Gastrointestinal Pharmacology - Laulima · Antrum Body (Corpus) Stomach Cells found in Base of Gastric Pits: • Base mucousal cell • Parietal cell • G cell • ECL cell • D

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Gastrointestinal Pharmacology

Instructor: DR. AARON JACOBS

UHH DNP PROGRAM

Antrum

Body (Corpus)

Stomach

Cells found in Base of Gastric Pits: • Base mucousal cell • Parietal cell • G cell • ECL cell • D cell • Chief cells

Pit Cells: • Surface mucosal cells

Cells found in Isthmus: • Stem cells (pit cell precursors)

Overview of Stomach Cell Types

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Gastric Pit

Gastric Acidity

Parietal Cells

Cl-

HCO3-

ATP

K+

Na+

K+

ATP

H+

CO2

H2CO3

+ H2O

H+

HCO3-

Cl-

HCl (100 - 150 mM) -log [H+] -log [0.100] = 1 -log [0.150] = 0.8 pH ∼ 0.8-1.0

pH ∼ 7.3

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Acidity in pH

basolateral

apical

Gastric Acidity FACTORS that REGULATE GASTRIC ACID (HCl) secretion: (+) Stimulate: Endocrine: Gastrin – CCK2 receptor Paracrine: Histamine – H2 receptor Neuronal: Acetylcholine – M3 receptor Nutritional: Amino acids (digested proteins) (-) Inhibit: Endocrine: Somatostatin – SST receptor Chemical: H+

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Gastric Acidity

Gαs

H2

AC

ATP cAMP

M3

PLC

PIP2 IP3

Gαq Gαq

CCK2

Endoplasmic Reticulum Ca2+

ATP

K+

H+

Histamine (Paracrine)

ACh (Neuronal)

Gastrin (Endocrine)

AC = adenylate cyclase PLC = phospholipase C 5

G Cells - Gastrin

G Cells

Antrum

Vagus

ACh

GRP

GRP receptor

G-17 Gastrin

Enteric ganglia

GRP = Gastrin-Releasing Peptide

Vagus

Capillary bed

Dietary Amino Acids, and Peptides

Stretch receptors

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“Vagovagal Reflex” medulla

CCK2 receptor

Enterochromaffin- like (ECL) Cells

Body

Gastrin

Vagus

ACh

ACh

Enteric ganglia

M3 receptor

Histamine Local

tissues

ECL Cells - Histamine

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CCK2 receptor

Gastrin

Vagus

ACh

ACh

Enteric ganglia

M3 receptor

Parietal Cells - HCl

Parietal Cells

H2 receptor

Histamine

ATP H+ (acid)

K+

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CCK2 receptor

D Cells - Somatostain

Delta (D) Cells

H2 receptor

Gastrin

Histamine

Vagus

ACh

ACh

Enteric ganglia

M3 receptor

(-) (+)

Somatostatin (SST)

Gastric acid (HCl, low pH)

Local gastric tissue

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Feedback regulation of HCl via SST

D cell

SST

G cells ECL cells

H+

K+

Parietal cells

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(-) H. pylori

FEEDBACK ENHANCE HCl SECRETION (BY BLOCKING SST):

Gastrin Histamine HCl (low pH)

ACh (+)

FEEDBACK INHIBIT HCl SECRETION BY RELEASING SST:

Defenses Against Acid

Protects esophagus from gastric acid reflux

Gastric mucus • Secreted primarily by surface mucous cells (pit cells) • Coats the mucosal surface of the stomach • Slows (H+) diffusion • Prevents damage by proteases (e.g. pepsin) • Consists of water + salts + mucins:

Branched sugars

Protein backbone 11

Prostaglandins and stomach acid

Prostaglandins O

HO

CO2H

OH

Nuclear/ER Membrane

COX COX

Arachidonic Acid (AA)

O

OH

PGE2

PGD2

PGF2α

PGI2 (prostacyclin)

TxA2 (thromboxane)

NSAIDs Alcohol

Mucus secretion

HCl secretion

COX1 PGE2 Protective

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CaCO3 Ca2+ + CO32-

+ 2H+

H2CO3 H2O + CO2

Antacids: Carbonates

MgCO3 Mg2+ + CO32-

+ 2H+

[+ Mg(OH)2]

+ Al(OH)3

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Al(OH)3 Mg(OH)2

+ 2H+ + 3H+

3 H2O 2 H2O

Mg2+ + 2 OH-

fast

Al3+ + 3 OH-

slow

Combinations Mg(OH)2 + Al(OH)3 provide quick onset and sustained action

Magaldrate = [Al3+][Mg2+]2[OH-]7[H2O] EU, Mexico, South America (Riopan®)

low pH Mg(OH)2 + Al(OH)3

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Antacids: Hydroxides

NON-US COMBINATION:

Antacids – Acid Neutralization

Converting between H+ conc. and pH pH ∼ -log[H+] [H+] ∼ 10-pH

If pH 1.0; [H+] ∼ 10-1 = 0.1 mol/L If pH 2.0; [H+] ∼ 10-2 = 0.01 mol/L If pH 3.0; [H+] ∼ 10-3 = 0.001 mol/L

• Raising pH by 1 unit removes 90% of acid • Raising pH by 2 units removes 99% of acid

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Antacids – Acid Neutralization USP Definition of Neutralization

lowest dose needed

10 ml of 0.5M HCl

Q1. How much H+ is there (in 10 ml of 0.5M)? 10 ml × 1 liter/1000 ml × 0.5 mol/liter = 0.005 mol H+

Q2. What do we need to do to get it down to pH 3.5? If pH 3.5; [H+] ∼ 10-3.5 = 0.0003 mol/liter 10 ml × 1 liter/1000 ml × 0.0003 mol/liter = 0.0000003 mol H+

0.005 – 0.0000003 = 0.0049997 mol H+ neutralized We must neutralize 99.994% of 0.005 mol H+ to get to pH 3.5

10 min

stirring pH 3.5

The test:

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Antacids – Absorption Sodium bicarbonate (NaHCO3)

• Rapidly and completely absorbed • Sodium intake may adversely affect patients with blood pressure or cardiac conditions • Alkali intake may raise blood pH in patients with renal failure

Calcium carbonate (CaCO3) • Ca2+ absorption is about 15% of dose • Not important UNLESS renal failure or large doses taken with other Ca2+ sources (milk-alkalai syndrome – next slide)

Aluminum hydroxide (Al(OH)3) Magnesium hydroxide (Mg(OH)2)

• Poorly absorbed • Multivalent cations - can chelate some drugs • Increase in Al3+ risk to patients with renal failure

• Osteodystrophy • Encephalopathies (e.g. Alzheimer’s)

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Antacids – Adverse Effects

CaCO3 • Bloating, belching • Modest elevation of urine pH (~1 unit) • Ca2+ can accumulate in patients with renal failure • Potential toxicity if high doses combined with

milk or calcium supplements (milk-alkalai syndrome) “Sippy diet” – 1920’s – 1950’s Hypercalcemia (cramps; constipation; kidney stones; renal insufficiency; confusion)

Mg(OH)2

Al(OH)3

laxative effect

slows GI motility (constipation)

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Antacids – Drug Interactions

Membrane Lipid Barrier

Stomach pH 1.0

pKa = 4.0 (weak acid)

[HA] [A-]

= 1000 1

Membrane Lipid Barrier

[HA]

[A-] =

10

1

+

Stomach pH 3.0

HA A- + H+

Gastric Absorption

99.90%

HA A- + H+

Gastric Absorption

90.90%

May cause delay in absorption of some weak acid drugs e.g. Isoniazid (pKa = 1.8) 19


Lipid Barrier

Stomach pH 1.0

pKa = 9.0 (weak base)

[B]

[BH+] =

108

1 BH+ B + H+

Gastric absorption Negligible

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Iron solubility

Fe3+ Fe2+

Gastric pH after antacids

Acidic pH Basic pH

• low ferric iron solubility • reduced iron absorption

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most dietary iron

Mg2+ Al3+ Chelation by Multivalent Cations

• Fluoroquinolone antibiotics • Tetracycline antibiotics • Ketoconazole (antifungal) • Most Bisphosphonates (except: Pamidronate; Zoledronic Acid)


Reduced absorption

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Anti-flatulents

Simethicone • Silica-based (siloxane) surfactant • Anti-foaming agent • Not absorbed • Decreases surface tension of gas bubbles • Prevents formation of gas pockets • Makes gas easier to “pass” • Often in antacid combinations • Or sold alone (e.g. Gas-X®; Phazyme®)

Got gas?

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Prostaglandin Analog: Misoprostol

EP3

Misoprostol (Cytotec®) PGE1 analog

luminal membrane

basolateral membrane

INCREASED MUCUS secretion 24

AC

ATP cAMP

ATP

K+

H+

DECREASED H+ secretion

Gαi

EP4

PARIETAL CELL

STOMACH LUMEN

Prostaglandin Analog: Misoprostol

• Absorption: Rapid, complete • Metabolism: Rapidly de-esterified to misoprotol acid

(active metabolite) • Serum half-life of misoprostol acid 20-40 min • Duration of action: up to 3 hr • Excretion: Urine (mainly as misoprostol acid)

Pharmacokinetics

Adverse Effects

• Diarrhea – 30% of patients (self-resolving) • Worsening of Inflammatory Bowel Disease (IBD) • Uterine Contractions – contraindicated in pregnancy

Misoprostol is used in combination with mifepristone (RU-486) for pregnancy termination

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Sucralfate Sucralfate (Carafate®)

• Slimy, cross-linked polymer • Not absorbed by GI tract • Binds to and coats ulcerated tissues • Buffer against excessive H+

• Absorbs BILE SALTS • Useful for duodenal ulcers (caused by bile salts)

“SUCRose-ALuminium-sulFATE complex”

+ Gastric Acid (HCl)

Drug interactions – may limit other drug bioavailability Adverse effects - few – constipation (2%)

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Tablet or Suspension

Proton Pump Inhibitors Omeprazole (Prilosec®; Rapinex®; Zegerid®) – racemic Esomeprazole (Nexium®) – S-enantiomer of omeprazole Lansoprazole (Prevacid®) Rabeprazole (Aciphex®) Pantoprazole (Protonix®) Dexlansoprazole (Dexilant®, formerly Kapidex®)

First Approved Drug: Omeprazole (1989) Newest Drug: Dexlansoprazole (2009)

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Administration: ORAL:

• All IV Injection:

• Esomeprazole • Pantoprazole

Proton Pump Inhibitors

Proton pump P-type ATPase

cytoplasmic ATPase domain

ATP

ADP + Pi

transmembrane pump domain

Cys - SH

PPI (benzimidazole)

active metabolite (cyclic sulfenamide)

[H+] H+ Parietal cells

• Forms covalent bond with Cysteine (Cys813)

Mechanism

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Ca2+ ATPase Na+/K+ ATPase

OTHER P-type ATPases

Cys - SH Cysteine is too hindered in these types of ATPases to be reactive with PPIs


• Not affected by PPIs

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PPI [H+]

Active metabolite “off target” reactions; drug degradation in stomach

Active metabolite (cyclic sulfenamide)

[H+] in

parietal cells

specific inhibition of proton pump

Proton Pump Inhibitors Stability

1. Enteric coating – Intestinal absorption a. enteric coated drug inside gel cap b. enteric coated powder for suspension c. enteric coated tablet

2. Co-administration with bicarbonate (raises pH of stomach, inhibits degradation)

3. Intravenous administration (if oral route unavailable – only some PPIs)

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pH 2: t1/2 of degradation - seconds • Omeprazole: 105 sec • Lansoprazole: 85 sec • Pantoprazole: 195 sec

Proton Pump Inhibitors Comparative Stabilities

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Drug is MUCH more stable at neutral pH (circulation)

pH 7: t1/2 of degradation - hours • Omeprazole : 23 hr • Lansoprazole : 13 hr • Pantoprazole : 39 hr

Proton Pump Inhibitors Comparative PK

Bioavailability

• Omeprazole 40% (R-omeprazole has high 1st pass) • Esomeprazole 90% (best, all S-omeprazole) • Lansoprazole 80% • Rabeprazole 52% • Pantoprazole 77%

Elimination t1/2: 1-2 hr

Protein binding: 95-98%

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Proton Pump Inhibitors Metabolism

Proton pump inhibitors Eliminated by Phase I reactions CYP2C19 (major pathway) CYP3A4 (minor; except for esomeprazole, 30%) Pantoprazole also undergoes Phase II metabolic reactions (conjugation)

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Proton Pump Inhibitors Patenting

S-omeprazole patent method = “Chiral Switching”

R-omeprazole + S-omeprazole

same active product at acid pH

(cyclic sulfenamide)

Prilosec® Patent protection 1989 – 2001

Nexium® Patent protection 2001 – 2014 (2010 sales: #2, $6.3 Bil) Teva will begin making generics in 2014 by license

If it’s the same active metabolite, what DID they patent?

65% 30% 95%


Omeprazole 50% R-omeprazole + 50% S-omeprazole

Metabolism

CYP2C19 CYP2C19 CYP3A4

R-omeprazole is more Rapidly AND more Extensively metabolized by CYP2C19 than S-omeprazole (esomeprazole)

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RAPID

Poor Metabolizers (CYP2C19) • Caucasian: 3-5% • Asian: 10-15% • Melanesians*: 40-80%

*Pharmacogenetics 9(5):581-590 (1999) higher risk of side effects?

high AUC for R-omeprazole

AstraZeneca – switching to pure S-enantiomer should eliminate some of this variability (since it is about 30% metabolized by CYP3A4)

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Proton Pump Inhibitors Metabolism

European Journal of Clinincal Pharmacology 60: 779–784 (2005)

Proton Pump Inhibitors Patenting

t1/2 for duration of action ∼ 15 hr

Is vs clinically significant? Where are the error bars?

Publication by AstraZeneca

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TWELVE SUBJECTS


ATP

K+

H+

ATP

pH 5

pH 1

Canalicular membrane

Intracellular vesicle

ACTIVE Pump

INACTIVE Pump

Gastrin ACh Histamine

• Active drug formed only at acidic pH – needs protonation • Take PPI before breakfast – breakfast (meal) causes pumps

to move to the cell membrane (an acid environment)

Proton pump activation

Canaliculi pH 0.8-1.0 when pumps are active

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ACTIVE DRUG

Proton Pump Inhibitors Drug duration / Recovery

Duration of action ∼ 15 hr

Elimination t1/2 for PPI’s: 1-2 hr Does PPI elimination rate influence duration of action?

• Not significantly What property mainly determines duration of action?

• “Recovery” of proton pumps

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Cys – S – S – Drug

ATP

INHIBITED PUMP

1. Protein turnover

Protein degradation

ATP

K+

H+

ATP

New protein synthesis and activation

t1/2 for proton pump TURNOVER ∼ 48 hr But t1/2 for recovery of HCl secretion ∼ 15 hr

40 There MUST be another way to recover...

Recovery


Cys-S-S-Drug

ATP

INHIBITED

Cys – S-H + G-S-S-Drug

ATP

REACTIVATED + GS-H

2. Reactivation

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Therefore: Recovery Rate = PROTON PUMP TURNOVER + PROTON PUMP REACTIVATION

Covalent does NOT necessarily mean irreversible

Recovery

Proton Pump Inhibitors Adverse Effects

Adverse effects – FEW: • Nausea, cramps, flatulence, constipation or diarrhea • LONG-TERM use may cause LOW Mg++ levels • LONG-TERM use may cause excessive gastrin secretion (Hypergastrinemia) – 5-10% of chronic users

• Causes REBOUND acidity upon discontinuation • Associated with ECL cell hyperplasia in lab animals • Gastric carcinomas? • Data do not suggest cancer link in human studies (30 years)

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active drug

Platelet aggregation

(clotting)

Proton Pump Inhibitors Drug Interactions

PPIs: MINOR inhibition of CYP2C19 Clearance of diazepam, disulfiram, phenytoin, warfarin (+ other CYP2C19 substrates) is REDUCED

Lansoprazole: MINOR induction of CYP1A2 isoform Clearance of theophylline, caffeine, imipramine (+ other CYP1A2 substrates) is INCREASED

Clopidogrel (Plavix®) prodrug

CYP2C19

PPIs

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H2 Receptor Antagonists

Cimetidine (Tagamet®) Ranitidine (Zantac®) Famotidine (Pepcid®) Nizatidine (Axid®)

First Approved Drug: Cimetidine (1979) Newest Drug: Nizatidine (1988)

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H2 Receptor Antagonists Mechanism

H2 receptor

ATP H+

K+

H2 receptor antagonists

parietal cells

Histamine

ECL cells

Mechanism • Competitive inhibition of H2 receptor • Negligible inhibition of H1, H3, or H4 receptors • Do NOT need proton pump activation

(unlike PPI’s) – no meal needed

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Efficacies - Similar, suppress 24 hr gastric acid secretion by only ∼70% (compared to >99% by PPIs!) Duration of Action - up to 12 hr (depending on agent, dose, route) Relative Potencies Famotidine >> Nizatidine, Ranitidine > Cimetidine most potent least potent

H2 Receptor Antagonists Comparisons

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Cimetidine: MULTIPLE P450 inhibitor (CYP isoforms: 1A2; 3A4; 2D6; 2C19)

INCREASES levels of the following drugs: • Warfarin • Cisapride (Propulsid®) – prokinetic agent • Phenytoin • Certain beta blockers (e.g. Propranolol) • Certain calcium channel blockers (e.g. Nifedipine) • Diazepam (+ other benzodiazepines) • Clozapine • Theophylline

May DECREASE the activation of tamoxifen

Drug Interactions

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H2 Receptor Antagonists Mechanism

H2 receptor antagonists useful for nighttime heartburn – why?

• BASAL gastric HCl production Histamine-mediated • BREAKTHROUGH (nighttime) heartburn sometimes occurs with PPIs • Do NOT need “activation” of proton pumps to work • Tolerated in combination with PPIs

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H2 Receptor Antagonists Adverse Effects

H1

• Awakeness, diurnal cycle • Intestinal motility (diarrhea) • Rash (pruritus) • Bronchoconstriction • Nausea

H3

• Inhibitory CNS autoreceptors

H4

• Mast cell chemotaxis (asthma, allergy)

Because they are H2 specific these agents do NOT cause the side effects of other H-receptor antagonists (nonspecific antihistamines cause sedation, constipation, inhibit nausea)

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Other Roles for H2-Receptors • Increased gastric motility • Relaxation of smooth muscle (airway and vascular) • Increased contraction (rate and force) cardiac muscle • Inhibition of immune responses

Am J Physiol Gastrointest Liver Physiol 273:987-996 (1997)

H2-Related side-effects?

