GI Flashcards
Gastrointestinal tract overview
GI tract consists of mouth, esophagus, stomach, small intestines, large intestines.
It has accessory glands:
Salivary glands in the mouth, pancreas, liver and all of these are involved in helping digestion and absorption in the GI tract.
Role of gut lumen?
The gut lumen is external to the body because conditions for digestion are tolerated in the gut but not in the body this is due to harsh acidic environment low PH.
Lumen of the gut has acid and that ph is very low, if acid got through the gut wall it would destroy tissues in the body.
We produce digestive enzymes in the pancreas and the mouth and if these enzymes can cross through the gut wall they will destroy our tissues.
Billions of Microorganisms exist in the large intestines and if we have a disease of the large intestine and microorganisms enter body they will cause lots of damage and infection will occur leading to massive inflammatory response.
Food itself is considered as foreign particles our body will mount an immune response against food because we wouldn’t recognise them. Food has to be broken down to its simplest forms of amino acids, glucose, free fatty acids and glycerol in order to recognise them in the body.
What are the 4 basic process of the digestive system?
Motility
Secretion
Digestion
Absorption
Motility?
Motility is both under voluntary and involuntary control
Voluntary control occurs due to Skeletal Muscles being responsible for chewing, swallowing and defaecation.
Smooth Muscle are in the gut wall they control contractions that mix and move forward content of the gut.
Smooth muscle contractions can either be tonic or phasic
Tonic constant low level of contractions used to maintain a steady pressure on the content of gut and prevents wall from being permanently stretched which actually cause damage.
In the presence of food we get Phasic action potential, induced bursts of contractions
Propulsive movements
Mixing movements
Secretion?
Main type of secretions in the gut is Digestive juices- secreted by exocrine glands
These digestive enzymes contain water, electrolytes, specific products for digestion or absorption eg mucus, enzymes breakdown carbohydrates and protein fats are produced by the pancreas, bile salts produced by liver and help fat digestion.
Secretion requires energy to occur and to release lots of water and raw materials but we reabsorb most of these material to resecrete.
Secretion is regulated by neural and hormonal stimulation. Secretions normally reabsorbed into the blood.
GI hormones are secreted by endocrine glands
Secreted into the blood by endocrine cells along tract wall
Regulate motility and exocrine glands secretion.
Digestion and absorption?
Digestion is the biochemical breakdown of complex proteins, carbohydrates, and fats by enzymes.
Enzymes digest by hydrolysis eg maltose is broken down into glucose by Maltese disaccharides and they require water to breakdown. They are specific on the bonds they hydrolyse.
Large molecules broken down to smaller units in stepwise manner through the gut that eventually are absorbed.
Water, electrolytes, vitamins are also absorbed.
Protein digestion?
Protein digestion begins in the stomach we have pepsinogen that is produced by the cells in the stomach wall and is present in the gastric juice
Pepsinogen is cleaved to pepsin by the presence of acid.
Pepsin starts off the process of breaking down the proteins to peptides in the stomach.
Once the proteins are in the small intestine the enzyme from pancreas will take over and break them further.
Trypsinogen in the pancreatic juice is converted to trypsin at basic pH
Trypsin breaks down proteins to peptides.
Peptides are produced by the small intestine and breaks down peptides to amino acids.
Amino acids are actively transported into epithelial cells of the villi and from there to blood
Protein digestion begins in stomach:
• Pepsinogen in gastric juice is converted to pepsin at low pH
• Pepsin breaks down proteins to peptides
Continues in small intestine:
• Trypsinogen in pancreatic juice is converted to trypsin at basic pH
• Trypsin breaks down proteins to peptides
• Peptidases are produced by the small intestine and breaks down peptides to amino acids
Amino acids are actively transported into epithelial cells of villi and from there to blood
Lipid digestion?
Lipids are only broken down in the duodenum and small intestines.
Dietary fat: triglycerides
In the duodenum, lipids combine with bile salts to form fat droplets.
Lipase from pancreas digests triglycerides to monoglycerides and fatty acids.
Monoglycerides and fatty acids diffuse into epithelial cells where the recombine with proteins to form
lipo-proteins called chylomicrons these enter lymphatic capillary and go to liver and other tissues where they are required
Carbohydrates digestion?
Carbohydrates consists of polysaccharides:
Starch is broken down by salivary amylase in the mouth and then by pancreatic amylase on the duodenum and small intestine to maltose.
Glycogen is broken down to glucose
Cellulose and other indigestible CHO are not broken down by the gut enzymes.
Disaccharides:
Enzymes in the small intestine break down simpler sugars.
1- Maltase breaks down maltose to glucose.
2- Sucrase breaks down sucrose to glucose and fructose.
3- Lactase breaks down lactose to glucose and galactose.
Glucose actively transported into epithelial cells of villi and then into blood.
Structure of the digestive tract wall?
The digestive tract wall is composed of several layers that play crucial roles in the process of digestion.these layers are important in the digestion, secretion, absorption and motility.
- Mucosa:
- Role: The innermost layer of the digestive tract wall that is responsible for secretion, absorption, and protection. It contains glands that produce digestive enzymes and mucus.
- Submucosa:
- Role: Provides support to the mucosa and contains blood vessels, lymphatic vessels, and nerves that supply the surrounding tissues.
- Muscularis Externa:
- Role: Consists of smooth muscle layers that are responsible for peristalsis, the wave-like contractions that propel food through the digestive tract.
- Serosa (or Adventitia):
- Role: The outermost layer of the digestive tract wall that provides protection and helps anchor the digestive organs in place.
Here are the roles of each component you mentioned in the digestive tract wall:
- Lamina Propria:
- Role: The lamina propria is a layer of connective tissue in the mucosa that contains blood vessels and lymphatic vessels. It supports the epithelial cells of the mucosa and helps in nutrient absorption.
- Lymphatic Nodules (Peyer’s Patches):
- Role: Lymphatic nodules are clusters of lymphoid tissue in the mucosa and submucosa of the small intestine. They play a role in immune response by monitoring and responding to pathogens in the digestive tract.
- Lymphatic Vessels:
- Role: Lymphatic vessels in the digestive tract wall help in the absorption of fats and fat-soluble vitamins. They also play a role in immune surveillance and transport lymphatic fluid containing immune cells.
- Circular Layer of Muscle (Muscularis Externa):
- Role: The circular layer of smooth muscle in the muscularis externa contracts to constrict and propel food through the digestive tract during peristalsis.
- Myenteric Plexus (Auerbach’s Plexus):
- Role: The myenteric plexus is a network of nerves located between the circular and longitudinal muscle layers of the muscularis externa. It regulates gastrointestinal motility and controls the contractions of the smooth muscle layers.
- Longitudinal Layer of Muscle (Muscularis Externa):
- Role: The longitudinal layer of smooth muscle in the muscularis externa contracts to elongate and shorten the digestive tract, aiding in the movement of food along the tract.
- Simple columnar epithelium.
These components work together to facilitate digestion, absorption of nutrients, immune response, and the movement of food through the digestive system.
Each component of the digestive tract wall works together to ensure proper digestion, absorption of nutrients, and movement of food through the gastrointestinal tract.
Mucosa
Mucosa lines up the lumen
Surface highly folded varies in different parts of tract (esophagus, stomach, small & large intestines)
Three layers
Mucous membrane
Lamina propria
Muscularis mucosa
The mucosa is a crucial component of the digestive tract wall that lines the lumen of the gastrointestinal tract.
- Esophagus:
- The mucosa in the esophagus is specialized to withstand the abrasion and friction caused by the passage of food. It is lined with non-keratinized stratified squamous epithelium.
