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gastrointestinal pharmacology - advances Flashcards

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1
Q

PPI long term limitations for hyperacidity - 7

A

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

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2
Q

attempts to overcome ppi issues - 8

A

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

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3
Q

potassium ion competitive acid blockers (P-CABs) mechanism of action

A

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

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4
Q

potassium ion competitive acid blockers (P-CABs) vs PPIs - which are better

A

potassium ion competitive acid blockers (P-CABs) sllow for longer lasting, rapid, consistent increase in intra gastric pH

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5
Q

PPIs require transformation to the active ____ form while P-CABs

A

sulfonamide

act directly on K+ H+ ATPase proton pump

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6
Q

PPIs have a lower concentration in the ____ while P-CABs

A

parietal cell acid space/ cannuliculi

have a higher concentration in parietal cell acid space

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7
Q

PPIs bind ___ while P-CABs bind ___ to K+H+ ATPase

A

covalently and irreversibly

competitively and reversibly (competes with K+ ions)

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8
Q

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 ____

A

sulphonamide-enzyme complex

drug in plasma

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9
Q

PPIs have a ___ onset of action while P-CABs have

A

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

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10
Q

PPIs have ____ inhibition of gastric acid while P-CABs have ____

A

food dependent

food independent acid inhibition

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11
Q

PPIs result in ____ acid suppression while P-CABs result in ___ acid suppression

A

incomplete

complete, prolonged

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12
Q

P-CAB example

A

vonoprazan fumarate - first in class

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13
Q

vonoprazan fumarate is effective for

A

endoscopic erosive oesophagitis - linked to GORD

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14
Q

vonoprazan fumarate is effective at __mg compared to ___ at ___mg

A

20mg

lansoprazole (PPI)

30mg

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15
Q

vonoprazan fumarate vs lansoprazole

A

faster healing - 8 weeks

more effective for GORD than PPIs

inc treatment efficacy

more effective long term treatment for severe Barrett’s oesophagus

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16
Q

vonoprazan fumarate has antisecretory effects. what does this mean in terms of advances in future

A

antisecretory effects - could be used as treatment for H. pylori treatment which is otherwise difficult to treat via antibiotics due to acquired resistance

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17
Q

P-CABs

A

still in trial phase, need to test and compare to PPIs

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18
Q

new developments in constipation pharma - 4

A

selective 5-HT4 receptor agonists

intestinal chloride channel activators

modifiers of bile acid recycling and synthesis

sodium/ hydrogen exchanger inhibitors

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19
Q

selective 5-HT4 receptor agonists examples - 2

A

prucalopride

velusetrag

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20
Q

intestinal chloride channel activators examples - 3

A

lubiprostone

linaclotide

plecanatide

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21
Q

modifiers of bile acid recycling and synthesis examples - 2

A

elobixibat

NGM282

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22
Q

sodium/ hydrogen exchanger inhibitor example for treating constipation

A

tenapanor

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23
Q

compare new constipation drugs to older ones

A

new - higher efficacy, but less comparitive studies, more expensive, conflicting studies

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24
Q

2 studies comparing old and new laxatives

A

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

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25
advances in constipation treatment
individualised therapy pelvic floor biofeedback therapy preffered over laxatives. if no worky, tailored therapy
26
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
27
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
28
nover receptor targets for treating ibs examples - 3
TLR - inhibits ibs symptoms HR - inhibits hypersensitivity TRPV1 - inhibits hypersensitivity
29
current therapy in ibd
currently incurable, but can relieve symptoms, and remission
30
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
31
treatments in ibd chron's disease - targeting MAP
RHB-104 antibiotic cocktail
32
RHB-104 antibiotic cocktail consists of - 3
clarithromycin rifabutin clofazimine
33
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
34
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
35
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
36
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)
37
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
38
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
39
vedonlizumab
new therapy for IBD biologic works specifically on GI tract, less risk of systemic circulation side effects
40
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
41
ibudilast mechanism of action
selective phosphodiesterase inhibitor with anti inflammatory properties well tolerated does not impact oxaliplatin pharmacokinetics or of other chemotherapeutic agents
42
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
43
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
44
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
45
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
46
drug delivery - peptides, proteins, antibodies, oligonucleotides ___ be delivered orally
cannot despite research efforts
47
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
48
sublingual admin
under tongue
49
buccal admin
between gums and teeth
50
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
51
example of sublingual drug admin - 3
liquid (sprays, drops) solid (tablets, patches) semi solid (gels)
52
oral vaccinations advantages
pain free, self admin rapid mass vaccination during pandemics oral cavity, stomach, small intestines can be targeted by oral vaccinations
53
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
54
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
55
sublingual tissue and buccal tissue have a pH of
approx 7
56
which has the bigger surface area - buccal or sublingual tissue
buccal - twice as much
57
both buccal and sublingual tissue have __ enzyme activity
low - less pre metabolism of meds
58
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
59
tenapanor side effects - 2
diarrhea - 16% of pts in clinical trials due to excess water retention abdominal distension (swollen)
60
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
61
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
62
TRPV1 antagonists in treating ibs
trpv1 channels involved in pain perceptionm associated with ibs hypersensitivity ginotonin derived from ginseng can inhibit this potentially
63
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
64
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

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