Drugs for Lipid Disorders - DSA Flashcards
HMG-CoA reductase inhibitors
“statins” - analogs of initial precursor of cholesterol
Atorvastatin (lipitor) Fluvastatin Lovastatin* Pitavastatin Pravastatin Rosuvastatin (crestor) Simvastatin* (zocor)
*prodrugs hydrolyzed in GI tract to active compounds
Niacin
nicotinic acid
vit B3
Fibric acid derivatives (fibrates)
Fenofibrate
Gemfibrozil
Bile acid sequestrants (resins)
Cholestyramine
Colesevelam
Colestipol
Cholesterol absorption inhibitors
Ezetimibe (Zetia)
Drug combinations
simvastatin and ezetimibe (Vytorin)
Niacin and lovastatin extended release (Advicor)
Niacin and simvastatin extended release (Simcor)
New tx for homozygous familial hypercholesterolemia
Lomitapide
mipomersen
Chylomicrons
contains dietary TGs and cholesterol
TG:Chol is 10:1
Synthesized in intestine
Mech of catabolism: TG hydrolysis by LPL, remnant uptake by liver
VLDL
contains endogenous TGs
TG:Chol is 5:1
Synthesized in liver
Mech of catabolism: TG hydrolysis by LPL
IDL
contains endogenous cholesterol esters and TGs
TG:Chol is 1:1
Product of VLDL catabolism
Mech of catabolism: 50% to LDL mediated by hepatic lipase, 50% uptake by liver
LDL
contains cholesteryl esters
Product of VLDL catabolism
Mech of catabolism: uptake by LDL receptor (75% in liver)
HDL
contains Phospholipids, cholesteryl esters
Synthesized in liver
Mech of catabolism: uptake of cholesterol by hepatocytes
Statin pharmacokinetics
extensive first pass metabolism by liver
t 1/2 1-3 h, exceptions: atorvastatin 14 hr, rosuvastatin 19 hr
most absorbed dose excreted as bile, 5-20% in urine
Lovastatin, simvistatin, atorvastatin metabolized CYP3A4
Fluvastatin, rosuvastatin CYP2C9
Pitavastatin limited CYP450 biotransformation
Pravastatin not metabolized by CYP450s
Statin MOA
inhibit HMG-CoA reductase - rate limiting enzyme in cholesterol synthesis
Inhibits de novo cholesterol synthesis, depletes intracellular supply of cholesterol - causes cell to increase number of specific cell-surface LDL receptors that bind and internalize circulating LDLs
Increased expression of surface LDL receptors reduces circulating LDL levels
therapeutic benefits of statins
plaque stabilization
improvement of coronary endothelial function
inhibition of platelet thrombus formation
anti-inflammatory effects
Reduce LDL levels 20-55%
Adverse effects of statins on liver
elevations of serum aminotransferase activity (up to 3x) in patients with liver disease or hx of etOH abuse
Levels decrease upon suspension of drug therapy
Adverse effects of statins on muscle
creatine kinase activity levels may increase, particularly in patients who have a high level of physical activity
rhabdomyolysis (leading to myoglobinuria) occur rarely and lead to renal injury
Myopathy can occur with monotherapy, increased risk when taken with drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin
Statin contraindications
increases warfarin levels
pregnant, lactating, likely to become pregnant
liver disease or skeletal muscle myopathy
use in children limited to homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia
avoid with agents inhibiting or competing with CYP450 enzymes such as inducers phenytoin, griseofulvin (except for pravastatin and pitavastatin)
Niacin
Most effective agent for increasing HDL levels (30-40%)
Lowers LDL and VLDL by 10-20% and TG 35-45%
ONLY agent that reduces lipoprotein(a) levels significantly (40%)
Niacin pharmacokinetics
well absorbed, distributed to hepatic, renal, adipose tissue
extensive first pass
t1/2 60 min - BID or TID dosing
Excreted in urine unmodified and its metabolites
MOA of niacin
inhibits lipolysis of TG in adipose tissue, reducing circulating FAs which leads to less VLDL produced by liver and decreased LDL levels
Plasma TG (in VLDL) and cholesterol (in VLDL and LDL) decrease
Fibrinogen levels reduced and tissue plasminogen activator levels are increased - can reverse some endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis
Therapeutic uses of niacin
combined with a bile acid sequestrant (resin) or reductase inhibitor in tx of heterozygous familiar hypercholesterolemia, other forms of hypercholesterolemia, and some cases of nephrosis
utilized in tx of mixed lipemia that incompletely responsive to diet
