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This is a wonderful presentation on hypolipidemic drugs by Dr.Sachin Kuchya.Kudos for him.
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Hypolipidemic Agents
Sachin Kuchya, MD
Assistant Professor,
Department of Pharmacology
NSCB Medical College, Jabalpur
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
2
Why do we need them?
• Low HDL & elevated LDL-c are known risk factor for CHD.
• Elevated TG’s are known to cause Pancreatitis.
• In well controlled clinical trials ,fatal & nonfatal CHD events & strokes was reduced by as much as 30-40% as per Scandinavian Simvastatin Survival Study.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
3
Overview of Presentation
• Physiology
• Pharmacological targets
• Drugs
• Clinical states
• Special populations
• Combination Drug Regimens
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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GLOSSARY
• Lipid – water insoluble compounds, comprising of FFA, TG, CHL, CHL- esters.
• LIPOPROTEIN- complex of lipids + apoproteins
• Chylomicrons – largest of lipoproteins, carry TG & CHL- esters from the gut to other tissues
• VLDL- very low density lipoprotein, principal form secreted by liver, represents triglyceride content in lipid profile.
• LDL- low density lipoprotein, derived from VLDL, represents CHL.
• HDL- high density lipoprotein, extracts CHL from body tissues.
• Lp(a)- LDL + apoprotein a, is known to be atherogenic.• CETP- Cholesteryl Ester Transfer Protein.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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PHYSIOLOGY
Enterohepatic circulation
- Bile acids
CHL Pool
Dietary
CHL
De novo CHL synthesis
HMG CoA reductase enz.
VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
•Adipose tissue (Storage)
•Skeletal M
•Cardiac M
•Breast tissue during lactation
To various body tissues,
Gut
HDL2 HDL3
CHL ester
TG
LDLCETP
Tightly regulated
Diurnal variation
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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1. Dietary restriction
2. Cholesterol absorption inhibitor
3. Bile acid binding resin
4. HMG CoA reductase inhibitor
5. VLDL secretion inhibitor
6. Fibric acid derivatives
7. CETP inhibitor
Dietary
Atheroma
HDL2
CHL Pool
CHL VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
Gut
HDL3
CHL ester
TG
LDLCETP
Bile acids
Non Pharmacological & Pharmacological targets
1
2
3
4
5
6
7
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Statins – effect on lipids
• LDL-c
Lowers LDL-c by 20-50%
• TG
If >250 mg/dl, then significant reduction is seen.
• HDL-c
Increases HDL levels by 5- 10%.
• Lp(a)
No effect is seen.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Statins – additional effects
• Improved endothelial function
• Prevents weakening & rupture of atherosclerotic plaque.
• Reduces platelet aggregation.
• Lowers C- Reactive protein levels – anti-inflammatory action.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Statins – Clinical Pharmacokinetics
• Should be administered orally• Lo – sim – pra – fluvastatin, should be
administered in evening / with dinner.• Ator – Rosuvastatin, can be given at any
time of day.• All statins will need dose adjustments with
gemfibrozil, cholestyramine, niacin.• Role of CYP3A4 & CYP2C9 enz.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Statins – adverse effects
• Major side effects– Myopathy (Diabetes, Advancing age & Drug)– Hepatotoxicity – Teratogenicity (Lo - Fluvastatin).
• Minor – Dyspepsia– Generalized eczematous rash (Simvastatin)
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Statins – indications
• Effective in almost all patients with elevated LDC-c levels
• Exception – familial homozygous hypercholesterolemia.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Bile acid binding resins
• LDL-c
Lowers LDL-c by 12 –28 %.
• TG
May increase transiently.
• HDL-c
Increases HDL levels by 4 –5%.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Bile acid binding resins – adverse effects
No systemic absorption, no systemic toxicity.
Only local GI side effects• Bloating• Dyspepsia
• Constipation
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Bile acid binding resins
• Indications – safest,Hypolipidemic of choice during pregnancy.
As a second line agent, if elevated LDL-c is not adequately controlled with statins.
• Drug interactions – Inhibits GI absorption of thiazides, furosemide, thyroxine,
statins, ezetimibe, fibrates, warfarin etc.Any additional drug should be administered 1 hr before or 4
hrs after the resins.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Ezetimibe
• Lowers LDL-c by 15- 20%.
(should be combined with a statin)
• Increases HDL levels by 1- 2%.
• Lowers TG’s by 5%.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Ezetimibe
• Adverse effects – almost none, well tolerated.
• No enzyme induction /inhibition is seen.
• Precaution: should not be simultaneously administered with bile acid binding resins.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Niacin
• LDL-c
Lowers LDL-c by 20- 30%
• TG
Lowers TG levels by 35-45%
• HDL-c
Increases HDL levels by 30- 40%.
• Lp(a)
Lowers Lp(a) level by 40%.
