Module 5: Dyslipidemia Pharmacology Flashcards
• Explain the principles of drug management of dyslipidemia.
A
• Discuss the mechanism of action and effects of major classes of antihyperlipidemics.
a
• List the major side-effects of the above medications.
a
Overall, the pharmacological treatment can be divided into treatment options for ______ and treatment options for ________.
- hypercholesterolemia
2. hypetriglyceridemia
What are the 5 main classes of pharmacological options:
- HMG CoA Reductase Inhibitors
- Niacin
- Fibrates
- Bile Acid Sequestrants (Resins)
- Cholesterol Absorption Inhibitors - Ezetimibe (Ezetrol)
3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are known as _____
Statins
Fxn of statins?
- Lower elevated levels of LDL-C and an overall reduction of Coronary Heart Disease.
- The overall benefit is to stabilize plaque buildup in the coronary artery, improve coronary endothelium functioning, anti-inflammatory effect and inhibition of platelet thrombus formation.
Mechanism of action for statins?
- Statins can inhibit HMG CoA Reductase, the rate limiting step in the cholesterol synthesis. Thus dec the intracellular supply of cholesterol.
- Dec in intracellular supply of cholesterol allow the cell to inc the # of LDL receptors on the cell surface. These receptors will bind to and internalize LDLs and therefore plasma cholesterol levels decrease by both; decrease cholesterol synthesis and increase LDL catabolism
Uses of statins?
Effective in lowering plasma cholesterol levels in all types of hypercholesterolemia. Patients who are homozygous for familial hypercholesterolemia lack LDL receptors so they benefit less from statin treatment.
Adverse effects of statin?
- Elevated liver enzymes. This means that physicians must continue to monitor liver function while the patient is taking statins.
- Myopathy and rhabdomyolysis have been reported.
How often do statins intolerance due to non-sensitive side effects occur?
5-10% of patients.
How does statins intolerance manifest?
Manifests primarily through muscle symptoms – may increase without increase in CK plasma. Muscle aches without any CK inc are fairly common in statin users. Histological changes of unknown significance were also described in a small percentage of statin users w/out muscle aches.
What are the: 1. Muscular symptoms 2. Joint symptoms 3. GI symptoms 4. CNS symptoms 5. Skin rash 6. Acute hypersensitivity 7. Increased transaminases 8. Other runcommon rxns That are associated w/statins intolerance
- Muscular symptoms: Aching, weakness, cramping, pain or stiffness ±↑CK
- Joint symptoms: Pain or stiffness.
- GI symptoms: Abdominal pain, dyspepsia and bowel disturbance.
- CNS symptoms: Headache, disturbances of sleep, mood or memory, and peripheral nerve dysfunction.
- Skin rash.
- Acute hypersensitivity: Swelling of the lips or tongue, wheeze, glottal edema.
- Increased transaminases.
- Other uncommon reactions: Fluid retention and increased plasma glucose levels.
If a patient has stain intolerance, what should he do?
Patients should be instructed to stop their statin and report back to the prescriber. Lower dose, decrease in the frequency (every other day or once or twice a week) or a different potency statin may be tried.
Are muscle symptoms reversible or irreversible w/stain intolerence?
The muscle symptoms are entirely reversible, usually in a week but sometimes it may take up to several months.
What are the 3 types of statin intolerance?
Complete, partial, and selective statin intolerance
Discuss complete statin intolerance? (how frequent,w hat does it mean, what are risk factors)
- Inability to tolerate all statins, regardless of dose.
- Uncommon.
- Previous history of musculoskeletal pain, fibromyalgia.
- Patients may not tolerate other classes of lipid-lowering agents (eg, fibrates, ezetimibe).
Discuss partial statin intolerance? (how frequent,w hat does it mean, what are risk factors)
- Intolerance to high doses only
- Relatively common
- Patient: thin elderly women
- Myalgia with high doses
- Small doses of less potent statins (eg, pravastatin and fluvastatin) are tolerated.
- Risk factors: Older age, low body weight.
What are the 3 clinical trial adverse muscle effects?
Myalgias, myopathy, and rhabdomyolysis
What is myagias?
Muscle ache, pain, or weakness with or without CK elevation (<10× the ULN )
What is Myopathy?
Muscle symptoms (myalgias) + CK ≥10× the ULN (Otherwise unexplained)
What is Rhabdomyolysis
- Marked CK elevation, typically substantially >10× the ULN +
- Creatinine elevation (usually with brown urine and urinary myoglobin).
- Elevations in other muscle enzymes may also occur, as well as the following:
-> Hyperkalemia
-> Hypocalcemia
-> Hyperphosphatemia
-> Hyperuricemia
-> Metabolic acidosis
-> Renal failure
-> Death
Symptoms of muscle weakness may be present, but perhaps only 50% of the time.
