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GI drugs Flashcards

1
Q

How do ulcers occur?

A

imbalance between defensive (mucous barriers) and aggressive (acid production) factors, leading to tissue damage

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2
Q

Where to peptic vs gastric ulcers form?

A 
peptide = duodenum, stomach
gastric = stomach
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3
Q

What are four protective factors against ulcer formation?

A

Mucous - continually secreted, protective effect bicarbonate - secreted from endothelial flow
blood flow - maintains mucosal integrity
prostaglandins - stimulate secretion of bicarbonate and mucous, promote blood flow, suppress secretion of gastric acid

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4
Q

What causes ulcers?

A
  • helicobacter pylori infection
  • increased gastric acid
  • decreased mucosal blood flow
  • increased pepsin
  • reduced bicarbonate
  • reduced thickness of mucous layer
  • NSAIDs: decreased constitutive PG’s and Cox-1 inhibition
  • smoking: nicotine stimulates gastric acid production by acting on ACh receptors
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5
Q

how many people are infected worldwide with helicobacter pylori? How many develop Peptic ulcer disease (PUD) or gastric cancer?

A

50-80% of world population; 10-20% develop PUD or gastric cancer

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6
Q

Which cell pumps H+ ions out into the stomach? What reaction leads to the production of H+ ions in these cells?

A

Parietal cells. CO2 and H20 react with carbonic anhydrase to produce carbonic acid. Carbonic acid then dissociates into bicarbonate and hydrogen ions. The hydrogen ions are pumped through an ATP dependent channel into the stomach lumen.

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7
Q

How does Cl- ions get into the stomach lumen?

A

Cl- ions are pumped from the plasma into the parietal cell. Then are pumped out the luminal side of the parietal cell and forms HCl with H+ ions.

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8
Q

What are the treatment strategies for peptic ulcers?

A
  • non pharmacological
  • anti-secretory agents
  • cytoprotective agents and mucosal strengtheners
  • treating helicobacter pylori
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9
Q

What are the groups of anti-secretory agents?

A

H2-receptor antagonists, proton pump inhibitors, antimuscarinic drugs

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10
Q

What are the groups of cytoprotective agents and mucosal strengtheners?

A

sucralfate, prostaglandins, bismuth, antacids

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11
Q

What are some non pharmacological measures to treat peptic ulcers?

A
  • avoid smoking
  • avoid alcohol
  • weight loss
  • avoid hot, spicy and greasy foods
  • administer NSAIDs with food or in low dosage
  • do not just eat before bedtime
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12
Q

What type of receptors do PGE2, gastrin, ACh and histamine bind to on the parietal cell membrane?

A

G-protein coupled receptors

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13
Q

What second messenger system is activated upon binding of gastrin, ACh and/or histamine to the parietal cell membrane?

A

GPCR - increases conversion of ATP to cAMP, increase in [Ca2+]i, increased activated protein kinases, increased H+/K+ ATPase pumps leads to increased H+ in stomach lumen

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14
Q

What happens when PGE2 binds to parietal cell membrane?

A

binds to GPCR - inhibits conversion of ATP to cAMP; inhibits gastric acid secretion by inhibiting production of H+/K+ ATPases

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15
Q

How does gastrin move around the body?

A

Hormone released in the bloodstream

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16
Q

What do enterochromaffin-like cells do?

A

Stimulated by ACh or gastrin, cause the release of histamine, histamine binds to H2 receptors stimulating gastric acid secretion

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17
Q

What is the mechanism of action of H2 receptor antagonists?

A

reversible competitive inhibitors of H2 receptors, compete against histamine - block the effects of histamine - reduce gastric acid secretion

  • inhibit nocturnal acid secretion
  • promote healing of duodenal ulcers
  • relapse on withdrawal (increased acid secretion)
    e. g. ranitidine ‘Zantac’, ‘Ranihexal’, ‘Ranoxyl’
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18
Q

What are the pharmacokinetics for H2 receptor antagonists like cimetidine, ranitidine, famotidine, nizatidine

A
  • famotidine 30x more potent than cimetidine; ranitidine and nizatidine 5-10 x more potent than cimetidine
  • 1/2 life of 1-4 hours
  • famotidine longest acting (12 hours)
  • all have renal elimination, ranitidine and famotidine have liver or biliary elimination
  • cimetidine is a potent inhibitor of cytochrome P450
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19
Q

ADRs of histamine receptor antagonists?

A
  • very low incidence of reversible side effects
  • e.g. headache, dizziness, skin rash, nausea, diarrhoea, confusion
  • more rarely: impotence and gynaecomastia
  • cimetidine may interfere with hepatic metabolism (CYP450) of certain drugs e.g. warfarin, theophylline, phenytoin, ethanol
  • absorbed orally: decreased absorption if taken with antacids
  • high renal excretion: blood levels rise quickly in patients with renal failure
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20
Q

Mechanism of action of proton pump inhibitors (PPI)?

A
  • first line treatment in peptic ulcer disease
  • block acid secretion by irreversibly inactivating the hydrogen-potassium pump (H+/K+) ATPase proton pumps at the parietal cell surface
    = prodrugs at neutral pH, activated in acidic environment
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21
Q

Features of PPIs

A
  • weakly basic: they accumulate in the canaliculi of parietal cells
  • are activated in canaliculi and bind covalently to extracellular domain of H+/K+ ATPase
  • irreversible inhibition of proton pumps, therefore acid secretion resumes only after the synthesis of new molecules
  • they are the most effective drugs in anti-ulcer therapy (~90% inhibition)
  • ‘prazole’ e.g esomeprazole
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22
Q

What are the pharmacokinetics of PPIs?

A
  • administered as capsules containing enteric coated granules to ensure they reach site of action
  • pantoprazole is given iv
  • t1/2 1-1.5 hours and affects acid secretion for 2-3 days
  • administered 1 hour before meals
  • other acid suppressing agents are not co-administered
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23
Q

ADRs of PPIs?

A
  • extremely safe (some headache, skin rashes, dizziness; rarely gynaecomastia, renal impairment)
  • inhibit CYP450 (less metabolism of warfarin, phenytoin, theophylline) but newer drugs like pantoprazole and rabeprazole have no significant interactions
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24
Q

Mechanism of anti-muscarinics?

A

rarely used due to significant ADRs
- constipation, dry mouth, blurred vision, urinary retention, gastric stasis, skin rashes = all ADRs are similar to atropine except skin rashes

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25
Q

Are gastrin antagonists used often? Why/why not

A

Largely experimental - poor effectiveness (used overseas, not in Australia)

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26
Q

route of administration for somatostatin analogues?

A

intravenous

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27
Q

What is sucralfate?

A

= complex of aluminium hydroxide and sulphated sucrose

  • viscous at acid pH and adheres to surface of ulcers, to act as a barrier to the aggressive luminal factors e.g. acid, pepsin, bile salts
  • stimulates mucosal protecting mechanisms e.g. mucous, bicarbonate, PG’s
  • taken on empty stomach 1hr before meals (4/day)
  • antacids and meals should not be taken within 30 minutes of sucralfate as they may raise the gastric pH and alter the physicochemical properties of sucralfate
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28
Q

ADRs of sucralfate?

A
  • constipation

- inhibit absorption of some drugs as it coats the lining of GIT

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29
Q

Mechanism of action of prostaglandin analogues?

A

PGE2 and PGI2 are protective of GIT lining

  • inhibit acid secretion, increase mucosal blood flow and mucous, cytoprotective on gastric mucosa
    e. g. misoprostol (PGE1 analogue) - produces same effects as prostaglandin E, has comparable ulcer healing efficacy with H2 receptor antagonists
  • only used in patients using NSAIDs with high risk of ulcer
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30
Q

What are ADRs and contraindications of prostaglandin analogues?

A

ADRs: - pain endings are sensitised so pain is often worse initially

  • diarrhoea, nausea, headache and dizziness
  • contraindicated in pregnancy as prostaglandins stimulate uterine contractions
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31
Q

mechanism of action of bismuth?

A
  • coats ulcer base
  • forms precipitate which binds to proteins on surface of ulcers at acidic pH providing barrier to aggressive factors in gastric juice
  • enhance PG synthesis, stimulates mucous and bicarbonate secretion (as per sulcralfate)
  • moderate direct antimicrobial activity against H. pylori
32
Q

How is bismuth administered?

