Antihyperlipidemic drugs

Antihyperlipidemic drugs
1
DR.R.Lavanya, Faculty of Pharmacy

• Lipids are necessary for human life
• Lipids are insoluble in plasma and must be
transported
• Cholesterol
– Precursor to the sterol and steroid compounds
– Fundamental building block of steroid hormones
– Essential for building cell membranes, the myelin sheath,
and the brain
– Core component of bile salts, which helps in digest
dietary fats
2DR.R.Lavanya,Faculty of Pharmacy

• Triglycerides (TG)
– Composed of 3 fatty acids and glycerol
– Main storage form of fuel, generate high-energy
compound such as ATP, that provides energy for
muscle contraction and metabolic reactions
• Main form of fat from diet

Lipoproteins
• Lipoproteins are formed from lipid and protein molecule complexes.
The primary function of lipoproteins is the transportation and delivery
of fatty acids, triacylglycerol, and cholesterol to and from target cells
in many organs.
• They have a single-layer phospholipid and cholesterol outer shell, with
the hydrophilic portions oriented outward toward the surrounding
water and lipophilic portions oriented inward toward the lipids
molecules within the particles.
• Thus, the complex serves to emulsify the fats in extracellular fluids.
• A special kind of protein, called apolipoprotein, is embedded in the
outer shell, both stabilising the complex and giving it a functional
identity that determines its fate.
DR.R.Lavanya,Faculty of Pharmacy 21 - 4

Lipoproteins
• There are several different lipoproteins:
–Low-density lipoprotein (LDL)
–Very-low-density lipoprotein (VLDL)
–High-density lipoprotein (HDL)
–Lipoproteins are distinguished according to
their buoyant density, lipid and protein
composition, role in lipid transport and
association with apoproteins
DR.R.Lavanya,Faculty of Pharmacy 5

• Chylomicrons:
– Very large lipoproteins that deliver triglycerides to
muscle and fat tissue
Structure of a chylomicron
ApoA, ApoB, ApoC, ApoE are apolipoproteins; green particles are
phospholipid T is triacylglycerol; C is cholesterol ester.

Basic Characteristics of Lipoproteins

8
Chylomicrons- transport
dietary lipids from the gut to
the adipose tissue and liver
Chylomicron remnants-
produced from Chylomicrons
by lipoprotein lipases in
endothelial cells and transport
cholesterol to the liver
VLDL-made in the liver and
secreted in to plasma deliver
triglycerides to adipose tissue
in the process get converted to
IDL and LDL
LDL- (bad cholesterol)
delivers cholesterol to
peripheral tissues via
receptors and is phagocytosed
by macrophages thus
delivering cholesterol to the
plaques (atheromas)
HDL- (good cholesterol)
produced in gut and liver
cells, HDL transports
cholesterol from atheromas to
the liver (reverse cholesterol
transport)
DR.R.Lavanya,Faculty of Pharmacy

Dietary sources of Cholesterol
Type of Fat Main Source Effect on Cholesterol
levels
Monounsaturated Olives, olive oil, canola oil, peanut oil,
cashews, almonds, peanuts and most other
nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated Corn, soybean, safflower and cottonseed oil;
fish
Lowers LDL, Raises
HDL
Saturated Whole milk, butter, cheese, and ice cream; red
meat; chocolate; coconuts, coconut milk,
coconut oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans Most margarines; vegetable shortening;
partially hydrogenated vegetable oil; deep-
fried chips; many fast foods; most commercial
baked goods
Raises LDL

Lipoprotein metabolism
LIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are
transported in the plasma as lipoproteins, of which there are four classes:
- Chylomicrons transport TG and CHO from the GIT to the tissues, where
they are split by lipase, releasing free fatty acids.There are taken up in muscle and
adipose tissue. Chylomicron remnants are taken up in the liver
- Very low density lipoproteins (VLDL) which transport CHO and newly synthetised
TG to the tissues, where TGs are removed as before.
- Low density lipoproteins (LDL) with a large component of CHO, some of which is
taken up by the tissues and some by the liver, by endocytosis via specific
LDL receptors
- High density lipoproteins (HDL) which absorb CHO derived from cell breakdown
in tissues and transfer it to VLDL and LDL

