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CV-1 > Pharmacological Treatment of Lipid Disorders > Flashcards

Pharmacological Treatment of Lipid Disorders Flashcards

1
Q

What are the 4 drug therapy goals?

A
  • reduce formation and rate of progression in coronary and peripheral atherosclerosis from childhood to old age
  • prevention of coronary events and strokes in apprently healthy persons at risk, particularly middle-aged and elderly
  • prevention of heart attacks, strokes, need for revascularization in persons with established atherosclerosis
  • prevention and treatment of pancreatitis in hypertriglyceridemia
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2
Q

What are 3 HMG CoA reductase inhibitors?

A

Atorvastatin (lipitor) (synthetic compound)

Lovastatin (mevacor) (fungal metabolite)

Simvastatin (zocor) (synthetic compound)

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3
Q

What is the mechanism of action for the statins?

A
  • competitive inhibitor for active site on HMG CoA reductase
    • rate limiting step in cholesterol biosynthesis
    • statins inhibiti HMGR by binding to the active site of the enzyme this sterically preventing substrate from binding
  • Structural analog of the HMG CoA Intermediate
    • all statins share a structural component that is very similar to the HMG portion of HMGCoA, but they are more bulky and hydrophobic
      *
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4
Q

what are the pharmacokinetics of statins? what metabolizes them?

A
  • extensive first pass metabolism by the liver
    • limits systemic bioavailability
    • targets liver/site of action
  • Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 to inactivate metabolite
    • not all statins are interchangeable
      *
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5
Q

How do statins decrease plasma LDL cholesterol?

A

Statins decrease intracellular cholesterol production in the liver therefore the liver sense that there is decreased cholesterol so it upregulates transcription factors that create LDL receptors so that plasma LDL is brought into the cell. this decreases plasma LDL

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6
Q

how does sterol mediated feedback repression of genes for LDL receptor work?

A

SCAP is a cholesterol sensing protein and when sholesterol is present it binds

when there is decreased (no) cholesterol for SCAP to bind to, it binds to SREBP. SREBP-SCAP is transported to the Golgi and is cleaved by S1P and S2P making it transcriptionally active. transcriptionally active SREBP travels to the nucleus where it activates transcription of target genes that increase production of LDL receptors elading to LDL being removed from the plasma

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7
Q

What are the major adverse effects from the statins?

A
  • myopathy
    • muscle pain without CK elevation
  • Rhabdomyolosis
    • muscle symptoms with marked CK elevation and creatine elevation
    • breakdown of muscle fibers that lead to release of myoglobin into the bloodstream. myoglobin is harmful to the kidney
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8
Q

What are the risk factors for statin induced myotoxicity?

A
  • high or increasing doses of statins
    • dose related
  • pharmacokinetic interactions with CYP450 inhibitors, resulting in increased concentration of active strain
    • lipid soluble statins
  • pharmacodynamic interactions with other myotoxic agents, resulting in additive adverse effects
    • ex: antoher statin or fibrate with niacin
  • female or old
    • associated with statin concentration that is higher than expected for a given dose
  • renal insufficiency, hypothyroidism
    • contribute independently
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9
Q

How does myopathy risk relate to dose and plasma concentration?

A

risk increases in direct relationship to statin dose and plasma concentration

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10
Q

What genetic factor is associated with increased risk of statin intolerance?

A

genetic variants of SCLO1B1

lead to reduced hepatic uptake and increased levels of statins in the blood

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11
Q

What things are contraindicated to statin therapy?

A

women who are pregnant, lactating or likely to become pregnant should not be given statins.

  • statins reaching embryo downregulate biosynthesis of cholesterol and other metabolic intermediated and may have secondary effects on sterol-dependent signaling molecules that contribute to development such as sonic hedgehog
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12
Q

What kind of drugs are risky to give with a statin? (increase risk of myotoxicity)

A
  • drugs metabolized primarily by CYP3A4 bc the statins are metabolized by CYP3A4
  • concurrent use of other lipid lowering medications
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13
Q

How do statins alter the lipid prolife?

