Gastrointestinal Pharmacology II Flashcards
What are immunomodulators and what are they used to treat?
- Thiopurines: 6-mercaptopurine and azathioprine
- prodrugs, metabolized to 6-thioguinine (active moiety)
- Used to treat inflammatory bowel disease
- mechanism of action
- inhibit purine synthesis,
- thus produce anti-proliferative side effects & indicue apoptosis in T-cells
- slow onset of action
- inhibit purine synthesis,
Mechanism of action for thiopurines?
- 6-mercaptopurine is converted to 6-thoguanine
- further converted to 6-thoguanine monophosphate
- Inhibit purine synthesis enzymes:
- ATP, GTP, dATP, dGTP
- this block RNA & DNA production
- decreases cell proliferation
- increases cell apopsosis
- this block RNA & DNA production
- ATP, GTP, dATP, dGTP
- can be futher converted to 6-thioguanine triphosphate
- it can itself be incorporated into DNA & RNA
- decreases cell proliferation
- increases cell apopsosis
- it can itself be incorporated into DNA & RNA
- Inhibit purine synthesis enzymes:
- further converted to 6-thoguanine monophosphate
What are the clinical uses of thiopurines?
- maintain remission (UC)
- induce and maintain remission (CD)
- Action
- assist steroid tapering
- treat steroid-dependent and steroid-resistant IBD
- decrease formation of antibodies TNF inhibitors when combined wtih TNF Ab
- Prevent CD recurrence after surgical resection
- Prevent rejection following organ transplant
- Rheumatoid arthritis
Adverse effects of tiopurines?
- AE
- common: nausea, vomiting
- major:
- bone marrow suppression
- pancreatisis
Pharmacogenetics and drug-drug interaction of thiopurines?
- 6-mercaptopurine is metabolized to its inactive form (6-thiouric acid) by xanthine oxidase
- xanthine oxidase is also responsible for synthesis of uric acid
- for patients on gout drugs (xanthine inhibitors) thiopurines will not be metabolized to their inactive form
- dose must be reduced for patients on gout drugs
- this means the serum concentration of 6-mercaptopurine will be high, increasing the chance of adverse effects
- specifically bone marrow suppression
- Some patients genetically have more Thiopurine methyltransferase (TPMT), which converts 6-mercaptopurine to 6-methyl-mercaptopurine
- this is a hepatotoxin, which can lead to abnormal liver function
- but if patients have very low TPMT activity, more 6-mercaptopurine will be conerted to 6-thioinosinic acid by HGPRT
- then to 6-thioguanine nucleotides, leading to bone marros suppression
Methotrexate mechanism of action?
- Methotrexate inhibits the convertion of dihydrofolate to tetrahydrofolate
- therefore decreasign the synthesis of DNA
What are the clinical uses and adverse effects of Methotrexate?
- Clinical uses
- induce and maintain remission
- moderate to severe steroid-dependent and steroid-resistant CD
- cancer
- rheumatoid arthritis
- psoriasis
- induce and maintain remission
- Adverse Effects
- uncommon for the dosage for IBD
- folate supplement reduces risk of adverse effects
What is the mechanism of action of cyclosporine and tacrolimus?
- Cyclosporin and Tacrolimus can bone & inhibit the function oc calcineurin
- The role of calcineuron is to dephosphorylate T-cell specific transcription factor NFAT
- NFAT binds to cytokine promoter DNA
- therefore increasing inflammtory response
What are the clinical uses of cyclosporine and tacrolimus?
- cyclosporine
- severe steroid-resistant UC to induce remission
- Tacrolimus
- alternative to cyclosporine
What are the biologics that are used to treat IBD?
- Anti-TNF-alpha – given by injection
- Infliximab
- adalimumab (CD and UC)
- golimumab (UC)
- Certolizumab (CD)
What is the mechanism of action for Anti-TNF-alpha agents?
- The TNFalpha antibodies bind to the TNFalpha preventing its interaction with its receptor;
- inhibiting its induction of transcription factor NFkB, which modulates
- proinflammaotry cytokine release
- T-cell activation proliferation
- Fibroblast collagen production
- Endothelial adhesion molecules
- hepatic acute phase reactants
- inhibiting its induction of transcription factor NFkB, which modulates
Clinical uses of Anti-TNF-alpha agents?