Adverse effects of niacin
intense cutaneous flush (PG mediated) with uncomfortable feeling of warmth - flushing mitigated by taking aspirin before niacin or ibuprofen QD
Pruritus, rashes, dry skin or mucous membranes, acanthuses nigricans
hepatotoxicity with extended release
Contraindications of niacin
hepatic disease or active peptic ulcer
DM due to niacin-induced insulin resistance which can cause hyperglycemia
Fibrates pharmacokinetics
derivatives of fibric acid well absorbed (>90%) when taken with meal highly bound to serum albumin t1/2 - gemfibrozil 1.5h, fenofibrate 20h excreted as glucuronide conjugates
Fibrates MOA
agonist ligands for peroxisome proliferator-activated receptor alpha (PPARalpha)
PPARa binds to response elements in DNA, regulating expression of genes in lipoprotein structure and function
Expression levels of lipoprotein lipase increased, induces lipolysis of TG and decreases plasma concentrations
VLDL decreases, LDL modestly decreases, HDL increase moderately
Therapeutic uses of fibrates
hypertriglyceridemias where VLDL predominate
Dysbetalipoproteinemia
Hypertriglyceridemia from tx with viral protease inhibitors (saquinavir, indinavir, or nelfinavir for HIV therapy
Adverse effects of fibrates
mild GI disturbances, usually subside as tx continues
Lithiasis due to increased biliary cholesterol excretion - formation of gallstones
myositis - inflammation of voluntary muscle - evaluate for muscle weakness and tenderness
Myopathy and rhabdomyolysis - risk increased taking fibrates and reductase inhibitors
Fibrate contraindications
drug interactions: potentiate actions of coumarin and indanedione anticoagulants
hepatic or renal dysfunction
pregnant or lactating
increased risk of gallstones, caution in biliary tract disease or those at high risk (women, obese, native americans)
Resins
insoluble in water
Neither absorbed or metabolically altered by the intestine; totally excreted in the feces
Resin MOA
sequestrants are positively charged bind to negatively charged bile acids (metabolites of cholesterol), increasing their excretion up to tenfold which enhance the conversion of cholesterol to bile acids in the liver via 7α-hydroxylation, (normally controlled by negative feedback by bile acids)
decline in hepatic cholesterol stimulates an increase in hepatic LDL receptor enhancing LDL clearance and lowers levels; however, this effect is partially offset by enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase (combined use of a statin substantially increases the effectiveness of resins)
Therapeutic uses of resins
tx primary hypercholesterolemia - reduces LDL by 20%
Mono therapy or with niacin to treat Type IIa and IIb hyperlipidemia
relieve pruritus in those with bile salt accumulation from biliary obstruction
used for digitalis toxicity due to interaction with digitalis glycosides
Adverse effects of resins
GI: constipation, N, flatulence
High doses of cholestyramine and colestipol impair absorption of fat soluble vits (ADEK)
Contraindications of resins
impair absorption of tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, thiazide diuretics - give at least 1 hr before or 2 hrs after sequestrant to ensure absorption
Avoid or caution with diverticulitis, preexisting bowel disease, or cholestasis
Ezetimibe pharmacokinetics
i) Highly water insoluble; after ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters enterohepatic circulation as an active compound
ii) Majority is excreted in the feces (10% in the urine)
iii) 22 hour half-life
MOA of Ezetimibe
selectively inhibits intestinal absorption of cholesterol and phytosterols (plant sterols); thought to inhibit the transport protein NPC1L1
ii) Effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile
iii) Inhibited intestinal cholesterol absorption reduces the incorporation of cholesterol into chylomicrons, which reduces the delivery of cholesterol to the liver by chylomicron remnants
iv) On average, ezetimibe lowers LDL by 18% and triglycerides by 6% while raising HDL levels slightly (1.3%)
Therapeutic uses of Ezetimibe
Used to treat various causes of elevated cholesterol levels [e.g., primary
