GIT pharmacology

GASTROINTESTINAL SYSTEM

NURSING II April 2011

Drugs acting on symptoms manifested in the

GASTROINTESTINAL SYSTEM

PEPTIC ULCERS AND GERD Physiology - participating cell-types 1. Parietal cells –

2. Peptic cells (chief cells) –

3. Neuroendocrine cells

4. Mucous and bicarbonate secreting cells

5. Prostaglandin-secreting cells

Phases of gastric acid secretion Basal ,

stimulated and nocturnal

3 phases of STIMULATED gastric acid secretion

1. Cephalic –2. Gastric phase-3. Intestinal phase –

HCL secretion stimulated by ACh Gastrin hormone Histamine

HCL secretion inhibited by prostaglandins Histamine Cells Stimuli

Secretion of gastric juice & cytoprotection of GIT

Proton pump

prostaglandin

HistamineACh

Gastrin

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H+

H+H+

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Pepsin

Pepsin

Pepsinogen

H+

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Pepsin

Gastrin secreting cell

Prostaglandin secreting cell

Hydrogen synthesizing & secreting cell

HistamineHistamine secreting cell

From nerveendings

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muc

us Mu

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ucus

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icar

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nsBicarbonate and Mucus secreting cell

Gastrin

Pepsinogen pumpPeptic cell

H+

H+

H+H+

H+H+

H+

H+

Pepsin

Pepsin

Pepsin

Pepsinm

ucus

PEPTIC ULCERSA breach in the mucosaLocation: Duodenum, stomach etc ♦ Basis: Imbalance between damaging factors

and mucosal defense mechanisms

CAUSES & DEFENSE MXN AGAINST PEPTIC ULCER

Normal stateDAMAGING FORCES1. Acid – gastric2. Peptic enzymes

Normal stateDEFENSIVE FORCES1. Surface mucus2. Bicarbonate3. Blood flow4. Prostaglandins5. Epithelial Regeneration

Mucus layer

Exogenous injurious factors

H.pyloriNSAIDS

Cigarettes

Alcohol

Endogenous injurious factors

IschemiaShockDelayed gastric emptying

Gastric refluxNo. of parietal cells etc

DRUGS FOR PEPTIC ULCERSPrinciple/Mxn:

♦ Reduction of gastric acid secretion1. H2-histamine receptor blockers2. Proton-pump inhibitors3. Anticholinergic agents

♦ Neutralization of secreted acid- Antacids

♦ Promoting mucosal protection (cytoprotectants)- Prostaglandins- Bismuth cpds- Sucralfate

♦ Eradication of H. pylori infection

1. H2-HISTAMINE RECEPTOR ANTAGONISTS

♦ Mxn: competitively bind and block Histamine H2 receptors reduce all phases of gastric acid secretion No effect on gastric emptying

►E.g. cimetidine, famotidine, ranitidine, nizatidine, roxatidine

P’kinetics♦ Rapid oral absorption, Parenteral

♦ Distribution – wide- breast milk, placenta

♦ Elimination – partial metab, urine

Uses of H2-HISTAMINE RECEPTOR BLOCKERS

1. Duodenal ulcer2. Gastric ulcer 3. GERD(gastroesophageal reflax desease)4. Prophylaxis 5. As pre-anesthetic agent 6. Zollinger-Ellison syndrome 7. with oral enzyme supplements

Adverse effects of H2-HISTAMINE RECEPTOR ANTAGONISTS

Hypergastrinemia CNS effects Muscular pains Skin rashes Cimetidine (only) is a weak anti-androgen – Nizatidine – urticaria, somnolence, sweating rapid infusion – release of histamine, bradykinin D/I Cimetidine & CYP 450 enzymes Cimetidine & tubular secretion

2. PROTON PUMP INHIBITORSMxn: are prodrugs, ► Block H+ /K + ATPase acid production reduced by ~95%

Duration of inhibition: Omeprazole irreversible, Lansoprazole is reversible

Specificity due to unique proton pump Activation in an acidic environment Protonated drug trapped

P’kinetics

Abs: Rapid, enteric coated, swallow whole;can be reduced by some drugs e.g. sucralfate

Metabolized (1st pass)- rapid

2. PROTON PUMP INHIBITORSUses of1. Zollinger-Ellison syndrome - DOC 2. GERD –2nd line3. Peptic ulcers –2nd line

Adverse effects Dry mouth, Hypergastrinemia CNS effects Skin Rashes Mild liver damage GIT disturbance - diarrhea can be severe

