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MSII Pharmacology > Unit 4 - Hyperlipidemia > Flashcards

Unit 4 - Hyperlipidemia Flashcards

1
Q

what are lipoproteins? materials?

A

spherical particles with hydrophilic monolayer surface made of phospholipid, protein, and cholesterol

  • shields hydrophobic lipid core of TG and cholesterol esters
  • apoliporoteins provide structural stability to prticle, are required for assembly/secretion, and act as ligands and cofactors
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2
Q

what are the three compartments of plasma lipoprotein metabolism?

A
  1. exogenous lipid transport
  2. endogenous lipid transport
  3. reverse cholesterol transport
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3
Q

explain exogenous lipid transport?

A
  • chol and TG ingested and emulsified in intestines bybile acids
  • combined with PRO to form chylomicrons in gut wall
  • secrted into circulation, delivering TG to adipose and muscles via LPL in plasma or vscular endothelial cells
  • remaining chol-rich remnants deliver cholesterol to liver
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4
Q

explain endogenous lipid transport

A
  • liver forms VLDL from TG, chol, and PRO, and secretes into circulation
  • VLDL deliver TG to adipose and fat, and are converted into IDL and LDL
  • chol-rich LDL delivers to peripheral tissues for cell membranes, steroids
  • -delivers to nascent atheromas to be oxidized and phagocytosed by MP –> foam cells
  • -deliver to liver (apo-100 binds to LDL-R to promote internalization)
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5
Q

what does intracellular cholesterol do to the cell?

A

3 regulatory effects

  • decreases activity of HMG CoA reductase (rate-limiting in chol synthesis)
  • activates ACAT (acetyl CoA: cholesterol acyltransferase) that esterifies free chol into chol ester for storage
  • inhibits transription of gene encoding LDL-R (decreases further uptake of chol by cell)
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6
Q

explain reverse cholesterol transport

A

nascent HDL particles with PRO and small amt of phospholipid are secreted by gut and liver
-as HDL circulate in blood, they use plasma LCAT to get chol from peripheral tissues and atheromas, to be transported to liver

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7
Q

explain the pathogenesis of atherosclerosis

A
  1. endothelial injury
  2. low-grade inflammatoryresponse causing LDL accumulation and oxidation
  3. blood monocytes adhere, becoming macrophages
  4. MP phagocytose ox-LDL to become foam cells
  5. platelets adhere
  6. SMC migration deposits collagen
  7. necrosis, plaque lysis
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8
Q

what are primary hyperlipidemic states?

A

relatively rare disorders, each of which is caused by monogenic defect
-LDL receptor deficiency

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9
Q

what are secondarycauses of hyperlipidemia?

A
  • hypothyroidism
  • early nephrosis
  • resolving lipemia
  • immunoglobulin-lipoprotein complex disorders
  • anorexia nervosa
  • cholestasis
  • hypopituitarism
  • corticosteroid excess
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10
Q

what is polygenic-environmental hyerlipidemia?

A

most cases, due to several genes that predispose patient to milder forms of hyperlipoproteinemia particularly in the presence of excessive dietary intake of lipids, or other risk factors

  • serum LDL cholesterol
  • age
  • HTN
  • smoking
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11
Q

what is the goal of the AHA step 1 diet?

A

for many, may be the only treatment necessary

  • attain normal bodyweight and minimize plasma lipids
  • cholesterol < 300 mg/day
  • total fat < 30% of total calories
  • saturated fat < 10% total calories
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12
Q

what increases/decreases HDL cholesterol concentrations?

A
  • estrogens > androgens
  • exercise > puberty (in males)
  • leanness > obesity
  • alcohol (in moderation) > cigarette smoking
  • familial hyperalphaproteinemia > familial HDL deficiency
  • antihyperlipidemic drugs > DM II or hypertriglyceridemia
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13
Q

when is drug therapy considered?

A

if diet and weight loss haven’t lowered total and LDL cholesterol to desired ranges (160/130) within 6-12 months, or for patients with moderate risk of CHD

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14
Q

what is niacin? what are its effects on lipids? when do you use them?

