Lipid metabolism and

Hypolipidemic drugs

Dr Urmila M. Aswar,

Sinhgad Institute of Pharmacy, Narhe, Pune -41

LIPIDS

• Esters of fatty acids and alcohols.

• Insoluble in water

• Saturated: lauric acid, palmitic acid, eg

DALDA, increase LDL

• Monounsaturated: oleic acid

• Polyunsaturated fatty acids: arachidonic

acid, abundant in corn oil, hypolipedemic.

• Trans fatty acid: harmful, increase LDL

Cont..

• Triglycerides (TG):

• Cholesterol (CH):

• LIPOPROTEINS: They are spherical

particles that transport neutral lipids that is

TG and CH in blood.

• Structure: Core-TG and CE, hydrophilic

surface -PL, unestrified CH and

Apoprotein

TG

• Over 93% of the fat that is consumed in

the diet is in the form of triglycerides (TG).

CH

• Dietary intake supplies only about 20 –

25% of the cholesterol needed everyday to

build cell membranes,

• synthesize bile acids/salts,

• synthesize hormones of the adrenal

glands (aldosterone, cortisol)

• and synthesize the sex hormones.

• The other 75 – 80%

of our daily need for

cholesterol is

synthesized in the

liver.

LIPOPROTEIN• Apolipoprotein: a protein that

binds to lipids

• cholesteryl ester: a

compound of cholesterol and a

fatty acid

• Triglyceride: a compound of

glycerol and three fatty acids,

an ordinary fat molecule

• Phospholipid: a compound of

glycerol, two fatty acids, and

choline phospate,

an emulsifier like lecithin

Types of LP

• Chylomicrons,

• VLDL,

• LDL,

• HDL

Density:HDL>LP(a)>LDL>IDL>VLDL>CM

DM:CM>VLDL>IDL>LDL>LP(a)>HDL

TG:CM>VLDL>IDL>LDL>LP(a)=HDL

CE:LP (a)= LDL>IDL>HDL>VLDL>CM

ATHEROGENOCITY:

LP(a)>LDL>IDL>VLDL=CM

HDL is antiatherosclerotic

Apoproteins

• These are surface proteins on LP

• Gives structural stability

• They help in metabolism/ Fate of LP.

• There are 9 types

• APO AP-I, AP-II, AP-IV

• APO B-48, APO B-100

• APO C-I, APO C-II, APO C-III

• APO E

Normal lipid metabolism:

Endogenous Pathway

VLDL

• Dietary TGs are packaged by the liver into

a lipoprotein known as very low density

lipoprotein (VLDL).

• This lipoprotein delivers the TG to adipose

tissue to be stored.

• The primary function of low density

lipoprotein (LDL) is the transport of the

cholesterol synthesized in the liver to the

periphery.

• As it travels through the circulation LDL

reacts with LDL receptors on various

nonhepatic cells.

• Dietary saturated fat in particular is one of

the primary dietary determinants of

hypercholesterolemia, as demonstrated by

numerous studies.

• These studies illustrate the importance of

substituting unsaturated fat for saturated

fat in the diet.

• Saturated fats raise LDL cholesterol by

decreasing the synthesis of LDL

receptors,

• Genetic effects involves dysfunction of

LDL receptors or mutation of LDL

receptors or absence of LDL receptors

• The overall results is cholesterol is not

removed from the circulation. LDL

cholesterol that does not react with a LDL

receptor continues to circulate.

Why LDL is BAD and HDL is

good• LDL’s are usually not particularly atherogenic

• LDL gets damaged and oxidised by smoking & other

factors producing free radicals

• Damaged LDL is recognised by the scavenger

receptor on macrophages & is engulfed by them

• Because the LDL is damaged & oxidised it causes

the macrophage to become poisoned & die.

• They then transform into a foam cell – which is the start

of the atherosclerosis process

• HDL can do some repair of LDL’s to make them less

damaged & less toxic to macrophages

• The oxidation of LDL is an important step in

atherogenesis as it activates further immune and

inflammatory responses (i.e. entry of monocytes

across endothelium).

• These LDL foam cells accumulate in

significant amounts, forming lesions called

fatty streaks. Once formed, fatty streaks

produce more toxic oxygen radicals and

cause immunologic and inflammatory

changes (production of more cytokines)

resulting in progressive damage to the

vessel wall.

