antihyperlipidemics lecture Flashcards
chylomicrons
Dietary triglycerides and cholesterol
synthesized in the intestine
TG hydrolysis by LPL
Remnant uptake by liver
VLDL
Endogenous triglycerides
synthesized in the liver
TG hydrolysis by LPL
IDL
Endogenous cholesteryl esters and triglycerides
Product of VLDL catabolism
LDL mediated by hepatic lipase
Uptake by liver
LDL
Cholesteryl esters
Product of VLDL catabolism
Uptake by LDL receptor
HDL
Phospholipids and cholesteryl esters
synthesized in the Liver
Uptake of cholesterol by hepatocytes
atherosclerosis pathophysiology
LDL retention in sub-endothelial space LDL oxidation Increased plasminogen inhibitor Induced expression of endothelin Inhibited expression of nitric oxide Massive accumulation of cholesterol Increased inflammatory response Rupture of unstable plaque
desirable cholesterol levels
LDL less than 100
total less than 200
HDL between 40 and 60
triglycerides less than 150
Risk Equivalents vs. Factors in CHD
Equivalents: Symptomatic carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm Diabetes
Factors: Age (men ≥ 45 years, women ≥ 55 years) Family history of premature CHD Cigarette smoking Hypertension Low HDL (
Treatment Options
Nonpharmacologic Therapeutic Lifestyle Change Diet Exercise Smoking Cessation
Pharmacologic HMG-CoA Reductase Inhibitors (Statins) Nicotinic Acid, Vitamin B3 (Niacin) Fibric Acid Derivatives (Fibrates) Bile Acid Sequestrants (Resins) Cholesterol Absorption Inhibitors
Nonpharmacologic Treatment
Therapeutic Lifestyle Change (TLC) – Dietary Therapy
May obviate need for drug therapy
Augment LDL lowering agents
Allow for lower doses
However, should not be used alone for: Severe hypercholesterolemia Known CHD CHD risk equivalents PVD
Dietary recommendations
total fat 25-35% of total calories sat fat less than 7% cholesterol less than 200 mg/day carbs 50-60% of calories dietary fiber 20-30 g/day
HMG-CoA reductase inhibitors: PK, ADRs, CIs
PK:
Oral absorption 40-75%; extensive first-pass
t1/2 1-3 hours [atorvastatin (14 hours), rosuvastatin (19 hours)]
CYP3A4 (lovastatin, simvastatin, atorvastatin) and CYP2C9 (rosuvastatin); pravastatin not metabolized via CYP’s
ADRs:
LFT elevation
CK elevation
Rhabdomyolysis
Myopathy
CIs: pregnancy
DDIs: statin ___accumulation____ with CYP inhibitors (cyclosporine, ketoconazole, fibrates); statin __conc. reduction___ with CYP inducers (phenytoin, rifampin)
niacin MOA, PK, ADRs, CIs
inhibits triglyceride lipolysis in adipose tissue, reduces circulating FFA’s
PK:
Well absorbed; distributed to hepatic, renal, adipose tissue
Extensive first-pass; t1/2 60 minutes (2-3x daily dosing)
ADRs:
Cutaneous flush (prostaglandin-mediated)
Pruritus
Acanthosis nigricans
Hepatotoxicity
CIs: hepatic disease, active PUD, caution DM
Fibric Acid Derivatives MOA, PK, ADRs, CIs, DDIs
MOA: PPARα agonists; regulate expression of proteins involved in lipoprotein structure and function; increase expression of LPL
PK:
Well absorbed
Highly protein bound
t1/2 gemfibrozil 1.5 hours, fenofibrate 20 hours
ADRs: Gastrointestinal Lithiasis Myositis Myopathy
CIs: avoid in hepatic or renal dysfunction, pregnancy
DDIs: potentiates action of warfarin; increased risk of rhabdomyolysis in combination with statins
Bile Acid Sequestrants (Resins) MOA, PK, ADRs, CIs, DDIs
Agents: colestipol, cholestyramine, colesevelam
MOA: bind bile acids increasing excretion 10x, enhanced conversion of cholesterol to BA’s, increased LDL clearance
PK:
Water insoluble; not absorbed; totally excreted in feces
ADRs:
GI (constipation, nausea)
Impaired ADEK absorption
CIs: caution in diverticulitis, bowel disease, cholestasis
DDIs: impairs drug absorption – separate administration times