- induce & maintain remission
- moderate to severe CD and/or UC
Adverse effects and contraindications of Anti-TNF-alpha agents?
- Adverse effects
- serious infections
- injection site reactions (antibody development)
- co-administration with immunomodulators: lymphoma
- rare but serious: acute hepatic failure
- Contraindication
- hypersensitivity
- uncontrolled infection
- concomitant administration of other biologics
- patients with moderate or severe heart failure
What is the mechanism of action of Anti-alpha 4 integrin?
What are the other two drugs in this category?
- Natalizumab
- vedolizumab
- MOA
- on leukocyte surface there are alpha4 integrins that interact with endothelial cells
- this interaction will let the leukocytes migrate through the endothelial cells, causing inflammation
- so, by inhibiting the alpha4 integrin via antibodies, it prevents the leukocytes from migrating through the endothelial cells into the tissue
- decreases inflammation
Clinical use and adverse effects of Anti-alpha4 integrin?
Drug-drug interactions?
Contraindications?
- Clinical use
- induce and maintain remission
- moderate to severe CD (Natalizuman) adn UC (Vedolizuman) who do not respons to or could not toldrate anti-TNFalpha
- induce and maintain remission
- Adverse effects
- progressive multifocal leukoencepalopathy
- severe hepatic toxicity
- Drug interactions
- with othe rimmunosuppressants risk of infection
- contraindications
- hypersensitivity, current or history of PML, immunocompromised patients
What is the mechanism of action fo Interleukin-12/23 inhibitor: Usterkinuman (stelara) mechism of action and clinical uses?
Adverse effects?
- Mechanism of Action
- bind to subunit of p40 of IL-12 and IL-23
- prevents them from binding to their specific receptors
- no intracellular signaling of TH1 and TH17 respectively
- prevents them from activating those T cells
- Clinical uses
- induce and maintain remission in patients with moderately to severely active IBD who failed or intolerant to treatment with immunomodulators or corticosteroids
- Adverse Effects
- see ibooks
What is the mechanism of action and clinical uses of inhibitor of janus kinase 1-3 (Tofacitinib)?
adverse reaction
drug-drug interactions?
- Mechanism of Action
- Tofacitinib inhibits the JAK 1-3 receptor (that responds to cytokines)
- inhibiting the STAT transcription factor that induces inflammatory response
- Clinical use
- adults with moderately to severely UC
- Adverse effects
- see ibook
- Drug-drug interactions
- tofacitinib is a substrate of CYP3A4 and interacts with CYP3A4 inhibitors and inducers
What is the hypothesis behind usign antibiotics of probiotics to treat IBD?
- imbalance of enteric bacteria and fungi play a rold in IBD
- Antibiotics:
- induce and maintain (?) remision of CD
- Probiotics
- maintain remission of UC, especially pouchitis.
- should not be used with antibiotics or antifungal medications
What are the 2 general pharmacological approaches to treatment of IBD?
- Step-up therapy
- mild to moderate IBD, starts wtih medications that are less potent and have few adverse effects
- advance to more potent medications if needed
- mild to moderate IBD, starts wtih medications that are less potent and have few adverse effects
- Top down therapy
- severe IBD
- start with more potent therapies to induce remission adn step down to less potent drugs if needed
- severe IBD
Question
- NaHCO3 is an antacid, so it can directly neutralize acid & reduce the symptoms
- He has a peptic ulcer
- need to us a more serious drug – PPI
A. antibiotics – address the bacterial infection
- Symptoms are not controlled by the less potent drugs
- advance her to oral corticosteroids (prednisone or prednisolone) to induce remission
- or, TNF-alpha antibody
- Long-term management options
- Use another drug to maintain remission (6-mercaptopurine)
What are the two general targets for drugs desigend to modulate GI motility?
- neutrotransmitter
- directly acting on GI tract
Which drugs increase GI motility?
Which drugs decrease GI motility?
- increase GI motility
- Laxatives
- prokinetic agents
- emetics
- Drugs decreasing Gi motility
- antidiarrheals
- antiemetics
What are the clinical uses of drugs tht increase GI motility?
- GERD (increase lower esophageal sphincter pressure)
- gastroparesis and postsurgical gastric emptying delay (increase gastric motility)
- postsurgical ileus or chronic pseudo-obstruction (increase small intestine motility)
- constipation (increase colon transit)
What are the D2 Dopamine receptor antagonists?
What is their mechanism of action?
- (Gastroprokinetic agents) Mainly increase upper GI motility
- metoclopramide: reglan
- domperidone: molax
- Mechanism of Action
- dopamine is an inhibitory neurotransmitter in the GI tract
- binds to D2 receptors and decreases
- gastroesophagela peristalsis
- lower esophageal sphincter pressure
- D2 receptor antagonists bind to the receptor & prevent dopamine from binding – inhibiting dopamines inhibitory effects (increasing gastric motility)
- Central action (CTZ): antiemetic action
Clinical uses of D2 Dopamine receptor antagonists?
Adverse effects?
contraindications?
- Clinical uses
- treat impaired gastric emptying
- gastroparesis, postsurgical disorders
- prevent emesis
- treat impaired gastric emptying
- Adverese effects
- metoclopramide:
- neuropsychiatric and extrapyramidal symptoms
- tardive dyskinesia
- parkinsonism (parkinson’s is due to lack of dopamine)
- both drugs:
- prolonged QT interval
- metoclopramide:
- Contraindication
- seizure
- GI obstruction
- hemorrhage
- Parkinson disease
What is the mechanism of action for macrolide antibiotics?
Clinical uses?
Special considerations?
Motilin agonists
- Mechanism of action
- directly stimulate motilin receptors on GI smooth muscle
- Clinical uses
- gastroparesis
- patients who failed to respond to D2 receptor antagonists
- Upper GI bleeding
- empty blood before endoscopy
- gastroparesis
- Tolerance develops rapidly
What are examples of cholinomimetic agents?
Mechanism of action?
Clinical use?
Adverse effects?
- Acetylcholineesterase (AChE) inhibitor:
- neostigmine: increase entire GI motility
- Mechanism of Action
- inhibits the metabolism of Acetylcholine
- increases GI motility
- Clinical uses
- IV neostigmine to treat acute colonic pseudo-obstruction
- Adverse effects
- excessive parasympathetic nervous system activity
Wat are the goals for laxatives mainly used for constipation?
- stimulate intestine peristalsis and soften bowel contents
Examples of bulk-forming laxatives?
Mechanism of action?
Clinical effects?
Adverse effects?
- Fiber-rich products: natural plant and synthetic fibers- indigestible
- Mechanism of action: in colon
- fermented by bacteria
- fatty acids, increase bacterial mass
- fermentation –> reduces stool water
- short-chain fatty acid –> prokinetic effect
- increased bacterial mass –> stool volume
- stimulate stretch receptors in the colon & promote peristalsis
- fatty acids, increase bacterial mass
- non-fermented
- retain water–> expand fecal volume
- onset of action is slow
- fermented by bacteria
- clinical uses
- prevent constipation
- Adverse effect
- bloating
- warning
- drink lots of fluid ot prevent the intestine blockade
What type of drugs are docusate (Colace, oral or enema) or glycerin suppository?
administration?
mechanism of action?
clinical uses?
- Stool surfactant agents (Stool softeners)
- orally or rectally administered
- mechanism of action
- permit water and lipids to penetrate feces and soften it
- clinical uses
- prevent constipation in patients who should avoid strain (MI and surgery)
What type of drug is mineral oil?
administration?
mechanism of action?
clinical uses?
Side effects?
- Stool softener
- lubricant
- administration
- orally or rectally administered
- mechanism of action
- lubricate stool and inhibit water absorption
- clinical uses
- treat and prevent constipation in young children and debilitated adult
- Side effects
- youngh children:
- severe lipid pneumonitis due to aspiration
- long-term use:
- malabsorption of lipid-soluble vitamins
- youngh children:
What is an example of a chlorid channel activator?
Mechanism of Action?
Clinical uses?
Adverse effects?
- Lubiprostone (Amitiza)
- Mechanism of Action
- stimulate chloride channels on small intestine lumen
- promote cloride to enter the lumen, causing water to follow the ion
- stimulate chloride channels on small intestine lumen
- Clinical uses
- chronic idiopathic and opioid-induced constipation
- constipation-predominant IBS
- Adverse effects
- nausea
- diarrhea
- abdominal pain
What are examples of osmotic laxatives?
Mechanism of Action?