There are two different pathways for exogenous and endogenous lipids:
THE EXOGENOUS PATHWAY: CHO + TG absorbed from the GIT are
transported in the lymph and than in the plasma as CHYLOMICRONS
to capillaries in muscle and adipose tissues. Here the core TRIGL are
hydrolysed by lipoprotein lipase, and the tissues take up the resulting
FREE FATTY ACIDS
CHO is liberated within the liver cells and may be stored, oxidised to
bile aids or secreted in the bile unaltered
Alternatively it may enter the endogenous pathway of lipid transport
as VLDL

Atherosclerosis and lipoprotein metabolism
CHO
may be
stored
oxidised
to
bile acids
secreted
in
the bile
unaltered
ENDOGENOUS
PATHWAY
EXOGENOUS
PATHWAY

CHO Bile duct
v.portae
GIT
bile acids
ENDOGENOUS
PATHWAY for lipids
EXOGENOUS
PATHWAY for lipids
chylomicr
TG CHO
chylomicr
remn
bile acids
CHO
Peripheral tissues
ENDOGENOUS
PARTHWAY
Fat
+ CHO
+ fatty acids
HEPATOCYTE
CHO TG
Fatty acids

THE ENDOGENOUS PATHWAY
CHO and newly synthetised TG are transported from the liver as VLDL to
muscle and adipose tissue, there TG are hydrolysed and the resulting
FATTY ACIDS enter the tissues
The lipoprotein particles become smaller and ultimetaly become LDL ,
which provides the source of CHO for incorporation into cell membranes, for
synthesis of steroids, and bile acids
Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins
CHO can return to plasma from the tissues in HDL particles and the resulting
cholesteryl esters are subsequently transferred to VLDL or LDL
One of LDL – lipoprotein - is associated with atherosclerosis (localised in
atherosclerotic lesions). LDL can also activate platelets, constituting a further
thrombogenic effect

CHO
Bile duct
v.portae
GIT
bile acids
ENDOGENOUS
PATHWAY for lipids
EXOGENOUS
PATHWAY for lipids
bile acids
CHO
Peripheral tissues
HEPATOCYTE
ACoA
MVA
LDL
receptors
VLDL
TG CHO
lipase
CHO
CHO
CHO
LDLHDL
CHO
Uptake
of CHO
Fatty
acids
CHO
from
cells
CHO

Lipids
• Chylomicrons transport fats from the intestinal mucosa to the
liver
• In the liver, the chylomicrons release triglycerides and some
cholesterol and become low-density lipoproteins (LDL).
• LDL then carries fat and cholesterol to the body’s cells.
• High-density lipoproteins (HDL) carry fat and cholesterol
back to the liver for excretion.
• When oxidized LDL cholesterol gets high, atheroma formation
in the walls of arteries occurs, which causes atherosclerosis.
• HDL cholesterol is able to go and remove cholesterol from the
atheroma.
• Atherogenic cholesterol → LDL, VLDL, IDL

19

Dyslipidemia
The normal range of plasma total CHO concentration < 6.5 mmol/L.
There are smooth gradations of increased risk with elevated LDL CHO
conc, and with reduced HDL CHO conc.
Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides,
cholesterol and/or fat phospholipids) in the blood. Dyslipidemia
increases the chance of clogged arteries (atherosclerosis) and heart
attacks, stroke or other circulatory concerns,
Dyslipidemia can be primary or secondary.
The primary forms are genetically determined
Secondary forms are a consequence of other conditions such as
diabetes mellitus, alcoholism, nephrotic syndrome, chronic renal
failure, administration of drug.

• Hyperlipidemia -Increased concentrations of lipids
• Hyperlipoproteinemia- Increased concentrations of
lipoproteins
• Hypercholesterolemia- high concentration of cholesterol
– Atherosclerosis and coronary artery disease
• Hypertriglyceridemia- high concentration of triglyceride
– Pancreatitis
– Development of atherosclerosis and heart disease

Causes of Hyperlipidemia
• Diet
• Hypothyroidism
• Nephrotic syndrome
• Anorexia nervosa
• Obstructive liver disease
• Obesity
• Diabetes mellitus
• Pregnancy
• Acute hepatitis
• Systemic lupus
erythematosus
• AIDS (protease
inhibitors, eg.
Saquinavir,indinavir)

