11

ANTIHYPERLIPIDEMICANTIHYPERLIPIDEMICSS

Prof. Dr. Shah MuradProf. Dr. Shah Murad

shahmurad655@yahoo.comshahmurad655@yahoo.com

22

As if we didn't have enough cholesterol As if we didn't have enough cholesterol in our diet, our liver actually makes the in our diet, our liver actually makes the stuff! stuff!

Our body uses cholesterol for building Our body uses cholesterol for building cellular structures and making steroid cellular structures and making steroid hormones. hormones.

33

>>>>>>> But, with high fat diets, we get >>>>>>> But, with high fat diets, we get way more than we need. way more than we need.

The extra cholesterol gets stuck to the The extra cholesterol gets stuck to the walls of our blood vessels and clogs them walls of our blood vessels and clogs them with disastrous effects to the heart and with disastrous effects to the heart and brain (heart attack and stroke). brain (heart attack and stroke).

44

If you can't bring down your If you can't bring down your cholesterol with diet and exercise, cholesterol with diet and exercise, you may need a prescription for one you may need a prescription for one of the HYPOLIPIDEMIC DRUGof the HYPOLIPIDEMIC DRUG

55

The most frequently prescribed drugs The most frequently prescribed drugs are generically called "statins", are generically called "statins", because their chemical names all because their chemical names all end with…..statin! They reduce the end with…..statin! They reduce the manufacture of cholesterol in our manufacture of cholesterol in our liver. liver.

66

There are also other drugs used to lower There are also other drugs used to lower cholesterol that work by different cholesterol that work by different mechanisms. mechanisms.

Niacin works indirectly to reduce total Niacin works indirectly to reduce total cholesterol by reducing the production of cholesterol by reducing the production of building blocks for low density lipoprotein, building blocks for low density lipoprotein, "bad" cholesterol, and increasing production "bad" cholesterol, and increasing production of high density lipoprotein, "good" of high density lipoprotein, "good" cholesterol.cholesterol.

77

HyperlipidemiaHyperlipidemia

        More than 650,000 people die More than 650,000 people die every year of coronary heart disease every year of coronary heart disease (CHD) in the US alone. (CHD) in the US alone.

88

In 1984 it was demonstrated for the first In 1984 it was demonstrated for the first time that there exists a link between time that there exists a link between serum cholesterol levels and risk to CHD. serum cholesterol levels and risk to CHD.

A 1% drop in serum cholesterol reduces A 1% drop in serum cholesterol reduces the risk for CHD by 2%. the risk for CHD by 2%.

99

Positive risk factors for CHD Positive risk factors for CHD include: include:

Age (men>45 yrs, women>55 yrs); Age (men>45 yrs, women>55 yrs); family history of premature CHD; family history of premature CHD; smoking; smoking; hypertension (>140/90 mm Hg); hypertension (>140/90 mm Hg); low HDL cholesterol (<35 mg/dl); low HDL cholesterol (<35 mg/dl); obesity (>30% overweight); obesity (>30% overweight); diabetes; and diabetes; and high LDL (>160 mg/dl). high LDL (>160 mg/dl). Negative risk factors include high Negative risk factors include high

HDL levels (>60 mg/dl). HDL levels (>60 mg/dl).

1010

1111

        The structure of The structure of ChCh suggests a highly suggests a highly non-polar nature indicating that it should non-polar nature indicating that it should be reasonably insoluble in aqueous be reasonably insoluble in aqueous solution. solution.

Thus we expect it to be not soluble in Thus we expect it to be not soluble in plasma. plasma.

Yet we see values as high as 250 mg per Yet we see values as high as 250 mg per deciliter which gives an amount of 2.5 g / deciliter which gives an amount of 2.5 g / L in plasma. How does this occur? L in plasma. How does this occur? 

1212

        This comes about because cholesterol This comes about because cholesterol does not occur alone in plasma. does not occur alone in plasma.

It is always associated with lipoproteins. It is always associated with lipoproteins.

Lipoproteins are proteins carrying lipids. Lipoproteins are proteins carrying lipids.

Cholesterol is one of the lipids. Cholesterol is one of the lipids.

1313

Long chain fatty acids are also carried by Long chain fatty acids are also carried by these lipoproteins in the form of these lipoproteins in the form of triglycerides (TG). triglycerides (TG).