HDL – a good cholesterol

• Nascent HDL takes CH from Foam cells

and periphery. CH is converted into CE by

LCAT(lecithin cholesterol acyl

transferase). The CE of HDL is

transported to VLDL, LDL, IDL by

CETP(cholesteryl ester transfer protein)

which further goes to liver via LDR

receptor: Reverse cholesterol transfer

Hyperlipedaemia

• Primary: genetic

• Secondary: associated with some disease,

diabetes, myxoedema, nephrotic

syndrome, chronic alcoholism.

• Till 30 yrs possibility of coronary artery

disease is less.

• Later yrs, appearance of angina, coronary

thrombosis and/or sudden death can

happen.

Factors causing CAD

• Age

• Obesity

• Menopause

• Hyperlipidemia,

• hypertension,

• Smoking,

• Diabetes

• Sedentary lifestyle

WHY hyperlipedaemia occurs

• The reason for this is that research from

experimental animals, laboratory

investigations, epidemiology and genetic

forms of hypercholesterolemia indicate

that elevated LDL cholesterol is a major

cause of CAD and that clinical trials

show that LDL-lowering therapy reduces

the risk for CAD.

Pharmacotherapy of

hyperlipidaemias• Healthy Diet

• HMG-CoA reductase inhibitors: Statins

• Bile acid binding agents: Cholestyramine,

colestipol

• Fibric acid derivatives: Clofibrate,

Gemfibrozil, Benzafiberate

• Inhibitors of absorption of cholesterol:

Stanol esters, Eztimibe

1. HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitors, or

statins are a class of hypolipidemic agents

that are competitive inhibitors of HMG-

CoA reductase. They inhibit conversion of

HMG-CoA to mevalonic acid and deplete

intracellular supply of CH.

• Liver compensate this biosynthesis and

take up CH from blood and by increasing

the no of LDR on liver.

• They are considered to be the most potent

cholesterol-lowering agents, lowering

LDL-cholesterol between 20–60%.

• They also increase the uptake of VLDL

and IDL remenants.

• Disadvantages: After prolong use only

LDL reduction happens by 6% even after

doubling the dose.

• Ceiling dose effect: induction of HMG-CoA

reductase- More synthsis of CH. This

decreases LDR further.

Lovastatin (Mevacor, Altocor) Merck

• Lovastatin was the first statin approved by

the FDA (August 1987).

• The dosage is 20-80 mg and should be

taken in the evening with food.

• Shows 25-40% reduction in LDL.

Simvastatin (Zocor) Merck

• Simvastin was approved in the late 1980’s.

• The dosage is 20-80 mg and should be

taken in the evening.

• Shows 35-50% reduction in LDL.

• Simvastatin is highly lipophilic, and there

tends to be more insomnia with the

lipophilic statins (unknown mechanism).

•

Pravastatin (Pravachol) Bristol Meyer

Squibb

• Pravastatin was “discovered” in Japan in

1979, produced by a chemical modification

of lovastatin. In terms of clinical trials,

pravastatin is the most studied statin.The

dosage is 20-80 mg and should be taken

in the evening, with or without food.

Pravastatin is less lipophilic than

simvastatin and is also less likely to cause

insomnia.

• 20-35% reduction in LDL

Atorvastatin (Lipitor) Pfizer

• Atorvastatin received FDA approval in

1997 and by 2004 was the best selling

drug in the world with sales of $10.9

billion.

• The dosage is 10-80 mg.

• Shows 35-60% reduction in LDL

• One of the advantages of Lipitor is that it

can be taken with or without food at any

time of the day.

Adverse effects of statins elevated liver

enzymes

1-2% can have liver disease. Within 6

weeks of the onset of statin therapy the

patient should have a blood test to

determine the concentration of the liver

enzymes aspartate aminotransferase, AST

(normal concentration is 0 – 35 U/L) and

alanine transaminase, ALT(normal

concentration is 4 – 36 U/L).

• Of these, the AST test is the most

sensitive marker of the impact of statin

therapy. If it is elevated more than 2-3

times the upper limit of normal, therapy

should be terminated.

• A fatty liver is the most common cause of

elevated AST and ALT in patients on statin

therapy.

