GI Histopathology and Visceral Afferents Flashcards

(200 cards)

1
Q

What is the difference between haematoxylin and Eosin stains?

A

Haematoxylin

  • Purple-blue basic stain
  • Stains acidic macromolecules , ie DNA, RNA- nuclei

Eosin

  • Pink acidic stain
  • Stains basic macromolecules, ie cytoplasm of cells, collagen
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2
Q

Special stains

A

Perodic acid Schiff (PAS) +/- diastase- stains glycogen
Alcian blue- mucin
Masson’s trichrome- collagen etc
Perl’s- stains iron

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3
Q

Immunohistochemistry

A

Modern technique for staining

First described by Coons in 1941

Relies on Antigen (Ag)- Antibody (Ab) link

Used to label specific antigens

  • indirect method, primary antibody targets antigen of interest and secondary antibody attaches to this- enzyme attaches to secondary antibody converts substrate into coloured product (diaminobenzidine- brown)
  • direct where enzyme or fluorescent molecule attached directly to antibody but indirect means multiple secondary antibodies attach to primary = amplification

Primarily diagnostic use
Increasingly used to guide therapy

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4
Q

Epithelium structure

A
  • Closely packed cells, with little to no extracellular material
  • Form membranes or glands
  • Epithelium separated from connective tissue by basement membrane
  • Squamous, columnar, cuboidal cells
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5
Q

Epithelium functions

A

Protection : skin

Secretion/ excretion

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6
Q

Epithelium types

A

Simple (one cell layer)

Stratified ( more than one cell layer)

Pseudo-stratified

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7
Q

What tissue is this?

A

Simple epithelium

lots of pin cytoplasm because of lots of mitochondria

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8
Q

What tissue is this?

A

Stratified epithelium

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9
Q

What tissue is this?

A

Transitional epithelium (urothelium)

Has ability to stretch and maintain a tight barrier to prevent urine leaving the bladder

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10
Q

Connective tissue structure

A

Composed of

  • Extracellular matrix
  • A few cells
  • Provides structural and metabolic support

Extracellular matrix

  • Fibres (collagen , elastin)
  • Amorphous ground substance (gel like matrix)
  • Extracellular fluid
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11
Q

Connective tissue cell types

A

Fibroblasts
Adipocytes
Macrophages
Lymphoid cells ( plasma cells, leucocytes)

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12
Q

What tissue is this?

Label diagram

A

Connective tissue

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13
Q

What type of tissue is adipose tissue?

A

Connective tissue

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14
Q

What type of tissue is this?

A

Adipose tissue

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15
Q

What type of tissue is cartilage?

A

Connective tissue

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16
Q

What tissue is this?

A

Cartilage

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17
Q

What cartilage type:
articulates bone surfaces?
is in the ear?
is in intervertebral discs?

A

Hyaline cartilage articulates bone surfaces

Elastic cartilage in ear

Fibrocartilage in intervertebral discs

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18
Q

What cells produce cartilage?

A

Chondrocytes (found in lacunae)

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19
Q

What are the bone cells that sit in lacunae in the bone matrix?

A

Osteocytes

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20
Q

Bone composition

A

Protein matrix containing collagen
Mineral substances - calcium hydroxyapatite laid down on matrix giving it calcified supportive structure

Osteoclasts also present to reabsorb bone

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21
Q

Where does haematopoiesis occur?

A

Bone marrow

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22
Q

Skeletal muscle

A

Attached to skeleton
Long cylindrical fibres with an eccentric nuclei
Striated

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23
Q

Smooth muscle

A

Present in hollow viscous organs
Shorter cells with centrally placed nucleus
No striations

