Anti-hyperlipidemic drugs Flashcards
What are hypolipidemics?
What is hyperlipoproteinemia?
Drugs used to lower increased levels of cholesterol or triglyceride containing lipoproteins in plasma.
Hyperlipoproteinemia is an elevated concentration of lipoproteins in the blood.
What specific lipoprotein has been show to have a clear relationship with occurrence of coronary heart disease?
LDL-C (low density lipoprotein with cholesterol)
What are the 2 main lipids in serum? What form do each circulate as?
- cholesterol circulates as LDL
2. triglycerides circulate as chylomicrons (diet) and VLDL (endogenous)
What is the biological importance of cholesterol?
- component of biological membranes
- precursor for steroids
- form bile acids
What has the closes correlation to the formation of atheromatous disease?
concentration of cholesterol in serum
What is the major function of transport of TGs in chylomicrons and VLDL?
Chylomicrons and VLDL deliver TGs that have been ingested or synthesized in the liver to extrahepatic tissue (muscle and adipose) to be stored.
What factor determines TG level in serum?
If you just ate, TGs will be high. Fasting TGs will be low
What are the 4 components of lipoprotein complexes?
What makes the outer shell and what is in the hydrophobic core?
- apoprotein- surface
- phospholipid- surface
- cholesterol - core
- triglycerides -core
What is the major lipid content in:
- Chylomicron
- VLDL
- IDL
- LDL
- HDL
- TG (very little Ch, PL or Pr)
- TG (little Ch, very little PL, Pr)
- TG, Ch, Pr, PL (decently equal, highest Ch)
- Ch (moderate PL, Pr, very little TG)
- Pr and PL (moderate Ch, very little TG)
What is the origin of:
- Chylomicron
- VLDL
- IDL
- LDL
- HDL
- diet (small intestine)
- liver and small intestine
- VLDL
- IDL
- liver and small intestine
Describe the pathway of TG and Ch absorbed from diet.
What are diseases that disrupt this pathway? What would the serum show as a result?
- absorbed from the intestine and packaged into chylomicron
- Chylomicron passes through capillaries in fat and muscle and TG are hydrolyzed by LPL to glycerol and FA and is absorbed by the tissue
- Chylomicron remnants are absorbed by the liver through receptor mediated endocytosis.
This pathway is interrupted by deficiency in LPL(increased TG) or inefficient removal of remnants (increased TG and Ch).
Describe the endogenous pathway of lipid transport and metabolism.
- Endogenous TG and cholesterol are released from the liver in VLDL (TG:Ch = 5:1)
- in capillaries, LPL reduces TG content converting the complex to IDL
- IDL is removed from circulation by the liver or converted to LDL (by removing more TG and apoE)
- LDL lasts 2-3 days serving as a reservoir of cholesterol for tissues
- HDL retrieves cholesterol released to serum when cells die or membranes turn over
- HDL transfers cholesterol to VLDL or LDL via CETP.
What is familial hypercholesterolemia?
A genetic defect in LDLR makes a serum elevation of LDL resulting in reduced rates of LDL removal
What is the main “clearinghouse” for cholesterol? What are the 3 ways it gets cholesterol?
The liver
- endogenous synthesis
- in fed state: chylomicron remnants
- in fasting: LDL from circulation
What are the three ways cholesterol is disposed of?
The liver makes 1000mg and we eat 500-700 mg day. This gets disposed of by:
- conversion to bile acids
- secretion into the intestine with bile acids
- conversion into cholesterol ester for storage in the liver
What are the effects of high intracellular cholesterol?
- inhibition of HMG-CoA reductase so no more cholesterol is synthesized
- decreased rate of production of LDLR
- increased cholesterol esterification into storage
What are the average FASTING levels of :
- VLDL
- LDL
- HDL
(include Ch and TG components)
- Ch (20-40) and TG (100-150)
- Ch (100-130)
- Ch (45-55)
How is total cholesterol calculated and what should be the average value?
VLDL-C + LDL-C + HDL-C
It should be around 200
What structure carries the bulk of TG in fasting state?
