pharmacology of the digestive system -...

Pharmacology of the digestive system

SecretionDecreased

Increased

Achlorhydria, hypochlorhydriabiliary secretory dysfunctioninsufficiency of pancreatic enzymesulcer disease, GERD

Motility (dysmotility)Slowed down

Accelerated

dysphagia, refluxgastric stasisconstipationdiarrhea

2

Accelerated

Mixed

diarrheavomitingsphincter of Oddi dyskinesis

AbsorptionDecreased malabsorption

Inflammation

Gallstones biliary colic

Mucosa associated limphoid tissueinflammatory bowel disease (IBD), gastroenteritisacute, chronic hepatitis, acute, chronic pancreatitis

I. DRUGS USED IN ACID-PEPTIC DISEASES

II. DRUGS STIMULATING GI MOTILITY

III. LAXATIVES

IV. ANTIDIARRHEAL AGENTS

V. DRUGS USED FOR THE TREATMENT OF

PHARMACOLOGY OF THE GI TRACT

3

V. DRUGS USED FOR THE TREATMENT OFIRRITABLE BOWEL SYNDROME (IBS)

VI. ANTIEMETIC AGENTS

VII. DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASES

VIII. PANCREATIC ENZYME SUPPLEMENTATION

IX. BILE ACID THERAPY, TREATMENT OF HEPATITIS B and C, PBC, AACH

X. DRUGS USED TO TREAT COMPLICATIONS OF CIRRHOSIS

defensive


Pathogenesis of ulcers

4

aggressive

Helicobacter pylori

NSAIDs

stress

mucosal defense

acid

DRUGS

- +blood flow

prostaglandins

bicarbonate

(smoking, alcohol)


vaguslocal stimulant

(food)G-cells

gastrinEnterochromaffin-

like (ECL) cell

M1

ganglionpirenzepine

X

+

muscarin-antagonist

+

CCKBM3

GRP

5

CCKBH2M3

histamineACh

H+/K+

ATP-ase

+

+

cAMP

+Ca++

+

K+

PPIXantacids X

H+

PGE2, PGI2

Ca++

+

H2 rec. inhib. X

HCl

Parietal cell

PG

-

Life-style changes

A, Neutralisation of gastric acid

aggressive

B, Inhibition of HCl secretion aggressive

ANTACIDS


C, Mucosal protective agents

D, Prostaglandin analogs

aggressive

defensive

defensive

7

H2-receptor inhib. Proton pump inhib.

A, Neutralisation of gastric acid

•Used worldwide

•Gastric burning

•Chemical salt of alkaline ion and counterion

•Neutralization of stomach gastric acid

Antacids


7

•Neutralization of stomach gastric acid

•Decreases pepsin activity

•Increases secretion of PGs and bicarbonate

•Solubility (water-soluble, non water-soluble)

•Influences the absorption of other drugs (digoxin,

iron, warfarin , AID, ranitidin, tetracyclin)

AntacidsSYSTEMIC ANTACIDS1. Sodium bicarbonate (baking soda)

formation of CO2 + NaCl

highly soluable in waterCo2 tension, post-acid production, sodium intake


8

2. Calcium carbonate

less soluble (partially absorbed)reacts more slowlyrarely used (S.E.)formation of CO2 + CaCl2constipation

S.E.: Increase gastrin secretion (gastric distension), metabolic acidosis, combined consuption with milk (milk-alkali syndrome)(systemic antacid + milk)

1. Mg-oxide, Mg-hydroxide (slower relief without belching)Mg-trisilicate (slow relief)

Absorped only slightlyLaxative effectpepsin adsorptionS.E.: osmotic diarrhea, bradycardia (renal failure-clearence inhibited)


NON-SYSTEMIC ANTACIDS

9

S.E.: osmotic diarrhea, bradycardia (renal failure-clearence inhibited)

2. Aluminium – hydroxide gel (slow acting)Neuralizing capacity is weakpepsin adsorption, increases mucous secretionforms Al-chloride in the stomach (coat the mucosa), Cl- is releasedand is reabsorbed in the intestine > Al-phosphateS.E.: hypophosphatemia, anorexia, constipation

3. Combined preparationsAl(OH)3+Mg(OH)2 e.g. MAALOX

Antacids (OTC, non-prescreption) (1-1½ hours after meal)


