Lipid-lowering drugs

Presented by: Y. Sri kala

11T21R00H3IV year B.Pharm

Under the guidance of:Mr.M.Raghavendra

Department of pharmacology

TABLE OF CONTENTSIntroductionNeed for studyAim and objectives of studyPathologyTreatmentConclusionReferences

INTRODUCTION

These are the drugs which lower the levels of lipids and

lipoproteins in blood.

The hypolipidaemic drugs have attracted considerable

attention because of their potential to prevent

cardiovascular disease by retarding the accelerated

atherosclerosis in hyperlipidaemic individuals.

GOALS OF DRUG THERAPY1. Prevent ATHEROSCLEROSIS i.e., the

presumptive cause of coronary heartdisease and stroke. Although treatment of

hyperlipidemia causes slow physical regression of

plaques (over the course of years), there is a documented decrease in acute coronary events in the

first few months following vigorous treatment that is thought to be chiefly due to decreased

inflammatory activity of macrophages.2. Prevent acute pancreatitis and retard

development of xanthomas.

PLASMA PROTEINSCholesterol, triglycerides,

phospholipids, free fatty acids.They transported as lipoproteins. core-hydrophobic lipids-

cholesteryl esters, triglycerides.

coat-hydrophilic lipids- cholesterol, phospholipids.

LIPOPROTEINSLipoprotein

class Diameter

(nm)Lipid

containedSource of

lipidFunction

chylomicrons100-500TG>>CHEDiet Dietary TG transport

Chylomicron remnant

30-50CHE>>TGDiet,chylomicrons

Dietary CH transport

VLDL40-80TG>>CHELiverEndogenous TG transport

IDL30-35CHE>_TGVLDLTransport CHE and TG

to liver, source of

LDLLDL20-25CHEIDLTransport

CH to tissues and liver

HDL5-10Phospholipids,

CHE

Tissues, cell membrane

Removal of CH from

tissues

TYPES OF PRIMARY HYPERLIPOPROTEINAEMIAS

Type Disorder Cause Occurrence Elevated plasma

lipoprotein

CHTG

IFamilial lipoprotein

lipase deficiency

GVery rareChylomicron

IIaFamilial hypercholest

erolaemia

GLess commonLDLN

IIbPolygenic hypercholest

erolaemia

MFCommonest LDLN

IIIFamilial dysbetalipopr

oteinaemia

GRare IDL,chy.rem.

IVHypertriglyceridaemia

MF,GCommon VLDLN

VFamilial combined

hyperlipidaemia

GLess commonVLDL,LDL

HYPERLIPOPROTEINAEMIASHyperlipoproteinaemias can be:i. Secondary: associated with

diabetes,myxoedema,nephrotic syndrome, chronic alcolism,drugs(corticosteroids, oral contraceptives,β-blockers)etc.

ii. Primary: due to:a. a single gene defect: is familial and called

‘monogenic’ or genetic.b. Multiple genetic, dietary and physical activity

related causes: ‘polygenic’ or multifactorial.

TREAMENT STRATEGIESLife style modificationDietRestrict intake of saturated fatRegular exerciseObesity reductionStop smoking and alcoholismPlenty of fruits and vegetablesHypolipidaemic drugs

HYPOLIPIDAEMIC DRUGS

Fibrates

Others

Resins

Statins

LIPID-

LOWERNG DRUGS

CLASSIFICATION OF HYPOLIPIDAEMIC DRUGS

1.HMG-CoA reductase inhibitors (Statins):Eg:

lovastatin,simvastatin,pravastatin,atorvastatin,rosuvastatin.

2.Bile acid sequesterants(Resins):Eg: cholestyramine, colestipol.3.Activate lipoprotein lipase(Fibric acid derivatives):Eg: clofibrate, gemfibrizil,bezafibrate,fenofibrate. 4.Inhibit lipolysis and triglyceride synthesis:Eg: nicotinic acid5.others:Eg: Ezetimibe, gugulipid.

HMG-CoA REDUCTASE INHIBITORS (“statins”):

Mechanism of Action: Competitive inhibitors of cholesterol

synthesis at the rate-limiting step. Action is more complicated than simply reducing

the amount of cholesterol synthesized. Compensatory induction of LDL receptors. Enhanced extraction of circulating LDL-CE from

serum. Synergistic with bile acid binding resins

(BABR) and EZETIMIBE.