Physiologic dose, as vitamin B3– 50mg/ day
Pharmacologic dose, as hypolipidemic agent – 2 – 6gm/day.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Niacin
• Adverse effects 1. Cutaneous flushing2. Dry skin, itching3. Gastritis4. Hepatitis5. Precipitation of acute gout6. Hyperglycemia
• Contraindications H/o of gastric ulcer, gout, diabetes milletus
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Niacin - indications
• Hypertriglyceridemia
• Elevated LDL-c,
Especially in those with low HDL-c levels.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Fibric acid derivatives
• LDL-c
Increases LDL-c by upto 10-30%.
• TG
Lowers TG’s by upto 50%
• HDL-c
Increases HDL levels by 15%.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Fibric acid derivatives
• Adverse effects – Gallstone (Clofibrate)– Dyspepsia & abdominal pain– Increased risk of myopathy (gemfibrozil +
statins)
• Contraindications– Hepatic & renal dysfunction
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Fibric acid - indications
• Hypertriglyceridemia
• Chylomicronemia
• Type III dysbetalipoproteinemia
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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CETP inhibitor - Torcetrapib
• Increases HDL levels by 45- 100%.
• Under clinical trial.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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ω3 – fatty acids
• EPA & DHA, found primarily in fish oils, when given in high doses upto 6 gm/day, result in inhibition of VLDL secretion.
• TG level falls upto 75%
• Are very useful in treatment of severe hypertriglyceridemia’s ( > 1000mg/dl).
• However, these often raise LDL-c levels, in a manner similar to that seen with fibric acid derivatives, the clinical impact is however unclear.
• Commonest side effect is belching with a fishy odour
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Clinical states
• In this section, we will have some clinical states.
• This exercise shall rationalize the use of hypolipidemic agents.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Chylomicronemia Dietary restriction 1
CHL Pool
Dietary
CHL VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
To various body tissues,
Gut
HDL2 HDL3
CHL ester
TG
LDLCETP
1
Bile acids
Clinical state - 1
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Hypercholesterolemia2
5
4
3
Cholesterol absorption inhibitor
Bile acid binding resin
HMG CoA reductase inhibitor
VLDL secretion inhibitor
CHL Pool
Dietary
CHL
De novo CHL synthesis
HMG CoA reductase enz.
VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
To various body tissues,
Gut
HDL2 HDL3
CHL ester
TG
LDLCETP
2
53
4
Bile acids
Clinical state - 2
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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CHL Pool
Dietary
CHL VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
atheroma
Gut
HDL2 HDL3
CHL ester
TG
LDLCETP
6
5
Hypertriglyceridemia
6
5 VLDL secretion inhibitor
Fibric acid derivatives
Clinical state - 3
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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CHL Pool
Dietary
CHL VLDL
Chylomicrons
50%
50%
VLDL
LDL
TG
CHL
Atheroma
Gut
HDL2 HDL3
CHL ester
TG
LDLCETP 7
5
Low HDL-c levels
VLDL secretion inhibitor
CETP inhibitor
5
7
Clinical state - 4
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Special Population
• Children
• Women – Adolescence / Pregnancy/ Lactation/ Postmenopausal.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Special population – Children
• Less than 2 yrs of age – no dietary restriction & no drug therapy.
• > 2yrs – 10yrs – Dietary restriction of saturated and total fats ; CHL restricted diet only.
• 10 yrs & above – Diet therapy
Drug therapy is indicated only after an adequate trial of dietary control for 6mo – 1 yr.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Special population – Children
• Drugs Bile acid sequestrants (resins) are the first line agents of
choice.
If not - tolerated then,Statins can be given,
Ator – lova – sim, approved for 11yrs & above.
Pravastatin, for 8 yrs & above.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Women
• Statins should be used with caution in adolescent girls / females, likely to conceive.
• Bile acid binding resins are the only CHL – lowering drugs used during pregnancy.
• In post menopausal women, who wish to have HRT, elevated TG’s if any should be controlled with Dietary restriction, weight control and fibrates/ statins + fibrates, prior to initiation of HRT.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Combination regimens – why?
• Maximize reduction of LDL & VLDL.• Minimize side effects by using smaller
doses of drugs.• Allow use of resins, patients with elevated
TG’s & LDL.• Treat increased LDL, found consequent to
treatment of elevated TG with fibric acid derivatives.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Combination regimens – when?
• After diet & a single drug have been found insufficient.
• Statins, being the most effective & well tolerated, should be the first drug.
• Effect on Plasma lipoprotein levels & side effects should be assesed only after 4 –8 weeks of therapy.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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LDL-c reduction
• Statin + Fenofibrate
• Statin + Niacin
• Statin + Resins
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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VLDL reduction
• Nicotinic acid + fibric acid
• Addition of fish oils, may be helpful.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Minimize doses and side effects
• Statin + Ezetimibe is the safest combination.
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Diabetic patient
The defect,• Elevated TG’s / LDL
• Low HDL-c
• Glycosylated LDL
The treatment,• Adequate glycemic control & dietary restrictions.
• Drugs
04/10/23 Sachin Kuchya, MD Department of Pharmacology, NSCBMC, Jabalpur
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Diabetic patient - drugs
Niacin – impairs glycemic control
Resins – increases TG
Fibric acid level – increases LDL
So, combination of hypolipidemics is must,
Statin + fenofibrate, is the ideal combination.
Thank you
Topic is open for queries