Properties of Anti-Hyperlipidemic Drugs

Atherosclerosis?

Disease in which a plaque of WBCs, fatty materials, calcium and scar tissue builds up on the walls inside the artery

What are fatty acids and what are the 2 types of them?

Long hydrocarbon carboxylic acids

Saturated and unsaturated

Saturated fatty acids?

Have no unsaturations → no C=C bonds

Ex; Palmitic and Stearic acid

Unsaturated fatty acids?

Have at least one unsaturated bond → C=C bonds

Considered “healthier”

Can be oxidized

Fatty acid nomenclature?

X:YΔⁿ

X = total number of carbons

Y = number of double bonds

Δⁿ = location of double bond(s), counting from the carboxyl (-COOH) end

Ω (omega) = location of the first double bond, counting from the methyl (CH₃) end

What are triglycerides and what happens during lipolysis?

Made up of glycerol + 3 fatty acids

Stored in adipose tissue as an energy reserve

Lipolysis breaks triglycerides → glycerol + fatty acids

Glycerol → glucose

Can contain saturated and/or unsaturated fatty acids

Main sources of cholesterol?

Diet → 300mg

Biosynthesis in liver and intestine→ 1g

What is the structure of cholesterol?

27 carbon hydrocarbon

Steroid nucleus

What are the roles of cholesterol in the body?

Structural component to membranes

Precursor to bile acids, hormonal steroids, and vitamin D3

What pathway synthesizes cholesterol?

Mevalonate pathway

Starts with Acetyl-Coenzyme A → Acetyl-CoA

What are bile acids?

Oxidization products of cholesterol

• Amphipathic molecule

How much and where are bile acids synthesized?

About 600mg~ synthesized in the liver daily to replace fecal excretion

What are plasma lipoproteins and what do they do?

They transport lipids through the blood

Ex → Chylomicrons, VLDL, LDL, HDL

Low density lipoproteins, LDL?

Lipoproteins that carry cholesterol from the liver to the peripheral cells

It contains ApoB-100 and is a major contributor to atherosclerosis

High density lipoproteins, HDL?

Lipoproteins that carry cholesterol from peripheral cells into the liver → which is then transformed into bile acids

It contains ApoA proteins and protects against atherosclerosis

Chylomicrons and VLDL?

Lipoproteins that carry triglycerides

Chylomicrons → carry dietary TG → from intestine → tissues

VLDL → carries TG made by the liver → from liver → tissues

Its main Apo protein is ApoB-100 → VLDL contributes to atherosclerosis.

What are the 4 major anti-hyperlipidemic drug classes?

Bile Acid Sequestrants

Nicotinic Acid → Niacin

Fibrates

Statins

How are anti-hyperlipidemics classified?

Reduce lipoprotein production

or

Enhance lipoprotein and/or cholesterol removal

What anti-hyperlipidemics reduce lipoprotein production?

Ezetimibe

MTP Inhibitors → Lopitamide

Fibric Acids → PPARa agonists

Nicotinic Acid → Niacin

What is niacin?

Vitamin B3 / Nicotinic Acid

Vitamin dose → ~20 mg/day

Lipid-lowering dose → 500–4,000 mg/day

What is pellagra?

Niacin deficiency

MOA of Niacin?

It activates the niacin receptor GPR1091

• Reduces → LDL, TGs

• Increases → HDL

Take with food

What are the major side effects of Niacin?

Vasodilation → flushing

Hyperglycemia → ↑ blood sugar

↑ Uric acid → gout

↑ Effect of blood pressure medications

What is niacin contraindicated in?

Pregnancy

Peptic ulcers

High liver enzymes

New-onset atrial fibrillation

How does niacin act as vitamin B?

It also acts as a precursor NAD, NADP+ → Redox factors

Why is niacin formulated in different formulations?

Comes in fast and extended release formulations to reduce flushing

Niacor ?

Acute short acting niacin → immediate release

Crystallized niacin tablet

Niacor concentration?

