Title: Pharmacology CVS / Antihyperlipidemic Drugs

Q: Conditions treated by antihyperlipidemic drugs: (5)
A: 1. Hyperlipidemias.
2. Hyperlipoproteinemias.
3. Hyperlipemia.
4. Dyslipidemias
5. Hypercholestrolemia.

Q: Niacin: (6)
A: 1. Nicotinic Acid or Vitamin B3, is one of the oldest drugs.
2. Water- soluble B-complex vitamin, functions only after conversion to NAD or NADP+ Nicotinamide.
3. Niacin has hypolipidemic effects only in large doses.
4. Affects all lipid parameters
5. Reduces fibrinogen levels.
6. Increases plasminogen activator

Q: The effect of Niacin on lipid parameters: (3)
A: 1. Best agent to  increase HDL-C(35-40%).
2. Lowers triglycerides (35-45%).
3. Decreases LDL-C production(20-30%).

Q: MOA of Niacin: (4)
A: 1. In adipose tissue, inhibits the lipolysis of triglycerides by inhibiting adipocyte adenylyl cyclase, which reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis.
-> May also inhibit a rate –limiting enzyme of  triglyceride synthesis, diacylglycerol acetyltransferase 2.
2 Reduction of triglyceride synthesis reduces hepatic VLDL and consequently LDL.
3. Inhibits intracellular lipase in adipose tissues leading to decreased FFA flux to the liver.
4. Completely absorbed, peaks within 1hr, half-life is about 1 hr, so needs to be given twice or thrice daily

Q: Toxicity of Niacin: (8)
A: 1. Harmless cutaneous vasodilation and sensation of warmth, can be prevented by NSAIDS.
2. Pruritus, rashes, dry skin and mucus membranes (acanthosis nigricans).
3. Nausea, vomiting, abdominal discomfort, diarrhea.
4. Elevations in transaminases and possible hepatotoxicity.
5. Insulin resistance and hyperglycemia.
6. Hyperuricemia and gout.
7. Cardiac arrhythmias.
8. Amblyopia, blurring of vision.

Q: Types of Fibrates or Fibric Acid Derivatives or “PPARs Activators”: (4)
A: 1. Clofibrate, 1962-1987.
2. Gemfobrozil.
3. Fenofibrate.
4. Bezafibrate.

Q: Fibrates or Fibric Acid Derivatives or  “PPARs Activators”: (6)
A: 1. Activate PPAR- α (Peroxisome Proliferator Activated Receptor- α) which stimulates fatty acid oxidation, increases LPL synthesis, and reduces expression of apoC-III, and increases apoA-I and apoA-II expression.
2. Increase lipolysis of lipoprotein triglyceride via LPL.
3. Decrease levels of VLDL and LDL.
4. Moderately increase HDL.
5. Also have anticoagulant and fibrinolytic activities.
6. Drugs of choice in severe hypertriglyceridemia.

Q: Toxicity of Fibrates: (6) [there is more than one in each point]
A: 1. Rashes, urticaria, hair loss, headache, GIT symptoms, impotence, and anemia.
2. Myalgia, fatigue, myopathy and rhabdomyolysis.
(Breakdown of muscle fibers resulting in the release of muscle fiber contents (myoglobin) into the blood stream).
3. Risk of cholesterol gallstones.
4. Interact with statins, levels of both drugs will increase.
5. Used with caution in renal failure.
6. Elevated transaminases or alkaline phosphatase.

Q: Types of bile acid-binding resins: (3)
A: 1. Colestipol.
2. Chlestyramine.
3. Colesevelam.

Q: Bile acid- binding resins: (4)
A: 1. These are large polymeric anionic- exchange resins, insoluble in water, which bind the negatively charged bile acids in the intestinal lumen and prevent their reabsorption leading to depletion of bile acid pool and increased hepatic synthesis.
2. Consequently,  hepatic cholesterol content is decreased, stimulating the production of LDL receptors. This leads to increased LDL clearance and lowered LDL-C levels.
3. However, this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase.
4. May  increase  triglyceride levels.

Q: Indications of bile acid-binding resins: (3)
A: 1. Lower LDL as much as  25%, but will cause GI side effects.
2. Relieve pruritus in cholestasis.
3. Digitalis toxicity, can bind digitoxin and enhance its excretion.

Q: Why are bile acid-binding resins the safest drugs to use (in case of hyperlipidemia)?
A: Probably the safest drugs, since they are not absorbed from the intestine because of their large size. Maximal doses are effective but cause side effects.