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24
Q

Cardiac muscle

A

Striated

Centrally located nucleus

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25
Identify which muscle type each one is
26
Nervous tissue: CNS vs PNS
``` CNS: Neurons Supporting cells Oligodendroglia, astrocytes Schwann cells, microglia ``` PNS: Bundles of parallel elongated fibres Wavy, zig zag configuration
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What tissue is this?
Nervous tissue
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What tissue is this?
29
Histopathology
Microscopic examination of cells and tissue to study disease The gold standard diagnostic technique
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Metaplasia
Transformation of one differentiated cell type to another differentiated cell type
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Dysplasia
An abnormality of development Epithelial dysplasia- loss of maturation
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Structure of wall of GI tract
33
Structure of the wall of GI tract
34
What lines normal oesophagus?
Pale pink squamous mucosal lining
35
Squamous mucosa structure
36
What is the deepest layer of normal oesophagus lined with?
Basal cells (single layer) including stem cells
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Features of normal oesophageal squamous epithelium
38
Causes of impaired oesophageal sphincter control in GORD/reflux oesophagitis?
``` Hiatus hernia Obesity/pregnancy Gastric distension by food/gas Stress Alcohol and tobacco/drugs ```
39
What does acid gastric contents damage?
Unprotected squamous mucosa
40
Acidic damage to unprotected squamous mucosa causes what?
infiltration of the damaged surface epithelium by neutrophil polymorphs and eosinophils basal cell hyperplasia as epithelium proliferates to replace damaged cells
41
What does reddened patches on lower oesophagus mean?
Inflammation, secondary to reflux of acidic gastric contents
42
What happens to basal cells in GORD/reflux oesophagitis?
Hyperplasia
43
Complications of GORD
Peptic ulceration, i.e. acid-induced benign ulceration Replacement of squamous mucosa by glandular mucosa. Columnar metaplasia = Barrett’s oesophagus Development of dysplasia in Barrett’s oesophagus Development of adenocarcinoma in Barrett’s oesophagus
44
What happens to mucosa in an ulcer?
Complete break in mucosa, discontinuation in mucosa. Inflammatory slough with fibrin on surface Base of ulcer formed from granulation tissue consist of early fibrosis with proliferation of new capillaries (later forms fibrosis or scar tissue)
45
What problems can arise from a healing peptic ulcer?
As peptic ulcer heals scar tissue can form leading to peptic stricture in oesophagus
46
Barrett's oesophagus
Complication of GORD The squamous mucosa undergoes metaplasia from the normal squamous epithelium to columnar epithelium (glandular type epithelium) (acid reflux causes metaplasia)
47
Metaplasia and reversability
Metaplasia is the reversible replacement of one mature type of epithelium by another in response to adverse circumstances. Columnar cell metaplasia in oesophagus = Barrett’s oesophagus 2º v(secondary) to GORD/reflux oesophagitis Mucus barrier of columnar epithelium protects against acid Metaplasia is reversible if the stimulus is removed.
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What replaces squamous epithelium in Barrett's oesophagus?
Metaplastic columnar epithelium
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What does Barrett's metaplasia consist of?
Barrett’s metaplasia is often a mixture of non-specialised gastric-type mucosa and intestinal metaplasia Intestinal metaplasia with goblet cells
50
Dysplasia
Premalignant change within the epithelium Characterised by: Impaired cell differentiation : disorganised, often failing to mature towards surface Atypical nuclear features, eg pleomorphism Increased numbers of mitoses
51
Dysplasia in Barrett's oesophagus
Dysplasia in Barrett’s oesophagus: surface epithelium shows multilayering of nuclei, with hyperchromatism, pleomorphism and increased mitoses Non-dysplastic metaplastic columnar mucosa in Barrett’s oesophagus
52
How does carcinoma of oesophagus present in Barrett's oesophagus?
Carcinoma of oesophagus presents with dysphagia due to luminal narrowing and infiltration of the wall, inhibiting peristalsis
53
What are the 2 types of adenocarcinoma of oesophagus?
Intestinal type formed by irregular glands Diffuse type (signet ring carcinoma)
54
Normal squamous vs dysplasia squamous
Normal squamous mucosa shows orderly maturation from the basal layer to the surface. Squamous epithelial dysplasia in the oesophagus. Disordered maturation and increased mitotic figures.
55
Where does squamous cell carcinoma typically occur?
Mid or upper oesophagus
56
Where does adenocarcinoma of oesophagus typically occur?
lower oesophagus and GOJ (gastroesophageal junction)
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What mucosa is on the surface of the body and fundus?
Specialised gastric mucosa Mucous neck cells secrete a blanket of mucus over the surface which protects it from digestion by enzymes and acid.
60
2 types of specialised body-type gastric mucosa
Parietal cells (pink-staining) secrete gastric acid Chief cells (purple-staining) secrete pepsinogen, which is activated by acid in the lumen of the stomach to form the active protease enzyme pepsin.
61
What cells are found on the antrum and pylorus?
Non-specialised gastric mucosa Glands formed by mucus producing cells
62
Protective mechanisms in stomach
MUCUS BLANKET continually secreted by mucus neck cells BICARBONATE BUFFER LAYER secreted by epithelial cells in gastric neck/isthmus
63
What can interfere with the mucus blanket?
Drugs, alcohol and H. pylori infection Mucus blanket relies on intact mucin neck cells for production so any inflammatory stimulus will interfere