• Not significant

H2 Receptor Antagonists Adverse Effects

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Adverse Effects Adverse effects (usually well tolerated)

• Headache, drowsiness, fatigue, muscular pain, constipation or diarrhea are most common

• Cimetidine: • Mental effects in elderly (confusion) • Competes with creatinine for clearance,

giving an “ILLUSION” of renal insufficiency • Long term use at HIGH DOSES:

• Antagonism of androgen receptor • Increased estradiol levels • Causes galactorrhea in women,

gynecomastia and infertility in men


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mucosa

circular muscle

longitudinal muscle

vasculature submucosal plexus

myenteric plexus – GI motility

Enteric Nervous System (ENS)

enterochromaffin cell

Intestinal Motility

from vagus

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5-HT (serotonin)

NO = nitric oxide VIP = vasoactive intestinal peptide

Enterochromaffin Cell

Myenteric plexus

contraction

relaxation

MOVEMENT

Intestinal Motility

circular muscle

(-) NO, ATP, VIP

INHIBITORY (+) ACh

EXCITATORY

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Intestinal Motility Cholinergic Agents

circular muscle

(+) ACh

EXCITATORY M2

M3

4 1

≈ M2

cAMP

M3

IP3 + DAG

Ca2+ Ca2+ / Calmodulin

Myosin P CONTRACTION

MLCK ACTIVATION

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Why isn’t ACh used to promote intestinal motility? • Cholinesterases • Multiple receptor subtypes (side effects)

Example: Bethanechol (Urecholine®) (unlabeled use for GERD) NOT an AChE substrate But DOES cause CHOLNIERGIC adverse effects:

• Bradycardia • Hypotension / reflex tachycardia • Diarrhea • Salivation • Bronchoconstriction • Blurred vision

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ACh

Choline + Acetate

Acetylcholinesterase (AChE) Butyrylcholinesterase (BuChE)

Neostigmine (Prostigmin®)

Also causes CHOLINERGIC adverse effects

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Dexpanthenol (Ilopan®) – pantothenic acid

Choline Choline Acetyltransferase

ACh

Pantothenic acid (Vitamin B5)

Acetyl CoA

DIETARY

• INCREASES amount of ACh • Used to prevent paralytic ileus after MAJOR SURGERY • Do NOT use simultaneously with depolarizing NMJ blockers (i.e. succinylcholine) – can cause respiratory paralysis by increasing ACh at neuromuscular clefts 57


Intestinal Motility Prokinetic Agents

Metoclopramide (Reglan®)

MECHANISM of ACTION: complex Dopaminergic: ANTAGONIST of D2 receptors* ,♦ Serotonergic: Antagonist of 5-HT3 receptors ♦ Agonist of 5-HT4 receptors ♦ Cholinergic: Sensitization of M3 receptors* * GI motility effect ♦ Antiemetic effect

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CONTRACTION

D2

M3

Dopaminergic neuron

Cholinergic neuron

ACh ACh ACh (+) EXCITATORY

DA DA

DA

INHIBITORY (-)

Metoclopramide

Metoclopramide

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Metoclopramide

Fourth ventricle

Chemoreceptor trigger zone (CTZ) (area postrema)

Vomiting center (medulla)

5-HT3 (+) H1 (+) M1 (+) NK1 (+)

Duodenal distension, irritation

VOMITING NAUSEA

Receptor effect on vomiting: (+) stimulates (-) inhibits

5-HT3 (+) 5-HT4 (-) NK1 (+)

D2 (+) 5-HT3 (+) MOR (+)

MOR = Mu opioid receptor NK1 = Neurokinin 1 receptor

H1 (+) M1 (+) Inner ear

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Metoclopramide EFFECTS:

• INCREASES: • lower esophageal sphincter tone • gastric contractions (faster emptying) • intestinal motility (peristalsis)

• NO EFFECT on GI secretions • INHIBITS vomiting and nausea

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Metoclopramide • Onset of action: Oral: 30-60 min IM: 10-15 min IV: 1-3 min • Duration of action: 1-2 hr (regardless of route) • Absorption: Rapid, 60-95% • DOES CROSS BBB • Excretion: Urine

Adverse Effects (CNS)

Pharmacokinetics

• Drowsiness • Akathesia • Extrapyramidal effects (dystonias) – movement disorder (after months – years of therapy) Tardive dyskinesia – potentially irreversible 62


Hypothalamus

Pituitary

DA

Prolactin

DOPAMINE a.k.a. Prolactin Inhibitory Factor (PIF)

