membrane. Cholesterol esters, oleate and
linoleate, are the storage molecules of cholesterol in
cells.1-3
Apolipoproteins In order for these water-insoluble lipids to be
transported around the body in the the aqueous medium, blood, they
are aggregated with apolipoproteins to form lipoproteins. These
multimolecular packages consist of a hydrophobic core containing
cholesteryl esters and triglyceride, surrounded by a hydrophilic
surface layer of phospholipids, proteins and some free cholesterol.
While structurally similar, lipoproteins vary in their proportions
of component molecules and the type of proteins present.1-3
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A.
Health Press Ltd, Oxford, 2000. 1–17.
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall
H. Williams & Wilkins, US, 1999. 2-10.
3. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective.
Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1-19.
Faculty of Medicine University of Riau
Department of Pharmacology
Classification of Lipoproteins
Based on density:
*
There are five major classes of lipoproteins based on their
density. The degree to which lipoproteins cause atherosclerosis
depends to some extent on their size, and thus their ability to
enter and form deposits within the arterial wall. Thus, smaller
VLDL, IDL and LDL are all atherogenic, whereas large VLDL and
chylomicrons are not. HDL, largely by its ability to carry
cholesterol away from the arterial wall, is anti-atherogenic.
Chylomicrons are the largest in size, lowest in density and are not
associated with atherosclerosis. They are synthesised in the
intestinal mucosal cells after a fatty meal. They transport dietary
triglyceride from the intestine to the sites of use and storage,
and are cleared rapidly from the bloodstream, generally being
undetectable 12 hours after a meal.1,2
VLDL are similar in structure to chylomicrons but are smaller. They
are produced in the liver and are the main carriers of endogenous
(synthesised in the liver rather then dietary) triglycerides and
cholesterol to sites for use or storage. As they are also involved
in the synthesis of LDL, VLDL are implicated in atherosclerosis
development.1,2
IDL are highly atherogenic. They are formed during the breakdown of
VLDL and chylomicrons and are also implicated in atherosclerosis
development. They contain less triglyceride and more cholesterol
than VLDL, and are involved in the recycling of cholesterol by the
liver as well as formation of LDL in the blood.1,2
LDL are generated from IDL in the circulation and are the principal
lipoproteins involved in atherosclerosis. Oxidised LDL is the most
atherogenic form of LDL. They are the main carriers of cholesterol,
accounting for 60–70% of plasma cholesterol. They comprise four
main subtypes: LDL I, II, III and IV, of which LDL-III is the most
atherogenic subclass.1,2
HDL are the smallest but most abundant of the lipoproteins. They do
not cause atherosclerosis, but actually protect against its
development. This is because they return about 20–30% of
cholesterol in the blood to the liver from peripheral tissue for
excretion. They also inhibit the oxidation of LDL and they decrease
the attraction of macrophages to the artery wall. There are two
main subtypes: HDL2 and HDL3.1,2
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A.
Health Press Ltd, Oxford, 2000. 1–17.
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall
H. Williams & Wilkins, US, 1999. 2–10.
Faculty of Medicine University of Riau
Department of Pharmacology
transpor TG makanan ke jaringan lemak & otot
transpor kolesterol dari makanan ke hati
VLDL:
IDL:
Faculty of Medicine University of Riau
Department of Pharmacology
transpor kolesterol ke jaringan perifer (untuk sintesis membran
plasma dan hormon steroid)
HDL:
penting untuk bersihan TG & kolesterol
transpor kolesterol dari perifer ke hati
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology
*
The exogenous metabolic pathway is concerned with the transport and
utilisation of dietary fats. Dietary fat is broken down in the
gastrointestinal tract into cholesterol, fatty acids and mono- and
diglycerides. These molecules, together with bile acids, form
water-soluble micelles that carry the lipid to absorptive sites in
the duodenum.1
Normally, virtually all triglyceride (TG) is absorbed, compared
with only 50% of cholesterol. Following absorption in the duodenum,
chylomicrons are formed which enter the bloodstream via intestinal
lymphatics and the thoracic duct. On entering the plasma, rapid
changes take place in the chylomicron. It is hydrolysed by the
enzyme lipoprotein (LP) lipase releasing the triglyceride core,
free fatty acids and mono- and diglycerides for energy production
or storage. The residual chylomicron undergoes further
delipidation, resulting in the formation of chylomicron remnants.
