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Cardiovascular > Pharmacology 4 > Flashcards

Pharmacology 4 Flashcards

1
Q

What are features of lipids? What are their functions? (4)

A
  • Insoluble in water
  • Component of membranes
  • Maintain membrane integrity
  • Energy sources
  • Pre-cursors for hormones and signalling molecules
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2
Q

How are non-polar lipids transported in blood? Examples of non-polar lipids? (2)

A
  • Within lipoproteins like HDL and LDL

* Cholesterol esters and triglycerides

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3
Q

What is cardiovascular disease (atherosclerosis) associated with? (2) Causes? (2)

A
  • Elevated LDL or particles rich in triglycerides
  • Decreased HDL
  • Diet and lifestyle (particularly Western)
  • Genetic factors (e.g. familial hypercholesterolaemia)
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4
Q

What are lipoproteins? What are their components? (2)

A
  • Microscopic spherical particles 7-1000 nM diameter
  • Inner hydrophobic core containing esterified cholesterol and triglycerides
  • Outer hydrophilic coat containing monolayer of amphipathic cholesterol, phospholipids and apoproteins (apo)
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5
Q

What are examples of lipoproteins? (4) What apoproteins does each contain? Rank from smallest to largest

A
  • HDL particles (contain apoA1 and apoA2), smallest
  • LDL particles (contain apoB-100)
  • Very-low density lipoprotein (VLDL) particles (contain apoB-100)
  • Chylomicrons (contain apoB-48), largest
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6
Q

What do apoB-containing lipoproteins do? Examples of apoB-containing lipoproteins? (3)

A
  • Deliver triglycerides (i) to muscle for ATP biogenesis and (ii) adipocytes for storage
  • LDL, LVDL and chylomicrons
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7
Q

What are the 2 pathways by which lipids are delivered to tissues?

A
  • Exogenous and endogenous
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8
Q

What are chylomicrons?

A

Lipoproteins formed in intestinal cells that transport dietary triglycerides – the EXOGENOUS pathway

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9
Q

What are VLDL particles?

A

Lipoproteins formed in liver cells that transport triglycerides synthesised in liver (non-dietary) – the ENDOGENOUS pathway

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10
Q

Explain the “life-cycle” of apoB-containing liposomes? (3)

A
  • Assembly (with apoB100 in the liver and apoB48 in intestine)
  • Intravascular metabolism (involving hydrolysis of triglyceride core of lipoprotein)
  • Following hydrolysis of core, end up with particle called REMNANT which is cleared form liver by receptor mediated clearance
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11
Q

What is the difference between apoB100 and apoB48?

A

ApoB48 is truncated version of apoB100

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12
Q

Explain the assembly of apoB-containing chylomicrons (8)

A
  • Digestion of fat produces monoglycerides and free fatty acid chains
  • These enter into cells lining intestine (enterocytes)
  • Once inside, monoglyceride and fatty acid molecules resynthesised into triglyceride molecule
  • Cholesterol is transported into cell by Niemann-Pick C1-like 1 Protein (NPC1L1)
  • Cholesterol is then esterified to form cholesterol ester
  • ApoB48 is synthesised by ribosomes and attached to developing lipoprotein in endoplasmic reticulum (lipidation by MTP) to form outer shell
  • Triglyceride incorporated into lipoprotein by MTP (microsomal triglyceride transfer protein)
  • Cholesteryl ester also incorporated, which together with ApoB48 and triglycerides forms chylomicron
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13
Q

Explain how chylomicron exits enterocyte (2)

A
  • Exocytosis following addition of second apoprotein apoA1

* Enters lymphatics and is carried in lymph to systemic circulation via thoracic duct into subclavian vein

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14
Q

Where are VLDL particles containing triglycerides assembled? What are they assembled from? Explain the assembly of apoB-contaiing lipoproteins? (3)

A
  • In liver hepatocytes
  • Triglyceride core formed from free fatty acids from (i) adipose tissue - particularly during fasting - and (ii) de novo synthesis
  • MTP lipidates apoB100 forming VLDL that coalesces with triglyceride droplets
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15
Q

How are chylomicrons and VLDL particles activated?

A

By transfer of apoCII from HDL particles

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16
Q

What is lipoprotein lipase?

A

Lipolytic enzyme associated with endothelium of capillaries in adipose and muscle tissue

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17
Q

What is the function of apoCII? What does this lead to? What are the particles that are depleted of triglycerides (but STILL contain cholesterol esters) called?

A
  • ApoCII facilitates binding of chylomicrons and VLDL particles to LPL
  • LPL hydrolyses core triglycerides to free fatty acids and glycerol WHICH ENTER TISSUES
  • Chylomicron and VLDL remnants
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18
Q

Explain the process of clearance of apoB-containing lipoproteins (5)

A
  • LPL causes chylomicrons and VLDL particles to become enriched with cholesterol due to triglyceride metabolism
  • Chylomicrons and VLDL dissociate from LPL
  • ApoCII transferred back to HDL particles in exchange for apoE - a high affinity ligand for receptor mediated clearance (particles now called remnants)
  • Remnants return to liver and further metabolised by hepatic lipase
  • All apoB48-containing remnants and 50% of apoB100-containing remnants are cleared by receptor-mediated endocytosis into hepatocytes
19
Q

If only 50% of apoB100-containing remnants are cleared, what happens to the other 50%? (2)

A
  • Lose further triglyceride through hepatic lipase - become smaller and enriched in cholesteryl ester
  • Intermediate density lipoprotein (IDL) converts them into LDL particles lacking apoE and retaining solely apoB100
20
Q

What is clearance of LDL particles crucially dependent on? What happens once endocytosis has occurred?

