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Drug action > Atherosclerosis & thrombosis (Block 3) > Flashcards

Atherosclerosis & thrombosis (Block 3) Flashcards

(54 cards)

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1
Q

Atheroma

A

a focal disease of the intima-endothelial layer of large and medium-sized arteries

(Means that in specific areas the endothelial cells that line the arteries start to form fatty deposits)

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2
Q

Unalterable risk factor for atheromatous disease

A

Family history of ischaemic heart disease

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3
Q

Modifiable risk factors for atheromatous disease

A

Raised or reduced LDL (low-density lipoprotein) hypertension
obesity
physical inactivity
smoking
diabetes mellitus
etc.

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4
Q

Stages to atherogenesis

A

1) Endothelial dysfunction
2) Endothelium injury leads to monocyte attachment
3) Attached monocytes and ECs generate free radicals, oxidising LDL bound to ECs
4) Oxidised LDL is taken up by macrophages, which become foam cells. These migrate sub-endothelially to form fatty streaks (precursors of atheroma)
5) SMC hyperplasia and matrix deposition; leads to a dense fibrous cap overlying a lipid-rich core
6) Rupture leading to thrombus formation

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5
Q

Endothelial dysfunction

A

altered PGI2 and NO biosynthesis

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6
Q

Endothelium injury cause example

A

From disturbed flow at vessel junctions

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7
Q

Major dietary lipids

A

Triacylglycerols (TAGs; more than 90%)
Cholesterol esters
Phospholipids
Free fatty acids

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8
Q

Digestion of lipids in the mouth

A

Enzymes are aqueous; little effect of lipids

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9
Q

Digestion of lipids in the stomach

A

Causes a large physical change - churned into droplets called “chyme”
20% of TAGs hydrolysed in stomach by gastric lipase

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10
Q

Lipoprotein transport

A

Lipids and cholesterol are transported in the blood as lipoproteins **

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11
Q

4 main classes of lipoprotein

A

Chylomicrons (exogenous transport)
HDL (endogenous)
LDL (endogenous)
VDL (endogenous)

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12
Q

Transport of exogenous lipids

A

Chylomicrons (100-1000nm dia) transport dietary lipids from the gut via lymph and plasma to capillary beds
• The core triglycerides are then hydrolyzed to free fatty acids (FFA) by lipoprotein(LP)-lipase
• Chylomicron remnants (30-50nm) transport cholesterol esters to the liver where they are endocytosed
• Released cholesterol is either stored, oxidised to bile acids (secreted in bile), or transported with triglycerides by the endogenous transport pathway

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13
Q

Transport of endogenous lipids

A

Cholesterol and triglycerides transport from the liver to the tissues by VLDL
• Triglycerides are taken up by the tissues, leaving LDL containing cholesterol esters
• Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoprotein
• Cholesterol can return to plasma from tissues in HDL particles (7-20nm dia.)

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14
Q

LDL and thrombosis

A

• Lipoprotein(A) in LDL contains lipids and Apo(A). Apo(A) inhibits plasmin formation, thereby inhibiting fibrinolysis and promoting thrombosis
• LDL also activates platelets, hence further driving thrombosis

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15
Q

Elevated LDL and reduced HDL cholesterol levels lead to what?

A

Increased risk of cardiovascular disease

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16
Q

Dyslipidaemias

A

Dyslipidemia refers to abnormal levels of lipids in the bloodstream. There are primary and secondary forms

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17
Q

Primary dyslipidaemias

A

Genetic
Classified into 6 phenotypes

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18
Q

Primary dyslipidaemia example - type IIa hyper-lipoproteinaemia

A

Caused by LDL receptor defects, leading to elevated LDL levels, dysfunction thrombosis, and increases risk of ischaemic heart disease

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19
Q

Secondary dyslipidaemias

A

Caused by environment/lifestyle
Risk factors for diabetes and renal, thyroid, and liver diseases

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20
Q

Lipid lowering drugs

A

Used in addition to control of modifiable risk factors

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21
Q

Main classes of clinically used lipid lowering drugs

A

Statins
Vibrates
Bile acid-binding resins
Ezetimibe

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22
Q

Statins examples

Study These Flashcards
A

Simvastin, Lovostatin, prevastatin

23
Q

Statins

Study These Flashcards
A

Competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis (catalyzing the conversion of HMG-CoA to mevalonic acid)
Lower cholesterol synthesis increases LDL receptor synthesis and leads to increased LDL clearance
Main effect is to reduce plasma LDL-cholesterol concentrations

24
Q

Other actions of statins include

Study These Flashcards
A

• Improved endothelial function (endothelial NOS)
• Reduced vascular inflammation
• Reduced platelet aggregration (NOS)
• Increased neovascularization under hypoxia
• Increased circulating endothelial cell progenitors
• Plaque stabilization
• Reduced atherosclerosis and plaque stabilization
• Increased fibrinolysis
• Possible increased bone mineral density

