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
What are the symptoms of GERD?
Heartburn (pyrosis) - discomfort leading into neck
Regurgitation
Occurs mainly after fatty meals
Alarm symptoms:
- dysphagia
- odynophagia
- bleeding / wt loss / anemia
- long duration of symptoms
What is the gold standard for monitoring GERD/
Ambulatory reflux (pH monitoring)
- trans nasally placed catheter and wireless device attached to distal esophageal mucosa
Collect pH -> 1-4 days with the wireless device
Other monitoring of GERD:
Esophageal manometry - measures LES spinchcter
Barium Swallowing - detects peptic ulcers
Endoscopy - upper GI exam
What is Barrett Syndrome?
Abrnormal change in cells that can lead to adenocarcinoma
What are some lifestyle modifications for GERD?
Elevate head of bed Decrease Fat Intake Avoid Acidic Foods - citrus, alcohol, caffeine Stop Smoking Avoid recumbency 3 hrs after eating Lose wt if necessary
Surgery for GERD indicated for:
Recurrent pulm symptoms
Barrett esophagus
Severe esophagitis
Success = best in pts with <50% and with symptoms that resolve with PPI
Tagamet
H2 Receptor Antagonist
Zantac
H2 Receptor Antagonist
Pepcid
H2 Receptor Antagonist
Protonix
PPI
Prilosec
PPI
Prevacid
PPI
Aciphex
PPI
Nexium
PPI
Clarithromycin
Antibiotic for H. Pylori, which might cause GERD
Amoxicillin
Anti-biotic for H. Pylori
Tetracycline
Antibiotic
Heartburn 2x/week
associated with GERD
What is GERD?
Mucosal damage produced by abnormal reflux of gastric contents in the esophagus
What causes GERD?
Excess acid production in stomach
Delayed gastric emptying
- acid builds up
- bc of hiatal hernia, changing in resting pressure (incompetent LES), acid enters esophagus
Acid Reflux occurs when…
LES - pressure is often low
No esophageal pinch in the diaphragm
GERD is made worse by…
Recumbuncy (reclining)
Occurs mainly after fatty meals
Symptoms of GERD
Regurgitation
Heartburn (pyrosis) - sterna burning discomfort that radiates towards neck
Alarm symptoms of GERD (to worry about complicated disease)
Dysphagia (difficulty swallowing)
Odynophagia (painful swallowing)
Bleeding Wt Loss Anemia Long Duration No Responses to treatment
Can assume a diagnosis of GERD if there is…
A symptomatic response to anti secretory therapy with a PPI or H2 Antagonist
If no response to treatment or alarm symptoms present, consider further testing.
What is an upper GI exam?
Endoscopy
- considered if there is a “complicated disease” or at risk for Barrett’s esophagus
What is Barrett’s Esophagus?
Abnormal change in cells that can lead to esophageal adenocarcinoma (a lethal form of cancer)
GI Endoscopy done if the pt is at risk for this
To confirm Barrett’s esophagus…
Biopsy needed
What is essential for a diagnosis of GERD?
typical esphagitis
a normal endoscopy does not rule out GERD
- possibility of non-erosive reflux disease
What is the gold standard for a GERD diagnosis?
Ambulatory reflux (pH) monitoring: Carried out if…
- trial of acid suppression has failed
- if there is no evidence of mucosal damage on endoscopy
Collection Time:
- 1-4 days with the wireless device
Barium Swallow
Used to detect GERD
- limited use in diagnosis
- useful in detecting peptic strictures
Esophageal Manometry
Measure LES pressure
Minimal use in diagnosis
Done usually to:
- evaluate peristaltic functioning before antireflux surgery to exclude major motility disorders
Treatment options for GERD: Lifestyle Modifications
Elevate head while in bed Decrease fat intake Avoid acidic foods - Stop smoking (as tobacco inhibits saliva and stimulates gastric acid) Avoid Recumbency 3 hrs after eating Lose weight if necessary
Antacids
Shown to provide relief in 20% of patients
- More RAPID response than H2Receptor Antagonists
H2 Receptor Antagonists
Lower in strength than antacids, yet longer acting
Does not promote healing!
Only approved for relief of occasional heartburn symptoms!
Omeprazole
Proton Pump Inhibitor
The dose is identical to a 14 day short-term treatment
What treatment for GERD suppresses acid?
Antacids
What do antacids do?
Used for heart-burn related symptoms
Most patients used 2x/week
Antacids are weak bases that react with…
HCl to form salt and water
They reduce acidity and therefore pepsin activity (pepsin is inactive in solutions above 4.0
Most antacids are:
NaHCO3, CaCO3, Mg(OH)2, Al(OH)3
What are the side effects of antacid use?
Mg2+ can cause diarrhea
Al3+ can cause constipation
What secretes gastric acid?
Three principal agonists
- histamine
- acetylcholine (Ach)
- gastrin
What agonists of gastric acid release bind to ECL cells?
Gastrin and Ach bind to ECL cells -> causes a Histamine release
Histamine then binds to H2 receptor on parietal cells -> H+/K+ pump active!!
Gastrin and Ach can also bind DIRECTLY to parietal cells…
Causing activation of the H+/K+ ATPase
Gastric Antisecretory Drugs
Inhibit the activity of:
- histamine
- Ach
- proton pump
Histamine Receptor Blockers (H2 receptor blockers)
Inhibit the binding of histamine to the H2 receptor on parietal cells, thereby DECREASING the acid production in the cell
- eliminates symptoms in 50% of pts with prescription strength dosing
- costs lower than PPIs
Cimeditidine
H2 Receptor Antagonist
AKA tagamet
Ranitidine
Zantac
H2R antagonist
Famotidine
Pepcid
H2R Antagonist
Cimetidine (Tagamet)
H2R antagonist
- contains an arginine-like tail, mimicking the NH2 group in histamine
Side effects of Cimetidine
Dizziness, drowsiness
Breast development in males
H2R Antagonist
Ranitidine (Zantac)
Replaced imidazole ring of cimetidine with a FURAN ring
10x more active than Cimetidine!
Rantitidine ran longer than Cimet!
Famotidine (Pepcid)
FTW (Famotidine is 30x more active than cimetidine)
- Best Buy for the money
PPIs and mucosal healing…
Provides mucosal healing of esophagitis at 6-8 weeks in 75-100% of cases
More expensive than H2 antagonists
PPIs
Eliminate symptoms and heal esophagitis more rapidly than other agents
Do PPIs exist in active or pro-drug form?
PRO DRUG
- they are converted into the active form under low pH
- they bind IRREVERSIBLY (covalently) to H/K ATPase, the terminal source of acid (H+) in parietal cells
Single dose inhibits 100% of gastric acid secretion - completely knocks out acid secretion
The acidic environment allows conversion of…
Pro-drug’s intramolecular activation to the active form
Requires acidic environment
Rabeprazole
PPI
Lansoprazole
PPI
Pantoprazole
PPI
Omeprazole aka Prilosec
PPI
Esomeprazole Mg (Nexium)
PPI
QD
Everyday
BID
2x daily
TID
3x daily
QID
4x daily
Treatment options for GERD…
PPI (-prazole) + antibiotic
Ranitidine bismuth citrate (RBC) + antibiotic
What are the indications of GERD for surgery?
- recurrent symptoms, severe esophagitis, recurrent pulm symptoms, Barrett esophagus
Success is in pts <50 yo
Complications of surgery:
- obstructive symptoms
- disruption of vagally-mediated relaxation of LES when swallowing
What is the most reliable objective indicator of GERD?
Ambulatory pH monitoring
