Drugs for Lipid Disorders Flashcards
Hyperlipoproteinemia defintion
Excess of lipoproteins in blood due to disorder in metabolism (acquired or familial).
Hyperlipidemia definition What class is effective at lowering all types of this?
Elevated concentration of any/all lipids in plasma.
Includes hyperTG, hypercholesterolemia.
Statins. (Resins for Type IIa and IIb; Ezetimibe for mixed)
Chylomicron - function
Formed in intestinal mucosa. Tranports TG to adipose/liver.
Degraded in caps of muscle and adipose tissue.
HDL
Transports cholesterol from tissues to liver for excretion in bile.
Synthesized by liver.
LPL
Lipoprotein lipase.
Located on inner surface of cap endothelial cells of muscle and adipose tissue.
Function - Hydrolzes TGs in chylomicron and VLDL»_space; forms FFA+glycerol in adipose
Tx for Primary hypertriglyceridemias
Fibrates
Tx for Primary hypercholesterolemias
Niacin, statins, resins, Cholesterol Absorption Inhibitors
What two lipoprotein disorders will always require drug therapy?
Familial hypercholesterolemia and familial combined hyperlipidemia
What three things can result in HDL deficiency?
1) Tangier Disease
2) LCAT deficiency
3) Familial hypoalphalipoproteinemia
What are the three things that are the principle factors for increasing TGs?
Fat, alcohol, excess calories
What are the three things that are the principle factors for increasing LDL?
Cholesterol, saturated fat, trans fat
When would a child with familial hypercholesterolemia or familial combined hyperlipidemia initiate drug therapy? And what drug?
Age 7 or 8 after myelination of CNS is complete. Use a resin or statin.
What is the most effective class for reducing LDL levels? By how much?
Statins
reduce LDL by 20-55%
Statin MOA (3) and results of each.
1) Inhibit HMG-CoA reductase (cholest precursor). Results in decreased concentration of cholesterol within the cell.
2) Low intracellular cholesterol»_space; increased LDL receptor synthesis AND decreased VLDL secretion
3) **Increased LDL receptors = promotes LDL reuptake from cell
Which two stains have the longest half lives?
Atorvastatin (14hrs)
Rosuvastatin (19hrs)
Primary method of metabolism of statins. Which one is not metab by CYP450s?
CYPs CYP3A4 - lovastatin, simvastatin, atorvastatin CYP2C9 - fluvastatin and rosuvastatin CYP450 - pitavastatin Not mebatolized by CYP450s - pravastatin
Therapeutic uses (2)
1) In all hyperlipidemias - lower plasma cholest levels
2) Reduce LDL levels - Can be used alone or with resins, niacin, or ezetimibe.
Potency of statins
(Atorva = Rosuva) > Simva > (Pitava = Lova = Prava) > Fluva
What time of day should statins be taken?
Evening - because cholesterol is synthesized at night.
When are statins contraindicated (3 groups)?
PREGNANT WOMEN, people with liver disease, people with skeletal muscle myopathy (esp those taking antibiotics).
What should not be used in conjunction with statins?
Other agents that inhibit or compete with CYP450 - decreases their metabolism.
Statins are limited to use in children with what 2 hypercholesterolemia conditions?
Homozygous familial hypercholesterolemia and Heterozygous familial hypercholesterolemia
What are the two statins that penetrate the CNS?
Lova and Simva
What two things does niacin (Vitamin B3) most effective at accomplishing?
1) Increasing HDL by 30-40% (also lowers LDL and VLDL)
2) Significantly lowering LPL levels
What three tissues is niacin (NAD) distributed to and absorbed?
Hepatic, renal, adipose.
Niacin MOA
INHBITS LIPOLYSIS of TGs in adipose tissue»_space; less circulating FFA»_space; liver produces less VLDL»_space; LDL levels decrease
When is niacin used in combo with resin or statin?
For heterozygous familial hypercholesterolemia, other forms of hypercholesterolemia, and nephrosis (sometimes).
Associate cutaneous flushing and uncomfortable warmth with what class?
What can be taken before niacin to mitigate flushing?
Niacin
Take aspirin or ibuprofen before.
What are adverse effects of niacin?
PURITIS, rash, burning pain
Hepatoxicity
Hyperuricemia=gout
Hyperglycemia=acanthosis nigrans
Niacin contraindicated when?
Liver disease or active peptic ulcer.
Precaution in DM.
Associate acanthosis nigrans with what?
Niacin-induced insulin resistance
MOA of fibrates and ultimate result.
Agonist ligands for nuclear transcription factor receptor PPAR-alpha.
Ultimately INCREASES LPL levels in adipose, DECREASing plasma TG.
???In muscle beds - increases LPL to breakdown more TG in circulation
When are fibrates most effectively absorbed?
90% absorbed when taken with a meal. Highly bound to serum.
Therapeutic uses of fibrin (3).
1) Management of hyperTGs where VLDL predominant
2) Dysbetalipoproteinemia
3) HyperTG due to tx with viral protease inhibitors
If a person is on HIV therapy, what hyper-emia do you associate it with and what class of tx?
hyperTGemia
Fibrin
Fibrates contraindicated in people with what conditions?
