Antihyperlipidemic Agents

Triglycerides and cholesterol essential constituents of the organism Triglycerides

a form of energy store

Triglycerides and cholesterol 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

Triglycerides and cholesterol 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 2025% 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-3methylglutaryl 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

Triglycerides and cholesterol small amounts of lipid are coated with a layer of phospholipids, embedded in which are additional proteinsthe 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

Metabolism and Excretion 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.

Metabolism and Excretion 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. b. c. d. High serum cholesterol Hypertension Cigarette smoking 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)

HMG CoA reductase inhibitors (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

HMG CoA reductase inhibitors (Statins)

Atorvastatin has the longest duration of action and highest LDL-CH lowering capacity Additional antioxidant property

HMG CoA reductase inhibitors (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 inhibitors

Significant Pharmacokinetic Properties: extensive first-pass effect converted to hydroxy acids, which are highly protein bound major route of excretion: liver

HMG CoA reductase inhibitors

outstanding record of patient acceptance and safety

HMG CoA reductase inhibitors

Most 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 activity Lipid-Profile Effects: for modifying atherogenic dyslipidemia particularly for lowering triglycerides moderately elevates HDL-cholesterol mild lowering of LDL-cholesterol

Fibrates
Generally well-tolerated Side effects: nausea/abdominal pain/diarrhea most common liver enzyme abnormalities gallstones skin flushes myalgias Drug 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

Fibrates
(Gemfibrozil, Fenofibrate) MOA: unclear increases catabolism of triglyceride-rich lipoproteins brought about by an increased lipoprotein lipase activity Lipid-Profile Effects: for modifying atherogenic dyslipidemia particularly for lowering triglycerides moderately elevates HDL-cholesterol mild lowering of LDL-cholesterol

Fibrates
Generally well-tolerated Side effects: nausea/abdominal pain/diarrhea most common liver enzyme abnormalities gallstones skin flushes myalgias Drug Interactions: potentiates oral anticoagulants

Fibrates
(Gemfibrozil, Fenofibrate) MOA: unclear increases catabolism of triglyceride-rich lipoproteins brought about by an increased lipoprotein lipase activity Lipid-Profile Effects: for modifying atherogenic dyslipidemia particularly for lowering triglycerides moderately elevates HDL-cholesterol mild lowering of LDL-cholesterol

Fibrates
Generally well-tolerated Side effects: nausea/abdominal pain/diarrhea most common liver enzyme abnormalities gallstones skin flushes myalgias Drug Interactions: potentiates oral anticoagulants

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 acid
MOA: 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 acid
Clinical 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 acid
Caution: 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

Bile acid sequestrants

(Cholestyramine and Colestipol) 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

Bile acid sequestrants

(Cholestyramine and Colestipol)
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

Bile acid sequestrants

(Cholestyramine and Colestipol) Drug Interaction:
adsorb and decrease the absorption of such drugs as digitoxin, vitamin K antagonists, and diuretics

Probucol
MOA: 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

Probucol
Problems: 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.