D/I (Omeprazole only)- inhibits microsomal enzymes

3. ANTIMUSCARINIC AGENTS

Mxn: block muscarinic receptors

E.g. Pirenzepine, telezepine more selective for receptors in stomach mucosal cells

Potency: telezepine more potent than pirezepine♦ Other antimuscarinicis –

P’kineticsAbs: Poor CNS entryLargely biliary & renal elimination

S/E –

UsesDuodenal and gastric ulcers

Cytoprotectants4. PROSTAGLANDIN ANALOGUES E.g. Misoprostol Effects of PGE2 & PGE1 -

● stimulate secretion of mucus and HCO3

● Increase blood flow● *Inhibit gastric acid secretion

Uses 1. Prevention/ prophylactic & NSAID(nonsteroidal anti-inflammatory drugs) 2. Peptic ulcers

Adverse effectsCommonest -Diarrhea, abdominal painUterus -, spotting, dysmenorrhoea, arbotifacient (to be taken

after day 1 of menses)

C/I in pregnancy

5. SUCRALFATE (a cytoprotectant)Mxn: form a viscous, sticky gel in the acidic environment & coats

the mucosa Adsorbs onto protein

P’kinetics Note on Administration: with food, 1hr or so with antacids Partial absS/EConstipation – High plasma [Al3+] w/ ↓renal function

D/I – Chelates some drugs ∟↓absorption e.g. phenytoin, digoxin

Uses Peptic ulcers – long term maintenance Prophylaxis – stress ulcers

6. BISMUTH COMPOUNDS

Mxn: Chelates w/ proteins of ulcer base thus coats it active against H. plylori

S/E Encephalopathy w/ ↓renal function Blackening of tongue, teeth, stool

Uses: Peptic ulcers H. pylori

7. ANTACIDSMxn: neutralize HCL

may inactivate Pepsin (pH 5)

E.g. Are AL3+, Mg2+ or Na+ hydroxides, carbonates or bicarbonates, Mg-trisilicates

Comparison of properties: differ in their capacities, rates, duration and adverse effects – Often prepared as mixtures

Na+ salts – most rapid, most potent, most absorbed, Mg2+ & Al3+ – slower, more sustained action Additive with presence of food Ca2+ can cause rebound hyperacidity Cations absorbed eliminated by kidney

Uses Symptomatic relief of dyspepsia

S/E of ANTACIDS

On GIT – abdominal distension, belching, flatulence Diarrhea (Mg) Kidney stones (silica) Constipation (Al) Encephalopathy, osteoporosis, myopathy (Al) Hypophosphotemia (Al) Systemic alkalosis (Na) Hypercalcemia & milk-alkali syndrome (Ca) Bismuth salts - encephalopathy and arthropathy.

D/I Change urine pH Alter gastric pH Chelate or adsorb drug

H. PYLORI ERADICATION

1. Penicillins – Amoxycillin2. Metronidazole, tinidazole3. Clarithromycin4. Tetracycline5. Bismuth compounds

E.g. Regimens used Amoxicillin, metronidazole + omeprozole Omeprozole + either amoxycillin or clarithromycin Bismuth + two antibiotics (metronidazole or

tinidazole with amoxicillin or tetracycline)

VOMITING(EMESIS)

PHYSIOLOGY OF VOMITING

♦ Vomiting - protective mxn ♦ Vomiting center (medulla) –muscarinic M1 and H1-histamine, maybe 5-HT3 and Neurokinin (NK1) receptors - Co-ordinates cpx abdominal

muscle movements Efferent pathways - vagus, phrenic and motor nerves to abdominal

muscles

Vomiting center receives stimuli from1. Chemosensitive trigger zone,(CTZ) – D2- dopamine receptors, opioid

receptors, 5-HT3 receptors, NK1 receptors2. Vestibular system (Cn VIII) – cholinergic (M1 and histaminergicH1

receptors3. Higher brainstem – serotonin 5-HT3 receptors4. Cortical areas – e.g. anticipatory vomiting 5. Periphery – Vagal afferents– various areas e.g.

