Statins

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  • Created by: LBCW0502
  • Created on: 21-01-19 20:34
What is atherosclerosis?
Build up of plaque in blood vessels which restricts blood flow and results in high BP. Familial hypercholesterolemia
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Describe features of cholesterol (1)
Synthesised in liver. Integral component in synthesis of hormones. Found in cell walls of animals/humans. Isolated cholesterol is a white flaky solid that is insoluble in aqueous environments. Approx 1000 mg/day, dietary cholesterol, animal products
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Describe features of cholesterol (2)
Transport of steroids in blood - attached to lipoproteins
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Describe features of HDL good cholesterol
Collects cholesterol particles in blood vessels. Deposits them in the liver. Transferred to bile acids and disposed off
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Describe features of LDL bad cholesterol
Deposits on the walls of blood vessels. Builds up into cholesterol plaque. Blocks blood vessels, especially arteries that feed blood to the heart
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Describe the biological role of cholesterol (1)
Important component of cell linings. Helps in the digestion of lipids. Kay component in the building of hormones. Hypercholesterolaemia (high blood cholesterol)
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Describe the biological role of cholesterol (2)
Results in high LDL/low HDL cholesterol levels. Leads to narrowing of artery walls (atherosclerosis), decreased blood and oxygen supply to heart, MI, death (leading cause of death in western countries)
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What are the ranges for total cholesterol?
<200 mg/dL, 200 - 239 mg/dL (borderline), >240 mg/dL (risk CVD increased 2-fold)
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Outline cholesterol biosynthesis
Acetyl-CoA - HMG CoA - Mevalonate - Mevalonate pyrophosphate - isopentenyl pyrophosphate - farnesyl pyrophosphate - squalene synthase - cholesterol
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Which type of mechanism is used in cholesterol biosynthesis?
Claisen condensation reaction (produce larger chain molecule each time until cholesterol is produced)
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Describe features of statins
HMG CoA reductase inhibitors. Acetyl CoA x 2 gives aceoacetyl CoA which reacts with a third acetyl CoA molecule, HMG CoA reductase (ester reduced to form alcohol, hydroxymethylglutarate)
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Describe the phosphorylation of malvalonate
2 ATP used to produce malvalonate pyrophosphate, ATP used to from 3-phospho-5-pyrophosphate mevalonate - form dimethylallyl pyrophosphate - isopentenyl pyrophosphate isomerase used to form 3-isopentylpyrophosphate (carbocation, geranyl pyrophosphate)
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Cholesterol is involved in producing which substances?
Steroids, vitamines and bile acids
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What are the desired features of a statin?
Block acetate to cholesterol, mevalonate to cholesterol unaffected
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What is the mode of action of statins?
Structure of statins resembles transition state of HMG CoA (highest affinity for enzyme)
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Give examples of semi-synthetic statins (with the R groups)
Compactin (H, H), lovastatin (H, CH3), simvastatin (CH3, CH3), pravastatin (H, OH) - compounds contains HMG CoA intermediate within structure
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Outline the metabolism of lovastatin
Hydrolysed to 6-hydroxy metabolite, beta oxidation and beta oxidation with dehydration reduction to form 6-hydroxymethyl metabolite and taurine conjugates used to form 6-exomethylene metabolite
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Summarise the clinical aspects of statins (1)
Coronary heart disease (caused by hypercholesterolaemia) is a major leading cause of death in most countries. Natural statins (lovastatin, compactin) lead to innovative approaches to treatment of high cholesterol. Template for synthetic statins
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Summarise the clinical aspects of statins (2)
Can improve effectiveness of drugs and limit side effects by looking at SAR of statins and their interactions with HMGR (bonding nature)
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Card 2

Front

Describe features of cholesterol (1)

Back

Synthesised in liver. Integral component in synthesis of hormones. Found in cell walls of animals/humans. Isolated cholesterol is a white flaky solid that is insoluble in aqueous environments. Approx 1000 mg/day, dietary cholesterol, animal products

Card 3

Front

Describe features of cholesterol (2)

Back

Preview of the front of card 3

Card 4

Front

Describe features of HDL good cholesterol

Back

Preview of the front of card 4

Card 5

Front

Describe features of LDL bad cholesterol

Back

Preview of the front of card 5
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