- Stomach:
- The mucosa in the stomach contains gastric pits and gastric glands that secrete gastric juice for digestion. The surface of the stomach mucosa is lined with simple columnar epithelium.
- Small Intestine:
- The mucosa of the small intestine has numerous folds called villi and microvilli, which increase the surface area for nutrient absorption. It is lined with simple columnar epithelium.
- Large Intestine:
- The mucosa of the large intestine has fewer folds compared to the small intestine and is lined with simple columnar epithelium. It contains numerous goblet cells that secrete mucus for lubrication.
The mucosa consists of three layers:
1. Mucous Membrane:
- The innermost layer of the mucosa that contains epithelial cells responsible for secretion and absorption.
- Lamina Propria:
- A layer of connective tissue beneath the epithelium that contains blood vessels and lymphatic vessels. It supports the mucous membrane.
- Muscularis Mucosa:
- A thin layer of smooth muscle that helps in the movement and folding of the mucosa to increase surface area for absorption.
The variations in the structure of the mucosa in different parts of the digestive tract reflect their specialized functions in digestion, absorption, and protection.
Other layers
1• Submucosa
- Connective tissue, allowing tract to distend and be elastic
- Contains larger blood and lymph vessels, sends branches to mucosa and muscularis externa
- Contains submucosa nerve plexus
2• Muscularis externa
- Major smooth muscle, usually two layers
• Inner circular layer
• Outer longitudinal layer
- Responsible for mixing and propulsive movements
- Myenteric nerve plexus lies between two layers
3• Serosa
- Outermost layer, connective tissue
- Secretes serous fluid which lubricates and prevents friction between tract and surrounding tissues and organs
ー
Continuous with the mesentery - suspends digestive organs from inner wall of abdominal cavity like sling
Regulation of digestive function?
How do we control secretion?
1-Autonomic smooth muscle function
2-Intrinsic nerve plexuses
3-Extrinsic nerves
4-Gastrointestinal hormones
Autonomic smooth muscle function?
Self induced electrical activity in digestive smooth muscle prominently slow wave potential basic electrical rhythm
Intrinsic cells of Cajal:
Pace maker cells that instigate cyclic slow wave activity
Located between circular and longitudinal muscle allow whole sheet of smooth muscle cells to contract together when threshold reached.
Reaching threshold to induce contraction depends on mechanical, neural and hormonal factors eg food present or absent.
Rate of contraction varies eg peristalsis in the stomach vs segmentation in small intestine compared to haustral contractions in large intestine.
Intensity of contraction depends on number of action potentials once slow wave potential threshold reached (depends on Ca2+)
Intrinsic nerve plexuses
Submucosa & myenteric nerve plexuses
Enteric nervous system- entirely and throughout digestive tract wall-100million neurons.
Primarily coordinate local activity in tract
Various types of neurons
Input neurons:
Input neurons sensory respond to local stimuli
Excitatory and inhibitory output neurons modules motility or secretion of hormones or enzymes
Acetylcholine promotes smooth muscle contraction.
Nitric oxide and vasoactive intestinal peptide act together to relax smooth muscle.
The submucosa and myenteric nerve plexuses play essential roles in coordinating the functions of the digestive tract through the enteric nervous system, which consists of 100 million neurons distributed throughout the digestive tract wall. Here is an overview of their functions and the types of neurons involved:
- Submucosa:
- The submucosa is a layer of connective tissue located beneath the mucosa in the digestive tract wall. It contains blood vessels, lymphatic vessels, and nerves that supply the mucosa. The submucosa helps in nutrient absorption and provides structural support to the mucosa.
- Myenteric Nerve Plexus (Auerbach’s Plexus):
- The myenteric nerve plexus is a network of nerve fibers and ganglia located between the circular and longitudinal muscle layers of the muscularis externa. It is part of the enteric nervous system and primarily coordinates local activities in the digestive tract, including motility and secretion.
Enteric Nervous System:
- The enteric nervous system is a complex network of neurons that are entirely contained within the walls of the digestive tract. It consists of approximately 100 million neurons that regulate gastrointestinal functions independently of the central nervous system.
Types of Neurons in the Enteric Nervous System:
1. Input Neurons:
- Sensory neurons that respond to local stimuli in the digestive tract, such as the presence of food or changes in pH. They transmit this information to the enteric nervous system for processing.
- Excitatory and Inhibitory Output Neurons:
- These neurons modulate motility and the secretion of hormones or enzymes in the digestive tract. Excitatory neurons stimulate muscle contractions, while inhibitory neurons relax the muscles.
1-Acetylcholine:
- Acetylcholine is a neurotransmitter that plays a key role in promoting smooth muscle contractions in the digestive tract. It is released by neurons in the enteric nervous system to regulate motility and other digestive functions.
2-Nitric oxide and vasoactive intestinal peptide (VIP) are two important neurotransmitters that act synergistically to relax smooth muscle in the digestive tract. Here’s how they work together to promote smooth muscle relaxation:
Nitric Oxide (NO):
- Nitric oxide is a key neurotransmitter released by neurons in the enteric nervous system. It plays a crucial role in regulating smooth muscle tone in the gastrointestinal tract.
- Nitric oxide acts by stimulating the production of cyclic guanosine monophosphate (cGMP) in smooth muscle cells, leading to muscle relaxation.
- The relaxation of smooth muscle mediated by nitric oxide helps to promote the movement of food and substances through the digestive tract.
- Vasoactive Intestinal Peptide (VIP):
- Vasoactive intestinal peptide is another neurotransmitter released by enteric neurons that plays a role in regulating gastrointestinal motility and secretion.
- VIP acts by binding to specific receptors on smooth muscle cells, leading to the activation of intracellular signaling pathways that promote muscle relaxation.
- VIP also stimulates the release of nitric oxide, further enhancing the relaxation of smooth muscle in the digestive tract.
Synergistic Action:
- Nitric oxide and VIP often act together synergistically to produce a more potent relaxation effect on smooth muscle in the digestive tract.
- The combined action of nitric oxide and VIP helps to coordinate smooth muscle relaxation, facilitating the movement of food through the gastrointestinal tract and promoting proper digestion and absorption.
By working together, nitric oxide and vasoactive intestinal peptide play key roles in regulating smooth muscle function in the digestive tract, contributing to the overall coordination of gastrointestinal motility and function.
Overall, the submucosa, myenteric nerve plexus, and the enteric nervous system work together to regulate the local activities of the digestive tract, ensuring proper digestion, absorption, and movement of food along the gastrointestinal tract.
Extrinsic nerves
Extrinsic Nerves
• Sympathetic and parasympathetic nerves influence motility and secretion by modifying activity of intrinsic nerve plexuses
- altering secretion of Gl hormones
- directly acting on smooth muscle and glands
• Sympathetic slows digestion
• Parasympathetic (vagus nerve)
Colon
Increases smooth muscle motility
Promote Gl hormone and enzyme secretion
Vagus nerve branches of the vagus nerve is connected to all parts of the gut. It is important in stimulating motility and secretion. Tells stomach to produce acid.
• Coordinates activity between different regions of tract, eg chewing causes increased salivary, stomach, pancreatic and liver secretion via vagal reflexes in anticipation of food arrival.
What receptors trigger nerves in the gut?
3 types of sensory receptors that sense chemical and food.
1- chemoreceptors
2- mechanoreceptors
3- osmoreceptors
Stimulation results in neural reflexes or secretion of hormones which alter activity of effector cells (smooth muscle cells, exocrine, and endocrine glands cells)
Also receptors on effector cells that are directly stimulated by GI hormones, neurotransmitters and local chemical mediators.
