Atherosclerosis Flashcards Preview

Year 2 - LCRS - Pharmacology > Atherosclerosis > Flashcards

Flashcards in Atherosclerosis Deck (28)
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1
Q

Pathogenesis of Atherosclerosis

A
  • INFLAMMATION is key
  • a) Endothelial dysfunction:
    1. increased endothelial permeability
    2. up-regulation of endothelial anhesion molecules
    3. leukocyte adhesion
    4. migration of leukocytes into artery wall
  • b) Fatty streak formation:
    5. formation of foam cells (macrophages that engulfed lipids)
    6. adherence and aggregation of platelets
    7. activation of T-cells
    8. migration of smooth muscle cells
    9. adherence and entry of leukocytes
  • c) formation of a complicated lesion
    10. formation of a necrotic core
    11. accumulation of macrophages
    12. formation of the fibrous cap (Migration of vascular smooth muscle cells (VSMCs) to the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core. )
2
Q

What are lipoproteins?

A
  • Lipoproteins are basically a core full of triglycerides and cholesterol esters, along with a lipid membrane that contains proteins called apolipoproteins. There are many types of lipoproteins, but the two most important ones are called LDL (Low Density Lipoprotein) and HDL (High Density Lipoprotein)
  • they transport lipids through the body
3
Q

Endogenous pathway of lipid metabolism

A
  • Whilst chylomicrons transport triglyceride from the gut to the liver, VLDL is the analogous particle that transports triglycerides from the liver to the rest of the body. - Triglycerides together with cholesterol, cholesterol ester and other lipoprotein particles are transported in VLDL in the bloodstream, where VLDL undergoes delipidation with the enzyme lipoprotein lipase in a similar way to chylomicrons; this is the endogenous pathway of lipid metabolism.
  • During this process, triglyceride is removed from the core and exchanged for cholesterol esters, principally from HDL.
  • Whilst most VLDL is transformed into LDL, the larger VLDL particles are lipolysed to IDL, which is then removed from the plasma directly. Lipoprotein lipase is the main enzyme used in the lipolysis of large VLDL particles, whereas hepatic lipase reacts with the small VLDL and IDL particles.
  • IDL is highly atherogenic.
  • The product of this metabolic cascade, LDL, exists in the plasma in the form of a number of subfractions; LDL I–IV. It has been shown that small dense LDL particles are the most atherogenic.
  • They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques.
  • The enterohepatic circulation provides a route for the excretion of cholesterol ads.
4
Q

Exogenous Pathway of lipid metabolism

A

= transport and utilisation of DIETARY fats

  • dietary fat is broken down into cholesterol, fatty acids and di- and monosaccharides.
  • These molecules, together with bile acids, form water-soluble micelles that carry the lipid to absorptive sites in the duodenum (chylomicrons)
  • Normally, virtually all triglyceride (TG) is absorbed, compared with only 50% of cholesterol.
  • Following absorption in the duodenum, chylomicrons are formed which enter the bloodstream via intestinal lymphatics and the thoracic duct.
  • On entering the plasma, rapid changes take place in the chylomicron. It is hydrolysed by the enzyme lipoprotein (LP) lipase releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage.
  • The residual chylomicron undergoes further delipidation, resulting in the formation of chylomicron remnants. These are taken up by a number of tissue (e.g. liver via remnant receptor or contribute to atheroma)
  • In the liver they undergo lysomal degradation, and are either used for a variety of purposes including remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts.
  • FFAs go to skeletal muscle or adipose tissue

=> there is only a small amount of cholesterol in the diet, most of the cholesterol is endogenous.

5
Q

Reverse Cholesterol transport

A
  • As cholesterol cannot be broken down within the body, it is eliminated intact.
  • It is transported via HDL from the peripheral tissues to be excreted by the liver.
  • HDL begins as a lipid-deficient precursor which transforms into lipid-rich lipoprotein.
  • In this form it transfers cholesterol either directly to the liver or to other circulating lipoproteins to be transported to the liver for elimination.
  • The observation that HDL acts as a vehicle for the transport of cholesterol for elimination has led to the identification of HDL as a protective factor against the development of atherosclerosis.
6
Q

What is the earliest recognisable lesion in atherosclerosis?

