Hypolipidemic Drugs Pharmd

HYPOLIPIDAEMIC DRUGS
Donatus Adongo
Department of Pharmacology, UHAS
donatusadongo@yahoo.com
dadongo@uhas.edu.gh
1
Objectives
On completion of this topic, students will be able to:
• Discuss the relevant hypotheses regarding the etiology of hyperlipidemias

• Describe the actions of each drug class on serum lipids, and compare and
contrast the mechanism of each of these actions.
• Characterize these agents according to their action to reduce lipid
synthesis or enhance removal.
• Discuss the advantages of combinations of agents in the management of
hyperlipidemia.
2
Lipids
• Molecules with very diverse chemical structures and

functions but are related by a common property: their
relative insolubility in water.
• Fatty acids and triacylglycerols

• Glycerophospholipids and sphingolipids
• Eicosanoids
• Cholesterol, bile salts, and steroid hormones
• Fat-soluble vitamins
3
Lipoproteins
• Transport of lipids
• Triacylglycerols (TG)
• Phospholipids (PL)
• Cholesterol (C) &
cholesterol esters (CE)
4
Lipoproteins - Classes
• Classified based on
physicochemical properties
• Density after separation in an
ultracentrifuge
• Chylomicrons
• Very low density (pre-b)
lipoprotein (VLDL)
• Low density (b-) lipoprotein (LDL)
• High density (a-) lipoproteins
(HDL)
5
Classification & characteristics
6
Classification & characteristics
7
LDL
• “Bad” cholesterol
• Major cholesterol carrier in the blood
• High levels cause slow build up of plaques in the walls of the
arteries
• A blood clot may form in the area of a plaque and block the flow
of blood causing a heart attack or stroke
8
HDL
• “Good” cholesterol
• Carries cholesterol away from the arteries and back to the
liver (reverse cholesterol transport)
• May remove excess cholesterol from fatty plaques and slow
their growth
• Antiatherogenic
• High levels of HDL appear to protect against heart attack
• Low HDL indicates a greater risk for heart attack
9
Dyslipidaemia
• One or more abnormalities of blood lipids
• Primary – genetically determined
• Secondary
• Complications of generalized metabolic disturbance
e.g. diabetes, hypothyroidism, alcoholism
Hyperlipidaemia
• Hyperlipoproteinaemia
• Elevated lipoprotein levels in the plasma
10
Classification of Primary
hyperlipoproteinaemias: Frederickson/WHO
11
Therapeutic strategies
•Diet
•Elimination of
aggravating
factors
•Drugs
12
Diet
• Ingestion of saturated fats and cholesterol  suppression of LDL receptors
retarding clearance and plasma LDL
▪ Avoid
▪ Meat (especially organ meat and obvious fat)
▪ Egg yolk
▪ Whole milk
▪ Creams
▪ Butter
▪ Cheeses
• Replace with foods low in saturated fats and cholesterol

• Vegetables, fish and poultry?
• Vegetable oils
• Corn, olive, sunflower, etc; not palm or coconut
13
Diet
• Omega-3 fatty acids found in fish oils—but not those from plant sources—
can induce profound lowering of triglycerides.
• In contrast, the omega-6 fatty acids present in vegetable oils may cause
triglycerides to increase.
Antioxidants
• Ascorbic acid and mixed natural tocopherols
• Other naturally occurring antioxidants such as resveratrol, b-catechin,
selenium, and various carotenoids found in a variety of fruits and
vegetables.
14
Lipid Lowering Agents
• HMG-CoA reductase inhibitors (statins)
• Bile-acid binding resins

• Cholestyramine, Colestipol
• Niacin (nicotinic acid)

