antihyperlipidemic agents.ppt

Antihyperlipidemic Agents

Triglycerides and cholesterol

• essential constituents of the organism

• Triglycerides – – a form of energy store


• Cholesterol – essential component of mammalian cell

membranes – for proper membrane permeability and fluidity

– important precursor molecule for the biosynthesis of bile acids, steroid hormones, and several fat-soluble vitamins


• Cholesterol – major dietary sources: cheese, egg yolks,

beef, pork, poultry, and shrimp• total fat intake, especially saturated fat and

trans fat, plays a larger role in blood cholesterol than intake of cholesterol itself

Cholesterol Synthesis

• 20–25% of total daily cholesterol production occurs in the liver– other sites of high synthesis rates: intestines,

adrenal glands, and reproductive organs

Cholesterol Synthesis

• one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)– HMG-CoA is then reduced to mevalonate by

the enzyme HMG-CoA reductase• irreversible step • site of action for the statins

Cholesterol Synthesis• directly regulated by the cholesterol levels

present– higher intake from food - leads to a net

decrease in endogenous production– lower intake from food – increase in

endogenous production

Cholesterol Synthesis• main regulatory mechanism: sensing of

intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2)

• when cholesterol levels are low:– LDL receptor - scavenges circulating LDL from

the bloodstream, and – HMG-CoA reductase – lead to an increase of

endogenous production of cholesterol

Plasma Transport

• Cholesterol is insoluble in blood

• Transport of cholesterol in circulatory system: within lipoproteins– complex spherical particles:

• exterior composed of amphiphilic proteins and lipids• inward-facing surfaces - lipid-soluble

(triglycerides and cholesterol esters are carried

internally)

– have cell-targeting signals that direct the lipids they carry to certain tissues


• small amounts of lipid are coated with a layer of phospholipids, embedded in which are additional proteins—the apolipoproteins– Apolipoproteins serve as ligands for specific

receptors on cell membranes

Lipoprotein

Triglycerides and cholesterol • 4 transport forms: (distinguished by the amount

and the composition of stored lipids and the type of apolipoprotein)

*the more cholesterol and less protein a lipoprotein has, the less dense it is

Plasma Transport

• Chylomicrons – transporters fats from the intestine to muscle

and other tissues that need fatty acids for energy or fat production.

– Cholesterol• is not used by muscles• remains in more cholesterol-rich chylomicron

remnants, which are taken up from the bloodstream by the liver

Plasma Transport

• VLDL molecules– produced by the liver– contain excess triacylglycerol and cholesterol

that is not required by the liver for synthesis of bile acids

– in the bloodstream, the blood vessels cleave and absorb more triacylglycerol to leave IDL molecules

Plasma Transport

• IDL molecules– contain an even higher percentage of

cholesterol – two possible fates:

• half are taken up by the liver for metabolism into other biomolecules

• half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, which have the highest percentage of cholesterol within them

Plasma Transport

• LDL molecules – have the highest percentage of cholesterol

within them– major carriers of cholesterol in the blood– LDL-apolipoprotein B complex - recognized by

the LDL receptor in peripheral tissues

Plasma Transport

• LDL molecules synthesis of the LDL receptor is regulated by SREBP*– abundant cholesterol in cell LDL receptor

synthesis blocked– cell is deficient in cholesterol more LDL

receptors made

sterol regulatory element-binding protein

Plasma Transport

• when the SREBP system is deregulated:– many LDL molecules appear in the blood

without receptors on the peripheral tissues– LDL molecules are oxidized and taken up by

macrophages, which become engorged and form foam cells

Plasma Transport

• when the SREBP system is deregulated:– foam cells often become trapped in the walls

of blood vessels and contribute to artherosclerotic plaque formation

– hence, the association of LDL cholesterol (actually a lipoprotein) with "bad" cholesterol

Plasma Transport

• HDL particles – transport cholesterol: back to the liver

• for excretion to other tissues that use cholesterol to synthesize hormones

• process known as reverse cholesterol transport (RCT)

– having large numbers of large HDL particles – correlates with better health outcomes

Metabolism and Excretion

• Cholesterol is oxidized by the liver into a variety of bile acids

• Cholesterol is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently


• Bile acids – conjugated with glycine, taurine, glucuronic

acid, or sulfate = bile salts: • solubilize fats in the digestive tract• aid in the intestinal absorption of fat molecules • aid in the intestinal absorption of the fat-soluble

vitamins, A, D, E, and K.