Causes of Hyperlipoproteinemia
• Genetics and environmental factors
• Increase the formation or reduce the clearance
of LP from circulation
• Factors
– Biochemical defects in LP metabolism
– Excessive dietary intake of lipids
– Endocrine abnormality
– Use of drugs that perturb LP formation or
catabolism

Primary Hyperlipoproteinemia
• Caused by a monogenic defect (a specific defect at a
single gene)
• LDL cholesterol levels are severely high
– Deficiency of LDL receptors
– Defect in the structure of apoprotien B
• LDL receptors do not recognize LDL, LDL
remains in circulation
• VLDL and TG levels are severely high
– Lipoprotein lipase deficiency
• Prevents delivery of TG to adipose tissue

• Polygenic-environmental hyperlipidemia
– Milder forms of hyperlipidemia
– Influence of several genes
– Excessive of dietary intake
– More common than primary form
– Responsible for most cases of accelerated atherosclerosis
• Secondary hyperlipidemia
– Alcoholism
– Diabetes melitus
– Uremia
– Drugs; beta blockers, oral contraceptives, thiazide diuretics
– Diseases: hypothyroidism, nephrotic syndrome, obstructive
liver disease

CH—Cholesterol; TG—Triglycerides; G—Genetic; MF—Multifactorial; Chy. rem.—Chylomicron remnants; VLDL—Very low density
lipoprotein; IDL—Intermediate density lipoprotein; LDL—Low density lipoprotein.
The genetic defect in some of the monogenic disorders is:
Type I : absence of lipoprotein lipase—TG in Chy cannot be utilized.
Type IIa : deficiency of LDL receptor—LDL and IDL are taken up very slowly by liver and tissues.
Type III : the apoprotein in IDL and Chy. rem. (apoE) is abnormal, these particles are cleared at a lower rate.
Type IV : this type of hypertriglyceridaemia is both multifactorial and monogenic, the former is more prevalent than the latter.
Types of primary hyperlipoproteinaemias

Atherosclerosis

Atherosclerosis
Atherosclerosis is a progressive condition that leads to CAD and
PAD.
Fat buildup inside the arteries—plaque
Plaque buildup can block arteries, causing: Angina,TIA,Stroke
Risk factors for atherosclerosis:
Age
History of smoking
Hypertension
Premature menopause
Obesity
Diabetes mellitus
Hyperthyroidism

Atherosclerosis
• The goals of treatment are:
– Lowering LDL cholesterol
– Reducing total serum cholesterol and triglycerides
– Increasing HDL cholesterol

Coronary Heart Disease (CHD)
• The main cause of premature death in industrialized
countries
• Modifiable risk factors
– Hypertension
– Cigarette smoking
– Low high density lipoprotein (HDL) <40 mg/dl
• Unmodifiable risk factors
– Male gender
– Family history of premature CHD; CHD in first-
degree male relative <55, female <65
– Advance age; Men>45, Women >55

32
Progression of CHD Damage to
endothelium and
invasion of
macrophages
Smooth muscle
migration
Cholesterol
accumulates
around
macrophage and
muscle cells
Collagen and
elastic fibers
form a matrix
around the
cholesterol,
macrophages
and muscle
cells

Goals for Lipids
• LDL
– < 100 →Optimal
– 100-129 → Near optimal
– 130-159 → Borderline
– 160-189→ High
– ≥ 190 → Very High
• Total Cholesterol
– < 200 → Desirable
– ≥240 → High
• HDL
– < 40 → Low
– ≥ 60 → High
• Serum Triglycerides
– < 150 → normal
– 200-499 → High
– ≥ 500 → Very High

Agents Used to Treat Hyperlipidemia
• Drugs used to lower lipid levels
Fibrates
Others
Resins
Statins
LIPID-LOWERING
DRUGS

Classification
1. HMG-CoA reductase inhibitors (Statins):
Lovastatin, Simvastatin, Pravastatin,Atorvastatin,
Rosuvastatin, Pitavastatin
2. Bile acid sequestrants (Resins): Cholestyramine, Colestipol
3. Lipoprotein lipase activators (PPARα activators, Fibrates):
Clofibrate, Gemfibrozil,Bezafibrate, Fenofibrate.
4. Lipolysis and triglyceride synthesis inhibitor: Nicotinic acid.
5. Sterol absorption inhibitor: Ezetimibe.

