Statins And GI Flashcards
PCSK9 Inhibitors
Decreases LDL by 60%
Side effects:
Hypersensitivity rxs, possibly neurocognitive events
Evolocumlab
Alirocumab
Decreasing incidence of heart disease
the longer and lower the reduction in circulating LDL-C, the lower the incidence of CHD
Lipoproteins in the gut versus liver
Gut = chylomicrons - LDL and TG Liver = VLDL - LDL and TG
Coronary Artery Disease Risk Factors
High TG High cholesterol High BP Smoking Gender/age/family hx
Drugs that decrease LDL-cholesterol -> heart disease
What is the RLS in cholesterol synthesis?
Enzyme HMG CoA reductase
HMG CoA -> mevalonate
What do LDL receptors in the liver control?
The production and catabolism of plasma LDL
VLDL -> IDL -> LDL
SREBP
Transcription factor = the master regulator of cholesterol levels in cells
In a low-cholesterol diet = SREBP is ACTIVE
In a high-cholesterol diet = SREBP is INACTIVE
When SREBP is active under conditions of low cholesterol diet…
Increase in cholesterol biosynthesis
Increase in receptor mediated LDL-endocytosis from plasma
Decrease plasma LDL
When SREBP is inactive under conditions of low cholesterol diet…
Decrease in LDL biosynthesis
Decrease in LDL receptors
Plasma LDL remains high
Statins are best tolerated for treating:
Dyslipidemia
HMG CoA reductase inhibitors (competitive inhibitors)
Statin function:
Inhibit cholesterogenesis
Increased expression of LDL receptor
Increased removal of LDL from the blood (levels decrease 20-55%)
Decreased VLDL production
TG levels decrease
HDL levels slightly increase
What part of the LDL molecule is recognized by the LDL receptor?
ApoB protein on the LDL
SLCO1B1
Gene that encodes for OATP1B1
When mutated, it reduces hepatic uptake of simvastatin acid
PCSK9
Proprotein convertase substilsilin/kexin
Degrades the LDLR
The antibody to PCSK9 (PCSK9-inhibitor) allows the LDLR to be recycled.
What is commonly used with statins to reduce LDL levels in plasma?
Evolucumab (PCSK9 inhibitor)
Ezitimibe
Cholesterol absorption inhibitor in the intestine
When combined with statins = 50-60% decrease
Alone = 19%
What does ezitimbe block?
NPC1L1 = cholesterol transporter in enterocytes
Inhibits cholesterol and plant sterol absorption.
Decreases delivery of cholesterol to the liver, slightly increases HDL
Increases expression of hepatic LDL receptor
Decreases the cholesterol content of atherogenic particles
Is Ezitimbe well tolerated?
Not systemically well tolerated
Resins
Also known as BAR - bile acid sequestrant resins
Cholestyramine
BAR
Colestipol
BAR
Colesevelam
BAR
Cholate
Bile Salt
Deoxycholate
bile salt
Therapeutic uses of BARs
Pts with bile salt accumulation must take with meals OR no effect!
Removes digitalis from the GI tract
Familial Hypercholesterolemia
Reduction in the number of LDL receptors, therefore LDL accumulates in the plasma
What is the net effect of Bile Acid Sequesterants (Resins)?
Decrease in LDL-C levels (2 weeks)
Increases LDL receptors
Increase in BA secretion
Increase in Cholesterol 7Alpha Hydroxylase
What is the mechanism of resins?
Bind to the (-) charged bile acids, excreted in stool
HMG-CoA reductase upregulated (this increase in LDL slightly offsets the reduction in LDL)
What increases the effectiveness of a resin?
coadministration of a statin, increases effectiveness of resin
What pts should be avoided with administration of a resin?
Pts with severe hypertrigylceremia, as HDL-C levels increase 4-5%
Concern is in pts that have >250mg HDL-C levels
Resins taken approx 4hrs before/after use of a statin/ezitimibe
What is the toxicity of a resin?
Constipation, bloating = relieved by fiber, psyllium seed
Heartburn
Diarrhea
Rare: malabsorption of folic acid, vitamin K (hypoprothrombinia)
SREBP
When active = in situations of low circulating LDL
- upregulates the receptor to bring more cholesterol into the cell
- increases cholesterol biosynthesis
When inactive = in situations of high circulating LDL
- reduces the number of receptors, so not as much cholesterol brought into cell
- decreases cholesterol synthesis
Statin as a competitive inhibitor of HMG CoA Reductase. Effects?
Inhibit cholesterolgenesis
Increase expression of LDL receptor
Increase removal of LDL (VLDL, IDL) from blood
Decrease hepatic VLDL production
Therapeutic Use of Statins
Alone or in combination with resins or ezetimibe
▪ Contraindicated in women who are pregnant, lactating or likely to become pregnant (category X, teratogenic)
▪ Some statins approved for use in children homozygous or heterozygous for familial hypercholesterolemia
Toxic Effects of Statins
Liver effects
Elevations in serum alanine aminotransferase (ALT) activity (up to 3x normal)
Medication should be discontinued if ALT >3x is persistent or signs of hepatotoxicity present (precipitous decrease in LDL, anorexia, malaise)
Myopathy from Statin use
increased incidence of myopathy associated with polymorphisms in gene encoding liver-specific OAT
Drug Interactions of Statins:
- seen when some statins given with other drugs & substances (e.g., grapefruit juice) metabolized by CYP3A4
CYP3A4 is responsible for degrading Statins, therefore if there are CYP3A4 inhibitors, then plasma levels of statins increase - Inhibitors of organic anion transporter (OAT)
Statin uptake by the liver - abrnomalities
Genetically impaired activity of organic anion–transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 reduces hepatic uptake of active simvastatin acid
- causing accumulation of simvastatin acid in plasma and an increased risk of myopathy.
How are PCSK9 inhibitors administered?
Subcutaneous administration
PCSK9 inhibitors
Decrease LDL-C by preventing degradation of the receptor
What BAR tends to not interact with statins?
Colesevelam does not appear to interfere with the absorption of most statins.
Peptic Ulcer symptom
Pain in gut 2-3 hours postprandial or in the middle of the night
Causes:
NSAID
Helicobaacter pylori (erodes the membrane)
Peptic Ulcer Syndrome by H. Pylori and Treatment
Treated with amoxicillin, tetracycline, clarithromycin
GERD
Gastroesophageal reflux disease
- symptoms of mucosal damage produced by gastric contents into the esophagus
- delayed gastric emptying
- excess acid production
- lower esophageal spinchter
- hiatal hernia