Hypolipaedimic drugs

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Atherosclerosis and
hyperlipidemia
What is the significance?
 Narrow –arterial lumen
 Thrombosis of artery
 Embolization
 Distal ischemia
 Ulceration
 Weaken arterial wall
 Aneurisms
The risk
 Hyperlipidemia major cause
o Atherosclerosis-associated
conditions
o CHD, ischemic cerebrovascular
disease, PVD
 ↑LDL & ↑ TG ↓(HDL-C), -
increased atherogenic risk
 Reduction plasma
cholesterol-lowers the risk of
PLASMA LIPOPROTEIN METABOLISM
 Hydrophobic lipids are
carried by lipoproteins in
aqueous envn. Of plasma
 Lipoproteins = lipids and
proteins
 Lipid=cholesterol,
triglycerides, and
phospholipids
Lipids & Lipoproteins
 2 main lipids in  Triglycerides are
blood -cholesterol important in
and triglyceride transferring
 Carried in energy from food
lipoproteins into cells.
 Cholesterol is an  Why lipids are
essential element: deposited into
 Animal cell the walls of large
membranes and medium-
 Backbone of steroid sized arteries—an
hormones and bile event with
acids; potentially lethal
Chol-HDL-VLDL-HDL-LDL

•Lipoproteins are –
classified on the basis of
density,
•Triglyceride (which
makes them less dense)
•Apoproteins (which
makes them more dense).
 Total Chol
 = HDL + VLDL + LDL
 VLDL
 = TG/5
 LDL
 = Total Chol. – HDL- VLDL
Metabolism of plasma lipoproteins and related
genetic diseases
•Liver expresses a
large complement
of LDL receptors
•Removes ~75% of
Excreted in Bile all LDL from the
plasma.
•Manipulation of
hepatic LDL
receptor expression
most effective way
to modulate plasma
LDL-C levels
The exogenous and endogenous lipoprotein metabolic pathways
 HDL metabolism and reverse cholesterol transport

•Liver & intestine →nascent HDLs

• Cholesterol from macrophages and other peripheral cells → esterified by LCAT →
mature HDLs
•HDL cholesteryl ester can be transferred by CETP from HDLs to VLDLs and
chylomicrons
•HDL cholesterol can be selectively taken up by the liver via SR-BI (scavenger receptor
class BI)

•LCAT=lecithin-cholesterol acyltransferase
•CETP=cholesteryl ester transfer protein
LDL Atherogenic
 Atherogenic when they are modified by oxidation
 Process leads to foam-cell formation in arterial
lesions
 Controlled clinical trials - antioxidant vitamins
found ineffective in prevention
 HDL Protective
 HDL -reverse cholesterol transport - excess
cholesterol is acquired from cells and transferred
to the liver for excretion
 HDL also may protect against atherogenesis by
mechanisms not directly related to reverse
cholesterol transport.

•ACoA, acetyl-
coenzyme A
• C, cholestero
CE, cholesteryl
ester
•HDL, high-
density
Lipoprotein
•HMG-CoA
reductase
•LDL, low-
density
Lipoprotein
•MVA,
mevalonate
•TG, triglyceride
•VLDL, very
low-density
lipoprotein.
 Clofibrate

Omega-3 Others: Probucol, Gugulipid, Fibre

 Statins
 6 statins
 Inhibit rate limiting step in the bio-synthesis
of cholesterol
 ↓
 Up regulates LDL receptors[Hepatocytes]
 ↓LDL levels by enhancing the removal of
LDL precursors (VLDL and IDL) and by
decreasing hepatic VLDL production
 Lovastatinn and Sim. –Pro-drugs
 LDL[20-25%], T.G.[35-40%] at high
doses, If T.G. ↓ by 25%, HDL↑ [5-10%]
↓cholesterol concentration activates
Sterol Regulatory Element Binding Protein
(SREBP),
Transcription factor that up-regulates
Statins…..

 Non-lipid lowering cardio-

protective effects
Improved endothelial function
↑ Plaque stability-↓
Inflammation
Improved circulation
↓ Lipo-Protein oxidation
Statins…..ADE
 Myopathy & Hepatotoxicity
 Myopathy = CK 10 times
normal[0.01%]
 If more than 5 times-consider
stoppage
 More in- ↑ 80 yrs, renal
dys., periop. period,
Untreated hypothyroid
Statins ADE….
 Myopathy rarely occurs in the absence of
combination therapy
 Routine CK monitoring is not recommended
unless the statins are used with one of the
predisposing drugs.
 Myopathy can occur months to years after
combined therapy is initiated
 Myoglobinuria, renal failure, and death have
been reported
 Pregnancy-safety not established
Statins…..ADE

