Pharmacology of Medicines for Hyperlipidaemia and Angina Flashcards
what is atherosclerosis?
a slowly progressing arterial disease in which intima (the innermost membrane of an organ) is thickened by fibrous deposits that gradually narrow the lumen and gradually becomes a site of thrombus formation
what is the earliest visible sign of atherosclerosis?
fatty streaks
what is accumulated to form a fibrous plaque?
- monocytes
- macrophages
- foam cells
- T-lymphocytes
- connective tissue
- tissue debris
- cholesterol crystals
what are foam cells?
- monocytes move to the subendothelium and are transformed into macrophages.
- these consume excess modified lipoproteins to become foam cells
how does a atherosclerotic plaque evolve from a fatty streak?
- fatty streak present
- soft atherosclerotic plaque develops which is vulnerable to fissure (cracks/narrow opening) or haemorrhage
- interaction of soft atherosclerotic plaque with circulating cells (platelets and macrophages) and neurohumoral factors
- fibrous cap develops when smooth muscle migrates to intima producing a tough fibrous matrix gluing cells together
what are unstable plaques?
- plaques with a lipid-core and substantial inflammatory cell infiltration.
- also has a thin fibrous cap
- prone to plaque disruption by ulceration (leading to thrombus formation)
what are stable plaques?
plaques with a thick fibrous cap
give an example of a local vasodilator?
nitric oxide
what effect does a long-standing coronary heart disease caused by an atheroma have?
it leads to collateral vessels, around the atheromatous, narrowing
what causes atherosclerosis?
1, hyperlipidaemia
- smoking
- hyperhomocysteinemia (as homocysteine favours plaque formation)
at what site do plaques form?
sites of high mechanical stress (making hypertension a risk factor)
what are the consequences of atherosclerosis?
- narrowing of the lumen leading to ischemia and coronary heart disease
- Stiffening of the vessel wall (calcification)
- Thrombus formation obstructing residual lumen and causing peripheral emboli (e.g. cerebral infarction, stroke)
- Bleeding into the plaques and vessel wall.
- Wall may be stretched, creating aneurysm, and even rupture
What are some prophylactic interventions that may take place to prevent/reduce chances of developing atherosclerosis?
- Dietary changes to reduce cholesterol & lipids
- Cessation of Smoking
- Control of Blood Pressure
- Control of Diabetes
- Regular, moderate exercise
- Drugs to reduce plasma cholesterol
explain how cholesterol is transported?
- chylomicrons transport lipids from the gut to the periphery
- in the liver, chylomicron remnants bind to LDL receptors via ApoE and are endocytosed producing new trigycerides and cholesterol which are exported as VDLP
- these activate LPL leading to fatty acid release
- some VLDL and IDL remnants leave as VLDL and LDLs
- this delivers cholesterol
what happens when there’s a rise in intracellular cholesterol levels?
- Key enzyme of cholesterol synthesis inhibited (3-HMG-CoA reductase)
- Cholesterol is esterified to its storage form
- LDL receptor synthesis inhibited
what do high density lipoproteins do?
- exchange certain apolipoproteins with chylomicrons and VLDLs and also take up excess cholesterol from extrahepatic cells and blood.
- Pass cholesterol and Chol-E to liver, and steroid hormone–producing glands
what is the effect of an elevated cholesterol-rich LDL in the serum?
it increases the binding of LDLs to the scavenger receptor that mediates the incorporation of cholesterol in macrophages, skin and vessel walls
what ways to drugs lower lipid levels?
- inhibition of cholesterol synthesis (e.g. HMG -CoA reductase inhibitors)
- prevent cholesterol reabsorption
- reduce VLDL secretion (e.g. niacin)
- Increase synthesis of lipoprotein lipase (e.g fibrates)
how do statins work to inhibit cholesterol synthesis?
by inhibiting HMG-Co- reductase that blosck de novo synthesis of cholesterol
what are some side effects to using statins?
- May damage skeletal muscle or liver
- Interfere with myelination of infants (contraindicated in pregnancy)
how do resins prevent cholesterol absorption?
resins or non-absorbable macromolecules so they bind to cholesterol preventing absorption from the gut
what are the side effects to using resins?
- Unpleasant gritty taste
- GI tract discomfort
- Interference of vitamin or drug absorption
what are side effects to using niacin?
- Occasional flush with itching reduced with aspirin
- Rarely causes glucose intolerance
How do Fibrates increase lipoprotein lipase synthesis?
Activate peroxisome proliferation-activated receptor-α (PPARα), increasing lipoprotein lipase synthesis and β-oxidation of lipids
what are some side effects to using fibrates?
- Nausea
- Skin Rash
- Occasional increase risk of gallstones
