STATINS: HMG-COA REDUCTASE INHIBITOR

- most effective in reducing LDL -Macrolide Tacrolimus

- standard practice Antibiotics Nefadozone
Cyclosporine Fibrate reduces clearance of
Chemistry and Pharmacokinetics Ketoconazole Paroxetine statins
-Lovastatin and Simvastatin Venlavaxine
- inactive lactone prodrugs
-Pravastatin Amiodarone myopathy
- open, active lactone Verapamil
-Atorvastatin, Fluvastatin, Rosuvastatin
- fluorine-containing, active -Phenytoin
-Absorption: 40% - 75% Griseofulvin
-except Fluvastatin (almost completely absorbed) Barbiturates increases clearance of statins
-Excretion: Bile Rifampin
- 5-20% (urine) Thiazolidinediones
-T : 1-3 hrs
-except Atorvastatin (14 hrs) - Pravastatin and Rosuvastatin
Pitavastatin (12 hrs) - statins of choice (w/ verapamil, ketoconazole,
Rosuvastatin (19 hrs) macrolides, and cyclosporine)
- 1 liter of grapefruit juice daily
Mechanism of Action - plasma levels of Lovastatin, Simvastatin, Atorvastatin
-mediates the first step in Sterol Biosynthesis -All statins undergo glcosylation
-partial inhibition of the enzyme - interaction w/ gemfibrozil
- HMG-CoA reductase
NIACIN (NICOTINIC ACID)
Therapeutic Uses and Dosage
- useful alone/ with resins, niacin, or ezetimibe -not niacinamide/ nicotinamide
- should NOT be given to pregnant, lactating or likely to -decreases VLDL and LDL and LP(a)
become pregnant -increases HDL
- used in children
- familial hypercholesterolemia/ common Chemistry and Pharmacokinetics
hyperlipidemia -vitamin B3
-Cholesterol Synthesis -incorporated into NAD (niacinamide adenine dinucleotide)
- predominantly at night -excreted in the urine
- given in the evening except: -unmodified
Atorvastatin, Rosuvastatin
-Absorption: enhanced by food except: Mechanism of Action
-Pravastatin -inhibits VLDL secretion
-Lovastatin = Pravastatin -decreases production of LDL
-Simvastatin - 2x potent -increases VLDL clearance via LPL pathway
-Fluvastatin - x potent - triglycerides
-Rosuvastatin - most efficacious (severe -Bile acid production: no effect
hypercholesterolemia) - catabolic rate of HDL
- Fibrinogen levels; tissue plasminogen activator
Toxicity
- serum aminotransferase activity (3x) Therapeutic and Dosage
- malaise, anorexia, precipitous increase in LDL - combination with resin/statin
- dosage (hepatic parenchymal disease, -normalizes LDL
Asians, and elderly) -heterozygous familial hypercholesterolemia
- fasting blood glucose level -nephrosis
- creatinine kinase (CK) -with omega-3 fatty acids
- myoglobinuria renal injury -decreases triglycerides (severe mixed lipemia)
- rhabdomyolysis - Useful in patients with:
- CYP3A4 - Lovastatin, Simvastatin, Atorvastatin -combined hyperlipidemia
- CYP2C9 - Fluvastatin, Rosuvastatin, Pitavastatin -dysbetalipoproteinemia
- Other + Sulfation - Pravastatin -MOST effective agent in increasing HDL
-ONLY agent that may reduce Lp(a)
 Toxicity BILE ACID-BINDING RESINS
-cutaneous vasodilation
-tachyphylaxis to flushing -decreases LDL
-Ibuprofen -may increase VLDL (hypertriglyceridemia)
-pruritus, rashes, dry skin, acanthosis nigricans
Association w/ insulin resistance Chemistry and Pharmacokinetics
-avoided: w/ severe peptic ulcer disease -large polymeric cationic exc
-Niaspan
-extended release Mechanism of Action
-given at bedtime -reabsorption of bile acid
-maybe given to diabetics -jejunum and ileum
-hyperuricemia gout -w/ resins
-allopurinol -excretion of bile acid: 10 fold increased
-red cell macrocytosis -cholesterol bile acid
-platelet deficiency 7 alpha-hydroxylation
-arrhythmias -improve glucose metabolism
-blurring of distance vision - insulin secretion
-potentiate antihypertensive agents
-birth defects Therapeutic and Dosage
-20% reduction in LDL
FIBRIC ACID DERIVATIVES (FIBRATES - VLDL (hyperlipidemia
-addition of second agent: NIACIN
-decrease levels of VLDL (and LDL) -relieves pruritus (cholestasis & bile salt accumulation)
-useful in digitalis toxicity
Chemistry and Pharmacokinetics -granular preparations (cholsetipol & cholestyramine)
-Gemfibrozil -mixed w/ juice or water
-readily passes the placenta -taken w/ meals
-t : 1.5 hrs -colesevelam (tab & suspension)
-elimination: 70% kidneys (unmodified)
-Fenofibrate Toxicity
-hydrolyzed completely -constipation & bloating
-t : 20 hrs -avoided: diverticulitis
-elimination: 60% kidneys (glucuronide) -heartburn & diarrhea
25% feces -steatorrhea
-malabsorption of Vitamin K
Mechanism of Action -hypoprothrombinemia
-ligands for the PPAR-alpha -malabsorption of folic acid
-up-regulate LPL, apo A-I and apo A-II -gallstone formation
-down-regulate apo C-III -digitalis glycosides
-inhibitor of lipolysis Thiazides
- VLDL Warfarin absorption is impaired
- secretion of the liver Tetracycline by Resins
Thyroxine
Therapeutic and Dosage
-hypertriglyceridemias -Niacin
-dysbetalipoproteinemia -should be given 1 hr before or 2 hrs after
-Gemfibrozil: 600 mg (OD / BID) -Colesevelam
-Fenofibrate (Tricor): 48 mg (1-3 tabs) or 145 mg (OD) -does not bind digoxin, warfarin, statin
-taken w/ food