64
What can interfere with bicarbonate buffer layer?
Bicarbonate (HCO3-) secretion is stimulated by prostaglandins, produced from arachidonic acid by COX pathway, inhibited by NSAIDs
65
How does pepsin form?
Pepsin forms from pepsinogen in acid-rich environment
66
What do parietal cells and chief cells secrete?
Parietal: acid Chief: pepsinogen, not activated until pH is low
67
Gastritis pathology
Infiltration by acute inflammatory cells like neutrophils and chronic inflammatory cells like plasma cells and lymphocytes
68
2 main causes of gastritis
NSAIDs and H. pylori
69
What is a consequence of gastritis?
Gastric peptic ulcer in stomach Duodenal peptic ulcer in duodenum Peptic-type ulceration is due to acid.Seen in oesophagus, stomach and duodenum
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Complications of peptic ulcers in stomach or duodenum
71
Intestinal-type adenocarcinoma vs ulcerated adenocarcinoma
Intestinal-type adenocarcinomas usually present as ulcers or polypoid tumours. Ulcerated adenocarcinoma has a ‘rolled’ everted edge, unlike the overhanging edge of benign peptic ulcer
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Gastric peptic ulcer vs ulcerated gastric adenocarcinoma
Gastric peptic ulcer: surface has granulation tissue with inflammatory slough, NO epithelial cells in submucosa Adenocarcinoma: nests of irregular glands invading from mucosa into submucosa and into muscularis propia
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Gastric peptic ulcer vs ulcerated gastric adenocarcinoma
Gastric peptic ulcer: surface has granulation tissue with inflammatory slough, NO epithelial cells in submucosa Adenocarcinoma: nests of irregular glands invading from mucosa into submucosa and into muscularis propia
74
Diffuse (signet-ring cell) type adenocarcinoma presentation in stomach
Stomach often shrunken, thickened and non-distensile; patient may present with early satiety.
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Somatic pain
musculoskeletal (joint pain, myofascial pain), cutaneous; often well localized
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Visceral pain
hollow organs and smooth muscle; usually referred
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Neuropathic
pain initiated or caused by a primary lesion or disease in the somatosensory nervous system.
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Hollow and solid organs
Not all internal organs sensitive to pain e.g. liver, lungs, kidneys – no nociceptors Stretching of hollow viscera such as gall bladder, ureters, colon can cause excruciating pain no close relationship between severity of damage and severity of pain
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Extrinsic sensory neurones work with what other cells?
Immune cells in gut wall
80
Interstitial cells of Cajal
Pacemaker cells
81
Sensations from the gut
``` Oesophageal distension Gastric distension – fullness Nutrient density in stomach/duodenum Nausea-toxins or excess nutrients Movement of gas Pain Awareness of rectal content Urgency ```
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Visceral afferent pathways in the GI tract
Vagal afferents Thoracolumbar (splanchnic) afferents (pain) Pelvic afferents (gut) Enteric afferents - viscerofugal neurons
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How many different types of sensory neurones give rise to sensation from the gut?
Serosal/Muscular/Mesenteric – distension/contraction – mechanoreceptors Mucosal – entero-endocrine mediators ``` Musculo-mucosal Vascular afferents (serosal) ```
84
What is the location of the sensory neurons of the gut?
Intra-ganglionic – low threshold mechanoreceptors primarily in vagal and pelvic pathways (longitudinal muscle) Intramuscular afferents – mechanosensitive (muscular propria) Mucosal afferents – mucosal distortion and entero-endocrine cell mediators (vagal and spinal) (mucosa) Muscular-mucosal – mucosal stroking and distension/contraction – in vagal and pelvic pathways (submucosa) Vascular afferents – on extramural and intramural blood vessels – mechano-nociceptors – splanchnic and pelvic pathways (submucosa to longitudinal muscle) Entero-viscerofugal – interneurons with mechanosensitivity (LM)
85
Visceral pain in clinical practice- pain caused by: 'structural' conditions? 'functional' conditions?
Pain caused by ‘structural’ conditions - Inflammatory e.g. acid-peptic disease, - Neoplastic Pain caused by ‘functional’ conditions - Irritable bowel syndrome (include bloating) - Functional dyspepsia (include nausea)
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Stimuli for visceral pain
``` Hollow organ distension Traction Ischaemia Acid/Irritant chemicals Inflammation Electrical stimulation ‘pinching’ does not cause pain except when hyperalgesic ```
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Somatic abdominal pain features
‘Painful rib’ syndrome Spinal pain Pain from abdominal wall or inguinal ligaments Constant, can be sharp and momentary with movement or straining Well localised Unaffected by food, defaecation Affected by position, movement, straining Localised Tenderness, reproduces pain Subluxation of costal cartiledge tips causing impingement of the intercostal nerves
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Example of visceral pain becoming somatic
Acute appendicitis: - In early phase visceral intestinal pain – central abdominal, colicky - With onset of inflammation of parietal peritoneum, somatic pain localised to RIF - Worse with movement and straining - Tenderness at McBurney’s point
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Treatment of visceral pain
1. Treat disease e.g. peptic ulcer 2. Anti-spasmodics e.g. for irritable bowel syndrome 3. For visceral hypersensitivity use tricyclics e. g. Amitryptiline 4. Used in sub-anti-depressant doses 5. Start at low dose e.g. 10 mg nocte and step up 6. Main problem is sedation – take at 6 pm