Muscle pain

• The most commonly reported adverse

effect with statin use is muscle pain. There

is a serious, but rare complication

associated with the breakdown of muscle

proteins called rhabdomyolysis. These

muscle proteins, especially myoglobin, are

released into the circulation, and result in

the potentially life-threatening

complications of myoglobinuric acute renal

failure and cardiac arrest.

• The most common

symptoms of

rhabdomyolysis

include: dark urine,

swollen, tender

muscles of the thighs

and lower back.

• Creatine phosphokinase (CPK) elevation

is one of the most important diagnostic

criteria of rhabdomyolysis. A value above

the upper limit of normal (range of 30 –

200 U/ L), indicates a problem.

GI problems

• Common GI problems with statin therapy,

which generally resolve within a couple of

weeks of initiating therapy include:

nausea, diarrhea, constipation, excessive

flatulence.

• Other effects: Headache, dizziness, taste

alterations, insomnia, and photosensitivity

are other reported effects.

II. Bile acid binding resins or Bile acid

sequestrants

Bile acid sequestrants are a group of

medications which bind bile in the GI tract.

By binding bile they prevent its

reabsorption, increasing its removal. As

the body loses bile acids, it converts

cholesterol into bile acids, thus lowering

serum cholesterol levels. It reults in

upregulation of LDL receptors and thus

decreases LDL in serum.

• Use of these agents has declined since

the introduction of the statins. They require

very large doses and need to be taken

with lots of water. They are most often

used as an adjunct to statins.

• lowering of LDL (generally, no more than

20%) and a very slight elevation of HDL is

seen with in 2-3 weeks.

•

Cholestyramine

• This is the major drug in this class.

• The usual dosage of this powder is 4 - 6 g,

mixed with a liquid, twice a day before

meals.

• No more than 24 g/day

Colesevelam

• The dosage is three 625 mg tablets, twice

daily, so 6 tablets/day.

Colestipol

• Dosage, if granules is 5 g, one or two

times daily

• Tablets, 2 – 4 g/day, tablets are 1 g each.

Adverse effects of the bile acid

sequestrants

• These adverse effects are generally GI

related and usually dissipate within a

couple of weeks. They include: nausea,

vomiting, heartburn, bloating, constipation

(most common), flatulence, fecal

impaction, fatty or black stools, and

intestinal obstruction (most severe).

•

• Transient increases in AST, ALT and

alkaline phosphatase have been observed

in patients on Colestipol.

III. Cholesterol absorption inhibitors

• CH comes from diet and hepatic secretion.

These drugs block dietary absorption of

dietary cholesterol in the small intestine,

this results in uptake of LDL and hence

reduces LDL cholesterol levels. Plant

stanol esters and Ezetimibe are used for

this.

Ezetimibe

• A cholesterol inhibitor,

Ezetimibe (Dose: 10 mg)

alone generally reduce

LDL between 10 – 20%.

• Adverse effects include:

fatigue, coughing, nausea,

diarrhea, rash, pancreatitis

and angioedema.

Fibrates

• The primary actions of this class of drugs

is to lower triglyceride levels.

• This occurs through stimulation of

lipoprotein lipase (which hydrolyzes

triglycerides) and by suppression of

apoprotein C-III production (this is the

protein component of VLDL, the primary

carrier of triglycerides from the liver to

other tissues).

• These drugs were first introduced in 1962

and were widely used before the discovery

of the statins.

a. gemfibrozil (Lopid)

• Dosage is 600 mg, bid at least 30 minutes

before eating

b. fenofibrate (Antara, Lofibra,

Tricor, Triglide)

• Antara dosage is 43 – 130 mg/day

• Lofibra dosage is 67 – 200 mg/day

• Tricor dosage is 48 – 145 mg/day

• Triglide dosage is 50 – 160 mg/day

adverse effects of fibrates

• These include GI disturbances (nausea,

vomiting, diarrhea, flatulence).

• In addition, dizziness, blurred vision,

muscle pain and weakness have been

reported.

• Some patients taking gemfibrozil have

reported gallstone formation.

• Combination therapy of gemfibrozil and a

statin may be associated with an

increased risk of rhabdomyolisis,

according to the Committee on Safety of

Medicines.

• Fenofibrate may be given with a statin, but

only if statin monotherapy is insufficient

(very high LDL AND very high

triglycerides).

• Dosage: 100 – 500 mg/day, increase up to

1 – 2 g tid