Fxn of niacin
decrease the levels of LDL-C, triglycerides and increase the levels of HDL-C.
Mechanism of action of niacin
Niacin inhibits lipolysis in adipose tissues, thereby dec the production of FFAs. The liver uses FFAs as a major precursor for TG synthesis. Dec liver TG dec hepatic VLDL production, which in turn dec LDL-C levels in the plasma.
- bottom line is niacin dec flux of FFAs, inc formation of HDL, and affects positively arterial wall/macrophages
What are the 3 formulations of niacin
- Immediate release (IR)
- Slow release (SR)
- Extended release (ER)
Discuss the a) absorption rate b) absorption time c) dosing frequency d) side effects of IR, SR, ER
- Immediate release (IR)
a) absorption rate
b) absorption time
c) dosing frequency
d) side effects - Slow release (SR)
a) absorption rate
b) absorption time
c) dosing frequency
d) side effects - Extended release (ER)
a) absorption rate
b) absorption time
c) dosing frequency
d) side effects
Discuss the a) absorption rate b) absorption time c) dosing frequency d) side effects of IR, SR, ER
- Immediate release (IR)
a) absorption rate: 500 mg/hr
b) absorption time: 1-2 hr
c) dosing frequency: 2-3 times a day
d) side effects: Flushing, Itching
e) therapeutic uses: FDA approved for the treatment of dyslipidemia (Niacor, and other several over the counter agents) - Slow release (SR)
a) absorption rate: 50 mg/hr
b) absorption time: >20 hr
c) dosing frequency: once daily
d) side effects: Hepatotoxicity
e) therapeutic use: Not FDA approved for the treatment of dyslipidemia. Available as over the counter nutritional supplement - Extended release (ER)
a) absorption rate: 100 mg/hr
b) absorption time: 8-12 hr
c) dosing frequency: Once daily
d) side effects: Flushing
e) therapeutic: FDA approved for the treatment of dyslipidemia (Niaspan)
What percentage in IR, SR, and ER is FLUSHING found
IR: 100%
SR: 82%
ER: 75%
Why is SR niacin not recommended
Cause metabolized mostly through NAM pathway which may cause hepatotoxicity.
Varied effects of niacin are mediated through a nicotinic acid receptor found in what 3 key tissues
- adipose tissue
- immune cells (e.g. spleen, lung)
- epidermal Langerhans’ cells
The nicotinic acid receptor has been found in 3 major locations: adipocytes, immune system cells, and epidermal Langerhans’ cells. Activation of the receptor in each location leads to different results.1
- In adipocytes, nicotinic acid inhibits lipolysis.
- In immune cells, the effects of nicotinic acid possibly contribute to the anti-inflammatory effect
- In epidermal Langerhans’ cells, nicotinic acid induces prostaglandin D2 (PGD2) production and then flushing
Describe the %reduction of LDL-C by the 3 different forms of niacin:
Niacin reduces LDL-C by up to ___% in a dose-dependent manner. To reduce the risk of _______, the dose of extended- and sustained-release forms of niacin is limited to ___ g/d, which reduces LDL-C by ____%. Immediate-release niacin can be titrated to ___ g/d (or more) and can reduce LDL-C in the ____% range.
Niacin reduces LDL-C by up to 25% in a dose-dependent manner. To reduce the risk of hepatotoxicity, the dose of extended- and sustained-release forms of niacin is limited to 2 g/d, which reduces LDL-C by 15-20%. Immediate-release niacin can be titrated to 3 g/d (or more) and can reduce LDL-C in the 25% range.
Is niacin’s effect on LDL-C, triglycerides, and HDL-C linear or curvilinear
- niacin’s LDL-C lowering is linear,
- effect on triglycerides and HDL-C is curvilinear
____ doses of niacin can significantly alter these two lipid (TGs and HDL-C) levels. For example, ___ g/d of immediate-release niacin can increase HDL-C by ____% and reduce triglycerides by a ____ margin. Niacin is the most effective drug available for raising HDL-C. It also lowers lipoprotein(a) by about ____%.
MODEST doses of niacin can significantly alter these two lipid (TGs and HDL-C) levels. For example, 1 g/d of immediate-release niacin can increase HDL-C by 25-30% and reduce triglycerides by a SIMILAR margin. Niacin is the most effective drug available for raising HDL-C. It also lowers lipoprotein(a) by about 30%.
What is the most effective drug for raising HDL-C
Niacin
Studies have consistently shown that niacin in combination with _____ agents or as monotherapy has produced consistent clinical and atherosclerotic burden benefit
- antidyslipidemic
What are Fibrates
derivatives of fibric acid and have the capacity to lower TGs and increase HDL levels.
