• Statins
• have -statin as ending of generic name

• Atrovastatin (Lipitor)
• Fluvastatin (Lescol, Lescol SL)
• Lovastatin (Mevacor, Altoprev, altocor, Advicor)
• Pravastatin (Prevachol)
• Rosuvastatin (Crestor)
• Simvastatin (zocor, Vytorin, simcor)

1. Inhibition of HMG CoA reductase
2. direct effect of HMG CoA reductase inhibition

• statins target hepatocytes and competitively inhibit HMG CoA reductase
• prevents the hepatic production of cholesterol resulting in ↓ hepatic cholesterol [ ]
• low intracellular cholesterol:

1.  stimulates the synthesis of LDL receptors, resulting in ↑ uptake of circulating LDL form blood and a ↓ in plasma [LDL]
2. ↓ the secretion of VLDL
   

hepatocellular enzyme that converts HMG-CoA into mevalonic acid, a cholesterol precursor

• this conversion is an early rate limiting step in cholesterol biosynthesis 

• majority are expressed by hepatocytes
• small fraction expressed by a variety of cell types in the body

• 2º and minor mech of action of statins
• statins inhibit hepatic synthesis of apolipoprotein B (apo B)
• results in inhibition of the apo B containing LDLs and VLDLs, which accounts for some of the cholesterol and triglyceride lowering effects of statins

• unlocks the doors to cells and thereby delivers cholesterol to them
• also helps provide structural integrity to LDL and VLDL

• ↓ plasma cholesterol by:
  
  • ↓ cholesterol synthesis
  • ↑ catabolism of LDL and VLDL precursors
• other very minor effects:
  • slight ↑ in HDL and apo-A
  • ↑ VLDL (LDL precursor) and apo-B
  • slight ↓ in triglycerides 

• anti-inflammatory effects
• caused by inhibition of isoprenoid (pro-inflammatory) formation in nonhepatic cells
• other pathways involved in anti-inflammatory effects of statins
• end result: ↓ macrophage accumulation in atherosclerotic lesions, ↓ vascular inflammation (ie ↑ stability of atherosclerotic lesions), ↓ platelet aggregation, and antioxidant effects (ie improved endothelial fxn)

• effects of restoring/improving endothelial fxn. and anti-inflammatory properties are implicated in possible cardioprotective effects (preventing coronary events) of early statin use in:
  • post MI
  • post percutaneous coronary interventions (e.g. stents)

• Extensive 1st pass effect
• systemic bioavailability = 5-30%
• Lovastatin and simvastatin are inactive prodrugs that are rapidly hydrolyzed to active forms. Others are administered in active forms
• Metabolites of all statins, except fluvastatin and pravastatin, have some HMG-CoA reductase inhibitory activity

• t_1/2 of parent compounds are 1-4 hrs, except atrovastatin and rosuvastatin, which = 20 hours
• longer t_1/2 may contribute to their greater cholesterol lowering efficacy

• cholesterol reduction seen within 1-2 weeks
• maximum therapeutic response occurs with in 4-6 weeks
• pleiotropic effects occur faster

single daily dose given in evening are more effective than in the morning

• cholesterol is synthesized mainly at night

• accumulation, generally only seen in pts with severe renal or liver dysfunction
• all destributed mainly to liver
• all highly protein bound: (88-99%)
• extensively metabolized in liver

• CYP3A4: Simvastatin, lovastatin, atrovastatin
• CYP2C9: Fluvastatin, 10% of rosuvastatin
• CYP independent: Pravastatin (undergoes enzymatic and nonenzymatic biotransformation (sulfation)

1. Hepatotoxicity (<1%)
2. Myopathy (10%)
3. Miscellaneous side effects (5%)

• ↑ hepatic aminotransferase (ALT, AST)
• mild in nature and rarely reaches 3x baseline
• seen more frequently in pts with fatty liver
• liver enzymes ↓ upon stopping or ↓ dose
• monitor ALT, AST at baseline, 6 and 12 weeks
• avoid in pts with active liver disease (or use pravastatin)
• consider different statin if persistent elevation in ALT/AST (Pravastatin, rosuvastatin)
• may be dose dependent (10mg=0.2% seen ↑; 80mg=1.2% seen ↑

