Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
53 Cards in this Set
- Front
- Back
|
ATHEROSCLEROSIS
|
- Leading cause of morbidity & mortality
- Underlying pathology of the most common cardiovascular diseases (coronary artery disease, ischemia, myocardial infarction) and stroke - It is not merely disorder of lipid accumulation but is a chronic inflammatory condition involving lipids, thrombosis, vascular wall elements and immune cells |
|
|
ATHEROSCLEROSIS
PATHOLOGICAL HALL MARKS
|
- Focal lesions in the inner lining of arteries
- Lesions evolve over decades during most of which time they are clinically silent, the occurrence of symptoms signaling advanced disease - Fatty streaks are the earliest structurally apparent lesions and progress to fibrous/and or fatty plaques - Angina is one of the first signs of atherosclerosis |
|
|
MODIFIABLE RISK FACTORS
|
- High levels of low density lipoprotein (LDL) cholesterol
Treatment goal is to reduce LDL - Low levels of high density lipoprotein ( HDL) cholesterol Treatment goal is to increase HDL |
|
|
MODIFIABLE RISK FACTORS
|
- Cigarette smoking
- Physical inactivity - Obesity - Hypertension - Diabetes mellitus - Raised C-reactive protein (marker for inflammation) - Raised coagulation factors (eg factor VII, fibrinogen) |
|
|
ATHEROSCLEROSIS
PREVENTION
|
- Diet and exercise (improve HDL-C)
- Treatment of Hypertension - Treatment of Diabetes - Drugs that reduce LDL-C - Anti-thrombotics |
|
|
ATHEROSCLEROSIS PREVENTION
|
Drugs that improve endothelial function
- ACE inhibitors - Drugs that increase NO synthesis or bioavailability Anti-inflammatory measures - Antioxidants - Vitamins C & E, estrogens, Folic acid supplements |
|
|
LIPOPROTEINS IN CIRCULATION
|
- Chylomicrons
- HDL-C - LDL-C - VLDL |
|
|
Chylomicron Pathway
|
pic
|
|
|
CHOLESTEROL TRANSPORT & SYNTHESIS: HDL
|
pic
|
|
|
CHD Risk: Relation to Lipid levels
|
pic
|
|
|
NCEP guidelines for managing patients with dyslipidemia
|
Risk level LDL goal (mg/dL)
CHD+ multiple risk factors < 60 Known CHD < 100 >2 risk factors < 130 0-1 risk factors < 160 |
|
|
Question:
Two or more risk factors post MI. What is your LDL goal for this patient? 1. <100mg/dL 2. <130 mg/dL 3. <160 mg/dL |
1. <100mg/dL
|
|
|
Lipid Lowering Drugs
|
pic
|
|
|
HMG CoA Reductase Inhibitors
STATINS
|
3 hydroxy-3 methylglutaryl-coenzyme A (HMG CoA)
Specific, competitive inhibitors - Fluvastatin (Lescol) - Lovastatin (Mevacor)-prodrug - Pravastatin (Pravachol) - Simvastatin (Zocor)- Prodrug Long Lasting Inhibitors - Atorvastatin (Lipitor) - Rosuvastatin (Crestor) |
|
|
ATHEROSCLEROSIS PREVENTION
|
Drugs that improve endothelial function
- ACE inhibitors - Drugs that increase NO synthesis or bioavailability Anti-inflammatory measures - Antioxidants - Vitamins C & E, estrogens, Folic acid supplements |
|
|
LIPOPROTEINS IN CIRCULATION
|
- Chylomicrons
- HDL-C - LDL-C - VLDL |
|
|
Chylomicron Pathway
|
pic
|
|
|
CHOLESTEROL TRANSPORT & SYNTHESIS: HDL
|
pic
|
|
|
CHD Risk: Relation to Lipid levels
|
pic
|
|
|
NCEP guidelines for managing patients with dyslipidemia
|
Risk level LDL goal (mg/dL)
CHD+ multiple risk factors < 60 Known CHD < 100 >2 risk factors < 130 0-1 risk factors < 160 |
|
|
Question:
Two or more risk factors post MI. What is your LDL goal for this patient? 1. <100mg/dL 2. <130 mg/dL 3. <160 mg/dL |
1. <100mg/dL
|
|
|
Lipid Lowering Drugs
|
pic
|
|
|
HMG CoA Reductase Inhibitors
STATINS
|
3 hydroxy-3 methylglutaryl-coenzyme A (HMG CoA)
Specific, competitive inhibitors - Fluvastatin (Lescol) - Lovastatin (Mevacor)-prodrug - Pravastatin (Pravachol) - Simvastatin (Zocor)- Prodrug Long Lasting Inhibitors - Atorvastatin (Lipitor) - Rosuvastatin (Crestor) |
|
|
STATINS-MOA
|
Denovo synthesis of cholesterol happens in the liver. If you inhibit HMG-CoA reductase you will decrease synthesis of cholesterol
PIC |
|
|
STATINS-Effect on lipid profile
|
- Reduction in plasma LDL
