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92 Cards in this Set

  • Front
  • Back
How many classes of Antihyperlipidemic drugs are there? What are the classes?
FOUR:
1. Hmg-CoA Reductase inhibitors
2. PPAR activators/fibric acid
3. Bile acid resins
4. Others
What are the HMG-CoA Reductase inhibitors called?
Statins
What are the 2 statins to know?
Lovastatin
Atorvastatin
What is the PPAR activator to know?
Gemfibrozil
What is the bile acid resin?
Cholestyramine
What are the 2 others?
Niacin
Ezetimibe
Acronym for all the antihyperlipidemics?
GLANCE
-Gemfibrozil
-Lovastatin
-Atorvastatin
-Niacin
-Cholestyramine
-Ezetimibe
How do the HMG-CoA reductase inhibitors work?
By acting as reversible competitive antagonists of HMG-CoA Reductase for its active site
What does inhibiting the active site of HMG-CoA Reductase do?
Prevents HMG-CoA from being converted to mevalonate which is the RLS in cholesterol biosynthesis particularly in liver hepatocytes.
How does the affinity of the statins compare to the natural substrate for HMGCoAR?
Statins have higher affinity!
How does inhibiting liver cholesterol biosynthesis de novo reduce plasma cholesterol levels?
The liver has an increased need for exogenous cholesterol so it upregulates LDL receptors and catabolizes more LDL from peripheral tissues.
In what patients are the statins not very useful?
Patients with familial hypercholesterolemia - their ldl receptors are defective so upregulating them won't have any effect.
What are the 2 statins to know?
-Lovastatin
-Atorvastatin
Where do all statins seem to preferentially upregulate LDL receptors by inhibiting HMG-CoA reductase?
In the liver
Why do the statins have a preferential effect on the liver?
Because there is significant first pass uptake which limits systemic exposure to the active drug.
Which statin is a prodrug and which is given in an active form?
Lovastatin - prodrug
Atorvastatin - active
Which statin has the longest half life and what is it?
What is the half life of the other statins?
Atorvastatin - 20 hrs
All others - 1-4 hrs
What are the statins metabolized by?
Liver Cyp3A4
What is the major adverse effect of the statins?
Myopathy and rhabdomyolysis
What can be detected in the blood as a result of the rhabdomyolysis?
CK
When is the risk of rhabdomyolysis even greater?
When statins are given in combo with naicin or fibrates
What may the increased risk of rhabdomyolysis in combo therapy be due to?
Inhibition of cyp3A4, thus higher levels of active drug
What inhibits Cyp3A4?
Drugs and grapefruit juice
What is a major contraindication for giving Statins?
Pregnancy or breastfeeding
How do the statins affect lipoprotein profiles?
-Reduce TG
-Increase HDL
-Significantly reduce LDL
So what is the major clinical use of the statins?
First Line Therapy for patients at high risk of MI dt hyper cholesterolemia
What is the bile-acid binding resin to know?
Cholestyramine
What is the mechanism by which Cholestyramine works?
-Binds bile acids in intestines
-Inhibits reabsorption of BA's via enterohepatic recycling
Why does blocking bile acid reabsorption from the intestines reduce blood cholesterol levels?
-Bile acids are the only way to excrete cholesterol
-By making more bile acids get excreted, more cholesterol gets converted to bile salts and thus excreted
What is the major way that the bile acid resins reduce plasma cholesterol?
The liver senses decreased plasma cholesterol so upregulates LDL receptor and thus more is cleared.
How exactly do the BA binding resins bind to them in the intestine?
By exchanging chloride for the bile acids
How exactly does the decreased enterohepatic recycling of BA's increase their synthesis in the liver?
By not giving feedback inhibition to 7a-hydroxylase, the RLS in BA synthesis.
What minor effect does increased cholesterol catabolism by 7a-hydroxylase have on liver HMG-CoA Reductase?
Its synthetic activity increases but only a little bit - not enough to compensate for lower plasma LDL levels
Why is it good that the compensation by HMG-CoA Reductase doesn't increase plasma cholesterol levels much?
Because then the liver still wants to upregulate LDL receptors which is the whole goal to lower plasma LDL anyway.
How is Cholestyramine administered?
Orally as a Chloride salt and insoluble in water
Is Cholestyramine absorbed into circulation?
No but it may interfere with the absorption of other agents.
How long will Cholestyramine take for its effects and lower serum LDL to be seen?
~ 1 month
What is the main problem with giving Cholestyramine?
Patient compliance due to gas, bloating, cramps, and nausea.
How will Cholestyramine affect the lipoprotein profile?
-TG will be increased!
-HDL will be increased
-LDL will be reduced
What is the major clinical use of Cholestyramine?
Treatment of hypercholesterolemia caused by dietary sources - NOT LDL receptor defects
How will cholestyramine affect patients with familial hypercholesterolemia?
-Homozygotes - no effect

-Heterozygotes - some effect
When is Cholestyramine NOT recommended?
For patients with hypercholesterolemia and increased TG - it may increase the TG even more.
What is Niacin?
Water soluble Vit B
What does Niacin do?
Activates a GPCR coupled to Gi in adipocytes
What is the effect of activating the Gi coupled receptor on adipocytes?