Lipoproteins are actually aggregrates. Lipoproteins are actually aggregrates.

There are several forms of lipoproteins, very There are several forms of lipoproteins, very low density lipoproteins (VLDL), low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density density lipoproteins (LDL), and high density lipoproteins (HDL), depending on the density lipoproteins (HDL), depending on the density of their packing or alternatively their size of their packing or alternatively their size

1414

The term hyperlipidemia refers to the The term hyperlipidemia refers to the excessive lipid content in the blood excessive lipid content in the blood plasma. plasma.

A lipid profile of patient's blood plasma is A lipid profile of patient's blood plasma is the distribution in concentration of the distribution in concentration of various forms of lipoproteins various forms of lipoproteins

1515

(5) Types of (5) Types of hyperlipidemiahyperlipidemia

I (familial hypertriglyceridemia)I (familial hypertriglyceridemia) IIa (familial hyperlipidemia)IIa (familial hyperlipidemia) IIb (familial dysbetalipoproteinemia)IIb (familial dysbetalipoproteinemia) III (familial III (familial

hypoalphalipoproteinemia)hypoalphalipoproteinemia) IV (familal hypercholesterolemia)IV (familal hypercholesterolemia)

1616

Lipoprotein ParticlesLipoprotein Particles

                                triglyceridestriglycerides                                 phospholipidsphospholipids                                 cholesterolcholesterol                                 cholesterol esterscholesterol esters

1717

Chylomicrons (TG >> C, CEChylomicrons (TG >> C, CE ) ) VLDLVLDL (TG > CE ) (TG > CE ) IDLIDL (CE > TG ) (CE > TG ) LDLLDL (CE >> TG ) (CE >> TG ) HDLHDL (CE > TG ) (CE > TG )

1818

Mechanism of Lipid Mechanism of Lipid TransportTransport Dietary fat including cholesterol and Dietary fat including cholesterol and

triglycerides are absorbed in the intestine and triglycerides are absorbed in the intestine and released in the blood stream as chylomicrons. released in the blood stream as chylomicrons.

These are least dense particles having very These are least dense particles having very high proportion of triacylglycerides. high proportion of triacylglycerides.

Lipoprotein lipase acts on these particles to Lipoprotein lipase acts on these particles to release some free fatty acids that deposit in release some free fatty acids that deposit in adipose tissues adipose tissues

1919

The remnants of chylomicrons are picked The remnants of chylomicrons are picked up by the liver which has a receptor up by the liver which has a receptor specific to chylomicron remnants. specific to chylomicron remnants.

After further clean up liver releases After further clean up liver releases particles called the very low density particles called the very low density lipoproteins in the blood. lipoproteins in the blood.

These have lower triacyl glycerides than These have lower triacyl glycerides than chylomicrons. chylomicrons.

Once again LPL works on these VLDL Once again LPL works on these VLDL particles releasing more free fatty acids particles releasing more free fatty acids and changing the content of the particles and changing the content of the particles to IDL and LDL. to IDL and LDL.

2020

There are LDL receptors on the cell There are LDL receptors on the cell membranes of the extrahepatic cells which membranes of the extrahepatic cells which can pick up the LDL particles. can pick up the LDL particles.

This is how cholesterol reaches the interior This is how cholesterol reaches the interior of normal cells. of normal cells.

Within cells, LDL particles are repackaged. Within cells, LDL particles are repackaged.

Excess cholesterol is esterified and stored. Excess cholesterol is esterified and stored.

Excess cholesterol suppresses the Excess cholesterol suppresses the biosynthesis of LDL-receptors so that biosynthesis of LDL-receptors so that intake of cholesterol decreases. It also intake of cholesterol decreases. It also suppresses cholesterol biosynthesis. suppresses cholesterol biosynthesis.

2121

Repackaged LDL particles called HDL Repackaged LDL particles called HDL particles are then released into the blood particles are then released into the blood stream. stream.

These particles are sensed by the liver These particles are sensed by the liver through the HDL-receptors. Thus the liver through the HDL-receptors. Thus the liver gets constant information as to how much gets constant information as to how much LDL and HDL are present in the blood LDL and HDL are present in the blood

2222

2323

2424

StatinsStatins

Statins inhibit the rate-limiting step in the Statins inhibit the rate-limiting step in the biosynthesis of cholesterol - HMG -CoA biosynthesis of cholesterol - HMG -CoA reductase. reductase.

