Anti-Hyperlipidemics I & II Flashcards
What is the Mevalonate Pathway?
Cholesterol Synthesis Pathway
What is the rate limiting enzyme for cholesterol synthesis?
Hydroxymethyl-Glutaryl(HMG)-CoA Reductase – rate limiting enzyme for cholesterol synthesis
Cholesterol lowering drugs mainly target this enzyme
What are chylomicrons and VLDL and where are they synthesized? What enzymes break them down?
How are breakdown products taken up into liver?
➢ Chylomicrons are the lipoproteins formed from intestine following dietary fat intake and VLDL is the
lipoprotein produced from the liver. Both contain triglycerides that undergo breakdown with the aid of Lipoprotein Lipase (LPL) and hepatic lipase (HL) to release free fatty acids.
- LPL and HL are targets of cholesterol medications
➢ The breakdown products or remnants of lipoprotein particles are taken up by the liver through the mediation of Apo B and Apo E (protein component), which act as ligands.
Which two receptors in the liver absorb lipoprotein remnant particles following breakdown?
LDL receptors and Remnant receptors
What part of a lipoprotein binds to liver receptors for entry?
Apoprotein portion
Identify the types of apoproteins on Chylomicrons, VLDL, LDL and HDL.
➢Diet or gut derived lipoproteins
Chylomicrons – Apo B-48 (major)
containing lipoproteins
➢ Liver derived VLDL and LDL lipoproteins are Apo B-100 (major) containing lipoproteins
➢ HDL is an Apo A (major) containing lipoprotein
Common gene mutations leading to hyperlipidemia
Mutation / Age of Onset / Molecular basis
Lipoprotein lipase (LPL) / Infancy or childhood / Severely reduced or absent LPL enzyme activity
Apolipoprotein C-II (APOC2) / Adolescence to adulthood / Absent or non-functional apo C-II
Glycosyl-phosphatidylinositol-anchored HDLbinding protein (GPIHBP1) / Later adulthood / Absent or deficiency in GPIHBP1
Apo A-V (APOA5) / Later adulthood / Absent or defective apo A-V
Lipase maturation factor-1 (LMF1) / Later adulthood / Defective or absent LMF1
What is used as a biomarker for atherosclerosis and CV disease? Above what blood concentration is considered a risk factor?
Lipoprotein (a)
Lipoprotein(a) is formed by bridging of Apo B 100 containing low-density lipoprotein (LDL) particle with Apo A by a disulfide bond
High = ≥75.0 nmol/L and is considered a risk factor
What are the good and bad cholesterols, and why?
LDL is considered bad because it deposits cholesterol in the artery walls and starts the process of atherosclerosis
HDL is considered good because it removes cholesterol from the bloodstream and artery walls. (scavengers)
How does HDL remove cholesterol from the blood stream?
Reverse Cholesterol Transport
Body’s innate ability to remove cholesterol from atherosclerotic plaques back to liver and finally into bile- a process mediated mostly by HDL
Briefly explain Reverse Cholesterol Transport
➢Reverse Cholesterol Transfer is the pathway that transports cholesterol from extrahepatic tissues mostly the vessel walls back to the liver and intestine for recycling and excretion.
➢High-density lipoprotein (HDL), and its apoprotein- apolipoprotein A-I (ApoA-I) forms the principal mediator for RCT.
➢HDL levels in your body is a mark of efficient RCT and also cholesterol efflux out of vessel walls.
Name 4 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors
common ending?
The statins
Atorvastatin, Simvastatin, Rosuvastatin & Pravastatin
3 bile acid-binding resins
Colesevalam, Cholestyramine and Colestipol
The Nicotinic Acid
Niacin
2 Fibric Acid derivatives
gemfibrozil, fenofibrate
The cholesterol absorption inhibitor
Ezetimibe
Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors
Common ending?
Evolocumab and Alirocumab
Cumab
MTTP Inhibitors
Lomitapide
Omega-3 fatty acids
New drug Vascepa-(Icosapent Ethyl)
Lovaza Omtryg
What are the 4 statins and their primary MOA
Statins- Atorvastatin, Simvastatin, Rosuvastatin & Pravastatin
MOA- Primary. Statins are selective competitive inhibitors of HMG-CoA reductase.
