2.2 gastrointestinal pharmacology Flashcards
Please give an overview of drug classes used for the treatment of gastritis/PUD and discuss their MOAs. Deduce typical ADR and CI of the respective drugs. Please give examples of specific drugs from each class of drugs.
PPI: - blocked ATpase (H+-K+)
- ADR: long term = risk of GI infections, rise of pneumonia, micronutrient definceny (Vit. B12, Mg, Ca, Fe), interaction with acid activated profrugs and inhibtion of CYP2C19 (except pantoprazol)
- CI: analphalaxis
H2 antihistamines: preferable for low symotoms
- MOA: antagonism at H2
- ADR: constipation, Vit B12 defiency, inhibtion of CYP (not for ranitidine) –> less than PPI
Antacids: only for minor symptoms
- MOA: Alakinee ions that neutralise stomach acid, but no effect on acid production (poor efficacy)
- ADR: constipation, diarrhoe, meterism, hypophophataemia
- CI: impared renal function (GRF < 30mL/min)
- interactions: high risk (renal/ionic)
What are the MOAs of proton pump inhibitors ?
Irreversible blockade of the gastric proton pump (H+/K+ ATPase) in pariental cell –> inhibits terminal step of acid production
PPI are acid-activated prodrugs that convert to sulfenic acids/sulfenamides taht react converlenty with cysteine at luminal surface of ATPase
–> inhibitory effect lasts longer than plasma half life
What are the MOAs of H2 blockers?
Antagonism at H2 receptors on pariental cells –> acid production decreased
eg. ranetidine, cimetidine
Please discuss the ADRs of proton pump inhibitors, including clinical symptoms and precautionary measures.
ADR through long-term inhibitory effect (irreversible blockade) making it difficult to determine the time of action or the duration of action as well as an appliction on demnad.
short-term: well-tolerated
long term = risk of GI infections (salmonella, E.coli), risk of pneumonia (translocating of bacteria from gut to lung), micronutrient definceny (Vit. B12, Mg, Ca, Fe) –> Vit B12 deficiency leads to cognitive deficits (alert in elderly people!) –> preventable through supplementation
interaction with acid activated prodrugs and inhibtion of CYP2C19 (except pantoprazol) –> preventable through TDM
Please discuss the advantages and disadvantages of proton pump inhibitors, H2 blockers and antacids for the treatment of gastritis/PUD.
PPI: very effective, but strong ADRs (risk of GI infections, risk of pneumonia, micronutrient definceny (Vit. B12, Mg, Ca, Fe), interaction with acid activated prodrugs and inhibtion of CYP2C19)
H2 blockers: less effective, less ADRs (constipation, Vit B12 defiency, inhibtion of CYP)
Antacids: poor efficacy, mild ADRs (constipation, diarrhoe, meterism, hypophophataemia)
What are the concepts of different Helicobacter eradication protocols? Which drugs are used and what are their MOAs?
antimicrobial therapy depends on antibiotic resistance and compliance
- -> bacterial culture is not routinely performed
- -> empirical antimicrobial therapy
PPI like Omeprazol and Pantoprazol are used in H. pylory eradication
Please explain the vicious circle of laxative use.
dependency possible as direct intestinal loss of Na+ K+ as well as renal K+ lead to less water in GI and therefore less motility where for laxatives are needed again to increase stool volume
–> (hypokalemia, hypertension, metabloci alkalosis)
Please discuss in detail the MOAs of stimulant laxatives. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs.
Stimulant laxatives (bisacodyl, sodium picosulfate, rhubarb): Prodrug of BHPM = bispyridylmethane (formed by colonic microbiata)
1) stimulation of enteric nerves -> peristalsis increased
2) increased H2O + salt secretion into gut lumen -> peristalsis increased
ADR: electrolyte imblance –> vicious cycle
Please give an overview of life-saving therapy and causal therapy of diarrheal diseases. Which approaches for symptomatic medication may be used?
- safe drinking water and hygiene
- rehydration through oral rehydration therapy (ORS) with fluid and electrolytes
- loperamide
- enkephalinase inhibitor
- chark coal
Please discuss in detail the MOAs of loperamide .
peripherically acts on µ-receptor as an agonist and therefore inhibtis GI motility to 100%
CI: children < 2 years, as they have immature liver functions
Please exemplify the principles of IBD pharmacotherapy.
Main goal of therapy: improving quality of life –> achieve or prolong remission
IBDs are not cureable through pharmacotherapy
Please give an overview of the different drug classes used for the pharmacotherapy of IBDs.