Pharnyx – GIT – e.g. serotonin 5-HT3, Dopamine receptors

ANTIEMETIC AGENTS

►Acting at the vomiting centre – e.g. anticholinergics (prinicipal), antihistamines

prevent vomiting from any source

►Acting at the CTZ - are effective only for vomiting mediated by CTZ –

►Many drugs act at more than one site

ANTIEMETIC AGENTS 1. Blockers of dopamine D2-receptors at CTZ(i) PHENOTHIAZINES – E.g. prochlorperazine, chlorpromazine

Uses♦Emesis due to cytotoxics

S/E - esp at high doses – Extrapyramidal effects Sedation, Restlessness Hypotension

(ii) METOCHLOPRAMIDEMxn: a dopamine D2 receptor antagonist

Some effect on 5HT receptors CTZ Peripheral on ENS (Enteric Nervous System)Prokinetic effect – sensitizing myenteric nerves to Ach thus ↑LES tone, ↑

Gastric emptying,

P’kinetics Distribution – wide including breast milk, placenta Largely liver degradation

S/E Extrapyramidal effects e.g. parkinsonian features Prolactin release – galactorrhea, gynecomastia, impotence, menstrual

disorders Motor restlessness e.g. occulogyric crises Diarrhea

Uses Nausea and vomiting e.g. due to anticancer drugs Prokinetic agent – in gastroparesis, post-op disorders e.g. vagotomy

(iii). BUTYROPHENONES e.g. Domperidone, haloperidolMxn: a dopamine D2 receptor antagonist

P’kinetics Crossing BBB –minimal

Uses: Nausea and vomiting Prokinetic agentS/E Hyperprolactinemia

2. 5-HT3-RECEPTOR BLOCKERS –(central and peripheral)

E.g. ondansetrom and granisetrom, Tropisetron, Ramosetron

5-HT3 receptors found in the terminals of vagus nerve

Uses: DOC for Chemotherapy induced N&V (give ½ to one hour

before cancer drug)Radiotherapy induced nausea and vomitingPostoperative nausea

S/EHeadache, dizziness, flushing, epigastrin pain and

constipation

3) NEUROKININ RECEPTORS ANTAGONISTS (NK1)

e.g. Aprepitant (oral), fosaprepitant (prodrug, IV)

Mxn: Block NKI receptors in CTZ

P’kineticsFatigue, Dizziness, DiarrheaInterferes with monitoring of warfarinD/IIs metabolized by CYP3A4 and thus competes with other

drugs metabolized by same enzymes

Uses: Acute and delayed N&V from Chemotherapeutic agents

(combined with others)

4. CORTICOSTEROIDSMxn; not clear, possibly block prostaglandin synthesisE.g. Dexamethasone

Uses:Moderate drug induced nausea and vomiting

S/E Hyperglycemia Insomnia Psychotic rxns

5. ANTIMUSCARINICS E.g. scopolamine, hyoscineUses: motion sickness

6. ANTIHISTAMINESMxn: competitively block H1 histamine receptors Have sig. anticholinergic & sedative effects E.g. diphenhydrazine, cinnarizine, cyclizine, dimenhydrinate, promethazineUses Motion sickness Combination

7. BENZODIAZEPINESMxn: largely due to their sedative-anxiolytic effectE.g. lorazepamUses: anticipatory vomiting

Combination

8. NABILONE, DRONABINOL – Cannabis class (synthetic) but lacks the euphoric effect of other

cannabinoids

Uses – cytotoxic drug induced vomitingS/E - very many

9. MIRTAZAPINE is a tetracyclic antidepressant with 5-HT3 antagonist effects and strong anti-emetic properties.

1. Uses: e.g. chemotherapy-related nausea and vomiting

2. motility disorder gastroparesis due to its anti-emetic effects.

10. OLANZAPINE, an atypical antipsychotic with anti-emetic properties similar to those of mirtazapine,

Uses: 1. chemotherapy-induced nausea and vomiting

EMETIC agentsApormorphine- stimulates the CTZIpecac syrup – stimulates both CTZ and GIT

afferent nerves to vomiting center

ADR and C/I: many, use only when necessaryAvoid in unconscious patients, caustic poisons

Uses: to induce vomiting in cases of very specific poisons ingested by mouth

PROKINETIC AGENTS (Agents promoting Gastrointestinal motility)

Need to (i) Increase LES tone – minimize GERD(ii) Incease gastric emptying – in gastroparesis and

post-surgical gastric emptying(iii) stimulate small intestine motility in post-op ileus

ENS- players Serotonin: presynaptically (5HT4)stimulate on

interneurons (of ENS) which release Ach that activates ENS resulting in ↑peristalsis and secretory activity

Motilin: may stimulate ENS or act directly on smooth muscles of GIT

Dopamine: is inhibitory - ↓GIT contractions

PROKINETIC AGENTS (Agents promoting Gastrointestinal motility)

Cisapride Mxn: a 5-HT4 receptor agonist & increases acetylcholine release in the

enteric nervous system.

