Theme 1: The GI System (L1&2) Flashcards
What does the enteric nervous system contain?
-108 neurones organised into the myenteric and sub mucous plexuses
- ENS provides local reflex control while receiving modifying inputs from the CNS, parasympathetic and sympathetic systems
- Neurotransmitters include serotonin, NO, purines and peptides
What does the myenteric plexus in the ENS control?
Longitudinal and circular muscle layers
What does the submucous plexus in the ENS control?
Secretion and communicates with the myenteric plexus
Give receptors found in smooth muscle
- M3 (ACh)
- α1 and β2 (norepinephrine)
- H1 (histamine)
- 5HT receptors
How do calcium channel blockers affect smooth muscle?
Inhibit contractions, potentially causing constipation
What is the guinea pig ileum used as a pharmacological model?
- Responsiveness to substances (e.g. ACh)
- Possesses both smooth muscle and an intrinsic nervous system (direct and indirect assessments)
- Drug responses selectively antagonised study of receptor actions
Describe the physiology of smooth muscle
- Capable of sustained contraction using little energy
- Displays intrinsic tone and spontaneous contractions independent of nerve stimulation
- Innervated by autonomic nervous system
Describe the structure of smooth muscle
- Smaller, lacks striations compared to skeletal muscle
- Relies on vesicular calcium stores near membrane (instead of SR/T-tubule)
- Connected via gap junctions (synchronised contraction)
Describe the electrical basis of smooth muscle activity
- Resting potential oscillates between -60 to -30 mV as slow waves initiated by pacemaker ICCs
- Action potentials triggered involve calcium influx for depolarisation and potassium effluent for repolarisation
What is the importance of gastrointestinal function?
Major metabolic and endocrine system
What is the importance of gastrointestinal pathology?
Wide range of diseases are involved
What is the pharmacological importance of gastrointestinal problems?
Gastric secretion
VOmiting
Bowel motility
What are the intrinsic layers of the GI tract?
Myentric/Auerback’s
Intramural plexuses
Submucous/Meissners
Mucosa
What are the 2 different muscle layers of the GI tract?
Longitudinal and Circular
What are the parts from brain stem to mucosa?
Nodose ganglia
Vagus nerve
What are the parts from spinal cord to mucosa?
Dorsal root ganglia
Pelvic/Splanchnic nerve
What are the different GI tract hormonal innervations?
- Endocrine secretions (bloodstream, reactions)
gastrin
cholecystokinin - Paracrine secretions (control)
histamine
acetylcholine
What are the parietal cells?
They are cells within the walls of the gastric gland
They are used for the production of HCl via the H+/K+ pump
Form a gland producing pepsin and HCl
What is the structure of the parietal cells?
Canalicular membrane
Canaliculus
Tubovesicles (contain pump, moves to c.membrane)
Basolateral membrane (expresses a range of receptors)
Mitochondria (ATP for pump)
Which hormones stimulate the H+/K+ pump?
Acetylcholine
Histamine
Gastrin
Which hormone inhibits the H+/K+ pump?
Prostaglandin E2
How is pH balanced in the parietal cells?
Using K+ to create an ios electrically neutral environment
What is gastrin?
Peptide hormone
Stimulates acid secretion, pepsi oven secretion, blood flow and increases gastric motility
Increase in cytosolic Ca2+
What is acetylcholine?
Neurotransmitter
Released from vagaries neurones
Increases cytosolic Ca2+
What is histamine?
Hormone
Sub-type specific action
Increases cAMP
What are the diseases associated with acid dysregulation?
Dyspepsia (upper abdominal pain, bloating and nausea)
Peptic ulceration (prolonged excess acid secretion - ulceration)
Reflux oesophagitis (damage to oesophagus by excess acid)
Zollinger-Ellison syndrome (gastrin producing tumour)
How can gastric acid secretion be decreased?
Reducing proton pump function
Blocking histamine receptor function
Neutralising acid secretions with antacids
What are commonly used proton pump inhibitors?
Omeprazole and lansoprazole
What are the functions of proton pump inhibitors?
Irreversibly inhibitors H+/K+ ATPase
When are proton pump inhibitors used?
In peptic ulcers, reflex oesophagitis and Zollinger-ellison
What are proton pump inhibitor pharmacokinetics?
Inactive at neutral pH
Weak bases - accumulation in acidic environments
Degrades rapidly at low pH
Single dosing
What is the structure of H+/K+ ATPase pump?