Indicated in what?
Hepatic or renal dysfunction, biliary tract disease.
Indicated in heterozygous mutation in LPL.
People taking niacin are predisposed for forming what?
Cholesterol Gallstones
Adverse effects of fibrates.
GI disturbances, lithiasis, cholesterol gallstones, rhabdo
What type of drug do fibrates potentiate the actions of?
Anticoagulants (coumarin, indanedione anticoags)
Which fibrate has a longer half life?
Fenofibrate = 20hrs Gemibirozil = 1.5 hours
Bile acid sequestrants are also called what?
Resins
MOA of sequesetrants
Positive charge, bind to neg charged bile acids, increasing bile secretion and increasing hepatic conversion of cholesterol to bile acids»_space; BLOCK BILE REABSORPTION.
Because resins decrease hepatic cholesterol, HMG-CoA reductase is upregulated. So resin effectiveness is greatly increased by combining resins with what?
Statins.
Statins block the enhanced cholesterol synthesis that is upregulated by the HMG-CoA reductase. ??? Why is HMG-CoA upregulated?
What 4 therapeutic uses are Resins used for?
1) Primary hypercholesterolemia
2) Hyperlipidemias (type IIa and Type IIb)
3) Relieves puritis in people with bile salt accumulation
4) Tx for digitalis toxicity
What are the adverse effects of sequestrants?
GI, Decreased absorption of Vitamin ADEK, drug absorption (cholestyramine and colestipol)
What do you need to do when taking other meds with cholestyramine or colestipol?
Give any other med except niacin 1+ hr prior or 2hrs after sequestrant to ensure adequate absorption.
Contraindications for sequestrant admin.
Diverticulitis, Preexisting bowel disease, Cholestasis
MOA of ezetimibe
Inhibits intestinal absorption of cholesterol and phytosterols
Why is ezetimibe effective even in absence of dietary cholesterol?
Because it inhibits reabsorption of cholesterol excreted in bile.
Therapeutic uses of ezetimibe (3).
Lowers cholesterol:
1) Primary hypercholesterolemia (+/- statin)
2) Homozygous familial hypercholesterolemia (+atrova/simvastatin)
3) Mixesd hyperlipidemia (+ fenofibrate)
Avoid concomitant admin of ezetimibe with what?
Bile acid sequestrants, due to inhibition of ezetimibe absorption.
What two things combine to form Vytorin?
What two things can CAIs be absorbed with?
the trade name of the combo of ezemitibe and simvastatin
Fibrates or statins can be combined with CAIs.
What 4 scenarios is combination drug therapy useful?
1) When VLDL significantly increased during tx of hyeprcholesterolemia with a resin.
2) When LDL and VLDL both initially elevated.
3) When LDL and VLDL not normalized by a single agent.
4) When an elevated Lp(a) or HDL deficiency coexists with other hyperlipidemias.
Combos of lipid lowering agents (4).
1) Niacin and bile acid sequestrants
2) Niacin and staitns
3) Statins and fibrates
4) Statins and ezetimibe *(Vytorin)
What class results in the largest decrease in LDL?
Statins (and lesser, but bile acid sequestrants)
What class results in the largest decrease in TGs?
Fibrates
What class results in the largest increase in HDL?
Niacin
What is the new tx for homozygous familial hypercholesterolemia?
Lomitapide
Mipomersen
Lopitamide MOA
Ultimate result
Oral.
Binds directly to and inhibits MTP in lumen of ER, which prevents lipoprotein contatining apo-B assembly in enteryocytes and hepatocytes.
Ultimate result is reduced VLDL and plasma LDL
Mipomersen MOA
Ultimate result
SubQ.
Antisense oligonucleotide that targets apoB-100 mRNA and disrupts its function.
Ultimate result is reduced LDL-C, VLDL, apoB, non-HDL-C and total cholesterol.
Adverse effects of lomitapide
GI, liver aminostransferase and fat elevation.
Adverse effects of mipomersen
Injection site reaction, flu0like symptoms, HA, 3x normal liver enzyme levels
Omega-3 PUFAs lower what?
Lower high plasma TGs and DON’T react with statins to increase risk of rhabdoyolysis
Who should take Omega-3 PUFAs?
People recovering form recent MI - shown to decrease risk of cardiac death.
Therapeutic benefits of statins (4).
Plaque stabilization, improvement of coronary endothelial function, inhibit platelet thrombus formation, anti-inflammation effects
What labs are elevated due to statins? Presentation?
Aminotransferase elevation (yellowing skin). Creatine kinase elevation (muscle pain due to rhabdo or myopathy).
What two drugs cause muscle pain?
statins and gemfibrozil
What class increases warfarin levels? Other anticoag potentiation?
Warfarin increased by statins.
Anticoags potentiated by fibrates.
Resins result in what adverse hyper-? affect? Why?
Resins decrease hepatic cholesterol, so there’s a compensatory mechanism of UPREGULATION of HMG-CoA reductase.
Therefore, use resin with statin.