- Aminosalicylates: mesalazine, sulfasalazine
- Glucocorticoids (steroids): prednisone, prednisolone (systemic) vs. budesonide (local)
Immunosuppressants: cyclosporine, tacrolimus, azathiophrine, methotrexate, TNF-alpha-blocker, vendolizumab
Please discuss in detail the MOAs of aminosalicylates. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA (synergistic)
1) COX inhibition
2) activation of PPAR gamma –> inhibition of proinflammatory cytokines
3) activation of Hsp72 –> decreased ROS production
4) inhibition of macrophage functions
eg Mesalazine with local effect (low BV of 20%), Sulfasalazine (prodrug of Sulfapyridine is absorbed = active systemically as immunosuppresssant and mesalazine = active in colon)
Drug-drug interactions with: antacids, NSAIDs, H2 receptor blocker, cardiac glycosides
ADR: headache, nausea, abdominal pain and cramping, loss of appetite, vomiting
CI: severe renal or hepatic impairment, hypersensitivity
Please discuss in detail the MOAs of glucocorticoids. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA: agonist at cytoplasmatic glucocorticoid (GC) receptor modulating the gene expression of interleukins and COX2 –> immunosuppressive and antiinflammatory
- systemic: prednisone, prednisolone
- topical: budesonide (presystemic elimination leads to a BV of 25% and therefore only few systemic ADRs
-ADRs: short term only few;
long term (>7days): diabetes, cushing syndrome
- limitations: primary or secondary steroid failure and remission dependency
Please discuss in detail the MOAs of immunosuppressants. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA:
ASA: mesalazine (local) and sulfalazine (systemic)
Calcineurin inhibition –> impaired TCR function in Th cells
eg Cyclosporine: forms complex with cyclophilin (blocks dephosphorylation of NF-AT)
eg Tacrolimus: form complex with immunophilin PKBP12 -> inhibits calcineurin –> reduces T cell function
–> Azathioprine (prodrug of 6MP) metabolised Via hepatic CYP3A4 –> inhibtion of purines
–> Methotrexate (MTX): competetive inhibtion of DHFR leading to an antifolate ffect through the inhibtion of DNA/RNA synthesis (cytostatic effect against lymphocyctes)
–> TNFalpha blocker: regulate chemotaxis of macrophages & granulocytes
–> Vedolizumab: integrine antagonist
CI: an infection.
cancer or malignancy.
high cholesterol.
high amount of triglyceride in the blood.
ADR: Hypertension, arrhythmia, Decreases glomerular filtration rate (GFR), dyslipedemia
Please discuss in detail the MOAs of MTX. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA: folate antagonism, competitive inhibition of dihydrofolate reductase (DHFH), no DHF converted to THF –> impaired DNA/RNA synthesis
cytostaic effect, especially in fast proliferating cell types
CI: pregnancy/breast feeding, regular alcohol consumption, hepatic or renal disease, active infectious disease, anemia
ADR: Nausea, vomiting, gastrointestinal ADR, elevated liver enzymes (hepatotoxic), leukopenia, drug hypersensitivity, rash, teratogenic effects
Please discuss in detail the MOAs of TNFα blockers. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA: (eg. adalimumab)
recombinant human IgG mab against soluble and membrane bound TNFa (proinflammatory cytokine) –> neutralise biological activity of TNFa through regulation of chemotaxis of macrophages and granulocytes which are proinflammatory mediators
CI: Previous untreated tuberculosis.
Recurrent chest infections/bronchiectasis.
Septic arthritis within 12 months.
Multiple sclerosis/demyelinating illness.
ADR: manifold, severe infections, reactivation of Hepatitis B, drug-induced lupus, demyelinating CNS disorders, leukopenia, neutropenia –> 3rd line therapy
Please discuss in detail the MOAs of integrin antagonists. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs. Deduce typical ADR and CI of the respective drugs.
MOA: (vendelizumab)
monoclonal Ab against the a4b7 integrin of intestinal CD4+ T cells –> crucial for invasion into endithelium, inhibition of lymphocyte adhesion to MadCAM-1 on gut endothelial cells
–> gut-selective antiinflammatory activity (less ADR)
CI: previous hypersensitivity reaction, active severe infections or opportunistic infections
ADR: Nasopharyngitis, Headache, Nausea, Upper respiratory tract infection, Fatigue
Please give a systematic overview of the different steps of pharmacotherapy to induce IBD remission.
UC: mesalazine –> glucocotricoids –> azathiophrirne or 6MP –> ciclosporine –> TNFalpha –> vedolziumab
CD: systemic glucocorticoids –> 6 mercaptopurine or azathiophorine –> TNFalpha-blocker –> methotextrate –> vedolziumab
dep. on level of severity
Please give a systematic overview of the different steps of pharmacotherapy to keep IBDs in remission.
► pharmacotherapy to keep disease in remission
UC :mesalazine (low dose) and if necessary azathioprine or 6-MP
CD: azathioprine or 6-MP, MTX and if necessary: TNFα blocker
Please discuss in detail the MOAs of saline laxatives. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs.
Saline laxatives (sodium sulfates, magnesium sulfate): hyperosmotic concentration binds water in intestinal lumen –> volume of stool increased, peristalsis increased
Disadvantages: Impaired electrolyte balance -> hypertension, renal damage
Macrogol: polyethylene glycol (same MOA without elytrolyte ADR)
Please discuss in detail the MOAs of PAMORAs. Give examples for specific drugs and explain advantages and disadvantages of each class of drugs.
PAMORA (Methylnatrexone MNTX): peripherically acting µ-opoid receptor antagonist -> antagonising mainly in GIT, limited ability to cross BBB (quarternary ammonium cation), analgesic effects in CNS are not impaired