Decreased cAMP, decreased PKA, decreased lipase activity and decreased FFA mobilization
What normally stimulates this pathway for FFA mobilization from adipocytes?
Beta receptors
What is the main way that Niacin reduces LDL levels then?
By reducing FFA supply to the liver, thus reducing VLDL production.
What sort of doses of Niacin are required for it to have these effects?
Much higher than normal vitamin levels
What are the major side effects of Niacin?
-Intense Flushing
-Pruritis
What can help reduce the flushing caused by niacin?
Decreasing prostaglandins by giving aspirin or an NSAID
How soon after taking Niacin does the pruritis/flushing occur?
Within 1-2 hrs; so giving at bedtime or time release tablets may help increase compliance.
What happens with continued use of Niacin?
Adverse symptoms dissappear, but return if the patient misses a few doses
How can tolerance to the flushing caused by Niacin be induced?
By starting at low doses and gradually increasing to full doses.
For what pre-existing condition would you want to not give Niacin?
Peptic ulcer disease - it has adverse GI effects.
What are 3 less common but more severe adverse effects of Niacin?
-Abnormal liver function tests
-Hyperuricemia
-Induced insulin tolerance resulting in high fasting glucose
So what are 3 patients for whom Niacin is contraindicated?
-Gout patients
-Hepatic dysfunction patients
-Peptic ulcer patients
In what patients should Niacin be used with CAUTION?
Diabetics
What can result from concurrent use of Niacin + Statins?
Myopathy/Rhabdo
How does Niacin affect the lipoprotein profile?
-REDUCES TG
-Increases HDL - quite a bit
-Reduces LDL
How long does it take for Niacin to reach its maximal effects in reducing LDL?
3-6 weeks
What else does Niacin reduce?
Lipoprotein A - the possible risk factor associated with CHD
What is the main clinical use of Niacin?
Treatment of Severe hypercholesterolemia that does not respond to resin therapy
Where does Niacin fall in the list of drugs for treating hypercholesterolemia? Why?
2nd or 3rd - bc of its adverse side effects and poor compliance.
What is something that Niacin is the only drug that can do?
Reduce Lipoprotein A by 40%
What is the PPAR activator?
Gemfibrozil
What is the primary thing that PPARs/Gemfibrozil do?
Activate genes to increase clearance and reduce triglycerides
What is PPAR?
A nuclear receptor that is activated by Gemfibrozil
What DOESN'T gemfibrozil do?
Doesn't change LDL levels - only triglycerides
What is the most important adverse effect of Gemfibrozil?
Myopathy if used with statins
What will the increased CK ultimately lead to?
Renal failure
What are the effects of Gemfibrozil like in general?
Well tolerated
What is the major effect that Gemfibrozil has on the lipoprotein profile?
Decreases TG by 50%
Increases HDL
May Increase LDL though
When should Gemfibrozil be used as therapy?
In patients with very high serum Triglycerides that pose a risk for pancreatitis and abdominal pain
When should Gemfibrozil NOT be used as therapy?
In patients with elevated hypercholesterolemia but w/out hypertriglycerides
What are 2 conditions for which Gemfibrozil has an important role?
-Metabolic syndrome patients
-Type 2 Diabetes patients
Why does Gemfibrozil have an important role in treating patients with Metabolic syndrome or type II diabetes?
Because it can reverse low HDL and high TG.
What is the mechanism of Ezetimibe?
Binds to a brush border protein on intestinal lumen to inhibit C transport into enterocytes.
What effect does Ezetimibe have on serum LDL?
-Decreases C delivery to liver
-Liver upregulates LDL receptor
-Reduces plasma levels of LDL
How is Ezetimibe administered? Metabolized?
Orally
By glucuronidation to an active metabolite
How does Ezetimibe affect the lipoprotein profile?
Not stellar.. but it does:
-Reduce LDL
-Reduce TG some
-Increases HDL a little
What is the main clinical use of Ezetimibe?
Treatment of primary hypercholesterolemia in patients resistant to statin therapy
What enhances Ezetimibe's effects?
Combination therapy with Statins
What is the advantage of combined therapy of Ezetimibe and Statins?
-Reduces intestinal sources of cholesterol
-Reduces de novo synthesis of cholesterol which would otherwise be increased to compensate for the reduced dietary source
What is the first line drug for treating hypercholesterolemia?
Statins - HMG-CoA reductase inhibitors
What must patients that begin Statin therapy understand?
That they'll be on it for life
What drug is used for patients that are 11-20 yrs old? Why?
Cholestyramine (bile acid binding resin) - because it is safe for women of child bearing age
What else is cholestyramine used as?
A 2nd line for treatment of patients for whom statins don't lower their LDL
What drug is used for treating increased TG and LDL?
Niacin
What added benefit does Niacin have?
Increased HDL
What should you always remember about niacin?
The bad side effects of pruritis and flushing, and that combined with statins it causes myopathy.
What is Ezetimibe approved for?
Monotherapy or combined with statins for hypercholesterolemia resistant to statins alone.
What are the 2 drugs of choice for hypertriglyceridemia?
-Gemfirozil (mostly)
-Niacin