Antihyperlipidemic

Drugs
→ Hyperlipidemia: ↑cholesterol and/or ↑TAGs, or ↓HDL
→ ↑risk of cardiovascular mortality linked to ↑LDL and ↓HDL; ↑TAG!independent risk factor & can cause acute pancreatitis
→ Other risk factors for cardiovascular diseases!smoking, HTN, obesity, and diabetes
→ Disorders are detected by measuring serum lipids after a 10 hr. fast!TAGs, cholesterol(TC) and HDL measured directly; LDL= TC- (HDL+TG/5) when TAGs are <400mg/dL and pts are fasting
→ Statins=Lipid-lowering agents of first choice; adjunct to diet, exercise, smoking cessation; can reduce the risk of first cardiovascular events and death in pts with risk factors
Primary (Familial) Hyperlipidemia Secondary Hyperlipidemia
→ Causes: monogenetic disease, genetic polymorphisms, gene-environment interactions → MCC: sedentary lifestyle with XS dietary intake of saturated fat, cholesterol, and trans FAs
→ Most common cause of dyslipidemia in children → Most common cause of dyslipidemia in adults
→ Fredrickson Classification of Lipid Disorder: → Excess alcohol!↑VLDL production
Disease Lipid Profile Etiology → Hypertriglyceridemia in Type II DM d/t ↑VLDL synthesis and ↓chylomicron/VLDL catabolism
Type I o Insulin resistance!increased VLDL production since insulin normally inhibits VLDLs
↑Chylomicrons Deficiency in LPL or apoCII (Rare)
Familial Hyperchylomicronemia
Type IIA
o Insulin resistance!increased apoCII!↓chylomicron/VLDL catabolism
Familial Hypercholesterolemia
↑LDL ↓/non-fxnal LDL receptor
Type IIB Overproduction of VLDL by liver Hypertriglyceridemia ( VLDL) Hypercholesterolemia ( LDL)
↑LDL, ↑VLDL
Familial Combined hyperlipidemia (relatively common) Diabetes Mellitus Hypothyroidism
Type III Chronic renal failure Nephrotic syndrome
↑IDL Abnormal ApoE
Familial dysbetalipoproteinemia
Overproduction/impaired
Hypothyroidism Obstructive liver disease
Type IV Alcohol excess glucocorticoids
↑VLDL catabolism of VLDL (relatively
Familial Hypertriglyceridemia
common) Contraceptives
Type V ↑production/↓clearance of VLDL β-blockers
↑Chylomicrons, ↑VLDL
Familial mixed hypertriglyceridemia &chylomicrons

Glucocorticoids
Drug Class Description MOA Uses Adverse Effects
Analogs of 3-OH-3-methylglutarate measure:
• baseline
(HMG) ↑aminotransferases (must be monitored) • 1-2 mo
Rosuvastatin • every 6-12 mo

Atorvastatin Lovastatin and simvastatin are Myopathy and rhabdomyolysis (measure CK) measure:
Competitively inhibit HMG-CoA reductase (RLE • baseline
Simvastatin prodrugs!inactivate lactones !myoglobinuria!renal injury • if symptomatic
HMG-CoA for de novo cholesterol synthesis) !↓
Lovastatin DOC for ↓LDL - discontinue
equal
reductase hydrolyzed in GI!active β- intracellular cholesterol!↑HMG-CoA reductase
Pravastatin Patients who are homozygous for familial
potency

inhibitors hydroxyl derivatives & ↑LDL receptors!↑LDL clearance

Fluvastatin ↓cardiovascular hypercholesterolemia benefit less from this TXT
Homozygous
mortality d/t lack of fxnal LDL-r
“Statins” ↓LDL, ↓TAG, small ↑HDL Best when used in combo with resins, niacin or type 2a: no LDLR
*in order of most
↑endothelial fxn ezetimibe
potent to least Contraindicated in women who are
↓platelet aggregation
potent pregnant/lactating/want to be pregnant!
↓inflammation
Category X
↓plasma CRP
Intense cutaneous flush after each dose (PG-
mediated so it can be blocked by aspirin)
Activate Gi !↓adenylyl cyclase! ↓cAMP & DOC for ↑HDL

↓PKA!inhibit HSL!↓FA transport!↓TAG
Pruritus, rashes, dry skin, and acanthosis nigricans
synthesis!↓VLDL production/release Useful in patients

with combined (LDL/VLDL)
type 2B
↑HDL significantly
Niacin Gi Nausea and abdominal discomfort
Niacin ↓VLDL, ↓LDL, and ↓Lp(a) ↑LPL activity!↑chylomicron & VLDL clearance hyperlipidemia and
(Nicotinic Acid)
Only one to ↓Lp(a) ↓HDL levels Rare:
[vitamin B3]
Hepatotoxicity!↑transaminases • atrial arrythmia
↓HDL catabolism!↑HDL
Insulin resistance!hyperglycemia
• toxic amblyopia
(lazy eye)
Adjunct therapy with
(Caution in pts with diabetes)
• toxic maculopathy