A

Fatty streak -> caused by aggregation of lipid-rich foam cells

7
Q

What are the possible outcomes of fatty streaks?

A
  • they may increase in size
  • remain static
  • or even disappear
8
Q

What are the types of atherosclerotic lesions?

A
  • TI: (coronary) artery at lesion prone location
  • TII: Macrophage foam cells
  • TIII: Proatheroma (small pools of ec lipid)
  • TIV: Atheroma (core of ec lipid)
  • TV: Fibroatheroma (fibrous thickening)
  • TVI: complicated lesion
9
Q

Remnant lipids and the endothelium

A
  • remnant lipids are the things that remain after e.g. breakdown of lipoproteins/lipid particles, remain in the circulation
  • highly atherogenic
  • chylomicron remnants
  • not routinely measured but important in pathogenesis in atherosclerosis.
10
Q

Is all atherosclerosis inflammatory?

A
  • no, one type is and the other one is not
  • Study:
  • elevated levels of LDL cholesterol are associated with IHD but not with low grade inflammation
  • this indicated that increased LDL cholesterol cause atherosclerosis without a major inflammatory component
  • inflammatory component of atherosclerosis is driven by elevated remnant cholesterol levels.
11
Q

Vulnerable atherosclerotic plaques

A
  • Vulnerable plaques are characterised by a thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation. In contrast, the stable plaque has a relatively thick fibrous cap protecting the lipid core from the contact with blood.
  • Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi. The size of the plaque does not appear to predict whether a plaque is prone to rupture, indeed clinical data suggest that stable plaques more often show luminal narrowing detectable by angiography than do vulnerable plaques.
  • Rupture usually occurs at sites of thinning (particularly at the shoulder area of the plaque) and is associated with regions where there are relatively few smooth muscle cells but abundant macrophages and T cells. Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen.
12
Q

Interheart study - RFs for MI

A
  • interaction between the RFs

- the more RFs the higher the risk

13
Q

What are the available lipid lowering drug therapies?

A
  • bile acid sequestrants
  • nicotinic acid (not used, high risk)
  • fibrates (gemfibrozil)
  • STATINS
  • ezetimibe
  • PCSK-9 inhibitors
14
Q

Facts about the different lipid lowering drugs

A
  • Bile acid sequestrants are potent cholesterol-lowering agents. However, compliance can be a problem as patients may object to the taste and texture, and common adverse events are gastrointestinal bloating, nausea and constipation.
  • Nicotinic acid, a B-complex vitamin whose lipid-lowering properties were first described in the 1950s, is very effective at increasing HDL cholesterol levels and is indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricaemia.
  • Fibrates are effective triglyceride-lowering drugs and, as such, are effective for patients with type III hyperlipoproteinaemia. In some patients they modestly lower LDL cholesterol and raise HDL cholesterol. However, in the majority of patients they are only moderately successful in reducing LDL cholesterol.
  • Probucol is prescribed for the treatment of high cholesterol levels. However, it has only a modest LDL cholesterol-lowering effect, and there is no evidence that it reduces CHD risk and there are limited long-term tolerability data.
  • Statins are highly effective in lowering LDL cholesterol and have a good tolerability profile.

=> They have all shown varying degrees of efficacy in delaying the progression of atherosclerosis and some have also been shown to reduce MI and sudden death.
A combination of two agents may be used to achieve greater efficacy in cases of severe hypercholesterolaemia. However, the most convincing evidence has been demonstrated with statins and, at present, they are first-line drugs in the treatment of dyslipidaemias.