A

lowers triglycerides (the higher the baseline TG level, the gretaer the TG lowering effect)

decrease LDL by 20-55%

increase HDL by 5-10%

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14
Q

when do you use statins?

A

first line therapy for hypercholesterolemia when at risk for myocardial infarction

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15
Q

What is the mechanism for statin induced myopathy?

A

depletion of secondary metabolic intermediates

the mevalonate pathway. by inhibiting HMG CoA you decrease cholesterol production, but also decrease formation of isoprenoids which are required for normal muscle formation

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16
Q

All the statins, xcept for simvastatin and lovastatin are administered in the __________ form, which is the form that _______

Simvasttin and lovastatin are administered as _________

A

All the statins, except for simvastatin and lovastatin are administered in the hydroxy acid form, which is the form that inhibits HMG CoA reductase

Simvastatin an Lovastatin are administered as inactive lactones which must be transformed in the liver to theri respective -hydroxy acids (active form)

**aka simvastatin and lovastatin are produrgs and the rest are not

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17
Q

What is the basis for bile production? how does this work> what happens to bile acids?

A
  • cholesterol is converted to bile acid by enzyme 7ahydroxylase
  • most bile acids are reabsorbed, returned to the liver via the portal vain and re-secreted
  • conversion to bile salts is the only mechanism by which cholesterol is excreted
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18
Q

What is Cholestyramine/what are the clinical uses? WHat age group is it recommended for? what is the MOA?

A

bile acid binding agent

  • MOA: is very positively charged and therefore binds negatively charged bile acids
  • bc of their large size, the resins are not absorbed and the bound bile acids are excreted in the stool. more than 95% of bile acids are normally reabsorbed,and interruption of this process depletes the pool of bile acids and hepatic bile-acid synthesis increases
  • use: hypercholestermeia
    • not recommended for individuals with hypercholesteremia AND increased TG
    • most often a second agent is statin therapy does not lower LDL-C levels sufficiently
    • recommended for patients 11-20 yo
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19
Q

What are the pharmacokinestic for cholestyramine? what are the adverse efects?

A
  • insoluble in water, not absorbed
  • most commone side-effect is constipation/bloating sensation, gritty consistency
  • modest increase in TGs but with time returns to baseline levels
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20
Q

WHat happens to intracellular cholesterol if more is needed for production of bile acids? What happens to plasma cholesterol when intracellular concentration of cholesterol decrease? WHat is the mechanism to explain decrease in plasms cholesterol in reposnse to cholestyramine?

A

What happens to intracellular cholesterol if more is needed for production of bile acids? decrease

What happens to plasma cholesterol when intracellular concentrations of cholesterol decrease? decrease (more LDL receptors)

What is the mechanism to explain decrease in plasma choelsterol in repsonse to cholestyramine? increase LDL receptors via SCAP-SREBP being modified in the golgi (S1P, S2P) then active SREBP increasing transcription of LDL receptors

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21
Q

WHat is the dominant way for controlling LDL plasma concentration?

A

regulation of hepatic LDL receptor pathway is dominant mechanism for controlling LDL plasma concentration

*****upregulation of Hepatic LDL receptors!*****

choletyramine workslike statins!, cholesterol absorption inhibitors lower intracellular cholesterol which activates SREBP transcription factor and increases LDL receptor gene transcription

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22
Q

How does cholestyramine alter lipoprotein prolife?

A
  • TG: normal levels=transient increase, levels above 250mg/dl further significatn increase
  • LDL: decrease by 12-25%
    • dose-dependent
    • larger dose=more side effects
  • HDL: increase by 4-5%
23
Q

What kind of drug is Ezetimibe? MOA?

A

Cholesterol absorption inhibitor (acts in GI tract)

blocks the protein transporter NPC1L1

leads to a decreased rate of cholesteryl ester incorporation into chylomicrons (reduced cholesterol flux from intestine to liver)

24
Q

what are the adverse effects fo Ezetimibe and how is it administered/metabolized?

