Drugs for Dyslipidemia Flashcards
(33 cards)
What is first approach to manage dyslipidemia?
- reduce total intake of cholesterol and saturated fats
Increasing what will lower CVD risk?
- increasing HDL will lower CVD risk
- weight reduction: 5-20%
- physical activity: 5-30%
What is the goal for lipid therapy?
- Lower LDL
- Increase HDL
High LDL is bad
Low HDL is bad
What is the Friedewald Equation?
LDL = total cholesterol - HDL - (triglycerides/5)
What is the role of Statins?
- block rate limiting enzyme HMG-CoA Reductase in cholesterol synthesis
- Simvastatin (Zocor)
- Atorvastatin (Lipitor)
- Rosuvastatin (Crestor)
What are common features of Statins?
- decrease LDL and VLDL
- inhibitor of HMG-CoA reductase which is the enzyme that converts HMG-CoA to mevalonate
- decreases cholesterol synthesis and upregulates LDL receptors (upregulation of LDL receptors increases rate of LDL extraction in blood and LDL precursors (VLDL remnants) in liver
- decrease oxidative stress and vascular inflammation
What therapy is standard to start immediately after MI irrespective of lipid levels?
- Statins
- cholesterol synthesis is highest at night and they should be taken then to maximize the inhibition of cholesterol synthesis
- Lovastatin must be taken at night due to short half life
- Atorvastatin and Pravastatin have longer half lives and it doesn’t matter
- absorption is better when taken with food except for Provastatin
Statin Contraindication?
- pregnancy (category X) or trying to conceive
What are Statin side effects?
- myalgia and myopathy
- rhabdomyolysis
- hepatotoxicity
- possible onset of Type 2 diabetes
What Drugs interact with Statins?
- Grapefruit juice
- Drugs that inhibit or compete for CYP3A4 or CYP2C9 will increase the plasma concentration of statins.
- Drugs that induce CYP will reduce plasma statin levels
- concomitant use of amiodarone or verapmil cause increased risk of myopathy
Why do CYP3A4 and CYP2C9 matter for Statins?
Statins are metabolized (broken down) in your liver by enzymes, especially CYP3A4 and CYP2C9. These are like little liver workers that help process many medications.
💊 If another drug inhibits or competes for CYP3A4 or CYP2C9:
* That liver enzyme gets blocked or overwhelmed.
* Statins don’t get broken down as quickly.
* Statin levels in the blood go up ✅
* Higher risk of side effects like muscle pain or damage (myopathy)
Examples of CYP inhibitors:
- Amiodarone (heart rhythm drug)
- Verapamil (blood pressure/heart drug)
- Grapefruit juice 🍊 (yes, really!)
Why amiodarone or verapamil increases myopathy risk with statins:
These drugs block CYP enzymes and may have additional muscle-toxic effects. So when taken with statins:
* More statin in the blood
* * muscle stress from both drugs
* = greater chance of muscle injury (ranging from mild pain to serious rhabdomyolysis)
What do Inducers of CYP do to Statins?
If a drug induces CYP enzymes (makes the liver work faster):
* Statins get broken down too quickly.
* Blood levels of statins go down.
* The statin might not work well 💔
Examples of inducers:
* Rifampin (antibiotic)
* Phenytoin (seizure med)
What is VLDL?
VLDL = Very Low-Density Lipoprotein
It’s a type of lipoprotein made by your liver to carry triglycerides (a type of fat) through your bloodstream.
So… is it bad?
Yes, in high amounts, VLDL is bad.
Here’s why:
✅ Normal role:
* Transports triglycerides from liver to tissues for energy or fat storage.
* Everyone has some VLDL — that’s normal and needed.
❌ When it becomes a problem:
* Too much VLDL means too many triglycerides in your blood.
* VLDL gets converted into LDL (“bad cholesterol”) in your bloodstream.
* High VLDL = higher risk of atherosclerosis, heart attack, stroke.
How do we measure it?
* It’s not usually measured directly.
* Often estimated from triglyceride levels.
* If triglycerides are high, VLDL is likely high too.
What is Cholestyramine?