Miscellaneous side effects of statins (5%)

• abd pain
• constipation
• flatulence
• nausea
• diarrhea
• headache 
• fatigue

• most common reason for discontinuation
• diffuse muscle ache, soreness, weakness, nocturnal cramping, tendon pain
• muscle symptoms are generalized and worse with exercise

Defined as 4 syndormes:

1. Myopathy: any muscle complaint
2. Myalgia: muscle complaint with out ↑ CK
3. Myositis: muscle symptoms with ↑ CK
4. Rhabdomyolysis: markedly ↑ CK with ↑ serum creatinine with pigment-induced nephropathy (rust colored urine)

1. depletion of isoprenoids (or mevalonate metabolites). Isoprenoids are lipids that prevent myofibre apoptosis and regulate mitochondrial fxn. Their depletion causes myotoxicity.
2. reduced cholesterol content of skeletal muscle cell membranes

• dose related (not related to ↓ in LDL)
• advanced age
• female
• low boy mass index
• decreased liver and renal fxn
• multiple comorbidities
• polypharmacy and drug interactions
• grapefruit (possibly pomegranate, starfruit) juice (can cause overdose of statins metabolized by CYP3A4)
• excess alcohol
• heavy exercise
• trauma or major surgery

• amiodarone (CYP3A4)
• Fibrates (esp. gemfibrozil), niacin
• CCBs (CYP3A4)
• many others

• grapefruit, pomegranate, starfruit juice
• contain irreversible inhibitor of intestinal CYP3A4 and can cause ↑ bioavailability of atorvastatin, lovastatin, and simvastatin
• grapefruit ↓ CYP3A4 activity by 50% within 4 hours and by 30% for as long as 24 hrs after ingestion (quick acting)
• effect of grapefruit disappears over 3-7 days (long lasting)
• continued daily intake of even small amounts of these juices can ↑ statin bioavailability b/c of irreversible inhibition of intestinal CYP3A4
• lower dose to counteract this effect

• Lipophilic statins: more likely to penetrate muscle tissue, enhancing potential for myotoxic effects
  • simvastatin, arorvastatin, lovastatin, fluvastatin 
• Hydrophilic statins: include pravastatin and rosuvastatin
• Rhabdomyolysis has occurred with all available agents: no conclusive evidence that water solubility is major factor in determining myopathic risk

• routine monitoring of CK levels is not required except high risk pts
• if tolerable symptoms, try coenzyme Q10
• if intolerable symptoms, stop statin and:
  • consider rechallenge with smaller dose of water soluble statin
  • coenzyme Q10 supplementation
  • alternative lipid lowering agents

• in adipose tissue, niacin inhibits breakdown (lipolysis) of TG by HSL (hormone sensitive lipase). this reduces FFA to the lifer and ↓ hepatic TG synthesis
• in liver, niacin ↓ TG synthesis by inhibiting synthesis and esterification of FA. Reduction of TG synthesis leads to ↓ VLDL production, which leads to↓ LDL levels
• niacin ↑ HDL by ↓ hepatic clearance (catabolism) of apo-A-I, a major protein component of HDL, rather than by enhancing HDL synthesis

• major component of HDL
• helps remove cholesterol form tissue (e.g arteries) into the liver where it is broken down and excreted via GI track

• ↓ normal mobilization of FFA form adipose tissue
• ↑ HDL by reducing its catabolism
• good effects on LDL, HDL and TG levels
• best drug on market to ↑ HDL levels

• absorption: (Niaspan): 60-76%, administered with a low fat meal or snack
• metabolism: rapid liver metabolism into nicotinamide (has no lipid-lowering activity)
• excretion: 60-76% renal, mostly as metabolites

Include:

• immediate release (IR) non-Rx
• sustained release (SR) non-Rx
• sustained release (ER) Rx (Niaspan)
• Niacin SR + lovastatin (Advicor)
• Niacin SR/simvastatin (Simcor)

• Nicotinic acid (used for cholesterol)
• Niacinamide or (nicotinamide)
• Inositol hexaniacinate (flush free, but cholesterol effects unknown)

