anti-hypercholesterolemic agents biosynthesis and metabolism of cholesterol what is...
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Anti-Hypercholesterolemic AgentsAnti-Hypercholesterolemic Agents
Biosynthesis and Metabolism of Cholesterol What is arteriosclerosis?
- Link between arteriosclerosis and cholesterol Lipoproteins particles
- Structure and classification of lipoprotein particles Hyperlipidemias
- Types and overall strategy to control hyperlipidemias Anti-hyperlipidemic Agents
- Classes Statins Fibrates Bile Acid Sequestrants Nicotinic Acid Ezetimibe
Biosynthesis of CholesterolBiosynthesis of Cholesterol
CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA
O
O
OH
CH3 acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA
HMG CoAreductase
CH3
CH3
CH3
CH3
CH3
OH
cholesterol
-OOC-CH2-C-CH2-CH2-OH
OH
CH3 mevalonate
Metabolism of CholesterolMetabolism of Cholesterol
CH3
CH3
CH3
OH
CH3
CH3
CH3
CH3
CH3
OH R7H
R12 R
O
CH3
CH3
CH3
OH
O
CH3
CH3
CH3
O
O
cholesterolcholic acids; R7 and R12 = H or OH; R = OHglycocholic acid R7 = R12 = OH; R = NHCH2COOHtaurocholic acid R7 = R12 = OH; R = NHCH2CH2SO3H
pregnenolone
Liver
Liver, tissues
progesterone
ArteriosclerosisArteriosclerosis
Arteriosclerosis is excessive formation and deposition of endogeneous products from blood.
In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%.
Lipoprotein ParticlesLipoprotein Particles
Structure
Lipoprotein ParticlesLipoprotein Particles
Classification of lipoprotein particles
Composition Density Size
Chylomicrons TG >> C, CE Low Large
VLDL TG > CE
IDL CE > TG
LDL CE >> TG
HDL CE > TG High Small
Transport of Lipoprotein ParticlesTransport of Lipoprotein Particles
LIVERINTESTINE EXTRA-HEPATICTISSUE
Dietary fatBile AcidsCholesterol
Chylomicrons
VLDL IDL LDL
HDL
Lipoprotein lipase
Free fatty acids adiposetissue
Lipoprotein lipase
Free fatty acids adiposetissue
LCAT
LDL
LDL-R
LIVERINTESTINE EXTRA-HEPATICTISSUE
Dietary fatBile AcidsCholesterol
Chylomicrons
VLDL IDL LDL
HDL
Lipoprotein lipase
Free fatty acids adiposetissue
Lipoprotein lipase
Free fatty acids adiposetissue
LCAT
LDL
LDL-R
HyperlipidemiaHyperlipidemia
Types of hyperlipidemias
I IIa IIb III IV V
Lipids
Cholesterol N- N- N- N-
Triglycerides N N-
Lipoproteins
Chylomicrons N N N N
VLDL N- N- N-
LDL N-
HDL N N N N-
N = normal, = increase; = decrease; = slight increase; = slight decrease
Strategy for Controlling HyperlipidemiaStrategy for Controlling Hyperlipidemia
Serum Cholesterol Cellular CholesterolLDL-R
Conversion to hormones withincells or storageas granules
HMG CoA reductase
STATINSDiet Biosynthesis
Bile Acids
Intestine
Feces
Re-absorption
BILE ACIDSEQUESTRANTS
Lipoproteincatabolism
FIBRATES
Ezetimibe
Anti-hyperlipidemic Drugs - StatinsAnti-hyperlipidemic Drugs - Statins
CH3
CH2CH2O
O
CH3
R'
R''
O
OOH
R' R''
Mevastatin H HLovastatin H CH3
Simvastatin CH3 CH3
RR
CH3
CH2CH2O
O
OH
CH3
OH
OH
COONa
Pravastatin
RR
Anti-hyperlipidemic Drugs - StatinsAnti-hyperlipidemic Drugs - Statins
N
OH
OH
COONa
CH3
CH3
CH3 CH3
OCH3
F
NH
NH
F
OH
OH
COO Ca
CH3
CH3
O
_+
N
OH
OH
COONa
CH3
CH3
F
Atorvastatin Cerivastatin Fluvastatin
N N
OH
OH
CH3
CH3
NS CH3
F
O
O
CH3
COO Ca_ +
N
OH
OH
COO Ca
F
_ +
Rosuvastatin Pitavastatin
Anti-hyperlipidemic Drugs - StatinsAnti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
O
OOH OH
OH
COONa OH
SCoA
COOH
O
For example, Mevastatin Lovastatin Simvastatin
For example, Fluvastatin Atorvastatin Cerivastatin
HMG CoA substrate
Anti-hyperlipidemic Drugs - StatinsAnti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin
Bioavail. Dosage (mg)
Protein Binding
Metabolites
Atorvastatin ~14% 10 – 80 >98% Active
Cerivastatin ~60% 0.2 – 0.3 >99% Active
Fluvastatin ~24% 10 – 80 98% Active
Lovastatin ~5% 10 – 80 >95%
Pravastatin ~17% 10 – 40 ~50%
Simvastatin ~5% 10 - 80 ~95%
Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles.
