Block 1: PUD, GERD, IBD Med Chem Flashcards
What is the primary mechanism of antacids?
As an antacids that neutralizes stomach acid, but doesn’t prevent acid over-production
What is the secondary mechanism of antacids?
Promotes gastric mucosal defense:
1. Secretion of mucus → protective barrier against HCl
2. Secretion of bicarb: buffer
3. Secretion of PG: prevent activation of proton pumps
Raising gastric pH from 1.3 to 1.6 neutralizes how much of gastric acid?
50%
Raising gastric pH from 1.3 to 2.3 neutralizes how much of gastric acid?
90%
Describe the interaction between sodium bicarb with H-Cl?
May cause gas and burps
Describe the interaction between aluminum hydroxide with H-Cl?
How does sodium bicarb and aluminum hydroxide differ?
Sodium: mono valent
Al: tri valent has DI due to chelation
What are the forms of Mg2+ salts?
Carbonate, hydroxide, oxide, trisilicate
What is the use of Mg2+ salts?
Laxative and commonly combined with aluminum antacids to counter
What are the CI of Mg2?
Renal failure
Failing kidneys can’t excrete Mg2+ → accumulation
What are the ADRs of calcium salts?
Constipation
Kidney stones
What are the products of mg antacids?
Maalox, Mylanta
What are the types of antacid?
- Mg
- Ca
- Na bicarb
- Alumin
ADRs and CI of sodium bicarb?
- Metabolic alkalosis
- CI: renul failure, HTN (Na overload)
ADRs and info about Aluminum?
- Constipation
- Used with Mg
What is bismuth subsalicylate?
- Mild antacid
- Anti-inflammatory
- Prevetn N/diarrhea
- Black stool/tongue -> Reyes syndrome (children)
How is gastric acid secreted?
- Gastin and Ach
- PG
What are the indication of H2RA?
- DU
- GERD
- Hypersensitivity
- Upper GI bleeding
- Acid reflux
What is the MOA of H2RAs?
Inverse agonist that blocks basal activity H2 receptors that inhibit cAMP and stimulation of PPI, however, gastin and Ach can still stimulate PPI
Describe the MOA of H2 receptors?
Gs -> increase cAMP
PG that inhibit this ppathway
What are the binding site of Histamine to receptor?
2 Aspartate (98 and 186) and Threonine 190
Describe the original SAR of H2RA and how it differs from modern? How did manufacturing improve?
Metiamide;
1. Thioester
2. Imidazole ring
3. Guanidine
4. 4 atom spacer
Failed: agranulocytosis and thiorea
To make better, they attached a EWG to guanidine to convert into N-CG -> CImetidine (Tagamet) (selective H2)
Is Cimetidine an inhibitor or inducer?
Cimetidine is CYP450 inhibitor: Imidazole replaces histidine that is used as a ligand to porphyrin iron
MOA of PPI?
Irreversiblly inhibit PP irrespective of the stimulation process
Describe the dosage form of PPIs?
- Acid-stable in order to be released in the duodenum and avoid activation in stomach
- Absorbed in canaliculus -> secreted from parietal cell -> disulfide binding to pump
- Add Na bicarb to raise gastric pH
- Spinocyclic intermediate -> sulfuric acid -> bind to CYS813 or CYS822
What is the most critical residue in inhibiting PPIs?
CYS813 in the luminal vestibule of the ATPase (most accessible)
PPIs that slowly activate may react with CYS822
Should PPIs be considered prodrugs?
Not true prodrugs since activation in pH driven not enzymatically induced
2 protonation is required
benzimadazole (EDG on R1-4) -> sulfemic acid analog -> sulfenamide analogue
What are the benefits of using a pyridine ring in PPI?
pKa: 3.83-4.53
Ensures that PPI will mostly be ionized at low pH 1.3 of the parietal cells
Rank the stability of the PPIs?
Pantoprazole (less reactive) > Omeprazole > lansorazole > rabeprazole (more reactive)
Describe the different binding of PPIs?
