Aznan Lelo

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
30 September 2012, SPF 2012, Medan

Why is this important?

Abdominal pain is one of the most
common reasons for outpatient and ER
visits
Variation in degree of pathology is vast,
some of which needs immediate attention
A lot can happen in the abdomen and you
need an organized approach

Abdominal Pain
Location
Work-up
Acute pain syndromes
Chronic pain syndromes

Scope of the problem

Anatomic Essentials
Visceral Pain
Parietal Pain
Referred Pain

Description of Abdominal
Pain

Local
General or diffuse
Referred
Colicky
Onset

Acute abdominal pain

Generally present for less than a couple
weeks
Usually days to hours old
Dont forget about the chronic pain that has
acutely worsened

More immediate attention is required

Acute abdominal pain

Surgical
Appendicitis
Cholecystitis
Bowel obstruction
Acute mesenteric
ischemia
Perforation
Trauma
Peritonitis

Non-surgical
Cholangitis
Pancreatitis
Non-abdominal
causes
Choledocholithiasis
Diverticulitis
PUD/-itis
Gastroenteritis

Types of Abdominal Pain

Visceral
Crampy, achy, diffuse,
Colicky abdominal pain is the major symptom

Poorly localized

Somatic, Parietal
Sharp, lancinating
Well localized

Referred
Distant from site of generation
Symptoms, but no signs

Visceral Pain

Originates in the walls of hollow organs,

In the capsules of solid organs,
Or in the visceral peritoneum
Three separate mechanisms can
produce this pain:
1. Inflammation
2. Distention (being stretched out or inflated)
3. Ischemia (inadequate blood flow)

Appendicitis
The inflammation also causes the internal
diameter to expand, blocking the artery, causing
infarction and necrosis. Leading to rupture.
Mild or early appendicitis causes diffuse, colicky
pain associated with N/V, and low-grade fever.
Pain is initially located in the periumbilical
region.
Patient also loses their appetite.
Continued dilation causes pain to localize in the
right lower quadrant.

Cholecystitis
Acalculus cholecystitis usually results from
burns, sepsis, diabetes, and multiple organ
failure.
Inflamed gallbladder usually causes an
acute attack of upper right quadrant
abdominal pain, with referred pain in the
right shoulder.
If gallstones are lodged in the cystic duct,
the pain may be colicky, due to
expansion and contraction.

Ulcerative Colitis
Typically are not hemodynamically unstable
More severe cases may present with bloody
diarrhea and intense colicky abdominal
pain.
Electrolyte derangements due to fluid loss
through the colon
Ischemic damage to the colon itself
Eventually perforation of the bowel
These patients will present with S&S of
hypovolemic shock

What is Colicky Pain?

a severe abdominal pain that felt like a muscle
spasm.
Babies more often experience colic, making them cry
even after they've been fed, burped and have had their
diapers changed.
Adult abdominal pain may come on suddenly or be a long
term condition, and is often accompanied by gas, bloating
and abnormal bowel functions.

pain which comes and goes; it is important to note

that in :
true colic there is a baseline of no pain.
while in renal and biliary colic always have a background
presence of pain

Character
Colicky pain - rhythmic pain resulting from
intermittent spasms - most commonly
associated with
biliary disease,
nephrolithiasis,
intestinal obstruction

Pain that begins as dull, poorly localized

ache and progresses to a constant, well
localized sharp pain indicates a surgically
correctable cause

14 causes of Colicky
abdominal pain

Adhesions - Colicky abdominal pain

Biliary colic
Bowel obstruction - early
Choledocholithiasis
Chronic lead poisoning
Gallstone
Gastroenteritis
Infantile colic
Intestinal colic due to obstinate constipation
Intussusception
Kidney stones
Peutz-Jeghers Syndrome - colicky abdominal pain
Renal colic
Wind colic

Functional Disorders
Functional disorders are conditions in which the
patient has a variable combination of symptoms
without any readily identifiable structural or
biochemical abnormality.
Several functional gastrointestinal disorders are
recognizable .

Functional dyspepsia
Irritable bowel syndrome (IBS)
Functional abdominal pain
Abdominal migraine
Aerophagia
15

Functional Abdominal Pain

The term is used in gastroenterology if no
specific structural, infectious, inflammatory, or
biochemical cause for the abdominal pain can
be determined.
Because the exact etiology and pathogenesis of
the pain are unknown and because no specific
diagnostic markers exist, a diagnosis of functional
bowel disorder often is viewed as a diagnosis of
exclusion.
The diagnosis is established by a constellation of
criteria based on a careful history, physical
examination, and minimum laboratory investigation.
16

Pathogenesis Of
Functional Bowel Disease

17

Pathogenesis Of
Functional Bowel Disease
Psychosocial
Factors

Neurotransmitt
er?

Altered
Motility
Spasm
Distention

Visceral
Hypersensitivity
Pain

Bloating
Urge to defecate

18

Physiology of CNS Control

CNS
Cerebral cortex,
Limbic system,
Brain stem & Hypothalamus
Vagal
pathway

Splanchnic
pathway

Motility
Blood flow

Vagal afferents

Secretion

Vagal efferents

Enteric Nervous
System (ENS)

Enteric afferents
& interneurons
Neurotransmitters,
Neuropeptides,
other chemical and
mechanical stimuli

Neurogenic control of GIT motility

serosa
Longitudinal Muscle
Myenteric Plexus
Circular Muscle
Submucosal Plexus
submucosal

Enteric nervous system (ENS)

is a collection of nerves within the wall of the GI

tract responsible for the autonomous
gastrointestinal activity.
myenteric (Auerbach's) plexus, responsible for
motor control
submucosal (Meissner's) plexus, regulates
secretion, fluid transport, and vascular flow.
Neurons in both plexuses release acetylcholine
at their terminals.