What are Peroxisome Proliferator Activated Receptors (PPARs)
nuclear receptors that regulate lipid metabolism
Fxn of peroxisome proliferator activated receptors (PPARs)
- When these receptors are activated, the inc expression of LPL and dec APO CII levels.
- They can also inc the levels of HDL by increasing the expression of APO AI and APO AII.
Fxn of Gemfibrozil
A fibrate, inc HDL-C and dec TGs
Treatment with fibrates significantly reduced the risk of major coronary events by ___%, but not coronary deaths.
25%
Adverse effects of fibrates
- Mostly GI disturbances.
- Myositis has been reported and muscle weakness should be evaluated.
- Patients who take both gemfibrozil and statins have reported myopathy and rhabdomyolysis.
What are bile acid sequestrants (resins)? Examples
Bile acid sequestrants such as cholestyramine, colestipol, and colesevelam are medications for lowering LDL cholesterol in conjunction with diet modification.
Mechanism of action for bile acid sequestrants (resins)
These drugs are anion exchange resins that bind negatively charged bile acids and bile salts in the SI. The newly formed complex (resin/bile acid) will be eliminated from the body by excretion into the feces and thus conc the bile acid concentration.
This will result in inc hepatic conversion of cholesterol into bile acids which is an essential key component of bile and eventually cholesterol levels will dec.
The bile acid sequestrants have to be used in large quantities, up to ___g a day
20g
Downfalls os using bile acid sequestrants (resins)
- Many patients object to the fact that they require either swallowing a large # of tablets (Colestid) or preparation of a resin to be mixed with water (cholestyramine).
- possible interference with absorption of other medications and fat-soluble vitamins makes their use limited to 1 hour before or 4 hours after other medications.
What are the cholesterol Absorption Steps
- Cholesteryl ester is converted into unesterified cholesterol in the intestine by cholesterol esterase and, together with unesterified cholesterol from the diet and bile, joins plant sterols from the diet in mixed micelles which, in addition to cholesterol, are composed of bile salts, monoglycerides, phospholipids, lysophospholipids and fatty acids.
- Cholesterol and other sterols enter the enterocytes through the Nieman-Pick C1-Like 1 (NPC1L1) transporter.
- Non-cholesterol sterols, such as plant sterols, are returned to the gut lumen via the ATP binding cassette G5/G8 transporter.
- Cholesterol is esterified by acetyl-CoAn cholesterol acyl transferase (ACAT) and then complexed with other lipids and apolipoprotein B48 in the endoplasmic reticulum (ER) and Golgi apparatus to form chylomicrons .
Multiple factors modulate cholesterol homeostasis: these include
genetic, circadian rhythm, body weight, plant sterols, and medications (statins and ezetimibe).
A genetic mutation of ____ is associated with decreased cholesterol absorption and increased synthesis.
apolipoprotein E
Obese patients have ____ cholesterol synthesis but ____ absorption. Plant sterols and stanols _____ cholesterol absorption and are associated with an _____ of cholesterol synthesis.
Obese patients have INCREASED cholesterol synthesis but REDUCED absorption. Plant sterols and stanols INHIBIT cholesterol absorption and are associated with an INCREASED of cholesterol synthesis.
What is the mechanism of action by Ezetimibe (Ezetrol)
- They selectively inhibit the absorption of dietary and biliary cholesterol in the small intestine and thus decreasing the delivery of intestinal cholesterol to the liver.
- Generally see LDL-C dec, HDL-C inc, TGs dec
When is the max LDL-C reduction reached for Ezetimibe
Maximum LDL-C reduction is reached after 2 weeks
effect of ezetimibe on absorption of fat-soluble vitamins (A, D, E, and carotenoids)
No effect of ezetimibe on absorption of fat-soluble vitamins (A, D, E, and carotenoids)
Additionally, the 4 major drug therapies used for treating dyslipidemia all lower low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) and reduce the incidence of major coronary events to varying degrees. Discuss each effect on LDL-C, HDL-C, and TG
- Statins
- > large LDL-C
- > small inc HDL-C
- > moderate dec TG - Niacin
- > moderate LDL-C
- > large inc HDL-C
- > large dec TG - Fibrates
- > moderate dec LDL-C
- > moderate inc HDL-C
- > large dec TG - Bile acid sequestrant (resins)
- > small dec LDL-C
- > moderate inc HDL-C
- > no effect on TG
Side effects of statins, niacin, fibrates, and resins
Statins
- Myopathy
- Inc liver enzymes
Niacin
- Flushing
- Itching
Fibrates
- Gallstones
- Indigestion
Bile acid sequestrants (resins)
- GI distress
- Constipation
Explain the principles of drug management of dyslipidemia.
a
Discuss the mechanism of action and effects of major classes of antihyperlipidemics.
a
List the major side-effects of the above medications.
a