15
Q

MoA of statins

A
  • HMG-CoA reductase inhibitors
  • decrease the amount of endogenous cholesterol produced
  • Reduction in LDL-C particles via increased number of LDL receptors on hepatocytes
  • The body obtains cholesterol and tg either by synthesising them in the liver or from the diet or storage sites in adipose tissue.
  • The cholesterol synthesis pathway is a complex process involving many biochemical pathways and feedback mechanisms in the liver.
  • Statins inhibit the HMG-CoA reductase, the enzyme involved in the rate-limiting step in the formation of cholesterol, which is usually responsible for two-thirds of the body’s cholesterol. In response to this the hepatocytes up-regulate and increase the number of LDL receptors, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma.
  • This results in an increase in HDL levels although the mechanism involved has not been fully established
16
Q

What is the rule of 6 in terms of statins?

A

double the dose but only 6% reduction in LDL

17
Q

What are some of the problems with statins?

A
  • Some people can’t tolerate them (e.g. GI problems, increased blood sugar)
  • If you double the dose you only reduce by 6%
  • If you want a bigger response that is a problem.
18
Q

Secondary prevention

A
  • in patients that already have angina, had MIs, CHD

- statin therapy in secondary prevention helps

19
Q

Pleiotropic effects of statins

A
  • improve endothelial function
  • enhance the stability of atherosclerotic plaques
  • decrease oxidative stress and inflammation
  • inhibit thrombogenic response/platelet activation
  • inhibit vasoconstriction (via decrease in ET-1 and AT-2R)
  • immune system, CNS, bone

Should you give everyone over 50 a statin? Arguments against in terms of SE or in terms of making everything a disease.

20
Q

Fibrates

A
  • Main MoA is activation of PPAR alpha receptors
  • PPAR = peroxisome proliferator activated receptors -> mediate the metabolism of TG and HDL
  • reduce TG by up to 50% and increase HDL by up to 20%; also decrease FFAs
  • usually given in combination with statins
  • PPAR gamma activators are the thiazolidinediones (glitazones) used in diabetes (OTHER DRUG but structurally and pharmacologically similar)
21
Q

Nicotinic acid

A

= niacin (precursor for NAD and NADP)

  • on paper it reduces inflammation and LDL, increases HDL
  • in reality the effects are not good and there is an increase risk of cytotoxicity
  • only prescribed by professionals to patients that are unresponsive to other therapy.
22
Q

Ezetimibe

A
  • inhibits cholesterol absorption from the small intestine
  • decreases the amount of cholesterol available to liver cells -> absorb more from circulation
  • pharmacokinetics: it is absorbed and activated as glucuronide
  • usually given together with a statin -> itself it is less effective than a statin (15-20% reduction in cholesterol) but if you give it with a statin you can enhance the effect of the statin and get around the rule of 6.
23
Q

Effects of inhibiting CETP

A

CETP inhibitors:

  • increases HDL, decreases LDL
  • biochemistry looks good but patients don’t

BUT: higher mortality and raised BP so not used!!!

24
Q

CETP

A

cholesterol ester transport protein

plasma protein that facilitates the transport of cholesterol esters and TGs between lipoproteins

25
Q

PCSK9

A
  • Proprotein converts subtilising/kexin type 9

- it is a protein secreted by cells that inactivates the LDL-R

26
Q

PCSK9 inhibition

A
  • PCSK9 inhibition enhances the lipid lowering effects of statins
  • MABs are the most advanced PCSK9 inhibitors at the moment
  • approved in the UK and in the US but EXPENSIVE! (e.g. 14,000$ per year)
  • statins not only increase LDL-R but also PCSK9 (which inhibits LDLRs)
  • patients with familial hypercholesterolemia seem to be in the biggest need of these treatments -> cannot give it to everyone because it is very expensive. Maybe also people who don’t tolerate statins.
  • '’Vaccine’’ against PCSK-9: inclisiran -> s.c. 2x/year; more convenient and cheaper
27
Q

Inclisiran

A
  • '’Vaccine’’ against PCSK-9
  • s.c.
  • 2x/year
  • more convenient and cheaper than MABs against PCSK-9
28
Q

Bile acid sequestrants

A
  • group of resins used to bind certain components of bile in the GIT
  • disrupt enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption from the gut
  • hypolipidaemic agents and used for lowering cholesteorl
  • less effective than statins