Mechanism of action and pattern of lipid lowering effect of important hypolipidaemic drugs

HMG-CoA Reductase inhibitors
• Atorvasatatin
• Simvastatin
• Lovastatin
• Pravastatin
• Fluavastatin
• Rosuvastatin

39
HMG-CoA Reductase Inhibitors
• Also referred to as statins
• MOA—inhibit enzyme that causes cholesterol synthesis
• A important step is the conversion of acetyl-CoA molecules into
HMG-CoA, which is then converted to mevalonic acid by HMG-
CoA reductase. Mevalonic acid is a rate-limiting pivotal step in
steroid and cholesterol biosynthesis
• The liver makes two-thirds of the daily cholesterol requirement.
• Improvement in endothelial function due to increased NO
production and reduction in LDL oxidation are proposed as
additional mechanisms by which statins may exert
antiatherosclerotic action.
• Recently, a reduction in venous thromboembolism has also been
observed with rosuvastatin

41
HMG-CoA Reductase Inhibitor
• All of the statins reduce LDL up to 30 percent at a daily dose of
lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, atorvastatin
10 mg, rosuvastatin 5 mg and pitavastatin 2 mg
• greater reduction of LDL with doses simvastatin (80mg) -45–50%
reduction, atorvastatin (80mg), and rosuvastatin (40mg) -55 %
reduction.
• All of the statins raise the HDL level. A greater rise in HDL-CH has
been noted with simvastatin than lovastatin or pravastatin (5–15% ).
• Simultaneous use of bile salt sequestrant augments the LDL lowering
effect up to 60% and addition of nicotinic acid to this combination
may boost the effect to 70% reduction in LDL-CH.
• In patients with raised TG levels, rosuvastatin raises HDL-CH by 15–
20% (greater rise than other statins).

• HMG-CoA reductase activity is maximum at midnight, so administered at bed time
• However, this is not necessary for atorvastatin and rosuvastatin, which have long
plasma t½.
• All statins, except rosuvastatin are metabolized primarily by CYP3A4. Inhibitors
and inducers of this isoenzyme respectively increase and decrease statin blood
levels.
• Use of pitavastatin in combination with gemfibrozil should be avoided, as the latter
decreases its clearance. Gemfibrozil inhibits the hepatic uptake of statins by the
organic anion transporterOATP2.
• Fenofibrate interferes the least with statin uptake/metabolism and should be
preferred for combining with them.
• Adverse effects:
– Headache, dizziness, alteration of taste, insomnia, abdominal cramping and
photosensitivity .Rise in serum transaminase can occur, but liver damage is rare.
Monitoring of liver function is recommended.
• May cause myalgias, leg ache, and muscle weakness.
• Few fatalities due to rhabdomyolysis are on record.
• Contraindicated during pregancy 42DR.R.Lavanya,Faculty of Pharmacy

Uses:
Adjunct to dietary treatment to decrease total serum and LDL
cholesterol
Statins are the first choice drugs for primary hyperlipidaemias
with raised LDL and total CH levels, with or without raised TG
levels (Type IIa, IIb, V), as well as for secondary (diabetes,
nephrotic syndrome) hypercholesterolaemia
The initial dose of selected statin should aim to bring down the
LDL-CH to the target level. It should then be adjusted by LDL-
CH measurements every 3–4 weeks.
They are the first choice drugs for dyslipidaemia in diabetics

These are basic ion exchange resins supplied in the chloride form.
Cholestyramine
Colestipol
Colesevelam
They are neither digested nor absorbed in the gut: bind bile acids
(Bileacids are necessary for absorption of cholesterol ) in the intestine
interrupting their enterohepatic circulation
MOA—bind bile salts and cholesterol in the GI tract, form insoluble
complex results in preventing absorption of both from small intestine.
Faecal excretion of bile salts and CH (which is absorbed with the help of
bile salts) is increased.
This indirectly leads to enhanced hepatic metabolism of CH to bile acids.
More LDL receptors are expressed on liver cells (to obtain more
cholesterol ): clearance of plasma IDL, LDL (as more cholesterol is
delivered to the liver) and indirectly that of VLDL is increased.
Bile acid binding resins

Bile acid binding resins
Adverse effects
• GI side effects, constipation and fecal impaction, which can be
prevented by increased water consumption, anal irritation and
skin rash, intestinal obstruction.
• Bind to digoxin, warfarin, thyroxin; take resins 2 h before or
after taking other medicines
Uses
• Hyperlipidemia
• Resins have been shown to retard atherosclerosis, but are not
popular clinically because they are unpalatable, inconvenient,
have to be taken in large doses, cause flatulence and other g.i.
symptoms, interfere with absorption of many drugs and have
poor patient acceptability.

