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
Another name for Niacin
pyridine-3-carboxylic acid
What vitamin family does niacin belong and which form has vitamin property?
water soluble B-complex vitamin family and posses the vitamin property only in amide form.
When does niacin show its anti-hyperlipidemic effects?
Niacin shows its anti-hyperlipidemic effects only at higher doses.
What receptors does niacin work through, and which family do they belong?
Act mostly through Niacin receptor 1/2 (Hydroxycarboxylic acid receptor, GPR 109 A / B)- belong to GPCR family
Niacin: MOA
Has actions in two different tissues
Depends upon its actions in adipose tissue and liver
Adipose: Inhibits lipolysis of triglyceride particle by hormone-sensitive lipase (HSL), resulting in decreased break down of triglycerides to free fatty acid
molecules
Liver: By blocking the adipose tissue triglyceride breakdown niacin prevents the hepatic triglyceride synthesis in the liver.
Niacin MOA continued. How does it effect LPL activity, Apo A-I content effect on monocytes / macrophages?
➢ Niacin also enhances LPL activity, which promotes the clearance of chylomicrons and VLDL triglycerides.
➢Increase Apo A-I content of plasma, major apoprotein in HDL, involved in reverse cholesterol transport.
➢In monocytes/macrophages, niacin enhance the cholesterol efflux process by upregulating the efflux transporters of cholesterol, like ABCA1.
Niacin adverse effects
skin / stomach, liver, blood suger
flushing, skin dryness and dyspepsia
incidence of flushing is increased when niacin is administered with caffeine containing ( coffee, tea) or ethanol
(MOST SERIOUS) hepatotoxicity, as observed with elevated transaminases (AST and ALT)
hyperglycemia- (due to increased hepatic gluconeogenesis
What is the mechanism responsible for flushing of skin caused by Niacin?
Niacin receptor (GPCR) mediated release of AA
produces glandins PGE2 and PGD2
PGE2 and PGD2 act on DP1/EP2/EP4 receptors in smooth muscle cells
leads to vasodilation and redness
Niacin: Contraindications
Patients with a history of gastrointestinal complications mostly peptic ulcer or ulcerative colitis
b) Diabetes
What to do if patient develops hyperglycemia following administration of Niacin?
Immediately niacin should be discontinued.
the patient should be switched to diabetes medication or insulin.
Niacin Metabolism:
peak plasma levels, t1/2, location, major metabolite
- They reach peak plasma levels in an hour.
- The t 1/2 is about an hour
- Metabolized by the liver
- The major metabolite is nicotinuric acid- nontoxic urinary metabolite of nicotinic acid
which is formed following biotransformation in hepatic tissue.
What are the 2 fibrates, the receptors they act on and their site of action?
The Fibrates: Gemfibrozil, Fenofibrate
- Act via receptors called peroxisome proliferator-activated receptors (PPARs).
- The site of action – mostly liver and adipose tissue and also
have shown to have some effects on kidney, heart, and
skeletal muscle.
Mechanism of Fibrate induced lipid lowering?
MOA - Fibrates are peroxisome proliferator-activated receptors (PPAR) α agonists
Binding promotes the heterodimerization of nuclear receptor PPAR
with Retinoid X receptor (RXR)
heterodimer complex binds to the PPAR Responsive Elements (PPRE) leading to up or down regulation of target genes
What are some of upregulated and
downregulated genes as a result of fibrates?
Upregulated genes include – LPL, LDL receptor, Apo CII, Apo A 1
Downregulated genes: include – Apo C111, and IL6
Fibrates: Drug interactions
Increase the activity of oral anticoagulants like warfarin. Patients must be monitored
gemfibrozil has a major interaction with statins,
Why does gemfibrozil cause a major interaction with statins?
receptor / enzyme
they prevent the uptake of statins in the liver by interfering with OATP1B1 transporter mediated statin uptake
compete for the same enzyme (- glucuronosyl transferases) which helps in their own metabolism
- As a result both of their plasma levels increase. If statin levels increase -> high incidence of myopathy
What is alternative strategy for taking fibrates with statins?
to use fenofibrate - because there are no major interactions
observed with statins. No events of myopathy has been reported with the combination of
fenofibrate and statin.