- they bind to bile acids in the intestinal lumen and prevent their normal reabsorption
- the fecal loss of bile acids results in an increased hepatic synthesis of bile acids from cholesterol
- fall in hepatic cholesterol content results in an up regulation of LDL receptors: If the liver loses cholesterol (for example, because a drug like cholestyramine is removing bile acids, and the liver uses cholesterol to make more), the liver needs to replenish that cholesterol.
How does the liver get more cholesterol?
It pulls cholesterol from the blood by increasing the number of LDL receptors on its surface.
* LDL receptors are like “catchers” that grab LDL cholesterol (the “bad” cholesterol) from your blood.
* More receptors = more LDL taken out of the blood.
So what does upregulation of LDL receptors mean?
* Upregulation = increasing the number or activity.
* The liver increases its LDL receptors.
* This helps the liver absorb more LDL cholesterol from the bloodstream.
* Result: Blood cholesterol levels go down.
What is Cholesterol?
Cholesterol is a fatty substance your body uses to build cells, hormones, and make bile acids.
- It’s made in the liver and also comes from food.
What are Bile Acids and Bile Salts?
➤ Bile acids
* These are made in the liver from cholesterol.
* Their job is to help digest fats in your food.
➤ Bile salts
* Once bile acids are made, they are combined with other substances (like sodium or potassium) to make bile salts.
* Bile salts are the active form that can mix with fats and break them down in the intestine.
💩 What happens in digestion?
1. Liver makes bile acids from cholesterol.
2. They’re stored in the gallbladder.
3. When you eat fatty food, bile is released into your small intestine.
4. Bile salts mix with fat and help digest it.
5. After doing their job, most bile salts are reabsorbed and sent back to the liver to be used again. (This is called the enterohepatic circulation.)
🧲 So how does this help remove cholesterol?
Here’s where drugs like cholestyramine come in:
1. Cholestyramine binds to bile salts in the intestine.
2. This prevents them from being reabsorbed.
3. So, more bile is lost in your poop.
4. Your liver says: “Hey, I need to make more bile acids!” and to do that…
5. It uses up more cholesterol to make new bile acids.
6. This lowers cholesterol levels in the liver and blood.
Where does Bile acid turn into Bile salts?
Bile acids are turned into bile salts in the liver — before they go into the gallbladder or the intestine.
Here’s the step-by-step breakdown:
- Liver makes bile acids
- Your liver takes cholesterol and turns it into primary bile acids.
- Examples: cholic acid, chenodeoxycholic acid
- Bile acids are conjugated (modified)
- Before they leave the liver, these bile acids are joined (conjugated) with either:
- Glycine or
- Taurine
- This chemical change turns them into bile salts — which are more water-soluble and active.
🧪 Example:
* Cholic acid (a bile acid) + glycine → Glycocholic acid (a bile salt)
- Bile salts are stored in the gallbladder
- Now that they’re bile salts, they’re stored in the gallbladder as part of bile (a yellow-green fluid).
- Bile also contains water, phospholipids, pigments, and waste products.
- Bile is released into the small intestine
- When you eat a fatty meal, the gallbladder squeezes out bile (including bile salts) into your small intestine (specifically the duodenum).
- The bile salts now help digest fats by emulsifying them — breaking them into small droplets for enzymes to work on.
⸻
🔁 After Digestion
Most bile salts are:
* Reabsorbed in the last part of the small intestine (the ileum)
* Sent back to the liver via the portal vein
* Reused again and again (this is the enterohepatic circulation)
Why is Cholestyramine and similar bile acid-binding drugs (like colesevelam and colestipol) are often contraindicated (not recommended) in patients with high triglycerides (hypertriglyceridemia?
🧠 Understanding Why — Step-by-Step:
- The liver is losing bile acids (because the drug is binding and removing them in the stool).
- The liver responds by trying to make more bile acids, which uses up cholesterol.
So far, so good. ✅
- The liver also increases LDL receptor activity to pull in more cholesterol from the blood.
(That’s why LDL levels drop, which is good.)
BUT…
⸻
- The liver also ramps up production of VLDL (very low-density lipoproteins), which are rich in triglycerides.
