gastrointestinal pharmacology - advances Flashcards
PPI long term limitations for hyperacidity - 7
risk of infractures
risk of pneumonia
c. difficile diarrhoea
vitamin b12 deficiency
chronic kidney disease
dementia
difficulties in drug delivery - enteric coated capsules used to avoid protonation when entering stomach so can reach small intestine e.g with omeprazole
attempts to overcome ppi issues - 8
major advance - potassium ion competitive acid blockers (P-CABs)
development of potent H2 receptor agonist
gastrin agonists
non-benzimidazole PPI
extended and delayed release PPIs
PPI combination
new agents with longer half lives
new generation of PPIs
potassium ion competitive acid blockers (P-CABs) mechanism of action
acid pump antagonists
block K+ H+ -ATPase K+ channel of proton pump
causes competitive reversible food independent inhibition of gastric acid secretion
works on parietal cells
rapid, more sustained
potassium ion competitive acid blockers (P-CABs) vs PPIs - which are better
potassium ion competitive acid blockers (P-CABs) sllow for longer lasting, rapid, consistent increase in intra gastric pH
PPIs require transformation to the active ____ form while P-CABs
sulfonamide
act directly on K+ H+ ATPase proton pump
PPIs have a lower concentration in the ____ while P-CABs
parietal cell acid space/ cannuliculi
have a higher concentration in parietal cell acid space
PPIs bind ___ while P-CABs bind ___ to K+H+ ATPase
covalently and irreversibly
competitively and reversibly (competes with K+ ions)
in PPIs, the duration of affect is related to the half life of the ____ while in P-CABs it is related to the half life of the ____
sulphonamide-enzyme complex
drug in plasma
PPIs have a ___ onset of action while P-CABs have
delayed as unstable in cannuliculi, rapidly degraded so few doses/days needed for effect, need to be activated to active form in stomach acid first
full effect from first dose as not prodrug, no need for activation and binds stable
PPIs have ____ inhibition of gastric acid while P-CABs have ____
food dependent
food independent acid inhibition
PPIs result in ____ acid suppression while P-CABs result in ___ acid suppression
incomplete
complete, prolonged
P-CAB example
vonoprazan fumarate - first in class
vonoprazan fumarate is effective for
endoscopic erosive oesophagitis - linked to GORD
vonoprazan fumarate is effective at __mg compared to ___ at ___mg
20mg
lansoprazole (PPI)
30mg
vonoprazan fumarate vs lansoprazole
faster healing - 8 weeks
more effective for GORD than PPIs
inc treatment efficacy
more effective long term treatment for severe Barrett’s oesophagus
vonoprazan fumarate has antisecretory effects. what does this mean in terms of advances in future
antisecretory effects - could be used as treatment for H. pylori treatment which is otherwise difficult to treat via antibiotics due to acquired resistance
P-CABs
still in trial phase, need to test and compare to PPIs
new developments in constipation pharma - 4
selective 5-HT4 receptor agonists
intestinal chloride channel activators
modifiers of bile acid recycling and synthesis
sodium/ hydrogen exchanger inhibitors
selective 5-HT4 receptor agonists examples - 2
prucalopride
velusetrag
intestinal chloride channel activators examples - 3
lubiprostone
linaclotide
plecanatide
modifiers of bile acid recycling and synthesis examples - 2
elobixibat
NGM282
sodium/ hydrogen exchanger inhibitor example for treating constipation
tenapanor
compare new constipation drugs to older ones
new - higher efficacy, but less comparitive studies, more expensive, conflicting studies
2 studies comparing old and new laxatives
study tegaserod (newer) vs polyethylene glycol (old) - old was better for symptoms, and better tolerated
study bisacodyl vs new laxatives meta analysis, old was superior in inc bowel movement per week
advances in constipation treatment
individualised therapy
pelvic floor biofeedback therapy preffered over laxatives. if no worky, tailored therapy
pelvic floor biofeedback therapy preffered over laxatives. if no worky, tailored therapy for constipation. what are some examples - 2
5-HT4 receptor agonist (prucalopride) for pt with slow intestinal transit
