Farmakoterapi

OBAT-OBAT YANG BEKERJA

PADA
SISTEM PENCERNAAN 2
Fathiyah Safithri

PROKINETIK AGENT

Indikasi

memotilitas gaster mengosongkan

lambung lbh cepat Tx Gatroparesis
me tonus spinkter bawah esofagus
spinkter bisa menutup sempurna Tx
GERD

DRUGS PROMOTE GI MOTILITY

Stimulate R/Muscarinic
- choline esters cholinomimetics (betanechol)

Prokinetic agents
selective motility stimulants
(metoclopramide, cisapride, erythromycin)

Conceptual model of prokinetic agents

Dopaminergic
neuron
(-)
3

2
D2

(-)

(+)
5HT4

5 HT3
serotonin

(+) Ach

serotonin

Effector
organ GI

Classification of prokinetic agents

Mech. Of action
Aktivasi R/ Musc.

Inhibisi R/D2

General pharm. class

Example of drug

Cholinergic agents

Betanechol

Antagonis R/Dopamin

Used
medications

neostigmin

Costipation
pseudoobstruction

Metoclopramide

GERD

Domperidone
Aktivasi R/5HT4

Agonis R/Serotonin

Cisapride

Inhibisi R/5HT3

Antagonis R/ Serotn

Metoclopramide

Aktivasi R/Motilin

Motilin like agents

Erytromycin

Gastroparesis

Gastroparesis

OBAT ANTI MUNTAH

Differential diagnosis of nausea and vomiting

10, Issue 12, December 2009, Anaesthesia &

Intensive Care Medicine Volume Pages 597601

Paediatrics and Child Health

Volume 20, Issue 3, March 2010,
Pages 129134

Anaesthesia & Intensive Care Medicine

Volume 13, Issue 12, December 2012, Pages 613616

Anaesthesia & Intensive Care Medicine

Volume 7, Issue 12, December 2006, Pages 453455

Chemotherapeutic drugs can trigger emesis by two

ways:
Direct activation of the medullary
chemoreceptor trigger zone. 5-HT3
(serotonin3), D2 (dopamine) and NK-1 receptors
play a critical role as neurotransmitters.
Cell damage of the GI tract. This causes
serotonin release from the enterochromaffin
cells, this molecule activates 5-HT3 receptors on
vagal and splanchnic afferent fibers that send
impulses to the medulla, activating the CTZ which
stimulates the vomiting center.

General classification of antiemetic agents

Antiemetic class

Examples

Type vomiting
most effective

5 HT3-antagonist

Ondansetron

Cytotoxic drug

Centrally acting dopamine Metoclopramide(5HT Cytotoxic drug

antagonist
3)

H1- antagonist

Promethazine(antim
usc&antihist)
Cyclizine
Vestibular(motion
sickness)

Muscarinic antagonist

Scopolamine

Motion sickness

Neurokinin rec

Investigational

Cytotoxic drug

Cannabinoid rec antag

Drobabinol

Cytotoxic drug

Antiemetik

Serotonin (5HT) Antagonists

Dopamine (DA) Antagonists
Anticholinergics (muscarinic blockers)
Cannabinoids

Dopamine Antagonists
Phenothiazines
prochloraperazine (Compazine)
promethazine (Phenergan)

Butyrophenones
haloperidol (Haldol)
droperidol (Inapsine)

metoclopramide (Reglan)

Serotonin Antagonists
Indikasi : mengatasi ES penggunaan kemoterapi
yg menginduksi muntah
Ondansetron (Zofran)
Tidak mempengaruhi R/ dopamine tdk ada
efek ekstrapiramidal
Granisetron (Kytril)

ANTIEMETIC AGENT

ANTIEMETIC AGENT

Farmakoterapi Obat

sistem hepato-bilier

LIVER
Aliran Darah Hepar:
a. vena portal (80%)
nutrients & xenobiotics dari GIT

b. arteri hepatic (20%)

oxygen, metabolite & circulating xenobiotics

potensial mengalami kerusakan

akibat intoksikasi

LIVER
Physiological role
* Nutrients metabolism
carbohydrates, lipids and proteins

* Synthesis and secretes bile

water, ions, lipids (bile salts), and bile pigments
(bilirubin).