Weak bases + acid = salt + water

10

H2 rec. antagonists (competitive)


- competitive antagonist of histamine

- reduce basal, meal-stimulated and nocturnal acid secretion

- gastrin, Ach-induced secretion

- decrease pepsin and intrinsic factor

B, Inhibition of HCl secretion

11

- decrease pepsin and intrinsic factor

- promote ulcer healing

- recurrence rate is 80-90%

- 60-70% HCl inhibition/24h (90% during night time)

- slight inhibition of gastrin, ACh effect

- prophylactic use (NSAID),

- no effect against H. pylori

- tolerance during the administration

- duodenal ulcers (4-8 weeks, 3 x 200 mg per day + night)

- maintenance therapy

H2 rec. antagonists (competitive)

PHARMACOKINETICS:

Absoption: intestine (quickly)Metabolism: in the liver first-pass

Biological efficiency: ~ 50%.T1/2: 1-4 hoursexcretio: glomerulus filtration

12

excretio: glomerulus filtrationrenal tubular secretion (renal failure!)

safe drugs, side effects in < 3% of patients: diarrhea, constipation,

headache, fatigue, mental status changes (confusion,

hallucination, agitation) bradycardia, hypotension (H2 receptors in the heart),

decreased libido, impotence and gynecomastia

SIDE EFFECTS:

interference with P450 drug metabolism pathways

(cimetidine) - (e.g. phenytoin, warfarin, TCA, BZD)

INTERFERENCE:

A savcsökkentő gyógyszerekfarmakológiája

3. A savtermelés csökkentése

H2-receptor antagonisták

Therapeutic indications:

• peptic ulcer (duodenal ulcers 4-8 weeks, gastric

ulcers (50-75% of patients are healed), H.P. eradication

reduced risk of recurrancereduced risk of recurrance

• NSAID induced ulcers (PPI!)

• Gastrooesophagalis reflux disease (GERD)

• other indications

• stress ulcer (unconscious patients)

• prevention of acid aspiration (emergency

surgery)

Cimetidine: (2x400-800 mg)

S.E.: androgen receptor binding (loss of libido, impotence)

increased prolactin, inhibition of oestradiol metabolism

gynaecomastia or impotence ♂, galactorrhea ♀cyt P450 inhibition, leading to effects on other drug metabolism

H2 rec. antagonists


14

cyt P450 inhibition, leading to effects on other drug metabolism

Ranitidine: (2x150 mg)

S.E.: less, but tolerance leading to increasing dosage requirement

Famotidine: (2x20 mg, most efficacious)

Does not potentiate the effect of alcohol (via dehydrogenase)

Nizatidine: (2x150 mg) little first pass effect, 90-100% bioavailability

Ranitidine-bizmuth combination: PYLORID

major adventage in combination with antibiotics

bioavailability

CIMETIDIN RANITIDIN FAMOTIDIN NIZATIDIN

80% 50% 40% 90%


Duration of action (hour)

Daily doses

relative efficiency 1 5-10 5-1032

6 8 12 8

800mg 300mg 40mg 300mg

12

PROTON PUMP INHIBITORS


• available from the late 1980s• H+/K+ ATPase catalyze the final step in acid secretion

16

secretion

• PPIs block any stimuli induced secretion

• any degree of inhibition

• even in a single dose



• Irreversible proton pump inhibition, resynthesis >18h

• block 98% of acid secretion, need 3-4 days of daily medication

• the „pro-drug” is acid sensitive (enteric-coated capsules)

• lipophylic weak bases (pKa 4-5), diffuse across the cell

17

a

membrane > concentrated within the parietal canaliculi (>1000-fold)

• protonated, converted to active, reactive sulfonamide

• optimal effect: 30-60 min before meal

• short half-life (0.5-2 h)

• hepatic metabolism, no renal clearence

S.E.: diarrhea, headache, abdominal pain, subnormal vitamin B12

levels, abnormal Ca2+ absorption, ECL-cell hyperplasia,

hypergastrinemia, achlorhydria, GI infection (Salmonella, Shigella)


Substituted benzimidazoles

Omeprazole LOSEC racemic mixture of R- and S-isomers

available as i.v. Formulation

hyperplasia of ECL cells – no clinical significance


18

hyperplasia of ECL cells – no clinical significance

sustained hypergastrinaemia due to acid inhibition

hypochlorhydria bacterial overgrown nitrate to nitrozamin

Esomeprazole NEXIUM S-isomer of omeprazole

Pantoprazole binds to two cysteins, available as i.v. formulation

(must be given as a continuous infusion over 24-48 h)

