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Agents used in dyslipidemia: DGK
1. Drugs used in Dyslipidemia
Dr. Divya Krishnan
Calicut medical college
2. CONTENTS
Introduction
Lipid physiology and lipid metabolism
Classification of drugs for dyslipidemias
Salient features of different drugs
Principles of treatment of dyslipidemias
Recent advances
Summary
3. What are Dyslipidemias?
Disorders of lipoprotein metabolism resulting in
abnormal plasma concentration of
lipoproteins/lipids .
Hyperlipidemias/ Low HDL levels
Hypercholesterolemias
( total cholesterol/ LDL/
Triglycerides)
6. Growing interest in drugs
for dyslipidemias…..???
Dyslipidemias are important risk factors for
atherosclerosis.
Drugs have potential to retard accelerated
atherosclerotic process and decrease
morbidity and mortality associated with
atherosclerosis.
7. LIPID PHYSIOLOGY
Heterogenous group of compounds related to
fatty acids insoluble in water but soluble in non
polar solvents.
Simple lipids compound lipids Neutral lipids
Triglycerides
Cholesteryl
esters
8. LIPOPROTEINS
Macromolecular complexes of lipid and proteins
apoproteins
-provide structural stability
-ligands for receptors
-activate enzymes
unesterified cholesterol
core (TG ,cholesteryl esters)
phospholipids
9.
10. Classification of lipoproteins
Lipoprotein
type
Density
(g/ml)
diameter
(nm)
Lipid core Apoprotein Source Function
Chylomicr
on
0.93 100-500 TG>>CHE ApoB48,
Apo E
diet Dietary lipid
transport
VLDL 0.93-
1.006
40-80 TG>>CHE Apo B100
Apo E
liver Endogenous
lipid transport
IDL 1.006-
1.019
30-35 CHE>>TG Apo B100
Apo E
VLDL Lipid transport
to liver
Source of LDL
LDL 1.019-
1.063
20-25 CHE Apo B100 IDL cholesterol
transport to
tissues & liver
HDL 1.05-
1.120
5-10 CHE ApoAΙ,
ApoAп tissues
Removal of
cholesterol
from tissues
Lipoprotein A /LP(a) : Similar to LDL but with an additional Apo A.
Linked to risk of atherosclerosis
15. Classification of drugs
First line agents : Lower LDL levels (mainly)
- HMG-CoA reductase inhibitors(statins)
- Bile acid binding resins
- Inhibitors of intestinal cholesterol absorption
Second line agents : Lower VLDL levels
- LPL activators (fibrates)
-VLDL secretion inhibitors(Niacin)
Miscellaneous : Gugulipid ,Fish oils
16. HMGCoA reductase inhibitors(Statins)
- Most effective & best tolerated drugs
History
- First isolated from Penicillium citrinum mould(1972)
- Compactin (Mevastatin) - first to be studied in man
- Lovastatin (from Aspergillus terreus) - first to be
approved for use in humans
- Pravastatin , Simvastatin chemically modified
derivatives
- Atorvastatin , Fluvastatin , Rosuvastatin , Pitavastatin-
synthetic products
17. Mechanism of action of statins
Acetyl Co A 3Hydroxy 3 methyl glutaryl CoA
HMG CoA
reductase
cholesterol mevalonate
STATINS
21. Pleiotropic effects of statins
1. Improves endothelial function
2. Decreases vascular inflammation(lowers CRP)
3. Decreases lipoprotein oxidation
4. Stabilisation of atheromatous plaque
5. Decreases platelet aggregation
6. Decreases fibrinogen levels
7. Enhances fibrinolysis
8. Neovascularisation of ischemic tissue
9. Protection from sepsis
10. Immune suppression
11. Inhibition of primordial germ cell migration
Beneficial effects
• Antiatherogenic
• Alzheimers disease
• Prostate cancer
Harmful effects
• Contraindication in
pregnancy
22. Statins-pharmacokinetics
o Variable absorption
o Extensive first pass hepatic uptake (OATP1B1)
Lovastatin Pravastatin Simvastatin Atorvastatin Rosuvastati
n
prodrug active prodrug active active
High PPB 50% PPB High PPB High PPB High PPB
Lipophilic hydrophilic lipophilic hydrophilic hydrophilic
T1/2=1-4hrs 1-3hrs 2-3hrs 18-24hrs 18-24hrs
CYP3A4 Sulfate
conjugation
CYP3A4 CYP3A4 CYP2C9
25. Indications for use
First choice drugs for 1 & 2 hypercholester-
olemias with or without raised TG levels
Drug combinations used in severe / combined
dyslipidemias.
