Cv Pharm - Antihyperlipidemic Drugs Part 2

Front 1

What are the therapeutic lifestyle changes for lowering cholesterol?

Back 1

-Diet
-Reduction of choleterol and saturated fats
-Addition of cholesterol lowering plant stanols/sterols and soluble fiber
-Weight reduction for the overweight
-Increased physical activity

Front 2

Describe metabolic syndrome

Back 2

-Refers to a constellation of consequences of obesity and insulin resistance
-Therapeutic lifestyle changes are particularly important
-Patients are at high rist for developing CHD
-Diagnosed when at least 3 of the following are present:
i. Waist circum >40in(m), >35 inches(f)
ii. Triglycerides >150
iii. Low HDL (<40(m),<50(f))
iv. Hypertension (SBP>130, DBP>85)
v. Fasting glucose >110

Front 3

Describe the diet for elevated LDL

Back 3

-Saturated fats and cholesterol suppressed LDL receptor activity thus reducing clearance
-Obesity-> increased hepatic secretion of VLDL
-The addition of certain plant steroles and of soluble fiber to the diet can reduce LDL
-Sat fat <7%
-Polyunsat fat <10%
-Monounsat fat <20%
-Total fat 25-35%
-Carbs 50-60%
-Fiber 20-30g/d
-Protein ~15%
-Cholesterol <200mg/d

Front 4

Describe the diet for hypertriglyceridemia

Back 4

-Same diet as for elevated LDL
-When due to metabolic syndrome calorie restriction and exercise to achieve ideal weight are very important
-Obesity and insulin resistance underlie the metabolic syndrome
-Alcohol restriction is part of the dietary restrictions

Front 5

Describe the diet for chylomicronemia

Back 5

A low fat diet decreases the production of chylomicrons from dietary triglycerides

Front 6

What are the HMG CoA Reductase Inhibitors?

Back 6

-Lovastatin
-Simvastatin
-Pravastatin
-Fluvastatin
-Atorvastatin
-Rosuvastatin

Front 7

Describe HMG CoA Reductase Inhibitors

Back 7

-"Statins"
-The mainstay of LDL-reducing therapy
-Inhibit the rate-limiting enzyme of cholesterol biosynthesis and are very effective in reducing LDL levels
-Increase HDL levels moderately
-Increase synthesis of NO by direct effect on vascular endothelial cells
-Diminish intracellular cholesterol levels
-LDL receptor activity increases as a result and the clearance of LDL from plasma is enhanced
-Safe and well tolerated
-Generally excreted through bile
-Not for pregnant women/women who plan to become pregnant

Front 8

Who do you use HMG CoA Reductase inhibitors for?

Back 8

-Patients with LDL excess resistant to diet therapy
-Patients with hypertriglycerideemia
-Not for pregnant women/women who plan to become pregnant

Front 9

Describe the side effects of HMG CoA Reductase Inhibitors

Back 9

-Hepatotoxicity manifested by transaminase elevation (dose dep, 1%)
-Acute myositis (dose-dep, <1%)
-Rhabodmyolysis
-Renal failure

Risk of myocitis increased in patients concurrently taking gemfibrozil, cyclosporin A, nicotinic acid, or erythromycin

Front 10

Where are HMG CoA Reductase Inhibitors metabolized? Where do they act?

Back 10

-Targets to the liver
-Act at the liver
-Undergo extensive first pass hepatic metabolism mediated by organic anion transporter OATP1B1

Front 11

Describe Pravastatin

Back 11

-HMG CoA Reductase Inhibitor
-Hepatic extraction is 46% of absorbed dose
-Administered in the active form
-Excreted through bile and kidney
-Reduces LDL by ~25-35%
-Maximal dose is 80mg/d

Front 12

Describe Simvastatin

Back 12

-HMG CoA Reductase Inhibitor
-Hepatic extraction is 80% of absorbed dose
-Administered as inactive prodrug with a lactone ring
-Lactone ring hydrolyzed enzymatically in the liver to produce the acid form which is active
-Excreted through bile
-Reduces LDL by ~40%
-Maximal dose is 80mg/d

Front 13

Describe Lovastatin

Back 13

-HMG CoA Reductase Inhibitor
-Administered as inactive prodrug with a lactone ring
-Lactone ring hydrolyzed enzymatically in the liver to produce the acid form which is active
-Excreted through bile
-Teratogenic in rodents
-Reduces LDL by ~40%
-Maximal dose is 80mg/d

Front 14

Describe Fluvastatin

Back 14

-HMG CoA Reductase Inhibitor
-Administered in the active form
-Excreted through bile
-Reduces LDL by 25-35%
-Maximal dose is 80mg/d

