Which drug is 40 times more potent than furosemide?
bumetanide
Where do the loop diuretics act?
thick ascending loop of Henle
Name the two 5-2-3 high ceiling/loop diuretics.
Furosemide (lasix)
Bumetanide (bumex)
Which drugs can be used off-label to treat end stage cancer when plasma calcium levels might be really high?
loop diuretics like furosemide and bumetanide
What are the 5-2-3 loop diuretics indicated for?
edema caused by CHF and hepatic cirrhosis
renal disease
acute pulmonary edema
hypertension (only oral dosage form)
symptomatic hypercalcemia
What is the MOA of 5-2-3 loop diuretics?
inhibit the Na-K-Cl-carrier system primarily in the Loop of Henle
some trace of activity in the proximal and distal tubules
These drugs are weak acids and therefore are excreted in the proximal tubule via OATS?
5-2-3 loop diuretics (furosemide and bumetanide)
T/F: 5-2-3 loop diuretics are extensively albumin bound and therefore diuresis takes 2-3 days if the drug is given orally.
true
When given in submaximal doses for HTN, which one has less frequency of hypokalemia? Thiazides or loops?
Loops = less hypokalemia because of shorter duration of action
What are some side effects of the 5-2-3 loop diuretics?
hypokalemia (use caution w/ glycosides like dig)
excess fluid and electrolyte loss (reduced GFR and loss of efficacy)
increased resorption of drugs normally excreted by proximal tubule (lithium and uric acid (gouty attack))
otoxicity (because of loss of K+)
N/V
myalgia
hyperglycemia
sulfa hypersensitivity
Name the 4-3 loop diuretic.
Torsemide (Demadex)
Which loop diuretic is metabolized by the CYP system and therefore has a lot of DIs?
torsemide (demadex)
This loop diuretic has the same indication and MOA as furosemide and bumetanide?
torsemide
This loop diuretic is 99% protein bound?
torsemide
This loop diuretic has side effects like ototoxicity, dizziness, muscle cramps, fatigue, nausea, and ORTHOSTATIC HYPOTENSION?
torsemide
What is the only loop diuretic that does not have a sulfa group?
Edecrin (ethacrynic acid)
Name the phenoxyacetic acid loop diuretic.
Edecrin (ethacrynic acid)
This is the loop diuretic of choice if you have a sulfa allergy?
Edecrin
This loop is indicated for ascites due to malignancy, idiopathic edema, lymphedema, pediatric congenital heart disease and nephrotic syndrome?
Edecrin
T/F: All three classes of the loop diuretics have the same MOA.
true
This loop is excreted 66% via OATS as unaltered drug and cysteine and glutathione conjugates and 33% goes into the bile?
Edecrin
Name some drugs that interact with loop diuretics.
aminoglycosides
cardiac glycosides
lithium
salicylates
NSAIDs
anticoagulants
clofibrate
beta blockers
thiazide diuretics
Should you take loop diuretics with or without food?
without food for max absorption
Describe GERD.
injury to the lumen of the esophagus by regurgitation of gastric or gastroduodenal contents (H+, pepsin, bile acids, pancreatic enzymes)
poor clearance of stomach contents and defective sphincter function
aka heartburn
Name some drugs that lower esophageal sphincter tone.
calcium channel blockers
nitrates
theophylline
anticholinergics
narcotics
beta agonists
estrogen
progesterone
Name 3 direct irritants on the GI tract.
NSAIDs
Potassium supplements
bisphosphonates
When might you suspect that a child has GERD?
if they:
cough at night
complain of abdominal pain
refuse to eat
have a bad taste in their mouth
How do you treat GERD?
stop alcohol
stop tobacco
avoid certain foods
eat 4-6 hours before bed
drugs like antacids, PPIs, H2RAs
What are some symptoms of severe GERD?
erosion
continual pain
stricture/spasm--Barrett's esophagus--adenocarcinoma risk is greatly increased
What are some symptoms of atypical GERD?
chest pain
hoarseness
throat tightness
asthma
chronic cough
hiccups
lingual dental erosion
recurrent otitis in kids
What are some symptoms of common GERD?
heartburn
hyper-salivation
belching
vomiting
regurgitation
Name the 3 steps of ulcers healing.
Exfoliation
Restitution
Recovery
What type of bacteria is H. pylori?
gram (-) rod
What causes peptic ulcers? Bacteria or stress?
Bacteria
How prevalent is the H. pylori infection that causes ulcers?
50% have it worldwide and it increases with age
How does H. pylori cause peptic ulcers (in basic terms)?
it colonizes the mucus of the gastric epithelium
Who proved that H. pylori was the cause of peptic ulcers and not stress?