P’kineticsSig. 1st pass effect

UsesReflux esophagitisGastroparesis

S/EGIT- cramping, diarrhea, Prolonged QT syndrome - arrhythmias (withdrawn in the USA market)

D/I and C/I co-adm with many drugs -as it results in serious cardiac arrhythmias

NB. Motilin on motilin receptors prokinetic effectMacrolides – stimulates motilin receptors

Carminatives (Antiflatulent) (anti-foaming) agentsDefn: preparations that either prevents formation of or

facilitates the expulsion gas in the gastrointestinal tract, thereby minimize flatulence. Often mixtures of essential oils and herbal spices

e.g. peppermint, dill water, anise and other herbs

Dimethicone, simethicone lower surface tension and allow removal of gas in the GIT

Uses: 1. Irritable bowel syndrome in babies2. Flatulence

ANTIDIARRHEAL AND ANTICONSTIPATING AGENTS

DIARRHEA

Some causes of diarrhea – Infection/inflammation Osmotic/malabsorption Secretory diarrhea – e.g. carcinoid syndromes Some Chronic diseases – e.g. thyrotoxicosis Some drugs Psychological factors A number are self-limiting in nature

Effect – increased GIT motility with loss of fluid and electrolytes

►Aim of anti-diarrheal therapy - reduce discomfort and inconvenience

ANTI-DIARRHEAL THERAPY AGENTS (but always find out cause and manage the cause)

A. 1st priority – rehydration e.g. ORAL REHYDRATION SALTS –

B. ANTIMOTILITY DRUGS –

1) Opioid agonistsMxn: opioid receptors in the myenteric plexus large intestines; decreases the tone of the longitudinal smooth muscles but increases tone

of anal sphincter, delay transit time for GIT contents

antagonism –by Naloxone♦E.g. Loperamide (imodium) and diphenoxylate (lomotil) (are syn opioids),

codeine

P’kineticsPenetration into CSF – poor for loperamide, significant for diphenoxylate

1. ANTIMOTILITY DRUGS –S/E Diphenoxylate - Tolerance and dependence (atropine)

Euphoria & Depression of CNS

C/I ♦ In children with acute diarrhea – ♦ Chronic ulcerative colitis or amoebic dysentery or

acute bacillary dysentery (bloody diarrhea)

Uses ♦ Most types of diarrheal esp Travellers diarrhea ♦ To control colostomies♦ For AIDS related diarrhea

2. OCTREOTIDE Mxn: A somatostatin analogue, thus inhibits many hormones,

thus ADR parenteral,

Uses:Intractable Diarrhea due to e.g.Carcinoid syndrome,

VIPomas, HIV, dumping syndrome after vagotomy(+ other – e.g. Acromegaly)

S/E GIT – N/V, Cholelithiasis, Steatorrhea CVS- Bradycardia, Conduction Disorder of the Heart, Injection Site – vasoconstriction

3. ADSORBENTS E.g. kaolin (activated attapulgite), pectin, methylcellulose, Mxn: adsorb toxins, microbes, fluid, coat and protect the

intestines

Uses: Not very effective, may increase bulkInterfere with a absorption of many drugs

4. AGENTS THAT MODIFY FLUID SECRETIONBismuth subsalicylate (Pepto-bismol) – the salicylate component- inhibits PG synthesis thus inhibit

fluid secretion

BILE SALT-BINDING RESINSUses: Diarrhea due to diseases of terminal

ileum- that result in ↓bile salt absorption

Mxn; Unabsorbable plant products that absorb bile salts thus deceasing the osmotic power of lumen of colon thus decreasing water content, and diarrhea

E.g. cholestyramine, cholestipolA/E: Bloating, flatulence, constipationD/I: Decreased drug absorption

LAXATIVES (PURGATIVES, CARTHATICS, ANTICONSTIPATING AGENTS)

Goal – To increase movement & facilitate smooth expulsion of material in the rectum.

Only used if certain conditions ruled out e.g. stenosis, toxic megacolon, obstruction with parasites

1. BULK FORMING AGENTSMxn: increase VOLUME of contentse.g. Methylcellullose, agar, bran, psyllium seeds, (are

indigestible matter)

Slow actingTake w/ plenty of fluidsMay affect absorption of drugsFew ADR – flatulence (bacterial digestion)

2. OSMOTIC LAXATIVES Mxn: osmotically absorb water, effective in about 1-3hrE.g. MgSO4, lactulose, sorbitol, mannitol, glycerin

Uses: ♦ Colonic lavage♦ Hepatic encephalopathy♦ Drug poisoning or overdose

S/E, C/I and precautions♦ Mg2+

♦ Na+

♦ Phosphate containing laxatives - ♦ those containing sugars - Diabetes

3. SURFACTANT LAXATIVES (stool softeners /stool wetners)Mxn: emulsify stoolE.g. mineral oil, docusate salts, glycerin, dehydrocholic acid S/E ♦ Docusates – can increase abs of some drugs, is a weak stimulant laxative♦ Mineral oil – many ADR

4. STIMULANT/ IRRITANT LAXATIVESMxn: stimulate GIT wall – increased peristalsis, take only (2, 6-12) hrs to act E.g. Bisacodyl, phenolpthalein, castor oil, Anthraquinones - Senna, danthron, cascara, rhubarb, aloes –

P’kinetics♦ Phenolphthalein abs (cardiac toxicity), ♦ Bisacodyl degradation:♦ Castor oil –degradation

S/E - general♦ water and electrolyte loss♦ enterocytes damage♦ Allergic reactions♦ Abdominal cramps

Anthraquinones S/E♦ Synthetic Danthron cpds associated /tumors♦ Long term use – pigmentation of colon

Castor oil S/E♦ reduce absorption of nutrients, water, etc – due to enterocyte damage♦ uterine contraction

►ENEMA – largely osmotic or soapywater laxatives delivered thro’ rectum, increase volume, stretches wall of rectum

Goal- rapid evacuation

Uses: ♦ Pre- surgery♦ Rectal exam♦ Pre-delivery♦ Fecal impaction

Therapeutic principals of use of antidiarrheal agents1. Treat underlying pathology2. Start w/ high fiber, fluids & exercise3. Then start w/ bulk forming, use stimulants as last resort4. Use lowest effective doses first5. Discontinue use as soon as reasonable

GallstonesBile acids e.g. Chenodeoxycholic acid –

reduces cholesterol stones by altering properties of bile thus prevent precipitation of cholesterol

IBD1. Corticosteroids e.g. budesonide2. Immunosuppressants e.g. azathioprine3. Aminosalycilates e.g.sulphasalazine

INFLAMMATORY BOWEL DSE (UC & CD)1) For Rx and maintainance• Aminosalicylates (5-ASA derivatives)• E.g. mesalazine, sulphasalazine (Salazopyrin),

olsalazine,balsalazide• Maintenance therapy with 5-ASA drugs may reduce the

risk of colorectal cancer esp w/UC than CD• Adverse effects of 5-ASA32–34

Most common, Dose-dependent. : Headache nausea, epigastric pain, and diarrhoea are

Rare, Serious idiosyncratic: including Stevens Johnson syndrome, pancreatitis,agranulocytosis, or alveolitis, renal impairment)

Mesalazine intolerance

Corticosteroids• (Oral, intravenous, Topical, suppositories, enemas

e.g. prednisolone, prednisone, budesonide ( poorly abs from GIT), hydrocortisone, betamethasone, budesonide).

• attempt to maximise topical effects while limiting systemic side effects of steroids.

Uses: moderate to severe relapses of both UC and CD but not maintenance for either disease.

Adverse effects of steroidsa)Early effects due to supraphysiological doses include cosmetic (acne, moon

face,oedema), sleep and mood disturbance, dyspepsia, or glucose intolerance.

b) Effects associated with prolonged use (>12 weeks) posterior subcapsular, cataracts, osteoporosis, osteonecrosis of the femoral

head,myopathy, and susceptibility to infection.

c) Effects during withdrawal: acute adrenal insufficiency (if sudden), myalgia, malaise, arthralgia, raised intracranial pressure

3)ThiopurinesE.g. Azathioprine (prodrug), and mercaptopurine

(unlicensed) Mxn: inducing T cell apoptosis by modulating cell

signalling. Uses: active disease and maintaining remission in

CD and UC.A/EMost common : flu-like symptoms (myalgia,

headache, diarrhoea) thatRare: Profound leucopenia, Hepatotoxicity and

pancreatitis, Small risk of lymphoma

4) Methotrexate (unlicensed)Mxn: probable Inhibition of cytokine and

eicosanoid synthesis + usualUses: treatment of active or relapsing CD in those

refractory to / intolerant of AZA or MPMonitoring therapy: FBH & liver function testsA/EEarly : GIT disturbance, Minimized by co-

prescription of folic acidSerious: hepatotoxicity and pneumonitis.