AI:
Chemoreceptors, mechanoreceptors, and osmoreceptors are three types of sensory receptors that play crucial roles in sensing chemical and food stimuli in the gastrointestinal (GI) tract. These receptors are involved in initiating neural reflexes or triggering hormonal responses that ultimately alter the activity of effector cells, such as smooth muscle cells, exocrine glands, and endocrine glands cells. Additionally, effector cells possess receptors that directly respond to GI hormones, neurotransmitters, and local chemical mediators. Here’s a brief overview of each type of sensory receptor and their functions in the GI tract:
- Chemoreceptors:
- Chemoreceptors are sensory receptors that respond to chemical stimuli, such as the presence of specific nutrients, pH changes, or other chemical signals in the GI tract.
- Stimulation of chemoreceptors can trigger neural reflexes or the secretion of hormones that regulate GI functions, such as motility, secretion, and absorption.
- Chemoreceptors play a key role in detecting and responding to different types of nutrients and signaling molecules present in the digestive system.
- Mechanoreceptors:
- Mechanoreceptors are sensory receptors that respond to mechanical stimuli, such as stretching, pressure, or movement in the GI tract.
- Activation of mechanoreceptors by physical stimuli can lead to the initiation of neural reflexes that control processes like peristalsis, sphincter function, and sensory feedback.
- Mechanoreceptors help in detecting changes in the mechanical environment of the GI tract and coordinating appropriate responses to maintain optimal digestive function.
- Osmoreceptors:
- Osmoreceptors are sensory receptors that detect changes in osmotic pressure or the concentration of solutes in the GI tract.
- Stimulation of osmoreceptors can trigger neural reflexes or hormonal responses that regulate fluid balance, electrolyte levels, and osmotic pressure in the digestive system.
- Osmoreceptors are essential for maintaining proper hydration levels and osmotic balance within the GI tract.
Effector Cell Receptors:
- Effector cells in the GI tract possess receptors that directly respond to GI hormones, neurotransmitters, and local chemical mediators released in the digestive system.
- These receptors play a crucial role in mediating the effects of signaling molecules on effector cells, regulating functions such as smooth muscle contraction, glandular secretion, and hormone release.
Overall, chemoreceptors, mechanoreceptors, osmoreceptors, and effector cell receptors work together to sense and respond to chemical and food stimuli in the GI tract, coordinating a range of physiological processes essential for proper digestion, absorption, and gastrointestinal function.
What role do gastrointestinal hormones play?
Gastrointestinal Hormones
• Endocrine gland cells in mucosa of specific regions of tract release hormones into blood upon stimulation
• Transported to other parts of digestive tract where stimulate or inhibit other exocrine gland cells or smooth muscle
Cholecystokinin
Gall bladder contraction
Gastrointestinal motility
Pancreatic exocrine secretion
Secretin
Pancreatic exocrine secretion
GIP
Incretin activity
Motilin
Gastrointestinal motility
• Many are also released from brain neurons and are neurotransmitters or neuromodulators
Ghrelin
Hunger
Growth hormone release
Gastrin
Acid secretion
Insulin and glucagon
Glucose homeostasis
Pancreatic polypeptide
Gastric motility
Satiation
Amylin
Glucose homeostasis
Gastric motility
GLP-1
Incretin activity
Satiation
GLP-2
Gastrointestinal motility and growth
Oxyntomodulin
Satiation
Acid secretion
PYY 3.36
Satiation
AI:
Gastrointestinal Hormones
• Endocrine gland cells in mucosa of specific regions of tract release hormones into blood upon stimulation
• Transported to other parts of digestive tract where stimulate or inhibit other exocrine gland cells or smooth muscle
Cholecystokinin
Gall bladder contraction
Gastrointestinal motility
Pancreatic exocrine secretion
Secretin
Pancreatic exocrine secretion
GIP
Incretin activity
Motilin
Gastrointestinal motility
• Many are also released from brain neurons and are neurotransmitters or neuromodulators
Ghrelin
Hunger
Growth hormone release
Gastrin
Acid secretion
Insulin and glucagon
Glucose homeostasis
Pancreatic polypeptide
Gastric motility
Satiation
Amylin
Glucose homeostasis
Gastric motility
GLP-1
Incretin activity
Satiation
GLP-2
Gastrointestinal motility and growth
Oxyntomodulin
Satiation
Acid secretion
PYY 3.36
Satiation
Summary of GIT: summary
Regulation in the GIT: Summary
[ENS]
Long reflex
•Myenteric plexus
Short reflex
Stretch receptors, chemoreceptors
Peristalsis and segmentation movements
Buffers, acids, enzymes released
(3)
Secretory cells
LOCAL FACTORS pH, physical stimulation, chemical stimulation
Emanate.
Via circulation
Enteroendocrine cells
2
Hormones released
In the gastrointestinal tract (GIT), regulation of various digestive processes involves a complex interplay of neural and hormonal mechanisms. Here is a summary of the key regulatory mechanisms in the GIT:
- Long Reflex:
- Involves the myenteric plexus, a network of nerve fibers in the muscular wall of the GIT.
- Regulates and coordinates peristalsis and segmentation movements along the digestive tract.
- Short Reflex:
- Triggered by stretch receptors and chemoreceptors in the GIT.
- Controls local responses such as the release of buffers, acids, and enzymes in response to physical or chemical stimulation.
- Secretory Cells:
- Release digestive enzymes, acids, and other substances in response to local factors such as pH changes, physical stimulation, and chemical stimuli.
- Circulatory System:
- Local factors emanate and are transported via circulation to affect distant parts of the GIT.
- Enteroendocrine Cells:
- Specialized cells located in the lining of the GIT.
- Release hormones into the bloodstream in response to various stimuli.
Overall, the regulation of gastrointestinal functions involves intricate interactions between neural reflexes, local factors, secretory cells, and enteroendocrine cells. These mechanisms ensure the proper coordination of digestive processes, including motility, secretion, and absorption, to maintain the optimal function and health of the gastrointestinal system.
Upper gastrointestinal system physiology
Mouth (oral cavity)
1-Lips form opening, help procure, guide and contain food in the mouth. Important in speech. Well developed tactile sensation.
2-Palate
Forms roof of oral cavity separates nasal cavity from mouth
Separates mouth from nasal passages
Uvula blocks airways (seals off nasal passages during swallowing)
3-Tongue forms floor of oral cavity, composed of skeletal muscle. Movements aid in chewing and swallowing, plays an important role in speech and it has 10,000 taste buds.
4- Pharynx is a cavity at rear throat, common passage way for digestive and respiratory systems
Tonsils: within side walls of pharynx, lymphoid tissue.
5- teeth responsible for chewing mastication and is the first step in digestive process.
Secretion in the mouth
Saliva
1-2L/day produced largely by 3 major pairs of salivary glands; parotid, sublingual and submandibular gland.
Basal 0.5ml/min stimulated by constant low level PNS
Max 5ml/min eg sucking on a lemon
Composition: very aqueous
*99.5% H2O
*0.5% electrolyses and proteins (amylase, mucus and lysozymes)
Some drugs cause dry mouth like diuretics.
Functions of Saliva?
1-Digestion of carbohydrates by salivary amylase.
2-Swallowing facilities by moistening food
3-Lubrication provided by mucus
4-Antibacterial action: lysozymes destroy bacteria and saliva rinses away material that could serve as food source for bacteria
5-Solvent for molecules that stimulate taste buds
6-Aids speech by facilitating movements if lips and tongue
7-Helps keep mouth and teeth clean
8-Rich in bicarbonate buffers
Control of salivary secretions?
