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M201 > W11 Antacids, H2 Antagonists & Proton Pump Inhibitors, Promotility Agents, Laxatives, Emetics & Antiemetics > Flashcards

W11 Antacids, H2 Antagonists & Proton Pump Inhibitors, Promotility Agents, Laxatives, Emetics & Antiemetics Flashcards

Lectures: Disorders of the GI System, Antacids, H2 Antagonists, PPI's, Promility agents, Constipation and the need for laxatives, Emetics, Genes and digestive, GI inflammatory diseases

1
Q

Name some GI conditions:

A

Heartburn
Dyspepsia (indigestion)
Gastritis
Nausea & Vomiting
Peptic Ulcer Disease
Constipation
Gastroparesis
GORD

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2
Q

Definitions:
What is Heartburn?

A

It is a burning feeling in the chest caused by stomach acid travelling up towards the throat (acid reflux). If it keeps happening, it’s called gastrooesophageal reflux disease (GORD)

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3
Q

What is Gastritis?
What is Gastroparesis?

A

Gastritis is when the lining of your stomach becomes irritated (inflamed). It can cause pain, indigestion and feeling sick.

Gastroparesis is a chronic condition where the stomach cannot empty in the normal way. Food passes through the stomach slower than usual. It’s thought to be the result of a problem with the nerves and muscles that control how the stomach empties

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4
Q

6 stages of dealing with food?

A
  1. Ingestion
  2. Mechanical Breakdown
  3. Propulsion
  4. Digestion
  5. Absorption
  6. Defecation
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5
Q

What are the 4 layers of alimentary canal?

A
  • Mucosa (epithelium, lamina propria, muscularis mucosa)
  • Submucosa
  • Muscularis Externis
  • Serosa
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6
Q

Nerves of the digestive system?

A
  • Short axis (submucosal plexus) & myenteric plexus
  • Long axis (From the brain) – Parasympathetic
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7
Q

Saliva:
What is it made up of?

A

Saliva can be secreted by intrinsic or extrinsic glands
Saliva is made of:
* Amylase
* Mucin
* Water
* Protective elements (Defensin, IgA, Lysozyme

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8
Q

What are the Stages of swallowing? (5)

A
  • Buccal phase
  • Pharyngo-oesophageal phase (blocking off nasopharynx)
  • Pharyngo-oesophageal phase (blocking off trachea)
  • Peristalsis
  • Sphincter opening
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9
Q

What are the types of cell in stomach? (4)

A
  • Mucus cells
  • Parietal cells
  • Chief cells
  • Enteroendocrine cells
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10
Q

How is gastric secretion regulated? (3 phases)

A

Cephalic
Gastric
Intestinal

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11
Q

which vitamins are fat soluble?

A

ADEK

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12
Q

Gastric glands :What are the different cells involved?

A
  • Parietal cells: mid portion secrete HCl & intrinsic factor for B12 absorption
  • Chief cells: base of gland; secretes pepsinogen a precursor molecule to pepsin (an enzyme that digests protein)
  • Enteroendocrine cells: secrete multiple hormonal products
  • Gastrin (G cells) PYLORIC ATRUM, histamine, endorphins, serotonin, cholecystokinin, which influence several digestive system organs. Stimulates HCl release from Parietal cells
    Somatostatin: Inhibits HCl release
  • EntChrL (ECL) cells produce histamine
    =lots of HCl production
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13
Q
A
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14
Q

Digestive Processes (Stomach)
What are the roles of the stomach?

A
  • Acts as a holding vessel for ingested food
  • Participates in mechanical & chemical digestion
    *Propulsion:Delivers its product(chyme) to the small intestine
  • Proteindigestion:
    -HCl denatures protein
    -HCl activates pepsinogen to pepsin
    -Pepsin breaks peptide bonds of proteins
    -Rennin: an enzyme that breaks down casein (milk protein) secreted in infants

*Intrinsic factor:required for Vit.B12 absorption (needed to mature RBC)
*Mucosal barrier:protects the stomach from its own secretions
* Thin viscous mucus overlies a thick coating of HCO3- rich mucus
* Tight junctions between epithelial cell PM of glandular cells are impermeable to HCl
* Epithelium is replaced every 3-6 days

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15
Q

Dyspepsia
What are the group of symptoms that contribute towards it? (4)

A
  1. upper abdominal pain or discomfort,
  2. heartburn,
  3. gastric reflux,
  4. nausea, or vomiting.
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16
Q

What are the pharmacological treatments used for dyspepsia?