- Smaller reduction in plasma triglyceride - Increase in HDL-C |
|
|
COMPARATIVE ANALYSIS OF STATINS
|
pic
|
|
|
STATINS: Pharmacokinetics
|
- Well absorbed orally
- Extensive first pass uptake of statins leads to variations in bioavailability (5-30% of administered doses) - Most statins have active metabolites - Simvastatin & Lovastatin: Inactive prodrug metabolized in the liver to their active form, β-hydroxy fatty acid |
|
|
STATINS: other considerations
|
- In the plasma, more than 90% of the statins & their metabolites are protein bound
- Short acting statins should be taken in the evening since peak cholesterol synthesis occurs between midnight & 2 AM |
|
|
Potential cardioprotective effects of statins
|
In addition to lowering LDL statins can
- Improve endothelial function by increasing nitric oxide (NO) synthesis - Stabilize plaque - Anti-inflammatory - Reduce C-reactive protein (CRP) - Reduce LDL oxidation - Reduce platelet aggregation |
|
|
STATINS
Survival rates in CHD patients
|
pic
|
|
|
After several weeks on Lipitor your patients LDL levels are almost around 110mg/dL but his triglycerides are still high. What do you do?
|
Combination therapy:
|
|
|
STATINS in combination with other lipid lowering drugs
|
pic
|
|
|
STATINS: Adverse effects
|
Well tolerated
Mild unwanted effects - Myalgia - Raised concentrations of liver enzymes in plasma - GI disturbances - Insomnia - Rash |
|
|
STATINS
Rare but serious side effects
|
HEPATOTOXICITY
- Liver damage is a class effect of Statins - Liver enzyme (ALT) levels must be monitored within 2-4 weeks of initiating therapy! MYOPATHY (myositis & rhabdomylosis) - Class effect of Statins & Fibrates - Dose related - Risk is more in combination therapy - Can cause kidney failure - CK /CPK level must be monitored! |
|
|
FIBRATES
|
Bezafibrate
Ciprofibrate Clofibrate (Not used due to gallstones) Fenofibrate (Lofibra) Gemfibrozil (Lopid) |
|
|
FIBRATES: MOA
|
Stimulators of LPL
PPARα agonists Activation of these receptors - Increases transcription of lipoprotein lipase (LPL) to enhance clearance of VLDL - Also promotes LDL uptake into the liver - Increases transcription of Apo AI & Apo AII to increase plasma HDL levels |
|
|
FIBRATES-Effect on lipid profile
|
- Reduce circulating VLDL & hence triglycerides
- Moderate (10%) reduction in LDL-C - Moderate (10%) increase in HDL-C Drugs of choice in patients with type III hypertriglyceridemia |
|
|
FIBRATES: PHARMACOKINETICS
|
- Well absorbed orally and widely distributed through the body including liver
- Half–lives vary from 1-20 hrs 60-90% of the oral drug undergoes glucorindation and excreted renally -- Use with caution in renal impairment -- Serum creatinine levels should be monitored (kidney function) |
|
|
FIBRATES
Adverse effects
|
These side effects are more than with Statins
- GI symptoms-lessen as therapy progresses - Pruritus - Rash |
|
|
FIBRATES-Rare but severe side effects
|
MYOSITIS can lead to
- Myoglobinuria / Rhabdomyolysis - Acute renal failure -- Risk is higher in patients with existing renal impairment, because of reduced protein binding & impaired drug elimination of fibrates LITHIASIS - Increased biliary excretion of cholesterol predisposes to the formation of gallstones - SIGNIFICANT WITH CLOFIBRATE |
|
|
FIBRATES-Contraindications
|
- Renal impairment
-- Use with caution in patients with mild-to-moderate renal impairment; dosage adjustment required. Contraindicated with severe renal impairment. - Clofibrate : Use only in patients whose gall bladder has been removed - Gemfibrozil crosses the placenta - Pregnacy |
|
|
Drugs That Inhibit Cholesterol Absorption/ Reabsorption in the GI tract
|
Bile Acid Sequestrants
- Colestyramine (Questran) - Colestipol (Colestid), - Colesevelam (Welchol) Cholesterol transporter blocker - (Zetia) |
|
|
Your patient is complying with all of your instructions incliding controlling his diet, yet his LDL keeps creeping up. What do you do?