A

not first line
used in combination therapy
given orally (p.o.) - 4/day

33
Q

ADRs of bismuth

A
  • may cause blackening of stools and tongue
  • not used for long periods: bismuth toxicity (could damage kidneys and CNS)
  • not be taken with meals, antacids or other medication
34
Q

Features of antacids

A
  • simplest therapies
  • weak bases that neutralise acid (raise gastric pH)
  • inhibit formation of pepsin (as pepsinogen is converted to pepsin at acidic pH)
  • more effective against duodenal ulcers (than gastric)
  • present day antacids: aluminium hydroxide (AlCl3 formed in gut), magnesium hydroxide (MgCl2 in gut)
  • over the counter drug for symptomatic relief of dyspepsia (indigestion)
35
Q

Duration of action of antacids

A

30 min when taken on empty stomach

2 h when taken after a meal

36
Q

Side effects for antacids

A

Al3+ antacids - constipation (relax gastric smooth muscle and delay gastric emptying)
- aluminium toxicity and encephalopathy in renal failure
Mg2+ antacids - diarrhoea
- hypermagnesemia in renal disease
Less commonly used:
- Na+ salts (e.g. sodium bicarbonate ‘baking soda’): promotes fluid retention, alkalosis of blood with prolonged use, can’t be used in patients on sodium restricted diet
- Ca2+ salts (e.g. calcium carbonate): hypercalcaemia - renal calculi (kidney stone)

37
Q

Why might antacids be mixed together for a treatment?

A

to minimise effects on motility e.g. Al3+ causes constipation, Mg2+ causes diarrhoea

38
Q

Do antacids interact with other drugs?

A
  • Yes, tend to interact with other drugs by forming insoluble complexes that are not absorbed
  • avoid interactions by taking antacids 2 hour before or after ingestion of other drugs
39
Q

What are common additives with antacids?

A
  • alginates: form a layer of foam on top of gastric contents and reduce reflux
  • simethicone: decrease surface tension thereby reduce bubble formation, added to prevent reflux
  • oxethazaine: local anaesthetic action
40
Q

What are important features of Helicobacter pylori?

A

= gram negative bacteria

  • major cause of gastric and duodenal ulcers
  • classified as class I carcinogen for gastric cancer
  • include eradication of H. pylori in all cases of PUD
41
Q

How is helicobacter pylori eradicated/treated?

A
  • PPI + antibacterial drugs (x2)
  • e.g. PPI + amoxycillin (penicillin - disrupts cell wall) + clarithromycin (macrolide - inhibits protein synthesis)
  • or e.g. PPI + metronidazole (if allergic to penicillin or bacterial resistance) + clarithromycin
42
Q

What type of therapy does treating H. pylori need?

A

Needs combination therapy, usually triple therapy

- eradication results of >90% with triple regimens (7-14 days)

43
Q

Characteristics of GERD/GORD (gastro-oesophageal reflux disease)?

A
  • back flow of acidic stomach/duodenal contents into the oesophagus
  • can lead to inflamed oesophageal mucosa (oesophagitis)
  • symptom: heartburn/chest pain
  • incidence 1:10
44
Q

Which drug groups promote reflux?

A

antimuscarinics, phosphodiesterase inhibitors (prolonged action of cAMP stimulating acid secretion), calcium channel blockers, dopamine receptor agonists
+ lifestyle behaviours: alcohol, smoking, stress, coffee, rich/greasy foods, overeating

45
Q

What drug group is used to treat GORD?

A

PPIs; can also use antacids, H2 receptor antagonists, sucralfate

46
Q

What are excitatory neurotransmitters of ENS?

A

ACh, 5-HT

47
Q

What are inhibitory neurotransmitters of ENS?

A

dopamine, NO, VIP (vasoactive intestinal peptide)

48
Q

what does ENS control?

A

gut movement, fluid exchange between the gut and its lumen, local blood flow

49
Q

What types of actions might drugs affecting motility have?

A
  • increase lower oesophageal sphincter pressure (e.g. in GERD/GORD)
  • increase gastric emptying (increase motility without causing purgation): post surgery gastric emptying delay, diabetic gastroparesis
  • accelerate passage of food (purgatives): constipation (IBS)
  • decrease motility (reduce colonic transit): diarrhoea (IBS)
  • decrease smooth muscle tone: antispasmodic drugs
50
Q

What is constipation?

A

symptom

  • measured in number of bowel movements in a time?
  • bowel movements decrease with age
  • when there are
51
Q

When does constipation commonly occur?

A 
pregnancy
post surgery
drug-induced (opioids, antacids, Ca2+ channel blockers)
lack of dietary fibre
IBS
dehydration
52
Q

When are purgatives (pro-kinetics) used? What are examples of purgatives?

A
  • used to relieve constipation or clear bowel prior to surgery/ examination. e.g. colonoscopy
  • laxatives, faecal softeners, stimulant purgatives
53
Q

What are laxatives?