• Long acting or sustained release forms
• Fibric Acid derivatives

• Gemfibrozil and Fenofibrate
• Ezetimibe
15
STATINS
16
Mechanism of Action
• Analogs of 3-hydroxy-3-methylglutarate
• Compete to inhibit HMG-CoA reductase, rate limiting enzyme in the de novo

synthesis of cholesterol
• ↓ hepatic cholesterol synthesis
• Compensatory increases in numbers of cell-surface LDL receptors
• ↑ LDL & LDL precursors (VLDL and IDL) clearance from plasma into liver cells
• reduction in hepatic VLDL production
• Primary site of action is the liver
• Small decreases in plasma TGs; slight increase in HDL

17
Mechanism of Action of Statins
18
Clinical uses
▪Treatment of elevated LDL plasma levels:-- monotherapy or
with bile acid-binding resins/ezetimibe or niacin
▪ 2º prevention of MI & stroke – symptomatic atherosclerosis disease (e.g.
angina, MI or stroke).
▪ 1º prevention of arterial disease in high risk pts --↑ Ch.
▪Children: only use in children with
▪ heterozygous familial hypercholesterolaemia
▪Statins with t1/2 ≤4 hours (all but atorvastatin and rosuvastatin)
should be taken in the evening.
Adverse effects
▪ Hepatotoxicity -- increased liver enzymes
▪ Myopathy & Rhabdomyolysis
▪ Mild gastrointestinal disturbances
19
BILE ACID-BINDING
RESINS
20
Mechanism
• prevent reabsorption of bile acids by binding
to them in the intestine
• Bile acids (cholesterol metabolites): 95%

reabsorbed in the jejunum and ileum
• In the presence of binding resins: excretion increases
up to 10X
• Increased bile acid clearance causes increased
conversion of cholesterol to bile
• Increased uptake of LDL and IDL from plasma

results from up-regulation of LDL receptors,
particularly in liver
21
Bile Acid-binding Resins
• Major actions
• Reduce LDL-C 15–30 %
• Raise HDL-C 3–5 %
• May increase TG
• Clinical uses
• Primary hypercholesterolaemia
• To reduce pruritus in patients with cholestasis and bile
salt accumulation
22
Adverse effects
▪Most common:
▪ Constipation, nausea, flatulence
▪ bloating {managed by increasing dietary fiber or adding
psyllium seed to the resin preparation}.
▪ Drug-Drug Interactions:-- reduced absorption of other

drugs (eg, thiazide diuretics, furosemide, digoxin, warfarin,
pravastatin, fluvastatin) & fat-soluble vitamins (A, D, E & K).
23
NIACIN (NICOTINIC ACID)
24
Mechanism(s) of action
▪ In adipose tissue, niacin inhibits the

lipolysis of TG by hormone-sensitive
lipase
▪ In liver, reduces TG synthesis &
inhibits hepatic VLDL secretion which
decreases LDL production
▪ Increased VLDL clearance (enhances
LPL activity)
▪ Decreased HDL catabolism
(increasing HDL cholesterol plasma
levels)
25
Clinical uses
▪Wide clinical usefulness in the treatment of

hypercholesterolaemia, hypertriglyceridaemia, and low
levels of HDL cholesterol.
▪Normally as adjunct to a statin and diet.
26
Adverse effects
▪ Intense cutaneous FLUSH

▪ aspirin pre-treatment (30 minutes before dosing) reduces this effect
{prostaglandin-mediated}
▪ Ibuprofen (once daily) alleviates this effect also
▪ laropiprant (a PGD2 antagonist)
▪ Hepatoxicity – elevated serum transaminases

▪ Pruritus
• Hyperuricaemia (gout may occur; allopurinol may be given with
niacin to manage hyperuricaemia).
• Hypotension, especially in patients receiving antihypertensive
medication.
• Avoid niacin in patients with severe peptic disease.
27
FIBRIC ACID
DERIVATIVES
28
Mechanism
• PPARα receptors
• Ligand-activated transcription factor (natural
ligands- FAs, eicosanoids or hypolipidemic drug)
•  triacylglycerol by increasing expression

of lipoprotein lipase
• Increase HDL by increasing concentration of
apo A-I and apo-A-II
•  apo C-III
• ↑ oxidation of FAs in liver & striated muscle
•  intracellular lipolysis in adipose tissue