ileal bile acid transport inhibitors if deficiency of bile acids reaching colon
chronic bowel disorder ibs advances - 2
difficult as multifactorial
partial agonists instead of full agonists/ antagonists to reduce side effects and cardiotoxicity
nover receptor targets
nover receptor targets for treating ibs examples - 3
TLR - inhibits ibs symptoms
HR - inhibits hypersensitivity
TRPV1 - inhibits hypersensitivity
current therapy in ibd
currently incurable, but can relieve symptoms, and remission
advances in ibd chron’s disease treatment research
mycobacterium avium paratuberculosis (MAP) infection shown to link to chron’s disease - potential for vaccine? in cows intestines
CD patients more likely to have MAP in intestine, but some have MAP without CD so we dk yet
treatments in ibd chron’s disease - targeting MAP
RHB-104 antibiotic cocktail
RHB-104 antibiotic cocktail consists of - 3
clarithromycin
rifabutin
clofazimine
RHB-104 antibiotic cocktail studies
1st clinical trial found link between its use and remission
after a year, 25% symptom dec vs 12% placebo
styll more research needed bc who had MAP?? also abx r old school theres resistance now so is there even a point
targeted therapy advancements for IBD - 4
TNF-alpha inhibitors
recognition of anti inflammatory cytokines that doenregulate T lymphocute proliferation
synthesis of selective adhesion molecule inhibitors that suppress T lymphocyte transport into gut epithelium
sustained drug release platforms
TNF-alpha inhibitors
most promising targeted therapy advancement for IBD
fabrication of inhibitors of inflammatory cytokines including TNF-alpha that results in T lymphocyte apoptosis
natural products can be useful for treating inflammatory effects of ibd, examples - 7
curcumin
silymarin
ginger-derived NPs
quercetin
grape exosome-like NPs
embelin
natural polysaccharides
(but, all low oral bioavaliability)
natural product drug delivery is aided with nanoparticles. stimuli responsive NP approaches - 3
pH-sensitive approaches
enzyme - sensitive approaches e.g. proteases
redox-sensitive NPs e.g. azo-prodrugs sulfasalazine
advantages of using NPs - 3
less toxicity
can deliver to specific site - in this context, colon (although this is a challenge for now)
degraded in colon
vedonlizumab
new therapy for IBD
biologic
works specifically on GI tract, less risk of systemic circulation side effects
GI cancer therapy study - oxaliplatin and ibudilast
oxaliplatin - improves survival in colorectal and upper GI cancer BUT can cause moderate to severe neurotoxicity in most patients
causing cold sensitivity in extremities, numbness
ibudilast - pilot study shows can prevent oxilaplatin neurotoxicity
ibudilast mechanism of action
selective phosphodiesterase inhibitor with anti inflammatory properties
well tolerated
does not impact oxaliplatin pharmacokinetics or of other chemotherapeutic agents
GI cancer therapy study - oxaliplatin and MRP2
oxaliplatin transporter candidate gene expression in tumours linked to patient response to med
MRP2 found to be a oxaliplatin transporter that limits oxaliplatin accumulation and response in human GI cancer
thus, MRP2 screening can help determine if patient needs MRP2 inhibitor AS WELL AS oxaliplatin
GI cancer therapy study - pembrolizumab and MMR deficiency
first immunotherapy
mismatch repair MMR deficiencies can predict response to immune checkpoint blockade targeting in CD274 and PDCD1 pathway in multiple cancer types (including metastatic GI cancers)
pembrolizumab is anti PDCD1 antibody to treat mismatch repair-deficient tumours
approved by FDA
precision GI oncology study - aspirin in colorectal cancer
colorectal cancer with PIK3CA mutations - basis of clinical trials
HPGD expression levels in normal colon combined with WNT signalling pathway polymorphism can help preduct efficacy of aspirin for chemoprevention
all these treatments btw consider diet, llifestyle, encironmental factors as a combined treatment alongside
precision GI oncology study 3 startegies for implementation
1 - implement clinical biomarkers and monitor them
2 - conduct comparative effectiveness research to assess clinical management schemes