Barry Marshall and J. Warren
Specifically, how does H. pylori create an ulcer?
H. pylori adheres to GI epithelial cells via a lipid raft-associated protein called HpA adhesion protein
translocation of the CagA protein of H. pylori into the host cells
T/F: H. pylori has been associated with gastric cancer.
true
How do you determine if H. pylori is the true cause of an ulcer?
H. pylori produces a urease enzyme that cleaves urea to carbon dioxide and ammonia
the ammonia allows the bacteria to penetrate the protective mucus layer in the GIT
patient eats isotopically labeled Carbon13 or radioactive Carbon14 urea
if patient has infection, the bacteria will cleave the labelled urea and patient will either have carbon dioxide on their breath, or bicarbonate in their blood plasma
(use a mass spec to measure increase in Carbon13 isotopic label)
What test is the gold standard for diagnosing H. pylori?
urea test
T/F: resistance to anti-microbials is high with H. pylori and that necessitates the use of multiple drugs.
true
Which anti-microbials can you use to treat an H. pylori infection?
amoxicillin
clarithromycin
tetracycline
metronidazole
tinidazole
rifabutin
Which anti-microbial drug could H. pylori develop a resistance to via the nitroreductase mutant?
metronidazole
What are some combo products used to eliminate H. pylori infection?
reversible competition at H2 receptors in gastric parietal cells
What are the 2 major pathways of metabolism/inactivation of histamine?
1. ring methylation by histamine N-methyl transferase
2. oxidative deamination by MAO
Where is histamine excreted?
in the urine
T/F: histamine is widely distributed (but unevenly) in all mammalian tissues.
true
Where can you find histamine, specifically?
mast cells
blood
basophils
What endogenous chemical in the body has 3 subtypes and is a member of the superfamily of G-protein coupled receptors?
histamine
H1
allergy
H2
GI
H3
CNS and peripheral
How do prostaglandins interact with histamine?
prostaglandins counter the histamine adenylate cyclase pathway
prostaglandins are cytoprotective (NSAIDs knock them out)
prostaglandins increase mucus and bicarbonate production
_____ is a hydrophillic molecule whose active form is the monocation and is synthesized from the amino acid histidine by L-histidine carboxylase? It also contains nitrogens...
histamine
Which one can a tolerance be developed to? H2 antagonists or PPIs?
H2 antagonists
Which H2 blocker does not undergo extensive first pass effect?
Axid
What are the biological functions of histamine?
allergic responses
gastric acid secretion (powerful)
neurotransmitter functions in the CNS
vasodilation
increased capillary permeability
constriction of large vessels and bronchial tissue
increases HR, but decreases BP due to baroreceptor responses
T-lymphocyte proliferation
This chemical has no positive charge at physiological pH and has electron withdrawing groups on the guanidine or guanidine-like group which decreases the basicity of the nitrogens in the molecule. What chemical is it?
histamine
Name the 4 H2 blockers mentioned in class.
Tagamet (cimetidine)
Zantac (ranitidine)
Axid (nizatidine)
Pepcid (famotidine)
What is the ultimate mediator of acid secretion?
H+K+ATPase proton pump
Why are PPIs so much better at treating GERD?
because they inhibit the proton pump (H+K+ATPase) system which is far more superior than blocking H2 receptors
This H2 blocker is a CYP450 INHIBITOR therefore has many drug interactions and should be the last choice?
Tagamet (cimetidine)
This H2 blocker can cause gynecomastia, drug fever, neutropenia, and depression? It also acidifies the urine...
Tagamet
What are the 2 OTC H2 blockers that are indicated for sour stomach, heartburn and acid indigestion?
Pepcid and Tagamet
(I thought Zantac was too...)
Which H2 blocker may cause an increase in transaminases?
Axid (nizatidine)
T/F: Ranitidine, famotidine, and nizatidine all inhibit CYP450 enzymes.
false; only cimetidine does
Which H2 blocker is 90% bioavailable (the highest of all of em)?
Axid (Nizatidine)
Where are the H+K+ATPase proton pumps located?
exclusively in the apical membranes of the parietal cells
they are transmembrane proteins
These have little to no effect on gastric juice production, secretion of pepsin, Intrinsic Factor, and GI motility?
PPIs
T/F: you do not need to stagger doses of antacids and H2 blockers.
false; you do to maximize bioavailability
Duexis
Ibuprofen + Famotidine
for arthritis
T/F: all PPIs are acid unstable.
true
If you have renal failure, would you use digitoxin or digoxin?
digitoxin
If you have hepatic failure, would you use digitoxin or digoxin?
digoxin
These should not be chewed and are in enteric coated tab form or capsule form?
PPIs
Which one has a narrower therapeutic index and is more toxic? Digoxin or Digitoxin?
