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روفارماكوويژيالنس و عوارض ناخواسته داروها و رض و و س وويژي ر1393دي ماه ي

Drug induced Gastrointestinal Disorders

Dr M.AbbasinazariAssociate Professor of Clinical Pharmacyy

Introduction

• Almost any drug can affect GI tractAlmost any drug can affect  GI tract• It has been estimated that 40% of ADRs affect the GI tract and 4% of admissions to hospitalthe GI tract, and 4% of admissions to hospital are caused by drug induced disorders2 i2 categories:

1.Direct injury to the GI tract2.Consequences of pharmacological mode of action

Direct injury to the GI tractDirect injury to the GI tract 

• Esophageal damage by potassium preparations • Gastro duodenal ulcers caused by cytotoxic drugs• Ulceration and colitis associated with NSAIDs independent of prostaglandin inhibition

Indomethacin

Iboprofen

Consequences of pharmacological mode of iaction

• Anticholinergic effects (e.g. antidepressants)t c o e g c e ects (e.g. a t dep essa ts)reduce LES pressure, resulting in reflux and heart burnheart burn

• NSAIDs act principally by inhibiting prostaglandin synthesisy

• Widespread use of antibiotics, particularly cephalosporins, is associated with an increased incidence of Clostridium difficile infection and pseudomembranous colitis

GI induced toxicity lregarding anatomical part 

• Oral• Esophagus• Stomach & Duodenum• Stomach & Duodenum• Intestine

Drug induced oral reactions

Antihistamines

Beta blockers

Clonidine & methyl dopa

Diuretics

PPIPPIs

Anticholinergics (TCA,….)

SSRIs

Opioids

& Ol i & i idCl i & Olanzapine & Risperidone Clozapine

Donepezil & Galantamine

Pilocarpine

Lamotrigine

Rivastigmine

Amidarone & DigoxinAmidarone & Digoxin

AARBs

ACEInhs

ASA & Clopidogrel

Flouxetine & Fluvoxamine

Phenytoin

SpirinolactoneSpirinolactone

Alendronate

ACEInhs

ASA

M t id lMetronidazole

Metformin

Beta blockers

Statins

AntibioticsAntibiotics

Inhaled stroids

Olanzapine

PPIPPIs

Calcium Channel Blockers

Cyclosporine

Phenytoin, Lamotrigine, Valproate

PPIs

Esophageal diseasep g

• Esophagitis esophagus ulcerationEsophagitis, esophagus ulceration, perforation, stricture, 

• > 20% benign stricture in esophagus: drugs• > 20% benign stricture in esophagus: drugsSigns & symptoms• Odynophagia, Dysphagia, chest pain• Confirmation with radiography / endoscopyg p y / py• In esophageal damages consider drug as a common causecommon cause

Mucosal injury and stricturesj yRelaxation of LES Direct irritant effect

CCBs Bisphosphonates

Nitrate Tetracyclines

Estrogens NSAIDs

Progestrone Iron

Alpha agonists KcL

Beta 2 agonists Qunidine

Dopamine ASA

Anticholinergics Clindamycin

• Taking at least 100 mL water and not to lie down for at least 10‐15 min

• If occur, withdrawal of offending drug damage usually resolve after 3‐4 daysusually resolve after 3 4 days

• In some cases analgesics/ sucralfate

D i d d d l lDyspepsia and gastroduodenal ulcers

NSAIDs

• About 1/3 of patients take NSAIDs experienceAbout 1/3 of patients take NSAIDs experiencedyspepsia

hi i h b f• In most cases, this occurs in the absence ofulceration• Some studies suggest that NSAID‐induced dyspepsia is particularly common in patientsdyspepsia is particularly common in patients infected with Helicobacter pylori

• Mechanism: Inhibition of PGsMechanism: Inhibition of PGs• Types of COX 

f di l S ↑ h i k f i• Use of tradi onal NSAIDs ↑ the risk of serious GI complications between 2.5 ‐5‐fold

• In the UK, it is likely that at least 2000 patients per year die as a result of NSAID use (because of GI complications)

Risk factors• Type of NSAIDs (selective/ non selective)• Geriatrics• Previous GI complicationp• ↑ Dose• Multiple NSAIDs usage• Multiple NSAIDs usage• Concomitant use of: Warfarin/Corticosteroids/ Clopidogrel/ ASA/ Bisphosphonates/ SSRIs

COX 2 Inhibitors and Cardiovascular Toxicity

• Risk factors: increased COX‐2 selectivity ↑ dosagesRisk factors: increased COX 2 selectivity, ↑ dosages, a ↑ duration of treatment, and preexisting cv risk

• Increasing evidence that certain non‐ and partiallyIncreasing evidence that certain non and partially selective NSAIDs (e.g., ibuprofen, diclofenac, meloxicam) may also increase the risk MI and thrombotic stroke

• The preferred nonselective NSAID: naproxen, it does not appear to increase cv risk

Proton pump inhibitors (PPIs)

• NICE: all patients taking an NSAID or a COX‐2 inhibitor should be given ulcer prophylaxisinhibitor should be given ulcer prophylaxis with a PPIs

• PPIs ma inhibit the acti ation of clopido rel• PPIs may inhibit the activation of clopidogreland lead to an ↑incidence of thrombo c events Giving the PPI in the morning andevents;  Giving the PPI in the morning and clopidogrel at night may avoid the problem or