Contraindications for fibrates?
In Renal failure and hepatic disorders.
Fibrates never recommended for children and pregnant women
Adverse Effects of Fibrates
none of this was highlighted on slides
- Gastrointestinal side effects are rare (in almost 5% of subjects).
- Minor hepatotoxicity as observed with raise in AST and ALT levels
- Has lithogenic property- resulting in formation of gall stones
What is PCSK9 and its role?
Where is it localized?
Proprotein convertase subtilisin/kexin 9 (highly expressed/formed in the kidneys, liver and intestine.
- Secreted into blood stream
** localized extracellularly**
PCSK9 bind to LDL-R ultimately leading to the degradation of the LDL receptor
PCSK9 (Evolocumab and Alirocumab): MOA
MOA:- The antibodies bind and inhibit PCSK9 activity
PCSK9 inhibition prevents a PCSK9 mediated LDL receptor degradation in the lysosomal system.
Causes LDL receptor in membrane to increase
The increase in membrane LDL
receptor increase LDL-C clearance from plasma.
PCSK9 inhibitor- Adverse effects and contraindications
Evolocumab and Alirocumab
➢ It can cause mild and severe allergic reactions
Contraindication:-
➢ In pregnant, and also breastfeeding women
➢ In patient with a prior history of auto-immune or allergic diseases
What is Inclisiran, and its MOA?
*** SiRNA based therapy
**
* MOA- Inclisiran is a SiRNA targeting PCSK9 mRNA
-resulting in degradation of PCSK9 mRNA and limiting PCSK9 protein synthesis.
-As a result, the LDLReceptor is spared, which could result in enhanced surface LDL-receptor expression and LDL clearance.
What is an inhibitor of dietary cholesterol uptake?
Ezetimibe
Ezetimibe: MOA
site of action / what they inhibit / what they block / secondary effect
The site of action of is the intestinal lumen.
- They inhibit luminal cholesterol uptake by small intestinal cells especially the jejunal enterocytes by blocking the** cholesterol transport protein NPC1L1.(Nieman Pick C1 like 1)**
**
Secondary beneficial effect- As the cholesterol delivery to liver is decreased,
the liver starts synthesizing more LDL- receptor to clear LDL cholesterol from
plasma.
Ezetimibe: Adverse Effects and DDI
nothing color coded on slide
➢Rarely allergic reactions have been reported.
➢ With statins contraindicated in pregnant and nursing women
Name the Microsomal Triglyceride Transfer Protein (MTTP) Inhibitor
Lomitapide
Lomitapide: MOA
**MOA **- Lomitapide binds to
MTTP in the ER thus preventing the packing or assembly of ApoB containing lipoprotein bodies.
which include both chylomicrons ApoB48 (enterocytes) and VLDLC- ApoB 100 (hepatocytes)
What does inhibition of MTTP cause?
Chylomicron generation, VLDL secretion, and LDL-C levels
this isnt highlighted
Inhibition of MTTP decreases Intestinal Chylomicron generation and hepatic VLDL-C
secretion into the system as a result the LDL-C level also drops
Lomitapide: Adverse Effects and DDI
Adverse effects;
➢ Gastrointestinal side effects
➢ Headache
➢ Hepatic toxicity with increased transaminase levels
Drug Drug Interactions
➢ With warfarins
➢ Should be avoided with strong CYP3A4 inhibitors itraconazole or ketoconazole,
erythromycin or clarithromycin, and HIV protease inhibitors.