10 transmembrane domains
α and β binding sites
ATP site
Where is the PPI binding site?
Between the 5th and 6th transmembrane domain
What are adverse effects of PPIs?
Uncommon to experience
Headache, diarrhoea and rash
Mask symptoms of gastric cancer
Care taken in high risk groups
What are examples of histamine receptor antagonists?
Cimetidine and ranitidine
When are histamine receptor antagonists used?
In peptic ulcers and reflux oesophagitis
What are the pharmacokinetics of histamine receptor antagonists?
Rapidly absorbed orally
DOsage varies with condition
Potential inhibitor of cytochrome P450s
What are the adverse effects of histamine receptor antagonists?
Rare to experience
Diarrhoea, dizziness and muscle pain
Cimetidine has antiandrogenic actions (reduce testosterone, create male breast tissue larger)
Potential inhibitor of cytochrome P450’s - reduce metabolism of anticoagulants and tricyclic antidepressants
What are antacids?
Bases that raise gastric luminal pH by neutralising gastric acid
When are antacids used?
In cases of dyspepsia and oesophageal reflux
What are the pharmacokinetics of antacids?
Relatively slow action
Effects often short lived
Acid rebound takes place due to faster gastric emptying
What are the adverse effects of antacids?
Diarrhoea, constipation and belching
Acid rebound
Alkalosis
Care taken with sodium content
What is Helicobacter pylori?
It is a gram negative bacteria
Factors in forming peptic ulcers (95% duodenal and 70% gastric)
Risk factor in gastric cancer
How is H.pylori infection treated?
Triple therapy (PPI, antibacterial and cytoprotective agent)
Often becomes quadruple therapy as resistance occurs
What is the testing that takes place when patients have H.pylori symptoms?
Urea breath test
What are the different types of cytoprotective agents?
Bismuth Chelate
- topic to bacillus
- coats ulcer base, inc. prostaglandin and HCO3- synthesis
Sucralfate
- Stimulates mucus production and prevents degradation
- Inc prostaglandin and HCO3- synthesis
Misoprostol
- Prostaglandin analogue
- Direct action on parietal cells
What are cytoprotective agents?
Enhance mucosal protection mechanisms or form barriers
What is the function of prostaglandins and NSAIDs on mucosa disruption?
Prostaglandins
- synthesised by gastric mucosa
- inc. mucus and HCO3- secretion
- dec. acid secretions
NSAIDs
- inhibit prostaglandin formation
- cause gastric bleeds, erosion then ulcer formation
- specific COX2 inhibitors cause less GI damage
What is the method of production of prostacyclin or thromboxanes?
1) Phospholipids in cell membrane
2) Phospholipase A2
3) Arachidonic acid
4) Cyclo-oxygenase (COX)
5) Various intermediates
6) prostacyclin or thromboxanes
How are leukotrines produced from phospholipids?
Phospholipase A2
Arachidonic acid
Lipoxygenase
Leukotrienes
What is the anatomy of the stomach?
Top: Oesophagus, Fundus, Cardia, Sphincter muscle, rugged
Bottom: Sphincter muscle, Pyloric sphincter, Antrum, Pyloric gland area and Duodenum
How is the frequency of gastric contractions controlled?
Pacemaker cells
Smooth muscle cells in upper fundus
Rhythmic, autonomous, partial depolarisation (sweep down stomach)
Contractions 3/min
Basic electrical rhythm (BER) of stomach
When do contractions occur in the stomach?
Slow wave exceeds resting membrane potential (3 peristaltic waves per minute)
How is the force of gastric contraction controlled?
By neural activity:
Increased by vagal nerve
Decreased by adrenergic activity
By hormonal activity:
Increased by gastrin
Decreased by secretin
What is the response when food is ingested?
Waves of peristaltic contraction in stomach
Forceful contractions increase pressure in antrum
Retro pulse on of food against closed pylorus
Mixing and grinding of food
What is receptive relaxation?
Stretch receptors activated
Activation of vagal inhibitory neurones
Relaxation of smooth muscle
Little changes in pressure
Occurs 2-3h after ingestion
What is emesis?
Forceful evacuation of stomach contents
What is emesis stimulated by?
Which centres control emesis?
Vomiting centre
Chemoreceptor trigger zone (CTZ)
What neurotransmitter stimulus is sensitive to emesis?
ACh
Histamine
5-HT
Dopamine
What is an example of a drug used to stimulate vomiting?