If you are given TG # how do you calculate total cholesterol?
VLDL is 5:1 of TG to Ch and is the majority of circulating TG.
Total Ch = TG/5 + HDL-C + LDL-c
What is the “lipid triad” that puts a person at increased risk for CHD?
- Elevated TG (also causes pancreatic and xanthomas)
- Elevated LDL-c
- Decreased HDL-c
In addition to cholesterol, what are the 5 major risks for CHD?
- Age (over 45 males, 55 females)
- hypertension
- smoking
- diabetes
- family history
What are diseases that cause elevation of circulating lipids with Ch>TG?
- Liver disease
2. hypothyroidism
What are diseases that cause elevation of circulating lipids with TG> Ch?
- nephrotic syndrome
- uremic
- alcohol
- oral contraceptives and estrogen
- glucocorticoids
What is the LDL range for:
- optimal
- normal
- borderline
- high
- very high
- 190
What is normal total cholesterol?
Borderline?
High?
Normal is 240
What is considered low HDL for men and women?
Why is low HDL bad?
Men <50
HDL clears cholesterols from dead cells and plasma. If it is not clearing lipids, this can lead to fatty streaks and eventually progress to atherosclerotic plaque
What is treatment for a patient who has no other CHD risk factors and borderline (130-160) LDL?
advise diet changes
What is treatment for a patient who has no other CHD risk factors and has high cholesterol (>160)
treat with the objective of reaching borderline to normal levels <160
If a person has 2 or more risk factors (family history, hypertension, smoking, diabetes) and borderline cholesterol, how do you treat?
What if they have high cholesterol?
Borderline- advise diet/exercise, drug treatment to get cholesterol <130 and ideally below 100
If CHD, diabetes or atherosclerotic disease are already present, what LDL level should be considered for drug therapy?
What is the goal for TG and LDL levels?
LDL of 100-130 should be considered for statins
You want to get patients <70 for LDL and below 200 for TGs
What is a favorable TC to HDL-c ratio?
<3.5 and there is an increased risk associated with ratios above 4.5
thus treatment should be considered if HDL makes the ratio to high even if LDL is normal.
What is the mechanism of action of statins?
they inhibit HMG CoA Reductase which:
- decreases synthesis of cholesterol
- increases LDLR to pull cholesterol in from plasma
- inhibition of hepatic synthesis of apoB100 which decreases VLDL production
What are the therapeutic uses of statins?
- lowering total and LDL cholesterol (40-50%)
- lowering high TG (20%)
- modest increase in HDL
How are statins metabolized?
By CYP3A4 in the liver (p450) so there is a lot of drug interactions
What are the side effects of statins?
- inhibition of cholesterol synthesis of essential components of fetal development (contraindicated in preggos)
- increased liver enzymes/decreased liver function
- proximal muscle myopathy
(2 and 3 are dose dependent and reversible so start low and work up)
How do you measure to see if a patient has statin-induced myopathy?
How frequently does it occur?
What 2 sequelae does it lead to?
The occurrence is more frequent when the statin is given with what other 2 drugs?
This occurs in 1/1000 patients and is associated with high levels of CK.
It occurs suddenly and can lead to myoglobinurea and acute renal failure.
Fibrates and niacin
What are the drug interactions with statins?
Other drugs that are metabolized by P40 CYP3A4 such as:
- macrolides
- cyclosporine
- azole antifungals
- warfarin **
- grapefruit increases circulating statins except with prevastatin
What is the main cholesterol uptake inhibitor? What is the mechanism of action?
Ezetemibe inhibits the reabsorption of cholesterol through the small intestine reducing intake of exogenous cholesterol.
What are the therapeutic uses of ezetimibe?
It treats hypercholesterolemia and sitosterolemia (plant sterol accumulation)
- lowers LDL (20%)
- lowers TG (5-10%)
- raises HDL (slight)
What limits the efficacy of ezetimibe for lowering LDL cholesterol?
It reabsorbs less cholesterol from the small intestine so HMG CoA Reductase will synthesize more.