These are taken up by a number of tissues. In the liver they
undergo lysomal degradation, and are either used for a variety of
purposes including remanufacture into new lipoproteins, production
of cell membranes or excretion as bile salts.1
Reference
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A.
Health Press Ltd, Oxford, 2000. 1–17.
1.bin
Department of Pharmacology
Lipid
Synthesis
*
Whilst chylomicrons transport triglyceride from the gut to the
liver, VLDL is the analogous particle that transports triglycerides
from the liver to the rest of the body. Triglycerides together with
cholesterol, cholesteryl ester and other lipids are transported in
VLDL in the bloodstream, where VLDL undergoes delipidation with the
enzyme lipoprotein lipase in a similar way to chylomicrons; this is
the endogenous pathway of lipid metabolism. During this process,
triglyceride is removed from the core and exchanged for cholesterol
esters, principally from HDL. Whilst most VLDL is transformed into
LDL, the larger VLDL particles are lipolysed to IDL, which is then
removed from the plasma directly. Lipoprotein lipase is the main
enzyme used in the lipolysis of large VLDL particles, whereas
hepatic lipase reacts with the small VLDL and IDL particles.1 IDL
is highly atherogenic.
The product of this metabolic cascade, LDL, exists in the plasma in
the form of a number of subfractions; LDL I–IV. It has been shown
that small dense LDL particles are the most atherogenic. They are
absorbed by macrophages within the arterial wall to form lipid-rich
foam cells, the initial stage in the pathogenesis of
atherosclerotic plaques.1
The enterohepatic circulation provides a route for the excretion of
cholesterol and bile acids.1
Reference
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A.
Health Press Ltd, Oxford, 2000. 1–17.
2.bin
Department of Pharmacology
*
As cholesterol cannot be broken down within the body, it is
eliminated intact. It is transported via HDL from the peripheral
tissues to be excreted by the liver. HDL begins as a
lipid-deficient precursor which transforms into lipid-rich
lipoprotein. In this form it transfers cholesterol either directly
to the liver or to other circulating lipoproteins to be transported
to the liver for elimination.1
The observation that HDL acts as a vehicle for the transport of
cholesterol for elimination has led to the identification of HDL as
a protective factor against the development of
atherosclerosis.1
Reference
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A.
Health Press Ltd, Oxford, 2000. 1–17.
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology
hiperlipoproteinemia poligenik/multifaktorial faktor genetik +
faktor lingkungan
Hiperlipidemia sekunder
Department of Pharmacology
Classification of Dyslipidaemias:
Fredrickson (WHO) Classification
in the Fredrickson classification.)
Prevalence
Rare
Common
Common
Intermediate
Common
Rare
Adapted from Yeshurun D, Gotto AM. Southern Med J
1995;88(4):379–391
Phenotype
I
IIa
IIb
III
IV
V
Lipoprotein
elevated
Chylomicrons
LDL
*
The Fredrickson classification was the first classification of
dyslipidaemias. It was based on the analysis of plasma for various
lipoprotein fractions, but took no account of the underlying
aetiology of any of the dyslipidaemias. In addition, high-density
lipoprotein (HDL) cholesterol levels are not considered in this
classification.1 Today it is more common to identify the
dyslipidaemias by the particular lipoprotein or apolipoprotein that
is abnormal. Once dyslipidaemia has been identified it is important
to determine the cause where possible. Dyslipidaemia may be
secondary to other disorders or a primary abnormality. Common
causes of secondary dyslipidaemia include: diabetes mellitus, the
nephrotic syndrome, chronic renal failure, hepatobiliary disease
(generally of the obstructive variety) and hypothyroidism. It
should be recognized that these cause some but not all
dyslipidaemias. For example, diabetes can lead to elevation of
triglyceride-rich lipoproteins and reduction of HDL, but does not
necessarily increase the levels of LDL. On the other hand,
hepatobiliary disease is associated with an increase in the levels
of LDL. Of the primary causes of dyslipidaemia, the most severe
forms are caused by genetic disorders of lipoprotein metabolism.