A
  • Antacids
  • Mucosal strengtheners:
    -Misoprostol
  • Reduction of acid secretion:
    -Proton pump inhibitors- omeprazole
  • Histamine H2 receptor antagonists- ranitidine
  • Muscarinc antagonists- pirenzapine
  • H pylori eradication regimes
    -Dual therapy PPI and antibiotics
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17
Q

PPI mechanisms

A
  • PPIs are prodrugs – converted to active moiety (sulfenamide) in the presence of acid
  • Sulfenamide binds covalently to exposed cysteine residues of the H+/K+ATPase pump
  • Most of the PPIs have a pKa (pH 50% of molecule is protonated) that ranges from 3.8 to 5.0
  • A subset of patients may not gain the full therapeutic benefit of these drugs, or may develop treatment-related adverse events.
  • The efficacy of PPIs to treat GORD and related conditions is closely linked to plasma concentrations.
  • PPIs are metabolised by CYP2C19 (except rabeprazole)
  • Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme.

Oral dosing with omeprazole 20 mg maintains an intragastric pH of ≥ 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients.

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17
Q

What is the mechanism of action of PPIs?

A

Proton-pump inhibitors such as omeprazole bind covalently to cysteine residues via disulfide bridges on the alpha subunit of the H+/K+ ATPase pump, inhibiting gastric acid secretion for up to 36 hours. This antisecretory effect is dose-related and leads to the inhibition of both basal and stimulated acid secretion, regardless of the stimulus

18
Q

Gastroparesis: Delayed gastric emptying in the absence of a mechanical obstruction
What are the conditions associated? (5)
What are the iatrogenic causes?
Symptoms?

A
  • Diabetes mellitus
  • Hypothyroidism
  • Neurological conditions like Parkinson’s disease
  • Viral infections
  • Autoimmune attack

Iatrogenic causes
* Vagal nerve damage during surgery
* Opioids
* Alpha-2-adrenergic agonists e.g clonidine
* Tricyclic antidepressants e.g amitriptyline
* Anticholinergics e.g atropine.

Treatment of gastroparesis is generally based on dietary modifications and avoiding medications that delay gastric emptying.

nausea, vomiting, upper abdominal pain, early satiety, bloating, and in severe cases, unintentional weight loss.

19
Q

What are Promotility agents?

A
  • Prokinetic agents refer to a class of drugs that promote the passage of ingested material in the GI.
  • Tx symptoms: dysmotility, visceral hypersensitivity and altered visceral tone
  • Gastroparesis and constipation
  • Neurogastroenterology and motility
  • Enteric neuro-modulation

Important considerations:
1. Is the simple stimulation of gut motility a valid target?
2. Target disorders are poorly defined
3. Non-selective drugs will have side effects

  • Gastroesophageal reflux disease
  • Chemotherapy-induced nausea and
    vomiting
  • Diabetic gastroparesis (digestive
    condition caused by diabetes)
  • Gastrointestinal dysmotility (muscles
    of the digestive system becomes
    impaired)
  • Chronic constipation due to unknown causes
20
Q

How do Promotility agents work?

A
  • Increase wave-like contractions in the esophagus * Increase contractions in the stomach
  • Promote emptying of stomach contents
  • Increase wave-like contractions in the intestines
  1. Stimulating excitatory chemical messengers (neurotransmitters) like acetylcholine (smooth muscle contractions)
  2. Suppressing inhibitory neurotransmitters like dopamine and serotonin
    …which stimulate specific receptors on the smooth muscle cells in the GI tract, thus promoting muscle contractions.
21
Q

What are the Four types of prokinetic drugs?

A

1.Cholinergic agonists
2. Dopamine Antagonists
3. Serotonergic Agonists
4. Macrolides

22
Q

Prokinetics- Dopamine antagonists:

A

Metoclopramide (first line) and Domperidone (sometimes used & torsades de pointes)
* block the effects of dopamine in the CNS and at the chemoreceptor zone (anti-emetic).
* stimulate peristalsis by releasing acetylcholine
* adverse effects (~25%) Px for hypomotility disorders associated with nausea

Metoclopramide
GIT: ↑ gastric peristalsis, relaxes pylorus and duodenum → gastric emptying, independent of vagal innervation
↑ LES tone ↓reflux
↑ intestinal peristalsis to some extent, no significant action on colonic motility and gastric secretion.

CNS: effective antiemetic; acting on the CTZ, blocks apomorphine induced vomiting.

Administration: orally three to four times a day
Side effects: drowsiness, restlessness, and diarrhoea.