Two types of control:
Simple reflex via pressure or chemoreceptors in the mouth pick up food and send a reflex to salivary centre in the medulla of the brain. This stimulates autonomic nervous systems to secrete saliva.
Conditioned reflex: complex reflex via sight or smell of food triggers cerebral cortex then salivary centre in the medulla then autonomic nerves —> salivary glands and increase salivary secretion.
Pharynx and oesophagus
Swallowing: moves food from mouth through pharynx into stomach.
Sequentially programmed all or none reflex can’t be stopped once initiated
Initiated when bolus is voluntarily forced by tongue to rear of mouth into pharynx.
Swallowing is complex reflex in the body consists of two phases
Oropharyngeal 1seconds
Oesophageal 5-9 seconds
In pharynx, bolus prevented from re-entering mouth or re-entering nasal passage or trachea
Swallowing centre briefly inhibits respiratory centre during swallowing.
Oesophagus role?
Fairly straight muscular tube, extends between pharynx and stomach.
Sphincters at each end; pharynogoesophageal sphincter
Gastroesophageal sphincter
Perstaltic waves push food through oesophagus
Swallowing centre controls progressions of wave
Secretions of mucus are entirely protective.
Stomach role?
J shaped sac like chamber between esophagus and small intestine
Stomach consists of 3 parts:
Fundus, body and antrum.
3 main functions:
1-Stores ingested food until it can be emptied into small intestine.
2-Secretes HCl and enzymes that begin protein digestion.
3- Mixing movements convert pulverised food to chyme.
Pyloric sphincter barrier between stomach and upper part of the small intestine.
Pyloric gland area thicker muscle bigger peristaltic movement pushes food towards pyloric sphincter but it won’t allow chyme in unless it is ready
What are the 4 aspects of gastric motility?
Filling, storage, mixing and emptying.
1-Filling: involves receptive relaxation, enhances stomach ability to accommodate the extra volume of food with little rise in stomach pressure. Triggered by act of eating and mediated by vagus nerve.
2-Storage: takes place in body of stomach.
3-mixing: takes place in the antrum of stomach
4-emptying largely controlled by factors in the duodenum.
What factors affect gastric emptying?
1-Factors in the stomach:
Amount of chyme in the stomach is main factor that influences strength of contraction
2-Factors in duodenum:
Fat digestion and absorption takes place only within small intestine, when fat is already in duodenum, further gastric emptying of additional fatty stomach content id prevented.
Acid:
In-neutralised acid in duodenum inhibits further emptying of acidic gastric contents until neutralisation can be accomplished
Hypertonicity:
Gastric emptying is reflexly inhibited when similarity of duodenal contents start to rise.
Distension:
Too much chyme in duodenum inhibits emptying of even more gastric contents.
Mechanism of gastric emptying?
1-Neural response:
Mediated through both intrinsic nerve plexuses short reflex and autonomic nerves long reflex. This is ENTEROGASTRIC Reflex.
2-Hormonal response:
Involves release of hormones from duodenal mucosa. This is ENTROGASTRONES, inhibit gastric emptying.
Secretin (produced by S cell)
Cholecystokinin (CCK produced by I cells)
Additional factors that influence gastric motility
Emotions:
Sadness fear tend to increase motility
Anger and aggression tend to increase motility
Intense pain tends to inhibit motility.
What parts of gastric mucosa releases gastric juices?
Two distinct areas of gastric mucosa that secrete gastric juices:
Oxyntic mucosa:
*Lines the body and fundus
Pyloric gland area
*Lines the antrum
Gastric pits at base of gastric glands
There are 3 types of gastric exocrine secretory cells
1-Mucus cells lines gastric pits and entrance of glands
Secrete thin watery mucus
2-Chief cells secrete enzyme precursor pepsinogen
3-Parietal oxyntic cells
Secrete HCl and intrinsic factor for vitB absorption in terminal ileum if we don’t have intrinsic factor we get anaemia.
Gastrointestinal secretion
Gastrointestinal secretions play a crucial role in the digestion and absorption of nutrients. Here are some key components involved in the process:
- Oxyntic Mucosa: This is the lining of the gastric glands in the stomach. It contains various types of cells that secrete different substances.
- Gastric Pit: These are small depressions in the surface of the stomach lining that lead to the gastric glands. They help in the secretion and release of gastric juices.
- Stomach Lumen: This is the inside space of the stomach where food and gastric secretions mix together for digestion.
- Surface Epithelial Cells: These cells line the surface of the stomach and secrete mucus, which forms a protective barrier against the acidic environment of the stomach.
- Mucous Cells: These specialized cells in the stomach lining secrete mucus, which helps lubricate and protect the stomach lining from the acidic gastric juices.
- Chief Cells: These cells secrete pepsinogen, an inactive form of the enzyme pepsin. Pepsinogen is activated by the acidic environment of the stomach and helps in the breakdown of proteins.
- Parietal Cells: These cells secrete hydrochloric acid (HCl) and intrinsic factor. HCl helps in the digestion of proteins and activates pepsinogen to pepsin. Intrinsic factor is necessary for the absorption of vitamin B12.
- Enterochromaffin Cells: These cells produce and release various hormones, such as serotonin, that regulate gastrointestinal functions.
- G Cells: These cells secrete the hormone gastrin, which stimulates the secretion of gastric acid and promotes gastric motility.
- D Cells: These cells secrete the hormone somatostatin, which inhibits the release of gastric acid and other gastrointestinal secretions.
These various secretions work together to create an optimal environment for digestion and absorption of nutrients in the gastrointestinal system.
Role of HCl?
• Functions of HCI
- Activates pepsinogen to active enzyme pepsin and provides acid medium for optimal pepsin activity
- Aids in breakdown of connective tissue and muscle fibers
- Denatures protein by uncoiling
Chief cell - Along with salivary lysozyme, kills most of the microorganisms ingested with food
Why is the gastric mucosal barrier important?
Enables stomach to contain acid without injuring itself.
The components of the gastric mucosal barrier enable the stomach to contain acid without injuring itself:
1-The luminal membranes of the gastric mucosal cells are impermeable to H* so that HCI cannot penetrate into the cells.
2-The cells are joined by tight junctions that prevent HCI from penetrating between them.
3- A mucus coating over the gastric mucosa serves as a physical barrier to acid penetration.
3-The HCO3, rich mucus also serves as a chemical barrier that neutralizes acid in the vicinity of the mucosa. Even when luminal pH is 2, the mucus pH is 7.
Gastric juice content?
Pepsinogen
- Stored in zymogen granules of chief cells
- HCI in stomach converts it to pepsin, which is autocatalytic
-Acts optimally in acid, breaking specific peptide bonds
• Mucus
- Protects mucosa against mechanical injury
- Protects stomach wall from digestion by pepsin
- Alkaline, neutralising HCI in vicinity of gastric lining
• Intrinsic factor
- Secreted by parietal cells
- Essential for vit-B12 absorption, allows binding to receptor in terminal ileum and absorption by receptor-mediated endocytosis
How does the endocrine system regulate gastric secretions?
Endocrine/Paracrine Cells
1-Enterochromaffin-
like (ECL) cells
Histamine ACh gastrin stimulates parietal cells
2-G cells Gastrin Protein products,ACh stimulates parietal chief cells and ECL cells.