The most easily identifiable in clinical practice are familial
hypercholesterolaemia (FH), polygenic hypercholesterolaemia and
familial combined hypercholesterolaemia, all of which increase the
risk of premature development of CHD. Patients presenting with
severe forms of hypercholesterolaemia should undergo family
screening to detect other family members for therapy.2
FH is an autosomal dominant disease with defects in the gene for
the LDL receptor. In its heterozygous form, it is present in about
1/500 of the population. It is a highly variable disorder, with the
age of onset of CHD ranging from 30–70 years for patients with the
same LDL-C levels at diagnosis, and with a poor prognosis when
using older lipid-modifying drugs. Women with FH tend to develop
CHD 10–15 years later than male siblings with the identical
LDL-receptor mutation.3
Therapy of these disorders is directed towards aggressive
management of hypercholesterolaemia with a target LDL-C that
depends on the overall coronary risk of the affected person.3
References
1. Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391.
2. National Cholesterol Education Program. Circulation
1994;98(3):1333–1445.
3. Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology
Dyslipidemia and Atherosclerosis
Elevated triglycerides
Elevated LDL cholesterol (LDL-C) with increased small, dense LDL
particles
Concomitant endothelial dysfunction leads to atherosclerosis:
Fatty deposits or plaques in blood vessels with blood flow
Local remodeling with Inflammatory process
Responsible for major complications (CHD)
*
Dyslipidemia and Atherosclerosis
Atherosclerosis is responsible for almost all cases of CHD,
beginning with fatty streaks which progress into plaques,
culminating in thrombotic occlusions and coronary events in middle
age and later life.
Raised total plasma cholesterol levels and certain other lipid
abnormalities, or dyslipidemias, are associated with increased risk
of CHD. The typical characteristics of atherogenic dyslipidaemia
include elevated plasma triglycerides levels and a low plasma HDL
cholesterol concentration, both of which are independent risk
factors for CHD. These abnormalities usually coincide with
increased circulating levels of atherogenic, small, dense LDL
particles – which are not usually assessed in clinical
practice.
Fatty deposits also play an important role in the pathogenesis of
atherosclerosis and CHD. This may increase the penetration of
cholesterol-rich lipoproteins and atherogenic cells into the
endothelium (intima) promoting the formation of fatty deposits, or
so-called plaques.
In addition to the detrimental effect of increased circulating
blood lipids, smoking, hypertension and type 2 diabetes can also
impair endothelial action and promote coronary heart disease.
Obesity and a lack of exercise can also influence its progress:
exercise improves circulating HDL levels and obese patients have
elevated triglycerides.
Faculty of Medicine University of Riau
Department of Pharmacology
Intervensi farmakologis
Department of Pharmacology
VLDL dalam 2-5 hari terapi, diikuti oleh penurunan kolesterol &
LDL
Pada tipe IIa dan IIb terjadi penurunan LDL
Pada tipe III kolesterol turun 50%, TG 80%
Mobilisasi kolesterol dari jaringan (xantoma mengecil)
Mekanisme kerja: meningkatkan aktivitas lipoprotein lipase
meningkatkan katabolisme
Faculty of Medicine University of Riau
Department of Pharmacology
Cmax tercapai beberapa jam setelah p.o.
