dr vivi_farmakotx obat git 2,2013

FarmakoterapiFarmakoterapiFarmakoterapiFarmakoterapi

OBAT-OBAT YANG BEKERJAPADA

SISTEM PENCERNAAN 2OBAT-OBAT YANG BEKERJA

PADASISTEM PENCERNAAN 2

OBAT-OBAT YANG BEKERJAPADA

SISTEM PENCERNAAN 2OBAT-OBAT YANG BEKERJA

PADASISTEM PENCERNAAN 2

Fathiyah Safithri

PROKINETIK AGENT

Indikasi

memotilitas gastermengosongkanlambung lbh cepatTx Gatroparesis

me tonus spinkter bawah esofagusspinkter bisa menutup sempurna TxGERD

memotilitas gastermengosongkanlambung lbh cepatTx Gatroparesis

me tonus spinkter bawah esofagusspinkter bisa menutup sempurna TxGERD

DRUGS PROMOTE GI MOTILITY

Stimulate R/Muscarinic- choline esters cholinomimetics (betanechol)

Prokinetic agents selective motility stimulants

(metoclopramide, cisapride, erythromycin)

Stimulate R/Muscarinic- choline esters cholinomimetics (betanechol)

Prokinetic agents selective motility stimulants

(metoclopramide, cisapride, erythromycin)

Conceptual model of prokinetic agentsDopaminergicneuron

(-)

(+)(-) D2

2 3

3

serotoninserotonin Ach

5HT45 HT3

1(+)

Effectororgan GI

Mech. Of action General pharm. class Example of drug Usedmedications

Aktivasi R/ Musc. Cholinergic agents Betanecholneostigmin

Costipationpseudoobstruction

Classification of prokinetic agents

Inhibisi R/D2 Antagonis R/Dopamin MetoclopramideDomperidone

GERD

Aktivasi R/5HT4Inhibisi R/5HT3

Agonis R/SerotoninAntagonis R/ Serotn

CisaprideMetoclopramide

Gastroparesis

Aktivasi R/Motilin Motilin like agents Erytromycin 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 HealthVolume 20, Issue 3, March 2010,Pages 129134

Anaesthesia & Intensive Care MedicineVolume 13, Issue 12, December 2012, Pages 613616

Anaesthesia & Intensive Care MedicineVolume 7, Issue 12, December 2006, Pages 453455

Chemotherapeutic drugs can trigger emesis by twoways: Direct activation of the medullarychemoreceptor trigger zone. 5-HT3(serotonin3), D2 (dopamine) and NK-1 receptorsplay a critical role as neurotransmitters.

Cell damage of the GI tract. This causesserotonin release from the enterochromaffincells, this molecule activates 5-HT3 receptors onvagal and splanchnic afferent fibers that sendimpulses to the medulla, activating the CTZ whichstimulates the vomiting center.

Chemotherapeutic drugs can trigger emesis by twoways: Direct activation of the medullarychemoreceptor trigger zone. 5-HT3(serotonin3), D2 (dopamine) and NK-1 receptorsplay a critical role as neurotransmitters.

Cell damage of the GI tract. This causesserotonin release from the enterochromaffincells, this molecule activates 5-HT3 receptors onvagal and splanchnic afferent fibers that sendimpulses to the medulla, activating the CTZ whichstimulates the vomiting center.

General classification of antiemetic agentsAntiemetic class Examples Type vomiting

most effective5 HT3-antagonist Ondansetron Cytotoxic drugCentrally acting dopamineantagonist

Metoclopramide(5HT3)Promethazine(antimusc&antihist)

Cytotoxic drugMetoclopramide(5HT3)Promethazine(antimusc&antihist)

H1- antagonist Cyclizine Vestibular(motionsickness)

Muscarinic antagonist Scopolamine Motion sickness

Neurokinin rec Investigational Cytotoxic drug

Cannabinoid rec antag Drobabinol Cytotoxic drug

AntiemetikAntiemetikAntiemetikAntiemetik

Serotonin (5HT) Antagonists Dopamine (DA) Antagonists Anticholinergics (muscarinic blockers) Cannabinoids




Dopamine AntagonistsDopamine AntagonistsDopamine AntagonistsDopamine Antagonists

Phenothiazines prochloraperazine (Compazine) promethazine (Phenergan)

Butyrophenones haloperidol (Haldol) droperidol (Inapsine)

metoclopramide (Reglan)










Serotonin AntagonistsSerotonin AntagonistsSerotonin AntagonistsSerotonin Antagonists

Indikasi : mengatasi ES penggunaan kemoterapiyg menginduksi muntah

Ondansetron (Zofran) Tidak mempengaruhi R/ dopamine tdk ada

efek ekstrapiramidal Granisetron (Kytril)










ANTIEMETIC AGENT

Farmakoterapi Obatsistem hepato-bilier

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

b. arteri hepatic (20%) oxygen, metabolite & circulating xenobiotics

potensial mengalami kerusakanakibat intoksikasi

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

b. arteri hepatic (20%) oxygen, metabolite & circulating xenobiotics

potensial mengalami kerusakanakibat intoksikasi

LIVERPhysiological role* Nutrients metabolism

carbohydrates, lipids and proteins

* Synthesis and secretes bilewater, ions, lipids (bile salts), and bile pigments(bilirubin).

