□
Antihyperlipidemics
Tomáš Goněc 7.11.2011
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Major lipids in blood stream
□ Cholesterol and its esters
□ Triglycerides
□ Phospholipids
□ Excess of one or more of these fractions = hyperlipidaemia
Cholesterol
Desmolase
(side-chain cleavage enzyme)
Cholesterol
Progesterone (progestin)
Hydrocortisone (glucocorticoid)
Aldosterone
OH
Androstenedione (androgen)
OH
HO
Estradiol
Testosterone
Cholesterol biosynthesis
CH 1
° 2 rH   ' JOH        HMG CoA ?H2
_I 1 ctQr,e »   CH3 ?  0H -*- CH3-C-OH
-1    ch3^scoA      steps L^SCoA    reductase I
J XH2OH
Acetyl-CoA HMG CoA Mevalonic acid
(C2) (C6) (°6)
a
steps
Lanosterol
(C30)
Cholesterol
(C27)
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Cholesterol - hepatobiliar circulation
Cholesterol
several^ steps
return to liver
cooh
7"oh
Cholic acid (a bile acid)
conjugation oh'
COCH2COO Na
Glycocholate (a bile salt)
Lipoproteins and lipid circulation
Dietary Lipids
exogenous pathway
I
n
t
e
s
t
t
n e
Bile (cholesterol or bile salts}
Lipoprotein Lipase
Chylomicrons ) —^-C Remnants
, FFA
\
Adipose tissue' and muscle
endogenous pathway
Chdl>
Cvldl>
Lipoprotein lipase
LCAT
FC -*
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Hyperlipoproteinaemias
□ primary - result of genetic mutations / insufficiencies of APO-lipoproteins and their tissue receptors
□ secondary - result of isufficient biosynthesis of APO-lipoproteins and their tissue receptors Associated with diabetes II, hypothyroidism, renal and liver diseases
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Diseases and disorders caused by hyperlipoproteinaemias_
□ Coronary heart disease (myocardial infarction, ischemic heart disease, angina pectoris)
s
Role of LDL cholesterol in atherosclerosis
Uptake by scavenger macrophages
Bite acids, Cell membranes
Extrahepatic tissue
Steroid hormones, cell membranes
Formation of fatty streaks
Normal, nonharmful uses and transport of LDL cholesterol
Initial stages of atherosclerotic plaque formation
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Drugs affecting lipoprotein metabolism
□ bile acid sequestrants
□ HMGCoA reductase inhibitors
□ fibrates
□ niacin and its derivatives
□ often used in combination
Bile acid sequestrants
CH=CH2
CH=CH2
Styrene (X = H)
CH=CH2 Divinylbenzene
Precursors for cholestyramine
---CH-CH?-CHCH2—
yJ
CH2-HC--
CH2N(CH3)3
n
Cholestyramine
H,N'
H i
.N.
'N' H
H i
• N,
'NH,
Tetraethyienepentamine
CH2CI Epichlorhydrin
Precursors for colestipol
RHN
HN ^
CH2 HC-OH
CH2
R i
.N,
'N' i
R
1ST CH2 HC-OH CH2
R
,N,
NHR
NH
CH2 HC-OH
CH2 HN^ ^
N' H
-1 n
Colestipol R = H or epichlorhydrin cross link
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Bile acid sequestrants - mechanism of action_
□ basic nitrogens binds bile acids and together are excreted in the feces
□ lower uptake of bile acids leads to increased LDL receptor expression and increased liver uptake of LDL fraction
□ contraindicated in patients with cholelithiasis or biliary obstruction
□ minimal side effects - decrease oral absorption of some drugs and lipid soluble vitamins
HMGCoA reductase inhibitors
3,5-dihydroxy acid O       S<° 0-.....?:7H.....j
H°f^C02H 4 ><0H
H3C
in vivo
H3C7>
hydrolysis
B'
CH< 2'
Inactive pro-drug
Mevastatin (R = H) Lovastatin (R = CH3)
& 4'
Active form
H3c1    o      HMG CoA
S-CoA HMG CoA
Reductase
H3C L^OH
H
HMG CoA
-!
Reductase
HOV^C02H H3C k___OH
.-J
S-CoA Intermediate
Mevalonic acid
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HMGCoA reductase inhibitors
Lovastatin (R = H) Pravastatin Simvastatin {R = CH3)
Fluvastatin Atorvastatin Cerivastatin
HMGCoA reductase inhibitors: Structure-activity relationships
□ Two main structural types
a
H°f^C02H
5 .OH
^6
g c_
r2  ch3 • h
Ring system 7-substituted-3,5-dihydroxyheptanoic acid
Ring A
Ring B
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HMGCoA reductase inhibitors
□ rare but serious adverse effect: rhabdomyolysis (massive muscle necrosis) -life threatening state
□ clinical monitoring necessary
□ 2001Cerivastatin withdrawn from the market
Fibrates
=v        CH3/p /=. CH3p
a
Clofibrate Clofibrate acid
(ethyl p-chlorophenoxyisobutyrate) (p-chlorophenoxyisobutyric acid)
Ciprofibrate
Bezafibrate
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Fibrates
- structure-activity relationship
CH3/p
[Aromatic ring]-0-[Spacer group]—C-Cx
CH3 0H
□ essential isobutyric acid group
□ p-chloro substituted aromatic cycle prolongs biological half-time
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Fibrates - mechanism of action
□ not fully elucidated yet
□ PPARs (peroxyzome proliferator activated receptors) activators
□ decreases VLDL (significantly)
□ increases HDL (moderate)
□ variable effect on LDL
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Fibrates
□ serious adverse effects
□ long-term administration of clofibrate increases morbidity and mortality
□ all fibrates may cause myopathy and rhabdomyolysis
Nicotinic acid (niacin)
	Or1™ N	Or1™* N
N CH3		
Nicotine	Nicotinic acid	Nicotinamide
□ niacin is a nicotinic acid metabolite
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Nicotinic acid - mechanism of action
□ NA acts via its specific tissue receptor (NA receptor)
□ inhibits lipolysis in adipose tissue
□ decrease all lipid fractions (VLDL, triglycerides and LDL)
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Nicotinic acid - side effects
□ often side effects (20 - 50% patients)
□ flushing and pruritus
□ gastrointestinal intolerance