Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Unit 12 > Lipid lowering drugs (c) > Flashcards

Lipid lowering drugs (c) Flashcards

1
Q

Define atheroma

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Describe the relationship between arteriosclerosis, arteriolosclerosis, atherosclerosis .

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the different types of lipids?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the different types of lipoprotein?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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

A

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

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the healthy lipid levels in serum?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What does omega mean in terms of fatty acids?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is EPA?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What substances is cholesterol a synthetic precursor for?

A

Vitamin D
Bile acids
Steroid hormones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

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

A

HMG CoA reductase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are the features of triglycerdies?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is a lipoprotein?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are apolipoproteins?

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What lipoprotein composition is associated with cardiovascular risk?

A

High LDL and low HDL.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe the structure of low-density lipoprotein?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What structures are important within Apoprotein B?

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is the main clinical feature of familial hypercholesterolemia?

A

High serum LDL

22
Q

What are the different types of familial hypercholesterolemia?

A

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.

23
Q

Describe how lipoproteins are taken up by the cell.

A

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.

24
Q

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

A

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.

25
Q

What is the endogenous pathway of lipid/cholestrol transport?

A

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

26
Q

How is cholesterol transported from the body to the liver?

A

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.

27
Q

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

A

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.

28
Q

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

A
  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.
29
Q

What are the enzymes involved in cholesterol synthesis?

A

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

30
Q

What enzyme do statins inhibit?

A

HMG-CoA reductase

31
Q

What are the different types of lipid lowering drugs?

A

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

32
Q

What is the mechanism of action of atorvastatin?

A

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

33
Q

What are the clinical indication of atorvastatin?

A

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

34
Q

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

A

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

35
Q

What is the mechanism of action of alirocumab and evolocumab?

A

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

36
Q

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

A

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

37
Q

What is the mechanism of action on inclisiran?

A

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

38
Q

What is the chemistry underpinning the use of inclisiran?

A

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

39
Q

How does inclisiran work on the cellular level?

A

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

40
Q

What is the clinical use of fenofibrate?

A

Used as adjunctive therapy in dyslipidaemia.
Including statins in hyperlipidaemia

41
Q

What is the moa of fenofibrate?

A

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.

42
Q

What is the clinical use of colestyramine?

A

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

43
Q

What is the mechanism of action for colestyramine?

A

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.

44
Q

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

A

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.

45
Q

What is the clinical use of ezetimibe?

A

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

46
Q

What is the mechanism of action of ezetimibe?

A

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.

47
Q

What is the clinical use of bempedoic acid?

A

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

48
Q

What is the mechanism of action of bempedoic acid?

A

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

49
Q

What is the clinical use of nicotinic acid?

A

Is a vitamin
Used as an adjunct in dyslipidaemia

50
Q

What is the mechanism of action of nicotinic acid?

A

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.

51
Q

What is the clinical use of icospent ethyl?

A

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

52
Q

What is the mechanism of action of icospent ethyl?

A

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.

Unit 12 (23 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions