24 - GI MedChem

Question 1

Pathophysiology of

Acid-Peptic Disease

Answer 1

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

Question 2

Gastrin

Answer 2

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

Question 3

Histamine Structure

Answer 3

• *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

Question 4

Biosynthesis of Histamine

Answer 4

L-Histidine Decarboxylase
Cofactor Vitamin B6

L-Histidine –> Histidine

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

INHIBITED BY:
a-fluoromethylhistidine
CH2F

Question 5

Histamine Receptor when Antagonized….

Treat Allergies

Answer 5

H1 Antagonist

Antihistamine

Question 6

Histamine Receptor when Antagonized​….

Inhibit GASTRIC ACID secretion

Answer 6

H2 Antagonist

Question 7

H3 / H4 Receptors

Answer 7

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

Question 8

Histamine METABOLISM

Answer 8

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

Question 9

Burimamide / Metiamide

Answer 9

H2RA

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

Question 10

Binding of Guanidine Structure
Cimetidine
into H2 Receptor

Answer 10

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

Question 11

Bidentate Hydrogen Bond

Binding of Cimetidine to H2Receptor

Answer 11

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

Question 12

Nitrile Group

Binding of Cimetidine to H2Receptor

Answer 12

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

Question 13

Imidazole Ring Structure

Binding of Cimetidine to H2Receptor

Answer 13

_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

Question 14

Cimetidine

ADR / Side Effects

Answer 14

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

Question 15

Ranitidine / Famotidine / Nizatidine
vs
Cimetidine

Answer 15

NO CYP450 INHIBITION / Anti-Adrogenic properties

• *More Potent** due to:
• *Increased Binding** by the Basic Moeity

Question 16

• *PPI**
• *MoA**

Answer 16

• *WEAK BASES**
• IRREVERSIBLE / COVALENT inhibition* of

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

Question 17

How do PPI’s Work?

Irreversible / Covalent Inhibition
of H+/K+ ATPase

Answer 17

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

Question 18

DexLansoprazole = Dexilant

Answer 18

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

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

Question 19

Revaprazan

PPI

Answer 19

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

binds @ potassium binding site of proton pump

RAPID onset of action

Question 20

Pantoprazole

Answer 20

Vs Omeprazole:
MORE POTENT
&
lower ACUTE TOXICITY

Question 21

RABEPRAZOLE

Aciphex

Answer 21

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

Question 22

Esomeprazole
Nexium

Answer 22

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

Question 23

Prostaglandin Analogues

MoA

Answer 23

MISPROSTOL // Enprostl

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

Question 24

PGE = Prostaglandin Analogues
Misoprostol
Enprostil / Ornoprostil / Benexate

ADR / Side Effects

Answer 24

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

Question 25

**PGE Analogue Structure**

Answer 25

**_Methyl Ester_** INCREASES BOTH: **AntiSecretory Potency & DURATION of Action** **_C-16 Methyl / Hydroxy_** confers **ORAL activity** & **EP3 Selectivity**

Question 26

**Somatostatin Analogues** **MoA** Somatosatin is produced in GI in **Antral Mucosal Endocrine Cells** is normally has *SHORT half life due to* **peptidases**

Answer 26

**_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_**

Question 27

**H.Pylori**

Answer 27

**​Bacterial cause for ULCERS** has **_UREASE_** which breaks down: **Urea --\> Ammonia (NH3) + CO2** thereby ***_reducing acidity of enviroment_***

Question 28

**Antimicrobial Agents for H.Pylori**

Answer 28

**_METRONIDAZOLE_** also for treatment of vaginal infections + **anaerobic bacterial infx** **Amoxicillin / Tetracycline** * *Macrolide ABx** - mycin's

Question 29

**How does METRONIDAZOLE WORK?** **ABx for H.Pylori**

Answer 29

**_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_***

Question 30

**Prokinetics MOA** Drugs Influencing GI Motility **Linaclotide // Lubiprostone // Alvimopan** GCC // ClChannel-2 // u-opioid antagonist

Answer 30

* *ENHANCE** the coordinated * *_GI Motility & Transit_** of material used : * *_INCREASE LES Pressure_** * *GERD** * *_IMPROVE Gastric Emptying_** * *Constipation** **_Stimulate Small Intestine_** post-op ileus obstruction

Question 31

**Lubiprostone = Amitiza** Prokinetic --\> Stimulate GI Motility

Answer 31

**_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

Question 32

**Linaclotide = Linzess Structure** Prokinetic --\> Stimulate GI Motility

Answer 32

**_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_**

Question 33

* *Linaclotide = Linzess** * *MoA** Prokinetic --\> Stimulate GI Motility

Answer 33

**_GC-C Receptor Agonist_** for **IBS-Constipation** INCREASED **cGMP** --\> **protein Kinase 2** **Phosphorylates --\> CFTR (ion Channel) loss of Chloride** *minimal systemic absorption*

Question 34

**Plecanatide** ​Structure Prokinetic --\> Stimulate GI Motility

Answer 34

* *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**

Question 35

**Alvimopan = Entereg** Prokinetic --\> Stimulate GI Motility

Answer 35

**_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