A

oral administration, metabolized (glucuronidation) to active metabolite so half life is 22 hours

well tolerated byt muscle reltaed side effects increase if combined with other drugs like statins

25
Q

How does Ezetimibe alter the lipoprotein profile? What are the clinical uses?

A

TG decrease by 5%

LDL decrease by 15%

HDL increase by 1-2%

Used for primary hypercholestermeia combined with statins (ex: simvastatin + ezetimibe=Vytorin) 2 diff approaches that result in increase in LDL receptors

26
Q

How does Ezetimibe decrese plasma LDL?

A

stops cholesterol absorption/ encorporation of cholesterol into chylomicrons. chylomicrons are how cholesterol travels to the liver. so by stopping this, less cholesterol travels to the liver. therefore the liver senses decreased choelsterol levels, and will increase production of LDL receptors leading to increased uptake of LDL from the plasa=decreased plasma LDL

27
Q

What are the clinical uses of Ezetimibe?

A
  • primary hypercholesterolemia
  • not typically a monotherapy
  • combined with satins:
    • simvastatin + ezetimibe=Vytorin
    • further decrease in LDL cholesterol
    • Two different pharmacological approaches that result in increased LDL receptors (enzyme inhibitor and transport inhibitor)
28
Q

What is another name for Nicotinic Acid? what is the main effect?

A
  • Niacin (B-complex vitamin, but lipid lowering effect is unrelated to its effect as a vitamin. to be a drug you need a much higher dose)
  • Main effect is to decrease TG, but it also decreases cholesterol!
29
Q

What is the MOA for Niacin?

A

In liver decreases synthesis of VLDL-TG.

Inhibits DGAT2 (diacylglycerol acyltransferase 2), which is enzyme that catalyzes the final reaction in TG synthesis

30
Q

How is Niacin adminstered?

A

oral administration. remember that doses used for lowering cholesterol/TG are MUCH greater than those used as a vitamin

31
Q

What are the adverse effects for Niacin? SO when is it contraindicated?

A
  • MAJOR: intense cutaneous flush/pruritis, mediated by vasodilatory Prostaglandins
  • MORE SERIOUS but less frequent:
    • GI, avoid in patients wiht peptic ulcer
    • elevated liver enzymes, usually no heptic toxicitiy, UNLESS combined with statins then this is a major concern
  • Hyperurecemia: contraindicated in patients with gout
  • Increases fasting glucose levels/niacin induced insulin resisitance so questionable use in patints with diabetes
  • so contraindicated in:
    • peptic ulcer, gout, hepatic disease, diabetes
32
Q

How does Niacin alther the lipid profile?

A

TG decreases by 35-50% (within 4-7 days)

LDL decreased by 25% (3-6 weeks for max effect)

HDL increased by 15-30% (added benefit is increased HDL)

Lp(a) reduced by 40% (may be a risk factor for CV disease)

33
Q

What are the clinical uses for Niacin?

A

hypercholesterolemia and hypertriglyceridemia (high LDL and low HDL)

typically not the first line therapy for hypercholesterolemia (and when used in combo w statins increases risk for myopathy)

Only lipid lowering drug that reduces Lp(a)

34
Q

what is the only lipid lowering drug that reduces Lp(a)

A

Nicotinic acid (niacin)

35
Q

What do Fibric Acids/Fibrates/PPAR activators do? what are 2 examples?

A

Gemfibrozil

Fenfibrate (2nd gen drug)

primarily lower the levels of TG-rich lipoproteins

36
Q

what is the MOA for the fibrates? (Gemfibrozil and Fenofibrate)

A

FIbrates are agonists for the PPAR (peroxisome proliferator-activated receptor)

firbate bound PPAR binds/heterodimerizes with retinoid X receptor (RXR) and together they regulate gene transcription of mulitple target genes that lower TGs

37
Q

what is the half life of fenofibrate? How does this change with renal impairment? How is it excreted?