 DI:
 Fibrates, Cyclosporine,
Digoxin, Warfarin, Macrolides,
Azoles
 If combined with above dose of
statin-25%N
 Precaution-Basic ALT→Repeat
after 3 months →If normal no
Pleiotropic effects of statins
 Cholesterol-independent
 Improving endothelial function
 Enhancing the stability of atherosclerotic
plaques
 Decreasing oxidative stress and
inflammation
 Inhibiting the thrombogenic response.
 Decrease macrophage infiltration
 Extrahepatic effects on the immune system,
CNS, and bone
 Mediated by
 Inhibition of isoprenoids
Why Statins administered
at night?
 Hepatic cholesterol
synthesis is maximal
between midnight and 2:00
A.M.
 Statins with half-lives of 4
hours or less (except
Atorvastatin and
Rosuvastatin) should be
Bile acid sequestrants
 Oldest and the safest -  Hepatic bile-acid synthesis
not absorbed from the increases.
GIT  Hepatic cholesterol content
 Cholestyramine,colestip declines
ol, Colesevelam  Stimulates the production
of LDL receptors- effect
MOA: similar to that of statins.
 Highly positively  The increase in hepatic LDL
charged [large in size] receptors increases LDL
 Bind negatively charged clearance and lowers LDL-C
levels
bile acids
 This effect is partially offset
 Bound bile acids are by the enhanced cholesterol
excreted in the stool synthesis caused by
 95% of bile acids are upregulation of HMG-CoA
reductase
normally reabsorbed
 Inhibition of reductase
 This process depletes activity by a statin -
the pool of bile acids increases the effectiveness
of the resins.
Bile acid sequestrants ADE and
DI
 Rarely- hyperchloremic acidosis [Chloride
salts]
 Severe hypertriglyceridemia is a CI
 Unpleasant to patients
 Bloating and dyspepsia [↓Dissolving several
h.before]
 Constipation
 ↓ Absorption - thiazides, furosemide,
propranolol, l-thyroxine, digoxin, warfarin,
and some of the statins [4 h. before or 1 h.
after above drugs]
Niacin: MOA
Adipose tissue
 Inhibits lipolysis of triglycerides by lipase
 ↓Transport of FFA to the liver- ↓ hepatic TG
synthesis
Liver
 ↓ TG synthesis by inhibiting - synthesis and
esterification of FA
 ↓ TG → ↓ VLDL production→ ↓ LDL
 Raises HDL-C levels
 Favorably affects virtually all lipid
Niacin-MOA
Niacin-ADE
 Flushing and dyspepsia – affects compliance
 Ceases in most patients after 1 to 2 weeks
of a stable dose
 Coffee, tea, alcohol –Increase flushing
 Minimized by low doses, aspirin
 Severe hepato-toxicity- [common with SR
prep, Crystalline form preferred]
 Causes insulin resistance
 CI
 Pregnancy, APD
Fibric Acid Derivatives: PPAR Activators
 Clofibrate, Gemfibrozil, Fenofibrate,
Bezafibrate, and Ciprofibrate
MOA:
 Bind to PPARα- liver and brown adipose
tissue [Kidney, heart, and skeletal muscle].
 Stimulate -fatty acid oxidation, increased
LPL synthesis,
 Increases in HDL-C -due to PPARa
stimulation of apoA-I and apoA-II expression
 ↑TG clearance and ↓ hepatic triglyceride
synthesis
 DOC -treating severe hypertriglyceridemia
and the chylomicronemia syndrome
Fibric Acid Derivatives: ADE & DI
 Gastrointestinal side effects
 Rash, urticaria, hair loss,
myalgias, fatigue, headache,
impotence, and anemia
 Increases in liver
transaminases
 Potentiate the action of oral
anticoagulants- displacing
them from PPB sites
 Myopathy [with Statin]
 Gemfibrozil inhibits hepatic
uptake of statins by OATP2.
 Gemfibrozil also competes
for the same glucuronosyl
transferases that metabolize
most statins.
 As a consequence, levels
 ↑ Lithogenicity of bile
 Renal failure and hepatic
dysfunction - relative
contraindication
 Combined statin-fibrate -
avoided in patients with
compromised renal
function.
 Fibrates should not be
used by children or
pregnant women
Ezetimibe
MOA
 Inhibits a specific transport process in
jejunal enterocytes-transport protein
-NPC1L1
 Does not affect intestinal triglyceride
absorption
 Also inhibits intestinal absorption of plant
sterols
 Compensatory increase in cholesterol
synthesis
 Can be inhibited with statin
 ↓Cholesterol absorption →↓ Cholesterol in
Ezetimibe….
 The diminished remnant cholesterol
content → decreases atherogenesis
directly
[ chylomicron remnants are very
atherogenic lipoproteins]
 Reduced delivery of intestinal
cholesterol - stimulates expression
LDL receptor expression and
cholesterol biosynthesis
 Enhances LDL-C clearance from the
Ezetimibe……
 Dual therapy with Ezetimibe & Statins
 Statin:
 “prevents the enhanced cholesterol
synthesis induced by ezetimibe”
 Ezetimibe
 “Prevents increase in cholesterol
absorption induced by statins”

 Ezetimibe-ADE

 Pregnancy-Not established
 rashes
OMEGA-3
 EPA + DHA
 FDA approved
 ↓ Hepatic TG synthesis,
 ↓TG 50%, HDL ↑ by 10%,
VLDL ↓ 40%.
 Increased bleeding with
anti coagulants
Actions of drugs
 Future
 Potent statins- ↓LDL 65%
 Inhibitors of MTP
 ACAT2 inhibitors- alt. to
Ezetimibe
 CETP inhibitors [↑ HDL] [JTT
705, Torcetradib][Torcetrapib
Torpedoed!]
 Antioxidants
 Surgical:
 Partial ileal bypass, Portacaval
LDL Goals & treatment cut points:NCEP

LDL Initiate Consider

Risk Goal Life style drug
category mg/dL change therapy

High risk <100 ≥ 100 ≥ 100

Mod.high risk <130 ≥ 130 ≥ 130

Moderate risk <130 ≥ 130 ≥ 160

Low risk <160 ≥ 160 ≥ 190

 Proof of the Pudding!

Befor After 3
e mo. Of
Chol 374 tt.
164A+E
TG 300 160
LDL 198 94
HDL 30 38
Lipoprotein lipase deficiency
Rare

Deficiency of LDL receptor

Less common

Polygenic, multifactorial
Commonest
Apoprotein in IDL, Chy.micro.-abnormal
Rare

MF & genetic
Common

Genetic
Less common
Be bold-Be different

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a
Th ou
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Not indifferent!!!!