Lansoprazole PREVACID

Rabeprazole AcipHex


Clinical uses of PPIs

1. Peptic Ulcer Disease (duodenal 4 w, gastric 6-8 w)

a. H. pylori associated ulcer b. NSAID associated ulcerOnce daily therapy

Eradication (2 antibiotics and PPI)7-14 day therapy

Lansoprazole 2x20mg

19

2. Gastroesophageal Reflux Disease (GERD)

most effective agentsonce or twice dailysymptoms recur (80%) within 6 months after discontinuation

Lansoprazole 2x20mg Clarithromycin 2x500mg

Amoxicillin 2x1g or Metronidazol 2x500mg+

PPI for additional 4-6 weeks

NOTE: pH>6 is necessary for platelet aggregation

Need high PPI dose in active GI bleed


3. Zollinger – Ellison syndrome

First choice drug

4. Gastrinoma

High doses

Clinical uses of PPIs

20

High doses

S. E.: - nausea- vomiting- abdominal pain- headache

5. Prevention of stress gastritis (unconscious patients)

PPI


Jansen JB Gut. 1988 Jan;29(1):75-80. rebound?

Waldum HL, Gut. 1996 Nov;39(5):649-53.

Half-life


Anticholinergic therapy

Pirenzepine Selective M1-receptor antagonistgreatly reduced in the terapy of ulcers

Not used

greatly reduced in the terapy of ulcersthey inhibit acid secretin at a dose which associatedwith parasympatholithic side effects3 x 50 mg dailyDoes not cross the blood-brain barrierAnticholinergic S.E.

mucus, bicarbonateCells of the gastric glandular mucosa

I. DRUGS USED IN ACID-PEPTIC DISEASES(ulcer disease, GERD, acid dyspepsia)

DRUGS WHICH STRENGHTEN DEFENSIVE MECHANISM(act on ulcer site and enhance mucosal defenses)

25

HCl, intrinsic factor

inhibition of H+

rediffusion(„tight junction”)

„repair” mechanismsmicrocirculation

prostaglandins etc.

neck cells

parietalcells

chiefcells

ECL-cells

endocrine cells

surface mucuscells

Pepsin(ogen)

H2O + CO2

H+ H+ H+

Mucus

From Aase S: Scand J Gastroenterol 24(suppl 163):17, 1989.

I. FEKÉLYBETEGSÉGEK KEZELÉSE

defensive

HCO3- HCO3

- HCO3-

Buffer

EpitheliumCl -

20

Sucralfate: ULCOGANT (mostly in suspension as a paste)

Al-salt of the sucrose-octasulfate,<0.01% of Al absorbed polymerizes

at <4 pH, mucoadhesive protective gel, layer (ulcer)Al dissociatesabsorb pepsin/bile and inhibits the rediffusion of H+-ionsstimulates the production of defensive factors (eg. PGs, HCO3

-)


C, Mucosal protective agents

27

stimulates the production of defensive factors (eg. PGs, HCO3 )1g x 4 daily, 1 h before mealsS.E.: constipation (Al salt), dry mouth, may bind other medicationsrarely used in gastric ulcers, but effective in stress induced bleedingShould not be taken parallel with other antacides

Colloidal bismuth compounds: -subsalicylate and -subcitrate

protective layer on ulcer surface (exudate), binds enterotoxins

inhibits pepsin activity, increases mucus and PG productionantibacterial (H. pylori eradication) (ulcer recurr. 20%)negligible bismuth absorption (<0.04%)S.E.: black colorisation of the mouth, tongue, stool; encephalopathy

For therapeutic purposes only PGE1 is on the market (misoprostol,

methyl analogue), serum half life less than 30 min. (4x daily)

protection against NSAID- or corticosteroid-induced gastric ulcer

D, Prostaglandin analog


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acid inhibition and mucosal protective effects:

reduces histamine-stimulated cAMP production

stimulates mucus and bicarbonate secretion

enhances mucosal blood flow

increases epithelial regeneration

(cytoprotective, vasodilatative, inhibits thrombocyte aggr.)

S.E.: diarrhoea, cramps, abortion

Strongly limited use



III. LAXATIVES




29







Prokinetic Agents:� Promote the coordinated contraction of the antrum and

duodenum� Esophagus

� GERD, enhances the tone of lower eosophageal spinchter� Esophagitis nausea and vomiting

� Gastric emptying


� Gastric emptying� gastroparesis or after stomach surgery� Rapid passage of food, heart burn

� Intestinum� postop. ileus, constipation� Duodenal motility, intestinal transit� Opening of the gastro-duodenal spinchter

� Colon� constipation


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Source: www.medicine.usask.ca

Motilin

Metoclopramide

dopamine (D2) antagonist (central and peripheral)no effect on colonic motilityS.E.: restlessness, drowsiness, insomnia, anxiety

extrapyramidal symptoms, prolactinemia

Domperidone

dopaminergic (D2) antagonist (selective)S.E.: similar to those of metoclopramide,


Increase the tone of the lower esophagus spinchter

Spontaneous motility of the stomach

Peristalsis of the small int

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S.E.: similar to those of metoclopramide,but does not cross Blood Brain Barrier (no neuropsychiatric or extrapyramidal effects)

Cisapride5-HT4 receptor agonist, motilin-like effectHas no effect on D2-receptors (no anti-emetic effect)S.E.: prolongation of the QT interval (K+ channel inhibitor), „torsade de pointes”

ventricular arrhythmia and sudden death, abdominal cramps, diarrheaInteraction with Cyt P450 inhibitor drugs

Influence the colon

withdrawn from the market


Macrolide antibiotics (e.g. erythromycin)

Motilin receptor agonistsPromote the onset of a migrating motor complexIncrease colon motility > watery diarrheaI.v. erythromycin (3 mg/kg) is beneficial in some patients

33

I.v. erythromycin (3 mg/kg) is beneficial in some patientswith gastroparesis

Acute toleranceCyt P450 inhibitionS.E.: nausea, vomiting, diarrhea, abdom. pain,

reversible hearing loss, arrhythmia



III. LAXATIVES




34







III. LAXATIVES

Laxatives: self-prescribed by a large proportion of the population –one of the most common causes of constipation!• normal bowel function is disturbed

• water and electrolyte loss, increased aldosteron production, K+ loss

(laxatives, chatartics, drastics)

Speed up and facilitate defecation

35

Vicious circle

Indications: constipationbefore surgical, endoscopic interventionabdominal X-ray examination (irrigoscopy)elderly, debilitated patientspatients with chest or abdominal surgeryfresh infarction (cerebral hemorrhage)

Prevention of constipation:high fiber diet, adequate fluid intake, regular exercise

ClassifictionClassifiction::

•• Bulk forming laxatives

•• Stool surfactant agents

III. LAXATIVES

•• Stool surfactant agents

•• OsmoticOsmotic laxativeslaxatives

•• StimulantStimulant purgativespurgatives

1. Bulk forming laxatives

A) Fiber

- dietary fiber content incomplete filling of the colon

- 20-60 g fiber

- reach the colon unchanged and absorb water

- polysaccharides (cellulose, hemicellulose, pectin)

III. LAXATIVES

37

- polysaccharides (cellulose, hemicellulose, pectin)

- bran, fiber-rich vegetables (carrrot), fruits, cereals

B) Hydrophilic colloids

- semisynthetic methylcellulose

- binds water, swell to 25X

- stomach fullness

- S.E.: obstruction of the intestine

- contraindicated in intestinal stenosis

- agar jelly, dried fruits (prunes, apples, fig), plum jam

III. LAXATIVES

2. Stool surfactant agents

A) Docusat (SINTOLAX)

- Anion surfactant

- promotes the flow of water into the faeces

- 1-3 days

- Indication: childhood constipation, postpartum women

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- Indication: childhood constipation, postpartum women

B) Paraffinum liquidum

- petroleum distillation

- emulsifies the gut content

- do not irritant and do not cause water loss

- absorption of vitamins

- C.T. proliferation in mesenterich lymph nodes, paraffinoma

- pneumonia, encephalophathy

- daily dose: 15-30 g

III. LAXATIVES

3. Osmotic laxatives

- Soluble but non absorbable sugars and salts

- Effect within 1-3 hours

A) Anorganic salts

- hypertonic solution

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- hypertonic solution

- strong effect

- KATIONS: Mg2+, Na+

- ANIONS: SO42+ , PO4

3-

- Na2SO4 – soda (20-25g) intracran. Pressure

- MgSO4 – Epsom salt (USA: Mg-citrate) (5-20 g)

- Contraindicated:

- Mg2+ renal insuff.

- Na+ renal and cardiac insuff

3. Osmotic laxatives

B) Non-absorbable polysaccharides

III. LAXATIVES

Lactuloz (DUPHALAC) – Semisynthetic disaccharide (fructose, galactose)

– Bacterial metabolism → organic acids→ luminalis pH motility and secretion

– Decreases the NH -content of the blood– chronic liver diseases

40

– Decreases the NH3-content of the blood– chronic liver diseases

– S.E.: flatulence, cramps (high doses)

– Lactitol (galaktoz+sorbitol) sorbitol, mannitol (oral or rectal)

– Use with caution in elderly, renal insufficiency, cardiac disease

Polyethilen glycol (PEG) FORLAX– Lavage solution, used for complete colonic cleaning

– Non absorbable osmotically active sugar (PEG)

– No significant intravascular fluid shift

– Consumption of 4 l over 2 hours

III. LAXATIVES

4. Stimulant purgatives

- Inhibit the Na+/K+ ATPase absorption of water and

electrolytes

- Direct stimulation of enteric nerves increasing intestinal

motility

- Forcefull agents

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- Forcefull agents

- Increase permeability

- Irritate mucosa

- cAMP and PG

ClassificationClassification::

- Anthraquinone derivatives- Synthetic agents- Intestine stimulating oils- others derivatives

III. LAXATIVES

Anthraquinone derivatives

- Found in dried drugs (oxidized form antranol)

- Reduction is only in the colon 6 h

- Poorly absorbed

- Brown-pigmentation of the colon, could lead dependency

- Senna leaves (TISACEN) abortion!

42

- Senna leaves (TISACEN) abortion!

- Rhubarb

- Aloe

III. LAXATIVES

Synthetic agents

- Individual sensitivity with very large differences

- 6-8 hours (specially act in the colon)

- S.E.: allergic reaction, dehydratation

- Phenophtalein

- 20 % extracted to the bile

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- 20 % extracted to the bile

- Children, elderly, dibiliated patients, pregnant

- Cardiotoxicity

- 30-200 mg orally

- Bisacodyl (DULCOLAX)

- Used since 50s

- Highly efficient, less toxic

- 5-10 mg single oral dose

- Sodium Picosulphate (GUTTALAX)

- Similar effects

III. LAXATIVES

Intestine stimulating oils

- Castor oil ricinoleic acid (lipase, hydrolysis, small

intstine)

- Increases peristalsis

- Prevents fluid absorption

- Slippery faeces

44

- Slippery faeces

- Very stong effect (defecation expected only after a few days)

- Single, acute dose

- No long-term administration

- S.E.: dehydration, abortion

- 1-3 hours



III. LAXATIVES




45








Diarrhea: increased stool liquidity and/or stool weight.Can be caused by many factors (infection, poisons, medicines, indigestion)

- osmotic (poor absorption of osmotically active compounds)- bacterial (Salmonella, Shigella, Coli) decreased reabsorption, increased secretion- changed permeability (IBD, colon carcinoma)

Acute (<2 weeks): infectious, toxic, drug-induced, dietary

46

Antidiarrheal agents - used safely in mild to moderate acute diarrhea- should not be used in patients with bloody diarrhea, high feveror systemic toxicity

Initial goals for both acute and chronic diarrhea:– Termination of fluid loss– Replacement of fluid and electrolytes

Acute (<2 weeks): infectious, toxic, drug-induced, dietaryChronic: Cancer, DM, Addison’s disease, Inflammatory Bowel Diseases(IBD), Irritable Bowel Syndrome (IBS)

Adsorbents (bacteria, toxins, fluid): Kaolin, pectin, charcoal

Opioid agonists:

- both central and peripheral components are involved

- Act on mű and sigma receptors

- codein, opium tincture (central effects!)

- diphenoxylat (REASEC)


47

- therapeutic doses 5-20 mg

- no central effect

- S.E.: respiratory insuff. (naloxon)

- often combined with atropine

- loperamid (IMODIUM)

- do not cross the BBB, less toxic

- S.E.: nausea, vomiting, abdominal cramps

Bismuth salts:

- subsalicylas bismuth (especially in Traveler’s diarrhea)

- anti-inflammatory effect


Somatostatin/Octreotide:- Inhibits hormone secretion (CCK, gastrin, etc.)