Metoclopramide

Adverse Effects

• Galactorrhea, Gynecomastia

Lactation

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Domperidone (Motilium®) – Clinical trials (Jannsen)

• SELECTIVE D2 Antagonist

• Administration: Oral, Rectal, IV • Does NOT cross BBB:

• Does NOT cause extrapyramidal side effects of D2 • Still inhibits nausea/vomiting (CTZ lacks BBB) • Still enhances prolactin release (Anterior pituitary lacks BBB)

Adverse effects (most common): • Gynecomastia, lactation

Adverse effects (rare but dangerous) • Hypernatremia – anecdotal, idiopathic • QTc prolongation (don’t combine w/QTc enhancing drugs)

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Tegaserod (Zelnorm®) – Emergency approval

Use: IBS-related constipation in females

Mechanism of action: partial 5-HT4 AGONIST Effects:

• Stimulates GI motility (esophagus to ascending colon) • Stimulates Cl- secretion (draws Na+ and H2O into lumen)

Pharmacokinetics • Administration: ORAL • Absorption: VERY POOR • Bioavailability: 10% • Excretion: FECES, mainly UNCHANGED

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Cisapride (Propulsid®) – limited access protocol in US

5-HT4 agonist Withdrawn from US market (2000) Adverse effect: QTc prolongation Effect on hERG channel (KIR)

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Prucalopride – phase III trials

• Advertized as “differs structurally from other serotonergic prokinetic agents” ..But actually shares very similar structural motifs • Data suggest it does NOT cause QTc prolongation

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http://www.movetis.com/

Intestinal Water Flux

from Goodman and Gilman (2006)

stool = 70-85% water

Constipation • Delayed motility • Enhanced water uptake • Dehydration

Water Flux • 2 liters: dietary • 7 liters: secretions

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Diarrhea • Enhanced motility • Osmotic (pulling water into bowel) • Secretory (secreting water into bowel) • Inflammatory / Infection

Wheat

Germ (flour) – carbohydrate

Bran (husk) – protein and lignins

• Fermentation = GAS + BACTERIA in intestines • Water mass in GI tract

Constipation Fiber

Plantago ovata Psyllium husk

• Fecal MASS

Insoluble fiber

Soluble fiber Non-fermentable

(semi-synthetic) Fermentable

• Water mass in GI tract

Methylcellulose Calcium Polycarbophil

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Saline Laxatives Constipation

Osmotic Water Retention

Intestinal Distension Peristalsis

Mg2+

Magnesium sulfide (Epsom salt) Magnesium hydroxide (Milk of magnesia) Magnesium citrate (Citroma®) bitter

taste

Magnesium or phosphate salts

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Constipation

HPO4-; PO4

2-

Sodium Phosphate (OsmoPrep®; Visicol®; Fleet Phospho-soda®) Oral or Enema

PO42- is better absorbed than Mg2+

Adverse Effects: • Electrolyte disturbances

• Dehydration • Renal failure • Metabolic acidosis • Tetany from hypocalcemia

• Acute Phosphate Nephropathy (phosphate crystals in kidney)

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Saline Laxatives

Nondigestible Sugars and Alcohols Constipation

Lactulose; Sorbitol; Mannitol • Non-absorbed • Fermented in colon to short-chain fatty acids • Increase water in colon by osmosis • Lowers intestinal pH (Lactulose for ammonia intoxication)

Proteins bacteria

NH3

Urea

DETOXIFICATION HEPATIC

ENCEPHALOPATHY

NH4+

fatty acids (pH) TRAPPING

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Polyethylene glycol (PEG) Constipation

PEG 3350 (MiraLax®) • Non-absorbed, hydrophilic polymers • Average 3350 daltons (PEG 3350) • Short-term for occasional constipation • Powder, suspended and taken orally

PEG – Electrolyte solutions (CoLyte®, GoLYTELY®, etc.) • Used to evacuate GI tract for exams • PEG 3350 + Electrolytes

sodium sulfate sodium bicarbonate sodium chloride potassium chloride

LOW dose

HIGH dose

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Constipation Stool Softeners

Docusate (Colace®, etc.) • Anionic surfactant (detergent) • Allows mixing of fats and water – makes stool softer • Generally safe for routine use

Mineral oil (heavy) • Hydrocarbons from petroleum distillation, not absorbed • Allows mixing of fats and water – makes stool softer • Do NOT use “light” (baby) mineral oil – topical use only • Harmful to lungs if aspirated • NOT safe for routine use:

• Can interfere with vitamin absorption • Can promote inflammation, elicit immune responses

• Contraindication – Docusate sodium • Can permit mineral oil absorption

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Stimulant Laxatives Constipation

Diphenylmethane Derivatives Bisacodyl (Dulcolax®; Correctol®, etc)

