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Pharmacology 3 > L15: Cardiovascular Pharmacology - Pathophysiology (Coronary Heart Disease) > Flashcards

L15: Cardiovascular Pharmacology - Pathophysiology (Coronary Heart Disease) Flashcards

1
Q

What is coronary heart disease?

A

Common but serious condition where the blood vessels supplying the heart are narrowed or blocked by build up of fatty acids.

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2
Q

What is atherosclerosis?

A

Thickening or hardening of the arteries

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3
Q

What can be an outcome of coronary heart disease?

A

Lack of oxygen and chest pain (angina) OR myocardial infarction

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4
Q

What does healthy vascular endothelium regulate?

A
  • vessel tone
  • leukocyte adhesion
  • platelet aggregation
  • tendency for thrombus formation
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5
Q

What do changes in vascular endothelium result in?

A

Changes in endothelial function precede lesion formation

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6
Q

What are the causes of endothelial dysfunction?

A
  • elevated and modified low density lipoprotein (high cholesterol levels)
  • oxygen free radicals caused by smoking, hypertension, activated inflammatory cells
  • infectious microorganisms: herpes virus, chlamydia pneuomoniae, H. pylori
  • physical damage and gene activation by turbulent flow, high blood pressure (increases the damage of endothelia)
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7
Q

How does a fatty streak in vessels form?

A

Fatty streaks appear when the presence of foam cells at the site of plaque formation expands. Foam cells: macrophages take up low density lipoprotein oxidised by interaction with oxygen free radicals.

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8
Q

How does advanced complex lesion form?

A
  • After foam cells formation.
  • Macrophages accumulate, smooth muscle cell proliferation and migration.
  • Fibrous-cap forms as a healing response to injury.
  • Necrotic core forms - leukocytes, lipid and cell debris from apoptosis, necrosis and proteolysis.
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9
Q

What are the risk factors for Coronary Heart Disease?

A

Risk factors:
- high lipid, low anti-oxidants diet
- genetic
- smoking
- hyperlipidaemia (elevated level of lipids in plasma)
- hypertension
- diabetes
- being a male

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10
Q

What is the difference in the outcome of stable/unstable cap formation in vessels?

A

Stable cap results in angina; unstable cap results in myocardial infarction / stroke.

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11
Q

What are the pharmacological tools for treatment of coronary heart disease?

A
  • Development reducing: lipid-lowering drugs - statins, fibrates, ezetemibe
  • treat symptoms: stable angina
  • prevent thrombosis
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12
Q

What is the surgical intervetion for treatment of coronary heart disease?

A
  • stent placement
  • balloon angioplasty for plaque removal
  • coronary artery bypass grafting
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13
Q

What are statins?

A

Lipid lowering drugs for prevention of coronary heart disease. They are HMG-CoA reductase inhibitors

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14
Q

How do statins lower lipid formation? What is the mechanism of LDL formation and clearance?

A
  • HMG CoA is converted to mevalonate by HMG CoA reductase, which is converted to cholesterol and finally to LDL.
  • LDL acts on LDL receptors, which induce clearance from circulation.
  • When HMG CoA reductase is inhibited, LDL receptors expression is increased, thus increased clearance from circulation.
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15
Q

What are the pleiotropic effects of statins?

A
  • improved endothelial function
  • inhibition of inflammation
  • plaque stabilisation
  • inhibition of thrombus formation
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16
Q

What are the side effects of statins?

A
  • muscle pain
  • increased risk of diabetes
  • liver damage
17
Q

How do fibrates decrease LDL in plasma?

A

Decrease circulating LDL and triglyceride, only small effect on LDL, but also increase ‘protective’ high density lipoprotein (HDL).
Activate peroxisome proliferator-activated receptors (PPAR-alpha) and increase expression of genes associated with lipid clearance, e.g. lipoprotein lipase.

18
Q

How does ezetimibe reduce LDL levels in plasma?

A

Blocks transport of cholesterol in gut, withour affecting absorption of fat soluble vitamins, triglycerides or bile acids.
Added to statin where response is inadequate alone

19
Q

What is thrombosis?