- Reduces intestinal and pancreatic fluid secretion

- Slows GI motility, inhibit contraction of the gallbladder

48

- Slows GI motility, inhibit contraction of the gallbladder

- Induces direct vascular contraction (reduce blood flow)

- Half life (i.v.) somatostatin: 3 min, octreotide: 1.5 h

- i.m. injection – long acting formulation

Traveller’s diarrhea

E. coli (45-70%), Campylobacter, Salmonella, Shigella, viruses,

parasites

Th: rehydration, bismuth subsalicylate, loperamide

antibiotics: severe diarrhea, fever, bloody stool, persistent inf.



III. LAXATIVES




49







V. DRUGS USED FOR THE TREATMENT OF IRRITABLE BOWEL SYNDROME (IBS)

Idiopathic chronic disorder characterized by abdominal discomfort

(pain, bloating, distention or cramps), and alteration in bowel habits

(diarrhea, constipation, or both)

Classification:

IBS-D (diarrhea),

IBS-C (constipation),

IBS-A (alternating)

50

2:1 women:men

Age 30-50

Pathophysiology:

Hypersensitive gut with enhanced visceral perception and pain

Psychosocial factors: panic, anxiety, depression, somatisation

Alcohol, smoking, use of drugs

Hormonal effect


IBS-C (constipation and bloating)

FOR CONSTIPATIONFibers (20-30 g/day)Osmotic laxatives (PEG, lactulose, milk of magnesia)Tegaserod- 5- HT4 receptor agonist- increases gut motility, fluid and Cl- secretion

51

- increases gut motility, fluid and Cl- secretion- Decreases visceral hypersensitivity- Treatment of women with IBS-C- Withdrawn from the market due to CV risk (2007)Lubiproston- used in both IBS and opioid-induced constipation

- Activator of CIC-2 (Cl- channel) → increased Cl- and fluid secretion loosen the

faeces, increases motility

- no rebound, rapid metabolism

- both in renal and hepatic insuff.

- S.E.: nausea

- >18 year-old women; indicated in chronic functional constipation


Antidepressants SSRIs- E.g. paroxetin, fluoxetin, sertralin

- Enhance intestinal transit

- Conventional dose

FOR BLOATINGsimethicone [Espumisan, Sab Simplex, Meteospasmyl, Rennie Deflatine]- 92.5% surfactant polydimethylsiloxane + 7.5% silicagelprobiotics

52

probiotics

IBS-D (diarhea and abdominal pain)

Anti-diarrheals Loperamide [Imodium], Diphenoxylate [Lomotil]- Opioid rec antagonist, inhibits the release of Ach and PG

- Act on intestinal circular and longitudinal muscle layer

- Reduce intestinal motility and inhibit fluid secretion, increases absorption rate

Tricyclic antidepressants (desipramin, nortriptylin, amitriptylin)- Modify pain-perception (by affecting visceral afferent sensation) and GI transit, low

dose (25-125 mg/day)

- desipramine (less anticholinergic → has less sedative and constipating effect) - good

for treatment of diarrhea and abdominal pain


Alosetron [Lotronex]5-HT3 antagonistTreatment of women with severe IBS-D0.5-1 mg BID x 4 weeks, may repeat course onceSE: risk of ischemic colitis and constipation (withdrawn in 2000)

Rifaximin [Xifaxan]- semisynthetic rifamycin-based non-systemic antibiotic

53

- semisynthetic rifamycin-based non-systemic antibiotic- prescribed if IBS is caused by bacterial overgrowth- in a small clinical (n=87) trial, patients in the treatment group received 400 mg of rifaximin orally three times daily for 10 days- over a 10-week follow-up period, rifaximin resulted in greater improvement in IBS symptoms- normalize bowel function and terminate infl. processes- also effective in Traveller’s disease (E. coli) and hepatic encephalopathy - S.E.: rare (not absorbed) nausea, vomiting



III. LAXATIVES




54







tumormeningitis

Direct mechanicalirritation

Vestibular irritation„sea sickness”air travel

VIII. cranial n.morphineapomorphinedigitalisnitrogenmustardsantibioticsuraemiagravidity

Bad smellvisual impulses

I. cranial n.II. cranal n.

IX. cranial n.cerebellum

cortex

Vomiting

55

CuSO4, emetin, ZnSOTepid water etc.

pharynx irritation

IX. cranial n.

X. cranial n.

veratrum-alkaloidsPeritoneal irritation

Vomiting center(formatio reticularis)

Vomiting

chemosensitivetrigger zone

(area postrema)

Histamine H1 rec.Muscarinergic rec.