hypercholesterolemia (as monotherapy or in combination with HMG-CoA reductase inhibitors); homozygous familial hypercholesterolemia (in combination with atorvastatin or simvastatin); mixed hyperlipidemia (in combination with fenofibrate)]
Adverse effects of ezetimibe
no drug interactions
avoid combining with bile acid sequestrants due to inhibition of ezetimibe absorption
Situations when combination drug therapy useful
i) When VLDL levels are significantly increased during treatment of hypercholesterolemia
with a resin
ii) When LDL and VLDL levels are both elevated initially
iii) When LDL or VLDL levels are not normalized with a single agent
iv) When an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias
the ENHANCE study
(a) A 2-year study in patients with familial hypercholesterolemia comparing the effects of ezetimibe and simvastatin together with those of simvastatin alone
(b) Results showed a 58% reduction in LDL cholesterol with the combination compared to a reduction of 41% with simvastatin alone
(c) However, results showed no additional effect of ezetimibe on carotid intima-media thickness, a surrogate marker for coronary atherosclerosis
(d) Direct measurements of clinical endpoints such as myocardial infarction, stroke, or cardiovascular death require trials with many participants followed for years and, as a result, surrogate endpoints are often used instead for FDA approval of medication (in the ENHANCE trial, the surrogate endpoint was lower LDL cholesterol levels)
SEAS study
found no reduction in major cardiovascular events with simvastatin plus ezetimibe compared to placebo, and actually found an increase in various types of cancer in patients taking the simvastatin-ezetimibe combination
Lomitapide
tx of homozygous familial hypercholesterolemia
MOA: directly binds to and inhibits microsomal triglyceride transfer protein (MTP) which is
located in the lumen of the endoplasmic reticulum. MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations.
substrate and inhibitor of CYP3A4
Adverse effects: GI symptoms, increased aminotransferase levels, hepatic fat accumulation
Mipomersen
Tx of homozygous familial hypercholesterolemia
MOA: antisense oligonucleotide that targets apoliporotein B-100 (apoB-100) mRNA and disrupts its function
(1) ApoB-100 is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids
(2) Elevated levels of apoB, LDL-C and VLDL are associated with increased risk of
atherosclerosis and cardiovascular diseases
Adverse effects include injection site reactions (administration via subcutaneous injection once per week), flu-like symptoms, headache, and elevation of liver enzymes ≥three times the upper limit of normal (discontinue if elevations persist or are accompanied by clinical symptoms, such as hepatic steatosis
Omega 3
modify membrane function inhibit thrombus formation decrease inflammation lower plasma TG alter electrical activity of myocardium
Type I
familial hyperchylomicronemia elevated TG deficiency of lipoprotein lipase or normal apoliporotein CII no increase CAD Tx: low fat diet
Type IIA
familial hypercholesterolemia
elevated LDL, normal VLDL due to block of LDL degradation - increased cholesterol but normal TG
Defects in synthesis or processing of LDL receptors
Ischemic heart disease accelerated
Tx: diet
Heterozygotes - cholestyramine and niacin or a statin
Type IIB
familial combined (mixed) hyperlipidemia
increased VLDL and LDL, elevated TG and cholesterol
overproduction of VLDL by liver
tx: diet, drug therapy like IIA
Type III
familial dysbetalipoproteinemia
high IDL, increased TG and cholesterol levels
overproduction or underutilization of IDL due to mutant poE
Xanthomas and accelerated vascular disease develop in patients by middle age
Tx: diet, niacin and fenofibrate, or a statin
Type IV
Familial hypertriglyceridemia
VLDL increased, LDL normal or decreased –> normal or elevated cholesterol and elevated TG
Overproduction and/or decreased removal of VLDL TG in serum
accelerated ischemic heart disease
assoc with obesity, DM, hyperuricemic
Tx: diet, niacin and/or fenofibrate
Type V
Familial mixed hypertriglyceridemia
serum VLDL and chylomicrons elevated, LDL normal or decreased, elevated cholesterol and greatly elevated TG
increased production or decreased clearance of VLDL and chylomicrons - genetic defect
Tx: diet, niacin and/or fenofibrate, or statin
