Lipid lowering drugs (c)

Question 1

Define atheroma

Answer 1

A focal disease of the intima of large and medius sized arteries
Build up of fatty material in the walls resulting in a soft lipid core
with a fibrous cap
endothelial cells dysfunction
Results of a chronic inflammatory response to vascular (endothelial cell injury)

Question 2

Describe the relationship between arteriosclerosis, arteriolosclerosis, atherosclerosis .

Answer 2

Arteriolsclerosis - is the umbrella heading for thickening and damage to blood vessel walls - hardening and loss of elasticity
Arteriolosclerosis - is a subtype mainly found in small arteries and arterioles, often related to hypertension (hyaline and hyperplastic)
Atherosclerosis - mainly in larger, medium arteries, develop an atheroma, lipid core with a soft fibrous cap.

Question 3

What are the different types of lipids?

Answer 3

Fatty acids - Saturated, mono-unstaruated, poly-unsaturated
Cholesterol
Triglycerides
Lipoproteins

Question 4

What are the different types of lipoprotein?

Answer 4

All consist of different quantities of lipids and proteins = greater protein proportion indicates more dense:
Least dense:
Chylomicrons (although are largest)
VLDL
IDL
LDL
HDL
Most dense

Question 5

How do you convert between cholesterol levels and triglycerides levels from mg/dl to mmol/l?

Answer 5

Chol - assumed Mr is 38.6, multiply to get mg/dl

Tri - assumed Mr is 88.5, multiply to get mg/dl

Question 6

What are the healthy lipid levels in serum?

Answer 6

Question 7

What does omega mean in terms of fatty acids?

Answer 7

Counting the carbons from the opposite end
Rather than the acid end as is conventional.
High omega 3 to omega 6 ratio - beneficial in prevention cardiovascular disease

Question 8

What is EPA?

Answer 8

Eicospentaenoic acid
C20:5 omega 3
Components in fish oils
May reduce CV deaths
Can be found in phospholipids in human cell surface membranes

Question 9

What are the features of cholesterol?
How does it link to atherosclerosis?

Answer 9

Found in lipid membranes - regulates fluidity and permeability
Amphipathic
Circulates in the blood in lipoproteins in the form of free cholesterol and cholesteryl esters.
Can accumulates in fatty streaks and plaques in arterial walls - helps form atheromas

Question 10

What substances is cholesterol a synthetic precursor for?

Answer 10

Vitamin D
Bile acids
Steroid hormones

Question 11

What enzyme catalyses the rate-limiting step in cholesterol synthesis?

Answer 11

HMG CoA reductase

Question 12

What are the features of triglycerdies?

Answer 12

Contains glycerol and 3 fatty acids (tri-ester)
Natural triglycerdies/fats can have varying FAs

Question 13

What is a lipoprotein?

Answer 13

A package of lipids and proteins that allow transport of lipids within the aqueous plasma

Question 14

What are apolipoproteins?

Answer 14

Are inactive protein components of lipoproteins - can bind to receptors on cells or enzymes to act as co-factors (form active holoenzyme)
There are multiple different types including ApoA, ApoB and ApoE.

Question 15

What lipoprotein composition is associated with cardiovascular risk?

Answer 15

High LDL and low HDL.

Question 16

Describe the structure of low-density lipoprotein?

Answer 16

Unilayer phospholipid surface membrane interlaced with unesterfied cholesterol
One copy of ApopB wrapped around structure
Central core of mainly cholesterol esters.

Question 17

What are the different version of ApoB
Where is apoprotein B found?

Answer 17

B-100 = A single copy is found in VLDL, IDL and LDL.
B-48 = found in chylomicrons

Question 18

What structures are important within Apoprotein B?

Answer 18

Contains a LDL receptor binding region made from RKR motif (not in B-48)
STRSS amino acid sequence is a site of mutation for familial hypercholesterolemia.

Question 19

What are the features of ApoE?
Where is is found?

Answer 19

Has an LDL receptor binding region - shares RKR motif with ApoB
There are multiple copies in chylmoicrones, VLDL, IDL.
Is NOT found in LDL.

Question 20

What are the features of an LDL receptor?
What is its function?

Answer 20

Single pass membrane protein
Is wiedley distributed
Binds LDL, the major cholestrol-carrying lipoprotein and transports in into cells by endocytosis

Question 21

What is the main clinical feature of familial hypercholesterolemia?

Answer 21

High serum LDL

Question 22

What are the different types of familial hypercholesterolemia?

Answer 22

Type 1 - mutation in LDL-R, autosomal dominant in cause, decreases expression of LDL-R co lower affinity and uptake of LDL
Type 2 - mutation in ApoB, autosomal dominant in cause R3500Q , results in defective ApoB-100, prevents binding to LDL-R so remains in serum.

Question 23

Describe how lipoproteins are taken up by the cell.