Front 15

Describe Atorvastatin

Back 15

-HMG CoA Reductase Inhibitor
-Administered in the active form
-Excreted through bile
-Reduces LDL levels by 55%
-Maximal dose is 80mg/d

Front 16

Describe Rosuvastatin

Back 16

-HMG CoA Reductase Inhibitor
-Reduces LDL levels by about 56%
-Maximal dose is 40mg/d

Front 17

Describe the combination of statins/HMG CoA reductase inhibitors and bile acid sequestrants

Back 17

The induction in LDL levels can be more than additive

Front 18

Describe Nicotinic Acid

Back 18

-For elevated levels of VLDL, IDL, and LDL
-Reduces LDL and VLDL
-Increases HDL levels and reduces Lp(a) levels substantially
-Long term use causes significant decrease in recurrent myocardial infarction and has beneficial effect on CV mortality and total mortality as well
-Assocaited with increased prevalance of a-fib, GI and derm effects

Front 19

Describe the mechanism of Nicotinic Acid

Back 19

-Molecular target is a G-protein Couples Receptors (GPR109A)
-Activation of receptors causes reduction of cAMP leading to reduced levels of hormone senstive lipase in apidose tissue
-This reduces FFA mobilization from adipose tissue stores
-GRP109A helps protect against ketoacidosis
-When blocked by nicotinic acid, the reduced mobilization of FFA means diminised delivery to the liver of FFA for VLDL production
-This, hepatic synthesis of VLDL is limited

-Nicotinic acid inhibits the activity of diglycerol-acyl-transferase-2 - a key enzyme of triglyceride syntehsis

Front 20

Describe the side effects of nicotinic acid

Back 20

-Intense cutaneous flushing and pruritis (prostaglandin mediated)
-Can be blocked by aspirin or NSAIDs
-Transitory and disappears after the initial weeks of therapy
-Dry skin
-Nausea
-Vomiting
-Diarrhea
-Elevations of uric acid and blood sugar
-May activate peptic ulcer disease
-Can sometimes cause hepatitis (dose related, resolves rapidly upon drug cessation)

Front 21

When should nicotinic acid not be used?

Back 21

Caution with patients with
-Liver disease
-Diabetes mellitus
-Gout
-May enhance the activity of some drugs such as vasodilating and postueral hypotensive effect of antihypertensive agents

Front 22

In who should you use nicotinic acid?

Back 22

Only in high-risk hyperlipoproteinemic patients in whom dietary therapy achieves insufficient lipid lowering

Front 23

Describe nicotinic acid therapy

Back 23

-Initiated with 100mg 3x/d
-Dose doubles every 4-7 days until maintenance level of 1.5-3g/d is reached

-A sustained release prep or an extended release prep may be given at bedtime in doses which gradually increase to 1000-2000mg daily

Front 24

What are the important bile acid sequestrants?

Back 24

-Cholestyramine
-Colestipol
-Colesevelam

Front 25

Describe the mechanism of bile acid sequestrants

Back 25

-Resins that act to reduce total plasma cholesterol and LDL levels by binding intestinal bile acids
-They interrupt the enterohepatic circulation of bile acids
-The feed back inhibition of bile acid synthesis is lifted and cholesterol is converted to bile acids within the hepatocyte
-This results in a fall in intracellular cholesterol levels which enhances the synthesis of LDL receptors
-The clearance of LDL from plasma is accelerated and is due to increased hepatic LDL receptor activity

Front 26

In whom are bile acid sequestrants useful?

Back 26

Patients with primary elevation of LDL

Front 27

Describe cholestryamine

Back 27

-Bile acid sequestrant
-Reduces CHD risk
-Dose is 8-16g
-Available as powder to mix with food

Front 28

Describe the side effects of cholestryamine

Back 28

-GI effects, particularly constipation, nausea, abdominal discomfort, indigestion
-Better tolerated than colestipol
-May interfere with absorption of anionic drugs

Front 29

Describe the side effects of colestipol

Back 29

-GI effects, particularly constipation, nausea, abdominal discomfort, indigestion
-Not as well tolerated as cholestryamine
--May interfere with absorption of anionic drugs

Front 30

In whom are bile acid sequestrants useless?

Back 30

Patients with excess levels of chylomicrons, IDL, or VLDL

Front 31

Describe colesvelam

Back 31

-Bile acid sequestrant
-Causes modest reduction in blood glucose levels in pateints with type II diabetes mellitus
-Approved for treatment of diabetes mellitus and reduction of LDL
-Available as tablets (usual dosing is 6 tablets/3.75g/d)

Front 32

Describe colestipol

Back 32

-Bile acid sequestrant
-Dose is 10-20g
-Available as powder to mix with food
-Available in tablet form