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PDAT2 > 24 - GI MedChem > Flashcards

24 - GI MedChem Flashcards

1
Q

Pathophysiology of

Acid-Peptic Disease

A

Imbalance between:
Aggressive Factors
Acid + Pepcin
&
Local Mucosal Defenses
Bicarbonate + Mucus

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2
Q

Gastrin

A

DIRECTLY
promotes the Release of ACID
&
Starts the Histamine Cycle
which is the WORK HORSE –> actually does the MOST acid production

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3
Q

Histamine Structure

A
  • *TWO pKa’s**
  • *9.40 - 1* Amine** /// 5.80 - His

Amine 4:1 His
in equilibirum of the 2 tautomeric structures
1* N Tautemer is PREFFERED in Salt form of histamie

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4
Q

Biosynthesis of Histamine

A

L-Histidine Decarboxylase
Cofactor Vitamin B6

L-Histidine –> Histidine

(L-aromatic AA decarboxylase, can ALSO do this conversion)

INHIBITED BY:
a-fluoromethylhistidine
CH2F

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5
Q

Histamine Receptor when Antagonized….

Treat Allergies

A

H1 Antagonist

Antihistamine

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6
Q

Histamine Receptor when Antagonized​….

Inhibit GASTRIC ACID secretion

A

H2 Antagonist

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7
Q

H3 / H4 Receptors

A

H3 Receptors
mainly present in the CNS –> improve attention / learning
no approved drugs

H2 Receptors
locolized on hematopoietic origin
can treat inflammatory conditions
no approved drugs

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8
Q

Histamine METABOLISM

A

Hydrophilic molecule degraded in 2 ways:

N-Methylation** –> **MAO Oxidation
forming N-methylmidazole acetic acid 46-55%

Non-Specific Oxidative Deamination
by histaminase –> imidazole acetic Acid

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9
Q

Burimamide / Metiamide

A

H2RA

that were NOT marketed due to:
Agrunuloctosis
caused by the presense of
Thiourea Moiety

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10
Q

Binding of Guanidine Structure
Cimetidine
into H2 Receptor

A

Ionic Bond

BIDENTATE HYDROGEN BOND
Thiourea / Amidine

Nitrile Group –> HydroPhobic Pocket
EWG –> less basic guanidine group

Imdazole Ring Struture –> weakly basic pocket
Nitrogen Tautemer –> required for H2 receptor binding
can be replaced by other groups

Methyl + Thiomethylene Groups
stabilize the Tautemer structure, Electron repelling
optimal 4-methylene distance

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11
Q

Bidentate Hydrogen Bond

Binding of Cimetidine to H2Receptor

A

includes formation of Ionic Bond
TWO HYROGEN BONDS
ALL H2RA’s have their own version​

Guanidine Group
for Cimetidine

Amidine
for ranitidine / nizatidine

Thiorurea
for Burimamide / Metiamide

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12
Q

Nitrile Group

Binding of Cimetidine to H2Receptor

A

Nitrile group –> Hydrophobic Pocket
Acts as an
EWG = electron withdrawing grou
that renders the
Guanidine group –> LESS BASIC
needed for better activity,
ensures the guanidine group is NOT protonated

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13
Q

Imidazole Ring Structure

Binding of Cimetidine to H2Receptor

A

_1* Amine N Tautomer_ of histamine is
REQUIRED
for binding to the H2Receptor // high affinity

BUT
the imidazole ring can be REPLACED by
other aromatic / heroaromatic groups

cimetidine –> liver elimination (toxicity/DI’s) –> replaced with other molecules

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14
Q

Cimetidine

ADR / Side Effects

A

Anti-Androgenic Properties
&
CYP450 INHIBITION

BOTH are related to the Imidazole Ring
so we REPLACE the ring
do NOT interact with cholinergic receptor or H1 receptors:
have LITTLE to NO AC side effects

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15
Q

Ranitidine / Famotidine / Nizatidine
vs
Cimetidine

A

NO CYP450 INHIBITION / Anti-Adrogenic properties

  • *More Potent** due to:
  • *Increased Binding** by the Basic Moeity
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16
Q
  • *PPI**
  • *MoA**
A
  • *WEAK BASES**
  • IRREVERSIBLE / COVALENT inhibition* of

H+/K ATPase (proton pump)
= last step of acid-secretory pathway

17
Q

How do PPI’s Work?

Irreversible / Covalent Inhibition
of H+/K+ ATPase

A

2nd reaction ONLY OCCURS @ ACIDIC PH
Periteal cell releases HCL, need that acidic environment
SELECTIVE DRUG only active on the stomach / acidic environment
if it worked at a NEUTRAL PH, it could harm other cells that have the CYSbond

Has to be ENTERIC COATED
as to pass the GI tract –> 1st pass then the GI cells
Cause for the SLOW EFFECT

18
Q

DexLansoprazole = Dexilant

A
  • *R-ISOMER**
  • Esomeprazole = S-isomer*

DUAL Delayed Release
combining
Fast = 1-2 hour /// Slow Release = 4-5 hours

19
Q

Revaprazan

PPI

A
  • instead of Covalent/irreversible*
  • *REVERSIBLY Inhibits –> H+/K+ ATPase**

binds @ potassium binding site of proton pump

RAPID onset of action

20
Q

Pantoprazole

A

Vs Omeprazole:
MORE POTENT
&
lower ACUTE TOXICITY

21
Q

RABEPRAZOLE

Aciphex

A

PPI that vs omeprazole has:
FASTER onset of action
&
BUT a Shorter duration of action

