Lipid Lowering Agents Flashcards
What are Lipid Carriers (Lipoproteins)?
Triacylglycerols and cholesterol can’t flow freely in blood at high levels
- require “carriers”
What are the 4 types of Lipid Carriers (Lipoproteins)?
- Chylomicron
- Very Low Density Lipoprotein (VLDL)
- Low Density Lipoprotein (LDL)
- High Density Lipoproteins (HDL)
What are Chylomicrons?
- Carrier of dietary lipids from intestine
to liver - TG-rich, some Chol
What are Very Low Density Lipoprotein (VLDL)?
- Carrier of lipids from liver to periphery * TG-rich, some Chol
What are Low Density Lipoprotein (LDL)?
“BAD chol”
* Carrier of lipids from liver to periphery * Chol-rich,someTG
What are High density Lipoproteins (HDL)?
“GOOD chol”
* Scavenge cholesterol from artery wall
Dietary and liver-synthesized lipids are absorbed @ _______
small intestine
_______ carry absorbed fat to adipose tissue (and ~muscle)
Chylomicrons
Lipoprotein lipases on endothelial cell surfaces liberates ________ + ______
free fatty acid + glycerol
Chylomicron remnant taken up by the ________ for processing
liver
Cholesterol is synthesized in the _____
liver
Describe the process of Cholesterol
- Cholesterol is synthesized in the liver
- Liver packages TG and cholesterol into VLDL
- VLDL carries these lipids to tissues, especially adipose
- Lipoprotein lipases on endothelial cell surfaces liberates free fatty acid + glycerol
- VLDL->IDL->LDL as FA are removed
- LDL carries cholesterol to other peripheral tissues; excess is taken up again by liver
- HDL carries excess cholesterol scavenged from vessels and tissues back to the liver
What are 2 Lipid Disorders?
- Pancreatitis
- Atherosclerosis
What is Pancreatitis?
Pancreatitis: Inflammation of the pancreas
* Caused by elevated plasma Triglycerides
* Primarily elevated chylomicrons, VLDL as well.
What is Atherosclerosis?
Atherosclerosis - Deposition of cholesterol in arteries
* Problem in coronary and cerebral blood flow
* Caused by elevated plasma CHOLESTEROL & TRIGLYCERIDES
* Primarily derived from low density lipoproteins (LDL’s)
- 50% of Western Society have ↑ LDL levels
- favors “abnormal deposition” to vessel walls
Where do emboli lodge in Atherosclerosis?
- Carotid artery thrombosis
- Coronary artery thrombosis
- Other sites?
What are risk factors for Coronary Heart Disease?
- Age
o Male >45 years of age or female >55 years of age - Family history of premature CHD
o 1st degree relative (male <55 years of age or female <65 years of age when the first CHD clinical event occurs) - Current cigarette smoking
- Hypertension
o Blood pressure ≥140/90 or use of antihypertensive medication
What steps in exogenous or endogenous pathway could you disrupt to ↓ plasma chol?
Cholesterol:
* ↓ GI uptake
- ↓ dietary intake in gut
- ↓ reabsorption of bile acids in gut
- ↓ absorption of cholesterol in gut
- ↓ endogenous cholesterol synthesis in liver
- ↓ LDL levels
- ↓ VLDL production by the liver
- ↑ LDL receptors on hepatocyte surface
What are the drugs for Hypercholesterolemia?
- Non-pharmacological approach – Dietary fiber
- Cholesterol synthesis inhibition - Statins
- Cholesterol Absorption Inhibitor – Ezetimibe
- Bile Acid Binding Resins –
Cholestyramine, Colestipol - Inhibiting LDL receptor degradation - Evolocumab
Non-pharmacological approach for Hypercholesterolemia?
Dietary fiber
Cholesterol synthesis inhibition drugs for Hypercholesterolemia?
Statins
Cholesterol Absorption Inhibitor drugs for Hypercholesterolemia?
Ezetimibe
Bile Acid Binding Resins drugs for Hypercholesterolemia?