Following 1000mg dose → peak concentration at 25mg/L plasma reached in 30min

Flushing !!

Niaspan ?

Extended release formulation of niacin → 8 hr release

Crystallized niacin tablet at 375, 599m 750 or 1000mg

Niaspan concentration?

Peak concentration reached 4-5 hours following oral intake

Nicotinic acid (50-80%)

Hydroxypropyl Methylcellulose → (releasing agent, 10-30%)

Povidone → (binding agent, 1-10%)

Stearic Acid → (solubilizing/lubricating agent, <1%)

Slo - Niacin ?

Sustained release niacin → 24 hr release

Tablets with crystallized niacin in a polygel matrix

How do IR and SR niacin differ in metabolism and side effects?

IR → Conjugation → more flushing

SR → Amidation → less flushing but more liver toxicity

What fibrates?

PPARα agonists

Amphipathic compounds

Derived from fibric acid → Isobutyryl carboxylic acids

Some are ester prodrugs → improve oral absorption

What are the MOA of fibric acids?

↓ Lipolysis → ↓ FFA delivery to liver → ↓ VLDL → ↓ LDL

↓ Hepatic VLDL synthesis → ↓ TGs

↑ Lipoprotein lipase (LPL) activity → breaks down TGs

All of these process decrease triglycerides

Side effects of Clofibrate?

Flu-like

Tumor → Rare after long period

Gall bladder stones

Contraindications with Clofibrate?

Renal and hepatic failure

Pregnancy

Clofibrate increase activity/toxicity of?

Coumarins → anti-coagulation drugs

Phenytoin → seizure med

Tolbutamide → BP med

What are other actions of gemfibrozil and fenofibrate?

Decrease platelet aggregation and fibrinogen levels → less clotting and clot formation

Increases t-PA production → helps breaks down clots

Drug interactions of gemfibrozil and fenofibrate?

Increases coumarin levels → ↑ risk of bleeding

With statins → increases risk of myositis → muscle aches

What should gemfibrozil NOT be used with?

Statins!

What should fenofibrate NOT be used with?

In kidney failure!

What are the key characteristics of fenofibrate formulations?

Prodrug → hydrolyzed by esterases to fenofibric acid (active form)

Lipophilic + neutral → insoluble in water

Most formulations should be taken with food → high fat meal

Which forms of fenofibrate formulations should be taken with food?

Nonmicronized tablets

Micronized capsules

Microcoated micronized tablets

Hard gelatin capsules

Which forms of fenofibrate formulations do NOT need to be taken with food?

Nanoparticle tablets

IDD-P tablets

Fenofibrate choline salt

Fenofibrate non-micronized tablets brand names?

Fenoglide

Lofibra

Generic

WITH FOOD

Fenofibrate micronized capsules brand names?

Lofibra

Generic

WITH FOOD

Fenofibrate micro-coated micronized tablets brand names?

Lofibra

WITH FOOD

Fenofibrate hard gelatin capsules brand names?

Lipofen

WITH FOOD

Fenofibrate nanoparticle tablets brand names?

Tricor

DOES NOT REQUIRE FOOD

Fenofibrate IDD-P tablets brand names?

Triglide

DOES NOT REQUIRE FOOD

Fenofibrate choline salt brand name?

Trilipix

GREAT BIOAVAILABILTIY OF ALL FORMULATIONS

DOES NOT REQUIRE FOOD

What is microsomal triglyceride transfer protein (MTP)?

An intracellular lipid-transfer protein in the endoplasmic reticulum of liver cells and intestinal absorptive cells

Helps package triglycerides into → chylomicrons and VLDL

What is lomitapide?

Juxtapid

Indicated for familial hyperlipidemia

MOA of lomitapide?

Inhibits MTP → prevents ApoB containing lipoproteins assembly in liver/absorptive intestinal cells

Which is required for microsomal TG transfer and essential for the formation of VLDL

Net effect → Decreases VLDL

Characteristics of lopitamide?