Answer 23

Lipoprotein often via ApoB RKR motif binds to LDL-R in pits on surface of cell.
These pits invaginate and pinch off inside the cell forming vesicles which fused to form an endosome
LDL dissociates from the receptor and the receptor is recycled to the surface
LDL is delivered to the lysosome where choelstryl ester is cleaved to free cholesterol to be used for membrane synthesis etc
Taking up cholesterol inhibits cells ability to synthesise their own cholestrol.

Question 24

Describe how lipids/cholesterol is transported around the body via the exogenous pathway.

Answer 24

Exogenous - external source of cholesterol - dietary through gut.
Lipase - hydrolysed TG to glycerol and FA.
Bile salts - emulsify fats to form micelles increasing surface area for lipase
Carry glycerol and FA to cell membrane
Protonated due to H+ Na+ exchanged - release Fa and glycerol, move across by facilitated diffusion as hydrophobic, FABPpm or FAT channels.
ER - Triglycerides
Golgi - cholesterol to form chylomicrons
Absorbed into lymphatic system via lacteal.
The lymphatic system through into systemic circulation - FA and GLycerol absorbed by cells (lipoprotein lipase in serum), chylomicron remnants containing mainly cholesterol are transported to the liver and enter the endogenous pathway or are converted to bile acids.

Question 25

What is the endogenous pathway of lipid/cholestrol transport?

Answer 25

Cholestrol transport to the body In the liver packaged into VLDL, released in blood stream. TG acted on by lipoprotein lipase. Cholesterol, Glycerol and FA absorbed by cells via LDL-R. LP density decreases as lipids delivered, IDL, LDL, HDL

Question 26

How is cholesterol transported from the body to the liver?

Answer 26

Cholesterol is moved from non-liver cells to the liver HDL picks up cholesterol using ABCA1 and loads on ApoA. Convert cholesterol to cholesteryl esters HDL binds to Scavenger Receptor B1 on the liver.

Question 27

What is the cyclic link between the liver and the gut relating to cholesterol?

Answer 27

Enterohepatic circulation Bile secreted into GIT Some bile acids are reasborbed in the gut, return to liver by enterophepatic circulation alongside dietary cholesterol Cholesterol secreted in bile Bile acids modified and secreted in bile.

Question 28

What are the different sources of cholesterol for hepatic synthesis of bile acid?

Answer 28

1. Synthesis de novo 2. Uptake from plasma LDL via LDL-R 3. Uptake from plasma HDL via SCARB1 4. Absoprtion of bile acides from gut via enterohepatic circulation.

Question 29

What are the enzymes involved in cholesterol synthesis?

Answer 29

Acetoacetyl-CoA thiolase - converts two Acetyl CoA molecules into Acetoacetyl CoA HMG-CoA synthetase - combines Acetyl Coa and Acetoacetyl CoA to produced HMG CoA HMG CoA reductase - convertes HMG-CoA into mevalonate Reference do not memorise

Question 30

What enzyme do statins inhibit?

Answer 30

HMG-CoA reductase

Question 31

What are the different types of lipid lowering drugs?

Answer 31

Statins PCSK9 inhibitors PPAR agonists (fibrates) Colestyramine Ezetimibe Bempedoic acid Nicotinic acid Icosapent ethyl

Question 32

What is the mechanism of action of atorvastatin?

Answer 32

Is a statin Chem - small molecule Pharmacology - is a competitive inhibitor of HMG-CoA reductase Physiology - decreases cholesterol synthesis, increases LDL-R expression in the liver, increases LDL uptake from the blood by the liver. This decreases circulating LDL/cholesterol

Question 33

What are the clinical indication of atorvastatin?

Answer 33

Familial hypercholestrolaemia Primary and secondary prevention of CV events e.g MI

Question 34

What are the clinical indication of alirocumab (& evolocumab)?

Answer 34

Familial hypercholesterolaemia and dyslipidaemia Used when statins do not work or are not tolerate well

Question 35

What is the mechanism of action of alirocumab and evolocumab?

Answer 35

Class - PCSK9 inhibitor Chem - monoclonal antibodies Pharmacology - PCSK9 blocker Physiology: prevents PCSK9 from binding to and internalisng LDL-R, this leads to higher LDL-R expression, increasing cellular uptake of LDL THis decreases circulating LDL/Cholesterol

Question 36

What is the clinical use of inclisiran (-siran)?

Answer 36

Given as an injection twice a year Used alongside statins when they are not tolerated or fail to work Helps reduce levels of circulating cholesterol. Used for familial hypercholesterolemia and dyslipidemia

Question 37

What is the mechanism of action on inclisiran?

Answer 37

Class - PCSK9 inhibitor Chem - double stranded siRNA Pharmacology - binds and degrades PCSK9 mRNA Physiology - reduces PCSK9 expression, leads in increased LDL R expression (as not internalised), this increases LDL uptake from blood, decreases circulating LDL/Cholesterol levels

Question 38

What is the chemistry underpinning the use of inclisiran?