What are the 2 major problems associated with ezetimibe?
- long term safety is not known
2. contraindicated with hepatic insufficiency
What is sitosterolemia?
What 3 things can it lead to?
How is it treated?
It is increased plant sterols in the blood. It leads to: 1. reduced cholesterol metabolism 2. formation of xanthomas 3. increased risk of CHD
Treat with ezetimibe, diet, bile acid binding resin
What is the major bile acid binding resin? What is its mechanism of action?
Cholestyramine binds bile acids in the gut to prevent reabsorption. As a result, the liver has to use more cholesterol to synthesize new bile acids, and LDLR are increased to pull cholesterol in from the plasma.
What are the therapeutic uses of cholestyramine?
What limits the efficacy?
- lower total and LDL (10-20%)
- increase HDL
Efficacy is limited because HMG CoA reductase will be upregulated which may lead to increased VLDL and mild TG increase.
What drug is avoided for treating combined hyperlipoproteinemia (elevated cholesterol and TG)?
cholestyramine because it upregulates HMG coa reductase which increases cholesterol synthesis and VLDL levels
What is the prime benefit of using cholestyramine pharmacokinetically?
It remains in the gut so there is no absorption or distribution limiting the toxicity of the drug.
It can be used in women of childbearing age (unlike statins), children with familial hypercholesterolemia, and patients with only modestly high cholesterol.
Even though cholestyramine is not absorbed and is relatively safe, why is it still not advised for use in pregnant women?
There will be a vitamin deficiency
What are the problems associated with cholestyramine?
What are the drug interactions?
How do you tailor treatment to avoid this?
- terrible taste
- constipation
- bleeding risk due to vit. K deficiency
Drug interactions:
ion exchange resins bind fat soluble vitamins, warfarin, thyroxin, digitalis
Give these drugs 1 hour before bile acid binding resin (cholestyramine) or give them 3-4 hours after
What are the clinical effects of nicotinic acid (niacin)?
- inhibit lipolysis in fat
- decrease hepatic synthesis of TG
- decrease apo B lipoprotein secretion
- reduce circulation lipoprotein A
- alter HDL metabolism
What are the therapeutic uses of niacin?
- lower cholesterol and TG
- decrease VLDL (30-70% decrease in TG)
- decrease LDL (10-20% decrease in Ch)
- increase HDL (20-30%)
What is the antihyperlipidemic drug of choice for young people and pregnant women?
Nicotinic acid (niacin)
What are problems associated with niacin?
- flushing- minimized by small doses and slow titration, NSAIDs and aspirin
- nausea
- abdominal discomfort
- dryness of skin
What are the 4 contraindications for niacin?
- diabetics- increases hyperglycemia
- gout- increases hyperuricemia
- PUD- increases chance of peptic ulcer
- liver dysfunction
What type of drug is gemfibrozil and what is the mechanism of action?
Fibrate - it activates PPAR (peroxisome proliferator activator receptors) leading to:
- decreased apo CIII synthesis
- decreased hepatic TG synthesis
- increased LPL activity
What are the therapeutic effects of gemfibrozil?
decrease VLDL
conversion of IDL
decrease Chylomicrons
modest increase in HDL
LDL may decrease or INCREASE
What are the fibrates used to treat?
Hypertriglyceridemia- especially in patients with high VLDL fasting.
You want to reduce TG to reduce the chance of pancreatitis when nicotinic acid is contraindicated.
In a patient with high TG and diabetes, what drug do you want to use to lower the TG and prevent pancreatitis?
Fibrates (gemfibrozil) because nicotinic acids (the other triglyceride lowering drug) is contraindicated in diabetics.
What are the problems associated with gemfibrozil?
- myopathy (especially if used with statins)
- abnormal liver function tests
Contraindicated in:
hepatic dysfunction and gallstones
What is mipomersin?
An apoprotein B-100 inhibitor so that VLDL can’t form
What is lomitapibe?
an inhibitor of microsomal TG transfer proteins used to load/form chylomicrons and VLDL
