Biochemistry, physiology and pathology of lipid metabolism in brief and its applied pharmacotherapeutics in details

1. HYPOLIPIDAEMIC
DRUGS
Dr Anshuman Parida
Department of Pharmacology

2. Introduction
• Hypolipidemic agents, or antihyperlipidemic
agents
• A diverse group of pharmaceuticals used in T/t
of high levels of fats (lipids), such as cholesterol,
in the blood (hyperlipidemia).
• They are also called lipid-lowering drugs.

3. Lipid transport and metabolism
• Lipids originate from two sources:
▫ Endogenous lipids : synthesized in the liver,
▫ Exogenous lipids: ingested and processed in
the intestine.
• Dietary cholesterol & triglycerides : packaged into
chylomicrons in the intestine into bloodstream via
lymphatics.
• Liver synthesizes TG and cholesterol packages them as
VLDLs before releasing them into the blood

4. • VLDLs in muscle and adipose blood vessels, their TG are hydrolyzed
by LPL to fatty acids.
• The fatty acids that are released are taken up by the surrounding
muscle and adipose cells.
• During this process, the VLDLs become progressively more dense
and turn into LDLs
• Most LDLs taken up by Liver for disposal,
• some circulate and distribute cholesterol to the rest of the body
tissues.
• HDLs, which are also secreted from the liver and intestine, have the
task of preventing lipid accumulation.
• They remove surplus cholesterol from tissues and transfer it to
LDLs that return it to the liver.

9. Hyperlipidemia
• Elevated concentrations of lipid i.,e, Hyperlipidemia 
development of atherosclerosis and CAD.
• Dyslipidemia can be primary or secondary.
• Primary forms : genetically determined
• Secondary forms : Consequence of other conditions such
as Diabetes mellitus,
Alcoholism,
Nephrotic syndrome,
Chronic renal failure,
Administration of drug…

11. • Minor (and emerging) factors include:
obesity, physical inactivity,
athrogenic diet, lipoprotein (a),
homocysteine, prothrombotic and
proinflammatory factors, impaired fasting
glucose.

12. Management of Dyslipidemia
• Drug therapy to lower plasma lipids is only one approach
to treatment
• Used in addition to dietary management
And
• Correction of other modifiable cardiovascular risk
factors
• Several drugs are used to decrease plasma LDL-CHO

13. CLASSIFICATION 1/2
• HMG - Co A Reductase inhibitors ( Statins ) :
Atorvastatin, Simvastatin,
Lovastatin, Pravastatin,
Fluvastatin, Rosuvastatin
• Bile acid binding resins :
Cholestyramine, Colestipol, Colesavelam.
• Inhibitors of intestinal absorption of cholesterol
: Stanol esters , Ezetemibe

14. CLASSIFICATION 2/2
• Activators of Lipoprotein lipase (LPL) (Fibrates)
:
Gemifibrozil, Bezafibrate, Fenofibrate, and
Ciprofibrate
• Inhibitor of VLDL secretion and lipolysis :
Niacin (Nicotinic acid)
• New drugs (CETP Inhibitors) :
Torcetrapib, Anacetrapib

15. Class: HMG-CoA reductase inhibitors
• Mechanism: ↓rate-limiting step in cholesterol synthesis.
• Clinical use: ↓ LDL, ↓ triglycerides
• Side effects: H : Hepatotoxicity
M : Myositis,rhabdoMyolysis
G : ↑ FPG
C : ↑ Creatinine phosphokinase
A : HeadAche, Joint pain
R : Rash

17. Drug Fluvasta
tin
Pravast
atin
Rosuva
statin
Lovast
atin
Simvas
tatin
Pitavast
atin
Atorva
satin
Dose
mg/day
10-80 10-40 5-40 10–40 5–20 1–4 mg 10-80
Absorpti
o
complete Incomplete, Varies from 45-75%
T ½
(hours)
1-3 1-3 18–24 1-4 2-3 12 14
CYP CYP2C9 CYP3A4
DRC Non linear linear
LDL-CH
lowering
efficacy
35% <25% 51-55% 40% 40% 40% 51-55%
Special
features
↓ Plasma
Fibrinoge
n
Max ↑
HDL
First
clinicall
y used
Inactive
pro drug
C/I - 80
mg
Latest &
Most
Potent
Antioxida
nt
property