CYS813 (surface) or CYS 822
GSH regenerates inactivated enzymes can only reach 813
1. Omeprazole/lansoprazole only react with Cys813
2. Pantoprazole can react with Cys822
3. Rabeprazole pyridine nitrogen has highest pKa-> much more reactive – faster onset of action
CYP enzymes important for PPI metabolism
2C19
3A4
CYP enzymes inhibited by omeprazole/esomeprazole
2C19
2C8
How does esomeprazole metabolism differ from omeprazole?
Lower dependenct on CYP2C19 and more reliant on CYP3A4 biotransofrmation
better bioavailability in extensive metabolizers and less variation between extensive and slow metabolizers
What PPI is not commonly metabolized by CYP?
Rabeprazole
PPI with the greatest risk for toxicity due to CYP inhibition of 2C19?
Omeprazole and esomeprazole
Poor metabolizers will have a greater response vs extensive metabolizers
2C19 polymorphism effects of PPI?
Polymorphism
Esomeprazole better F and less variation
Dexlansoprazole: consistent
DDI: Clopidogrel
What are prostaglandins?
20C molecules from Omega 3 FA that have anti-secretory effects on gastric acid and stimulates bicarb and mucous secretion
Example of PG analogue?
Misoprostol (Cytotec)
Misoprostol? MOA? Structure? Indication?
- Synthetic analogue of PGE1 -> Prodrug
- C15-16 changes to prevent rapid metabolism
- Allylic secondary alcohol shift from C15 to 16 as a tert alcohol
Indication: Non-NSAID GU and bleeding prevention
ADRs and CI od Misoprostol?
ADRs: Diarrhea, abdominal cramping
CI: Pregnancy and not for DU
MOA of sucralfate?
- Sulfuric acid ester complex of sucrose and aluminim hydroxide
- Anionic (-) sulfate esters bind to (+) charged edges on ulcers - procting from erosion
- Stimulate PG, Bicarb, and epidermal and fibroblast GF
CI and ADRs of Sucralfate?
CI: Renal impairment (aluminum)
ADRs: H2RA, quinolone, Pheytoin, Warfarin, Anatacids (di or tri)
Aluminum can cause chelation on the absorption of other drugs
What is the precation of using prokinetics like Cisapride?
Can cause arrhythmias because it mimic procainamide
Long QT syndrome
What is the MOA of prokinetic agents?
- Increase LES pressure (tone)
- 5-HT4 partial agonists (seratonin)
What is mesalamine?
- 5ASA anti-inflammatory drug that treat CD and mild-moderate UC
- Antioxidant by trapping ROS
What is the MOA of sulfasalazine?
5ASA -> IBD and RA
1. Reducing synthesis of inflammatory mediators
2. Reduced inflammatory cytokine
3. No immunosuppressant activity
Sulfonamide protion contributes to antimicrobial activity
What is a pruine RNi? MOA?
Mercaptopurine is an immunosuppressive drug that treats leukemia and Pediatric non-Hodgkin’s lymphoma
Inhibitons de novo purine nucleotide biosynthesis
Azothioprine MOA?
Immunosuppresant prodrug used in organ transplantation, RA, IBD, pemphigus
MOA of Cyclosporin A?
Binds to Protein cyclophillin of immunocompetant lymphocytes: inhibits calcineurin and lymphokine production -> reducted effector T cell function
SAR of H1 antihistamine?
Ar1- aryl (cis)
Ar2- aryl or arylmethyl (tras)
Chain can be part of another ring
x- several atoms/functionalities N or C
Difference between C2 and C4 substituents on aromatic ring?
C2: direct activity towards anticholinergic activity
C4: direct activity towards antihistaminic activity
Increasing alkyl group size (tBu>iPr>Et>Me)
Common anti-H1 for N?
- Meclizine
- Demenhydrinate
- Promethazine
What is dimenhydrinate?
8-chlorotheophyllinate salt of Benydryl
- Lowers potency
- chlorotheophylline added -> sedation than Benydryl
- Anticholinergic ADRs, sedation
MOA of prmethazine? Why is it better than Dimenhydrinate?
Phenergan
Phenothiazine: branched 3 carbon side chain between R10, opposed to unbranched found on antipsychotics
Longer DOA, higher sedative
MOA of meclizine?