Low bioavailability → little reaches the bloodstream

Highly protein bound → most binds to blood proteins

Extensively metabolized in the liver → by CYP3A4

Excreted in feces and urine

Adverse effects of lomitapide?

GI → not serious

Hepatic fat accumulation → hepatic steatosis

What is mipomersen?

An antisense phosphorothioate oligonucleotide that binds to ApoB-100 mRNA

Prevents the mRNA from making ApoB-100 protein

Weekly injections

Why does mipomersen have a phosphorothioate linkage?

The phosphorothioate linkage makes mipomersen more resistant to nucleases → enzymes that break down DNA/RNA

Side effects of mipomersen?

Injection site reactions

Hepatic steatosis

What is Ezetimibe?

An inhibitor of cholesterol absorption → exclusively at the brush border of the small intestine

Blocks uptake via jejunal enterocytes by inhibiting the transport protein NPC1L1

How selective is ezetimibe?

Very selective → Does not interfere with absorption of TGs, lipid soluble vitamins (A, E) or other nutrients

CANNOT BE USED WITH BILE ACID SEQUESTRANTS → They inhibit it from reaching its site of action

What anti-hyperlipidemics enhance circulating cholesterol/lipoprotein removal?

Anion exchange resins → Bile acid sequestrants

HMG CoA reductase inhibitors → Statins

PCSK9 Inhibitors

Bile acid sequestrants?

Have positively charged polymers (N+) → bind negatively charged bile acids

Exchange chloride (Cl⁻) for bile acids

Not absorbed from the intestine

Excreted in feces

Examples of bile acid sequestrants?

Cholestyramine

Colestipol

Colesevelam

Colestilan

Colextran

How do bile acid sequestrants lower LDL-C?

They decrease bile acids → liver uses more cholesterol to make new bile acids → lowering LDL-C in the blood

What effect can bile acid sequestrants have on fat-soluble vitamins?

They can also bind fat-soluble vitamins A, D, E, and K in the GI tract → decreasing vitamin absorption → possible vitamin deficiency with long-term use

How are bile acid sequestrants formulated?

Made of long, cross-linked polymers

Contain positively charged amines and Cl⁻

Come in powder formulations

What is an advantage of colesevelam over other bile acid sequestrants?

Fewer GI side effects

Does not significantly reduce vitamins A or E

Side affects of bile acid sequestrants?

GI upset

Taste

Bile acids reduce the absorption of?

Thiazides

Digoxin

Warfarin

Iron

Propranolol

Contraindications of bile acid sequestrants?

should NOT be used if TGs are over >300 mg/dL

What is Mevastatin?

The first statin

Potent HMG-CoA reductase inhibitor

Binds the enzyme ~10,000× more strongly than its natural substrate

Discovered in 1970s from penicillium brevicompactum → never marketed

What is mevinolin / lovastatin ?

Lovastatin = Mevinolin

Developed by Merck → marketed as Mevacor

Developed in the 1970s

Prodrug → converted to its active acid form

What are natural statins and the decaline ring?

Natural statins → Originally isolated from fungi

Decaline ring → Key 2-ring structure found in natural statins that helps bind HMG-CoA reductase.

What are synthetic statins associated with structurally?

Synthetic statins → Man-made statins

Contain a dihydroxy-heptanoic acid group that mimics the natural substrate of HMG-CoA reductase

Which statins are metabolized by CYP3A4?

ALS!

Atorvastatin

Lovastatin

Simvastatin

CYP3A4 inhibitors/inducers can increase risk of myopathy and liver injury

How do statins lower cholesterol?

They inhibit HMG-CoA reductase → decreasing cholesterol production in the liver → increasing LDL receptors activity → increasing LDL removal from blood → overall decreasing circulating cholesterol

What risks are associated with statin use?

Increase risk of diabetes mellitus and transaminase (liver enzyme) elevations

Cataracts reported in a large retrospective study

No increased cancer risk

What are the most potent statins?