18. Interactions
CYP3A4 CYP2C9
INHIBITORS INDUCERS INHIBITORS
Macrolide Phenytoin Ketoconazole
Cyclosprin Gresiofulvin Metronidazole
Tacrolimus Thiazolidinediones Cimetidine
Ketoconazole Rifampicin Sulphinpyrazone
Protease inhibitor Barbiturates
Paroxetine
Venlafexine
Verapamil
Amiodarone

19. Contraindications
• Pregnancy & lactation
• Children < 7-8 years
• Active liver diseases

22. Class: Fibrates
• Mechanism: binds with PPAR α
↑ lipoprotein lipase → ↓ VLDL
↓TG
• Clinical use: Elevated TG and remnants.
• Side effects: GI upset (dyspepsia),
Cholelithiasis,
Myositis
Hepatitis Rare
• Drug interaction: Warfarin ,OHA

24. Drug Gemfibrozil Fenofibrate Benzafibrate Clofibrate
Dose 600 mg BD 145mg QID 200 mg TDS
T ½ (hours) 1.5 20 18-24
Absorption Intestine,
Enterohepatic
circulation
Completely
intestine
Distribution
Tightly bound to plasma protein
Excretion Kidney, liver urine, faeces Kidney
Special feature Trial for
Cancer,
Alzheimer
Discontinue
d

25. Interactions
• Increased risk of myopathy when combined with
statins.(fenofibrate)
• Displace drugs from plasma proteins( e.g. oral
anticoagulants and oral hypoglycemic drugs).
Contraindications:
• 1- Patients with impaired renal functions.
• 2- Pregnant or nursing women.
• 3-Preexisting gall bladder disease

26. Class : Nicotinic Acid
• Mechanism: ↓ fatty acid release from adipose
tissue, ↓ hepatic synthesis of LDL
• Clinical use: ↑ HDL, ↓ LDL, ↓TG
• Side effects: Skin flushing, paresthesias,
pruritus, GI upset, ↑LFTs, hyperglycemia,
hyperuricemia
• Prevention of side effects: Aspirin

29. • Wide spectrum antilipidemic drugs
• Most effective in reducing TG level.
• Dose: Start with 100 mg TDS, gradually increase
to 2–4 g per day in divided doses.
• To be taken just after food to minimize flushing
and itching.

30. Class: Cholesterol absorption inhibitors
• Ezetinib
• Mechanism: inhibits the luminal cholesterol
uptake by inhibiting the transport
protein on NPC1L1
• Clinical use: ↓ LDL
• Side effects: Diarrhea, abdominal pain
Angioedema.

32. • Reduces both dietary and billiary cholesterol.
• Dose : 10 mg OD
• T 1/2 ~ 22 hours
• Long half-life:
▫ Permits once-daily dosing
▫ May improve compliance

33. Class: Bile acid resins
• Mechanism: Bind intestinal bile acids → ↓bile acid
stores & ↑ catabolism of LDL from plasma.
• Clinical use: ↓ LDL
• Side effects: Constipation,
↑ Gallstone formation,
GI upset,
LFT abnormalities,
Myalgias.
↓ Absorption of drugs
ADEK vitamins from the small intestine.

34. • Dose : 4 to 8 g OD/BD, max dose 24 g/d.
• Drug interactions : due to the risk of decreased
absorption of these drugs.
Digitalis, Estrogens and progestins,Oral diabetes drugs,
Penicillin G,Phenobarbital,Spironolactone,Tetracycline
Thiazide-type diuretic pills,Thyroid medication
Warfarin,Leflunomide
• Contraindication
▫ 1- Complete biliary obstruction( because bile is not
secreted into the intestine).
▫ 2- Chronic constipation.
▫ 3-Severe hypertriglyceridemia(TG >400 mg/dL)

35. Class : CETP INHIBITORS
• Torcetrapib and Anacetrapib  banned.
• Dalcetrapib (Clinical trails)
• Anacetrapib – Increases HDL-C by 129%
• Obicetrapib (TA-8995), Phase II results reported in
2015
• Cholesteryl ester transfer protein (CETP) Facilitates
transfer of cholesteryl esters (CE)
from HDL-C to LDL-C, VLDL-C during “reverse
cholesterol transport”

36. Antihyperlipedemic combinations
Indications:
• Increased VLDL during treatment of
hypercholesterolemia with resins.
• Combined increase in LDL & VLDL.
• High LDL or VLDL not normalized with a single drug.
• Severe hypertriglycerdemia or hypercholesterolemia.
• To take lower doses of each drug

37. SUMMARY

40. Thank you……