They prevent the interaction between HMG CoA and the enzyme HMG CoA reductase.
As a result, the mevalonate pathway is brought to a stop. Statins inhibit an early and rate-limiting step in cholesterol biosynthesis.
Statins: Secondary MOA
▪ HMG CoA inhibition results in increased expression of the LDL receptor gene.
▪ As a result of reduced synthesis of cholesterol
within the cells, Endoplasmic Reticulum (ER)
membrane and Golgi bound SREBPs proteins (Sterol
Responsive Element Binding Protein) are cleaved by
Site proteases (S1P, S2P) leading to translocation of
SREBP to the nucleus.
▪ The SREBP in the nucleus then increase LDL receptor
gene, as a result there is more LDL receptors on the surface of cell which helps in removal of LDL cholesterol from blood
6 pharmacological effects of Statins
**Decreasing LDL-C Levels.
**
Cardioprotective effects: Independent of lipid lowering
Improve Endothelial Function: eNOS mediated NO increase.
Regulate Plaque Stability: inhibit monocyte infiltration into the artery wall
Anti-inflammatory role: They reduce the C reactive protein level in the circulation
Anti-coagulant role: They have shown to reduce the venous thromboembolic events
Statin: Metabolism
First pass / enzyme
Simvastatin and Lovastatin (inactive lactones) need to be converted to β-hydroxy acid
derivatives (in the liver)-to their active forms- simvastatin hydroxy acid (SVA) and lovastatin
hydroxy acid (LVA).
There is extensive first-pass hepatic metabolism for all statins and is regulated by an
Organic anion transporter (OATP1B1)
Statins: Adverse Effects
Liver, Muscle (what is given as supplement) what increases risk?
Hepatotoxicity:-They cause an increase in hepatic transaminase (AST and ALT) to
values greater almost more than 3 times the normal.
Myopathy:-A major adverse effect - Statin induced reduction in Co-enzyme Q10
synthesis could be a possible cause, so supplementing Co-enzyme Q10 could
help.
Rhabdomyolysis (rapid muscle damage) - incidence increase with statin dose –a rare effect – risk increases with grapefruit consumption- eg: drug-food
interaction.
-The furanocoumarins in grapefruit inhibit CYP enzymes (CYP 3A), preventing statin metabolism and increasing their systemic presence and toxicity.
What happens as a result in depletion of bile acids by using bile acid sequestrants
➢The process of depletion of bile acids is accompanied by an increase in new bile acid synthesis by the liver.
➢ Increase in bile synthesis decrease hepatic cholesterol content.
➢ As a result, there is an increase in hepatic LDL Receptor membrane localization and thus enhanced LDL clearance from the circulation
3 Bile Acid Sequestrants (the resins) and their MOA
Colesevelam, Cholestyramine and Colestipol
MOA - It is based on charge based interaction.
➢The bile-acid sequestrants (resins) are (+ve) positively charged and they bind to bile acids which are negatively charged (-ve).
➢The large sized bile-resin complexes are not reabsorbed
➢ As a result, they are eliminated from the body through stools as resin-bile complex. As a result,
there is a compensatory increase in LDL Receptor mediated LDL-C uptake.
Bile Acid Sequestrants: Adverse Effects
➢The resin mediated hepatic bile acid synthesis could also trigger an increase in hepatic triglyceride synthesis, and in some patients, it may cause significant hypertriglyceridemia (where their basal levels always remain >250 mg/dL).
➢Use of these drugs should always be accompanied by regular and frequent
monitoring of triglyceride levels.
➢ Almost 25 % of patients suffer from poorly tolerated gastrointestinal side
effects accompanied by bloating, dyspepsia and constipation
Contraindications and DDI of bile acid sequestrants
Patients with severe hypertriglyceridemia should not be prescribed the resins
Drug - Drug Interactions:-
◆The resins could interfere with thiazides, furosemide, propranolol,
L-thyroxine, digoxin, and warfarin.
◆It is better to administer resins at least few hours before or after
administration of above mentioned drugs