/usage Pantoprazole/Rabeprazole

Recommendations for prophylaxisRecommendations for prophylaxis

• A 2008 consensus statement regardingA 2008 consensus statement regarding prevention strategies in patients taking antiplatelet agents has been issued jointly byantiplatelet agents has been issued jointly by the American College of Cardiology Foundation The American Heart AssociationFoundation, The American Heart Association, and the American College of Gastroenterology 

Recommendations for prophylaxis

Those with a history of ulcer complications or a history of ulcer disease (non bleeding) undergo testing for H P andulcer disease (non‐bleeding) undergo testing for H.P and treatment if positive.Those with a history of ulcer complications or a history ofThose with a history of ulcer complications or a history of ulcer disease (non‐bleeding), a history of GI bleeding, those receiving dual antiplatelet therapy or concomitantg p pyanticoagulants be treated with a PPIs.Patients without the above risk factors but who have otherrisk factors for GI complications (including age 60 or more, use of corticosteroids, dyspepsia/GERD) should also be treated with a PPI

Other agents involved for dyspepsiaOther agents involved for dyspepsia

• Dyspepsia occurs with the nonaspirin salicylates (e.g.mesalazine) used in IBD

• For most drugs, the precise mechanism by which dyspepsiaarises is unknown, though there are a few exceptions (e.g.erythromycin, which causes epigastric pain and generalcramp as a consequence of its prokinetic activity )

• Drugs such as cytotoxic agents, oral gold and pivampicillinhave been associated with peptic ulceration, though theevidence for the association is often informal

• Recently, calcium channel antagonists have been implicatedy g pin peptic ulcer bleeding.

PancreatitisPancreatitis

• DefinitionDefinition• Alcohol & bile duct stones: 80% of acute pancreatitis• 2% of acute pancreatitis: drugs2% of acute pancreatitis: drugs• Signs: acute abdominal pain, vomiting, tachycardia, ↑amylase(4 times) ,…↑amylase(4 times) ,…

Criteria• Pancreatitis develops during drug therapyPancreatitis develops during drug therapy• Other causes are not present• Pancreatitis resolves upon discontinuation of drug• Pancreatitis resolves upon discontinuation of drug• Recur after rechalenge of drug

Class 1• At least 20 reported cases of acute pancreatitis

At least 1 case with positive rechalenge

• Asparaginase ,Azathioprine• Cytarabine, Didanosine, Estrogens, Frusemidey g• Mercaptopurine, Mesalamine• Opiates, Pentamidinep ,• Tetracycline, Sulfonamides, Sulindac, Steroids,

Valproate sodium p

8831000 883

750

500

177 86 80 79 69 59 42250

9 2 16 11 2 10 12 110

No of Reported

Didanos inesparaginaseAza thioprin

eValproic acid

Pentam idineaptopurin

eMesa lam ine

Estrogens

No of ReportedcasesNo of Reported D

Asp Az Valp Pe

Mercap M after rechalenge

Class2 

• >10 but <20 reported cases of acute pancreatitis ith or itho t positi e rechalengewith or without positive rechalenge

• Acetaminophen• Acetaminophen• Carbamazepine, Cisplatin• Enalapril Erythromycin• Enalapril, Erythromycin• HCTZ, Interferon Alfa• LamivudineLamivudine• Octerotide, Phenformin• RifampinRifampin

Class 3Class 3

• All medications implicated in pancreatitis with < 10 reported cases or unpublished reports in pharmaceutical or FDA files

Management of DIP

• Withdrawal of offspring drugSupportive therapy

• Intravenous fluid• Parenteral pain management• Bowel rest and nutritional support• Bowel rest and nutritional support

Drug induced Constipation

• Opioids and antimuscarinic drugs are the main causes of drug‐induced constipation

• Reduced bowel frequency also occurs with SSRIs and locally acting antispasmodics (e.g. mebeverine, peppermint oil)

• Insoluble dietary fiber is often used to treat constipation but it can cause pain, bloatingconstipation but it can cause pain, bloating and occasional impaction if excessive amounts are ingested unaccompanied by adequateare ingested unaccompanied by adequate volumes of liquid. Soluble fiber(porridge, bananas) is better tolerated by many patientsbananas) is better tolerated by many patients

D i d d Di hDrug induced Diarrhea

• Deliberate use of laxatives• Antibiotics: disturb the colonic flora and tend to select C. difficile

• B‐blockers: antagonizing antiperistalticadrenergic stimulationadrenergic stimulation

• Bile acids: direct irritant action in the colonM i t i i t id• Magnesium‐containing antacid

• All salicylates particularly olsalazine• H2‐antagonists and PPIs predispose to entericsuperinfectionsuperinfection

ColitisColitis

Exacerbation of ulcerative colitisExacerbation of ulcerative colitis

• Analgesic drugs (NSAIDs and paracetamol)Analgesic drugs (NSAIDs and paracetamol) provoke relapse of colitis in some patients

• COX 2 drugs have also been implicated in the• COX‐2 drugs have also been implicated in the exacerbation of IBDTh h i i k• The mechanism is unknown

Melanosis coli

• Anthranoid laxativesAnthranoid laxatives • Pass unabsorbed to the large bowel, metabolized to aglyconesmetabolized to  aglycones

THE END