- Nonabsorbable sugars or salts
- active components:
- magnesium hydroxide
- sodium phosphate
- sorbitol
- lactulose
- magnesium citrate
- lacitol
- Mechanism of Action
- draw water into intestine and prevent water absorption, thus increase fecal fluid, and stimulate colonic peristalsis
Clinical uses and adverse effects of osmotic laxatives?
Cautions and contraindications?
- Clinical uses
- treat acute constipation or prevent chronic refractory constipation
- magnesium hydroxide (Milk of Magnesia): commonly used
- high dose: purgation
- commonly used: magnesium citrate and sodium phosphate (Fleet Enema)
- treat acute constipation or prevent chronic refractory constipation
- Adverse effect
- flatus and cramps, water and electrolyte loss
- Caution & contraindications
- frail or elderly patients, renal insufficiency, significant cardiac disease
- unable to maintain hydration
- on diuretics
The osmostic laxatives lactulose and lacitol are used to treat what specific condition?
Mechanism of Action?
- hepatic encephalopathy
- Mechanism of Action
- ingested proteins will be converted to ammonia
- with normal liver function
- ammonia is converted to gluatmine, which is excreted in the urine
- patients with cirrhosis
- cannot convert ammonia to glutamine
- ammonia levels increase in circulation
- diffuses into central nervous system
- causes hepatic encephalopathy
- lactulose or lacitol can be metabolized by bacteria to produce an acidic pH
- in this acidic pH, ammonia is converted to amonium
- it can also draw ammonia from circulation into the intestine
- decreasing the toxicity to the central nervous system
What are examples of stimulant laxatives?
Mechanism of Action?
Clinical uses?
Adverse effects?
- Examples
- anthraquinone derivatives
- senna, aloe, cascara
- diphenylmethane derivatives
- bisacodyl
- anthraquinone derivatives
- Mechanism of Action
- stimulate smooth muscle contraction
- increase secretion
- Clinical uses
- treat acute and chronic constipation
- diphenymethane derivatives + PEG: colic cleansing
- Adverse effects
- severe abdominal pain
- water and electrolyte loss
- anthraquinone derivatives
- melanosis coli (brown pigment in coli)
What are the opioid receptor antagonist drugs?
Mechanism of action?
Adverse effects?
Contraindications?
- drugs
- methylnaltrexons (Relistor)
- alvimopan (Entereg)
- naloxegol (movantik
- nademedine (symproid)
- Mechanism of Action
- block neuroreceptors in the GI tract
- therefore increase activity of GI smooth muscle
- Adverse effects
- mainly GI related
- abdominla pain
- nausea
- flatulence
- vomiting
- diarrhea
- contraindications
- GI obstruction
Opoid receptor antagonists in treating opioid-induced constipation
What are the FDA approved drugs used to treat opioid-induced constipation
- Opioid receptor antagonists
- methylnaltrexone
- naldemedine
- naloxegol
- Chloride channel activator
- lubiprostone
What is the 5-HT4 receptor agonist?
Mechanism of Action?
Clinical use?
Adverse effects?
Contraindications?
- Prucalopride (resotrans)
- Mechanism of Action
- activate seratonin receptors
- increase the release of ACh release
- leads to GI motility
- Clinical use
- chronic functional constipation in adults who fail to respond to at least two other laxatives
- Adverse Effects
- headache, abdominal pain, nausea, and diarrhea
- Contraindications
- previous hypersensitivity reaction to it
- intestinal perforation or obstruction dueto a gut wall disorder
- obstructive ileus
- severe inflammatory intestinal disease (ie. Chrohn’s disease)
What is the most common use of polyethylene glycol electrolyte solution (1~4L):
Mechanism of Action?
Active components?
- Clinical use (safe for all patients b/c does not cause significant fluid shift)
- bowel preparation
- small dose (miralax): treat or prevent occasional chronic constipation
- Active components
- polyethylene glycol (PEG3350) balanced with sodium and potassium salts
- Mechanism of Action
- draw water into intestine adn prevent water absorption, thus increase fecal fluid, and stimulate colonic peristalsis
What is the clinical use of sodium picosulfate-based preparation (320ml)?
Types?
contents?
- used for bowel preparation
- Powder
- Prepopik
- solution
- Clenpiq
- Powder
- Contains
- sodium picosulfate: stimulant laxative
- magnesium oxid adn anhydrous citric acid: form magnesium citrate, and osmotic laxative