Why does this happen?
* The liver interprets the cholesterol loss as a need to produce more lipids overall.
* This includes more triglyceride-rich VLDL.
* Also, insulin resistance or metabolic syndrome (common in people with high triglycerides) can make this effect worse.
🧬 So the key mechanism is:
Bile acid sequestrants increase liver demand for cholesterol — and in trying to meet that demand, the liver also ramps up triglyceride production.
Do we only treat patients with an ISOLATED INCREASE IN LDL with Cholestyramine?
Yes.
this drug may also interact and inhibit the absorption of fat soluble vitamins ADEK
What are LDL reducing but hypertriglyceride decreasing drugs?
Cholestyramine
Colesevelam
Colestipol
What are 3 FIbrates?
💊 Common fibrates:
1. Gemfibrozil (Jim 😄)
2. Fenofibrate (also sold as Tricor)
3. Clofibrate (older, rarely used now)
How do Fibrates work?
Fibrates are used to treat:
* High triglycerides
* Mixed dyslipidemia (when both cholesterol and TGs are abnormal)
* Sometimes to prevent pancreatitis in people with very high triglycerides
Here comes the key:
They activate a receptor in your cells called PPAR-alpha (Peroxisome Proliferator-Activated Receptor Alpha).
⸻
🔓 What is PPAR-alpha?
Think of PPARα as a “gene switch” that lives mostly in liver cells (hepatocytes) and muscle cells (like skeletal muscle).
When turned on (activated), it tells the cell to do things that reduce triglycerides.
⚙️ So what happens when fibrates activate PPARα?
- ↑ Lipoprotein Lipase (LPL) expression
- This enzyme breaks down triglycerides in blood (especially in VLDL and chylomicrons).
- More LPL = faster clearance of triglycerides from the blood.
- ↓ VLDL production
- The liver makes less VLDL, the triglyceride-rich particles.
- ↑ Fat oxidation
- Muscle and liver cells burn more fatty acids for energy instead of storing them.
- ↑ ApoA-I and ApoA-II
- These proteins help make HDL → slightly increases HDL cholesterol.
💥 Why this works:
Triglycerides are mainly carried in VLDL and chylomicrons. If you:
* Make less VLDL
* Break down VLDL faster (via LPL)
* Burn more fat in cells
→ Your triglyceride levels drop.
Why is a side effect of using Fibrates the formation of Gallstones?
🧱 Step 1: Triglycerides ≠ Cholesterol
They’re both lipids (fats), but:
* Triglycerides = energy storage fat (3 fatty acids + glycerol)
* Cholesterol = building block for hormones, bile acids, membranes
They don’t directly convert into each other in normal metabolism.
⚙️ Step 2: What does fibrate actually do?
Fibrates activate a receptor called PPAR-alpha, mainly in the liver and muscles.
When PPAR-alpha is turned on:
* The liver:
* Breaks down fatty acids
* Makes less VLDL → less triglycerides in blood
* Slightly shifts cholesterol metabolism too
* One of the effects of this shift is:
* The liver excretes more cholesterol into bile
So fibrates do NOT create more cholesterol, but they change where cholesterol goes — more gets sent into bile.
🚚 Step 3: Why is cholesterol going into bile?
Think of bile like a garbage truck. The liver uses bile to get rid of excess cholesterol.
The liver:
1. Takes some cholesterol and converts it to bile acids
2. Dumps the rest of it unchanged into bile
Fibrates increase this dumping by upregulating transporter proteins (like ABCG5/8) that shuttle cholesterol from liver cells into bile.
🪨 Step 4: So what’s the problem?
When there’s too much cholesterol in bile, and not enough bile salts to keep it dissolved:
* Cholesterol crystallizes
* That leads to gallstones
So it’s not that fibrates are making cholesterol from triglycerides — it’s that they tell the liver to lower triglycerides, and as a side effect, the liver dumps more of its existing cholesterol into bile, which can form stones.
What fibrate will reduce statin metabolism and increase the risk of rhabdomyolysis and myoglobinuria?
Gemfibrozil