A
  • Expression of LDL receptor by the liver
  • After internalisation of receptor and LDL by endocytosis and subsequent hydrolysis, LDL receptor is recycled to pick up more LDL
21
Q

How does cellular uptake of LDL particles occur in the liver? What happens to LDL particles within the hepatocyte? What does release cholesterol cause? (3)

A
  • Occurs via receptor-mediated endocytosis
  • Within the cell at the LYSOSOME, cholesterol (C) is released from cholesteryl ester (CE) by hydrolysis
  • inhibits synthesis of cholesterol by hepatocyte via inhibiting HMG-CoA reductase
  • down regulation of LDL receptor expression
  • storage of cholesterol as cholesterol ester
22
Q

How do statins work?

A

Blocks synthesis of cholesterol so leads to increased expression of LDL recpetor on surface of hepatocyte, meaning LDL particles more readily cleared from plasma

23
Q

What is atherosclerosis?

A

Focal disease of large and medium sized arteries

24
Q

What causes atherosclerosis? What are risk factors?

A
  • Dysfunction and injury of the lining (endothelium) of blood vessels
  • Risk factors include diabetes, high BP, smoking)
25
Q

Explain the disease progression of atherosclerosis (6)

A
  • Uptake of LDL from blood into intima of the artery
  • LDL oxidized to atherogenic oxidised LDL (OXLDL) - it is the oxidised form that causes the plaques
  • Migration of monocytes across endothelium into intima where they become macrophages
  • Uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a FATTY STREAK
  • Release of inflammatory substances causes division and proliferation of smooth muscle cells into intima and deposition of collagen
  • Formation of an atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
26
Q

What does the lipid core of atheromatous plaque consist of? Fibrous cap?

A
  • Dead foam cells

* Smooth muscle cells and connective tissue

27
Q

What is the function of HDL? Why the liver?

A
  • Removing excess cholesterol from cells by transporting it in plasma to the liver
  • Liver is only organ that has capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesize bile salts)
28
Q

Explain the formation of HDL (3)

A
  • HDL is formed in the liver, initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-B-HDL)
  • Pre-B-HDL matures in plasma to spherical -HDL
  • Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
29
Q

What is the purpose of mature HDL? What is this process known as?

A
  • Accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver
  • Reverse cholesterol transport
30
Q

What are the mechanisms by which HDL delivers excess cholesterol to the liver? (2)

A

Direct and indirect

  • Direct - HDL interacts with receptor (scavenger receptor-B1, SR-B1) allowing transfer of cholesterol and cholesteryl esters into hepatocytes
  • In plasma, cholesterol ester transfer protein (CETP) allows transfer of cholesteryl esters from HDL to VLDL/LDL, indirectly returning cholesterol to the liver
31
Q

What is dyslipidaemia? What are the different types? (2)

A
  • Excess lipids i.e. cholesterol in the blood

* Primary and secondary dyslipidaemia

32
Q

What causes primary dyslipidemia?

A
  • Primary - combination of diet and genetic factors

* Secondary - other diseases (e.g. type II diabetes, hypothyroidism, alcoholism, liver disease)

33
Q

What is type IIa IIa hyperlipoproteinaemia caused by? What condition does this cause? What is a risk associated with this condition?

A
  • Gene defect in LDL receptor
  • Familial hypercholesterolaemia
  • Ischaemic heart disease
34
Q

What are statins? Examples?

A
  • Drugs of choice to reduce LDL – very effective in reducing total and LDL cholesterol (up to 60%), decrease triglycerides (up to 40%) and increase HDL (about 10%)
  • Simvastatin and atorvastatin
35
Q

What is the mechanism of statins? What is the effect of this?

A
  • Act as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - rate limiting step in cholesterol synthesis in hepatocytes
  • Decrease in hepatocyte cholesterol synthesis causes a compensatory increase in LDL receptor expression and enhanced clearance of LDL
36
Q

When are statins not of use in treating high cholesterol?

A

Statins are ineffective in homozygous familial hypercholesterolaemia where LDL receptors are lacking (but work in heterozygous)

37
Q

Other than enhanced LDL clearance, what are other beneficial effects of statins? (4)

A
  • Decreased inflammation in vasculature
  • Reversal of endothelial dysfunction (damage)
  • Decreased thrombosis
  • Stabilization of atherosclerotic plaques
38
Q

How/when are statins administered? What are adverse effects of statins? (2)

A
  • Orally at night
  • Myositis (inflammation of skeletal muscle)
  • Rhabdomyolosis (damage to skeletal muscle e.g. plaque distribution)
39
Q

What are 2 classes of lipid-lowering drugs?

A

Statins and fibrates

40
Q

What are the effects of fibrates? Examples?

A
  • Decrease in triglycerides (up to 50%) and decrease in LDL (up to 15%) and increase (up to 20%) in HDL
  • Bezafibrate and gemfibrozil
41
Q

What are fibrates? What is their mechanism?

A
  • First line drugs in patients with very high triglyceride levels
  • Act as agonists of a nuclear receptor (PPAR) to enhance the transcription of several genes, including LPL
42
Q

What are adverse side effects of fibrates? (5)

A
  • Rare but can cause myositis
  • Rhabdomyolosis
  • GI upset
  • Pruritus
  • Rash
43
Q

When should administration of fibrates be avoided?

A

Avoided in alcoholics who are predisposed to hypertriglyceridaemias

Cardiovascular (28 decks)

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