Hyperlipidemia Drugs

Question 1

Pravastatin
Simvastatin
Atorvastatin

Answer 1

• Pravastatin and Simvastatin are derived from fungi
• Atorvastatin is synthetic and has a long half life (> 12 hrs); has the longest effect on HMG-CoA reductase
• HMG-CoA reductase inhibitor; statins competitively inhibit the first committed step in the synthesis of cholesterol
• lowers serum TG’s modestly
• increases HDL cholesterol by a bit
• inhibits the hepatic formation of lipoproteins
• alters VLDL composition so that VLDL clearance is also increased
• variable oral absorption
• extensive first-pass hepatic clearance (60%)
• substrate for CYP P450 except for pravastatin
• highly bound to plasma proteins
• primarily biliary excretion
• administer as a single dose at bed time because HMG-CoA enzyme is active most at night
• side effects: generally free of dose-limiting side effects
• mild GI upset = most common adverse run
• headache, loss of concentration
• rarely, hepatotoxicity (mild increases in hepatic transaminases) and myopathy/myositis
  Risk of myopathy is increased when statins are given with fibrates or nicotinic acid
• contraindicated in pregnancy, nursing mothers, and young children
• drugs that inhibit statin metabolism: macrocodes, cyclosporine, azalea antifungals, fluoxetine, metronidazole, ritonavir, zafirlukast
• drugs that increase statin metabolism: barbiturates, carbamazepine, rifampin, phenytoin
• statins lower LDL-cholesterol in: familial hypercholesterolemia, polygenic hypercholesterolemia, familial combined hyperlipidemia
• in addition to bile acid sequestrants, only drugs shown to reduce CV events

Question 2

Cholestyramine
Colestipol
Colesevelam

Answer 2

• bile acid sequestrants
• positively charged binding resins which ionically bind bile acids
• in addition to statins, only drugs shown to reduce CV events

adverse effects:

• palatability: resins have a consistency of sand
• bloating, flatulence, constipation - dietary fiber may relieve
• steatorrhea or cholestasis
• increase in serum triglyceride
• rare: malabsorption of vitamin K or folic acid; dry, flaking skin
• many drug interactions because resins can bind many things –> other drugs should be given either 1-2 hours before or 4 hours after the resin
  Niacin absorption is not interfered with

Bile acid sequestrants are polymeric compounds that serve as ion-exchange resins. Bile acid sequestrants exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from the enterohepatic circulation. The liver then produces more bile acids to replace those that have been lost. Because the body uses cholesterol to make bile acids, this reduces the amount of LDL cholesterol circulating in the blood.[1]

Question 3

Nicotinic acid aka niacin

Answer 3

• water soluble vitamin which is converted into an amide and incorporated into NAD

mechanisms:

• inhibition of VLDL secretion
• interference with apolipoprotein synthesis
• increased clearance of VLDL via lipoprotein lipase
• inhibition of intracellular lipase
• decrease clearance of HDL
• decrease levels of Lp(a)

pharmacokinetics:

• well absorbed orally; peak levels in 30-60 minutes
• short half-life requiring 3 times a day dosing
• primarily excreted unchanged in the urine

adverse effects: significantly limit te usefulness of niacin

• majority of patients have intense flushing and pruritis of the face and upper body - aspirin relieves these Sx
• GI: dyspepsia, vomiting, diarrhea - reduced if taken with meal or antacid
• dry skin
• increased plasma glucose and decreased glucose tolerance - contraindicated in diabetics
• increased uric acid levels, may cause gout
• conjunctivitis
• nasal stuffiness
• cardiac arrhythmias
• hepatotoxicity at doses of 2g/day or more
• birth defects
• increased risk of myositis when used with a statin
• -> niacin is often used in combo since this permits the use of lower doses
• used as an adjunctive therapy with a resin to lower LDL in familial hypercholesterolemia
• use for familial combined hyperlipoproteinemia to lower TG’s and to raise HDL

Question 4

Fenofibrate

Answer 4

• fibric acid derivative

mechanism of action:

• upregulate lipoprotien lipase, increases the clearance of VLDL
• upregulate apo A1 genes
• decrease expression of Apo C-III (lipoprotein lipase inhibitor)
• increased oxidation of fatty acids in liver and muscle
• decreased platelet reactivity and aggregation

effects on lipids:

• decrease in VLDL
• increased HDL
• effective in the treatment of familial hypertriglyceridemia and familial dysbetalipoproteinemia

pharmacokinetics:

• well absorbed orally, particularly with a meal
• extensively protein bound
• enterohepatic circulation
• half-life of about 20 hrs
• renal elimination of glucuronide conjugates

adverse effects:

• GI upset
• skin rash
• muscular pain
• elevated aminotransferases
• myopathy particularly when given with statins
• cholelithiasis (women, obese pts, and native americans are at greatest risk)
• potentiation of warfarin anticoagulant action
• contraindicated in pregnancy and in children

Question 5

Ezetimibe

Answer 5

• inhibitor of luminal cholesterol uptake by enterocytes by inhibiting the transport protein NPC1L1
• effects are additive with statins
• well tolerated
• interactions: resins bind ezetimide
  can lower gallbladder disease
  cyclosporine raises plasma levels