Serotonin 5-HT3 rec.Dopamin D2 rec.

Irritation of the gastricchemoreceptors

H1-receptor blockers (antihistamines)

also have anticholinergic effect on M1 receptors

Diphenhydramine, Dimenhydranate, Cinnarazine

- weak antimetics

- poorly effective in vomiting caused by the kemosensitive trg. Z

- seasick, emetic compounds, pregnancy

S.E.: sedation, drowsiness, headace, confusion, cycloplegia,


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S.E.: sedation, drowsiness, headace, confusion, cycloplegia,

dry mouth, urinary retention

5-HT3-receptor antagonistsOndansetron [Zofran] , Granisetron [Kytril], DolasetronIndication: chemotherapy-, irradiation- or postoperative-induced

vomiting(combined with dexamethasone or other drugs)

before the cancer therapy, followed by 5 days of oral treatmentS.E.: headache, dizziness, constipation, prolongation of QT interval


Phenothiazines (PT) és butyrophenones (BP)

PT: Dopamin, H1, M-receptor antagonists

1. Chlorpromazin HIBERNAL2. Prochlorperazin STEMETIL3. Thiethylperazin TORECAN

57

Indication: uremia, radiotherapy, gastroenteritis, chemotherapyS.E.: constipation, drowsiness, vision changes, dry mouth,

dizziness, lightheadedness

BP: Dopamin antagonist

1. Droperidol [DROPERIDOL] i.m., i.v. – extremely sedating in antiemetic dosesIndication: postoperative vomitingS.E.: extrapyramidal, hypotension, QT interval prolongation

Substituted benzamidesD2-receptor antagonists- directly effect the chemosensitive trig. z.

1. Metoclopramid CERUCAL, REGLANAnti-tumor cytotoxic agentswell absorbedoral (10-15 mg)


58

oral (10-15 mg)first pass metabolism only 75% get into the circulatonBBBS.E.: extrapyramidal dystonia, gynecomastia, lactation, diarrhea

2. Domperidon MOTILIUM

antiemetic, prokinetic effect (similar to metoclopramid)does not penetrate the BBB, not as many S.E.s, less effective!oral (10-15 mg), well absorb„first pass” metabolism only 15% get into the circulaton

Cannabinoidsdronabiol: tetrahydrocannabinol (THC)mode of action is not knownAct through cannabinoid (CB) receptors and on the chemosensitive trigger zonenabinole (synthetic) CB1 and opioid receptors

S.E.: euphoria, dysphoria, sedation, hallucination, dry mouth,


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S.E.: euphoria, dysphoria, sedation, hallucination, dry mouth, increased appetite

Other drugsBenzodiazepines (lorazepam), corticosteroids (dexamethasone)- There mode of action is unknown- In combination with metoclopramid + dexamethasone- Effective in late vomiting



III. LAXATIVES




60








Ulcerative colitits, Crohn’ disease

AMINOSALICYLATES

- Especially effective in the treatment of UC (first choice)- Mechanism in not completely known- Used as a suppositorium or in a slow releasing form (acid-resisitant granule)- Asacol, Pentasa

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(N=N)

5-ASA ASO

Bacteria: azoreductase enzyme

Indication: Mild-moderate IBD (CU)Remission induction and maintenaceDecrease incidence of colorectal cc.