Cholestyramine, Colestipol
Inhibiting LDL receptor degradation drugs for Hypercholesterolemia?
Evolocumab
What is Dietary Fiber?
is dietary material that is resistant to the action of digestive enzymes (soluble and insoluble)
What is insoluble fiber?
is indigestible
* Sources: vegetables, whole grains
What is soluble fiber?
can be broken down by gut microbiome * Sources: oatmeal, oat bran, fruit
What does the non-pharmacological approach for dietary fiber do?
Soluble fiber binds chol in gut to reduce plasma chol
What does 100g/day oat bran diet (cereal and muffins) for 3 weeks do?
- Total Cholesterol 19%
- LDL Cholesterol 23%
What are the Choleterol Synthesis Inhibition drugs?
- Rosuvastatin, atorvastatin, simvastatin, lovastatin etc
- Drug of 1st choice for most patients with risk for coronary heart
disease (atherosclerosis) - ↓ LDL levels (modest HDL increase).
- Also ↓ triglyceride levels.
- In patients with coronary artery disease – decreased cardiac morbidity, mortality, reduced incidence of stroke
- Benefits seen with initial high or normal cholesterol
What is the mechanism of action for Statins?
- Inhibit HMG-CoA Reductase, the rate limiting step of cholesterol synthesis
- Results in compensatory increase in LDL receptors
- Best given in evening
- Diurnal pattern of cholesterol synthesis
What are the adverse effects & contraindications of Statins?
- Generally well-tolerated
- Major: Myopathy
- Major (but rare): Hepatotoxicity
- Contraindication – pregnancy
- First pass metabolism
- CytochromeP450 3A4 (CYP3A4) metabolizes some statins
- Interactions
- Avoid CYP3A4 inhibitors (Eg. in grapefruit juice)
What would happen to plasma [Statin] if you washed the pill down with a CYP3A4 inhibitor?
metabolize less therefore increase levels (we count on most of it to be graded down therefore have more in circulation & we’re not counting on more)
What is the order of bioavailability?
- Simvastatin
- Lovastatin
- Atorvastatin
Where is the majority of Statin LDL-C efficacy?
with the Starting Dose
Statins appear beneficial toward…
BOTH males & females
LDL chol ↓seems GREATER with ________ and __________
Rosuvastatin
and
Atorvastatin
What are the pleotropic effects of Statins?
- May increase bone formation - possible osteogenic effect
- May reduce fracture risk in elderly patients
- Hypertension - may lower blood pressure?
- Dementia - decrease risk of developing dementia
- Renal function - may help preserve renal function
- Asthma - trials as drug for asthma
- Cancer – under investigation
What is an ex of pleotropic effects of Statins?
Eg. Rho-family GTPases involved in immune activation, Cancer cell proliferation
What is the Cholesterol Absorption Inhibitor: Ezetimibe?
- ↓ LDL levels ~15-20% when used alone
- No effect on triglycerides or fat-soluble vitamins
- Compensatory ↑ in hepatic cholesterol synthesis
What is the mechanism of action for Cholesterol Absorption Inhibitor: Ezetimibe?
- Inhibits a cholesterol transport protein: NPC1L1 (Neimann-pick C1-like1)
- ~50% ↓ in dietary and biliary cholesterol absorption at the intestinal brush border
What are the adverse effects of Ezetimibe?
- Reports of myalgia, hepatitis, rhabdomyolysis, acute
pancreatitis - Causal relationship unclear
- In combination with statins – possible greater elevation of transaminases (rel. to statins alone)
What are the interactions with Ezetimibe?
- Bile acid sequestrants interfere with Ezetimibe’s actions
Why combine Statins + Ezetimibe?
- Combination is additive at lowering cholesterol
- Ezetimibe ↓ cholesterol uptake in gut but get compensatory ↑ in cholesterol synthesis in liver
- HMG-CoA reductase inhibitors block this increased synthesis
What are the Bile acid binding resins?