25
Clinical use of statins
Reduce the risk of myocardial infarction and stoke in patients with symptomatic atherosclerotic disease Prevention of arterial disease in patients who are at high risk
26
Atorvastatin
Has long lasting effects and is used to lower serum cholesterol levels in patients with LDL-R mutations
27
Side effects of statins
Muscle pain in some patients (rhabdomyolysis) -> can be quite severe in some patients but is often very mild
28
Fibrates
Agonists of the nuclear receptor PPAR-alpha, activation of which stimulates lipoprotein lipase production. Fibrates reduce SMC inflammation by inhibiting transcription factor NF-?B levels (this reduces fibrinogen)
29
Bile acid binding resins
Anion exchange resins Sequester bile acids in the intestine and prevent their réabsorption and recirculation This results in decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acids in the liver LDL receptor expression on liver is increased, causing further removal of LDL from blood
30
Common side effects of bile acid binding resins
Nausea, bloating, and diarrhoea
31
Drugs that inhibit cholesterol reabsorption
• Ezetimibe is one of a group of azetidione cholesterol absorption inhibitors. • Used as an adjunct to dietery changes and statins in hypercholesterolaemia. • Inhibit absortion of cholesterol in duodenum and small intestine by blocking transport protein (NPC1L1). • Administered by mouth
32
Haemostasis
The arrest of blood loss from damaged blood vessels
33
Main elements of haemostasis
Platelet adhesion and activation Blood coagulation (fibrin formation)
34
Thrombosis
Abnormal formation of a haemostatic plug within a blood vessel, in the abscene of bleeding A blood clot
35
3 main factors predispose to thrombosis
Damage to endothelium Poor or turbulent blood flow Hyper-coagulability
36
Blood cots vs thrombus
A clot form in static blood in vitro; they are amorphous and consist of a diffuse fibrin meshwork with random distribution of red and white blood cells A thrombus forms in vivo; they are organised aggregates of white and red blood cells, bound with fibrin. They are fixed to the blood cell wall, but may break off ad travel as an embolus to lodge in small blood vessels
37
First step in the formation of arterial thrombosis
Platelet activation
38
Platelet activation is induced by
Collagen (exposed when endothelial cell lining blood vessels are damaged) Thrombin (produced when they lood coagulation cascade is activated) Activated platelets (produce substances that cause further aggregation)
39
What substances produced by activated platelets lead to the further activation of other platelets?
Thromboxane A2 5-HT Platelet activating factor (PAF)
40
Coagulation cascade key facts
First step is conversion by thrombin of soluble fibrinogen to insoluble strands of fibrin • This is mediated by an enzyme (coagulation) cascade involving serine proteases (clotting factors) • Vitamin K is required for formation of clotting factors • The main clotting inhibitor is antithrombin III (neutralises all serine proteases in cascade) • Heparin is a major cofactor for antithrombin III activity • Clot lysis mediated by action of plasmin (activated via plasminogen)
41
Drugs affecting haemostasis and thrombosis
Anticoagulants Anti platelet drugs Fribronlytic drugs
42
Anticoagulants
Anticoagulants prevent formation of thrombi (clots), but will not break down existing clots. Used in treatment of venous thrombosis and embolism (e.g. DVT)
43
Anticoagulants - 2 examples
Heparin Warfarin
44
Anticoagulants - Heparin
Naturally occurring acidic mucopolysaccharide, administered by i.v. injection • Reduces blood clotting by inactivating thrombin (via antithrombin III)
45
Anticoagulants - warfarin
Given orally, interferes with the synthesis of vitamin K which is a natural coagulation factor • Potential for dangerous drug interactions; e.g. aspirin can increase its effect causing bleeding
46
Anti platelet drugs
Act of arterial thrombosis
47
Examples of antiplatelet drus
Aspirin Clopidogrel Epoprostenol Endothelial cells EDRF Heparin sulphate
48
Antiplatelet drugs - aspirin
Low doses reduce platelet aggregation by preventing thromboxane A2 formation
49
Antiplatelets - clopidogrel
irreversibly blocks the effects of ADP on platelets
50
Antiplatelet drugs - Epoprostenol (synthetic PGI2)
given as an intravenous infusion. It promotes vasodilation and inhibits platelet aggregation
51
Thombolytic drugs
A thrombus can be ‘dissolved’ using fibrinolytic drugs that activate plasminogen into plasmin, which degrades fibrin
52
Thrombolytic drugs - examples
Streptokinase Tissue plasminogen activator (tPA, alteplase)
53
Thrombolytic drugs - Streptokinase
Large protein molecule obtained from Streptococci cultures. Activates plasminogen
54
Thrombolytic drugs - tissue plasmingoen activator (tPA, altepase)
present in endothelial cells. Made recombinantly for drug use

Drug action (20 decks)

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