Lipid-lowering drugs Presented by: Y. Sri kala 11T21R00H3 IV year B.Pharm Under the guidance of : Mr.M.Raghavendra Department of pharmacology
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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