Ipecacuanha
Locally acting in stomach
Irritant effects of alkaloids emetine and cephaeline
What are the different anti-emetics?
H1 receptor antagonists
Muscarinic antagonists
D2 receptor antagonists
5-HT3 antagonists
Cannabinoids, antipsychotics and steroid antagonists
What are examples of H1 receptor antagonists that are anti-emetics?
Cyclizine
Promethazine
What are the properties of the H1 receptor antagonist anti-emetics?
Most effective for motion sickness
Before onset of nausea and vomiting
Act on vestibular nuclei
Commonly used
ADVERSE EFFECTS: mild drowsiness and sedation
What are examples of muscarinic antagonists anti-emetics?
Hyoscine
What are the properties of muscarinic antagonists anti-emetics?
Useful in motion sickness
Effective against vestibular apparatus stimuli and local gut stimuli (NOT CTZ)
ADVERSE EFFECTS: mild dry mouth and blurred vision
Sedation - less than H1
What are examples of D2 receptor antagonists anti-emetics?
Metoclopramide
Phenothiazines
What are properties of D2 receptor antagonist anti-emetics?
Useful in vomiting caused by renal failure and radiotherapy
Work in CTZ
ADVERSE EFFECTS: CNS effects, prolactin stimulation (menstrual disorders)
What are examples of 5-HT3 antagonists anti-emetics?
Ondansetron
What are properties of 5-HT3 antagonist anti-emetics?
Useful anti-emetic chemotherapy and post surgery
CTZ (high expression of receptors)
5-HT3 release in gut can follow from endogenous toxins and chemo
ADVERSE EFFECTS: mild headache and diarrhoea
What is diarrhoea classed as?
Passage of loose or watery stools at least 3 times in 24 hours
What are the different causes of diarrhoea?
Viral (rotavirus)
Bacterial
Systemic disease (IBS)
Drug induced (antibiotics)
How do anti-diarrhoeals work?
Stimulate opiate receptors in bowel
Increase tone of smooth muscle (contracted + rigid stopping peristalsis)
Suppresses propulsive peristalsis
Raises sphincter tome at ileo-catcalls valve and anal sphincter
Reduces sensitivity to rectal distension
Delay in passage - increase water + electrolyte absorption
What is the mechanism of opioid agonists?
E.g. codeine and morphine
Activate μ receptors on myenteric neurones
Hyperpolarisation - inhibit ACh release
Reduce bowel motility
What are the disadvantages of opioid agonists used as anti-diarrhoeals?
Susceptible to misuse - tolerance and dependence
Codeine preferred as less likely to cause dependence
What are the different opioid analogues?
Loperamide (imodium)
Binds to opiate receptors
Free of CNS side effects
Diphenoxylate (lomotil)
Combined sub-therapeutic dose of atropine (discourage abuse)
Adverse effects mimic morphine
Atropine causes side effects in susceptible individuals
What is constipation described as?
Passage of hard stools less frequently than the patients normal pattern
What are the different types of laxatives?
Bulk forming agents
Osmotic laxatives
Stimulants
Faecal softeners
What are bulk forming agents laxatives?
Contain polysaccharide and cellulose (not digested, retain fluid and increase faecal bulk, stimulate peristalsis)
Onset action 12-36 hours
Taken with plenty fluids
SIDE EFFECTS: Flatulence and bloating
What are osmotic laxatives?
Osmosis to retain water in bowel (soften)
Onset action: 30mins rectal preparations, 2-5h magnesium salts, 48h lactulose
SIDE EFFECTS: Abdominal cramps, flatulence, electrolyte disturbance
What are stimulant laxatives?
Stimulate colonic nerves (movement faecal mass, reduce transit time)
Onset action 8-12 hours
SIDE EFFECTS: Abdominal cramps, colonic agony with long term use
How can stimulant laxatives be abused?
In eating disorders, used so much causes colonic atony meaning doesn’t respond causing long term damage
What are faecal softener laxatives?
Non-ionic surfactant with stool softening properties
Reduce surface tension
Penetration of fluid into faecal mass
Weak stimulant
What are the different inflammatory bowel diseases?
Crohn’s disease (entire gut)
Ulcerative colitis (large bowel)
What are characteristics of IBD?
Cyclical bouts of diarrhoea, constipation and/or abdominal pain
What are the treatments of IBD?
Work to fix inflammation
Glucocorticoids - oral/local anti-inflammatory
Aminosalicylates
Sulfasalazine - unknown mechanism
Immunosuppression - infliximab