60% diekskresi melalui urin (glukoronid)
Faculty of Medicine University of Riau
Department of Pharmacology
Ruam kulit, alopesia, impotensi, leukopenia, anemia
Miositis (flu-like-myositis)
Batu empedu
Kontra Indikasi:
Faculty of Medicine University of Riau
Department of Pharmacology
Menurunkan TG plasma VLDL dan apoprotein B di hati berkurang
Meningkatkan aktivitas lipoprotein lipase
Department of Pharmacology
T ½ 1,5 jam
Metabolisme dengan hidroksilasi & konjugasi
Faculty of Medicine University of Riau
Department of Pharmacology
Kontra Indikasi:
Faculty of Medicine University of Riau
Department of Pharmacology
Bau dan rasa tidak enak
Hidrofilik tapi tidak larut dlm air
Tidak dicerna dan tidak diabsorpsi
Faculty of Medicine University of Riau
Department of Pharmacology
RESIN
KOLESTIRAMIN
Farmakodinamik
Menurunkan LDL yang nyata pada hari 4-7, maksimal dalam 2
minggu
Efek ~ dosis
Mempengaruhi sirkulasi enterohepatik sehingga ekskresi steroid yang
bersifat asam dalam feses meningkat
Faculty of Medicine University of Riau
Department of Pharmacology
Asidosis hiperkloremik
Department of Pharmacology
Menghambat absorpsi HCT, tiroksin, digitalis, besi
Pemanjangan PTT jika diberikan bersama antikoagulan
Faculty of Medicine University of Riau
Department of Pharmacology
Faculty of Medicine University of Riau
Department of Pharmacology
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
Menurunkan VLDL dan TG 25%; HDL meningkat 10-13%
Efektif untuk hiperkolesterolemia pada DM dan SN
Efek aditif dengan kolestiramin dan kolestipol
Menurunkan sintesis kolesterol di hati LDL plasma berkurang
Meningkatkan jumlah reseptor LDL katabolisme LDL meningkat sehingga
kadar LDL berkurang
Faculty of Medicine University of Riau
Department of Pharmacology
Cmax dicapai dalam 2-4 jam
Steady state setelah 3 hari
95% obat dan metabolit terikat protein plasma
Ekskresi sebagian besar oleh feses, <10% oleh urin
Faculty of Medicine University of Riau
Department of Pharmacology
Setelah 4 minggu dosis naik sampai maksimal 80 mg/hari
Faculty of Medicine University of Riau
Department of Pharmacology
ASAM NIKOTINAT (NIASIN)
FARMAKODINAMIK
Menurunkan produksi VLDL sehingga kadar IDL dan LDL juga akan
menurun
Menurunkan lipolisis di jaringan lemak sehingga FFA untuk sintesis
VLDL berkurang
Meningkatkan aktivitas lipoprotein lipase
Meningkatkan kadar HDL plasma
Department of Pharmacology
ASAM NIKOTINAT (NIASIN)
Gangguan GIT
Gangguan hati
Department of Pharmacology
ASAM NIKOTINAT (NIASIN)
DOC untuk semua jenis hipertrigliseridemia dan hiperkolesterolemia
(kecuali tipe I)
Posologi: 2-6 g/hari dalam 3 dosis dimulai 3x100-200 mg/hari, lalu
dinaikkan setelah 1-3 minggu
Faculty of Medicine University of Riau
Department of Pharmacology
Menurunkan kadar LDL dan HDL, sedangkan kadar TG tidak
berubah
Meningkatkan kecepatan katabolisme LDL lewat jalur non
reseptor
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
KI: pasien infark
Faculty of Medicine University of Riau
Department of Pharmacology
ES:
Department of Pharmacology
ES: gangguan GIT
Department of Pharmacology
Nicotinic acid is more effective at HDL-C raising than fibrates:
results of a meta-analysis
-40
-30
-20
-10
0
10
20
Birjmohun RS et al. J Am Coll Cardiol . 2005; 45: 185-97
Mean % change
Nicotinic acid (29–33 trials, n=2268–4749)
*
Nicotinic acid is more effective at HDL-C raising than fibrates:
results of a meta-analysis
A meta-analysis has compared the effects on lipids of fibrates and
nicotinic acid preparations (all available nicotinic acid
preparations were included in this analysis, so the results do not
necessarily predict the effectiveness of any single
preparation).
Nicotinic acid was more effective in raising HDL-C than the
fibrates, as would be expected, and also provided useful additional
efficacy on LDL-C. The larger effect of the fibrates on
triglycerides is consistent with the known therapeutic profiles of
these agents.
Birjmohun RS, Hutten BA, Kastelein JJ et al. J Am Coll Cardiol
2005;45:185-97
Faculty of Medicine University of Riau
Department of Pharmacology
Department of Pharmacology
Department of Pharmacology