Domperidone less CNS effects
doesn’t cross BBB

23
Q

Mechanism Of Action of dopamine receptor antagonists: (prokinetics)

A

Metoclopramide acts through both dopaminergic and serotonergic receptors

Multiple actions
* Dopamine D2 antagonist
* Serotonin (5-HT4) agonist
* Serotonin (5-HT3) antagonist
* ↑ amplitude and frequency of contractions
* inhibits fundic receptive relaxation
* coordinates gastric, pyloric, and duodenal motility
=moderate acceleration of gastric emptying

24
Q

Prokinetics- Serotonergic Agonists (substituted benzamides)

A

Cisapride and Prucalopride
* Cisapride activate serotonin receptors (5HT4 receptors) to release acetylcholine * Their actions are also blocked by atropine
* Treat mild to moderate gastroesophageal reflux, gastroparesis
* Minor side effects —— serious cardiac risks
Aim:
ability to accelerate intestinal transit, reduce esophageal acid exposure, and promote gastric emptying ….Lots of drugs developed and withdrawn

  • Prucalopride a selective serotonin 5HT4-receptor agonist with prokinetic properties
  • Prucalopride is recommended as an option for the treatment of chronic
  • Tx constipation only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to
    provide adequate relief and invasive treatment for constipation is being considered.
25
Q

Motilides (prokinetics)

A

Erythromycin (macrolide antibiotic)
* Indicated for GI stasis - enhances peristalsis by acting on motilin receptors or by releasing motilin
* Their actions appear to be mediated by acetylcholine since they are also blocked by atropine.
* Motilin agonists may increase gastric tone or inhibit gastric accommodation and, potentially, worsen symptoms, even when gastric emptying improves

26
Q

Colon

A
  • By the time the digested food (chyme) reaches the large intestine, most of the nutrients have been absorbed
  • The primary role of the large intestine is to convert chyme into faeces for excretion
  • Lacks villi and has many crypts of Lieberkühn
  • The crypts consist of simple short glands lined by mucus-secreting goblet cells
  • The epithelial cells contain almost no digestive enzymes
  • The mucosa, like that of the small intestine, has a high capability for active absorption of sodium, Cl and water.
  • The outer longitudinal muscle layer is modified to form three longitudinal bands called tenia coli visible on the outer surface.
  • Since the muscle bands are shorter than the length of the colon, the colonic wall is sacculated and forms haustra.
27
Q

Secretion in the colon

A
  • Mucus – neutralises any acid, protects against irritation, lubricates, and provides a binding medium for faeces.
  • Stimulation of the pelvic nerves (nerves of defecation reflex) cause:
  • Increaseinperistalticmotilityofthecolon * Marked increase in mucus secretion
  • Bacterial infection – mucosa secrete water and electrolytes & alkaline mucus to dilute irritating factors through rapid bowel movement (stimulant laxatives)
    Absorbs water, NaCl, K, vit K
28
Q

Absorption in the large intestines

A

Water
* About 0.5- 1.5L/day is absorbed. Water
* The net water loss is 100-200 ml/day
Sodium
* In the presence of Na+-K+ ATPase at the basolateral membrane, Na+ is actively absorbed and K+ is secreted into the lumen of colon
Chloride
* Cl- is absorbed in exchange for HCO3 - which is secreted
Vitamins
* Vitamins as vit. K, biotin, B5 , folic acid and some aa and short chain FA from bacterial fermentation of CHO are absorbed
* It does not absorb vitamin B12!
Misc
* Certain drugs as steroids and aspirin may be absorbed
* Reabsorption of organic wastes (urobilinogens & Stercobilinogen) and toxins
* Reabsorption of bile salts

29
Q

Control of motility in the colon

A

Haustrations - Mixing Movement
* Themotoreventsinproximalcolon(cecum&ascendingcolon).
* Ring-like contractions (2.5 cm) of circular muscles divide the colon into pockets (haustra). (The longitudinal
muscle also contracts at the same time)
* Uniform repetition of haustra occurs along the colon.
* Net forward propulsion happens when sequential migration of haustra occurs along the length of bowel.
Segmenting contractions
throughout the day
Mass propagated contractions 3 – 10 time as day

Propulsive - Mass Movement
* Themotoreventsindistalcolon(transverse&descending colon).
* Startsinthemiddleoftransversecolon,15minsafter breakfast.
* Constrictive ring occurs at a distended point, then 20 cm of the colon distal to constriction, contracts as a unit forcing the faecal mass down the colon.
* Precededbyrelaxationofcircularmuscle&downstream disappearance of haustral contractions.