3-D cells
Somatostatin
Acid inhibits parietal G and ECL cells
Phases of gastric secretion
• Cephalic phase
Increased secretion of HCl and pepsinogen that occurs in response to stimuli acting in the head before food reaches stomach
• Gastric phase
- Begins when food actually reaches the stomach
- Presence of protein increases gastric secretions
- Presence of caffeine or alcohol
• Intestinal phase
- Inhibitory phase - acid, fat, hypertonicity, distension
- Helps shut off flow of gastric juices as chyme begins to empty into small intestine
Lower GI physiology
Role of pancreas
Pancreas has an exocrine and endocrine function, it’s located behind and below the stomach.
Endocrine function
Islets of langerhans
Found throughout pancreas
Secrete insulin and glucagon
Exocrine function
Secreted pancreatic juices containing:
Pancreatic enzymes actively secreted by acinar cells that form the acini
Aqueous alkaline solution actively secreted by duct cells that line pancreatic ducts rich in NaHCO3 for neutralising HCl
List and state function of Pancreatic enzymes?
Exocrine secretion is regulated by hormones (entrogastrones) released by presence of chyme in duodenum
Secretin stimulates NaHCO3 secretion from pancreatic duct cells
CCK stimulates enzymes from acinar cells
Proteolytic enzymes
Digest proteins
Trypsinogen converted to active form trypsin by enterokinase
Chymotrypsinogen converted to active form chymotrypsin
Procarboxypepridase converted to active form carboxypeptidase
Pancreatic amylase:
Converts polysaccharides into disaccharides amylase
Pancreatic lipase
Only enzyme secreted throughout entire digestive system can digest fat.
Hormonal control of pancreatic secretions
Once acid gets into duodenal lumen it stimulates secretin release from duodenal mucosa.
Secretin is carried by the blood to pancreatic duct cells, this stimulates secretion of aqueous NaHCO3 solution into duodenal lumen. This neutralise the acid.
Fat and protein products in the duodenal lumen stimulate CCK release from duodenal mucosa, CCK is carried by blood to pancreatic acinar cells. This increases secretion of pancreatic digestive enzymes into duodenal lumen. This starts the digestion of fat and protein.
Hormones control pancreas secretions
Summary:
• Gastric endocrine glands
- Gastrin, released by protein presence and Ach from G cells, stimulates HI and pepsinogen
- Somatostatin, released from D cells, inhibits HCI, pepsinogen and gastrin
• Duodenal endocrine glands
- Secretin, released by presence of HCI, stimulates
NaHCO, secretion
- CCK, released by presence of fat and protein, stimulates pancreatic enzyme release
Role of liver?
Main role of liver is digestion of fats, largest metabolic organ in the body. Body’s major biochemical factory and liver is important to digestion as it secreted bile salts. Has two sources of blood hepatic artery brings oxygenated blood and nutrient and hepatic portal vein brings in nutrient from gut and hepatic vein takes away CO2 away from liver to be excreted.
Liver functions not related to digestion
- Metabolic processing of the carbohydrates, proteins and lipids after absorption
Detoxifying or degrading body wastes and hormones, drugs, and other foreign compounds
- Synthesizes plasma proteins
- Stores glycogen, fats, iron, copper, and many vitamins
- Activates vitamin D (along with kidneys)
- Removes bacteria and worn-out red blood cells
- Produces acute phase proteins and hormones, eg hepcidin, thrombopoietin and IGF-1
Excretes cholesterol and bilirubin
The liver plays a vital role in digestion by performing several important functions:
- Bile Production: The liver produces bile, a greenish-yellow fluid that helps in the digestion and absorption of fats. Bile is stored in the gallbladder and released into the small intestine when needed. Bile contains bile salts that aid in the emulsification of fats, making them easier to break down by enzymes.
- Detoxification: The liver is responsible for detoxifying harmful substances in the body, including drugs, alcohol, and metabolic waste products. It processes and eliminates these toxins, preventing them from entering the bloodstream and affecting other organs.
- Nutrient Processing: The liver processes and metabolizes nutrients absorbed from the intestines. It converts carbohydrates, fats, and proteins into forms that can be used by the body for energy or for storage. The liver also stores certain vitamins and minerals, such as vitamins A, D, E, K, and B12, iron, and copper.
- Protein Synthesis: The liver synthesizes various proteins essential for the body’s functioning. It produces blood clotting factors, albumin (a protein that helps maintain osmotic balance), and many other proteins involved in immune function and hormone regulation.
- Storage and Release of Glucose: The liver maintains blood glucose levels by storing excess glucose as glycogen and releasing it when needed. This helps regulate blood sugar levels, ensuring a steady supply of energy for the body.
- Production of Cholesterol: The liver synthesizes cholesterol, an essential component of cell membranes and a precursor for the production of certain hormones and bile acids.
- Metabolism of Drugs and Hormones: The liver metabolizes drugs and hormones, altering their chemical structure to make them more easily excreted by the body. This process helps regulate the levels of hormones in the bloodstream and eliminates drugs from the system.
Overall, the liver plays a multifunctional role in digestion, nutrient processing, detoxification, and metabolism, making it an indispensable organ for maintaining the body’s overall health and well-being.
Role of bile?
Actively secreted by liver and actively diverted to gallbladder between meals
- Stored & concentrated in gallbladder
- Aqueous alkaline fluid containing. Involved in emulsification of fats
• Bile salts
• Cholesterol
• Lecithin
• Bilirubin is also antioxidants - After meal, bile from gallbladder enters duodenum
Gall bladder diseases gall stone calcification of stones which prevents gall bladder from releasing bile causes severe acute pain which causes lipid malabsorption.
Bile salt function?
Derivatives of cholesterol
Converts large fat globules into a lipid emulsion forms Micelle has hydrophobic core and hydrophilic shell helps in breaking fat down as this allows lipase to enter and break down fat.
After participation in fat digestion and absorption most are reabsorbed into the blood.
Small intestine role?
It is the site where most digestion and absorption occurs
Consists of 3 segments
Duodenum
Jejunum
Ileum
Motility includes two parts
Segmentation
Migrating motility complex
Small intestine is 15ft long, the mesentery holds together in the GI abdominal cavity and mesentery keeps it apart as it is part of the serosa which secretes mucus fluid to keep it form sticking together and if intestine gets stuck we get issues like hernia and damage like blood clot ischemia.
Structure increases surface area of intestine because the finger like projection folds the villi and microvilli on the epithelial cells of the surface of intestine.
Segmentation:
Primary method of motility in small intestine
Consists of ring like contractions along length of small intestine
Within seconds contracted segments relax and previously relaxed areas contract
Action mixed and propels chyme throughout small intestine lumen till it reaches the ileum and large intestine.
Small intestine segmentation and migrating motility
Segmentation: is primary method of motility in small intestine
Initiated by pacemaker cells in the small intestine which produces basic electrical rhythm BER
Circular smooth muscle responsiveness is influenced by distension of intestine, gastrin and extrinsic nerve activity
Functions:
Mixing chyme with digestive juices secreted into the small intestine lumen
Exposing all chyme to absorptive surfaces of small intestine mucosa
Migrating motility complex
Sweeps intestines clean between meals
Small Intestine secretion , digestion and absorption?
Secretion juices secreted by small intestine doesn’t contain any digestive enzymes
Synthesised enzymes act within brush border membrane of epithelial cells
Enterokinase
Disaccharidases
Aminopeptidases
Digestion:
Pancreatic enzymes continue carbohydrates and protein digestion.
Brush boarder enzymes complete digestion of carbohydrates and proteins.
Fat is entirely digested within small intestine lumen by pancreatic lipase.
Absorption:
Absorbs almost everything presented to it 9L/day
Most of the absorptions occur in the duodenum and Jejunum.