A

Inappropriate platelet activation and coagulation. Can be arterial and deep vein thrombosis.

20
Q

What is the result of arterial thrombosis?

A
  • Heart attacks (MI)
  • Stroke
  • peripheral vascular disease
21
Q

What is the deep vein thrombosis?

A
  • ‘economy class syndrome’
  • oral contraceptives
22
Q

What is myocardial infarction?

A

Loss of supply to part of heart caused by blockage in coronary artery. Acute: pain or fatal arrythmias. Also injury and chronic heart failure.

23
Q

What is the effect of anti-thrombotic drugs on myocardial infarction?

A

They can reduce the risk of clot formation on a ruptured atherosclerotic plaque.

24
Q

What are platelets?

A

Platelets (thrombocytes) are small, colorless cell fragments that form clots and stop or prevent bleeding. Made in bone marrow.

25
Q

How endothelial cells prevent clot formation in healthy blood vessel?

A

Endothelial cells produce agents that prevent platelet activation and coagulations.

26
Q

How does a clot form in a vessel?

A
  • Damage to the endothelial cells allows bleeding and exposes platelets to collagen in the vessel wall.
  • Platelets are activated and aggregate to prevent blood loss, endothelial cells reduce secretion of anti-aggregant.
  • Fibrin is formed by the coagulation cascade to stabilize the platelet plug
    For summary see L15, slide 46
27
Q

What is the precise mechanism of platelets activation?

A

For diagramm see L15, slide 49
- stimulus (collagen, thrombin) gets converted to arachidonic acid by phospholipase A2.
- arachidonic acid gets converted to cyclic endoperoxidases by COX
- then cyclic endoperoxidases are converted to thromboxane A2 by Tx synthase
- thromboxane A2 acts on TxA2 receptor, which induces release of calcium ions, which activate the platelets

28
Q

What are the drugs of anti-platelet formation? What is their mechanism?

A
  1. COX inhibitor: aspirin; irreversibly inhibits cyclooxygenase to prevent thromboxane formation
  2. P2Y12 receptor antagonists: clopidogrel, irreversibly block the receptor.
29
Q

What is the drawback of anti-platelet drugs?

A

As platelets have no nucleus, these platelet activation pathways cannot be overcome until new platelets are made, can increase problems with bleeding.

30
Q

What are the 2nd generation reversible anti-platelet drugs?

A

reversible P2Y12 antagonists, cangrelor, ticagrelor; non-covalent binding, no need for new platelets

31
Q

How do the Thrombin-receptor antagonists work?

A

Prevent activation of PAR-1 receptors on platelets by thrombin. Potential for use in place of, or in addition to existing anti-platelet, effective in reducing risk of ischaemia but risk of intracranial bleeding so not suitable for all patients.

32
Q

Describe precise coagulation mechanism

A

Series of clotting factors (serine proteases) get activated by one another. When blood vessel gets damaged, last factor gets activated. It induces formation of prothrombin to thrombin. Thrombin acts on fibrinogen conversion to fibrin. Last factor stabilises fibrin.

33
Q

What is Antithrombin III (ATIII)? How does it act?

A

It’s a protease, which inhibits coagulation by acting on clotting factors. ATIII is activated by Heparin.

34
Q

What is the importance of heparin in blood clotting?

A

It’s an activator of antithrombin II through binding to both ATIII and a protease. Accelarates neutralisation of serine proteases (clotting factors). NOT active orally.

35
Q

What are the orally active anti-coagulants?

A
  • Factor Xa inhibitor. Blocks intrinsic and extrinsic coagulation pathways.
  • Direct inhibitor of thrombin (factor II) enzyme activity, bleeding risk
36
Q

What are clot-busting fibrinolytic drugs?

A
  • effective at reducing mortality if given immediately after MI or stroke
  • act to accelerate conversion of plasminogen to plasmin, which degrades fibrin in thrombus

Pharmacology 3 (21 decks)

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