Lecture 14 - Hypolipidemic and Antianginal Drugs Flashcards
What medical conditions could result from vessel blockage?
- Coronary artery disease and heart attack
- Angina
- Stroke or transient ischemic attack
- Peripheral artery disease
- Intermittent claudication (pain and numbness in the limbs)
What is the physiological function of cholesterol?
- Building block of steroid hormones
- Essential for building cell membranes and myelin sheath
- Important for building signal domains
- Core component of bile salts secreted by the gallbladder to digest dietary fats
Source: 75-80% is synthesized in the liver and intestine, 20-25% via absorption
What are lipoproteins?
Apoproteins attached to cholesterol and fat
Types of lipoproteins
Chylomicrons
- Apoproteins B48 and triglycerides (90%)
- Transport dietary triglycerides and exogenous cholesterol
Types of lipoproteins
Very-low-density lipoprotein (VLDL)
- Apoproteins A1, B100, triglyceride (55%), and cholesterol (20%)
Types of lipoproteins
Low-density lipoprotein (LDL)
- Apoprotein B-100, cholesterol (53%)
Types of lipoproteins
High-density lipoprotein (HDL)
- Apoproteins E and cholesterol (20%)
Chylomicron processing pathway
- Lymph absorbs chylomicron from small intestine
- Lymph drains into bloodstream
- Lipoprotein lipase removes lipids from chylomicrons
- Lipids stored in adipocytes or used by other cells while liver disposes remnants of the chylomicron
VLDL/LDL processing pathway
- Liver produces VLDLs
- Triglycerides are removed and stored in adipocytes. VLDLs become LDLs containing mainly cholesterol
- cells absorb LDLs by receptor-mediated endocytosis
HDL processing pathway
- Liver produces empty HDL shells
- HDL shells pick up cholesterol and phospholipids from tissues
- Filled HDLs return to liver
- Liver excretes excess cholesterol and bile acids
How is plaque formed?
Plaque begins as streaks of fat in the arterial wall. When a vessel is damaged through infection, inflammation, diabetes, or high blood pressure, LDL-cholesterol migrates to the injured area. LDL is then consumed by macrophages
which transform into cholesterol-rich foam cells. Foam cell production continues over time and causes buildup of atherosclerotic plaque.
What is stable plaque?
Has a cholesterol core with fibrous cap and may contain calcium
What is unstable plaque?
Has a cholesterol core with a thin cap that can erode and rupture
Why is LDL cholesterol considered ‘bad cholesterol’?
LDL is atherogenic. It transports cholesterol to damaged areas in the arteries and forms plaques
Why is HDL cholesterol considered ‘good cholesterol’?
HDL is anti-atherogenic. it goes looking for cholesterol to return to the liver for disposal
What is lipidemia?
The presence of excess lipids in the blood
List the types of hypolipidemic drugs
1) HMG-CoA reductase inhibitors
(statins)
2) Bile acid sequestrants
3) Cholesterol absorption inhibitors
4) Fibric acid derivatives
5) Nicotinic acid (Vitamin B3, Niacin)
Statins - Clinical indications
- Treatment of primary hyperlipidemias
- To slow the progression of atherosclerosis
Statins - Mechanism of action
- Competitively inhibit HMG-CoA reductase (first commited reaction of cholesterol synthesis)
- Reduces plasma levels of LDL and cholesterol
- Decrease plasma levels of triglycerides
- Increase HDL-cholesterol levels
- Lower the levels of C-reactive protein
What is C-reactive protein?
A protein released during injury and inflammation. High levels may increase the risk for atherosclerosis.
List some statins
Simvastatin, Atorvastatin, Fluvastatin, Prevastatin, etc.
Statins - Contraindications
Pregnancy and breastfeeding
- cholesterol is an essential component for fetal and infant sythesis of steroids and cell membrane development
Statins - major side effects
Muscle weakness, myopathy (rare), and liver damage
Ezetimibe - Mechanism of action
Cholesterol absorption inhibitor
- Acts on the surface of the small intestine to selectively block the absorption of cholesterol
- Decreases VLDL and circulating LDL-cholesterol
How does fat absorption occur?
Bile acid-containing micelles aid lipases to digest lipids and bring them near the intestinal brush border membrane
Cholestyramine (and colestipol, colesevelam) - Mechanism of action
Bile acid sequestrants
Binds bile salts and cholesterol in the intestinal tract
- prevents the absorption of both
- cholestyramine is an ion-exchange resin
- recommended in the management of partial biliary obstruction
What is a copolymer?
