Gastric Acid Modifiers

or
Gastric Acid Suppression
(GAS)

Dr. Anton Bahtiar, M.Biomed

Drug list for gastric acid modifiers
cimetidine (Tagamet & generic, OTC)
famotidine (Pepcid & generic, OTC)
lansoprazole (Prevacid, )
misoprostol (Cytotec)
nizatidine (Axid)
omeprazole (Prilosec)
ranitidine (Zantac)
sucralfate (Carafate)
Trivial mechanisms of
gastric acid modification
Acid neutralization and/or physical protection

Sucralfate (Carafate)
( duodenal>gastric>>>GERD)
(may decrease bioavailability of other drugs)

Aluminum hydroxide + magnesium hydroxide

(Gelusil, Maalox, Mylanta)
Bismuth subsalicylate (Pepto-Bismol) & other
bismuth compounds
Calcium carbonate (Tums)
Gastric acid secretion
Factors affecting gastric acid secretion

MC = mast cell like cell

or enterochromaffin like cell
Histamine receptors
H1 - smooth muscle, exocrine glands, vascular
endothelium, brain; coupled to phospholipase C,
leading to IP3 and diacylglycerol (DAG)

H2 - parietal cells, heart, vascular smooth muscle,

mast cells, brain; coupled to cAMP production

H3 - presynaptic, brain, myenteric plexus

(no therapeutic applications, yet)
H2 antihistamine prototypes:
decreased gastric acid secretion

cimetidine (Tagamet)
binds the androgen receptor
inhibits CYP (2C19 ; 1A2, 2D6)
well absorbed, poor CNS penetration
half life ~ 2 hours
(800 mg HS, 300 mg QID, 400 mg AM &
HS)
ranitidine (Zantac
half life ~ 2.5 hours
(150 mg BID, 300 mg HS)
famotidine (Pepcid)
nizatidine (Axid) (better bioavailability)
Table 2. Drugs that induce gynecomastia by known mechanisms

Estrogen- Supply
Stimulate Direct Block Block Displace
like, or binds aromatizable
estrogen Testicular testosterone androgen estrogen
to estrogen estrogen
synthesis Damage synthesis action from SHBG
receptor precursors
Estrogen Gonadotropin Exogenous Spironolacton
Busulfan Ketoconazole Flutamide
vaginal cream s androgen e
Androgen
Estrogen-
precursors (ie
containing Growth Spironolacton
androstenedio Nitrosurea Bicalutamide Ethanol
embalming Hormone e
ne and
cream
DHEA)
Delousing
Vincristine Metronidazole Finasteride
powder
Digitalis Ethanol Etomidate Cyproterone
Clomiphene Zanoterone
Marijuana Cimetidine
Ranitidine
Spironolacton
e
5-Hydroxytryptamine (5-HT)
Serotonin
 Tryptophan
Tryptophan Hydroxylase 5-Hydroxytrophan (5-HTP)
Synthesis
Amino Acid
5-Hydroxytryptamine (5-HT) Decarboxylase
Metabolism
Monoamine
5-HT Oxidase
5-HIAA

5-HIAA: 5-Hydroxy indole amine acid

Inactivation- 5HT reuptake
Distribution(PNS)
Majority released from gut
Responsible for smooth muscle contractions
Release stimulated by food intake
Inhibits release of gastric acid
Softens stool
Cardiovascular system
vasoconstrictor/vasodilator of vessels
Bonchioconstriction
Uterine contractions
Distribution: rodent

(Cooper, Bloom, Roth, 2003)

 5HT Receptors
receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6 5HT7

subtype 5HT1A 5HT2A, 5HT3A, 5ht1A,

, 5HT2B, 5HT3B 5ht1B
5HT1B 5HT2C
,
5HT1
D,
5ht1E,
5HT1F

major cAMP IP3 ion cAMP cAMP? cAMP cAMP

signaling channel
pathway
A few words about
signal transduction
mechanisms
4 Families of Receptors
Channel linked (Ionotropic)
G-protein coupled (Metabotropic)
Kinase- linked (enzymatic)
Intracellular (gene transcription)
Ionotropic receptors
G-Protein coupled receptors