Fibrates
• Major actions
• Lower LDL-C 5–20%
• Lower TG’s 20–50%
• Raise HDL-C 10–20%
Clinical uses
• Hypertriglyceridaemia -- (VLDL predominates)
• Useful for treating the hypertriglyceridaemia that
results from treatment with viral protease inhibitors
30
Adverse effects
• Gastrointestinal disturbances -- nausea
• Predisposes to gallstones (esp. clofibrate)
• Myositis (inflammation of a voluntary muscle)
• Myopathy
• Minor increases in liver transaminases and alkaline
phosphatase.
Contraindications
• Avoid in patients with hepatic or renal dysfunction
• Patients with preexisting gallbladder disease
31
EZETIMIBE
32
Ezetimibe
• A cholesterol absorption inhibitor.
• It inhibits luminal cholesterol (and of plant stanols) uptake by jejunal

enterocytes, by blocking the transport protein NPC1L1.
▪ Lowers total and LDL-C levels; lowers LDL-C levels by ~20%.
▪  incorporation of cholesterol into chylomicrons.
▪  LDL receptor expression which enhances LDL-C clearance from the

plasma.
• used as an adjunct to diet and statins in hypercholesterolemia.
• Does not affect the absorption of fat-soluble vitamins, triglycerides

or bile acids.
33
Pharmacokinetics & toxicity
▪Bile-acid sequestrants inhibit absorption of ezetimibe.
▪Contraindicated for women who are breastfeeding.
▪It is generally well tolerated but can cause diarrhoea,

abdominal pain or headache; rash and angioedema have
been reported.
34
35
Actions of antihyperlipidermic drugs
36
Drug Summary Table: Treatment of
Hyperlipidaemias
37
QUESTIONS???
• Which one of the following drugs decreases de novo cholesterol synthesis by
inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase?
• A. Fenofibrate.
• B. Niacin.
• C. Cholestyramine.
• D. Lovastatin.
• E. Gemfibrozil.
• Which one of the following drugs binds bile acids in the intestine, thus
preventing their return to the liver via the enterohepatic circulation?
• A. Niacin.
• B. Fenofibrate.
• C. Cholestyramine.
• D. Fluvastatin.
• E. Lovastatin.
38

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HYPOLIPIDAEMIC DRUGS

On completion of this topic, students will be able to:

• Discuss the relevant hypotheses regarding the etiology of hyperlipidemias

• Molecules with very diverse chemical structures and

• Fatty acids and triacylglycerols

• Replace with foods low in saturated fats and cholesterol

• Bile-acid binding resins

• Niacin (nicotinic acid)

• Fibric Acid derivatives

• Compete to inhibit HMG-CoA reductase, rate limiting enzyme in the de novo

• Primary site of action is the liver

• Small decreases in plasma TGs; slight increase in HDL

• Bile acids (cholesterol metabolites): 95%

• Increased uptake of LDL and IDL from plasma

▪ Drug-Drug Interactions:-- reduced absorption of other

▪ In adipose tissue, niacin inhibits the

▪Wide clinical usefulness in the treatment of

▪Normally as adjunct to a statin and diet.

▪ Intense cutaneous FLUSH

▪ Hepatoxicity – elevated serum transaminases

•  triacylglycerol by increasing expression

•  intracellular lipolysis in adipose tissue

• It inhibits luminal cholesterol (and of plant stanols) uptake by jejunal

▪ Lowers total and LDL-C levels; lowers LDL-C levels by ~20%.

▪  incorporation of cholesterol into chylomicrons.

▪  LDL receptor expression which enhances LDL-C clearance from the

• used as an adjunct to diet and statins in hypercholesterolemia.

• Does not affect the absorption of fat-soluble vitamins, triglycerides

▪Bile-acid sequestrants inhibit absorption of ezetimibe.

▪Contraindicated for women who are breastfeeding.

▪It is generally well tolerated but can cause diarrhoea,

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