1 prevention of arterial disease in patients with
hypercholesterolemias
2 prevention of MI/stroke (initiated soon after
an event irrespective of lipid levels)
Tried in Alzheimers disease , prostate cancer
26. Bile acid binding
resins
Oldest & safest
MOA----explained with the fig
Cholestyramine
, Colestipol
, Colesevelam
-lower LDL levels
(15-25%)
-3-5% rise in HDL
-Increase TG levels
-induces HMGCoA
reductase
activity
27. Bile acid binding resins contd…..
Adverse drug reactions (mild)
- unpalatable , unpleasant
- bloating , dyspepsia
- constipation
Drug interactions
-interferes with absorption of :-
fat soluble vitamins
thiazides , frusemide
digoxin , warfarin , statins , tetracycline ,
thyroxine
Colesevelam
has less side
effects & is
devoid of
interactions
28. Bile acid binding resins contd…
Indications for use
- Primary hypercholesterolemias.~20% fall in
LDL levels.
Monotherapy less popular.Used in combinations for
better control of hypercholesterolemias
- Relief of pruritus (cholestasis)
- Bile acid diarrhoea
- Digitalis toxicity
29. Intestinal cholesterol absorption
inhibitors
Inhibit absorption of dietary & biliary
cholesterol absorption from intestine-reduced
hepatic cholesterol-LDL receptor expression
& increased uptake of LDL from plasma.
Plant sterols &stanols
Sitostanol competes with
cholesterol for NPC1L1
Sitosterol interferes with
cholesterol transfer in the
enterocyte
Ezetimibe
Inhibits NPC1L1 &
inhibits absorption of
cholesterol&phytosterol
30. EZETIMIBE……………
Pharmacokinetics
-Poorly absorbed
-Conjugated form gets absorbed & undergoes
enterohepatic circulation.
-T1/2=22hrs.Dose -10mg/day
-Excreted in feces
ADR
-Diarrhoea/abd pain/headache
-Allergic rxn ,hepatic dysfunction,myositis(rare)
-Contraindicated in pregnancy
31. Ezetimibe contd……………
Drug interactions
-Bile acid sequestrants inhibit ezetimibe
absorption
Indications
Mild hypercholesterolemia when statin is
contraindicated/not tolerated.(~15-20%
decrease in LDL otherwise monotherapy less
efficient than statin
Adjunct to statin in hypercholesterolemia
Additive reduction in LDL levels occurs.
32. Second line agents
Marked reduction in VLDL(TG)
Modest fall in LDL & modest rise in HDL
Includes :-
Activators of LPL (Fibrates)
Inhibitors of VLDL secretion (Niacin)
33. Fibrates
(Clofibrate) , Gemfibrozil ,Fenofibrate ,
Bezafibrate , Ciprofibrate
MOA : Activate PPARα resulting in:-
Increase in LPL activity
Decrease in Apo CШ
FFA oxidation
Decreased VLDL synthesis
Increased hepatic SREBP
Increased Apo AΙ , Apo AЦ
Fall in VLDL (20-50%)
Fall in LDL (10-15%)
HDL rise (10-15%)
35. Fibrates
ADR
GI distress , headache
Rash , urticaria
Myalgia , fatigue
Hair loss , impotence
Minor elevations in AST , ALP
Myopathy—more when combined with statins
Lithogenicity of bile
Contraindication
Pregnancy , children , kidney disease
36. Fibrates
Drug interactions
Myopathy risk with statins (OATP1B1
inhibition & interference with statin
metabolism)
Toxicity of oral anticoagulants(displacement
from plasma protein binding sites)
37. Fibrates…………………
Clofibrate - Abandoned
- Doesn’t prevent atherosclerosis
- Risk of gallstones
Gemfibrozil - Higher risk of myopathy with statin
Short t1/2
Bezafibrate - More LDL lowering than gemfibrozil
- Less risk of myopathy with statin
Fenofibrate - More LDL lowering & more HDL
- Raising effect than gemfibrozil
- Less risk of myopathy with statin
- Uricosuric action
38. Fibrates
Indications for use
- Drug of choice for 1 & 2 severe hyper-
triglyceridemia
-Mixed dyslipidaemia (Bezafibrate/fenofibrate)
-Combined with other drugs like statins for
resistant dyslipidaemias (fenofibrate preferred)
39. Nicotinic acid(Niacin)
B group vitamin at higher doses reduces plasma
lipids
MOA
Inhibits lipolysis in adipose tissue
decreased FFA for TG & VLDL synthesis in liver
Decreases VLDL(20-50%),LDL (15-25%)
Raises HDL (20-35%) & reduces lipoprotein A &
has antiatherogenic properties
41. Niacin
Drug interactions
-Postural hypotension with antihypertensives