• ORAL (slow-acting, 6-10 hr), RECTAL (rapid acting, 0.5-1 hr) • Mechanism of Action: irritant, stimulates enteric nervous system, increases peristalsis

Agents Withdrawn from US market:

• Phenolphthalein (formerly Ex-Lax®) – potentially carcinogenic • Oxyphenisatin – liver toxicity

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“OLD Ex-Lax”

Anthraquinones

Sennosides (Sennakote®; Ex-Lax®, etc)

• Natural products (senna; cascara; aloe; rhubarb) • Plant products are dimers or glycosides (not active) • Converted in colon to active anthraquinones – irritants • Produces large colon contractions 6-12 hr after ingestion

Senna hebecarpa

Rhamnus purshiana (cascara)

Cascara

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“NEW Ex-Lax”

Stimulant Laxatives Constipation

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Chloride Channels Constipation

Na+

Na+ K+

K+

2Cl-

Cl-

Cl- Na+ (+ H2O) Intestinal Lumen

K+

Cl-

Channel

Na+/K+

ATPase Na+/K+/2Cl-

Symporter

K+

Channel K+

apical

basolateral

78

Chloride Channels Constipation

Mechanism: Prostaglandin E1 (PGE1) analog. Increases expression and activity of apical Cl- channels ( Na+ and H2O)

Lubiprostone (Amitiza®) Prostaglandins

Na+

Na+ K+

K+

2Cl-

Cl-

Cl-

K+

Cl-

Cl-

Cl-

Cl-

Administration: Oral Metabolism: Lubiprostone is a pro-drug that is metabolized in the gut by carbonyl reductase to active metabolite that acts directly on luminal EP receptors (prostaglandin E receptor) Absorption: Negligible Adverse effects: Nausea, diarrhea (common)

EP

(+)

active drug

prodrug

Diarrhea

1980’s – 2004 Attapulgite (Mg2+ Al3+ silicate; clay) + Pectin (fiber)

2004 – present Bismuth subsalicylate

Kaopectate

Kaolin (Al3+ silicate; clay) + Pectin (fiber) Until 1980’s

Clays

79

Diarrhea Bismuth Subsalicylate

Bismuth subsalicylate (Kaopectate®; Pepto-Bismol®)

Bismuth subsalicylate

Salicylic acid (absorbed) – Antisecretory Antiinflammatory

Bismuth (not absorbed) - Antimicrobial

H+

+ sulfur

BLACK tongue

BLACK stool

Bismuth sulfide (BLACK color)

80

Diarrhea Opioids

Loperamide (Immodium A-D®, etc) • Increases anal sphincter tone • Anti-diarrheal potency 50X morphine • Slowly absorbed (peak 5-6 hr)

Diphenoxylate + Atropine (Lomotil®; Motofen®) • Diphenoxylate is similar to meperidine, but unlike meperidine, is anti-diarrheal • Atropine is ANTICHOLINERGIC, has side effects:

constipation, dry mouth, blurred vision, urinary retention

• Mu Receptor AGONISTS • POOR CNS penetration • INHIBIT GI tract motility

81

Antiemetics

Fourth ventricle


5-HT3 (+) VOMITING NAUSEA


5-HT3 (+)


5-HT3 (+)

Nonspecific: • Metoclopramide

5-HT3 Specific: • Ondansetron (Zofran®) • Dolasetron (Anzemet®) • Granisetron (Kytril®) • Palonosetron (Aloxi®)

First approved: Ondansetron (1992) Newest: Palonosetron (2003)

82

5-HT3 Antagonists

Mechanism: INHIBIT stimulation of: Vomiting center CTZ Duodenum They do NOT inhibit vomiting due to motion sickness (inner ear) Adverse effects (minor, usually well tolerated): Headache, fatigue, constipation

Drug Interactions: QTc prolongation – ondansetron and dolasteron worst offenders

83

Antiemetics 5-HT3 Antagonists

Antiemetics

Fourth ventricle

VOMITING NAUSEA


D2 (+)

Prochlorperazine (Compazine®) Chlorpromazine (Thorazine®)

Dopamine Antagonists

“Typical” antipsychotics

• Antagonists of D2 receptor in CTZ • Also inhibit H1 and M1 receptors

...so are useful for treating vertigo

H1 (+) M1 (+)

Inner ear

84

Antiemetics Antihistamines and Anticholinergics

Fourth ventricle


H1 (+) M1 (+) VOMITING

NAUSEA

H1 (+) M1 (+) Inner ear

Antihistamines: Cyclizine (Marezine®) OTC Hydroxyzine (Vistaril®) Promethazine (Phenergan®) Diphenhydramine (Benadryl®, etc)

• Drowziness

Anticholinergics: Scopolamine (hyoscine)