Anti-hyperlipidemic Drugs - StatinsAnti-hyperlipidemic Drugs - Statins
Metabolic properties of statins
Rapid first pass metabolism significantly reduces bioavailability
Metabolism is complex
Extensive conversion between the lactone and open-chain forms
Glucuronidated forms as well
Other than these three, many other lesser metabolites
Inhibitors of cytochrome P450 increase bioavailability of statins …..
Greater incidences of myopathy ….. E.g., cyclosporin, gemfibrozil,
erythromycin, itraconazole, etc.
Rhabdomyolysis …. A rare complication of statin treatment ….
Characterized by breakdown of muscles ….. Release of myoglobin into
blood, which travels to kidneys and stops working of its tubules …. Also
muscle breakdown increase K+, which induces cardiac arrythmias and
death
• Older generation drugs; introduced in 1981• Second most useful anti-hyperlipidemic drugs• Primarily decrease serum triglycerides• Increase lipoprotein catabolism; increase TG usage by the body• activate PPAR- (peroxisome proliferator-activated receptor • Most used in Type III, IV and V hyperlipidemias
Anti-hyperlipidemic Drugs - FibratesAnti-hyperlipidemic Drugs - Fibrates
Anti-hyperlipidemic Drugs - FibratesAnti-hyperlipidemic Drugs - Fibrates
O
CH3
CH3
CH2CH2CH2 COOH
CH3
CH3
OCl COOCH2CH3
CH3
CH3
ON
H
O
Cl
COOH
CH3
CH3
OO
Cl
COOCH(CH3)2
CH3
CH3
O
Cl Cl
COOH
CH3
CH3
Gemfibrozil Clofibrate
C C
C
Bezafibrate
C
Fenofibrate
C
Ciprofibrate
{No longer recommended because of an increase in overall mortality and adverse events}
{rhabdomyolysis … highest PPAR- affinity clinical trials
stopped in the US}
Anti-hyperlipidemic Drugs – Bile Acid SequestrantsAnti-hyperlipidemic Drugs – Bile Acid Sequestrants
• Anion exchange resins• Water insoluble and inert to digestive enzymes• Not absorbed through the GI tract• Positively charged nitrogens sequester bile acid re-absorption• Lower serum LDL levels• Most useful in type IIa and IIb hyperlipidemias
Anti-hyperlipidemic Drugs – Bile Acid SequestrantsAnti-hyperlipidemic Drugs – Bile Acid Sequestrants
N CH2CH2 N
CH2
CHOH
CH2
N CH2CH2N
CH
CH2
CH
CH2N(CH3)3
nnCH2CH2
Cl-
+
Cholestyramine Resin Colestipol hydrochloride
NH
(CH2)9CH3
NH
(CH2)6NMe3+
NHNH2
NH
(CH2)9CH3
NH
(CH2)6NMe3+
NH
OH
NH2
Colesevelam
Anti-hyperlipidemic Drugs – Nicotinic AcidAnti-hyperlipidemic Drugs – Nicotinic Acid
N
COOH
• Administered in large doses (0.5 to 6 grams daily)• Reduces triglycerides and total cholesterol• Increases biliary secretion of cholesterol, but not bile acids• Useful in Type IIa, IIb, III, IV and V hyperlipidemias
N
NCH3
N
CONH2
N
O
F
F
OHOH
Anti-hyperlipidemic Drugs – EzetimibeAnti-hyperlipidemic Drugs – Ezetimibe
• Approved in October 2002• Reduces serum LDL, TC, and TG and increases HDL• Prevents the absorption of cholesterol from diet• Useful in Type IIa, IIb, III, IV and V hyperlipidemias