Hypolipidemic Drugs, by Baqir Naqvi.pptx

Anti-Hyperlipidemic Drugs
(Hypo-Lipidemics)
(Pharmacology & Therapeutics-1)
Lecture By
Dr. Syed Baqir Raza Naqvi
(BSc, Pharm-D, M. Phil-Pharmacology)
Nazar College of Pharmacy
DAKSON Institute of Health Sciences, Islamabad
1

LDL cholesterol (Bad Cholesterol)
• LDL cholesterol transports cholesterol particles throughout the body, and can
build up in the walls of the arteries, making them hard and narrow. High level is
defined as above 160 mg/dl.
• LDL cholesterol is produced naturally by the body, but eating a diet high in
saturated fat can increase LDL levels.
• Elevated LDL levels are associated with diabetes, hypertension,
hypertriglyceridemia, and atherosclerosis.
HDL cholesterol (Good Cholesterol)
• HDL cholesterol carries cholesterol from other parts of the body back to the
liver and then removes the cholesterol from the body.
• It can be affected by acquired or genetic factors, including tobacco use, obesity,
inactivity, hypertriglyceridemia, diabetes, high carbohydrate diet, medication side
effects (beta-blockers, corticosteroids, diuretics, oral estrogens, etc.) and genetic
abnormalities.
• Low level is defined as less than 40 mg/dl. 4

Hypolipidemic Drugs
• These are the drugs which lower the level of lipids and lipoproteins
in the blood.
• Some of these are used to decrease the production of lipoprotein
carriers of cholesterol and triglycerol, while others increase
degradation of lipoprotein.
• These drugs have considerable attraction because of their potential
to prevent cardiovascular diseases by retarding the atherosclerosis
in hyperlipidimic patients. 7

Classification of Hypolipidemic drugs
8

1. HMG-CoA reductase Inhibitors
• These drugs lower cholesterol levels by
inhibiting the formation of HMG-CoA
reductase, which is an enzyme that is
required for the liver to synthesize
cholesterol. Effective in decreasing low-
density lipoprotein (LDL) and increasing
high-density lipoprotein (HDL) levels and
may lower triglycerides in some
patients.
9

Mechanism of Action
• Statins are analogue of HMG, which is the precursor of cholesterol.
• Statins have strong affinity to inhibit HMG-CoA reductase which is
responsible for the conversion of Acetate into Cholesterol.
Acetyl CoA HMG – reductase Mevalonic acid Cholesterol
• Depletion of intracellular cholesterol causes the cell to increase the
number of specific cell surface LDL receptors that can bind and
internalize LDLs.
• Thus the end result is reduction in plasma cholesterol, both by
lowered cholesterol synthesis and by increased catabolism of LDL.
12

Clinical Uses of Statins
• Statins are the 1st drug of choice for the primary
hyperlipidemia with raised LDL (low density
lipoproteins) and total cholesterol level.
• These are often given in combination with other
anti-hyperlipidemic drugs to enhance their
effects.
• These are also indicated for symptomatic
treatment of atherosclerosis and in patients who
are at high risk of coronary disease due to
increased cholesterol level.
13
Other Uses of
Statins
• Statins improves
endothelial
functions.
• Reduce platelets
aggregation.
• Reduce vascular
inflammation.
• Statins enhances
fibrinolysis.

Adverse effects
• Few adverse effects related to liver and
muscles.
• Liver: Statins causes biochemical abnormalities
in liver functions by elevation of serum
aminotransferase activity.
• Muscles: Myopathy and rhabdomyolysis
(disintegration of skeletal muscles) takes place.
• In most cases is causes is renal insufficiency.
• Osteoporosis is the main adverse effect of
statins' prolong use.
• Abdominal cramps, skin rashes etc.
14
Drugs
Interactions
• Erythromycin
decrease their
metabolism.
• Statins increase
warfarin level.
Contraindications
• Pregnancy
• Nursing mothers.
• Children, teenagers.

• Niacin can reduce LDL-C by 10% to 20% and is the most effective
agent for increasing HDL-C.
• It also lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3
grams/day.
• Niacin can be used in combination with statins, and a fixed-dose
combination of lovastatin and long-acting niacin is available.
16
2. Niacin (vitamin B3)

Mechanism of action
• The liver normally uses circulating free fatty
acids as a major precursor for triglyceride
synthesis.
• Niacin strongly inhibits lipolysis in adipose
tissue, thereby reducing production of free
fatty acids.
• Reduced liver triglyceride levels decrease
hepatic VLDL production, which in turn
reduces LDL-C plasma concentrations.
17

Therapeutic Uses
• Since niacin lowers plasma levels
of both cholesterol and
triglycerides, it is useful in the
treatment of hyperlipidemias.
• It is also used to treat other
severe hypercholesterolemia,
often in combination with other
agents.
19
Pharmacokinetics
R/A: Niacin is administered orally.
Metabolism: It is converted in the body
to nicotinamide, that incorporated into
the cofactor nicotinamide adenine
dinucleotide (NAD+).
Excretion: Niacin, its nicotinamide
derivative, and other metabolites are
excreted in the urine.