A

it varies. (1 hour for gemfibrozil and 20 hours for fenofibrate) half life inreased with renal impairment

  • fenofibrate is metabolized to active metabolite and Gemfibrozil is metabolized to an inactive metabolite
  • 60-90% of an oral dose in excreted in the urine
38
Q

What are the adverse effects of the fibrates? when is it contraindicated? What is an important drug interaction?

A
  • increased creatine kinase if also being treated with a stain, can lead to renal failure
  • use is contraindicated in patients with renal impairment
  • Gemfibrozil inhibits uptake of active hydroxy caids forms of statins by transporter (not taken up into the liver via the OATP1B1 so increased plasma concentration so increased systemic efect :( )
39
Q

how do fibrates alter the lipoprotein profile?

A

TG decrease 30-50%

LDL (HIGHLY VARIABLE) decrease 15-20% with

HDL increase 5-15%

40
Q

what are the clinical uses of Fibrates?

A
  • patients with high TGs and low HDL associated with metabolic syndrome of type 2 diabetes
  • not used as primary therapy in patients with elevated hypercholesterolemia without hypertriglyceridemia
41
Q

what is the result of (Omega 3FA) fish oil? what is the clinical use?

A
  • reduced rate of secretion of very low density lipoprotein (VLDL) TG
  • except recent study shows that there was no effect on serious vascular events, cancer or mortality
  • there is onyl 1 FDA approved omega 3 FA
  • adjunct to diet therapy
42
Q

wat is the mechanism of action of Alirocumab? how is it administered?

A

PCSK9 antibody prevents binding of PCSK9 to the LDLR-LDL complex increasing the availability of the cell surafce LDLRs

injectable cholesterol lowering drug

43
Q

What s the therapeutic use for ALirocumab?

A

adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia

44
Q

What is the MOA of Lomitapide?

A

directly binds to and inhibits MTP

this prevents the asembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations

45
Q

What is the clinical use of Lomitapide?

A

adjunct to dietary therapy and other lipid lowering treatments to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL-C in patients wtih homozygous familial hypercholesterolemia

46
Q

What is the MOA of Mipomersen? what is the clinical use?

A

20 base sequence second generation antisense oligonucleotide developed to inhibit synthesis of apoB-100 in the liver

No VLDL

use: first in class drug for treatment of homozygous familial hypercholesterolemia

47
Q

What are the first choice drugs for hypercholesterolemia?

A

HMG CoA reductase inhibitors-first choice agents

48
Q

Drugs of choice for hypertriglyceridemia?

A

Gemfibrozil/ Fenofibrateshoudl be first choice

49
Q

Common adverse effects and common drug interactions for HMG CoA recuctase inhibitors

A

adverse effects: elevated serum levels of hepatic enzymes, hepatitis, and myalgia, rhabdomyolysis and other myopathies

common drug interactions: increase risk of myopathies when taken with erythromycin, gemfibrozil or niacin

50
Q

Common adverse effects and common drug interactions for bile acid biding resins

A

AE: constipation, fecal impaction, and rash

drug interactions: decrease absorption of digoxin, thyroxin, warfarin, and warfarin

51
Q

Common adverse effects and common drug interactions for fibric acid derivatives

A

AE: allergic reactions, blood cell deficiencies, and myalgia, rhabdomyolysis and other myopathies

Drug: increase risk of myopathy when taken wiht HMG CoA reductase inhibitors or niacin

52
Q

Common adverse effects and common drug interactions for Ezetimibe?

A

AE: headache, myalgia

Drug interactions: absorption decreased by cholestyramine

53
Q

Common adverse effects and common drug interactions for Niacin?

A

gastric irritation, glucose intolerance, myalgia, rhabdomyolysis, and other myopathies, and vasodilation, flushing, and pruritis

drug interactions: increase risk of myopathy when taken with gemfibrozil or HMG-CoA reductase inhibitors

CV-1 (7 decks)

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