Cardiovascular System - Drugs for Lipid Disorders

What are the three main types of lipids?

1. Triglycerides - energy storage

2. Phospholipids - formation of plasma membranes

3. Steroids (includes cholesterol) - formation of plasma membranes and precursor to bile, vit D, cortisol, estrogen, and testosterone

How are lipids transported in the plasma?

Lipids are not soluble in plasma (water soluble) and thus require to be packaged into apoproteins in order to be transported throughout the blood stream

What is LDL?

Low-density lipoprotein, aka the "bad" cholesterol

Consists mostly of cholesterol

Responsible for transporting cholesterol from the liver to the tissues - to be used for plasma membranes and creation of steroids

What is VLDL?

Very low-density lipoprotein

Consists mostly of triglycerides

Responsible for carrying triglycerides to the tissues, where it is then converted into LDL

What is HDL?

High density lipoprotein

Consists mostly of protein

Responsible for transporting cholesterol from the tissues back to the liver, where it is then excreted via bile in the feces

What is dyslipidemia?

High LDL and low HDL, resulting in increased risk of atherosclerosis and coronary artery disease

Men are more susceptible than women (estrogen as protective factor)

Postmenopausal women are more susceptible due to loss of estrogen

What are lifestyle interventions for management of dyslipidemia?

1. Diet

-> Reduced saturated fat, trans fat, and cholesterol

-> Increase consumption of plant sterols/stanols, and soluble fiber - can trap cholesterol in gut, inhibits absorption

-> Do not exceed 300mg/day of cholesterol

-> Consumption of nuts, olive oil, corn, rye, oats, rice and wheat

2. Weight and waist circumference maintenance

-> Exercise and stress reduction

3. Smoking Cessation/ Reduce alcohol intake <2 drinks/day

What are dietary changes as lifestyle interventions for management of dyslipidemia?

-> Reduced saturated fat, trans fat, and cholesterol

-> Increase consumption of plant sterols/stanols, and soluble fiber - can trap cholesterol in gut, inhibits absorption

-> Do not exceed 300mg/day of cholesterol

-> Consumption of nuts, olive oil, corn, rye, oats, rice and wheat

What is the primary pharmacological intervention for dyslipidemia?

Statins

What are statins? (Use, Mechanism of Action, Contraindications, Adverse Effects, Drug-Drug Interactions)

Use

Used as first-line therapy in treatment of dyslipidemia. Can slow progression of coronary artery disease and reduced cardiovascular diseases associated mortality

Mechanism of Action

Inhibits activity of HMG-COA reductase, which blocks synthesis of cholesterol in the liver.

This causes the liver to increase it's LDL receptors, causing increased removal of LDL from the blood. Results in lower LDL, lower VLDL, and higher HDL levels

Contraindications

Pregnancy -> until breastfeeding is complete

(some hydrophilic statins can be considered for prescription)

Alcohol and grapefruit juice consumption (impact on metabolism + liver enzymes)

Adverse Effects

Headache

Heartburn

GI upset (take with evening meals)

Rhabdomyolosis (elderly patients, high dose, co-administration)

Pharmacology induced T2DM (prolonged dosing - associated with increased pressure on liver)

Drug-Drug interactions

Can cause rhabdomyolosis if administered with other drugs that inhibit CYP 450 enzymes or drugs that increase bioavailability of statins

Can increase effects of warfarin

What is the use of statins?

Used as first-line therapy in treatment of dyslipidemia. Can slow progression of coronary artery disease and reduced cardiovascular diseases associated mortality

What is the mechanism of action of statins?

Inhibits activity of HMG-COA reductase, which blocks synthesis of cholesterol in the liver.

This causes the liver to increase it's LDL receptors, causing increased removal of LDL from the blood. Results in lower LDL, lower VLDL, and higher HDL levels

What are contraindications of statins?

Pregnancy -> until breastfeeding is complete

(some hydrophilic statins can be considered for prescription) -> required for formation of plasma membranes in cells of fetus + estrogen

Alcohol and grapefruit juice consumption (impact on metabolism + liver enzymes)

What are adverse effects of statins?

Headache

Heartburn

GI upset (take with evening meals)

Rhabdomyolosis (elderly patients, high dose, co-administration) -> resulting in significant muscle pain

Pharmacology induced T2DM (prolonged dosing - associated with increased pressure on liver)

What are drug-drug interactions of statins?