• Bile acids– a mixture of conjugated and non-conjugated

bile acids along with cholesterol itself is excreted from the liver into the bile

– approximately 95% of the bile acids reabsorbed from the intestines

– essential for the digestion and absorption of dietary fats

– when more concentrated (as in the gallbladder) cholesterol crystallizes

Hyperlipoproteinemias

• primary – genetic– various drugs are available

• secondary – in obesity and metabolic disorders– immediate goal: lower lipoprotein levels by

diet and treatment of primary disease

Elevated LDL-cholesterol serum concentrations:

• associated with an increased risk of atherosclerosis– especially when there is a concomitant decline

in HDL concentration (increase in LDL:HDL quotient).

Total Fat Intake

• plays a larger role in blood cholesterol than intake of cholesterol itself

• Saturated fat intake - present in full fat dairy products, animal fats, several types of oil and chocolate

• Trans fats intake - derived from the partial hydrogenation of unsaturated fats– margarine and hydrogenated vegetable fat– consequently in many fast foods, snack foods,

and fried or baked goods

Studies have shown that:

1. Higher values of LDL cholesterol (4.5-7.5 mmol/L) were more common in CAD (coronary artery) patients

2. Lower values of HDL cholesterol (0.2-0.8 mmol/L) were more common in CAD patients. 3. High baseline levels of cholesterol correlated

with an increased risk of subsequent coronary heart disease (CHD) after 40 years of follow-up

4. Hyperlipidemia was by far the most important risk factor for CHD

Major Independent Risk Factors for Coronary Heart Disease

a. High serum cholesterol

b. Hypertension

c. Cigarette smoking

d. Diabetes mellitus

Major Modifiable Risk Factors for Coronary Heart Disease

a. Physical inactivity

b. Obesity

c. Atherogenic diet

Exercise

• elevates HDL levels to an extent

dependent on the level of aerobic

exercise

Diet

1. high saturated fat diet:

• increases levels of VLDL & LDL

2. low fat diet

• reduces LDL & HDL levels

3. alcohol

• increases VLDL levels

Major Non-Modifiable (Independent)

Risk Factors for Coronary Heart Disease

a. Advancing age

b. Male sex

c. Positive family history in a first

degree relative

Secondary hyperlipidemias

- may be due to: a. Hypothyroidism b. Nephrotic syndrome c. Diabetes mellitus (NIDDM) d. Chronic renal failure

Hormones

1. Thyroxine

• reduces LDL levels

2. Androgens

• reduce HDL levels

3. Estrogens

• increase LDL receptor function

• help keep LDL levels down in

premenopausal women

Antihyperlipidemic Agents

HMG CoA reductase inhibitors

(Statins)First isolated from cultures of Penicillium sp.

MOA:

competitive inhibition of HMG CoA reductase,

the enzyme that catalyzes the rate-limiting step

in cholesterol synthesis in the in the liver

MOA Contd.

• Reduction in synthesis of Cholesterol

• Compensatory increase in LDL receptor on Liver cells

• Increased receptor mediated uptake and catabolism of LDL

Important HMG-CoA reductase inhibitor drugs:

• Atorovastatin(A)

• Lovastatin(L)

• Simavastatin(S)

• Pravastatin(P)

• Fluvastatin(F)


(Statins)• active group of L, S, P, and F (or their

metabolites) resembles that of the physiological

substrate of the enzyme– P and F represent the active acidic forms :

Hydrophilic– L and S are lactones


(Statins)• Atorvastatin has the longest duration of

action and highest LDL-CH lowering capacity

• Additional antioxidant property


(Statins)Lipid Profile Effects:

• reduces total cholesterol, LDL, & triglycerides

• increases HDL cholesterol

Clinical Efficacy:

• powerful LDL-lowering drugs:

- reduces coronary risks in both primary

and secondary prevention

- reduces risk for stroke in

secondary prevention

HMG CoA reductase inhibitorsSignificant Pharmacokinetic Properties:

• extensive first-pass effect

• converted to hydroxy acids, which are

highly protein bound

• major route of excretion: liver


outstanding record of patient acceptance and safety

HMG CoA reductase inhibitorsMost Important ADRs:

muscle pain/myopathy/rhabdomyolitis

– most serious

liver enzyme abnormalities

– increase transaminases, but liver damage is rare

Other Adverse Effects:

nausea

insomnia/fatigue/headache

skin rashes

Fibrates(Gemfibrozil, Fenofibrate)

MOA: unclear increases catabolism of triglyceride-rich lipoproteins brought about by an increased lipoprotein lipase activityLipid-Profile Effects: • for modifying atherogenic dyslipidemia particularly for lowering triglycerides • moderately elevates HDL-cholesterol • mild lowering of LDL-cholesterol