* Synthesis protein enzymesalbumin, cytochrome P450s, transaminase

Physiological role* Nutrients metabolism

carbohydrates, lipids and proteins

* Synthesis and secretes bilewater, ions, lipids (bile salts), and bile pigments(bilirubin).

* Synthesis protein enzymesalbumin, cytochrome P450s, transaminase

LIVERLIVER Nutrient metabolism :a. Carbohydrate metabolism

synthesis glycogen from glucose and reverse

b. Lipid metabolismtriglyceride, FFA, HDL, LDL, VLDL

c. Protein metabolismenzymes, albumin, amino acid

Nutrient metabolism :a. Carbohydrate metabolism

synthesis glycogen from glucose and reverse

b. Lipid metabolismtriglyceride, FFA, HDL, LDL, VLDL

c. Protein metabolismenzymes, albumin, amino acid

LIVERxenobiotic metabolism :a. enhance excretionby change any substance become polar,hydrophilic.

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

xenobiotic metabolism :a. enhance excretionby change any substance become polar,hydrophilic.

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

Parasetamol

NABQI conjugation(N-aetylbenzoquinoneimine) (sulphate or glucuronate)

conjugation

(sulphate or glucuronate)

renal excretion renal excretion

7 10% 90 93%

glutathione

oxidation

Parasetamol

NABQI conjugation(N-aetylbenzoquinoneimine) (sulphate or glucuronate)

conjugation

(sulphate or glucuronate)


NABQI : hepatotoxic

Liver Diseases - Disorders1. Acute hepatitis (acute viral hepatitis, alcoholic

hepatitis)2. Chronic hepatitis (chronic persistent hepatitis,

chronic active hepatitis autoimmune type)3. Liver cirrhosis (compensated and non-compensated cirrhosis, liver cirrhosisencephalopathy, cirrhosis edema and ascites,bleeding from esophageal varices, and cirrhosisrenal failure)

1. Acute hepatitis (acute viral hepatitis, alcoholichepatitis)

2. Chronic hepatitis (chronic persistent hepatitis,chronic active hepatitis autoimmune type)

3. Liver cirrhosis (compensated and non-compensated cirrhosis, liver cirrhosisencephalopathy, cirrhosis edema and ascites,bleeding from esophageal varices, and cirrhosisrenal failure)

Liver Diseases - Disorders

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

5. Gallstones

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

5. Gallstones

Drugs in Hepatitis1. 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

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 isrecommended

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 isrecommended

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 towardinfection

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 towardinfection

Chronic active hepatitis Autoimmune hepatitischaracterized by histopathologicalfeature : chronic hepatitis, presence ofautoantibody

Interferon-a inhibit viral replication (+ 40% ofchronic hepatitis-B) may cause influenza like symptom,bone marrow suppression, depression,irritable

Autoimmune hepatitischaracterized by histopathologicalfeature : chronic hepatitis, presence ofautoantibody

Interferon-a inhibit viral replication (+ 40% ofchronic 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 hepaticparenchyma

Extensive fibrosisin association with regenerative nodules

As a final common pathwayof many types of chronic liver injury,

Clinical featuresreflect the severity of hepatic damage rather than theetiology of underlying liver diseases

A pathological features caused by irreversible chronic injury of the hepaticparenchyma

Extensive fibrosisin association with regenerative nodules

As a final common pathwayof many types of chronic liver injury,

Clinical featuresreflect the severity of hepatic damage rather than theetiology of underlying liver diseases

Clinical features ofClinical features of

Liver cirrhosis Loss of functioning hepatocellular mass jaundice, edema, coagulopathy, metabolicabnormalities,

Fibrosis and distorted vasculature portal hypertension and its sequelae(gastroesophagel varices and splenomegaly)

Ascites and hepatic encephalopathy resulted from both hepatocellularinsufficiency and portal hypertension

Loss of functioning hepatocellular mass jaundice, edema, coagulopathy, metabolicabnormalities,

Fibrosis and distorted vasculature portal hypertension and its sequelae(gastroesophagel varices and splenomegaly)

Ascites and hepatic encephalopathy resulted from both hepatocellularinsufficiency and portal hypertension

Alcohol induced hepatic lesion1. Alcoholic fatty liver

accumulation of fat in the liver result from an impairment of fatty acid oxidation,

increase uptake and esterification to formtriglyceride and diminished lipoprotein biosynthesis

2. Alcoholic hepatitishepatocyte degeneration and necrosis balloonedcells, infiltrate alcoholic hyaline

3. Alcoholic cirrhosisdestruction of hepatocytes and fibroblastcollagenization

1. Alcoholic fatty liveraccumulation of fat in the liver result from an impairment of fatty acid oxidation,

increase uptake and esterification to formtriglyceride and diminished lipoprotein biosynthesis

2. Alcoholic hepatitishepatocyte degeneration and necrosis balloonedcells, infiltrate alcoholic hyaline

3. Alcoholic cirrhosisdestruction of hepatocytes and fibroblastcollagenization

Liver cirrhosis compensated cirrhosis

- regularly reviewed for sign of hepatocellularfailure serum analysis for LFT

- long term care includes control of ascites- avoid drugs that induce coma do not give unnecessarily drugs

compensated cirrhosis- regularly reviewed for sign of hepatocellularfailure 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 orcoma)

- oral vitamin K if there is high prothrombin time avoid unnecessarily drugs

decompensated cirrhosis- diet should be as nutritious as possible. high protein diet

(provided that there is no evidence of precoma orcoma)

- 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 isused

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 isused

Hepatic encephalopathy- oral lactulose acidifying the colonic contents

(reducing absorption of ammonia and possibletoxins)the dose is increased until desired effect isobtained

- neomycin (reduce urease producing intestinalbacteria) avoid unnecessarily drugs

Liver cirrhosis Hepatic encephalopathy

- oral lactulose acidifying the colonic contents

(reducing absorption of ammonia and possibletoxins)the dose is increased until desired effect isobtained

- neomycin (reduce urease producing intestinalbacteria) avoid unnecessarily drugs

HEPATOTOXICITY

Manifestation ofHEPATOTOXICITY

1. Fatty liver2. Hepatitic reactions3. Obstructive jaundice cholestatic jaundice

4. Liver necrosis5. Liver cirrhosis6. Liver cancer

1. Fatty liver2. Hepatitic reactions3. Obstructive jaundice cholestatic jaundice

4. Liver necrosis5. Liver cirrhosis6. Liver cancer

Drug induced Fatty LiverDrug induced Fatty Liver

1. Carbontetrachloride (CCl4)2. Tetracycline3. Ethionine4. Ethanol chronic5. Phalotidine alkaloids

1. Carbontetrachloride (CCl4)2. Tetracycline3. Ethionine4. Ethanol chronic5. Phalotidine alkaloids

Intrahepatic cholestasis1. Carbimazole, methylthiouracil (antithyroiddrugs)

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. chlorpromazineantipsychotics)

1. Carbimazole, methylthiouracil (antithyroiddrugs)

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. chlorpromazineantipsychotics)

Intrahepatic cholestasis

1. Anabolic steroids (methyltestosterone,norethindrolone)

2. Azatrioprine (antiviral)3. Mercaptopurine (antimetabolite for acute leukemia)

4. Oestrogen (contraceptive agents)

1. Anabolic steroids (methyltestosterone,norethindrolone)

2. Azatrioprine (antiviral)3. Mercaptopurine (antimetabolite for acute leukemia)

4. Oestrogen (contraceptive agents)

DrugDrug // toxin inducedtoxin inducedLIVER NECROSIS

1. Aflatoxin2. INH3. Carbontetrachloride4. Paracetamol5. Chloroform6. Tetracycline7. Dinitrophenol8. Ethionine9. Halothane10. Ibuprofen11. Indomethacin12. Amanita phaloides

1. Aflatoxin2. INH3. Carbontetrachloride4. Paracetamol5. Chloroform6. Tetracycline7. Dinitrophenol8. Ethionine9. Halothane10. Ibuprofen11. Indomethacin12. Amanita phaloides

Liver NecrosisLiver NecrosisParasetamol

NABQI conjugation(N-cetylbenzoquinoneimine) (sulphate or glucuronate)

conjugation(sulphate or glucuronate)


7 10% 90 93%

Parasetamol

NABQI conjugation(N-cetylbenzoquinoneimine) (sulphate or glucuronate)

conjugation(sulphate or glucuronate)


NABQI (n(n--acetylbenzoquinoneimineacetylbenzoquinoneimine))NABQI

binding (covalent) to celluler hepatic proteins

damage endoplasmic reticulumswelling mitochondriadestruction of nucleus

mesruption of plasma membrane

cell necrosis

NABQI

binding (covalent) to celluler hepatic proteins

damage endoplasmic reticulumswelling mitochondriadestruction of nucleus

mesruption of plasma membrane

cell necrosis

Acutehepatocellular damage(non dose dependent)(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. desipramineantidepresant)

8. Barbiturate (hypnotics, anticonvulsant)7. Sulfonamide (sulfamethoxazolchemotherapeutics)

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. desipramineantidepresant)

8. Barbiturate (hypnotics, anticonvulsant)7. Sulfonamide (sulfamethoxazolchemotherapeutics)

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)a7. Methotrexate (antimetabolite, antifolic acid for cancer)8. Acetaminophen (analgesics antipyretics)7. Tetracycline (intravenous large dose)

Acutehepatocellular damage( dose dependent)( 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)a7. Methotrexate (antimetabolite, antifolic acid for cancer)8. Acetaminophen (analgesics antipyretics)7. Tetracycline (intravenous large dose)

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 tonemasking effect stone captures duct rupture spasmolytics (hyoscin, papaverin)

Antibiotics, antiinflammatory drugs

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 tonemasking effect stone captures duct rupture spasmolytics (hyoscin, papaverin)

Antibiotics, antiinflammatory drugs

Drug Induced Liver Injury andIts Patterns

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

dr vivi_farmakotx obat git 2,2013

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