• Amnesia • Sedation • Antiemetic • Decrease secretions

85

Antiemetics Substance P Antagonists

Fourth ventricle

VOMITING NAUSEA


NK1 (+)


NK1 (+)

Aprepitant (Emend®) - capsule Fosaprepitant (Emend injection®)

Oral Bioavailability: 60% Metabolism: CYP3A4 Adverse Effects:

Fatigue, weakness Drug Interactions:

Strong CYP3A4 inhibitors may INCREASE levels of aprepitant

86

Irritable Bowel Syndrome (IBS) Antispasmotics (Anticholinergics)

circular muscle (+)

ACh

EXCITATORY myenteric plexus

M3

Muscle Contraction (SPASMS)

Anticholinergics Tertiary amines:

• Dicyclomine (Bentyl®) • Hyoscyamine (Levsin®)

Quaternary ammonium compounds: • Glycopyrrolate (Robinul®) • Methscopolamine (Pamine®)

Side effects (CNS): anxiety; light-headedness; dizziness

LESS CNS penetration; = Less side effects

87

Inflammatory Bowel Disease (IBD) Crohn’s Disease (CD) or Ulcerative Colitis (UC)

bacteria

intestinal/colon lumen

ulceration

antigen

macrophage Th0

APC

Th1

Th2 B IL-1 IL-12 TNF-α

INFLAMMATORY CYTOKINES

IFN-γ

INFLAMMATORY CYTOKINES

ANTIBODIES 88

Inflammatory Bowel Disease 5-ASA

Mesalamine (5-aminosalicylic acid; 5-ASA) Sulfasalazine (Azulfidine®) Olsalazine (Dipentum®) Balsalazide (Colazide®)

macrophage

IL-1 IL-12 TNF-α

IFN-γ

Th1 5-ASA

ABSORBED in stomach

NOT absorbed in stomach; MUST BE ACTIVATED by colon bacteria

• Antioxidant • NF-κB inhibitor

89

Mechanism:

stomach intestine colon

D J I

Mesalamine, delayed release (Pentasa®)

Mesalamine, pH sensitive (Asacol®)

Sulfasalazine Olsalazine Balsalazide

Sites of release, activation

Modified from Goodman and Gilman (2006) 90


Mesalamine, conventional

Sulfasalazine Olsalazine Basalazide

Mesalamine (active drug)

N-acetyl-ASA (inactive metabolite)

Sulfapyridine (metabolite)

“Sulfa” drug SIDE EFFECTS

4-ABA (inactive metabolite)

• Headache • Nausea • Fatigue

91


Inflammatory Bowel Disease Thiopurine Immunosuppressants

6-Mercaptopurine (6-MP; Purinethol®) Azathioprine (AZA; Azasan®) • Both are inactive PRO-DRUGS (Metabolic activation needed)

PURINE biosynthesis

Incorporation into DNA

6-MP

Azathioprine

92

6-TGTP (AKA thioguanine

triphosphate)

Methyl TIMP

Immunosuppression

Hepatic Detoxification

6-MP 6-Methyl-MP TPMT (inactive)

Xanthine Oxidase (XO)

6-Thiouric acid (inactive)

• 10% of population have TPMT deficiency (poor metabolizers of 6-MP) • Requires 6-MP dose-reduction

Allopurinol • Used for hyperuricemia (often for leukemia – tumor lysis) • Requires 6-MP dose-reduction

93


6-MP, AZA Typical Indication: Acute lymphoblastic leukemia (ALL) - childhood Administration: ORAL Absorption: 6-MP: POOR and erratic AZA: GOOD Serum half-life: 6-MP: 1-3 hr AZA: 12 min (quickly forms 6-MP, which = 1-3 hr) Precautions: Dose-reduction NEEDED with allopurinol Dose-reduction NEEDED in TMPT poor metabolizers (genetic testing is available) Potential adverse effect: CANCER

94


Glucocorticoids Inflammatory Bowel Disease

IκB P

IκB

(+) NF-κB

Inflammatory Gene Expression

IKK complex (kinase)

(+)

Anti-inflammatory

(-)

Glucocorticoids

CD3(+)

Antibody

TNF-α

TNFR

95

Inflammatory Bowel Disease

Prednisone Adverse Effects of Prednisone

• Immunosuppression – (risk of infection, sepsis) • Hyperglycemia • Osteoporosis • Appetite; Weight gain • Muscle loss

Budesonide (Entocort®) • Enteric coating • EXTENSIVE FIRST PASS metabolism • Less severe adverse effects than prednisone

96

Glucocorticoids

Documents

Gastrointestinal Pharmacology - Laulima · Antrum Body (Corpus) Stomach Cells found in Base of Gastric Pits: • Base mucousal cell • Parietal cell • G cell • ECL cell • D