↓fibrinogen, ↑t-PA!reverse endothelial dysfxn statins

↑uric acid!gout
↓TAG (best one) Activate PPAR-α (peroxisome proliferator
Mild GI disturbances
↑HDL activated receptor α) expressed in liver and DOC for severe
Myositis fenofibrate less AE:
Gemfibrozil brown adipose tissue hypertriglyceridemia • does not inhibit hepatic statin uptake
Rhabdomyolysis
hepatic
Fibrates
Fenofibrate Gemfibrozil inhibits uptake of type 4 (LDL)
Cholelithiasis d/t ↑cholesterol excretion
statins!↑concentration of both ↓TAG d/t ↑LPL, ↓apoC-III & ↑hepatic oxidation
Avoid in pts with hepatic/renal dysfxn
drugs!↑rhabdomyolysis of FA
increased dietary C --> gallstones

Antihyperlipidemic Drugs Continued
Drug Class Description MOA Uses Adverse Effects
ion trapping at GIT Little effect on pts with dysfxn LDL-r Type 2a
homozygous
H20 insoluble, ↑MW, polymeric Binds to anionic bile acids in
anion exchange resins!NOT Used with statins/niacin Bloating, cramping & constipation
intestine!prevents
Cholestyramine Bile Acid- absorbed or metabolized! 100% to ↑LDL reduction (Colesevelam is better tolerated than others)
reabsorption!↑production in liver!↓
Colestipol Binding excretion in feces
intracellular cholesterol!upreg LDL-r!↓LDL
Colesevelam Resins DOC for children and Contraindicated in pts. w/ very high LDL
(partially offset by ↑cholesterol synthesis)
Useful only in pregnant Contraindicated in hyperTAGemia: will ^ VLDL
isolated
Modest ↑HDL liver senses decreased C:
hypolipoproteinemia’s with ↑LDL increases LDL expression Cholestyramine & Colestipol interfere with fat soluble
vitamins
(Type 2a only) absorption of other drugs and Vit. ADEK
Selectively inhibit NPC1L1 in jejunal
dietary
enterocytes!↓ cholesterol!↑cholesterol Reversible impaired hepatic fxn
Inhibits absorption of cholesterol Combo with statin in pts.
Cholesterol synthesis & upreg of LDL-r! ↓LDL
and phytosterols! ↓LDL who can’t reach their LDL
Ezetimibe absorption Myositis :risk if combined with statins
goal
inhibitors Effective even in absence of cholesterol b/c it
Complimentary actions to statins
inhibits reabsorption of cholesterol excreted in Absorption inhibited by bile acid sequestrants
bile :compensatory increase in HMG-CoA reductase
EPA Fish oils that ↓TAG in a dose
DHA dependent way ↑LDL-C Adjunct to
↓TAG synthesis and ↑FA oxidation in the liver
Lovaza ω-3 Fatty Contains both EPA and DHA diet in adults
May ↑ total LDL as they ↓TAG
Acids ↓TAG with very
impact on HDL varies
Vascepa Ethyl ester of EPA without high TAG
when TAG≥400 mg/dL
↑LDL

SUGGESTED DRUG THERAPY FOR DYSLIPIDEMIAS

Lipid Profile Initial Drug Additions

Niacin, Resin,
Elevated LDL Statin
Ezetimibe
Niacin, Fibrate,
Elevated LDL and TG Statin
ω-3 Fatty acid

Isolated low HDL Statin Niacin

Isolated severe Fibrate (or Niacin

Statin
hypertriglyceridemia or ω-3 Fatty acid)

80

Effects of Antihyperlipidemics ANTIHYPERLIPIDEMIC DRUGS IN PREGNANCY

Drug Effect on LDL Effect on HDL Effect on TG • Statins: absolutely contraindicated in pregnancy.
Category X.
Statins ↓25%–60% ↑5%–15% ↓10%-40% • Fibrates: Category C.
Fibrates ↓ or ↑ ↑10%–30% ↓30%–60%
best drug
vs TAGs
• Niacin: Category C.
• Ezetimibe: Category C.
Resins ↓15%–30% ↑3%–5% ↑5%
• Cholestyramine & colestipol: might interfere
Ezetimibe ↓15%–20% ↑1%-2% ↓5% -10% with absorption of nutrients. Category C.
best drug
• Colesevelam: Category B. Should be used during
Niacin ↓10%–30% ↑20%–35% ↓30%–50% for HDL pregnancy only if clearly needed.
best drug vs
ω-3 Fatty acids ↑5%–10% ↑5%–10% ↓20%–50%78 only TAGs
81