A

vitamin only after conversion to NAD, but require larger amounts to show hypolipidemic effects

  • affects virtually all lipid parameters
  • increase HDL 15-35% (best)
  • lower TG by 20-50% (as effective as fibrates and statins)
  • reduces LDL by 5-25%
  • useful for patients with both hypertriglyceridemia andlow HDL levels, but has numerous and serious side effects
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15
Q

what is the mechanism of niacin?

A
  1. reduced TG synthesis in liver, reducing hepatic VLDL production (and thus LDL levels)
  2. decreased lipolysis in adipose tissue, reducing transport of FFA to liver (thus decreasing hepatic TG synthesis)
  3. reduced hepatic clearance of HDL-apo A-1 (thus raising HDL levels)
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16
Q

what are adverse effects of niacin? resulting contraindications/

A

not serious, but lipid patient compliance

  • flushing, pruritis of face and upper trunk (prostaglandin-mediated)
  • skin rashes, acanthosis nigricans
  • dyspepsia and reactivation of peptic ulcer disease

medically serious

  • common hepatotoxicity, hyperglycemia, and hyperuricemia
  • -contraindicated if DM or history of gout
  • rarer toxic amblyopia, tachyarrhythmias, atrial fibrilation (in elderly), and myopathy (max doses)
17
Q

what are fibrates? what are its effects on lipids? when are they used?

A

older family of related synthetic ethyl chlorophenoxyisobutyrates

  • decrease VLDLs (20-50%), thus TGs
  • variable effects on LDL levels
  • increased (10%) HDL (modest)
  • used for hypertriglyceridemia
18
Q

what is clofibrate?

A

ester form of fibrates used in the past, but with declining usage due to adverse effects (gallstones), conflicting results during clinical trials, and better drugs vailable

19
Q

what is the mechanism of fibrates?

A

ligands for nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-a)

  • reduce TGs via PPAR-mediated:
  • -stimulation of LPL synthesis, which would enhance clearance of TG-rich lipoproteins
  • -inhibition of apo-C expression, enhancing clearance of VLDL
  • increase HDL via PPAR-a stimulatio of apo AI and AII expression
20
Q

what are adverse effects of fibrates?

A

usually well-tolerated, especially 2nd generation; ASE seen in 5-10% of patients, but doesn’t cause discontinuation

  • GI side effects
  • myositis flu-like syndrome
  • potentiate action of oral anticoagulants (compete with albumin)
  • increase lithogenicity of bile, but newer ones (like gemfibrozil) result in less gallstones
21
Q

what are bile acid sequestrants? effects on lipids?

A

anion-exchange resins (+ charge to bind - bile acids)

  • among oldest of hypolipidemic drugs, and also the safest (not absorbed from intestine)
  • max doses reduce LDL up to 30%
  • produce slight increase in both TG and HDL levels
22
Q

what is cholestyramine?

A

polymer of styrene and divinylbenzene with quaternary amine active site group
-bile acid sequestrant that is a hygroscopic powder given with Cl- salts, insoluble in water

23
Q

what is colestipol?

A

mixture of tertiary and quaternary amines

-bile acid sequestrant that is a hygroscopic powder given with Cl- salts, insoluble in water

24
Q

what is the mechanism of bile acid sequestrants?

A

highly positively charged and bine negatively charged bile acids

  • due to large size, they aren’t absorbed, and bound bile acids are excreted in stool
  • over 95% of bile acids are normally reabsorbed, so interruption of this process depletes liver’s pool of bile acids, and hepatic bile acid synthesis increases
  • thus hepatic cholesterol content declines, stimulating production of LDL receptors
  • increased receptors increases LDL clearance and lowers LDL levels
  • resins produce slight increase in both TG and HDL levels
25
Q

what are adverse effects of bile acid sequestrants? contraindications?