1. Glycine conjugate = flushing
   • Low affinity, high capacity 
2. Amidation pathway = hepatoxicity 
   • high affinity, low capacity

• byproducts cause vasodilation and flushing
• only utilized when amidation pathway is saturated
• IR niacin saturates the amidation pathway, causing most of the drug to be metabolized by conjugation

• byproducts cause hepatotoxicity
• high affinity, low capacity
• SR niacin causes majority to be metabolized by amidation

Dermatologic adverse effects of niacin

• severe generalized flushing, sensation of warmth, and itching particularly in the area of the face, neck and ears may occur within 2 hrs after ingestion
• Flushing is prostaglandin-mediated
• administration of 325 mg of aspirin (or other NDAID) 1 hr prior to niacin recommended to reduce flushing 
• increase niacin dose gradually to min. flushing, consider using niaspan

• stimulation of peptic ulcers, nausea, diarrhea
• hepatoxicity 
  • dose related ↑ in AST/ALT and alk PO4
  • seen more often with SR niacin products than IR niacin (SR>ER (Niaspan)>IR)

• myopathy, Rhabdomyolysis
• muscle toxicity increases sig when niacin is given in combination with statins
• Myopathy with statin-niacin comb: dose related
• Simvastatin package insert cautions against using > 10mg of the drug when combining with niacin
• use caution in elderly, especially women, and in patients with renal failure

• deterioration of glycemic control
• increase in plasma uric acid levels

• Cholestyramine (Questran) Powder for suspension
• Colestipol (Colestid) - Tablets and granules
  • better palatability than cholestyramine b/c odorless and tasteless
• Colesevelam (Welchol) - Tablets
  • side effects occur less often than with older BAS

• act locally in the small intestine
• BAS bind bile acid in the small intestine to form an insoluble complex that is secreted in the feces
  • prevents bile acid reabsorption and enterohepatic cycling, depleting bile acid storage

• cholesterol is sole precursor of bile acids
• in normal digestion, bile acids are secreted via the bile from the liver and gallbladder into the intestines to emulsify fat and lipid materials in food, thus facilitating absorption
• major portion of bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, which completes the enterohepatic cycle
• compensatory increase in hepatic synthesis of cholesterol may occur

• ↑ oxidation of cholesterol to bile acids (in the liver via cholesterol 7α-hydroxylase)
• ↓ intra-hepatic cholesterol stores
• ↑ expression of LDL receptor
• ↑ LDL clearance and ↓ LDL levels

• up-regulation in hepatic synthesis of cholesterol and triglycerides may occur with BAS administration
• May partially offset efficacy of BAS, but overall plasma cholesterol levels still fall. Serum TG levels may slightly increase

LDL: ↓↓↓

HDL: 0 to ↑

TG: 0 to ↑

• virtually water insoluble (99.75%), not hydrolyzed by digestive enzymes, and not absorbed
• not metabolically altered
• totally excreted in feces

• Primarily GI: due to local action in small intest
  • most common: constipation, nausea, flatulence, abdominal discomfort or cramps 
  • Colesevelam seems to have lower incidence of GI side effects
• at high doses: cholestyramine and colestipol  (not Colesevelam) impair absorption of fat soluble vitamins (A,D,E,K)
• Adverse effects are dose related
• Those with colesevelam are similar but occur less often than with others

• Gradually increase dose
• increase fluid intake
• modify diet
• take stool softeners

• increasingly used in combination with other drugs because low doses are tolerated well
• BAS work in complementary fashion with other agents

• reduced bioavailability of other drugs such as warfarin, digoxin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, folic acid, mycophenolate, thyroid hormones, and possibly iron
• Take other drugs at least 1 hour before BAS or 4-6 hours after (as with any bulky drugs)

• bind to Niemann-Pick C1-like 1 (NPC1L1) protein at the brush-border membrane of the enterocyte
• reducing blood cholesterol by inhibiting the absorption of cholesterol at the intestinal brush border
• ↓ in delivery of intestinal cholesterol to liver
  
• End result: ↓hepatic cholesterol stores and ↑ cholesterol clearance from blood (↓ LDL)
• may precipitate a compensatory ↑ in cholesterol syntheses