Lipoprotein-lipase Activators (Fibric Acid Derivatives
(Fibrates))• Gemfibrozil
• Bezafibrate
• Fenofibrate
• Ciprofibrate
• The fibrates, (isobutyric acid derivatives) primarily activate lipoprotein
lipase is a key enzyme in the degradation of VLDL resulting in lowering of
circulating TGs.
• This effect is exerted through peroxisome proliferator-activated receptor α
(PPARα) that is a gene transcription regulating receptor expressed in liver,
fat and muscles.
• Activation of PPARα enhances lipoprotein lipase synthesis and fatty acid
oxidation.
• PPARα may also mediate enhanced LDL receptor expression in liver seen
particularly with second generation fibrates like bezafibrate, fenofibrate.
Fibrates decrease hepatic TG synthesis as well.
• A peripheral effect reducing circulating free fatty acids has also been
shown.

Lipoprotein-lipase Activators (Fibrates)
• They primarily lower TG levels by 20–50%, generally accompanied
by 10–15% decrease in LDL-CH and a 10–15% increase in HDL-
CH.
• In some patients with hypertriglyceridaemia LDL-CH may rise,
partly because of inability of LDL receptor to clear the excess
number of LDL particles generated by enhanced VLDL catabolism.
• The increase in HDL-CH is at least in part due to transfer of surface
lipid components from catabolized VLDL to HDL, and partly due to
increased production of HDL apoproteins (apo A-I, apo A-II) by
liver.
• Gemfibrozil and bezafibrate have been shown to shift small dense
LDL particles (believed to be more atherogenic) to larger less dense
particles.

Fibric Acid Derivatives (Fibrates)
• Gemfibrozil:
– MOA—Reduce the synthesis of triglycerides by inhibiting the breakdown
of fat into triglycerides, and limits liver production of triglycerides
– Decrease VLDL and LDL, Increase HDL
– Additional actions to decrease the level of clotting factor VII-phospholipid
complex and promotion of fibrinolysis have been observed, which may
contribute to the antiatherosclerotic effect.
– Uses: In a dose of 600 mg BD taken before meals, is a first line drug to
decrease high triglycerides. It is most effective in type III
hyperlipoproteinaemia
– absorbed orally, metabolized by glucuronidation , undergoes some
enterohepatic circulation, excreted in urine; elimination t½ is 1–2 hr.
– Side effects—epigastric distress, loose motions,skin rashes, body ache,
eosinophilia, impotence, headache and blurred vision.
– contraindicated during pregnancy.

Bezafibrate
second generation fibric acid derivative is an alternative to gemfibrozil in mixed
hyperlipidaemias (type III, IV and V) Also been indicated in hypercholesterolaemia
(type II) but inferior to statins and resins.
greater LDL-CH lowering action than gemfibrozil. Circulating fibrinogen and
glucose levels may decrease
side effects : g.i. upset, myalgia, rashes. Dose reduction is needed in elderly and in
renal insufficiency.
Action of oral anticoagulants may be enhanced.
In contrast to gemfibrozil, combination of bezafibrate with a statin does not increase
the incidence of rhabdomyolysis
Fenofibrate
2nd generation prodrug fibric acid derivative
greater HDL– CH raising and greater LDL-CH lowering action than other fibrates:
adjunctive drug in subjects with raised LDLCH levels in addition to raised TG levels.
t½ is 20 hr.
Adverse effects : myalgia, hepatitis, rashes. Cholelithiasis and rhabdomyolysis are
rare.
Fenofibrate appears to be the most suitable fibrate for combining with statins, because
statin metabolism is minimally affected and enhancement of statin. Myopathy risk is
lower.
Fibric Acid Derivatives (Fibrates)