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Hyper vigilance and pain
Mild pain can become difficult to bear when patients are worried about it – leads to anxiety, panic etc Pain may not be noticed when engaged in other activities e.g. Watching TV ‘Painful rib’ syndrome – continuous pain day and night. Many patients cope with it much better once they understand it is not serious. Analogous to rheumatism
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Achalasia
An oesophageal motility disorder causing dysphagia Degeneration of ganglion in myenteric plexus in oesophageal wall leading to motility disorder: - Aperistalsis - Incomplete lower sphincter relaxation - Treat by myotomy, pneumatic dilatation or botulinum toxin injection
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Gastro-oesophageal reflux
Incompetent lower oesophageal sphincter, but resting pressure may be normal Gastric acid secretion usually within normal limits Oesophagitis seen at endoscopy but normal appearances in non-erosive gastro-oesophageal reflux Ambulatory lower oesophageal pH monitoring
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Oesophageal exposure to acid causes...
Hypersensitivity | (hyperalgesia aka primary, local OR allodynia aka to non painful stimuli OR, secondary hyperalgesia aka generalised)
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Hyperalgesia
an increased sensitivity to feeling pain eg overuse of opiods ie exaggerated response
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Allodynia
things that don’t normally cause pain eg very sensitive to touch/temperature
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Secondary hyperalgesia
generalized response not just at the area of injury
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Ion channels in the oesophagus
1. Transient Receptor Potential Vanilloid-1 (TRPV-1) 2. Acid-Sensing Ion Channel (ASIC) Acid excites primary sensory neurons by activating TRPV1 and ASIC – leads to release of pro-inflammatory mediators and neurogenic inflammation Sensitive to mechanical, electrical and thermal stimuli
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Erosive reflux disease vs NERD
Erosive- mucosal damage | NERD- no mucosal damage
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What organs does Gi tract share neural pathways with?
Lungs and trachea
100
Using pH testing on a patient with GORD the result is abnormal what is the likely diagnosis?
NERD Posiitve result- abnormal acid exposure
101
What would pH result be if a patient with GORD had functional heartburn?
Normal pH test May have symptoms associated with pH changes- hypersensitive oesophagus or just functional heartburn
102
Gastric motility and secretion
Fundus – accommodates Antrum – grinding effect Food boluses converted into chyme Greasy and rich food delays gastric emptying Stomach secretes acid and pepsin Vagus, gastrin (secreted by G cells) and acetylcholine promotes acid secretion Proton pump - final common pathway for acid secretion
103
Delayed gastric emptying
Often occurs in dysmotility type dyspepsia, sometimes associated with nausea, vomiting and weight loss Severe gastric emptying delay in gastro-paresis, often diabetic, sometimes post-infective Pro-kinetic drugs: domperidone, metoclopramide also helps nausea and vomiting Isotope gastric emptying study
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IBS demographics
``` 10-15% of the population 30% consult a physician Greater anxiety, lower quality of life Female preponderance No excess mortality Rome and Manning Criteria ```
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Rome IV criteria
Recurrent abdominal pain, on average, at least 1 day/week in the last 3 months, associated with two or more of the following criteria: Related to defecation Associated with a change in frequency of stool Associated with a change in form (appearance) of stool ``` Disorders of gut-brain interaction Related to: - Motility disturbance - Visceral hypersensitivity - Altered mucosal and immune function - Altered gut microbiota - Altered CNS processing ```
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IBS and abnormal perception of normal stimuli
Distension in IBS -> abnormal sensory response, pain, urgency, feeling unwell normal sensory stimulus giving rise to different sensation increases with increasing distension (higher pressure = more sensitive to discomfort)
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Importance of physician-patient interaction
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IBS phenotypes
IBS with constipation >25% hard stools, <25% loose stools IBS mixed - both hard and loose stools IBS with diarrhoea >25% loose stools, <25% hard stools
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Constipation
Many possible causes: low fibre diet, medications such as opiates, hypercalcaemia, hypothyroidism Chronic constipation not a symptom of colon cancer Does not produce toxins, ill health or increase risk of colon cancer Functional types: colonic inertia – slow transit (can assess by marker studies), pelvic floor dys-synergia: pelvic muscles do not relax with defaecation Management similar for both types of constipation
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Constipation demographics
More common in lower socioeconomic class Less fibre and less exercise F:M – 2.2:1
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Constipation demographics
More common in lower socioeconomic class Less fibre and less exercise F:M – 2.2:1
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Beneficial diet for constipation
Diet: Meta-analyses - Bran – less effect if constipated - Ispaghula RCTs - Prunes (sorbitol) - Kiwifruit - Vegetable and wholegrain powder - Fruit and fibre to porridge
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What is the most effective osmotic laxative?
Macrogol (polyethylene glycol) more effective and better tolerated than lactulose Macrogol - Proven efficacy in long term treatment - Improved stool frequency - Improved pain - Less need for other laxatives SE – diarrhoea, bloating
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First line laxatives for: Osmotic? Stimulant? Stool softeners?
Osmotic: - Macrogol - Avoid lactulose Stimulant - Sodium picosulphate - Bisacodyl - Senna Stool softeners - Sodium docusate SE – osmotic – bloating SE – stimulant - cramps
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Individualised diet for patients with IBS
``` Regular, small meals Fat reduction Caffeine Reduce lactose and fructose Reduce gas-producing foods Modify soluble/insoluble fibre Reduce wheat Low FODMAP diet (reduces bifidobacteria) ```
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What do we know about bifidobacteria in relation to helping IBS patients?
Gas related symptoms | Inverse relationship between pain and bifidobacteria
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``` Sites of abdominal pain- what organs are implicated in: Chest Upper Mid Lower Back pain? ```
* Chest - oesophagus * Upper- oesophagus, stomach, duodenum, pancreas, gallbladder, colon * Mid – Small intestine * Lower – Colon, gynaecological Radiation to back with severe pain, biliary pain, pancreatic pain, spinal pain
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Visceral vs non-visceral pain
Visceral pain lasts minutes/hours, intense can come and go Non visceral pain well localised, lasts for seconds or constant Exacerbated by movement, coughing, straining Nerve pains- shooting and needle-like, sharp Musculoskeletal- spinal, painful rib syndrome, pain over ligaments, bones and joints
118
Character and severity of upper abdominal pain: Acid peptic pain? Intestinal pain? Biliary colic?
Acid peptic: burning or dull (mild or moderately severe) Intestinal/colonic: colicky (extremely severe, bad or worse than labour pains) Biliary/pancreatic pain: constant or colicky (extremely severe)
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Associated symptoms with oesophageal pain
heartburn, regurgitation, dysphagia, odynophagia
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Associated symptoms with gastric pain
early satiety, post-prandial fullness, nausea
121
Associated symptoms with biliary pain
dark urine, pale stools, jaundice
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Associated symptoms with colonic pain
diarrhoea, constipation, distension
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Causes of upper abdominal pain
* gastro-oesophageal reflux * functional dyspepsia * gastric ulcer/duodenal ulcer * ca stomach/oesophagus/pancreas/liver * cholelithiasis * acute or chronic pancreatitis * irritable bowel * Non-visceral pain: musculo-skeletal, neuralgic, cardiac * More than one cause of pain
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``` Exacerbating/aggravating factors in: Oesophagitis Gastro-oesophageal reflux Peptic ulcer IBS ```
* Oesophagitis – exacerbated by swallowing * Gastro-oesophageal reflux - exacerbated by food, drink, lying down, bending over, relieved by antacids, milk, sitting up * Peptic ulcer – nocturnal, worse on hunger, improved by food and antacids * Irritable bowel syndrome – pain gives an urge to defaecate, relieved by defaecation, distension
125
Investigations for abdominal pain
• ‘Test and treat’ for Helicobacter (if no alarm symptoms) • Blood count, ESR, LFTs, amylase • Plain X ray, urgent CT, if acute abdomen suspected • Ultrasound • CT • Upper endoscopy • Colonoscopy- not normally indicated for abdominal pain • Lower oesophageal pH study
126
In primary care, dyspepsia is defined as:
* recurrent epigastric pain, heartburn or acid regurgitation, with or without bloating, nausea or vomiting * Also... postprandial fullness, early satiation and heartburn... * GORD and dyspepsia symptoms often overlap * Lower quality of life than pts with DM/CHF1
127
Initial presentation of dyspepsia
* Differential Diagnosis – cardiac and biliary disease * FBC * Medication review – calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and NSAID’s * Offer H. pylori 'test and treat' to people with dyspepsia.
128
What to do if initial therapy for dyspeptic patient doesn't work?
• H.Pylori Eradication – 83% had Symptoms (Sx) at 12 mths – 34% incurred further costs • PPI Therapy (proton pump inhibitor) – 84.5% had Sx at 12mths – 33% incurred further costs
129
What are the predictors of a positive response to a 4 week trial of PPI?
``` • Fewer days of Sx during the 1st week of treatment • Age>40 • Symptoms > 3 mths • High Score for heartburn at baseline • Low Score for Epigastric Pain, bloating, diarrhoea at baseline • Low impairment of vitality at baseline ```
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CASE: • 46 year old man, 6 week history of ‘indigestion’ • FBC, LFT’s, ECG normal • Medication review – calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and NSAID’s – none taken • H. pylori Stool Ag - negative Persistent symptoms • Would you send him for an OGD? • What are the indications for a TWR OGD (2 week rule GI endoscopy)?
CT If expect a cancer, investigation done much more rapidly eg TWR- doesn't seem to be the case here Patient is under 5 so not seen as urgent to do this
131
When would you want to perform URGENT direct access upper GI endoscopy TWR?
dysphagia or aged 55 and over with WEIGHT LOSS and any of the following: • upper abdominal pain • reflux • dyspepsia (weight loss may be an indication of cancer- urgent)
132
Reflux oesophagitis grades
A - 1 or more mucosal breaks no longer than 5mm, does not extend between tops of 2 mucosal folds B - 1 or more mucosal breaks more than 5mm long, does not extend between tops of 2 mucosal folds C - 1 or more mucosal breaks continuous between tops of 2 or more mucosal folds, involves less than 75% of circumference D - 1 or more mucosal break involving 75% at least of oesophageal circumference