Decreased cholesterol biosynthesis steps up the Decreased cholesterol biosynthesis steps up the levels of the LDL-receptor resulting in the levels of the LDL-receptor resulting in the positive cycle for lowered cholesterol levels in positive cycle for lowered cholesterol levels in serum.serum.

For patients who have familial For patients who have familial hypercholesterolemia due to defective hypercholesterolemia due to defective LDL-receptor genes these drugs are LDL-receptor genes these drugs are not not effective.effective.

2525

Statins are most effective cholesterol Statins are most effective cholesterol lowering drugs. lowering drugs.

Statins lower total cholesterol and LDL Statins lower total cholesterol and LDL particles. particles.

These are competitive inhibitors. These are competitive inhibitors.

The HMG-CoA has a conformation similar to The HMG-CoA has a conformation similar to the lactone moiety of statins resulting in the lactone moiety of statins resulting in binding at the same site without any binding at the same site without any productive effect productive effect

2626

2727

All statins are highly protein bound (95-All statins are highly protein bound (95-98%) except for pravastatin (50%, due to 98%) except for pravastatin (50%, due to carboxylate moiety). carboxylate moiety).

Most statins have a short half-life of Most statins have a short half-life of about 1-3 hr except for atorvastatin about 1-3 hr except for atorvastatin which has a t1/2 of about 14 h. which has a t1/2 of about 14 h.

2828

A 15-30 point drop in LDL could be A 15-30 point drop in LDL could be reasonably expected with most statins reasonably expected with most statins after a therapy of about 1 month. after a therapy of about 1 month.

A combination therapy (with bile acid A combination therapy (with bile acid sequestering agents) is helpful for sequestering agents) is helpful for particularly difficult cases. particularly difficult cases.

2929

FibratesFibrates Gemfibrozil was introduced in 1981 and Gemfibrozil was introduced in 1981 and

remains the second most useful remains the second most useful antilipidemic agent. antilipidemic agent.

It primarily decreases serum triglycerides. It primarily decreases serum triglycerides.

Newer drugs including beclofibrates, Newer drugs including beclofibrates, ciprofibrates, fenofibrates,  are more ciprofibrates, fenofibrates,  are more effective in lowering serum LDL effective in lowering serum LDL cholesterol. cholesterol.

3030

However, the fibrates are almost However, the fibrates are almost never used alone. never used alone.

They are mostly used in combination They are mostly used in combination with bile acid sequestering agents. with bile acid sequestering agents. 

3131

3232

The antitriglycedemic effect of clofibrate in The antitriglycedemic effect of clofibrate in human is related to the increased human is related to the increased catabolism of serum TG-rich proteins (VLDL catabolism of serum TG-rich proteins (VLDL and VLDL remnants), but not to any effect and VLDL remnants), but not to any effect on hepatic TG or VLDL synthesis and on hepatic TG or VLDL synthesis and release from liver. release from liver.

The action of clofibrate is related to an The action of clofibrate is related to an increase in adipose tissue or muscle LPL increase in adipose tissue or muscle LPL activity which accelerates the rate of activity which accelerates the rate of intravascular catabolism of VLDL to IDL intravascular catabolism of VLDL to IDL and LDL.and LDL.

3333

Clofibrate is metabolized to Clofibrate is metabolized to chlorophenoxyisobutyric acid (CPIB) chlorophenoxyisobutyric acid (CPIB) which is the active form of the drug. which is the active form of the drug.

The drug is high protein bound with a The drug is high protein bound with a half-life of around 15 hrs. half-life of around 15 hrs. 

3434

Bile Acid Sequestering Bile Acid Sequestering (BAS) Agents(BAS) Agents

Colestipol and cholestyramine are anion Colestipol and cholestyramine are anion exchange resins that are approved in exchange resins that are approved in 1970s for the reduction of elevated 1970s for the reduction of elevated serum cholesterol in patients with serum cholesterol in patients with hypercholesterolemia. hypercholesterolemia.

These resins are water insoluble, inert to These resins are water insoluble, inert to digestive enzymes in the intestinal tract digestive enzymes in the intestinal tract and are not absorbed. and are not absorbed.

3535

Both resins are quaternized at stomach pH Both resins are quaternized at stomach pH and exchange anions for bile acids and exchange anions for bile acids dramatically reducing the reabsorption of bile dramatically reducing the reabsorption of bile acids. acids.

