Gastrointestinal Pharmacology II Flashcards
1
Q
What are immunomodulators and what are they used to treat?
A
- 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,
2
Q
Mechanism of action for thiopurines?
A
- 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
3
Q
What are the clinical uses of thiopurines?
A
- 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
4
Q
Adverse effects of tiopurines?
A
- AE
- common: nausea, vomiting
- major:
- bone marrow suppression
- pancreatisis
5
Q
Pharmacogenetics and drug-drug interaction of thiopurines?
A
- 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
6
Q
Methotrexate mechanism of action?
A
- Methotrexate inhibits the convertion of dihydrofolate to tetrahydrofolate
- therefore decreasign the synthesis of DNA
7
Q
What are the clinical uses and adverse effects of Methotrexate?
A
- 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
8
Q
What is the mechanism of action of cyclosporine and tacrolimus?
A
- 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
9
Q
What are the clinical uses of cyclosporine and tacrolimus?
A
- cyclosporine
- severe steroid-resistant UC to induce remission
- Tacrolimus
- alternative to cyclosporine
10
Q
What are the biologics that are used to treat IBD?
A
- Anti-TNF-alpha – given by injection
- Infliximab
- adalimumab (CD and UC)
- golimumab (UC)
- Certolizumab (CD)
11
Q
What is the mechanism of action for Anti-TNF-alpha agents?
A
- 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
12
Q
Clinical uses of Anti-TNF-alpha agents?
A
- induce & maintain remission
- moderate to severe CD and/or UC
13
Q
Adverse effects and contraindications of Anti-TNF-alpha agents?
A
- 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
14
Q
What is the mechanism of action of Anti-alpha 4 integrin?
What are the other two drugs in this category?
A
- 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
15
Q
Clinical use and adverse effects of Anti-alpha4 integrin?
Drug-drug interactions?
Contraindications?
A
- 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
16
Q
What is the mechanism of action fo Interleukin-12/23 inhibitor: Usterkinuman (stelara) mechism of action and clinical uses?
Adverse effects?
A
- 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
17
Q
What is the mechanism of action and clinical uses of inhibitor of janus kinase 1-3 (Tofacitinib)?
adverse reaction
drug-drug interactions?
A
- 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
19
Q
What are the 2 general pharmacological approaches to treatment of IBD?
A
- 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
20
Q
Question
A
- 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
21
Q
A
A. antibiotics – address the bacterial infection
22
Q
A
- 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)
26
Q
What are the D2 Dopamine receptor antagonists?
What is their mechanism of action?
A
- (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
29
Q
What are examples of cholinomimetic agents?
Mechanism of action?
Clinical use?
Adverse effects?
A
- 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
34
Q
What is an example of a chlorid channel activator?
Mechanism of Action?
Clinical uses?
Adverse effects?
A
- 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
35
Q
What are examples of osmotic laxatives?
Mechanism of Action?
A
- 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
37
Q
The osmostic laxatives lactulose and lacitol are used to treat what specific condition?
Mechanism of Action?
A
- 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
38
Q
What are examples of stimulant laxatives?
Mechanism of Action?
Clinical uses?
Adverse effects?
A
- 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)
39
Q
What are the opioid receptor antagonist drugs?
Mechanism of action?
Adverse effects?
Contraindications?
A
- 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
40
Q
Opoid receptor antagonists in treating opioid-induced constipation
A
42
Q
What is the 5-HT4 receptor agonist?
Mechanism of Action?
Clinical use?
Adverse effects?
Contraindications?
A
- 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)