The Major G Proteins

Gs Stimulatory- Activates Ca channels,
activates adenylyl cyclase
Gi Inhibitory- Activates K channels,
inhibits adenylyl cyclase
Gq Activates phospholipase C
Go - Inhibits Ca channels
G12/13 Diverse ion transporter
interactions
 Second Messengers-
Adenylyl Cyclase

http://www.endocrinesurgeon.co.uk
 Second Messenger-
Phospholipase C

http://www.endocrinesurgeon.co.uk
5HT1A receptor

CNSforum.com
5HT1A Partial Agonist mechanism
5HT1A Antagonist mechanism
5HT2 receptor mechanism
5HT2 Antagonist mechanisms
The Swiss army knife of
Neurotransmitters
Depression Migraine
Anxiety Hypertension
Social phobia Pulmonary hypertension
Schizophrenia Eating disorders
Obsessive-compulsive Vomiting
Panic disorder Irritable bowel syndrome
Serotenergic Drugs
5HT1A Buspirone, ipsapirone treat anxiety, depression (partial
agonist)

5HT1D Sumatriptan, treat migraine (partial agonist)

5HT2A/2C methysergide, trazodone, risperidone, ketanserin treat

migraine, depression, schizophrenia (antagonist)
Drugs continued

5HT3 Ondansetron treat chemotherapy- induced emesis

(antagonist)
5HT4 Cisapride treat GI disorders (agonist)
5HT transporter SSRIs (Fluoxetine, sertraline) treat
depression, OCD, panic disorder, social phobia, post
traumatic stress disorder (inhibitor)
Antidepressants
Decreased amounts and impaired function of 5-HT
associated with aggression, depression and other forms of
antisocial behavior
Antidepressants attempt to increase 5-HT levels
Serotonin Syndrome
Toxic, potentially fatal effects
require a combination of serotonergic agents,
such as an SSRI with an MAOI.
Symptoms: euphoria, drowsiness, sustained
rapid eye movement, overreaction of reflexes,
rapid muscle contraction,abnormal movements
of the foot, drunk, dizzy feeling,high body
temperature, shivering , diarrhea ,loss of
consciousness, death
Treatment
suspected agents should be discontinued
OTC drugs containing ingredients known to
increase serotonin levels, such as
dextromethorphan, pseudoephedrine or
phenylpropanolamine, also should be
discontinued.

Benzodiazepines for mild to moderate cases

Cyproheptadine, Methysergide, and Propranolol

for severe cases
Non-selective 5HT agonist/partial agonist
Ergot derivative
Mimics 5HT at 5HT1A autoreceptors on raphe cell
bodies, slows firing rate of serotonergic neurons
Current theories focus on glutamate release in
thalamocortical terminals, causing dissociation
between sensory relay and cortical output
Hallucinogens and drug
discrimination trials
Animal model thought to reflect subjective effects
Mediated by activation of 5HT2A receptors
Acts as partial or full agonist at 5HT2A and 5HT2C
receptors
Phenethylamine derivatives (psilocybin) are selective
5HT2A/2C agonists
Human Studies

Psilocybin and PET imaging studies- pattern resembles brain

activation in schizophrenic patients
Action of psilocybin is blocked by pretreatment with
5HT2A/2C antagonists
Yeah rub Vaseline on my eyelids 5-
HT & MDMA

MDMA causes an increased release of 5-HT and blocks reuptake

High affinity for SERT
Effects fine axons
Responsible for temperature increases
Receptor Overview
5HT2 subtypes
EICOSANOIDS
(prostaglandins,
thromboxanes, leukotrienes)
Eicosanoids
Major classes of eicosanoids.
Precursors of eicosanoids.
Major pathways of eicosanoid synthesis
(cyclooxygenase and lipoxygenase).
Important functions of eicosanoids.
Important inhibitors of eicosanoid
synthesis
Eicosaniods
Derived from 20-crabon polyunsaturated fatty acids
Paracrine or autocrine messengers molecules
Short half-lives (10 secs 5 mins) so that functions are usually limited
to actions on nearby cells.
Bind to specific cell surface G-protein coupled receptors, and
generally increase cAMP levels. May also bind to nuclear receptors
and alter gene transcription.
Wide variety of functions
Major Classes of Eicosanoids
Prostaglandins
Thromboxanes
Prostacyclins
Leukotrienes
HETES
Effects of Eicosaniods
Induction of inflammation
Mediation of pain signals
Induction of fever
Smooth muscle contraction (including uterus)
Smooth muscle relaxation
Protection of stomach lining
Simulation of platelet aggregation
Inhibition of platelet aggregation
Sodium and water retention
Precursors of Eicosanoids
Arachidonic acid (6)
Eicosatrienoic acid (g-linolenic acid, 6)
Eicosapentaenoic Acid (3)
Dietary Linoleic Acid (C18: 9,12) (from plant oils)