Answer 38

Contains anti-sense and sense strand. Antisense strand is complimentary to PCSK9 RNA is extremely unstable

Question 39

How does inclisiran work on the cellular level?

Answer 39

Is injected in body Binds to a receptor (ASGR1 and ASGR2) found only on the liver - is specifically taken up by hepatocytes RNA induced silencing complex binds to antisense strand forming a complex PCSK9 mRNA is produced by cell Binds to RISC antisense strand complex (as complimentary to antisense strand), this enables the complex to cleave PCSK9. Specifically, it cleaves the non-coding sequence of genes. This results in less PCSK9 delivery to the Golgi apparatus so less PCSK9 synthesis and excretion leading to less degradation of LDL receptors

Question 40

What is the clinical use of fenofibrate?

Answer 40

Used as adjunctive therapy in dyslipidaemia. Including statins in hyperlipidaemia

Question 41

What is the moa of fenofibrate?

Answer 41

Class - fibrate Chemsitry - small molecule Pharmacology - agonist as PPARα receptors, these are intracellular nuclear receptors Physiology - promotes reverse cholesterol transport, Agonist bound PPAR forms a complex with RXR, this increases the transcription of ABCA1, ABCA1 transport cholesterol from cells and loads onto ApoA-1, this increases levels of HDL and decreases levels of VLDL.

Question 42

What is the clinical use of colestyramine?

Answer 42

For hyperlipidaemias and primary prevention of CHD in men for patients who do not response adequately to diet and other appropriate measures.

Question 43

What is the mechanism of action for colestyramine?

Answer 43

Class - bile acid sequestrant Chem - resin/polymer, is a powder that is mixed with water and given orally Pharmacology - strong basic ion exchange with bile acids in the gut Physiology : Cl- is exchanged for negatively charged bile salts charged bile salts, and excreted in faeces as trapped in resin. This decreases bile acid reabsorption so less in EHC, therefore increase bile acid synthesised by the liver, this decreases cholesterol store in the liver, increases LDL-R expression increasing LDL uptake from the blood Decreases circulating LDL/cholesterol.

Question 44

Describe the formation of bile salts and how is this relevant to the moa of colestyramine.

Answer 44

Bile acids such as cholic acid are conjugated with glycine or taurine to form a bile salt This conjugation decreases the pKa, this results in a negatively charge as H+ more readily dissociates. This enables bile salts to be exchanged for Cl- on colestyramine.

Question 45

What is the clinical use of ezetimibe?

Answer 45

Class - cholesterol absoprtion inhibitor Is used as an adjunct for primary hypercholesterolemia

Question 46

What is the mechanism of action of ezetimibe?

Answer 46

Is a small molecule is a cholesterol absorption inhibitor Pharmacology: is an antagonist as NPC1L1 Physiology: NPC1L1 mediates cholesterol uptkae in the gut, therefore drug action reduces cholesterol absorption, this decreases hepatic cholesterol stores, leading to increases LDL-R expression in the liver. This increases LDL uptake from the blood decreases circulating LDL/cholesterol.

Question 47

What is the clinical use of bempedoic acid?

Answer 47

Used in primary hypercholesterolaemia or mixed dyslipideamia in patients who have not responded or are contraindicated for other measures (often secondary to statins)

Question 48

What is the mechanism of action of bempedoic acid?

Answer 48

Is a cholesterol synthesis inhibitor Is a small molecule, is a prodrug metabolised in the liver to and active thioester. Pharmacology - inhibits ATP-citrate lyase Physiology ATP-citrate lyase catalyses the formation of acetyl-CoA from citrate, therefore drug reduces Acetyl-CoA formation hence decreases cholesterol synthesis, this leads to increased LDL-R expression in liver This increases LDL uptake from the blood leading to a decrease in circulating LDL/cholesterol

Question 49

What is the clinical use of nicotinic acid?

Answer 49

Is a vitamin Used as an adjunct in dyslipidaemia

Question 50

What is the mechanism of action of nicotinic acid?

Answer 50

Is a vitamin - VitB3 Is given in high doses Is an agonist of the HCA2 receptor, this promates fatty acid oxidation and decreases liver triglyceride production and VLDL secretion.

Question 51

What is the clinical use of icospent ethyl?

Answer 51

Is a fish oil - ester, a prescription form of EPA Adjunct to statin in prevention of cardiovascular events in hyperlipidaemia.

Question 52

What is the mechanism of action of icospent ethyl?

Answer 52

Can be found in fish oil. Is a prescription version of EPA. Is a pro-drug, as is de-esterified to EPA. Acts as a substrate for COX enzymes. Is converted to Thromboxane A3 and PGI3. This has reduced activity at TP receptors compared to thromboxane A2, this decreases platelet adhesion and aggregation.