-Myopathy risk with statins
Indications
-Severe hypertriglyceridemias
-Adjunctive drug to statins / fibrates in severe
dyslipidaemia
-Combined dyslipidemias
-Shown to decrease recurrence of MI
42. Miscellaneous agents
Gugulipid : Ayurvedic prep
-Inhibits synthesis & increases excretion of
cholesterol
- Modest lowering of LDL , TG & rise in
HDL
Fish oils
-lower TG levels but raise LDL
-Antiatherogenic property due to production
of 3 series Prostanoids & 5 series LTs
44. Treatment of hyperlipidemias
Treatment modalities
Lifestyle modifications
Pharmacotherapy
Treatment plan decided on the basis of :-
lipid profile
risk assessment for CAD
45. Plasma lipid levels (NCEP-2001)
mg/dl
Total
cholesterol
LDL HDL TG
Optimal <200 <100
<70(CAD)
>40(M)
>50(F)
<150
Borderline
high
200-239 130-159 - 150-199
high ≥240 160-189 >60 200-499
Very high - ≥190 - ≥500
46. Risk factors for CAD
Men >45, Women>55yrs
Family h/o MI/sudden cardiac death before 55yrs in
men & 65yrs in women in first degree relative
Smoking
HTN
High LDL (>160mg/dl) or total cholesterol(>240mg/dl)
Low HDL (<40 in men , <50 in women)
Obesity
##CAD equivalent : DM / PVD /abdominal aortic
aneurysm / symptomatic carotid artery disease
47. Patient stratification
Low risk : 0-1 CAD risk factor
Moderate risk : ≥2 CAD risk factors + 10yr CAD risk <
10%
Moderately high risk : ≥2 CAD risk factors + 10 yr CAD
risk 10- 20 %
High risk : CAD / CAD equivalent
Very high risk : CAD/CAD equivalent + 1 of the below
≥2CAD risk factors
Single uncontrolled CAD risk factor
DM
Metabolic syndrome
Acute coronary syndrome
48. NCEP-ATPШ Guidelines
Risk category LDL goal
(Mg/dl)
Lifestyle Drug
Very high risk < 70 all
subjects
All
subjects
High risk < 100 All
subjects
All
subjects
Moderately high risk < 130
(or < 100)
≥ 100 ≥ 130
Moderate risk < 130 ≥ 130 ≥ 160
Low risk < 160 ≥ 160 ≥ 190
49. Drug treatment
Low dose statin(as per target LDL level &
cost effectiveness)
Double the dose every six weeks till max
dose if inadequate response with low dose
Add another drug (ezetimibe / fibrate
/niacin) if needed
50. Treatment of raised TG levels
TG < 150mg/dl – No TG lowering needed .Treat as per LD
levels
TG 200-499 mg/dl ( High)
-lifestyle modification
-treatment of cause if identified
-statin therapy to achieve goal LDL level
-TG lowering drug (fibrate/niacin) considered if:--CAD
present/family h/o premature CAD/non HDL≥190/HDL<40/
1 hypertriglyceridemias
TG > 500mg/dl (Very high)
-vigorous measures including TG lowering drugs indicated
51. Treatment of low HDL
-Total cholesterol: HDL < 3.5 desirable
-Statin therapy targeted at LDL lowers the ratio
-Treatment of metabolic syndrome helps
-Niacin can be added 2 statin therapy
52. Combined Drug Therapy
Combined drug therapy is useful when:
LDL or VLDL levels are not normalized with a
single agent
LDL and VLDL levels are both elevated
initially
VLDL levels are significantly increased during
treatment of hypercholesterolemia with a resin.
An elevated level of Lp(a) or an HDL deficiency
coexists with other hyperlipidemias.
53. Combined Drug Therapy
Statins & Resins
synergistic combination in the treatment of
hypercholesterolemia.
Niacin & Resins
Effective in familial hypercholesterolemia/combined
hyperlipidemias.Resin neutralises acid production
by niacin
Statins & Niacin
More effective than either agent alone in treating
hypercholesterolemia & combined hyperlipidemia
54. Combined Drug Therapy
Statins & Ezetimibe
Is highly synergistic in hypercholesterolemia.
Statins & Fenofibrate
Fenofibrate with certain statins is useful in
combined hyperlipidemias
The combination of fenofibrate with
rosuvastatin is particularly effective.
56. Future Drugs
CETP inhibitors ( anacetrapib & dalcetrapib )
lower LDL while increasing HDL to an extent
not possible with existing HDL-raising therapies.
Darapladib inhibits lipoprotein associated
phospholipase A2 (enzyme produced by
inflammatory cells & involved in atherosclerosis)
Mipomerson (antisense drug ) directed against Apo B
(present in LDL)