Hypolipaedimic drugs

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 Hypolipaedimic drugs
• Importance or why to
study?
• Lipoproteins
• The diseases
• Drugs
• How to use?
 Atherosclerosis and hyperlipioprotenimia
What is the significance?

• Narrow –arterial lumen

• Thrombosis of artery
• Embolization
• Distal ischemia
• Ulceration
• Weaken arterial wall
• Aneurisms
 Importance or why to study?

• CHD –Cause half of all deaths

• CHD correlated LDL, Cholesterol ,
Triglycerides and low levels of HDL
• Cholesterol levels elevated because of
• Lifestyle-Genetic OR Genetic + Lifestyle
factors
• Lowering CHE levels reduces the risk of
CHD-30-40%
• Life style modifications and hypolipedemics
• Life long treatment
 Lipoproteins

Hydrophobic lipids are carried by

lipoproteins in aqueous envn. Of
plasma
 Lipoproteins

• Classified on the basis of density,

• Triglyceride (which makes them
less dense)
• Apoproteins (which makes them
more dense).
Metabolism of plasma lipoproteins and related
genetic diseases
Liver expresses
LDL receptors

Removes ~75% of
LDL from plasma.
Excreted in Bile

Manipulation of
hepatic LDL
receptor
expression most
effective way to
modulate plasma
LDL-C levels
he exogenous and endogenous lipoprotein metabolic pathways
 HDL metabolism and reverse cholesterol transport

Transport
Liver of excess
& intestine cholesterol
→nascent HDLsfrom periphery to liver for excretion in the bile
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
• LDL →modified by oxidation →
foam-cell formation → arterial lesions

• 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.
• Antiinflammatory, antioxidative, platelet
antiaggregatory, anticoagulant, and profibrinolytic
activities
five
 Statins

Clofibrate
Fibric Acid…
Nicotinic Acid
Resins

Omega-3 Others: Probucol, Gugulipid, Fibre

 Statins
• 6 statins
• Inhibit rate limiting step in the bio-synthesis
of cholesterol [Decreased production]
• ↓
• Up regulates LDL receptors [Increased
clearance]
• Lova. 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
 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
 Statins…..ADE
• Myopathy & Hepatotoxicity
• Myopathy = CK 10 times
normal
• 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…..DI
• Fibrates, Cyclosporine,
Warfarin, Macrolides, Azoles
• If combined with above drugs-
dose of statin=25%
• Precaution-Basic ALT→Repeat
after 3 months →If normal no
further monitoring
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 taken in the
evening.
 •Oldest and
the safest
•Not
absorbed
from the
GIT
Bile acid 1.Cholestyr
sequestrant amine,
s 2.Colestipol,
3.Colesevelam
 Bile acid sequestrants

MOA:
• Highly positively charged
• Bile acids -Negatively charged
• Bound bile acids are excreted in
the stool
• 95% of bile acids are normally
reabsorbed
• This process depletes the pool of
bile acids
 Bile acid sequestrants..
• Bile-acid synthesis increases.
• Cholesterol content declines
• Stimulates the production of LDL receptors-
effect similar to that of statins.
• Increase in hepatic LDL receptors increases LDL
clearance and lowers LDL-C levels
• This effect is partially offset by the
enhanced cholesterol synthesis caused by
upregulation of HMG-CoA reductase
• Inhibition of reductase activity by a
statin - 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]
• Colesevelam- ↓ Absorption of Verapamil
Niacin
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
parameters
 Niacin-ADE
• Flushing and dyspepsia – affects
compliance
• Ceases in most patients after 1 to 2
weeks
• Coffee, tea, alcohol –Increase
• 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 adipose tissue
• Stimulate -Increased LPL synthesis,
• Increases in HDL-C
• ↑TG clearance and ↓ hepatic triglyceride
synthesis
• DOC -Severe hypertriglyceridemia
• Paroxisome-Proliferator-Activated-Rec.
 Fibric Acid Derivatives: ADE & DI
• GIT
• 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 of both drugs may be
increased when they are co-administered
Fibric Acid Derivatives: ADE
& DI
• ↑ Gall stones
• Renal failure and hepatic dysfunction –
relative CI
• 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
• ↓Cholesterol absorption
• Compensatory increase in cholesterol
synthesis
• Can be inhibited with statin
 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
Actions of drugs
LDL Goals & treatment cut points:NCEP

LDL Goal Initiate Consider

Risk category mg/dL Life style drug
change therapy

High risk <100 ≥ 100 ≥ 100

Mod.high risk <130 ≥ 130 ≥ 130

Moderate risk <130 ≥ 130 ≥ 160

Low risk <160 ≥ 160 ≥ 190

Be bold-Be different! Not indifferent!!!!

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