* Synthesis protein enzymes

albumin, cytochrome P450s, transaminase

LIVER
Nutrient metabolism :
a. Carbohydrate metabolism
synthesis glycogen from glucose and reverse

b. Lipid metabolism
triglyceride, FFA, HDL, LDL, VLDL

c. Protein metabolism
enzymes, albumin, amino acid

LIVER
xenobiotic metabolism :
a. enhance excretion
by change any substance become polar,
hydrophilic.

b. inactivate detoxication
it is often (but not always) achieved,
sometime activation.

Parasetamol
oxidation

7 10%

90 93%

NABQI
(N-aetylbenzoquinoneimine)
glutathione

conjugation
(sulphate or glucuronate)

conjugation
(sulphate or glucuronate)

NABQI : hepatotoxic

renal excretion

renal excretion

Liver Diseases - Disorders

1. Acute hepatitis (acute viral hepatitis, alcoholic
hepatitis)
2. Chronic hepatitis (chronic persistent hepatitis,
chronic active hepatitis autoimmune type)
3. Liver cirrhosis (compensated and noncompensated cirrhosis, liver cirrhosis
encephalopathy, cirrhosis edema and ascites,
bleeding from esophageal varices, and cirrhosis
renal failure)

Liver Diseases - Disorders

4. Special liver cirrhosis
(hemochromatosis, Wilson disease,
primary biliary cirrhosis)
5. Gallstones

Drugs in Hepatitis
1. Acute hepatitis
Symptomatic teraphy
cholestyramine, reduce pruritus but may cause
hepatotoxicity use this drug as it really needed
corticosteroids no benefit
active immunization hepatitis-B vaccine
passive immunization immune serum globulin
(HBIG) effective? side effects?

2. Chronic hepatitis
corticosteroids or other immunosuppressant avoid

Cholestyramine
Acid bile chelator
Bind to acid bile in the intestine lumen
block acid bile reabsorption
serum bilirubin pruritus
Unpleasant taste
May causes diarrhea and abdominal
discomfort
If pruritus is not controlled by
cholestyramine antihistamine is
recommended

Corticosteroids
May have a benefit in cholestasis
secondary to hepatitis-A viral infection
(not for other type of viral hepatitis)
May suppress RES
decrease self protection toward
infection

Chronic active hepatitis

Autoimmune hepatitis
characterized by histopathological
feature : chronic hepatitis, presence of
autoantibody
Interferon-a
inhibit viral replication (+ 40% of
chronic hepatitis-B)
may cause influenza like symptom,
bone marrow suppression, depression,
irritable

LIVER CIRRHOSIS

Liver cirrhosis
A pathological features
caused by irreversible chronic injury of the hepatic
parenchyma

Extensive fibrosis
in association with regenerative nodules

As a final common pathway

of many types of chronic liver injury,

Clinical features
reflect the severity of hepatic damage rather than the
etiology of underlying liver diseases

Clinical features of

Liver cirrhosis
Loss of functioning hepatocellular mass
jaundice, edema, coagulopathy, metabolic
abnormalities,
Fibrosis and distorted vasculature
portal hypertension and its sequelae
(gastroesophagel varices and splenomegaly)
Ascites and hepatic encephalopathy
resulted from both hepatocellular
insufficiency and portal hypertension

Alcohol induced hepatic lesion

1. Alcoholic fatty liver
accumulation of fat in the liver
result from an impairment of fatty acid oxidation,
increase uptake and esterification to form
triglyceride and diminished lipoprotein biosynthesis

2. Alcoholic hepatitis
hepatocyte degeneration and necrosis ballooned
cells, infiltrate alcoholic hyaline

3. Alcoholic cirrhosis
destruction of hepatocytes and fibroblast
collagenization

Liver cirrhosis
compensated cirrhosis

- regularly reviewed for sign of hepatocellular

failure serum analysis for LFT
- long term care includes control of ascites
- avoid drugs that induce coma

do not give unnecessarily drugs

Liver cirrhosis
decompensated cirrhosis

- diet should be as nutritious as possible.

high protein diet
(provided that there is no evidence of precoma or
coma)

- oral vitamin K if there is high prothrombin time

avoid unnecessarily drugs

Liver cirrhosis
Edema and ascites
- mobilise intraperitoneal fluid
decrease Na+ dietary intake
(1 1,5 g/day : 40 60 mmol/day)