|
Add a drug that inhibit cholesterol absorption.
|
|
|
BILE ACID SEQUESTRANTS
|
- First generation drugs
- Reduce cholesterol reabsorption & lower plasma cholesterol levels - Relegated to use as adjuncts in the treatment of patients with severe dyslipidemias - Bulky & Unappetizing - Treatment with these drugs translates to reduced risk of CHD & myocardial infarction |
|
|
BILE ACID SEQUESTRANTS
MOA
|
↓ Absorption of dietary cholesterol & increased excretion of bile acids in feces
↑ Synthesis & secretion of bile acids, decreasing hepatic cholesterol content ↑ in LDL receptor expression ↑ Clearance of LDL from plasma HDL-C concentration is unchanged Transient ↑ in TG |
|
|
BILE ACID SEQUESTRANTS Adverse effects
|
Low systemic toxicity because they are not absorbed
GI disturbances - Bloating - Dyspepsia Decreased absorption of fat soluble vitamins (eg Vitamin K) - Reduces coagulation & causes bleeding gums |
|
|
BILE ACID SEQUESTRANTS
PHARMACOKINETIC INTERACTIONS
|
Interfere with absorption of fat soluble drugs
- Chlorthiazide, Digoxin, Warfarin - Should be taken atleast an hour before or 4-6 hrs after taking the bile acid resins |
|
|
EZITEMIBE (Zetia)
|
- Specifically inhibits absorption of cholesterol from the duodenum by blocking cholesterol transporter NPC1L1 in the intestine
- Used as an adjunct to diet and statins -- Inhibition of hepatic cholesterol synthesis by statins increases intestinal cholesterol absorption. Combination with Zetia prevents this effect - Only used as monotherapy in patients who cannot tolerate statins |
|
|
Ezetimibe-Pharmacokinetics
|
Taken orally and absorbed into the intestinal epithelial cells in the brush border
Long Half life ~ 22 hrs - Extensively metabolized to - glucuronide complex which is active - Total (Parent + active glucuronide) concentration peaks 1-2 hrs after administration - Slow elimination |
|
|
Ezitemibe : Adverse effects
|
Generally well tolerated
- Diarrhea - Abdominal pain - Headache - Rash - Angioedema - enters milk (resins don’t) and is therefore contraindicated in women that are breast feeding |
|
|
Ezetimibe vs Bile acid sequestrants
|
- Does NOT affect absorption of fat soluble vitamins & drugs
- Higher potency (10 mg vs 36 g of colestyramine |
|
|
VYTORIN (ZETIA + ZOCOR)
|
Combination of Ezetimibe and Simvastatin
Average of 60% reduction in LDL-C -- However, recent findings from ENHANCE trial showed there was no significant difference between Vytorin and Simvastatin alone in the amount of atherosclerotic plaque in the inner walls of the carotid arteries -- Effect on risk/incidence of CAD is yet to be determined - Basically lowered LDLs but didn't change lumen of Arteries. |
|
|
NIACIN (NICOTINIC ACID)
|
- Oldest drug
- Water soluble B-complex vitamin - In high doses (gm) can lower lipids - Niacin - Nicotinamide (Nicobid, Nicolar) -- has to be converted to niacin |