133
Duration of treatment for someone with severe oesophagitis (Grade C/D)?
8-12 weeks PPI works best over 8 week period Healing lasts up to 12 weeks
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While being taken, when are PPIs more effective?
Better acid suppression when taken BEFORE a meal
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If patient is still symptomatic after PPI therapy, what is added in?
Add in PPI BID (twice daily) and H2 receptor antagonist Improves gastric acid control and decreases nocturnal acid breakthrough (bc taken morning and night)
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What do do if patient has refractory reflux symptoms?
• Step 1 check adherence • Step 2 confirm diagnosis – Does the patent really have GORD? do endoscopy if necessary What % of patients with PPI refractory reflux symptoms (heartburn and regurgitation) do not have GORD? – 50%
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When is surgery considered for GORD?
If PPIs not tolerated (cause diarrhoea, headaches, dizziness, tiredness) or patient has concerns about long term use of tablets
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Montreal classification of GORD
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Alarm symptoms in patients with dyspepsia
* Anorexia * Weight loss * Persistent vomiting * Anaemia * Haematemesis and melaena * Abdominal mass
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Treatment of GORD
• Lifestyle – Wt loss, elevation of head of bed, smoking, meal times, (CBT, psychological therapies in dyspepsia) • Medical – Antacids, alginates, H2RA,PPI, prokinetics • Surgical – Fundoplication • New endoscopic and surgical techniques
141
Management of gastro-oesophageal reflux disease (GORD)
• Lifestyle and postural measures: - Avoid alcohol, smoking, greasy food, caffeine, weight reduction - Small meals, eat and drink separately - No food or drink for 3 hours before going to bed - Elevate the head of the bed * Pharmacological treatment - PPI * (Endoscopic treatment) * Fundoplication
142
Grade A/B vs Grade C/D treatment
Non-erosive, Grade A and B – treat symptomatically Grade C and D – probably need long- term treatment When it does heal some patients will habe Barrett's oesophagus- 0.5% annual risk of adenocarcinoma, endoscopy to look for dysplasia
143
Laproscopic nissen fundoplication
``` • Most common procedure • Under general anaesthetic • Upper portion of stomach is wrapped around distal oesophagus • Common side effects include: – dysphagia – belching – bloating – flatulence ```
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Stretta procedure
Augment oesophageal sphincter and increase barrier function of lower sphincter
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LINX procedure
Metallic bead wrapped around lower sphincter to augment barrier function
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Peptic ulcer
* Gastric or duodenal * Most cases due to H pylori infection or aspirin/NSAIDs * ‘No acid, no ulcer’: reduction in gastric acid heals ulcers * Can be uncomplicated, Bleeding or perforated * Gastric ulcer can be malignant: need follow-up to healing, but not duodenal ulcer won't be
147
Why do gastric ulcers need follow up?
They can be malignant (cancerous), unlike duodenal ulcers
148
Gastric vs duodenal ulcer effects on patient sleep and meals
149
Treatment of peptic ulcer
* Treat Underlying Cause: H pylori infection or aspirin/NSAIDs * Acid Suppression – PPI * Gastric ulcer to be followed up to healing, not necessary for duodenal ulcer * Check for Helicobacter eradication if history of complications * Bleeding ulcer – maintain haemodynamic stability, endoscopic treatment * Perforated ulcer - surgery
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What abdominal pain is H pylori infection associated with?
* H pylori infection associated with peptic ulcer which can be cured by antibiotic treatment * Most patients with H pylori infection do not have ulcer, only gastritis. Some have dyspepsia. * Dyspepsia cured by treatment of H pylori infection in <10% of patients with functional dyspepsia and H pylori.
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Barrett's BSG guidelines 2014
``` BO occurs in patients with longstanding reflux symptoms (perhaps >10 years) But screening for BO not routinely justified ``` ``` Only consider if ≥3 risk factors: • Males • Obese individuals • those aged >50 • Caucasian • FH of Barrett’s or oesophageal ca, • Smoking ```
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What in OGD would guide management of Barrett's oesophagus?
Length of lining of oesophagus Prague classification: Circumference length = C number Maximum length = M number image: C3M5
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Surveillance intervals BSG guidelines 2014 for Barrett's oesophagus- how often to survey the patients?
Take into account two endoscopic factors: presence/absence of Intestinal Metaplasia and length of segment: • Without intestinal metaplasia and <3cm – single repeat endoscopy in 3-5 years • With intestinal metaplasia: <3 cm - 3-5 yearly >3 cm – every 2-3 years • Patient co-morbidity and preference
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Where are pre-ganglionic parasympathetic fibres found?
Brainstem cranial nerves Sacral S2-S4
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What are the parasympathetic pre ganglionic nerves in the brainstem?
3- oculomotor 7- facial 9- glossopharyngeal 10- vagus
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Length of parasympathetic pre ganglia?
LONG
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Length of parasympathetic post-ganglionic fibres?
