Ross S3M3: Pharmacology Of Hyperlipidemia

Front 1

Lovastatin: 'Statins'
Pharm
MOA
Use
AE

Back 1

- Analogs of 3 hydroy 3 methylglutaryl coenzyme A , low oral bioavailability, liver metab and bile excretion
- competitive inhibition of HMG COA REDUCTASE (rate limiting step in cholesterol synthesis) -> reduced cholesterol -> hepatic LDL receptor upregulation -> increased extraction of LDL from blood, reduction of hepatic VLDL production (need chol. to make); Result: 20-55% LDL red., 10-35% TG red., 5-10% HDL increase
- all hyperlipidemias with high chol. or LDL, atherosclerosis, primary prevention of CAD, stroke prevention in at risk patients
- AE low incidence - nausea, abdominal pain, constipation, flatulence, hepatotoxicity in at risk patients, mild increase in creatinine phosphokinase, myopathy (with drug combos), headache,discontinue if aminotransferase is 3 times normal and persistent; C/I in hepatic disease, jaundice, cholestasis, alcoholism, pregnancy, fertile age (TERATOGEN), reduced renal perfusion or insuff. and concurrent use of niacin, fibrates, or cyp450 inhibitors (increases myopathy risk)

Front 2

Cholestyramine (Colestipol)
Pharm
MOA
Use
AE

Back 2

- Anion exchange resins; not absorbed from intestine
- Binds bile acids in intestinal lumen by exchanging Cl to form nonabsorbable complex -> prevents enterohepatic circulation of bile acids -> increased bile acid excretion causing upregulation of hepatic LDL receptors and increased synthesis of cholesterol in the liver but plasma cholesterol is NOT increased since newly made cholesterol is shunted into bile acid syntheisis pathway) ; Result: 10-35% LDL red.
- all hyperlipidemias with isolated LDL increases, itching associated with partial biliary obstrucion, diarrhea due to excess of fecal bile acids or to pseudomembranous colitis
- Constipation, fecal impaction, bloating, hypertriglyceridiemia, metabolic acidosis at high doses bc of Cl- absorption, decreased intestinal absorption of fat soluble vitamins and some drugs (digoxin, warfarin, thyroxine, statins, thiazides, aspirin); C/I cholelithiasis, biliary obstruction, hypertriglyceridemia, pre-existing coagulopathy (resins prevent Vit K absorption), constipation

Front 3

Niacin
Pharm
MOA
Use
AE

Back 3

- Niacin = nicotonic acid, vit. B3; water soluble vitamin; good oral bio; in all tissues and partially converted to nicotinamide which is in NAD
- INHIBITION of lipolysis in adipose tissue -> reduces plasma TG and decreased TG delivery to liver and decreased synthesis and VLDL secretion by hepatocytes, reduced LDL in plasma (degradation product of VLDL) and also reduces apolipoprotein A1 catabolized from HDL (HDL preserved); Results - 10-25% LDL red, 15-40% VLDL red, 30-50% TG red, 15-30% HDL increase; ALSO decreases fibrinogen levels (improves atherosclerosis and thrombosis), stimulates PG and histamine, inhibits tubular uric acid secretion, decreases glc tolerance
- ALL hyperlipidemias with high VLDL and LDL and low HDL
- cutaneous flush, headache, dizziness, skin rashes, vomiting ,diarrhea, peptic ulcers worsen due to histamine increase, hyperuricemia, hyperglycemia (drug induced insulin resistance), hepatotoxicity (dose dependent), rhabdomyolysis (when givenwith statin); C/I in peptic ulcer, liver disease, diabetes, gout, hyperuricemia, bleeding coagulopathy, surgery

Front 4

Gemfibrozil (Fenofibrate)
Pharm
MOA
Use
AE

Back 4

- in all tissues, good oral bio; fibric acid derivatives
- activation of nuclear Tx R (PPAR alpha), in liver and brown adipose -> increased synthesis of lipoprotein lipase, enhanced hyrdolysis of VLDL; 30-60% TG red, 20-30% VLDL red; 5-10% HDL increase; LDL same
- choiceof drug for TYPE III HYPERLIPOPROTEINEMIA, hypertryglyceridemias
- Dyspepsia, dysgeusia, cholelithiasis, myopathy, rhabdomyolysis with statins; C/I in gallbladder disease, biliary cirrhosis, hepatic disease

Front 5

Ezetimibe
Pharm
MOA
Use
AE

Back 5

- oral, metabolized by glucornidation
- inhibitors of intestinal sterolabsorption; localizes at SI brush border and inhibits absorption of cholesterol and related sterols -> 15-20% LDL red, 5-8% TG red, 16% APOB red (apoprotein of LDL and chylomicrons); little on HDL
- hyperlipidemias often given with statins to produce greater reduction in LDL
- AE - myalgia, diarrhea, hypersensitivity, C/I severe hepatic disease

Front 6

disorder? increased? drug? 1.Primary chylomicronemia 2. Familial hypercholesterolemia 3. Familial mixed hypertriglyceridemia 4. Familial dysbetalipoproteinemia

Back 6

1. type I, chylomicrons, low fat diet
2. type iia, LDL, statin or statin plus one or 2 (resin, niacin, ezetimibe)
3. type V, VLDL and chylomicrons; niacin, gemfibrozil,statin or niacinand gemfibrozil
4. type III, VLDL and remnants, niacin gemfibrozil statin, niacinandgemfibrozil or niacin and statin

Front 7

disorder? increased? drug? 1. Familial mixed hyperlipidemia 2. Familial hypertriglyceridemia

Back 7

1. type IIb, LDL, VLDL, statin or statin plus 1 or 2 (resin, niacin, ezetimibe)
2. type IV, VLDL, niacin gemfibrozil, or niacin and gemfibrozil

Front 8

How do you treat hyperlipidemias?

Back 8

Lifestyle changes: low fat andl ow cholesterol diet, weight reduction, increased activity, smoking cessation
Drugs added when cholesterol can't be reduced by diet and lifestyle changes alone or when both cholesterol and TG are elevated
Main goal is to achieve maximal expression of hepatic LDL receptor activity