HMG-CoA REDUCTASE INHIBITORS (“statins”):

Pharmacokinetics: 30-90% oral absorption, 5-30% oral

bioavailability Evening dosing (liver cholesterol synthesis

is greatest between midnight and 2 am) Maximal effects in one month followed by slow

regression of plaques as LDL is extracted Most have extensive hepatic metabolism

(first pass effect) by CYP3A4 and CYP2C9 Excreted in bile and feces, with some renal

excretion (degree varies among statins)

HMG-CoA REDUCTASE INHIBITORS (“statins”):

Therapeutic Effects:1.plasma LDL by 18-55%2. Slight in HDL (depending upon the statin)3. Modest VLDL, TG(not shown to be of therapeutic

benefit)4.Other cardio protective effects (vasorelaxation,

stabilization of plaques, decreased inflammation and coagulation, decreased LDL oxidation)

5. LOVASTATIN and SIMVASTATIN may have estrogenic effect

6. 20% reduction in likelihood of cancer (particularly prostate and renal cancer)

HMG-CoA REDUCTASE INHIBITORS (“statins”):

Adverse Effects: Liver and muscle function must be monitored throughout

treatment - liver function is especially important (PRAVASTATIN may be a better choice in patients with liver disorders because of its renal excretion).

Birth defects Hyperurecemia and gout Drug interactions: cyclosporine, itraconazole,

erythromycin, GEMFIBROZIL,NICOTINIC ACID, BABR, cytochrome P450 inhibitors (warfarin)

Mild headache and GI disturbances (nausea, dyspepsia, diarrhea, cramps)

C/I: patients with hepatic and renal disorders, gout, diabetes mellitus, cardiac arrhythmias, pregnant women or pre-pubertal children.

LIPID-LOWERING DRUGS

FibratesFibrates- stimulate the beta-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle

- increase the activity of lipoprotein lipase, hence increasing hydrolysis of triglyceride in chylomicrons and VLDL particles

- reduce hepatic VLDL production and increase hepatic LDL uptake

LIPID-LOWERING DRUGS FibratesFibrates

O t h e r e f f e c t s :Improve glucose tolerance.Inhibit vascular smooth muscle inflammation.

A d v e r s e e f f e c t s: In patients with renal impairment myositis (rhabdomyolysis) myoglobulinuria, acute renal failure.Fibrates should be avoided in such patients and also in alcoholics.Mild GIT disturbances

LIPID-LOWERING DRUGS FibratesFibrates

mixed dyslipidemia (i.e. raised serum TG and CHO)

patients with low HDL and high risk of atheromatous disease (often type 2 diabetic patients)

patients with severe treatment- resistant dyslipidemia (combination with other lipid-lowering drugs)

LIPID-LOWERING DRUGS Bile acid bindingBile acid binding resinsresins sequester bile acids in the GIT prevent their reabsorption

and enterohepatic recirculation

The r e s u l t is: decreased absorption of exogenous CHO and increased metabolism of endogenous CHO into bile acid acids

increased expression of LDL receptors on liver cells

increased removal of LDL from the blood

reduced concentration of LDL CHO in plasma (while an unwanted increase in TG)

LIPID-LOWERING DRUGS Bile acid binding resinsBile acid binding resins

Colestyramin colestipolanion exchange resins

C l i n i c a l u s e s: heterozygous familiar hypercholesterolemia an addition to a statin if response has been inadequate hypercholesterolemia when a statin is contraindicated uses unrelated to atherosclerosis, including: pruritus in patients with partial biliary obstruction bile acid diarrhea (diabetic neuropathy)

LIPID-LOWERING DRUGS Bile acid binding resinsBile acid binding resins

A d v e r s e e f f e c t s:

GIT symptoms - nauzea, abdominal bloating, constipation or diarrhea resins are unappetising. This can be minimized by suspending them in fruit juice interfere with the absorption of fat-soluble vitamins and drugs (chlorothiazide, digoxin, warfarin) These drugs should be given at last 1 hour before or 4-6 hours after a resin These drugs should be given at last 1 hour before or 4-6 hours after a resin Pharmacokinetics

Dry, gritty powders suspended in fluids taken just before or with mealsOral administration; excreted in feces (obviously!)

Frequently prescribed in combination with other agents due to synergistic effect

LIPID-LOWERING DRUGS

OthersOthers Nicotinic acid inhibits hepatic TG production and VLDL secretion modest reduction in LDL and increase in HDL

A d v e r s e e f f e c t s:flushing, palpitations , GIT disturbances

LIPID-LOWERING DRUGS

OthersOthers Fish oil (rich in highly unsaturated fatty acids)the omega-3 marine TG - reduce plasma TG but increase CHO (CHO is more strongly associated wih coronary artery disease)-the effects on cardiac morbidity or mortality is unproven( although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)

Conclusion:Nowadays, hypolipidemic drugs are

widely used to treat hyperlipidemia and obesity. So, there is an necessity to develop new formulations without more adverse effects.

References:An review article by Dr. Janet

fitzakerley.An article by Stephanie durlin.An article by Mr.petra hirsova.Essentials of medical pharmacology

by K.D. tripathiPharmacology by rang and dale.A review article by varsha menghani

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