- Cholestyramine, Colestipol
- (+) charged non-digestible resins which bind to bile acids in the gut
- ↓ LDL-Chol
- Effective alone for mild to moderate elevated LDL-C
- Effective with statins for highly elevated LDL-C
What is the mechanism of action for Bile acid binding resins?
- Binds bile acids in intestinal
lumen - Prevents reabsorption (normally 95%)
- Less bile acid recirculated to liver
In the presence of Bile acid binding resins, to produce new bile acids, the liver must:
- Take up cholesterol (↑LDL receptors)
- Increased cholesterol de novo synthesis
What are adverse effects of Bile acid binding resins?
Major:
* May ↑ VLDL levels – unknown mechanism
Minor
* ↓ absorption of fat-soluble vitamins (-> vit K deficiency)
* Nausea, constipation, and bloating (may be helped by fiber)
* Unpleasant taste and texture
* Absorption of drugs altered (effect can be +ve, -ve, neutral)
- Ie. Digitalis, thiazides, warfarin, aspirin, etc
Why combine Statin + Bile acid binding resins?
- Combination is additive at lowering cholesterol
- BABRs ↓ cholesterol uptake in gut but get compensatory ↑ in cholesterol synthesis in liver
- HMG-CoA reductase inhibitors block this increased synthesis
What are add-on to Statin Therapy: Drug options to lower LDL-C?
- Double statin dose
- Ezetimibe
- Bile acid binding agent (colestipol, cholestyramine)
- Niacin
- Fenofibrate
- Gemfibrozil
High-risk Patients Achieving LDL-C Goal in Canada
Failure to achieve:
- Poor adherence to treatmet
- High baseline LDL-C (FH patients)
- High-cholesterol diet
- High cholesterol absorption
- Variable statin response
- Inability to tolerate (higher-dose) statins
What are the Inhibiting LDL receptor degradation drugs?
- Alirocumab, Evolucumab
- Injectable antibody to PCSK9 (Proprotein convertase subtilisin kexin type 9)
- ↓ LDL-C
- Newest therapy for patients that can’t meet target LDL-C with Statins
- HIGH COST
What is the mechanism of action for Alirocumab, Evolucumab?
- Antibody travels to liver, binds PSCK9, inhibits its interaction with LDL receptor
- This interaction normally targets LDL-receptor for degradation (instead, it targets for recycling)
What are other drugs for cholesterol lowering?
Lomitapide (Juxtapid)
* Microsomal triglyceride transferase protein inhibitor
- Reduces chylomicron and VLDL synthesis
- For Familial Hypercholesterolemia patients with defective LDL receptors
- Expensive!
Which step in exogenous or endogenous pathway could you disrupt to ↓ plasma TG?
- ↓ dietary intake of TGs
- ↑ Lipoprotein lipase (LPL) activity
- ↓ VLDL secretion from liver
What are the drugs for Hypertriglyceridemia?
- Non-pharmacological approach – Dietary fiber, fish oil
- Increase lipoprotein lipase – Fibrates, gene therapy?
- Reduce VLDL secretion – Niacin
What are the non-pharmacological approach for Hypertriglyceridemia?
Dietary fiber, fish oil
What are the increase lipoprotein lipase drugs for Hypertriglyceridemia?
Fibrates, gene therapy?
What are the reduce VLDL secretion drugs for Hypertriglyceridemia?
Niacin
What is the non-pharmacological approach for Dietary Fiber?
Both types of fiber appear effective
* Insoluble fiber is indigestible
- Sources: vegetables, whole grains
* Soluble fiber can be broken down by gut microbiome
- Sources: oatmeal, oat bran, fruit
- Other benefits
- Increase bulk of stool; Good for constipation
- Decrease colonic cancer?
What are the problems & adverse effects of Dietary Fiber?
- Need large amounts
- Gaseous distention
- Long term effect and safety unknown
What is the non-pharmacological approach for Fish Oil?