Elongase

Desaturase

Arachidonic Acid (C20: 5, 8, 11, 14)

Membrane Phospholipids
Arachidonic acid release from membrane
lipids
Stimulus

Phosphatidyl choline Phosphatidylinositol bisphosphate

Phospholipase A2 Phospholipase C
Ca++
1,2 Diacylglycerol
Arachidonic acid
DAG
lipase
Arachidonic acid Monoacylglycerol
MAG
lipase

Arachidonic acid
Pathways for Arachidonic Acid Metabolism

Arachidonic acid

Cyclo-oxygenase lipoxygenase
Pathway Pathway

PGG2 HPETE

Prostaglandins Leukotrienes Lipoxins

Thromboxanes HETE
Prostaglandins Structural Features

PGA, PGD, PGE, PGF, PGG, PGH, PGI

Depending on the functional groups present at X and Y
PGF 1, 2 or 3
Depending on the number of double bonds present in the linear hydrocarbon
chain
PGF 1, 2 or 3
Thromboxane A2 (TXA2) - structure
 CYCLO-OXYGENASE
PATHWAY
PG and TX synthesis

PGD synthase PGD

2

PGE synthase PGE

2
2GSH PGE 9-keto
reductase
2GSSG
PGF2a
PGI synthase PGI
2

TXA synthase TXA2

Some Functions of Prostaglandins
PGI2, PGE2, PGD2
Vasodilation, cAMP
Platelet and leukocyte aggregation, IL1 and
IL2, T-cell proliferation, lymphocyte migration
PGF2a
Vasoconstriction, Bronchoconstriction,
smooth muscle contraction
TXA2
Vasoconstriction, Platelet aggregation,
lymphocyte proliferation, bronchoconstriction
Lipoxygenase pathway
Some Functions of Leukotrienes
LTB4
Vascular permeability, T-cell proliferation,
leukocyte aggregation, IL -1, IL-2, IFN-g

LTC4 and LTD4

Bronchoconstriction, Vascular permeability,
IFN-g
Leukotrienes and allergies
Leukotrienes are a hundred
times more potent than
histamine
Histamine provided a rapid
response to an allergen
In the later stages leukotrienes
are principally responsible for
inflammation, smooth muscle
constriction, constriction of the
airways and mucous secretion
form mucosal epithelium
Anti inflammatory Drugs inhibit
Eicosanoid Synthesis

Membrane lipids
Steroids

Phospholipase A2

NSAIDs Arachidonic Acid

Prostaglandins, Leukotrienes
thromboxanes
Mechanism of Aspirin Action
Aspirin and cardiovascular disease
Low dose aspirin has an anti -
thromobogenic effect and lowers the
risk of heart attacks and strokes.
It inhibits the formation of TXA2 in
platelets, by inhibition of COX-1 which
cannot be overcome because platelets
have no nucleus.
Endothelial cells have a nucleus and
synthesis more COX-1 enzyme needed
for the normal prostaglandin functions
Omega-6/omega-3 fatty acid balance

w6 and w3 are not interconvertible in

humans (mammals).
Diets rich in w3 fatty acids result in high
content of these fatty acids in membrane
phospholipids

Recommended ratio: 1-4: 1 (w6 : w3)

Typical western diet: 14-25: 1 (w6 : w3)

Omega-6/omega-3 fatty acid balance

A diet rich in omega-6 FAs shifts the

physiological state to one that is
proinflammatory, prothrombotic and
proaggregatory leading to heart disease
in susceptible individuals
 Prostaglandin, Leukotriene, and Thromboxane
Synthesis

Pathway overview

Prostaglandin receptors

Pathway details

Differential actions of cyclooxygenases

COX-1 and COX-2 comparison

COX-1 specificity of common NSAIDs

Tissue comparison

Eric Niederhoffer
SIU-SOM
 Pathway Overview
Linoleic acid
NSAIDs
Anti-inflammatory steroids
Benoxaprofen
Glucocorticoids
Arachidonic acid
Zileuton
NSAIDs
aspirin
Prostaglandin H2 synthase Lipoxygenase

Prostaglandins (PG) Leukotrienes (LT)

Thromboxane A2 synthase

Thromboxanes (TXA)