Can cause rhabdomyolosis if administered with other drugs that inhibit CYP 450 enzymes or drugs that increase bioavailability of statins

Can increase effects of warfarin

What medications for treatment of dyslipidemia are contraindicated and recommended in pregnancy?

Contraindicated

Statins

Ezetimibe - selective cholesterol absorption inhibitors

PCSK9 Inhibitors

Recommended

Bile acid sequestrants/resins

What are selective cholesterol absorption inhibitors? (Use, Mechanism of action, Adverse Effects, Contraindications)

Includes Ezetimibe

Use

Used as add-on therapy for treatment of dyslipidemia, or used as monotherapy in patients who have an intolerance of statin therapy

Mechanism of Action

Inhibits intestinal cholesterol absorption

Adverse Effects

Gi distress

Contraindications

Pregnancy

What is the use of selective cholesterol absorption inhibitors?

Primary add-on therapy (on top of statins) for treatment of dyslipidemia, or used as monotherapy in patients who have an intolerance of statin therapy

What is the mechanism of action of selective cholesterol absorption inhibitors?

Inhibits intestinal cholesterol absorption

What are PCSK9 inhibitors? (Use, Mechanism of Action, Dosing Regimen, Contraindications)

Use

Used as add-on therapy (on top of statins and/or ezetimibe) for treatment of dyslipidemia. Associated with reduction in clinical outcomes due to atherosclerotic cardiovascular disease

Mechanism of Action

Inhibits binding of PCSK9 to LDL receptors on the liver - PCSK9 is a ligand responsible for flagging LDL receptors for degradation- therefore the drug works to increase LDL receptor density on the liver, increasing hepatic removal of LDL from the bloodstream

Dosing Regimen

SUBQ every 2 weeks

Contraindications

Pregnancy

What is the use of PCSK9 inhibitors?

Used as add-on therapy (on top of statins and/or ezetimibe) for treatment of dyslipidemia. Associated with reduction in clinical outcomes due to atherosclerotic cardiovascular disease

What is the mechanism of action of PCSK9 inhibitors?

Inhibits binding of PCSK9 to LDL receptors on the liver - PCSK9 is a ligand responsible for flagging LDL receptors for degradation- therefore the drug works to increase LDL receptor density on the liver, increasing hepatic removal of LDL from the bloodstream

What are Bile Acid Resins? (Use, Mechanism of Action, Adverse Effects, Drug-Drug interactions)

aka Bile Acid Sequestrants

Use

Used as alternative add-on therapy (on top of statins) for treatment of dyslipidemia. Also used as recommended pharmacological treatment for patients who are pregnant and have familial hypercholesterolemia (otherwise, lifestyle interventions would be prioritized)

Mechanism of Action

Binds to bile acids and impedes enterohepatic circulation - prevents reabsorption of bile acids (with cholesterol) and increasing excretion of cholesterol

Reduction of cholesterol results in increased LDL receptors on the liver, resulting in increased removal of LDL from the bloodstream

Adverse Effects

GI upset (abdominal pain, bloating, diarrhea, steatorrhea, constipation)

Vitamin Deficiency (A,D,E,K)

Vitamin K deficiency can lead to increased bleeding time due to role in coagulation

Drug-Drug Interactions

Interferes with absorption of

-Thiazide diuretics

-Warfarin

-Thyroid Hormones

-Corticosteroids

Recommended to take these medications 1 hour before or 4 hours after administration of Bile Acid Sequestrants

What is the use of bile acid sequestrants?

Used as alternative add-on therapy (on top of statins) for treatment of dyslipidemia. Also used as recommended pharmacological treatment for patients who are pregnant and have familial hypercholesterolemia (otherwise, lifestyle interventions would be prioritized)

What is the mechanism of action of bile acid sequestrants?

Binds to bile acids and impedes enterohepatic circulation - prevents reabsorption of bile acids (with cholesterol) and increasing excretion of cholesterol

Reduction of cholesterol results in increased LDL receptors on the liver, resulting in increased removal of LDL from the bloodstream

What are adverse effects of bile acid sequestrants?

GI upset (abdominal pain, bloating, diarrhea, steatorrhea, constipation)

Vitamin Deficiency (A,D,E,K)

Vitamin K deficiency can lead to increased bleeding time due to role in coagulation

What are drug-drug interactions of bile acid sequestrants?

Interferes with absorption of

-Thiazide diuretics

-Warfarin

-Thyroid Hormones

-Corticosteroids

Recommended to take these medications 1 hour before or 4 hours after administration of Bile Acid Sequestrants