- Omega-3 polyunsaturated fatty acids DHA and EPA
- Main effect: ↓ VLDL production
- Secondary effect: ↑ VLDL clearance
- 4g/day found to reduce TG by 20-30%
- In some trials, LDL-C somewhat increased by DHA alone
- May not be pro-athlerogenic b/c complex effects on LDL density, oxidation status, etc
- REDUCE-IT Trial (EPA combo with statin): 25% decrease in major adverse CV events
- Currently available as food/dietary supplement (not regulated, label can include health claim) or prescription (regulated)
What is the mechanism of action for Fish Oil?
- Reduces NEFA delivery to liver to be used for TG synthesis by:
- ↓ lipolytic release of FA from adipocytes (result of suppressing inflammation?)
- ↑ NEFA uptake and B-oxidation in other tissues incl. heart and skeletal muscle
- Several other complex cellular bioactivities likely contributes to TG lowering and other beneficial effects
What are the problems & adverse effects of Fish Oil?
- Gastrointenstinal complaints, nausea, “fish burps”
What is the Increase Lipoprotein Lipase: Fibrates?
- Fenofibrate, Gemfibrozil
- Fibric acid derivatives
- Activator of the nuclear receptor PPARα (peroxisome proliferator activated receptor-α)
- Primary effect: ↓ triglycerides
- Secondary effects: May ↑ HDL, ↓ LDL
- Men with Coronary heart disease- after 5 yrs
- Incidence of death was decreased even though LDL levels were unaltered
What is the mechanism of action for Fibrates?
- Activation of PPARα results in increased expression of LPL
- Get ↑ LPL activity at various tissues (adipose, muscle)
- Increases chylomicron and VLDL clearance from circulation
LESS TG left in chylomicron remnant & LESS TG left in VLDL remnant
What are the adverse effects of Fibrates?
- Major
- Flu-like – muscle cramps, tenderness, stiffness, weakness
- Increased risk of myopathy when combined with statins
- Not as common
- Avoid in case of hepatic or renal dysfunction
- May potentate oral anticoagulants and hypoglycemic
agents (↓ metabolism) - Use with cation with increased risk of biliary tract disease
(ie. women, obese patients, First Nations) - Commonly reported in large studies
- Non-cardiac death, incl accidents, suicide, violence etc
– Later studies – no correlation with lipid lowering
What is the Increase Lipoprotein Lipase: Gene therapy?
Alipogene Tipatvovec (Glybera)
* AAV1 delivery of LPL to patients with rare genetic LPL deficiency
* Expensive - $1.2M/yr to treat!
What is the Reduce Hepatic VLDL Secretion: Niacin?
- Water-soluble vitamin (B3) nicotinic acid aka Niacin
- NOT nicotinamide
- Low dose: ↑ HDL
- Higher dose: ↓ triglycerides
- May also ↓ LDL
- Men with previous myocardial infarction
- Reduced incidence of non-fatal myocardial re-infarction
- Decreased mortality rate at 9 years
What is the mechanism of action for Niacin?
- Activates niacin receptors on adipocytes to decrease TG hydrolysis
- Less NEFA released into circulation
∴ Less NEFA taken up by liver
∴ Less NEFA converted to TG
and secreted as VLDL
What are the adverse effects for Niacin?
- Most serious are:
- liver enzymes in blood (evidence of hepatoxicity?)
- Hyperglycemia due to insulin resistance
– Use with caution in diabetes - Short term:
- Acute skin flushing and pruritus (1-2 weeks?)
– Blunted by asprin - Use with caution
- Exacerbation of peptic ulcer ∴ avoid if at risk
- Minor:
- Dry eyes, blurred vision, fatigue, GI distress
Which carries mainly TG from the liver to peripheral tissues?
VLDL
Which carries mainly cholesterol to peripheral tissues?
LDL
Which carries dietary lipids from the intestine to the liver?
Chylomicrons
Which acts as a cholesterol “scavenger”? What does this mean?
HDL - brings it back to liver
High levels of which puts you most at risk for arteriosclerosis?
LDL - why it’s the most targeted