NSAIDs
Dazoxiben
 Prostaglandin Receptors
Receptor (PG) Signal Distribution
Transduction
DP1 (PGD2) AC, [cAMP] Platelets, VSM,
nervous tissue,
retina, small
intestine, ileum, lung,
stomach, uterus
DP2 (PGD2) Mobilize intracellular Eosinophils,
[Ca2+] basophils, Th2 cells
EP1 (PGE2) phosphoinositol Kidney, lung, spleen,
turnover, [Ca2+] skeletal muscle,
testis uterus
EP2 (PGE2) AC, [cAMP] Lung, placenta
EP3 (PGE2) Most receptors AC, Kidney, stomach,
uterus, pancreas,
[cAMP], some AC
adrenal, testis, ovary,
and [cAMP] small intestine, brain,
spleen, colon, heart,
liver, skeletal
muscle, lung,
thymus, ileum
EP4 (PGE2) AC, [cAMP] Small intestine, lung,
thymus, kidney,
uterus, pancreas,
spleen, heart,
stomach, brain,
ileum, peripheral
blood mononuclear
cells
FP (PGF2) phosphoinositol Corpus luteum,
turnover, [Ca2+] uterus, stomach,
kidney, heart, lung,
eye, liver
IP (PGI2) AC, [cAMP] Platelets, VSM,
kidney, thymus, liver,
lung, spleen, skeletal
muscle, heart,
pancreas
TP (TXA2) phosphoinositol Platelets, VSM,
turnover, [Ca2+] thymus, spleen, lung,
kidney, heart, uterus

http://www.caymanchem.com/app/template/scientificIllustrations%2CIllustration.vm/illustration/2018/a/z
 Pathway Details
IL-1 (inflammation)

IL-1R
Membrane phospholipids

Anti-inflammatory steroids
Glucocorticoids
Phospholipase A2 (mediated by lipocortin-Ca2+)
(or PLC)
Arachidonic acid LTA4

NSAIDS (aspirin) Glutathione S-

O2 transferase
Cyclooxygenase LTB4 LTC4

PGH2 PGG2

synthase 2GSH
LTD4

PG hydroperoxidase GSSG
PGJ2 LTE4

PGD2 PGD2 synthase PGH2 TXA2 synthaseTXA 2

PGI2 synthase PGE2 synthase

PGI2 (PC) PGF2 PGE2

PGF2a
synthase
 Differential Actions of
Cyclooxygenases
Housekeeping
Unwanted side- Endothelial integrity
effects PGI2
Vascular patency
Gastric mucosal integrity
COX1
Constitutive PGE2
Bronchodilation
TXA2
Renal function
NSAIDs Platelet function

PGE2
PGF2a

Inducible COX2
Inflammation
Inflammatory Proteases

Therapeutic anti-
inflammatory effects
 COX-1 and COX-2
Comparison
Parameter COX-1 COX-2

Regulation usually inducible

constitutive

Range of gene 2 to 4-f old 10 to 80-f old

induction

Rate of gene 24 h 0.5 to 4 h

activation

Effect of inhibits inhibits

glucocorticosteroids expression expression

Relative size of active smaller larger

site

Rate of arachidonic 34 39
acid consumption nmol/min/mg nmol/min/mg

Effect of aspirin on inhibited affected

COX activity
http://elfstrom.com/arthritis/nsaids/actions.html
 COX-1 Specificity of Common
NSAIDs

Piroxicam 250
Tolmetin 174
Aspirin 166
Sulindac 100
Indomethacin 60
NSAID

Ibuprofen 15
Acetaminophen 7.4
Sodium salicylate 2.9
Flurbiprofen 1.2
Carprofen 1
Diclof enac -1.4
Naproxen -1.7
Meloxicam -3
-50 0 50 100 150 200 250
Relative specificity ratio COX-1 to COX-2

Generally, the more selective for COX-1, the more

serious side-effects appear

http://elfstrom.com/arthritis/nsaids/actions.html
 Tissue Comparison
Brain/nerve Synovial cells Vascular beds

Ar Ar Ar

PGH2 PGH2 PGH2

PGD2 PGE2 PGI2 (PC) PGE2 PGI2 (PC) PGE2

PGF2a TXA2

So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues?
 Review Questions

How are prostaglandins, leukotrienes, and

thromboxanes synthesized (substrates, enzymes,
cofactors)?
What is the nomenclature for prostaglandin receptors?
How do NSAIDs work?
How do steroids work?
What are the important characteristics of COX-1 and
COX-2?