Lipolysis and Triglyceride Synthesis Inhibitor
• Niacin (Nicotinic acid) ,B group vitamin in much higher doses reduces
plasma lipids. This is unrelated to its vitamin activity and not present in
nicotinamide.
• The most effective drug to raise HDL-CH (20–35%), at relatively lower
dose by decreasing rate of HDL destruction.
• MOA— binds to a cell surface Gi-protein coupled receptor which
negatively regulates adipocyte adenylyl cyclase .
• inhibit lipolysis in adipose tissue by decreasing hormone stimulated
intracellular cAMP formation through this receptor and increases the
activity of lipoprotein lipase that clears TGs
• Hepatic VLDL production is decreased by inhibiting TG synthesis
(inhibits triglyceride lipase ) and due to reduced flow of fatty acids from
adipose tissue to liver –thereby VLDL degradation products IDL and LDL
are also reduced.
• It also reduces lipoprotein Lp (a), which is considered more atherogenic

Vitamin B3 Niacin
• Requires higher doses and poorly tolerated than when used as a vitamin
• Side effect
cutaneous vasodilator: marked flushing, heat and itching (especially in
the blush area) occur after every dose. (associated with release of PGD2 in the
skin)- minimized by starting with a low dose taken with meals and gradually
increasing as tolerance develops.
Use of sustained release (SR/ ER) tablet also subdues flushing. Aspirin taken
before niacin substantially attenuates flushing by inhibiting PG synthesis.
Laropiprant is a specific antiflushing drug with no hypolipidaemic action
combined with nicotinic acid to minimize flushing.
(ER tablet containing 1.0 g nicotinic acid and 20 mg laropiprant is used in UK
and Europe.)
Dyspepsia , vomiting and diarrhoea occur when full doses are given.
Peptic ulcer may be activated. Dryness and hyperpigmentation of skin
• long-term effects are:
Liver dysfunction and jaundice. Serious liver damage is the most important
risk. Hyperglycaemia, precipitation of diabetes (should not be used in
diabetics). Hyperuricaemia and gout, atrial arrhythmias. It is contraindicated
during pregnancy and in children.

Interaction
Postural hypotension when taken with antihypertensives .
Risk of myopathy due to statins is increased.
Use
• Wide spectrum hypolipidaemic drug, highly efficacious in
hypertriglyceridaemia (type III, IV, V) whether associated with raised CH
level or not.
• Effective drug to lower VLDL,TG levels and raise HDL levels.
• Adjunctive drug to statins/fibrates.
• Control pancreatitis associated with severe hypertriglyceridaemia, (genetic
type IV and V disorders).Prevents further attacks on long term use.
• Long-term use reduce recurrences of MI and overall mortality in post-MI
patients
• However, doses above 2 g/day are poorly tolerated; should seldom be
exceeded for maintenance purposes.
• Restricted to high risk cases because of potential toxicity
Vitamin B3 Niacin

Intestinal Cholesterol Absorption Inhibitors (or) Sterol
Absorption Inhibitor
• Ezetimibe- a novel drug that acts by inhibiting intestinal absorption of
cholesterol and phytosterols.
• It interferes with a specific CH transport protein NPC1L1 in the intestinal
mucosa and reduces absorption of both dietary and biliary CH. --
compensatory increase in hepatic CH synthesis, but LDL-CH level is
lowered by 15–20%.
• The enhanced CH synthesis can be blocked by statins, and the two drugs
have synergistic LDL-CH lowering effect. It is a weak
hypocholesterolaemic drug with 15–20% reduction of LDL-CH and can be
used when statins are contraindicated/not tolerated. Mainly used to
supplement statins without increasing their dose.
• The combination of ezetimibe + low dose of a statin is effective in
lowering LDL-CH as high dose of statin alone. Upto 60% decrease has
been obtained with a combination of simvastatin + ezetimibe.
• statin + niacin has cause greater reduction in IMT of carotid than statin +
ezetimibe.