- diuretics (furosemide, or spironolacton if needed)

avoid dehydration if diuretic is

used

Liver cirrhosis
Hepatic encephalopathy
- oral lactulose
acidifying the colonic contents
(reducing absorption of ammonia and possible
toxins)
the dose is increased until desired effect is
obtained
- neomycin (reduce urease producing intestinal
bacteria)

avoid unnecessarily drugs

HEPATOTOXICITY

Manifestation of
HEPATOTOXICITY
1. Fatty liver
2. Hepatitic reactions
3. Obstructive jaundice
cholestatic jaundice

4. Liver necrosis
5. Liver cirrhosis
6. Liver cancer

Drug induced Fatty Liver

1. Carbontetrachloride (CCl4)
2. Tetracycline
3. Ethionine
4. Ethanol chronic
5. Phalotidine alkaloids

Intrahepatic cholestasis
1. Carbimazole, methylthiouracil (antithyroid
drugs)

2. Benzodiazepines (anxiolytics, anticonvulsant)

3. Clavulanic acid (b-lactamase inhibitor)
4. Imidazole (i.e. ketokonazole antimycotics)
5. Sulphonylurea (oarl antidiabetics tolbutamide,
glibenclamide, chlopropamide)
6. Tricyclic antidepressants (imipramine,
amitryptiline, desipramine, iprindole)
7. Phenothiazines (i.e. chlorpromazine
antipsychotics)

Intrahepatic cholestasis
1. Anabolic steroids (methyltestosterone,
norethindrolone)
2. Azatrioprine (antiviral)
3. Mercaptopurine (antimetabolite
for acute leukemia)
4. Oestrogen (contraceptive agents)

Drug / toxin induced

LIVER NECROSIS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

Aflatoxin
INH
Carbontetrachloride
Paracetamol
Chloroform
Tetracycline
Dinitrophenol
Ethionine
Halothane
Ibuprofen
Indomethacin

Amanita phaloides

Liver Necrosis
Parasetamol

7 10%

NABQI
(N-cetylbenzoquinoneimine)

90 93%

conjugation
(sulphate or glucuronate)

conjugation
(sulphate or glucuronate)
renal excretion

renal excretion

NABQI (n(n--acetylbenzoquinoneimine
acetylbenzoquinoneimine))
NABQI

binding (covalent) to celluler hepatic proteins

damage endoplasmic reticulum

swelling mitochondria
destruction of nucleus
mesruption of plasma membrane
cell necrosis

Acute hepatocellular damage

(non dose dependent)

1. INH, pyrazinamide, rifampicin

(antituberculosis)
2. Carbamazepine (muscle realxant,
anticonvulsant)
3. Halothane (inhalant general anesthetics)
4. Imidazole (i.e. ketokonazole antimycotics)
5. Ibuprofen, indomethacin (NSAIDs)
6. Methyldopa (antihypertensive)
7. MAO inhibitor (i.e. desipramine
antidepresant)
8. Barbiturate (hypnotics, anticonvulsant)
7. Sulfonamide (sulfamethoxazol
chemotherapeutics)

Acute hepatocellular damage

( dose dependent)

1. Alcohol (beverage)
2. Amiodarone (cardiac stimulant)
3. Azatrioprine (antiviral)
4. Chlorambucil (alkylating agent for CLL)
5. Hydrocarbons (glue glue sniffing)
6. Overdose iron salt (antianemics)a
7. Methotrexate (antimetabolite, antifolic acid
for cancer)
8. Acetaminophen (analgesics antipyretics)
7. Tetracycline (intravenous large dose)

CHOLELITHIASIS
Previous cholecystitis
Rapid weight loss
during treatment of overweight, morbid-obesity
cholesterol is the main substance forms the stone

Ursodiol
decrease cholesterol secretion into the bile
decrease intestine cholesterol absorption

increase bile flow cholesterol stone disolve

Opioid analgesics
analgesia, increase duct smooth muscle tone
masking effect stone captures duct rupture
spasmolytics (hyoscin, papaverin)

Antibiotics, antiinflammatory drugs

Drug Induced Liver Injury and

Its Patterns

Navarro, V. J. et al. N Engl J Med 2006;354:731-739