A
  • bulk laxatives: are poorly digested compounds (methyl cellulose, psyllium) often occurring in natural foods
  • polysaccharide polymers: not broken down by normal digestive processes in upper GIT
  • form bulky hydrated mass (retain water): in GI lumen promoting peristalsis
  • can affect pharmacokinetics of drugs due to faster movement through GIT
  • bacterial digestion of plant fibres may cause bloating
  • e.g. metamucil
54
Q

What are osmotic laxatives?

A

= poorly absorbed solutes

  • salts: magnesium sulphate, magnesium hydroxide
  • sugars: lactulose, semisynthetic disaccharide of fructose and galactose; polyethylene glycol (PEG): evacuate bowel before endoscopy
  • draw water into the gut accelerating transfer of contents through small intestine
  • sugars broken down by bacteria in GIT creating acidic metabolites which attract water (also produce gas)
  • can cause abdominal cramps
  • risk of systemic effects of ‘salts’ e.g. Mg2+: avoid in children/patients with poor renal function
  • PEG doesn’t cause significant cramping or flatus
55
Q

How to faecal softeners work?

A
  • e.g. docusate sodium, glycerin suppository
    detergent like effect that softens the faeces, weak laxative effect
    = surfactant: reduces surface tension of water which produces softer faeces
  • useful in patients where straining should be avoided e.g. after childbirth, surgery
  • previously liquid paraffin was used
56
Q

What are stimulant laxatives?

A

other forms of purgatives
e.g. plant derived aloe, senna, cascara
e.g. orally or suppository: bisacodyl
e.g. glycerol suppositories
= increase electrolyte and water secretion by mucosa
- increase peristalsis (stimulate enteric nerves)
* long term use of senna may cause a lazy bowel; that won’t undergo peristalsis to the same degree

57
Q

What do D2 receptor antagonists do?

A

increase GIT motility without purgation (emptying bowels)

e. g. domperidone, metoclopramide
- antagonism stimulates cholinergic smooth muscle activation
- increases lower oesophageal sphincter pressure, enhance gastric emptying
- no effect on small intestine or colonic motility
- may also block D2 (dopamine receptors) in chemoreceptor trigger zone: have an antiemetic property

58
Q

What is diarrhoea?

A
  • defined by frequency and looseness of bowel movements
  • can be acute or chronic
  • frequent passage of liquid faeces
  • defence mechanisms for rapidly ridding the gut of poisonous/irritating substances
  • globally: one of the major causes of death in malnourished infants
59
Q

What are some of the causes of diarrhoea

A

Viral gastroenteritis, food poisoning (bacterial), drug-induced

60
Q

How is diarrhoea treated?

A
  • maintenance of fluid and electrolyte balance (replace Na+, water) - primary and often only treatment
  • in ileum, Na+ and glucose are co-transported. Therefore, glucose drinks enhance Na+ (and water) absorption.
  • use of anti-infective agents if necessary (bacterial, viral, self resolving)
  • E. coli responsible for “traveller’s diarrhoea”
  • use of antidiarrhoeal agents
61
Q

What drugs are used as antidiarrhoeal agents?

A

opioids and muscarinic receptor antagonists

62
Q

Effects of opioids as antidiarrhoeal agents?

A
  • doesn’t cross bbb; no CNS effects
  • relatively selective for GIT: interact with opioid receptors in the GIT
  • decreases activity for myenteric plexus (decreased tone of longitudinal muscle, increased tone of circular muscle) - enhanced segmentation (pushing contents back and forwards - constipating effect)
63
Q

Effects of muscarinic receptor antagonists as antidiarrhoeal agents?

A
  • enteric nervous system
  • intrinsic NS of the GIT
  • controls gut movement, fluid exchange between the gut and its lumen, and local blood flow
  • excitatory (ACh; tachykinins) and inhibitory (NO, VIP) neurons
64
Q

What is vomiting?

A

= forceful evacuation of gastric contents through mouth

  • often preceded by nausea
  • accompanied by retching
  • evolutionary mechanism to protect against ingestion of toxic substance
  • unwanted ADR of many clinically used drugs (e.g. chemotherapy, general anaesthetics)
  • occurs in motion sickness, pregnancy, migraine
  • multifactorial pathogenesis
  • many parallel pathways are involved making development of a single treatment strategy difficult
  • current therapeutics vary in their efficacy depending on the primary cause of emesis
  • some of the drugs used are non-selective receptor antagonists which contributes to their efficacy
  • ‘rescue treatment’ can be given i.v. or i.m. (oral not much use)
  • combination therapies are often used: particularly for chemotherapy-induced nausea and vomiting (CINV)
65
Q

What are the inputs into the vomiting centre?