22
Q

Esomeprazole
Nexium

A

S-ISOMER vs Omeprazole = R isomer
claims to provide better control of intragastric pH

  • *S-Enantiomer** is metabolized by CYP3A4
    but. …

R-Omeprazole
C-5 Methyl group–>CYP2C19
which there are some Inter-Individual BV issues,
some CYP2C19 poor metabolizers

23
Q

Prostaglandin Analogues

MoA

A

MISPROSTOL // Enprostl

Binds to the EP3 Receptors
–> INHIBITING the formation of cAMP
resulting in:
Increased Cytoprotection in gastric mucosa
&
PREVENTION of HCL Release

24
Q

PGE = Prostaglandin Analogues
Misoprostol
Enprostil / Ornoprostil / Benexate

ADR / Side Effects

A

UTERINE CONTRACTION
EP3 receptor, misprostol SIMILAR to CARBOPROST (abortifacent)

DIARRHEA
mediated through EP1 / EP3 receptors
Enprostil is more potent @ EP3 receptor, but it also has more affinity for EP1 receptor

25
Q

PGE Analogue Structure

A

Methyl Ester
INCREASES BOTH:
AntiSecretory Potency & DURATION of Action

C-16 Methyl / Hydroxy
confers ORAL activity & EP3 Selectivity

26
Q

Somatostatin Analogues

MoA

Somatosatin is produced in GI in
Antral Mucosal Endocrine Cells

is normally has SHORT half life due to peptidases

A

OCREOTIDE
more stable analogue of somatostatin,
w/ D-AA (not degraded by peptidases)
also used to treat Acromegaly + Esophageal Variceal Bleed

INHIBITS BOTH:
Gastrin & Histamine Secretion

–> inhibiting BOTH g_astric / pepsin secretion_

27
Q

H.Pylori

A

​Bacterial cause for ULCERS

has UREASE which breaks down:

Urea –> Ammonia (NH3) + CO2
thereby reducing acidity of enviroment

28
Q

Antimicrobial Agents for H.Pylori

A

METRONIDAZOLE
also for treatment of vaginal infections + anaerobic bacterial infx

Amoxicillin / Tetracycline

  • *Macrolide ABx**
  • mycin’s
29
Q

How does METRONIDAZOLE WORK?

ABx for H.Pylori

A

Reactive Intermediates are formed during
the microbial reduction of metronidazole (in mito)

Nitro -> Amine
6 step, 1st step forms the Nitro Anion RADICAL
this radical
REACTS w/ DNA of bactaria

Resistance is partly due to decreased level of FERREDOXIN

30
Q

Prokinetics MOA
Drugs Influencing GI Motility

Linaclotide // Lubiprostone // Alvimopan
GCC // ClChannel-2 // u-opioid antagonist

A
  • *ENHANCE** the coordinated
  • *GI Motility & Transit** of material used :
  • *INCREASE LES Pressure**
  • *GERD**
  • *IMPROVE Gastric Emptying**
  • *Constipation**

Stimulate Small Intestine
post-op ileus obstruction

31
Q

Lubiprostone = Amitiza

Prokinetic –> Stimulate GI Motility

A

CHLORIDE CHANNEL 2 ACTIVATOR
Increased
Intestestinal Fluid Secretion –> increased GI transit

for CHRONIC CONSTIPATION

minimal systemic absorption
Metabolism within the lumen of the GI tract

Microsomal carbonyl reductase
reduction of the C 15 carbonyl group followed by b-oxidation

32
Q

Linaclotide = Linzess
Structure

Prokinetic –> Stimulate GI Motility

A

Guanylate Cycalase-C agonist

Homologue of Enetrotoxin =ST
responsible for secretory diarrhea
2 AA’s Changed:
4: Leucine –> Tyrosine
11: Alanine –> Threonine

THREE DISULFIDE BONDS

Active metabolite

33
Q
  • *Linaclotide = Linzess**
  • *MoA**

Prokinetic –> Stimulate GI Motility

A

GC-C Receptor Agonist
for IBS-Constipation

INCREASED cGMP –> protein Kinase 2

Phosphorylates –> CFTR (ion Channel)
loss of Chloride

minimal systemic absorption

34
Q

Plecanatide
​Structure

Prokinetic –> Stimulate GI Motility

A
  • *GCC Receptor Agonist**
  • still in phase 3 trials, for CIC*

Homologue of Uroguanylin

only 1 AA changed:
3: Aspartic Acid –> Glutamic Acid

also an active metabolite

35
Q

Alvimopan = Entereg

Prokinetic –> Stimulate GI Motility

A

u-Opioid Antagonist
approved for POI = post operative Ileus

antagonizes the same receptors as
Opioid Analgesics for the pain treatment

Zwitterionic Form + Polarity –> does NOT cross BBB
only peripherally active

PDAT2 (22 decks)

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