A

quite safe because not systemically absorbed

  • bloating, dyspepsia, gritty, unpleasant taste, and can cause constipation
  • bind many other drugs (cardiac glycosides, coumarin anticoagulants) to interfere with absorption
  • decrease absorption of fat-soluble vitamins
  • contraindicated in hypertriglyceridemia (because increase TG levels)
26
Q

what are HMG-CoA reductase inhibitors?

A

statins

  • most effective and best-tolerated agents for treating dyslipidemia
  • reduce LDL by 25-60% depending on dose and type used
  • lower TG levels by at least 25%
  • increase HDL levels by 5-10%
27
Q

what is the mechanism of statins?

A

side group is structurally similar to HMG-CoA, to reversibly, competitively inhibit reductase-affect blood cholesterol levels by inhibiting cholesterogenesis in the liver

  • reduced free cholesterol levels in hepatocyte causes membrane-bound transcription factor (SREBP) to be cleaved by protease, and translocated to nucleus
  • transcription factor binds to sterol-responsive element of LDL receptor gene, enhancing trascription and ultimately increasing synthesis of LDL receptors
  • degradation of LDL receptors is reduced
  • decreased choleterol, which is needed in VLDL, thus decreases VLDL production, thus TG decreases
28
Q

why are lovastatin and simvastatin special?

A

lactone prodrugs that must be modified in liver to active (ring-opened) hydroxy acid forms

29
Q

explain the pharmacokinetics of statins?

A

plasma concentrations peak in 1 to 4 hours

  • half-lives of older statins vary from 1 - 4 hours
  • atorvastatin (Lipitor) and Rosuvastatin (Crestor) have longer half-lives, thus only given once a day
  • since hepatic cholesterol synthesis is max between midnight and 2 AM, all other statins should be taken in the evening
30
Q

what are adverse effects of statins? contraindications?

A

very few

  • major: myopathy and rhabdomyolysis
  • -concomitant administration of fibrate or niacin increases risk (enhanced inhibition of skeletal muscle sterol synthesis)
  • hepatic dysfunction (serious is rare)
  • contraindicated in pregnant or nursing women
31
Q

what inhibits statin catabolism?

A
  • advanced age > 80 yo
  • hepatic/renal dysfunction
  • perioperative periods
  • hypothyroidism, diabetes
32
Q

when can statins be used in combo with fibrate or niacin?

A

should be avoided to prevent myopathy

-can be used if no more than 25% of max dose

33
Q

what is the mechanism of ezetimbe?

A

new compound, first one approved for lowering total and LDL levels that inhibits cholesterol absorption by enterocytes in SI

  • inhibits specific transport PRO in jejunal enterocytes that takes up both biliary and dietary cholesterol from the lumen
  • inhibits intestinal cholesterol absorption by 54%, but not TG absorption
  • -reduced incorporation of cholesterol into chylomicrons, thus diminishing delivery of cholesterol to liver by remnants
  • -may decrease atherogenesis directly, since chylomicron remnants are very atherogenic
34
Q

what are therapeutics of ezetimbe?

A

max efficacyfor lowering LDL by10-20% when used as monotherapy
-complementaryactions tostatins

35
Q

what happens during dual therapy with statins and ezetimbe?

A

statins: inhibit cholesterol biosynthesis, while increasing intestinal cholesterol absorption
ezetimbe: enhance cholesterol biosynthesis
together: prevent enhanced cholesterol synthesis and prevent increased cholesterol absorption

at highest dose, average LDL reduction was 60%

36
Q

what are adverse effects of ezetime?

A

none, other than rare allergic reactions

37
Q

what are the potential serum cholesterol lowering effects of:

  • resin alone
  • niacin alone
  • statin alone
  • ezetimbe alone
  • statin and ezetimbe
  • statin and resin
  • statin and niacin
  • statin, resin, and niacin
A 
resin alone: 20%
niacin alone: 15%
statin alone: 30%
ezetimbe alone: 18%
statin and ezetimbe: 65%
statin and resin: 55 to 65%
statin and niacin: 45 to 50%
statin, resin, and niacin: 70-75%

MSII Pharmacology (43 decks)

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