• highly water insoluble
• rapidly absorbed
• peak concentration in 2-3 hours
• food does not affect bioavailability 

• rapidly metabolized in intestinal epithelium to active metabolite (phenolic glucuronide form)
• then absorbed and enters enterohepatic recirculaton (excreted in bile and delivered back to site of action) prolongs drug action
• t_1/2 = 24 hours
• both parent and metabolite inhibit cholesterol absorption

80% in feces

10% in urine

• BAS inhibit absorption of ezetimibe (co-administration not recommended)
• Cyclosporine- ↑ exposure of both ezetimibe and cyclosporine. Monitor cyclosporine levels
• Fibrates may ↑ cholesterol excretion into the bile, leading to cholelithiasis. Ezetimibe may ↑cholesterol in g.b bile. co-admin not recommended

• maximal efficacy for lowering LDL is 15-20% when used as monotherapy
• addition of statin will complement its action by preventing enhanced cholesterol synthesis induced by ezetimibe. A further ↓ of 15-20% in LDL is observe 

1. pts on high dose statins, but have not reached lipid-lowering goals
2. pts who can not tolerate statins
3. Pts who can only tolerate low dose of statins

• Gemfibrozil (lopid)
• Fenofibrate (Tricor, Antara, Lipofen, Triglide)

• act as PPARα agonists mainly in liver, and adipose tissue
• Result in:
  •  ↓TG (major source of circulating FAs)
  • ↑ HDL (breakdown of HDL prevented)

• transcriptive factors, when stimulated, affect fat and glucose metabolism
• PPARα target genes include multiple proteins essential for FA uptake, intracellular transport, and oxidation

• ↑ lipoprotein lipase (LPL) production, which hydrolyzed TG-rich lipoproteins (speed up breakdown of triglycerides)
• stimulation of FFA oxidation
• activationof transcription of major HDL apolipoproteins, Apo-AI, Apo-AII
• = ↓ TG, ↑ HDL

pharmacokinetics of Fibrates 

• rapidly and efficiently (>90%) absorbed, especially if taken with food
• Protein binding = 95% (albumin)
• t_1/2 widely variable (gemfibozil = 1.1 hr, fenobibrate = 20 hrs)
• wide tissue distribution with high [ ] in liver
• excreted as glucuronide conjugates mostly in urine (60-90%) then feces. Use caution in renal dysfunction

• GI: dyspepsia, abd pain, diarrhea, nausea, vomiting, cholelithiasis
• Myopathy: can occur with monotherapy, but more freq. when given with high dose of statin
  • Gemfibrozil inhibits hepatic uptake of statins. also competes for same enzyme that metabolizes statins → levels of both drugs may ↑
  • Fenobibrate: metabolized by different enzyme, so combination with statin less likely to cause myopathy
  • failure to discontinue drug can cause rhabdomyolysis
  • monitor CK every 3 months initially

• severe hyperthiglyceridemia
• hypertrigylceridemia and low HDL

• Warfarin = ↑ INR
• Statins = ↑ myopathy
• Ezetimibe = ↑ [ezetimibe] and ↑ risk of cholelithiasis

• eicosapentaenoic acid (EPA) and docosachexaenoic acid (DHA), AKA fish oils or polyunsaturated fatty acids
• EPA and DHA are essential FAs and cannot be synthesized

Lovaza (formerly called Omacor) only Rx product

all others have lower doses

• inhibit lipogenesis (multiple pathways)
• induce peroxisomal β oxidation in liver (mediate hypolipidemic effects)
• End result is a ↓↓ in VLDL, TG and small ↓ in total [cholesterol], and a small ↑ in HDL

• antiarrhythmic effects
• ↓ platelet aggregation
• ↓ BP
• anti-inflammatory effects
• vasodilation
• plaque stabilization

Hypertriglyceridemia

1. ↑ pt compliance - 4 capsules/day vs 10-18 commercially available fish oil concentrations
   
2. Better tolerability profile compared with other drugs, ie gemfibrozil and nicotinic acid, which are currently used for hypertriglyceridemia