Cholestyramine is a copolymer
A polymer formed when two (or more) different types of monomers are linked in the same polymer chain
Niacin (or vitamin B3) - Mechanism of action
Nicotinic acid
Affects cholesterol synthesis through a G protein-coupled receptor
- Inhibits triglyceride lipase and stimulates lipoprotein lipase
- decreases free fatty acid release and removes triglycerides
- increases HDL and reduces total cholesterol and LDL
Gemfibrozil and fenofibrate - Mechanism of action
Fibric acid derivatives
Inhibit triglyceride lipolysis
- Decrease free fatty acid uptake by the liver and hepatic VLDL-triglyceride synthesis
- Increases HDL
Describe what happens after fibrate activation of peroxisome proliferator-activated receptor-alpha (PPARa)
- Increased apoA-I, apoA-II synthesis in hepatocytes –> increased plasma HDL
- Increased fatty acid oxidation in hepatocytes –> decreased triglyceride synthesis –> decreased plasma triglycerides
- Decreased apoC-III synthesis in hepatocytes and increased lipoprotein lipase expression in muscle vascular beds –> increased fatty acid uptake in muscle cells and increased fatty acid oxidation in muscle cells –> decreased plasma triglycerides
What does the activation of PPAR-gamma cause?
Insulin sensitization and enhnced glucose metabolism
Other hypolipidemic drugs
Evolocumab
- PCSK9 inhibitor
- Increase the number of receptors on the liver that remove LDL cholesterol from the blood
Other hypolipidemic drugs
Apo Antisense Oligonucleotide
New class of drug that can lower LDL cholesterol
Lomitapide and Mipomersen
Used to treat familial hypercholesterolemia by limiting the liver’s production of apolipoprotein B, which is used to make VLDL and LDL
List the types of antianginal drugs
- Nitrates
- Beta antagonists
- Calcium channels blockers
What is angina?
- Chest pain
- Most common symptom of coronary artery disease
- occurs when too much plaque builds up inside arteries, causing them to narrow
Nitrates - Indications
Used during angina attacks to relieve pain
- Used on a daily basis to prevent angina attacks
- can be administered prophylactically on a daily basis to prevent attacks of angina
Nitrates - Mechanism of action
Produces a general vasodilation of systemic veins and arteries
- provide nitric oxide to relax vascular smooth muscle
- Vasodilation decreases preload and afterload
Mechanism of viagra
- Release of nitric oxide –> activates guanylate cyclase which converts GTP to cGMP –> cGMP action results in arterial smooth muscle relaxation, increasing blood flow
- Phosphodiesterase-5 (PDE-5) breaks down cGMP to GMP <– viagra inhibits PDE-5
Nitrates - Clinical use
Sublingual nitroglycerin
- relieves acute angina attacks
- avoid first-pass metabolism and provides the fastest relief for acute angina
Nitroglycerin ointment 2%
- helps prevent the occurence of angina
Nitroglycerin extended-release capsules
- Used daily as a form of prophylaxis (8-12 hrs)
Beta-adrenergic blocking drugs - Mechanism of action
Reverse the effects of sympathetic activation
- Decrease heart rate and force of contractions
- Decrease cardiac work and oxygen consumption
- Thereby prevents development of myocardial ischemia and pain
Beta-andrenergic blocking drugs - Indication
Long-term (chronic) management of angina pectoris
Propanolol
Beta-Adrenergic blocking drug used as an antianginal
Calcium channel blockers - Mechanism of action
- Inhibit the influx of calcium ions into vascular smooth muscle –> enables arteriolar vasodilation and reduces blood pressure
- Administered daily
- Relax ARTERIAL smooth muscle (has little effect on veins)
- Primary effect is arteriolar vasodilation and reduction of blood pressure –> reduces cardiac and oxygen consumption
Calcium channel blockers
Verapamil
- Direct cardiac effects (vasodilation; also decrease heartrate, AV conduction, and the force of myocardial contraction)
- Used to treat supraventricular arrhythmias and angina
Calcium Channel Blockers
Diltiazem
- Direct cardiac effects (vasodilation; also decrease heartrate, AV conduction, and the force of myocardial contraction)
- Possesses greater vasodilating effects in comparison to verapamil
Calcium Channel Blockers
Nifidepine
- No direct cardiac effects
- L-type calcium channel blocker
- Potent arterial vasodilator
Calcium channel blockers
Nicardipine
- No direct cardiac effects
- Causes vasodilation and relaxation of coronary artery system
Other calcium channel antagonists
Amlodipine, felodipine, isradipine