Autonomic nervous system (ANS)

Parasympathetic : causes contraction of

muscles in the wall of the intestine and relaxation
of the sphincters and increases gland secretion
M2 and M3 receptors present in the GIT in a 4:1 ratio.
M3 receptor is more important in muscle contraction

mucosal

Sympathetic: causes relaxation of muscles in

the wall of the intestine and contraction of the
sphincters

How to optimize
treatment of colicky
abdominal
pain?
For a true colicky pain
No pain before
Mainly due to physiological spasm of smooth
muscle
Related to increase the action of acetylcholine
Antispasmodic of anti-cholinergic agents
(hyoscine butylbromide)
Add a pure analgesic paracetamol

For the false colicky pain

How to optimize
treatment of colicky
abdominal pain?

For the false colicky pain

Related to inflammation with or without

distention
Inflammation release prostaglandin, then
treated with NSAID
Distention release prostaglandin and
acetylcholine, then combined NSAID and
antispasmodic
NSAID induces vasoconstriction, GI
bleeding, renal and CV impairment

Rational approach
Pain
Spasm

Acetylcholine

No-Pain
Relaxation

Hyoscine

SAR Atropine and Hyoscine

Atropine

Hyoscine

NMe3
CH2

CH2
Me

Me
N
H
O

C
O

O
CH2 OH
CH

C
O

CH3

O
H
H

CH2 OH
CH
*

Relative positions of ester and nitrogen similar in both molecule

Nitrogen in atropine is ionised
Tertiaryamine(ionised)oraquaternarynitrogen
Amine and ester are important binding groups (ionic + H-bonds
Atropine binds more strongly than acetylcholine

Pharmacodynamic of
Hyoscine-N-butylbromide

Efek pada kelenjar saliva

: 1/50 atropin
Efek pada denyut jantung
: 1/30 atropin
Efek pada mata
: 1/500 atropin
Efek pada kelenjar keringat : 1/1000 atropin
Efek yang paling besar di organ abdomen berongga

LD 50 ORAL : 3.000 MG / KG BB PADA MENCIT

Hyoscine butylbromide acts on both muscarinic and
nicotinic cholinergic receptors

Muscarinic: smooth muscle GI, biliary and urogenital tracts

Nicotinic: skeletal muscle (Neuromuscular junction)

Mechanism of anticholinergic Hyoscine

butylbromide
reversible blockade of Ach at
muscarinic receptors

Pharmacokinetic of
Hyoscine-N-butylbromide
Routes of administration: po, iv or rectal (suppository)
Rapid absorption in the intestine, but high first pass
metabolism. Systemic bioavailability of < 1% (very low),
however high tissue concentration.
Hyosine rapidly and strongly deposit into gastrointestinal
tract, liver and kidney tissues.
Protein binding capacity is low (8 13%).
As a quaternary ammonium, hyoscine butylbromide
cannot pass across the blood brain barrier.
Plasma half-life is short (2 3 minutes), but after oral
administration its elimination half-life is 5 hours.
Excretion via renal (50%) and fecal

Buscopan
contains the active ingredient hyoscine-N-butylbromide, which is an antispasmodic alkaloid.
It is used to relieve abdominal pain that is
caused by painful spasms in the muscles of
Gastrointestinal (GI)
Billiary or
Genitourinary (GU) tract.

Hyoscine stops the spasms in the smooth muscle

by preventing acetylcholine from acting on the
muscarinic receptors.
This allows the muscle to relax and reduces the
painful spasms and cramps.

Pain scores at baseline in IBS

patients and in response to
hyoscine treatment
Buscopan
preparation

Oral

Constipation
(n=36)

Diarrhea
(n=21)

Pain and
bloating (n=39)

Before

After

Before

After

Before

After

8.2
2.1

5.3
2.2

10.3
2.3

3.2
1.1

13.5
3.4

6.1
2.6

Suppository
7.8 Symptoms
5.0 10.2
4.3
13.6 Sensory
8.4
Interactions between
and Motor
andVisceral
Responses of Irritable
2.6 Bowel
2.6 Syndrome
2.2 Patients
1.6 to Spasmolytics
3.8
2.2
(Antispasmodics)
Khalif IL, et al. J Gastrointestin Liver Dis 2009;18(1):17-22

Hyoscine butylbromide and its

combination with paracetamol

Optimizing monotherapy of
colicky abdominal pain
Colicky abdominal pain is severe and serious pain, it should
be immediately treated
Colicky abdominal pain related with visceral pain due to
inflammation, distension and or ischemia. Those will
stimulate cholinergic nerve activity.
Stimulation of cholinergic nerve produces smooth muscle
contraction and ischemia.
Hyoscine butylbromide will antagonize the action of
acetylcholine then reduce muscle contraction and colicky
pain.
Combination hyoscine butylbromide with paracetamol gives
a synergic effect in reducing colicky abdominal pain