Adaptions that increase small intestine surface area: inner surface has permanent circular folds
Microscopic finger like projections called villi
Brush broader microvilli arise from liminal surface of epithelial cells
Lining is replaced about every three days wear and tear
Products of fat digestion undergo transformations that enable them to be passively absorbed and eventually enter lymph
Carbohydrate absorption?
Dietary carbohydrates starch glycogen
Broken down by salivary amylase and pancreatic amylase by disaccharidases maltase lactase and sucrase into glucose, the monosaccharides enter cell by passive facilitated diffusion via GLUT-5 then enters the blood by simple diffusion to where its needed in the body
SLGT symporter absorb Glucose, galactose, and fructose into epithelial cell by Na+ and active transport. The monosaccharides fructose enters the cell by passive facilitated diffusion via GLUT-5
Glucose, galactose and fructose exist exist cell at the basal membrane by passive facilitated diffusion via GLUT-2
These monosaccharides enter the blood by simple diffusion
Fat absorption?
Fat is broken down in the duodenum and it is emulsified via bile salts that is released by gall bladder then pancreatic lipase can hydrolyse the fat micelle droplets into monoglycerides and free fatty acids. They get absorbed into epithelial cell and reaggregate to form triglycerides that aggregate and coated with lipoprotein to form chylomicrons that transport lipids around the body. These passively diffuse through lipid bolster of the liminal membranes.
Protein absorption
Dietary protein is broken down by pepsin and pancreatic proteolytic enzymes into small peptides and amino acids.
1-Dietary and endogenous proteins are hydrolyzed into their constituent amino acids and a lew small peptide fragments by gastric pepsin and the pancreatic proteclytic enzymes
2-Many small peptides are converted into their respective amino acids by the aminoceptidases located in the brush borders of the small-intestine epithelial cells.
3-Amino acids are absorbed into the epithelial cells by means of Na and energy-dependent secondary active transport via a symporter
Various amino acids are transported by carers specific for them
4-Some small peptides are absorbed by a different type of symportor driven by H, Na-, and energy-dependent tertiary active transport
5-Most absorbed small peptides are broken down into their amino acids by intracellular peptidases
6-Amino acids ext the call at the basal membrane via various passive carriers
7-Amino acids enter the bicod by simple diffusion. (A small percentage of di- and tripeptides also enter the blood intact)
Large intestine
Primarily a drying and storage organ
Consists of colon, cecum, appendix, rectum
Chyme from small intestine consists of indigestible food residues unabasorbed biliary components and remaining fluids.
Colon:
Extracts more water and salts from contents
Feces what remains to be eliminated
Large intestine has mucosa submucosa and circular muscle but it has three strings of longitudinal muscle called taeniae coli, can contract and relax the haustra.
Haustra pouches or sacs, actively change location as result of contraction of circular smooth muscle layer.
Haustral contractions
Main motility, initiated by autonomous rhythmicity of colonic smooth muscle cells.
Mass movements via large contraction that moves colonic contents into distal part of large intestine.
Gastrocolic reflex:
Mediated from stomach to colon by gastrin and by autonomic nerves.
Most evident after first meal of the day
Often followed by urge to defecate.
Defecation reflex:
Initiated when stretch receptors in rectal wall are stimulated by distension. This causes internal anal sphincter to relax abs rectum and sigmoid colon to contract more vigorously. If external anal sphincter (skeletal muscle under voluntary control is relaxed, defecations occurs.
Large intestine
Secretion:
Alkaline mucus protects and lubricates helps feces movement
Digestion:
No digestion occurs as no digestive enzymes exist in the large intestine but large intestine has colonic micro flora >500 species that can digest cellulose to short fatty acids
Absorption:
Salt and water
Vitamin K synthesised by bacteria
Excretion:
Approx 2/3 water
Undigested cellulose, bilirubin, bacteria and salt.
Gut microbe role
Gut microbe has different roles:
1-modulation of bone mass density
2-protection against epithelial injury
3-resistance to pathogens
4-breaking down food compounds
5-modification of the nervous system
6-metabolism of therapeutics
7-biosynthesis of vitamins and amino acids
8-Development and training of the immune system
9-promotion if angiogenesis
10- promotion of fat storage
Gastrointestinal hormones:
Gastrin
Gastrin release is stimulated by presence of proteins in the stomach.
Secretion is inhibited by accumulation of acid in the stomach.
Functions:
Acts in several ways to increase secretion of HCl and pepsinogen
Enhances gastric motility, stimulates ileal motility, relaxes ileocecal sphincter, induced mass movements in the colon.
Helps maintain well-developed, functionally viable digestive tract lining.
Secretin
Secretin release is stimulated by the presence of acid in the duodenum.
Functions:
Inhibits gastric emptying in order to prevent further acid from entering duodenum until acid is neutralised
Inhibits gastric secretion to reduce amount of acid being produced.
Stimulates pancreatic duct cells to produce large volumes of aqueous NaHCO3 secretion.
Stimulates liver to secrete NaCO3 rich bile which assist in neutralisation process.
Along with CCK, is trophic to exocrine pancreas
CCK
Functions
Inhibits gastric motility and secretion
Stimulates pancreatic acinar cells to increase secretion of pancreatic enzymes.
CCK causes contractions of the gallbladder and relaxation of sphincter of Oddi
Along with secretin is trophic to exocrine pancreas
Implicates in long term adaptive changes in the proportion of pancreatic enzymes in response to prolonged diet changes
Important regulator of food intake.
GIP
Glucose dependent insulin trophic peptide
Stimulates insulin release by pancreas
Stimulated by presences of glucose in the digestive tract.
GIP is a hormone that stimulates the release of insulin by the pancreas. It is primarily stimulated by the presence of glucose in the digestive tract. GIP helps regulate blood sugar levels by promoting the release of insulin, which facilitates the uptake and utilization of glucose by cells in the body.
Upper gastrointestinal conditions
Epidemiology
Pathophysiology
Aetiology
Treatment of common upper GI conditions
Define gastro-oesophageal reflux disease, peptic ulcer disease, gastritis and functional dyspepsia
Lost alarm symptoms requiring referral
Provide appropriate pharmaceutical and non-pharmaceutical advice for the management of common dyspeptic diseases
Why do upper GI conditions occur
Occur due to Acid overproduction, faults with protective mechanisms (sphincters), dyspepsia and acid in the wrong location in oesophagus or duodenum.
Symptoms: gastric reflex, heart burn, dyspepsia, abdominal pain, nausea and vomiting, wind.
Treatment:
Prevent acid from relocating, reduce acid production or neutralise it or remove the main cause.
List common upper GI conditions? And reason why they occur?
Gastric-oesophageal reflux disease GORD 10-20%
Duodenal and stomach ulcer disease PUD 10-25%
Gastritis 30%
Functional dyspepsia 30%
Oesophageal and gastric cancer 2%
Upper gastrointestinal (GI) conditions occur in the upper part of the digestive system, which includes the esophagus, stomach, and the first part of the small intestine (duodenum). These conditions can occur due to various reasons, including:
- Gastroesophageal Reflux Disease (GERD): This occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back into the esophagus. Common symptoms include heartburn, chest pain, and difficulty swallowing.
- Peptic Ulcers: These are open sores that develop on the lining of the stomach or the first part of the small intestine. They are often caused by a bacterial infection (Helicobacter pylori) or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Symptoms may include abdominal pain, bloating, and nausea.