Source of Omega-3 fatty acid derivatives, and the 2 active ingredients
Comes from Dietary Source-** fish liver oil**. The active ingredients are Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA)- (Lovaza, Omtryg)
Omega- 3 fatty acids derivatives: MOA
anti-inflammatory, gene inhibition, metabolic benefits, NO release
➢ MOA involves various actions;
a) As anti-inflammatory – prevents formation of Arachidonic acid derived inflammatory agents (prostaglandins, thromboxanes, leukotrienes, and the inflammatory cytokine expression)
b) Inhibit NF Kappa B mediated increase in inflammatory gene transcription
a) Metabolic benefits through upregulating PPAR (peroxisome proliferator-activated
receptors) activity
b) Known to enhance Nitric Oxide release by upregulating endothelial NOS
protein
Adverse effects of Omega – 3
increases what whats an alternative drug
* Mostly importantly: DHA component in Omega – 3 supplements are known to
increase LDL- C levels.
* FDA approved alternative – Vascepa (Icosapent ethyl)- EPA component only.
- Chronically may cause gastrointestinal and hepatic disturbances.
- Studies demonstrate associated risks with high dose and chronic use on
cardiovascular system
What is the FDA approved drug for lowering circulating triglycerides without increasing bad cholesterol (LDL-C)
Icosapent Ethyl- only EPA (Eicosapentaenoic acid)
Icosapent Ethyl (VASCEPA) is devoid of unwanted adverse effects of DHA (increasing the LDL- C levels)
4 cardiovascular benefits of Icosapent Ethyl (Vascepa)
➢ Improves endothelial function,
reduces oxidative stress and prevents foam cell formation
➢ Prevents inflammatory cytokine generation and release
➢ Prevents plaque formation,
progression and rupture.
➢ Inhibits platelet aggregation and thrombus generation
2 Newer Agents for Treating Hyperlipidemia
Bempedoic Acid /ETC 1002 (FDA approved 2020)
Evinacumab
Bempedoic Acid /ETC 1002: MOA
Where is inactive prodrug activated?
Effect on LDL-R uptake
MOA – Inhibits ATP citrate lyase (ACL), the enzyme involved in the synthesis of Acetyl- CoA
-As a result cellular cholesterol synthesis is decreased.
The inactive / prodrug needs to be activated in the hepatic tissue
-cause a decrease in liver cholesterol and increase in LDL uptake via upregulation of LDL-R
- **decreasing blood
LDL-C levels. Very effective in lowering LDL-C levels
**
Indications and DDI for Bempedoic Acid /ETC 1002
*** Indications - Heterozygous Familial Hypercholesterolemia or with persistent long term atherosclerotic cardiovascular disease – as adjunct to diet and max tolerated statin therapy.
* DDI – with statins higher incidences of myopathy – (more than 20 mg Simvastatin and 40 mg of Pravastatin should be avoided)
Bempedoic Acid: Warning and Contraindications
Other than statins, what other drug is it administered with?
*** Warning – Bempedoic acid causes a rise in blood uric acid levels.
*** Contraindications – Not administered in patients with gout and during pregnancy and also in breast feeding women. Potential to cause fetal toxicity
**
Also administered as a combination **with Ezetimibe **
What is evinacumab and what does it target?
recombinant human IgG4 monoclonal antibody
targets angiopoietin-like protein 3 (ANGPTL3).
When did Evinacumab receive FDA approval? What is it an adjunctive therapy for?
In February 2021, evinacumab received FDA approval as an adjunctive therapy for homozygous familial hypercholesterolemia (HoFH)
Evinacumab: MOA
receptor, result
➢ Evinacumab binds directly and blocks ANGPTL3.
➢ Blocking ANGPTL3, spares LPL and EL activity and improves triglyceride breakdown
➢ Finally, reducing LDL-C levels
Evinacumab: Serious Warnings
➢ Severe hypersensitivity reaction
➢ Embryo- Fetal toxicity, so contraindicated in pregnant women