FibratesGenerally well-toleratedSide effects: nausea/abdominal pain/diarrhea – most common liver enzyme abnormalities gallstones skin flushes myalgiasDrug Interactions: potentiates oral anticoagulants

Omega-3 Fatty Acids(Linolenic Acid, DHA, EPA)

MOA:

reduce hepatic secretion of triglyceride-rich

lipoproteins

Clinical Efficacy:

• alternatives to fibrates or nicotinic acid for

treatment of hypertriglyceridemia

• reduce risk for major coronary events in

patients with established CHD

• recommended only as an option at present

Omega-3 Fatty Acids(Linolenic Acid, DHA, EPA)

• Also results in:

decreased synthesis of VLDL and

apolipoprotein B

improved clearance of remnant particles

• Total and LDL cholesterol are not decreased or are even increased

Nicotinic acidMOA: • mechanism uncertain• activate endothelial lipoprotein lipase and thereby

lower triglyceride levels– reduces triglyceride & hepatic synthesis of

apolipoprotein B-100, an essential component of VLDL

Other Lipid Profile Effects:

• increases HDL cholesterol

- the most effective among the lipid

lowering agents

• moderate reduction in LDL cholesterol

Nicotinic acidClinical Efficacy:

• recommended:

- for higher-risk persons with atherogenic

dislipidemia with moderate increase in

LDL-cholesterol levels

- in combination, for higher risk persons

with atherogenic dislipidemia and elevated

LDL-cholesterol

Nicotinic acidCaution:

active liver disease

recent peptic ulcer

hyperuricemia and gout

type 2 diabetes

Availability:

100 mg tablets

Daily dose: 2-6 grams per day!!!

Bile acid sequestrants Cholestyramine and Colestipol

Originally designed to control pruritus in

obstructive liver disease

MOA:

- anion exchange resins: exchange

chloride for the negatively charged acid

→ excretion of bile acids → increase

hepatocyte cholesterol content →

- increases removal of LDL from the

blood by hepatic LDL receptors

Bile acid sequestrants (Cholestyramine and Colestipol)

• by virtue of binding bile acids, they promote consumption of cholesterol for the synthesis of bile acids

• non-absorbable– no systemic toxicity

• gritty texture makes ingestion an unpleasant experience


Clinical Efficacy:

produce moderate reductions in LDL

cholesterol

• for persons with moderate elevations

in LDL cholesterol, younger patients,

women considering pregnancy

• for very high LDL - combine with statins


Side effects:

• dose-dependent; limits their widespread use– at the required dosage, the resins cause diverse GIT

disturbances

intestinal bloating/obstruction

nausea/flatulence/constipation - more

common


Drug Interaction:• adsorb and decrease the absorption of

such drugs as digitoxin, vitamin K antagonists, and diuretics

ProbucolMOA: uncertain

may enhance conversion of cholesterol to

bile acids followed by increased fecal

sterol secretion or inhibitory effects on

the synthesis of lipoproteins or

cholesterol

ProbucolProblems: • erratic ability to lower LDL • potent and persistent ability to lower HDL - no longer a first line lipid-lowering agent - appears effective in reducing atherogenesis, possibly by reducing LDL oxidation

Side effects: abdominal pain/nausea fetid perspiration flatulence/diarrhea angioneurotic edema hyperhydrosis prolonged Q-T interval

Plasma Expanders

• They are high molecular weight substances which exert colloidal osmotic pressure, and when infused i.v. retain fluid in the vascular compartment.

Desirable Properties

• Should exert osmotic pressure comparabe to plasma.

• Should remain in circulation and not leak out in the tissues.

• Should be pharmacodynamically inert.

• Should not be pyrogenic or antigenic.

• Should not interfere with grouping and cross matching of blood.

• Should be stable, easily sterilizable and cheap.

Egs.

• Human albumin

• Dextran

• Degraded gelatin

• Hydroxy ethyl starch (HES)

• Polyvinyl pyrrolidone (PVP)

Uses

• As substitutes for plasma in conditions where plasma has been lost or moved to extravascular compartments-

• Burns

• Hypovolemia

• Endotoxin shock

• Severe trauma

• Extensive tissue damage.

Contraindications

• Severe anaemia

• Cardiac failure

• Pulmonary edema

• Renal insuffiency.

antihyperlipidemic agents.ppt

Documents

blood cholesterol

bloodtransport of cholesterol

cholesterol esters

fat production

shrimptotal fat intake

hmgcoa reductase lead

methylglutaryl coa hmgcoahmg

trans fat