- Gastritis: This is inflammation of the stomach lining, which can be caused by infection, excessive alcohol consumption, prolonged use of NSAIDs, or certain autoimmune disorders. Symptoms may include stomach pain, nausea, vomiting, and loss of appetite.
- Hiatal Hernia: This occurs when a part of the stomach pushes up through the diaphragm into the chest cavity. It can cause symptoms such as heartburn, chest pain, and difficulty swallowing.
- Esophagitis: This is inflammation of the esophagus, often caused by GERD, infections, or certain medications. Symptoms may include difficulty swallowing, chest pain, and heartburn.
- Barrett’s Esophagus: This is a condition in which the lining of the esophagus changes, increasing the risk of developing esophageal cancer. It is often associated with long-term GERD.
Part 2:
Upper gastrointestinal (GI) conditions occur in the upper part of the digestive system, which includes the esophagus, stomach, and the first part of the small intestine (duodenum). These conditions can occur due to various reasons, including:
- Gastroesophageal Reflux Disease (GERD): This occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back into the esophagus. Common symptoms include heartburn, chest pain, and difficulty swallowing.
- Peptic Ulcers: These are open sores that develop on the lining of the stomach or the first part of the small intestine. They are often caused by a bacterial infection (Helicobacter pylori) or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Symptoms may include abdominal pain, bloating, and nausea.
- Gastritis: This is inflammation of the stomach lining, which can be caused by infection, excessive alcohol consumption, prolonged use of NSAIDs, or certain autoimmune disorders. Symptoms may include stomach pain, nausea, vomiting, and loss of appetite.
- Hiatal Hernia: This occurs when a part of the stomach pushes up through the diaphragm into the chest cavity. It can cause symptoms such as heartburn, chest pain, and difficulty swallowing.
- Esophagitis: This is inflammation of the esophagus, often caused by GERD, infections, or certain medications. Symptoms may include difficulty swallowing, chest pain, and heartburn.
- Barrett’s Esophagus: This is a condition in which the lining of the esophagus changes, increasing the risk of developing esophageal cancer. It is often associated with long-term GERD.
Epidemiology
Prevalence varies from 20-40%, quarter of these patients have peptic ulcer disease
Majority of patients self medicate
90% self treat
9% see GP
1% see consultant
Common community pharmacy problem
Many patients self select treatment but this could mask potential serious conditions.
Pharmacist plays key role in offering support and advice to patients:
Life style changes
Use of correct OTC meds
Review prescribed medications
Advice on referral and when should patient see a doctor
Record adverse side effects of medication this is important due to risk of gastric cancer.
Gastric cancer
54% of cases are preventable
If cancer is diagnosed within 1yr patient will have 42% survival rate in comparison to late diagnosis of 5yrs which means survival rate will only be 19%
7 in 10 cases at late stage
Age and sex risk factor for gastric cancer
Mid age 40-over 55 if patients comes for the first time with dyspepsia it is an alarm symptom so refer to GP
Males at higher risk than females
More common in smokers and drinkers
Related to H.pylori infection 32%
Slat intake
Less common in vegetarians
Pathophysiology of upper GI diseases
Gastric stomach secretions
Pepsinogen from chief cells:
Breakdown proteins
Hydrochloric acid from parietal cells
Activate pepsinogen+ kills bacteria
Intrinsic factor from parietal cells
Acid absorption of vitamin B12
Gastric physiology
Acid secretions via parietal cells is controlled by:
Nervous control: Cephalic phase, parasympathetic via thoughts smell taste or sight of food
Local: Gastric phase parasympathetic
Distension of stomach and chemical make up
Hormonal: intestinal phase
Food in the duodenum chyme causes secretion of somatostatin which inhibits acid production
Basal phase occurs in times between the meals inter-digestive phase level of acid secreted is regulated by body weight, number of parietal cells genetic factor circadian rhythm.
Secretion of H+ from parietal cells is stimulated by histamine, gastrin and acetylcholine ACh
Gastrin is produced in response to vagal stimuli, rise in pH and ingested protein and calcium
Stimulates growth of gastric mucosa
Within parietal cell H+ is produced via the proton pump, exchanges H+ with K+ in the gastric lumen.
AI:
The production of acid in parietal cells of the stomach involves a complex biochemical and physiological process. Here is an overview of the steps involved:
- Stimulation: Acid production in parietal cells is stimulated by various factors, including the release of the hormone gastrin, which is triggered by the presence of food in the stomach. Gastrin binds to specific receptors on the surface of parietal cells, activating a signaling cascade that leads to acid production.
- Carbon Dioxide and Water Formation: Inside the parietal cell, carbon dioxide (CO2) and water (H2O) combine to form carbonic acid (H2CO3) with the help of an enzyme called carbonic anhydrase. This reaction occurs in the cytoplasm of the parietal cell.
- Proton Pump Activation: Carbonic acid in the cytoplasm dissociates into bicarbonate ions (HCO3-) and hydrogen ions (H+). The bicarbonate ions are transported out of the cell in exchange for chloride ions (Cl-), which enter the cell. This exchange is facilitated by a protein called the chloride-bicarbonate exchanger.
- Acid Secretion: The hydrogen ions (H+) generated within the parietal cell are actively transported across the membrane into the stomach lumen by an ATP-dependent proton pump called the H+/K+ ATPase. This pump exchanges the hydrogen ions with potassium ions (K+), which are taken up from the lumen into the parietal cell.
- Acidification of the Stomach Lumen: The hydrogen ions that are pumped into the stomach lumen combine with chloride ions (Cl-) that passively diffuse into the lumen from the parietal cell. This combination forms hydrochloric acid (HCl), which is the main component of stomach acid.
The overall process of acid production in parietal cells is tightly regulated to maintain the appropriate pH in the stomach for efficient digestion. Various factors, including hormones, neurotransmitters, and other signaling molecules, can influence this process. Disruptions in acid production can lead to conditions such as gastric ulcers, gastritis, or gastroesophageal reflux disease (GERD).
Draw parietal cell and the chemical reaction for H+ production? How can we stop this mechanism pharmacologically
Acetylcholine act in M3
Histamine acts on H2
Gastrin acts on G cells
ATP is converted to cAMP via Ca2+ ions to form
Acid secretion can be decreased pharmacologically by blocking these receptors or blocking intracellular cAMP or blocking the proton pump inhibitor
Parietal cells are a type of stomach cell found in the gastric glands. They have a distinctive structure that includes an extensive network of tubulovesicles and mitochondria. This structure allows parietal cells to perform their specialized function of acid production.
The chemical reaction involved in H+ production within parietal cells is as follows:
CO2 + H2O → H2CO3 → H+ + HCO3-
Here’s how the reaction proceeds:
- Carbon dioxide (CO2) and water (H2O) combine in the cytoplasm of the parietal cell with the help of an enzyme called carbonic anhydrase.
- This combination forms carbonic acid (H2CO3).
- Carbonic acid then dissociates, releasing a hydrogen ion (H+) and a bicarbonate ion (HCO3-).
To pharmacologically inhibit acid secretion and decrease H+ production, several approaches can be used:
- Blocking Receptors: Certain medications, such as proton pump inhibitors (PPIs), histamine H2 receptor antagonists, or muscarinic receptor antagonists, can be used to block specific receptors on parietal cells. These receptors are involved in stimulating acid secretion, and blocking them can reduce acid production.
- Inhibiting Intracellular cAMP: Cyclic adenosine monophosphate (cAMP) is a signaling molecule involved in the activation of acid secretion. Medications that inhibit cAMP production or its downstream signaling pathways can help decrease acid production.
