Anti-Dyslipidemic Drugs in Pharmacology

What is dyslipidemia?

Abnormal elevation of cholesterol or fat levels in the blood. Mainly caused by: Sedentary lifestyle, More intake of fat, Abnormal lipid metabolism

Causes of Dyslipidemia

• Diabetes mellitus
• Excessive alcohol intake
• Sedentary lifestyle
• Lack of exercise
• Excessive intake of fatty substances.

Symptoms of Dyslipidemia

• Indigestion
• Heartburn
• Chest pain
• Chest tightness
• Leg pain,etc.

Also read: Introduction to Adrenergic drugs

Antidyslipidemic Agents

• Other names: Lipid lowering agents, or hypolipidemic agents, cholesterol lowering drugs, or antihyperlipidemic agents.
• Mostly used to treat hyperlipidemia.
• Use: To lower the amount of lipids and lipoproteins (cholesterol) in the body.

1. Statins

• Atorvastatin, Lovastatin, Simvastatin, Rosuvastatin, Fluvastatin, and Pravastatin

MOA

Statins act by inhibiting the enzyme HMG CoA reductase, so there is less formation of cholesterol by the liver. Now there is upregulation of LDL receptors on the surface of the liver. They will take up cholesterol from the blood. Statins have maximum LDL cholesterol lowering potential . Drugs included are (-vastatin)

• Atorvastatin
• Rosuvastatin
• Pravastatin
• Simvastatin
• Fluvastatin
• Cerivastatin

Some drugs end in '-statin' but they are not HMG-CoA (-). These include

i. Cilastatin: Given with Imipenem to inhibit its breakdown.

ii. Pentostatin: It inhibits the enzyme adenosine deaminase (ADA)

iii. Somatostatin: It is a hormone

Also read: Rational Drug Prescribing and Essential Medicine

Special Points of Statins

i. Food increases absorption of statins, so they are given just after meals. Exception → Pravastatin. It can be given irrespective of meals

ii. HMG CoA enzyme is maximally active at night. So statins should be given late in the evening or at night for maximum effect. Exception → Atorvastatin, Rosuvastatin. They are very long acting and can be given anytime of the day.

iii. Statins are metabolized by CYP3A4, except pravastatin. So if we give them enzyme inhibitors, it can lead to toxicity. For e.g. Ciprofloxacin, Erythromycin

iv. Statin toxicity (features)

• M - Myopathy (seen with Fibrates and CYP inhibitors)
• D - DM
• H - Hepatotoxicity

So, whenever statins are started, we should check for Creatinine phosphokinase (CPK) levels for monitoring the muscle damage.

v. Pleiotropic effect

Any other beneficial effects, apart from the antidyslipidemic effect, are called pleiotropic effects

• Atorvastatin & Rosuvastatin are longest acting statins
• Pravastatin
  • Minimum food interaction
  • Minimum drug interaction
  • Minimum CNS penetration
  • Minimize fibrinogen levels
• Simvastatin & Lovastatin are prodrugs. They have maximum CNS penetration

2. Intestinal Cholesterol Absorption Inhibitors

• They act by inhibiting a pump in the intestine called the Neimen pick-like 1C1 pump (NPL1C1). This pump helps in the absorption of cholesterol
• Ezetimibe drug inhibits this pump. So dietary cholesterol is not absorbed and level decreases in blood.

Also read: Pharmacogenetics: Gene Response to Medicine

3. Fibrates 

Drugs included are

• Clofibrate
• Fenofibrate
• Bezafibrate
• Gemfibrozil

Fibrates stimulate the PPAR a receptors. These receptors ↑LPL concentration. This results in reduction of LDL, VLDL. Fibrates have maximum triglyceride lowering potential. Fibrates are commonly combined with statins. But this combination increases the risk of myopathy

4. Niacin (Vitamin B3) 

• It is a very inexpensive and easily available drug.
• It causes max. increase in HDL cholesterol.
• It causes max. decrease in Lipoprotein-A.
• It is not used commonly because it causes side effects like: Itching, Flushing

To avoid these S/E, we can use Aspirin which is COX (-). So, there is less production of PGD2. We can also use a drug called Laropiprant. It is an oral PGD antagonist

Niacin can cause other S/E like

• ↑Uric acid
• Insulin resistance
• Hepatotoxicity

5. Bile acid binding agents (BABA) 

• Drugs included are
  • Cholestyramine
  • Colestipol
  • Cholesevalam
• Enterohepatic cycling means that the same bile acid can be utilized repeatedly
• Bile acids act as carriers and carry cholesterol from GIT to blood.
• BABA drugs bind to bile acids in the GIT. Now cholesterol cannot bind to the bile acids. This BABA-bile acid complex cannot be absorbed. So it is removed, as a result there is decrease in bile acids in the GIT.
• Now the liver will start forming bile acids. So there is decreased cholesterol in the liver. This will induce LDL receptor synthesis in the liver. Thus, it will take up cholesterol from the blood.
• BABA are DOC in children and in pregnancy.

Also read: Anti-Emetic Drugs

New Hypolipidemic drugs

1. PCSK-9 inhibitors

• Pre-protein Convertin Subtilisin Kexin type 9 (PCSK-9) is a protein that binds to LDL receptors and takes it to lysosomes. This results in breakdown of LDL receptors.
• PCSK -9 inhibitors prevent the breakdown of LDL receptors. When more LDL receptors are present, they can take up more LDL cholesterol from blood.

These drugs act by two methods:

i. ↓Synthesis of PCSK-9

• Inclisiran: It is a small molecule inhibitor of RNA.

ii. Monoclonal Ab against PCSK-9

• Alirocumab
• Evolocumab

These drugs are indicated in Homozygous hypercholesterolemia

2. Lomitapide

• It is microsomal triglyceride transport protein inhibitor (MTP inhibitor)
• Triglyceride is packed into VLDL & chylomicrons by MTP protein
• Lomitapide will inhibit the formation of VLDL etc, so LDL will not be formed.

Also read: Drugs Used for Cough

3. Anacetrapib

• It is a Cholesterol Ester triglyceride Transport Protein inhibitor (CETP inhibitor)
• HDL normally takes up the cholesterol from the tissues and brings back to the liver (Reverse cholesterol transport)
• HDL exchanges its cholesterol & TG b/w LDL & VLDL with the help of CETP enzyme.
• When CETP is inhibited, HDL will not be able to exchange its cholesterol, so there is less degradation of HDL and the HDL level increases.

4. Mipomersen

• Drugs ending with '-rsen' are Antisense oligonucleotide against mRNA of Apo B100
• It will decrease all the Apo B containing lipoproteins like 100 LDL, VLDL, etc.

5. Evinacumab

• It is the only drug that acts independent of LDL receptors.
• It is a monoclonal antibody against angiopoetin-like 3 proteins.
• This protein normally inhibits two enzymes: Lipoprotein lipase (LPL) & Endothelial lipase (EL)
• This drug results in↑action of LPL & EL, so this results in ↓level of VLDL, LDL and chylomicrons. This also results in↓HDL levels.

Summary

Also read: Corticosteroids: Uses, Side Effects, and Treatment

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