The liver senses that bile acid concentrations The liver senses that bile acid concentrations have gone down and hence turns on have gone down and hence turns on cholesterol metabolism. cholesterol metabolism.

Serum HDL and TG levels remain unchanged. Serum HDL and TG levels remain unchanged. LDL levels are found to decrease. LDL levels are found to decrease.

3636

3737

The fall in LDL concentration is apparent in 4 to 7 The fall in LDL concentration is apparent in 4 to 7 days. days.

The decline in serum cholesterol is usually The decline in serum cholesterol is usually evident by 1 month. evident by 1 month.

When the resins are discontinued, the serum When the resins are discontinued, the serum cholesterol usually returns to baseline within a cholesterol usually returns to baseline within a month. month.

When bile acid secretion is partially blocked, When bile acid secretion is partially blocked, serum bile acid concentration rises. serum bile acid concentration rises.

For these patients, cholestyramine reduces bile For these patients, cholestyramine reduces bile acid deposits in the dermal tissues. acid deposits in the dermal tissues.

3838

One of greatest advantage of these One of greatest advantage of these polymeric agents is that they can be polymeric agents is that they can be safely used for pregnant women. safely used for pregnant women.

However, exercise caution for nursing However, exercise caution for nursing women because presence of these women because presence of these cationic polymeric agents in the GI tract cationic polymeric agents in the GI tract might lower the absorption of vitamin D. might lower the absorption of vitamin D.

3939

BAS agents may also lower the BAS agents may also lower the amount of anticoagulants (warfarin, amount of anticoagulants (warfarin, coumadin) absorbed due to coumadin) absorbed due to sequestration sequestration

So >>>>> drug-drug interactions So >>>>> drug-drug interactions may be watched and controlledmay be watched and controlled

4040

Nicotinic Acid (Vitamin Nicotinic Acid (Vitamin B-3)B-3)       Pharmacologic doses of nicotinic acid Pharmacologic doses of nicotinic acid

reduce serum cholesterol and TG levels in reduce serum cholesterol and TG levels in types II, III, IV, and V types II, III, IV, and V hyperlipoproteinemias. hyperlipoproteinemias.

TG and VLDL are reduced by 20 to 40% in TG and VLDL are reduced by 20 to 40% in 1 to 4 days, LDL reduction may be seen in 1 to 4 days, LDL reduction may be seen in 5-7 days. 5-7 days.

4141

The decrease in LDL is usually greater if The decrease in LDL is usually greater if niacin is used with a BAS resin. niacin is used with a BAS resin.

HDL is increased by 20%. HDL is increased by 20%. MOA>>>>> It is known that niacin MOA>>>>> It is known that niacin

decreases lipolysis in adipose tissue, decreases lipolysis in adipose tissue, decreases TG esterification in the liver decreases TG esterification in the liver and increase LPL activity.  and increase LPL activity. 

Niacin is rapidly absorbedNiacin is rapidly absorbed

4242

Nicotinic Acid (Niacin)Nicotinic Acid (Niacin)

4343

n Administered in large doses (0.5 Administered in large doses (0.5

to 6 grams daily)to 6 grams daily)

RDA (45-60 mg)/day RDA (45-60 mg)/day JUST IMAGINE RELATION BETWEEN JUST IMAGINE RELATION BETWEEN

RDA and HYPOLIPIDEMIC effects RDA and HYPOLIPIDEMIC effects of this VITAMINof this VITAMIN

4444

SEsSEs

Flushing on dependant parts o body Flushing on dependant parts o body due to synthesis of PG-D3due to synthesis of PG-D3

Titer the dose to avoid flushingTiter the dose to avoid flushing

LFT must be routinely checkedLFT must be routinely checked

4545

Abdominal cramps when taken in empty Abdominal cramps when taken in empty stomachstomach

DiarrheaDiarrhea

NauseaNausea

TSH may be alteredTSH may be altered HypervitaminosisHypervitaminosis

4646

N

O

F

F

OHOH

Very new Anti-hyperlipidemic Drug – EzetimibeVery new Anti-hyperlipidemic Drug – Ezetimibe• Approved in October 2002• Reduces serum LDL, TC, and TG and increases HDL• Prevents the absorption of cholesterol from diet• Useful in Type IIa, IIb, III, IV and V hyperlipidemias