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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