Ezetimibe
• Poor aqueous soluble, and is not absorbed as such. Absorbed
after getting conjugated with glucuronic acid in the intestinal
mucosa.
• Secreted in bile and undergoes enterohepatic circulation
• Excreted in faeces. Plasma t½ - 22 hours
• Adverse effect: reversible hepatic dysfunction and rarely
myositis has been noted

CETP-Inhibitors
• The Cholesteryl ester transfer protein (CETP) facilitates
exchange of CHEs with TGs between HDL particles and
chylomicrons, VLDL, LDL, etc.
• It plays an important role in the disposal of HDL-associated
CH.
• Inhibitors of this protein, Torcetrapib, Anacetrapib -
markedly raise HDLCH and lower LDL.
• They have antiatherosclerotic action.
• However, torcetrapib was found to increase cardiovascular
events like angina, MI, heart failure and death. Further
development of the drug was stopped in 2007.
• Whether other CETP inhibitors will have therapeutic value
is being investigated, but appears doubtful.

PCSK9 Inhibitors
• Evolocumab,Alirocumab
• They are monoclonal antibodies that inactivate proprotein convertase
subtilsin-kexin type 9 (PCSK9).
• They target and inactivate proprotein convertase subtilsin-kexin type 9
(PCSK9), a hepatic protease that attaches and internalizes LDL receptors
into lysosomes hence promoting their destruction.
• By preventing LDL receptor destruction, LDL-C levels can be lowered
50%-60%
Mechanism and role of PCK9 in low-density lipoprotein-cholesterol metabolism. LDL: Low-density lipoprotein.
World J Cardiol. 2017 Feb 26; 9(2): 76–91.

Miscellaneous: Gugulipid and fish oil
derivatives
• Consists of Z and E gugulsterone
• Inhibit cholestrol biosynthesis and also enhance rate
of cholesterol excretion
• Dose 25 mg 3 times a day
• Reduced total CH, LDL-CH with an elevation of
HDL-CH
• It is well tolerated, no side effect, except loose stool

Fish oil derivative
• Omega-3-fatty acids
• Eicosa-pentanoic and docosa-hexanoic acid
• Prophylaxis use in high risk patient of CAD
• Usually formulated with vit.E

Combination drug therapy
• Bile acid binding resins+Fibrates
• Bile acid binding resins+Niacin
• Bile acid binding resins+Statins
• Bile acid binding resins+Niacin+ Statins
• Niacin+Statin (Atorva 10+ Nia 500)
• Statins+Ezetimibe
• Statins+Fibrate

61
Sites and mechanism of drugs for hyperlipidemia

Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drugs affecting lipoprotein
metabolism. C, cholesterol; CETP, cholesteryl ester transport protein; HDL, high-density lipoprotein; HMG-CoA
reductase, 3-hydroxy-3- methylglutaryl-coenzyme A reductase; LDL, low-density lipoprotein; MVA, mevalonate;
NPC1L1, a cholesterol transporter in the brush border of enterocytes; VLDL, very-low-density lipoprotein.

Medications for Hyperlipidemia
Drug Class Agents Effects (% change) Side Effects
HMG CoA reductase
inhibitors
Lovastatin
Pravastatin
LDL (18-55), HDL (5-15)
 Triglycerides (7-30)
Myopathy, increased liver
enzymes
Cholesterol absorption
inhibitor
Ezetimibe  LDL( 14-18),  HDL (1-3)
Triglyceride (2)
Headache, GI distress
Nicotinic Acid LDL (15-30),  HDL (15-35)
 Triglyceride (20-50)
Flushing, Hyperglycemia,
Hyperuricemia, GI distress,
hepatotoxicity
Fibric Acids Gemfibrozil
Fenofibrate
LDL (5-20), HDL (10-20)
Triglyceride (20-50)
Dyspepsia, gallstones,
myopathy
Bile Acid sequestrants Cholestyramine  LDL
 HDL
No change in triglycerides
GI distress, constipation,
decreased absorption of other
drugs

64
Hypolipidemic Drugs

65
Drug Interactions

References:
1.Essentials of Medical Pharmacology, 7th Edition, KD Tripathi
2.Rang and Dale’s Pharmacology , 7th Edition, H.P.Rang ,M.M.Dale

Thank you

Antihyperlipidemic drugs

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Antihyperlipidemic drugs

Similar to Antihyperlipidemic drugs (20)

More from lavenyaramamoorthi

More from lavenyaramamoorthi (7)

Recently uploaded

Recently uploaded (20)

Antihyperlipidemic drugs