SHORT (close to end organs)
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What neurotransmitter is released at parasympathetic post ganglionic fibres (at the end organ)?
Acetylcholine at muscarinic receptors
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What neurotransmitter is released at parasympathetic pre ganglionic fibres?
Acetylcholine at nicotinic receptors
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In the heart, stimulation of vagus nerve releases what neurotransmitter acting at what receptor?
Acetylcholine at M2 receptors
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Where are M2 receptors found?
SA node | AV node
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In the heart what happens when the vagus nerve is stimulated?
Stimulation of vagus nerve releases Ach which acts at M2 receptors ↓ Pacemaker potential frequency at SA node leading to  in heart rate ↓ Electrical conduction through atria-ventricular node to balance ↓ heart rate to contraction Using : CO = HR x SV Stimulation of vagus nerve (↓ HR) will DECREASE CARDIAC OUTPUT
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Parasympathetic nerves in the heart do NOT...
do not innervate ventricles, most blood vessels -> do not affect contractility (SV) or TPR
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What is the exception to parasympathetic not innervating blood vessels?
Exception : male genitalia, where release of NO (not Ach) causes dilatation of vessels to cause erection
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How does stimulation of Mus receptors produces reduction in HR?
Pacemaker cells have hyperpolarised Na channel (If) -> hyperpolarisation, then repolarisation influx of Na depolarises membrane and strikes up another AP Parasympathetic stimulates M2 receptors = activation of GPCRs (Gi class) Gi causes inhibition of Adenylate cyclase → decreased conversion of ATP to cAMP → less cAMP = ↓ If current = ↓ pacemaker potentials in SA node → reduced HR
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How do drugs increase heart rate?
Drugs that inhibit Mus receptors can increase HR by inhibiting parasympathetic action Mus antagonist, e.g. Atropine used to  HR following sinus bradycardia after MI Caution Tachycardia - potential side effect of Mus antagonists given for other reasons
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Muscarinic agonists
Mus agonists, e.g. Bethanechol, used to treat urinary incontinence may induce bradycardia
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What do parasympathetic nerves regulate in the eye?
Pupil diameter Intra-ocular pressure Accommodation (focusing)
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How do parasympathetic nerves regulate pupil diameter
Stimulation of M3 receptors lead to constriction of the circular smooth muscle of the iris (constrictor pupillae), constrict of the pupil (miosis)
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How do parasympathetic nerves regulate intra-ocular pressure?
Constriction of the pupil (M3) has a secondary action on opening the canal of Schlemm at the side of the pupil Drains aqueous humour from eye, reducing pressure within the eye
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Action of muscarinic agonists vs antagonists on parasympathetic nerves in eye
Mus agonist, e.g. Pilocarpine - lowers intraocular pressure in glaucoma Mus antagonists – dilate pupil to examine retina Eye drops have less systemic side effects
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Distance vision mechanism
Ciliary muscle relaxed Suspensory ligaments taut - pulls lens Long thin lens Little refraction to focus
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How do parasympathetic nerves control accommodation of the eye?
CLOSE VISION: stimulates parasympathetic nerves Stimulation of oculomotor nerve (3) → Ach release → acts on M3 receptors → contracts smooth muscle cells → Ciliary muscle contracted causes Ciliary bodies moving inwards/forwards so Suspensory ligaments relaxed Bulged lens shape → Increased refraction to focus
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How can drugs affect accommodation of the eye?
Both Muscarinic agonists and antagonists can cause blurred vision
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Bladder voiding involves interactions with...
Parasympathetic, sympathetic, motor and sensory afferent nerves
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Brainstem micturition centre
Coordinates bladder reflex to cause voiding
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Where are pre ganglionic sympathetic nerves found?
Lumbar region of spinal cord
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SNS in bladder voiding
Pre ganglionic SNS fibres get info from micturition centre -> send info via pre and post ganglionic fibres to bladder and innervate: 1. Muscle wall (detrusor muscle - smooth muscle cells) 2. Internal sphincter Release Noradrenaline to act on B2 receptors on detrusor muscle to cause relaxation, expanding bladder enabling bladder to fill more NA also at A1 receptors at internal sphincter constricting smooth muscle to 'close the tap' so no leaky bladder
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PNS in bladder voiding
Parasympathetic pre ganglionic fibres in Sacral region of spinal cord - receive info from micturition centre and send info via pre and post ganglionic fibres to detrusor muscle of bladder → Release Ach acting on M3 receptors of smooth muscle cells in bladder wall → contraction Increases pressure and helps eject urine from bladder
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Motor nerves in bladder voiding
Motor nerves travel to smooth muscle cells of external sphincter of bladder, act at nicotinic receptors to contract (hold) or relax (void) Motor nerves travel from sacral region of spinal cord