Digoxin, but it is the one that is still on the market
Which one is 100% renally excreted? Digoxin or Digitoxin?
digoxin
What do you give in a digoxin OD?
Digibind
What do you die from in an OD of digoxin?
cardiac arrhythmia
What are the two most common side effects of PPIs?
headache and diarrhea
Which ones are more highly protein bound- PPIs or H2 blockers?
PPIs are highly protein bound (95-98%)
What is the consequence of PPIs being highly protein bound?
prolonged duration of action (24-72 hours)
How are PPIs metabolized?
hepatically
rapid
What is the MOA of PPIs?
within the parietal cells (at an acidic pH) they undergo an intramolecular rearrangement which generates a sulfenamide that covalently reacts with thiol functional groups forming a disulfide on the extracellular luminal domain of the pump protein
T/F: PPIs are prodrugs.
true
In order to get full inhibition of the proton pump, how many molecules of the PPI do you need?
2
T/F: PPIs are permanent inhibitors of the proton pump system.
true
T/F: PPI action can be overridden after a few days.
true
How long does it take for the protein/membrane turnover to occur after a PPI has inhibited the system?
3-5 days
Where do PPIs act?
not in the stomach!!!
in the parietal cells
What is hypochlorhydria?
poor absorption of calcium salts which leads to malabsorption
What can cause hypochlorhydria?
taking a PPI without a meal
What do PPIs do to bone?
they decrease bone resorption of calcium by inhibiting osteoclastic vacuolar H+K+ATPase
High dose PPI use for ____ long can significantly increase your risk for _____?
1 year
hip fracture
T/F: women have a higher risk of hip fracture while taking a PPI than men
false!
If you are taking a PPI, what should you supplement with?
calcium supplements
dairy products
if insoluble calcium salts, take with a meal
Omeprazole
Prilosec
Rabeprazole
Aciphex
Pantoprazole
Protonix
Lansoprazole
Prevacid
Esomeprazole
Nexium
What enzyme metabolizes the R enantiomer of omeprazole?
CYP2C19
What enzyme metabolizes the S enantiomer of omeprazole?
CYP3A4
This drug is the S enantiomer of omeprazole? And what enzyme metabolizes it?
esomeprazole
3A4
Which one would you recommend for an Asian? Prilosec or Nexium?
Nexium because it is metabolized by 3A4, not 2C19 (Asians have trouble with 2C19)
Asians show prolonged plasma levels of which drug?
omeprazole
T/F: if patient has hepatic disease, you should decrease the dose of omeprazole.
false; don't need to because it is urinally and fecally excreted
T/F: protonix can be taken with antacids, with food, or without food
true
This PPI is indicated for the maintenance of healing of GERD?
Aciphex
Kids aged 1-11 years old can take which PPI?
Prevacid
This drug is the pure enantiomeric form of Prevacid?
Dexilant
Dexlansoprazole
Dexilant
This PPI can decrease levels of the AIDS drug atazanvir by more than 70%?
Omeprazole
This PPI is not a CYP inhibitor, but is metabolized by 3A4 and 2C19?
lansoprazole
Consider dosage adjustment or use caution with which PPIs if hepatic impaired?
aciphex
protonix
prevacid
T/F: you can take PPIs if you are pregnant.
false
T/F: PPIs can cause hypomagnesemia.
true
What 2C19 metabolized cardiac drug displays significant interactions with omeprazole?
omeprazole
What are some important pearls to watch for if recommending an antacid?
be aware of sodium content in hypertensive patients
do not abuse antacids = rebound hyperacidity
use extreme caution with aluminum and magnesium products in renal failure patients
Basaljel
aluminum carbonate
Riopan, Iosopan
Magaldrate
Amphojel, Alu-Cap, Dialume
aluminum hydroxide
MOM
magnesium hydroxide
CitrapH
sodium citrate
Do not take antacids 30 minutes before or after which drug?
sucralfate
90% of this drug is excreted in the feces and most of it is not absorbed?
sucralfate
What is sucralfate indicated for?
active duodenal ulcer
What is the MOA of sucralfate?
under acidic pH, the aluminum is split off, which produces a sulfated sucrose which forms a complex with proteinaceous exudate protecting the ulcer against acid, pepsin, and bile salts
Sucralfate
Carafate
Cytotec
Misoprostol
This drug is indicated for the prevention of ASA and NSAID induced gastric ulcers?
Cytotec
What is the MOA of cytotec?
it is a synthetic prostaglandin analog with anti-secretory and mucosal protective properties
increases bicarbonate and mucus production
it counters histamine and increases adenylate cyclase activity
this drug is absolutely contraindicated in pregnant women due to abortifacient properties?