- Asacol, Pentasa - 5-ASA is the active form- 5-ASA bind to an other molecule with an Aso bond-


GLUCOCORTICOIDS

- Moderate and severe IBD

- Strong anti-inflammatory drugs

- Commonly used are Prednizolon, Prednizone and hydrocortison

- foam or suppositorium

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Budesonide: synthetic prednisolone analogue (distal ileum - Crohn)

- cytotoxic

- rapid first pass hepatic metabolism, low oral bioavailability

- few systemic effects

- One daily dose dose (40-60 mg/d)


PURINE ANALOGUES

Azathioprine, 6-mercaptopurine;

- Cytotoxics with a very short half-life (2 h)

- Active metabolite (6-thioguanin) concentrated inside the cell

- After the treatment (3-6 months) 50% of patient are in remission

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- After the treatment (3-6 months) 50% of patient are in remission

-Inhibition of cell proliferation, migration (immunosuppressant, antimetabolite)

- Used in moderate IBD – in combination with glucocorticoids

S.E.: Nausea, vomiting, bone marrow depression (leukopenia, macrocytosis, anemia, thrombocytopenia), hepatic toxicity, hypersensitivity, lymphoma (?)

Anti TNF-α monoclonal antibody Infliximab, Adalimumab

- inhibition of TNF-α activity,

- i.v. infusion 3x, after chest X-ray and Mantoux test

- Moderate and severe IBD (CD)

-Clinical response in 2 wks,

- Symptomatic improvement and disease remission


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- Symptomatic improvement and disease remission

S.E.: infection, pruritus, urticaria, hemodynamic instability, TBC reactivation,

abscess, hepatosplenic T-cell lymphoma

Antibiotics – Metronidazole, CiprofloxacinIn patients with mild IBD of colon (oral, i.v. administration)



III. LAXATIVES




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- Pancreatic enzyme insufficiency digestive insuff, steatorrhea, weight loss

- enzyme secretion is less than 10% severe abdominal pain

- Aim: restoration of the quantity and compostion of d. e.

- Management of carbohydrates, protein and fat malabsorption

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- Elimination of steatorrhea

- 25 000-40 000 U lipase

- S.E.: diarrhea

- Pancreatin (produced from the pancreas of pig)

- pancreatin strongly pH-dependent

- Uncoated Cotazym + PPI

- Creon, acid-resistant capsule

- Intestinosolvens coating



III. LAXATIVES




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VIII. PANCREATIC ENZYME SUPPLEMENT


IX. BILE ACID THERAPY

- Bile acids, cholesterol, mucin and bilirubin

- Bile acids and bilirubin reabsorbed in the small intestine

- Cholic acid, chenodeoxycholic acid deoxycholic acid

- Ursodeoxycholic acid, litocholic acid

Choleretic effect: increasing bile production, hydrocholeretic effect result in diluted bile

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result in diluted bile

Cholekinetic effect: stimulate the excretion of bile from the gallbladder (oil substances, CCK, chochlate, bitter and Glauber salts)

Gall bladder stone

Dissolution of the stone can be achived by the BA or cholesterol

Dehydrocholate, chenodeoxycholate (CHENOFALK), ursodeoxycholate (URSOFALK)

-Inhibit cholesterol synthesis, increases the ratio of BA

- after the treatment restone formation is frequent, S.E.: diarrhea

Vaccination – HBV surface antigen

Interferon alfa:antiviral, antiproliferative and immunosuppressive

endogenous protein, increases viral clearence

Pegylated interferon alfa:conjugation with PEG, longer effect - single weekly injections

S.E.: Flu-like symptoms, headache, nausea, vomiting, diarrhea,

IX. THERAPY OF HEPATITIS B AND C

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S.E.: Flu-like symptoms, headache, nausea, vomiting, diarrhea,

depression, irritability, anxiety, injection site reactions, partial

alopecia, hematologic abnormalities, autoimmune disorders

Ribavirin: guanosine analogue, 800-1200 mg/day p.o.

phoshorylated intracellularly, inhibits replication of several

viruses

Optimal effect (HCV) = complex therapy: ribavirin capsules and

parenteral PEG-IFN-alfa – remission in up to 70%Newer antiviral drugs (HBV): lamivudine [ZEFFIX], adefovir, etc.

Autoimmune active chr. hepatitisresponds well to immunosuppressive therapy

prednisolone (effective in 80% of cases) +/-azathioprine 1 mg/kg/day > steroid sparing agent(hematological toxicity – monitor blood count)

Primary biliary cirrhosis

IX. TREATMENT OF AACH and PBC

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Primary biliary cirrhosis1:3-4000 peopleautoimmune disease – prednisolon, budesonidechronic cholestasis: malabsorption of fat-soluble vitamins

D-vitamin supplementationpruritus – cholestyraminliver function : ursodeoxycholic acid (10-15 mg/kg/day) – does not influence complications, survival

pharmacology of the digestive system -...

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