3 - develop systems to optimize clinical practice based on new evidence
drug delivery - peptides, proteins, antibodies, oligonucleotides ___ be delivered orally
cannot despite research efforts
novel drug delivery - what is used now and why
sublingual and buccal routes
highly vascularised
local and systemic drug delivery
allow for direct absorption via venous drainage to superior vena cava
fast onset
good for patients who suffer swallowing and also bypasses first pass hepatic metabolism
good for highly suitable drugs
few enzymes needed - only salivary amylase, less likely interactions and modifications
mouth is neutral so facilitates admin of srugs stable in neutral ph
easy to self admin
sublingual admin
under tongue
buccal admin
between gums and teeth
disadvantages of sublingual and buccal admin - 6
risk of patient swallowing
not suitable for all drugs
usually small doses best work
bitter taste
may irritate mucosa
not for sustained admin
example of sublingual drug admin - 3
liquid (sprays, drops)
solid (tablets, patches)
semi solid (gels)
oral vaccinations advantages
pain free, self admin
rapid mass vaccination during pandemics
oral cavity, stomach, small intestines can be targeted by oral vaccinations
disadvantages of oral vaccinations
current limited to live-attenuated and inactivated vaccines against enteric diseases
degradative process digest biologics and mucosal barriers in GI tract limit absorption - research needed to understand how to overcome
wirelessly contolled ingestible capsule
ingested
electronic pill
release pill in response to smartphone commands
allow long term drug release over several days using polymers
can stay in stomach for a month and help monitor gastric environment
can help monitor heart and breathing rate
battery can eventually if research works be replaced with antenna or STOMACH ACID WTF
sublingual tissue and buccal tissue have a pH of
approx 7
which has the bigger surface area - buccal or sublingual tissue
buccal - twice as much
both buccal and sublingual tissue have __ enzyme activity
low - less pre metabolism of meds
tenapanor mechanism of action
inhibits sodium/hydrogen exchanger 3 (NHE3) in GI tract
inc intestinal fluid by dec sodium absorption from intestinal lumen, inc osmosis, inc water retential in intestine lumen
softer stool
clinical trials shown useful in relieving constipation in IBD
minimal systemic absorption, no dependence unlike stimulant laxatives
tenapanor side effects - 2
diarrhea - 16% of pts in clinical trials
due to excess water retention
abdominal distension (swollen)
intestinal chloride channel activator mechanism of action
gulanylate cyclase c agonists
guanylate cyclase c receptors in intestine activation
inc intracellular cGMP - cyclic guanosine monophosphate
activates CFTR which promotes secretion of Cl- and bicarbonate ions into intestine lumen
osmosis, inc water into lumen
softens stool
also can cause diarrhoea
tlr inhibitors in ibs treatment/ case study
toll like receptor inhibitors
still investigating
e.g. tranilast, anti allergy drug, shown effect in alleviating visceral hypersensitivity in ibs rat models by suppressing TLR4 signalling
TRPV1 antagonists in treating ibs
trpv1 channels involved in pain perceptionm associated with ibs hypersensitivity
ginotonin derived from ginseng can inhibit this potentially
jst a summary list of advances tbh
overcoming PPI issues: potassium ion competitive acid blockers (P-CABs)
constipation pharma - selective 5-HT4 receptor agonists, intestinal chloride channel activators
pelvic floor biofeedback therapy preffered over laxatives e.g. selective 5-HT4 receptor agonists
ibs new novel drug targets
ibd symptom relief - RHB-104 antibiotic cocktail targets MAP, naturals like ginger-derived NPs , biologics like vedonlizumab
ibd therapy research - TNF-alpha inhibitors
nanoparticles
examples of advances
p cab example - vonoprazan fumarate for oesophagitis
selective 5-HT4 receptor agonists - prucalopride
intestinal chloride channel activators - plecatanide
new laxative tegaserod
ibs new targets e.g. HR - inhibits hypersensitivity, sublingual and buccal routes delivery
RHB-104 antibiotic cocktail - clarithromycin, rifabutin, clofazimine