30
Q

Defecation – when its time to go
1. Convenient timing
What steps occur in the process? (5)

A
  • Allow defecation reflex.
  • Stretch of rectal wall is sent to SC by pelvic nerve.
  • Efferent pelvic impulses cause reflex contraction of rectum & relaxation of internal anal sphincter.
  • Followed by reduction in tonic impulses to external anal sphincter, so it relaxes voluntary.
  • Faeces leave rectum assisted by voluntary straining & contraction of pelvic floor muscles.
31
Q

Defecation – when its time to go
Inconvenient timing

A
  • Inhibited defecation reflex from cerebral cortex
  • Maintain voluntary tonic contraction of external
    anal sphincter.
  • Override tonic contraction of internal anal sphincter
  • Urge passes
  • People who too often inhibit their natural reflexes are likely to become severely constipated.
32
Q

Defecation reflexes

A
33
Q

Constipation

A
  • Decrease in stool passage frequency = small, hard stools faecal impaction
  • Difficulty initiating bowel movements (normal -3 x week on Western diet)
    Poor diet – lack of fibre (resists digestion – bulking agents)
    Decreased motility of GI tract – disorders: IBS, medications: opioids
    Blockage – colonic carcinoma, swollen diverticulum, anal fissures, Haemorrhoids (painful)

Medications:
1. Bulk-forming agents
2. Stimulant laxatives
3. Osmotic laxatives
4. Stool softeners

34
Q

Saline laxatives- what are the issues?

A

e.g. Magnesium citrate and sodium phosphate can be used rectally to cleanse bowels prior to procedures
* Magnesium containing laxatives should be avoided in children, renal impairment, cardiac conditions, pre-existing electrolyte imbalance
* INCREASED risked of hypermagnesemia [heart block/ neuromuscular block/ CNS depression]
* INCREASED risked of hyperphosphatemia [acute renal failure, metabolic acidosis, hypocalcemia/ death]

35
Q

Diarrhoea - 3 liquidy stools in 24 hours
What are the 2 types?

A
  1. Inflammatory diarrhoea causes inflammation of the gastrointestinal epithelium and this usually happens with invasive pathogens or as a result of a chronic inflammatory bowel disease, and usually there are systemic symptoms like fever.
  2. Non-inflammatory diarrhoea can be either secretory or osmotic
    * Secretory water and electrolyte secretion and decreased absorption
    * Osmotic ingested nutrients aren’t fully absorbed (e.g. lactose), and they remain in the intestinal lumen and pull in water through the process of osmosis
36
Q

Acute diarrhoea <14 days
What are the symptoms?
What are the causative factors?

A
  1. Bloody, mucus stools, severe pain and fever – Slamonella, Shigella, Yersinia, Campylobactor and Enteroinvasive E.coli
  2. Non-inflammatory: stress, medication, toxins, pathogens (timing of onset gives clues to bacteria), and virus – assoc. vomiting
37
Q

Treatment of Diarrhoea?

A
  • Tx dehydration – oral rehydration solutions (isotonic to replace electrolytes)
  • Dietary adjustments – avoid dairy
  • Antibiotics
  • Antimotility drug loperamide
  • Codeine phosphate - μ and ƍ receptors
38
Q

Chronic diarrhoea
Causes?
How is it diagnosed? (tests)

A

Geographic disparity in cause
* West- inflammatory bowel disease OR malabsorption syndromes (e.g.lactose intolerance, celiac disease)
* East–Infectious organisms
*Persistence of acute diarrhoea despite Tx=immunocompromised

Diagnosis
* Inflammatorymarkers:ESR,C-reactiveprotein
* Anaemia:bleeding
* Malnutrition: protein, albumin
* StoolculturesandAbtestingforHIV

39
Q

Physiology of Vomiting - Vomiting reflex

A

CTZ- chemoreceptor trigger zone
Signals Vomiting Center

Or Motion/Morning sickness- vestibular and cerbellar nuclei- signal to vomiting centre= vomiting reflex

look at diagram on slide

40
Q

3 phases of vomiting reflex?

A
  1. Pre-ejection phase
    − Prodromal nausea
    − Salivation
    − Retrograde intestinal contraction which forces intestinal contents into the stomach
  2. Retching Phase
    − Deep inspiration and breath-holding to
    splint the chest
    − Epiglottic closure
    − Elevation of the soft palate (prevents nasal soiling)
  3. Expulsive phase
    − Relaxation of oesophageal sphincters
    − Pyloric contraction
    − Violent contraction of the diaphragm and abdominal muscles
41
Q

9 steps in vomiting reflex?

A
42
Q

What are some Anti-emetics? (4)

A
  1. Histamine 1 Receptor antagonists (antihistamines) e.g. promethazine (used for motion/morning sickness)
  2. 5-HT3 Receptor antagonists
    * …setron drugs e.g. ondansetron
    * GI and CTZ (used for chemo/radiation/post-op sickness)
  3. Dopamine 2 Receptor antagonists
    * antipsychotics (…azine)
    * Metaclopromide
    * Droperidol
    * Haloperidol (used for chemo/radiation/post-op sickness)
  4. Muscarinic Receptor antagonists e.g. Ayucine (used in prophylaxis)
43
Q

How do anti-emetics work on pregnant women?

A

Drug selectively binds to its receptor
Blocks signalling pathway
Inhibits stimulation of GI tract, diaphragm and abdominal muscles
(not given in 1st trimester usually)

M201 (81 decks)

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