A

the chemoreceptor trigger zone (CTZ)
= key structure in mediating nausea and vomiting
- located in area postrema
- lacks effective bbb (allows it to detect emetic agents in systemic circulation and CSF)
- sensitive to chemical stimuli
- has dopaminergic/tryptaminergic (serotonin) input
- labyrinths via vestibular nuclei = cholinergic/histaminergic e.g. motion sickness (run to the cerebellum and the CTZ)
- mechano/chemoreceptors in GIT = tryptaminergic, can pass to the autonomic nervous system; can stimulate CTZ and the vomiting zone (CTZ triggers the vomiting centre) + higher emotional centres can impact on CTZ and vomiting centre
- toxins in bloodstream stimulates CTZ
- pain, CVS, cortex are inputs

66
Q

What is the vomiting centre? Where does it receive inputs from?

A
  • in the medulla, not a discrete brain area

- receives inputs from CTZ, GIT, CVS, limbic system (olfactory, emotional, hormonal, stress, pain)

67
Q

What are the main neurotransmitters associated with vomiting and nausea?

A

ACh, histamine, 5-HT, dopamine - largely trying to block these pathways

68
Q

How is vomiting treated?

A
  • assess cause, treat if appropriate
  • anti-emetic if appropriate
  • treat: dehydration, alkalosis, hypochloremia, hypokalaemia
69
Q

Features of antimuscarinics ?

A

e. g. hyoscine (atropine-like drugs)
- mainly for motion sickness
- prophylaxis and treatment
- oral, transdermal patch
- non-selective, competitive antagonist
- side effects: blurred vision, urinary retention, decreased salivation, drowsiness

70
Q

Features of antihistamines?

A
  • e.g promethazine, diphenhydramine
  • mainly motion sickness/ ‘morning’ sickness
  • inhibit H1 receptors in area postrema (blocks input from vestibular apparatus)
  • may also possess anticholinergic activity (non selective)
  • contributes to therapeutic action and side effects
  • many are sedating as well (due to central effects): unlike 2nd generation antihistamines which do not cross bbb
  • not very useful against chemotherapy-induced vomiting
  • side effects: blurred vision, urinary retention, dry mouth (sedation, sleepiness)
71
Q

Features of the dopamine receptor antagonists?

A
  • domperidone, metoclopramide
  • abundance of D2 receptors in CTZ
  • dopamine agonists e.g. apomorphine induce vomiting
  • domperidone crosses bbb poorly, good access to area postrema due to lack of bbb
  • also facilitates gastric emptying (potential subgroup 5-HT4 agonist effect) may contribute to efficacy
72
Q

Features of the 5HT3 antagonists?

A

e. g. ondansetron
- significant advance in treatment of CINV
- good for postoperative vomiting (PONV)
- central and peripheral action
- CTZ is the main site of action (also GIT - sensory nerve transmission of nausea and vomiting), nucleus tractus solitarius)
- prevent vomiting in 70-80% of patients on chemotherapy
- ADRs: constipation due to GIT effect

73
Q

What are some alternative or natural therapies for vomiting?

A
  • vitamin B6 - some effect
  • ginger; acts on GIT not central, some studies showing effect
  • carob bean
  • cannabinoids e.g. nabilone
  • ADRs: dizziness, dysphoria, hallucinations
74
Q

How to glucocorticosteroids achieve an antiemetic effect?

A 
e.g. dexamethasone
= anti-inflammatory drug
- potentiate effects of other agents
- PG/inflammation reduction
- unclear mechanism, since some substances might be causing damage to GIT lining to stimulate sensory nerves, the reduction of PGs may be its main approach for using in  combination with antiemetics
75
Q

How do benzodiazepines achieve an antiemetic effect?

A

anxiolytics (anti-anxiety)- adjunct therapy

- e.g. chemotherapy patients, reducing anticipatory induced nausea and vomiting

76
Q

NK1 (neurokinin e.g. substance P) receptor antagonists

A

e. g. aprepitant
- good adjunct treatment
- substance P (tachykinin) acts at NK1 receptors
- NK1 receptors abundant in GIT, CTZ and other CNS nuclei
- effective against vomiting associated with chemotherapy, motion, alcohol
- inhibits CYP450 (drug interactions)

pharmacology (17 decks)

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