Roustatin (crestor) and Atorvastatin (Lipitor)

Follow by simvastatin (Zocor) and pravastatin (pravacor)

What is important to know about statin protein binding?

Most statins are highly protein-bound

Pravastatin is the exception → less protein-bound

Pravastatin is therefore less likely to displace albumin-bound drugs like warfarin

Why are rosuvastatin and atorvastatin administered at anytime in the day?

They have longer half lives, so they can administered at any time in the day

When should other statins be administered?

At night, during the biosynthesis of endogenous cholesterol

How does food affect lovastatin depending on the formulation?

Lovastatin IR → Food → bioavailability ~50% → take with the evening meal

Lovastatin ER → Fasting → increased bioavailability when fasting

What are some benefits from statins that are independent from LDL?

Improved vasodilation

Reduced vascular smooth muscle proliferation

Anti-inflammatory actions → reduced CRP, CGRP

Reduced lipoprotein oxidation → antioxidant effect

Reduced platelet aggregation

How does food affect statin absorption?

Lovastatin absorption increases with food

Other statins can be taken on an empty stomach

How are statins primarily eliminated?

Mainly through hepatic metabolism

What statins have significant renal clearance?

Simvastatin

Lovastatin

Pravastatin

10-20%

What happens to statins after they are absorbed?

About 30–90% are absorbed

But they undergo rapid and extensive first-pass metabolism in the liver

Side effects with statins?

Myalgia → pain related to statin based myopathy

Myositis → inflammation confirmed via muscle biopsy

Myopathy → muscle damage/weakness related/unrelated, occurs with cyclosporine and statins → less common with fluvastatin/pravastatin

Rhabdomyolysis → extreme myopathy, muscle tissue breaks down resulting in high serum myoglobin that overwhelms the kidney → better prevented then treated

Drug-drug interactions with statins?

Coumarin action

Contraindications with statins?

Pregnancy

Simvastatin/Zocor alone or with ezetimibe with amiodarone/cordarone/pacerone causes severe muscle injury requiring hospitalization

Simvastatin 80mg should be used unless patients have been on it for 12 months with no evidence of myopathy

Which enzymes should be monitored with statins?

Hepatic Transaminases (ALT and AST) → Liver injury

Creatine phosphokinase (CPK) → Muscle Injury

Why should pharmacists care about statins and exercise?

Statins can cause muscle symptoms → may blunt exercise adaptations

MOA of PCSK9 inhibitors?

Monoclonal antibody binds PCSK9

Prevents LDL receptors from being broken down

More LDL receptors remain on the liver cell surface

Increasing LDL removal from blood → lowering LDL blood concentrations

Sides effects of PCSK9?

Hypersensitivity and allergic reactions

Increased risk of upper respiratory infections and nasopharyngitis

No noted DDI or contraindications

What are the PCSK9 inhibitors and why are they used in familial hypercholesterolemia?

Alirocumab & evolocumab → mABs that block PCSK9

Decreasing PCSK9 → more LDL receptors → increases LDL removal → decreases blood LDL

Some familial hypercholesterolemia is caused by a PCSK9 mutation → excessive PCSK9 activity → fewer LDL receptors → very high LDL

Alirocumab / Praluent ?

mAB → IgGI → 146,000MW

CHO cells with rDNA

SubQ injections → every 2 weeks

Yearly cost → 15k (vs. ~$100,000/year for LDL apheresis)

What are the PK characteristics of alirocumab / praluent?

SubQ bioavailability → ~85%

Tmax → 3–7 days

Max PCSK9 suppression → 4–8 hours

Half-life → 12–18 days

How is alirocumab / praluent eliminated and what is its immunogenicity?

Eliminated by proteolytic breakdown and binding to PCSK9

~5% develop antibodies

~1% develop neutralizing antibodies

Evolocumab / Repatha ?

mAB → IgG2

CHO cells using rDNA

SubQ injection every 2–4 weeks

Cost is similar to alirocumab