Aznan LeloDep. Farmakologi & Terapeutik,

Fakultas Kedokteran

15 Juli 2012, KONAS NYERI 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

• Abdominal pain and diarrhea present in most patients

• A lot can happen in the abdomen and you need an organized approach

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

Abdominal Pain

• Location• Work-up

– Acute pain syndromes– Chronic pain syndromes

• Scope of the problem • Anatomic Essentials

– Visceral Pain– Parietal Pain– Referred Pain

Acute abdominal pain

• Generally present for less than a couple weeks– Usually days to hours old– Don’t 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

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

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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.

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Pathogenesis Of Functional Bowel Disease

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Pathogenesis Of Functional Bowel Disease

10

Psychosocial Factors

Altered Motility

Visceral Hypersensitivity

SpasmDistention

PainBloating

Urge to defecate

Neuro-transmitter

?

Physiology of CNS ControlCNS

Cerebral cortex, Limbic system,Brain stem &

Hypothalamus

Enteric Nervous System (ENS)

Secretion

MotilityBlood flow

Vagal pathway

Splanchnic pathway

Vag

al e

ffere

nts

Vag

al a

ffere

nts

Enteric afferents & interneurons

Neurotransmitters, Neuropeptides, other chemical and mechanical

stimuli

Neurogenic control of GIT motilityEnteric 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 acetylcholineat 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

• Sympathetic: causes relaxation of muscles in the wall of the intestine and contraction of the sphincters

serosa

Longitudinal Muscle

Myenteric Plexus

Circular Muscle

Submucosal Plexus

submucosal

mucosal

Rational approach

AcetylcholineAcetylcholine HyoscineHyoscine

SpasmPain

RelaxationNo-Pain

SAR Atropine and Hyoscine

Atropine Hyoscine

*

N

H

OC

O

Me

CH

CH2OHO

HH

N

OC

O

Me

H

CH

CH2OHC

O

O CH3

NMe3

CH2CH2

• Relative positions of ester and nitrogen similar in both molecules• Nitrogen in atropine is ionised

• Tertiary amine (ionised) or a quaternary nitrogen• Amine and ester are important binding groups (ionic + H-bonds)• Aromatic ring of atropine is an extra binding group (vdW) • Atropine binds with a different induced fit - no activation• Atropine binds more strongly than acetylcholine

Farmakodinamikhyoscine-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

•

Farmakokinetik Hyoscine-N-butylbromide

• Absorpsi :– cepat diserap oleh jaringan mukosa,deposit di traktus

gastrointestinal, hati dan jaringan ginjal• Distribusi :

– t½ plasma 2-3 menit afinitas jaringan tinggi– bioavailabilitas sistemik rendah, kadar tinggi di lokasi kerja

• Metabolisme : – ikatan plasma 8-13%, – tidak melewati sawar darah otak

• Ekskresi :– melalui ginjal– t½ eliminasi terminal 4.8 jam setelah penggunaan oral

Buscopan• contains the active ingredient hyoscine-N-butyl-

bromide, 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 treatmentBuscopan

pre-paration

Constipation (n=36)

Diarrhea (n=21)

Pain and bloating (n=39)

Before After Before After Before After

Oral 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 ±2.6

5.0 ±2.6

10.2 ±2.2

4.3 ±1.6

13.6 ±3.8

8.4 ±2.2

Interactions between Symptoms and Motor and Visceral Sensory Responses of Irritable Bowel Syndrome Patients to Spasmolytics (Antispasmodics)

Khalif IL, et al. J Gastrointestin Liver Dis 2009;18(1):17-22

Hyoscine butylbromide tunggal dan kombinasi (+ parasetamol)

Terapi rasional nyeri abdomen• Bergantung pada lokasi nyeri, nyeri akut atau kronis, perlu

tindakan surgical atau non-surgical yang harus memahami mekanisme kejadiaan nyeri kolik.

• Saluran cerna memiliki system persyarafan tersendiri ENS, disamping ANS.

• Perangsangan syaraf parasimpatis akan menyebabkan kontraksi otot polos, bisa diikuti dengan nyeri kolik.

• Antimuskarinik hyoscine butylbromide dapat mengurangi spastic sal.cerna, sal.empedu dan sal.kemih.

• Pemberian tunggal sediaan hyoscine butylbromide dapat mengatasi nyeri abdomen.

• Kombinasi hyoscine butylbromide dengan parasetamol secara sinergis memberikan khasiat antinyeri abdomen yang sangat bermakna.

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