Toxicity
-rashes, GI symptoms, myopathy, arrhythmias,
hypokalemia
- WBC, hematocrit
v
-Fenofibrate
-fibrate of choice (w/ statin)
-avoided: hepatic and renal dysfunction
-cholesterol gallstones
INHIBITORS OF INTESTINAL STEROLS C. Niacin & Resins
- VLDL & LDL (FCH)
-inhibits intestinal absorption of phytosterols & cholesterol -heterozygoys hypercholesterolemia
- LDL
D. Niacin & Statins
Chemistry and Pharmacokinetics -hypercholesterolemia
-conjugated to active glucuronide -FCH
-peak blood levels (12-14 hrs)
-t : 22 hrs E. Statins & Ezetimibe
-80% - excreted in feces -primary hypercholesterolemia
- levels w/ fibrates -homozygous familial hypercholesterolemia
Levels w/ resins (cholestyramine & others)
-Warfarin & Digoxin F. Statins & Fenofibrate
-no significant interaction - LDL & VLDL

Mechanism of Action G. Resins, Ezetimibe, Niacin, and Statin

-inhibits transport protein, NPCILI

Therapeutic and Dosage

-primary hypercholesterolemia
-phytosterolemia
-synergistin w/ statins
-25% LDL

Toxicity
-Myositis

CETP INHIBITORS

-Torcetrapib
- VLDL, LDL
- CV events

-Anacetrapib & Dalcetrapib

-analogs

DRUG COMBINATIONS

1. VLDL (hypercholesterolemia)
-tx w/ resin

2. LDL & VLDL (initially)

3. not normalized by a single agent

4. Lp(a), HDL

A. Fibrates & Resins

-familial combined hyperlipidemia
-intolerant of statins / niacin
-cholelithiasis

B. Statins & Resins

-familial hypercholesterolemia
-do not control VLDL
-FCH (familial combined hyperlipoproteinemia)
-statin
-1 hr before or 2 hrs after resins