Q: Toxicity of bile acid- binding resins: (6)
A: 1. Gritty sensation is unpleasant but can be tolerated.
2. Constipation and bloating.
3. Heartburn.
4. Malabsorption of  Vitamin K.
5. Gall stones.
6, Impaired absorption of many drugs( digitalis, propranolol, thiazides, warfarin, folic acid, statins, aspirin….etc)..

Q: Types of Competitive Inhibitors of HMG-CoA Reductase 
“Statins”: (7)
A: 1. Mevastatin
2. Simvastatin
3. Lovastatin
4. Pravastatin
5. Fluvastatin
6. Atorvastatin.
7. Rosuvastatin.

Q: Competitive Inhibitors of HMG-CoA Reductase  “Statins”: (3)
A: 1. Most commonly prescribed drugs worldwide.
2. Isolated from a mold Penicilliun citrinum, in 1976.
3. Most effective drugs in lowering LDL.

Q: MOA of Competitive Inhibitors of HMG-CoA Reductase  “Statins”: (4)
A: 1. Competitively inhibit the early rate- limiting enzyme in de novo synthesis of cholesterol (3-hydroxy-3methylglutaryl coenzyme A reductase). This results in increased expression of the LDL receptor gene.
2. Reduced free cholesterol in hepatocytes activates a protease which  will cleave membrane- bound SREBPs which will be translocated to the nucleus to enhance transcription of LDL receptors.
3. Increased number of LDL receptors will increase removal of LDL-C from the blood thus lowering LDL-C.
4. Also, can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production.

Q: Other effects of Statins: (4)
A: 1. Higher doses can reduce triglyceride levels caused by elevated VLDL levels.
2. Some (simvastatin and rosuvastatin) can raise HDL-C levels.
3. Decrease oxidative stress and vascular inflammation by enhancing NO production.
4. Reduce platelet aggregation.

Q: Factors that toxicity of Statins: (7)
A: 1. Dose-related
2. Associated with advanced age
3. Hepatic or renal dysfunction
4. Small body size
5. Associated diseases
6. Hypothyroidism
7. Concomitant drugs.

Q: Toxicity of Statins: (4)
A: 1. Elevation of transaminases, this is intermittent and not associated with strong evidence of liver failure.
2. Elevation of creatine kinase (CK) activity.
3. Rhabdomyolysis,  causing myoglobinuria and renal injury and failure or even death. It is extremely rare (less than one in 10,000 people).
4. Lupus-like disorder and peripheral neuropathy.

Q: Less Important Side Effects to
Statins: (13)
A: 1. Headache
2. Difficulty sleeping
3. Flushing of the skin
4. Muscle aches, tenderness, or weakness (myalgia)
5. Drowsiness
6. Dizziness
7. Nausea and/or vomiting
8. Abdominal cramping and/or pain
9. Bloating and/or gas
10.Diarrhea
11. Constipation
12. Rash
13. Statins also carry warnings that memory loss, mental confusion, high blood sugar, and type 2 diabetes are possible side effects. It is important to remember that statins may also interact with other medications.

Q: Pharmacogenetics of Statins:
A: Statins  are good example of the principles of pharmacogenetics. This is because they are metabolized by the CYP450 enzyme system, which is a subject to individual genetic differences. These differences will be exhibited for their: therapeutic response and side effects.

Q: Types of Inhibitors of Sterol Absorption: (4)
A: 1. Ezetimib
2. Torcetrapib (withdrawn)
3. Anacetrapib
4. Dalcetrapib

Q: Ezetimib: (6)
A: 1. Can reduce LDL.
2. Inhibitor of NPC1L1, a specific transport process in jejunal brush border.
3. Reduces cholesterol absorption and reabsorption by 54%, precipitating a compensatory increase in cholesterol synthesis.
4. Reduces cholesterol delivery to the liver by the chylomicron remnants. This will stimulate the expression of the hepatic genes regulating the LDL receptor expression leading to enhanced LDL-C clearance from the plasma(15-20%).
5. Action is complementary to statins(60% reduction in LDL-C)..
6. Can cause allergic reactions, reversible impairment of liver function tests and myopathy.

Q: What is the function of CETP? (2)
A: 1. CETP is a plasma glycoprotein synthesized by the liver that mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins and LDL in exchange for a molecule of triglyceride.
2. Can increase HDL levels by 45-106% in humans.