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Mechano-sensitive afferent fibres and bladder voiding
Sensory nerves (mechanoreceptors) found in wall of smooth muscle of bladder wall, sense when bladder is full Stimulated when bladder is full → send info to micturition centre that bladder is full
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Process of bladder voiding through innervation
When bladder full- SNS innervation = relaxation of wall + contraction of internal sphincter Stimulates sensory nerves = send info to micturition centre to switch off SNS, turn on PNS → M3 receptors in bladder wall contract So internal sphincter opens bc SNS gone and detrusor muscle wall contracts = increased pressure and tap open so able to void Motor system allows external sphincter to relax in order to void
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Muscarinic activist effect on detrusor muscle
Mus agonists, e.g. Bethanechol – urinary incontinence due to detrusor neuropathy Helps bladder to void in cases where PNS innervation may not be able to work (incontinence bc without contraction of detrusor muscle person can't void)
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Muscarinic antagonist effect on detrusor muscle
Mus antagonists, e.g. oxybutynin – urinary incontinence due to over activity bladder Overactive bladder, too much stimulation so bladder doesn't fill properly and always wants to void so block M3 receptors to slow down this frequency
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What PNS nerve innervates GI tract?
Vagus nerve
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What receptors do parasympathetic nerves act on in the GI tract?
M3 receptors
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Parasympathetic innervation of GI tract
Stimulation of vagus nerve releases Ach which acts on M3 receptors ↓ Contraction of circular and longitudinal smooth muscle in GI tract ↓ Increased motility Vagus also contains afferent (sensory) fibres – peristaltic reflex control
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GI tract secretions: Salivary gland innervation
Salivary glands- VII (facial) & IX (glossopharyngeal) Stimulate acinar cells ↑ Amylase / mucins
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GI tract secretions: Gastric glands
Gastric glands - X (vagus) Stimulate parietal cells ↑ Gastric acid
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GI tract secretions: Pancreatic glands
Pancreatic glands - X (vagus) Stimulate acinar + islet cells ↑ Pancreatic secretions, e.g. insulin
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Side effects of Muscarinic antagonists that treat GI tract
Mus antagonists, e.g. Hyoscine (Buscopan) – treat IBS-like symptoms May cause tachycardia, blurred vision etc
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Stimulation of what receptors contracts bronchi m=smooth muscle cells?
Stimulation of M3 receptors contracts bronchi smooth muscle cells causing bronchoconstriction Parasympathetic innervation
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Why are ipratropium and tiotropium used as bronchodilators?
Stimulation of M3 receptors contracts bronchi smooth muscle cells causing bronchoconstriction- need to reduce this aka reduce M3 stimulation to increase airflow Thus, anti-muscarinic drugs are used as bronchodilators, e.g. Ipratropium Tiotropium Used in COPD (chronic obstructive pulmonary disease) Need to increase airway flow
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Problems with muscarinic antagonists in patients with bladder outflow problems?
In patients with bladder outflow problems and glaucoma Mus antagonist will reduce urine outflow, increase intraocular pressure Conditions also associated with elderly (as is COPD) These are potential contraindications
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How does stimulation of M3 receptors lead to contraction of smooth muscle cells?
IN SM CELL: ``` Ach binds to M3 M3 is GPCR → Gq pathway stimulated → activates phospholipase C = PIP2 broken down into DAG + IP3 → IP3 water soluble so moves to cytoplasm → binds to IP3R on sarcoplasmic reticulum → opens ligand gated calcium channels (IP3 MEDIATED CALCIUM RELEASE) = rise of calcium in cell ``` (meanwhile DAG → activates protein kinase C → acts on ion channels to increase membrane excitability = depolarisation) Depolarisation = activation of voltage gated calcium channels → calcium enters cell = rise in calcium in cell ``` So now rise in calcium → Calcium calmodulin → myosin light chain kinase → myosin light chain- phosphorylated → actin-myosin interactions = contraction ```
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PNS innervation of male genitalia
Specialised sacral parasympathetic ‘vasodilator’ nerves innervate erectile tissue Stimulation of these nerves release nitric oxide (NO) NOT Ach Remember this is an exception to the normal rule NO is a lipophilic, membrane-permeable gas NO causes relaxation of vascular smooth muscle cells composing the corpus cavernosum Corpus cavernosum dilates and fills with blood Produces and maintains erection
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Sildenafil (viagra)
Sildenafil (Viagra) - erectile-dysfunction, prevents breakdown of the actions of NO – increasing it vasodilator effects
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Stimulation of parasympathetic nerves leads to a reduction in heart rate. What best describes the receptor subtype involved?
M2 receptor
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A new anti-histamine drug is being designed to treat hay fever. Clinical trials indicate that the drug produces side effects of blurred vision, constipation, and tachycardia. What most likely describes the off target actions of this drug?
Muscarinic antagonist | remember M2 receptors in heart slow down HR