Adverse effects
• The most common side effects of niacin are an intense cutaneous
flush (accompanied by an uncomfortable feeling of warmth) and
pruritus.
• Administration of aspirin prior to taking niacin decreases the flush,
which is prostaglandin mediated.
• Some patients experience nausea and abdominal pain.
• Niacin inhibits tubular secretion of uric acid and, thus,
hyperuricemia and gout may occur.
• Impaired glucose tolerance and hepatotoxicity also reported.
• The drug should be avoided in hepatic disease.
20

21
Ezetimibe
Ezetimibe selectively inhibits absorption of
dietary and biliary cholesterol in the small
intestine, leading to a decrease in the
delivery of intestinal cholesterol to the
liver.
This causes a reduction of hepatic
cholesterol stores and an increase in
clearance of cholesterol from the blood.
3. Cholesterol absorption inhibitor
Neimann pick C1 Like1(NPC1L1) is a protein, present in GIT Epithelial cells for trafficking of Cholesterol from GIT to liver.

• Recovery Ratio: Ezetimibe lowers LDL cholesterol by
approximately 17%. Due to its modest LDL-lowering
effects, ezetimibe is often used in statin-intolerant
patients.
• Metabolism & Excretion: Ezetimibe is metabolized in
the small intestine and liver, and subsequently undergoes
biliary and renal excretion.
• Cautions: Patients with severe hepatic insufficiency
should not be treated with ezetimibe. Adverse effects are
uncommon with use of ezetimibe.
22

• Fenofibrate and gemfibrozil are derivatives of fibric acid that lower
serum triglycerides and increase HDL levels.
23
4. Fibrates

Mechanism of Action
• The peroxisome proliferator–activated receptors
(PPARs) are members of the nuclear receptor
family that regulates lipid metabolism.
• PPARs function as ligand-activated transcription
factors. Upon binding to their natural ligands
(fatty acids) or antihyperlipidemic drugs, PPARs
are activated.
• They then bind to peroxisome proliferator
response elements, which ultimately leads to
decreased triglyceride concentrations through
increased expression of lipoprotein lipase.
24

Pharmacokinetics
• R/A: Gemfibrozil and fenofibrate are completely absorbed after
oral administration,
• Distribution: distributed widely throughout body and has
affinity to bind with albumin.
• Metabolism: Fenofibrate is a pro drug, which is converted to the
active moiety fenofibric acid.
• Excretion: Both drugs undergo extensive biotransformation and
are excreted in the urine as glucuronide conjugates.
26

Adverse effects
• The most common adverse effects are mild gastrointestinal (GI) disturbances.
• formation of gallstones, because these drugs increase biliary cholesterol
excretion.
• Myositis (inflammation of a voluntary muscle) can occur, and muscle weakness or
tenderness should be evaluated.
• Myopathy and rhabdomyolysis, in patients taking gemfibrozil and statins
(Simvastatin) together.
Contra-indications
The use of gemfibrozil is contraindicated with simvastatin. Both fibrates may
increase the effects of warfarin.
Patients with renal insufficiency may be at risk.
• Fibrates should not be used in patients with severe hepatic or renal dysfunction or
in patients with pre-existing gallbladder disease. 27

• Bile acid sequestrants (resins) have significant LDL cholesterol–
lowering effects, although the benefits are less than those observed
with statins.
Pharmacokinetics
• Bile acid sequestrants are insoluble in water and have large
molecular weights.
• After oral administration, they are neither absorbed nor
metabolically altered by the intestine. Instead, they are totally
excreted in feces.
28
5. Bile Acid-binding Resins

Mechanism of action
• Cholestyramine, colestipol and colesevelam are anion-
exchange resins that bind negatively charged bile acids
and bile salts in the small intestine.
• The resin/bile acid complex is excreted in the feces, thus
lowering the bile acid concentration.
• This causes hepatocytes to increase conversion of
cholesterol to bile acids, which are essential components
of the bile.
• Consequently, intracellular cholesterol concentrations
decrease, which activates an increased hepatic uptake of
cholesterol- containing LDL particles, leading to a fall in
plasma LDL-C. 30

Therapeutic uses
• The bile acid–binding resins are useful (often in combination with
diet or niacin) for treating hyperlipidemias.
• Cholestyramine can also relieve pruritus caused by accumulation of
bile acids in patients with biliary stasis.
• Colesevelam is also indicated for type 2 diabetes due to its glucose-
lowering effects.
31

Adverse effects
• The most common side effects are GI disturbances, such as constipation,
nausea, and flatulence.
• Colesevelam has fewer GI side effects than other bile acid sequestrants.
• These agents may impair the absorption of the fat-soluble vitamins (A, D,
E, and K), and they interfere with the absorption of many drugs (for
example, digoxin, warfarin, and thyroid hormone).
• Therefore, other drugs should be taken at least 1 -2 hours before, or 4-6
hours after, the bile acid–binding resins.
• These agents may raise triglyceride levels and are contraindicated in
patients with significant hypertriglyceridemia (≥400 mg/dl).
32

• Omega-3 polyunsaturated fatty acids (PUFAs) are essential
fatty acids that are predominately used for triglyceride
lowering.
• Essential fatty acids inhibit VLDL and triglyceride synthesis in
the liver. The omega-3 PUFAs contains;
1. Eicosa-pentaenoic acid (EPA)
2. Docosa-hexaenoic acid (DHA)
• These are found in marine sources like tuna, halibut, and
salmon fish.
• Approximately 4 g of marine-derived omega-3 PUFAs daily
decreases serum triglyceride concentrations by 25% to 30%. 33
6. Omega-3 Fatty Acids

• Icosapent ethyl is a prescription drug that contains only EPA and,
unlike other fish oil supplements, does not significantly raise LDL-C.
35

• Over-the-counter (OTC) or prescription (Rx) fish oil capsules
(EPA/DHA) can be used for supplementation, as it is difficult to
consume enough omega-3 PUFAs from dietary sources alone.
37

Hypolipidemic Drugs, by Baqir Naqvi.pptx

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