Bonine and Antivert: Cyclic ethylenediamine
Block H1 and muscarinic
Chloro -> Blcoks aromatic hydroxylation (Longer DOA) -> drug distribution
ADRs of antimuscarinics?
- Blurred vision
- Dry mouth
- Tachycardia
- Uriranry retention
- HA
SARA of anticholinergics?
N-tert: CNS activity (not as potent)
N-quat: more potent antagonist, ANS (bicyclic)
X: ester (prone to breakdown), ether (stable), C (rare)
A: 1-phenyl group
B: aromotic ricg
C: -OH, -CH2OH, -CONH2
Products that are +/-Hyoscyamine Solanaceous alkaloids?
Atropine (Tropin, Eumydrin, Atropisol)
Products that are -Hyoscyamine Solanaceous alkaloids?
- Levisin
- Symax
- Anaspaz
- Cytospaz
Indication of Hyoscyamine? ADRs?
- Mydriatic, antispasmodic
Dry mouth, urine retention, blurred vision, constipation
Brand name of scopolamine? Indications
Scop/Scopderm: antiemetic (motion sickness), mydriatic, antispasmotic, preanesthetic medicant
Brandname Methscopolamine? Indication?
Pamine
GI antispasmotic and adjuct tx for DU
Types of synthetic anticholinerigcs?
- Propantheline
- Dicyclomine
- Isopropamide
Indication for propantheline?
Pantheline
2. 1. hyperhidrosis
2. Cramps and spasm of GI and bladder
3. Enuresis
4. IBD
Indication of dicyclomine?
(Bentyl, Procyclomin, Wyovin)
GIT spams, dysmenorrhea and biliary dysfunction
Decreased side effects compared to atropine
Incidaction of Isopropamide?ADRs? CI?
PU and GI hypermotility and acidity
Long DOA
ADRs: dry mouth, mydriasis, urinary difficulty
CI: glaucoma
Example of selective seratonin antagonist?
- Dolasetron (Anzemet)
- Ondansetron (Zofran)
- Granisetron (Kytril)
MOA of 5-HT3 receptor antagonists?
- Blocks receptors on nerve terminals of vagus in P and C in the CTZ -> postema
- Modied cocaine
- Little or no affinity for other serotonin receptors
Medication for bacterial diarrea?
E. coli, Shigella sp., Salmonella sp: Fluoroquinolone (ciprofloxacin) or TMP-SMX
Campylobacter sp. : macrolide (erythromycin)
C. difficile: Fidaxomicin, Metronidazole, Vanc
Medications for parasitic diarrhea?
Metronidazole, Tinidazole, Nitazoxanide
MOA of opioid antidiarrheals?
µ and 𝛿 receptors have strong inhibitory action on the peristaltic reflex of the intestine
µ: abuse potential and constipating effects
Combos of meperidine and methadone
MOA of diphenoxylate?
Difenoxin: low µ-agonist
1. Rapidly metabolized by ester hydrolysis 2. Zwitterion is 5x more potent (active form) -> prevent CNS
2. Atropine to block the block of ACh-induced peristalsis (synergistic)
MOA of loperamide?
- Potent opioid agonist
- Highly lipophilic but no CNS activity (first pass, slow dissolution, P-gp efflux)
MOA of octreotide? Indication?
Sandostatin
1. Mimic somatostatin and inhibits gastrin, secretion, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, TSH, and vasoactive intestinal peptide
2. Analgesic effect at µ
Tx of diarrea in VIPomas
MOA of polycarbophil?
Stool stabilizer for constipation, diarrhea, and abdominal discomfort
Absorbs liquid in intestine and sweel -> solft bulky stool
Stimulates the intestinal muscles, speeding stool transit time through the colon
INdications of Linaclotide?
Linzess (IBS-C, chronic C)
- Mimic of guanylin and uroguanylin
- Increases cGMP stimulate secretion of chloride, bicarb, and water in lumen
- increases intestinal fluid and accelerated transit
BBW of Linzess?
CI in children under 6
Avoid people 6-18 -> severe dehydration
MOA of docute?
Colace
Anionic surfactant that lower ST at oil-water interace of feces (more fat and water combo): easy pass
Systemic action as well