- Proton Pump Inhibitors (PPIs): PPIs are a commonly used class of drugs that directly target the proton pump (H+/K+ ATPase) in parietal cells. By irreversibly inhibiting this pump, PPIs can significantly reduce acid secretion and provide long-lasting acid suppression.
Summary
Parietal cells produce acid and directly stimulated by:
Vagus nerve-Acetylcholine M3 receptors, due to though sight or smell
Gastrin G receptors
Due to content of stomach
Histamine H2 receptors
Stimulation of ECL cells by gastrin and vagus nerve
Somatostatin prostaglandin
Negative feedback due to content of duodenum
Upper GI conditions
Gastric cytoprotection?
Auto-digestion of the stomach is prevented by a thin layer above the mucosa surface
Complex matrix of bicarbonate and mucus pH7 unstirred layer.
H+ taken away by sub-mucosal blood flow.
Low blood pressure or low blood perfusion causes a Decrease in blood flow lead to necrosis of mucosa by increase if of H+ conc and decrease in O2
Stress ulcer in shocked or critically ill patients
Prostaglandins COX-1 e.g. Somatostatin
Increase mucus secretion, bicarbonates, blood flow, and decrease acid.
NSAIDs especially COX-1 interfere with prostaglandin synthesis.
Patient need protective drugs like PPI if they are on long term use of NSAIDs
Oesophageal protection by lower oesophageal sphincter LOS permanent state of tonic contraction except when relaxed to allow passage of food.
Gastritis?
Extremely prevalent amongst population and can be asymptomatic and symptoms can manifest as dyspepsia
Gastritis precedes ulceration
Gastritis inflammatory response of GI mucosa to H. pylori this leads to chronic gastritis and PUD which can develop into Gastric cancer
Gastritis 40x increase risk of PUD and 6x at increased risk of gastric cancer
Helicobacter Pylori?
1-H.pylori protects themselves by hydrolysing urea to produce ammonia and this effectively buffers H+ ions.
2-Colonisation beneath the mucus layer in the antrum leads to chronic inflammation and decrease in somatostatin and increase in gastrin production which leads to increased acid production.
3- Increase in stomach acid production leads to chronic inflammation in the duodenum. H.Pylori moves into duodenum and reduces local protection which leads to duodenal ulcer.
H.Pylori causes gastritis throughout stomach and this causes cell damage and decrease in acid production and decrease in mucosa which long term lead to gastric ulcer and gastric cancer.
50% of population over 60yrs old are infected, almost all over 80
Some strains more pathogenic than others
How do we test for H.Pylori infection?
Identified breath test or stool antigen test:
*given radio labelled urea and CO2 produced in breath
*Stools need to be stored at -20C before testing stool.
With these tests patient must avoid antibiotics 4 weeks before test to avoid false negative results.
Blood test available but has poor sensitivity.
Endoscopy is not recommended for H.Pylori testing
In the UK, several clinical tests are commonly used to detect H. pylori infection. Here are three main types of tests:
- Helicobacter pylori stool antigen (HpSA) test: This test detects the presence of H. pylori antigens in a stool sample. It is a non-invasive and reliable method, especially for monitoring treatment response. The sample can be collected at home and sent to a laboratory for analysis.
- Helicobacter pylori breath test: This test measures the presence of H. pylori by analyzing the breath for the presence of specific gases produced by the bacteria. The patient consumes a special substance, usually urea, which is metabolized by H. pylori if present. Breath samples are collected at specific intervals and analyzed to determine the presence of H. pylori.
- Helicobacter pylori blood test: This test detects the presence of antibodies against H. pylori in the blood. It is a serological test that can determine if a person has been exposed to H. pylori in the past or currently has an active infection. However, it cannot distinguish between a current or past infection, so it may not be the best method for monitoring treatment response.
*Duodenal ulcer >90% H.Pylori infection
Stomach gastric Ulcer 70-80% H.pylori infection.
Eradication of infection improves healing rates and reduces relapse rates
>50% to >10% in 3 years
Eradication is a cure for H.pylori associated ulcers
What is peptic ulcer disease?
10-15% of the population will suffer from peptic ulcer disease
Gastric ulcers GU rare in under 40
Duodenal ulcers predominantly males between 20-50
*That is why it is important to ask patients for their age to determine the type of ulcer they have.
Factors:
gastric hyper-secretion genetic factor mainly
Reduced mucosal resistance-occurs mainly in smokers as smoking reduces mucosal protective secretion
DU- higher than average acid output
GU- lower mucosal resistance
Patients can be healed but not cured by suppression of acid secretion
AI:
Peptic ulcer disease (PUD) is a condition characterized by the formation of open sores, known as ulcers, in the lining of the stomach, upper small intestine, or esophagus. Peptic ulcers can occur when the protective lining of these areas is damaged, allowing stomach acid and digestive juices to irritate the underlying tissues.
The primary cause of peptic ulcer disease is an infection with the bacterium Helicobacter pylori (H. pylori). This bacterium is estimated to be responsible for about 80% of peptic ulcers. Other factors that can contribute to the development of peptic ulcers include long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin, excessive alcohol consumption, smoking, and stress.
The most common symptom of peptic ulcer disease is abdominal pain. The pain is usually described as a burning or gnawing sensation and may occur in the upper abdomen, often between meals or during the night. Other symptoms can include bloating, belching, nausea, vomiting, weight loss, and loss of appetite.
Complications of peptic ulcer disease can include bleeding, perforation (when the ulcer creates a hole in the wall of the stomach or intestine), and obstruction (when the ulcer blocks the passage of food through the digestive system). These complications can be serious and require immediate medical attention.
The diagnosis of peptic ulcer disease is typically made through a combination of medical history, physical examination, and diagnostic tests. These tests may include an upper gastrointestinal endoscopy, which allows the doctor to visualize the ulcer and take a tissue sample for biopsy, as well as tests to detect the presence of H. pylori infection.
Treatment for peptic ulcer disease usually involves a combination of medications to reduce stomach acid production, eradicate H. pylori infection (if present), and protect the lining of the stomach and intestines. Lifestyle modifications, such as avoiding NSAIDs, reducing stress, and avoiding alcohol and smoking, may also be recommended.
With appropriate treatment and lifestyle changes, most peptic ulcers heal within a few weeks to a couple of months. However, it’s important to follow the prescribed treatment plan and attend regular follow-up appointments to monitor the progress and ensure complete healing.
Prognosis?
Bleeding occurs in 10-15% of all PUD patients
5-10% of patients with duodenal ulcers will perforate. 1 in 7 of these will die.
5-10% of gastric ulcers eventually found to be malignant
60% of patients with PUD relapse after 1 year
50% of patients with GU relapse after 2 years
What are the risk factors for PUD?
H.pylori major cause of PUD
NSAIDS common cause of PUD
More common in smokers
Increase number of cigarettes in a day increases PUD prevalence
Rate of healing slower in smokers and relapse is twice as common
Genetic link with people with parents with PUD 3x more likely
Stress related to PUD?
No strong evidence
What drugs induce dyspepsia?
NSAIDs risk increased further if patient is elderly, has history of peptic ulcer disease or is a smoker.
Sulfasalazine
Iron preparations
Corticosteroids
Potassium particularly modified releases
Bisphosphonates
SSRI
Some antibiotics
These drugs predispose patients to PUD
*Theophylline
*Calcium antagonists
*Nitrates
These three drugs lower oesophageal sphincter pressure therefore predispose patients to GORD.
Drugs induced dyspepsia?
1/3 of patients with rheumatoid arthritis suffer with PUD
*ibuprofen safest NSAID
Even patients on 162.5mg aspirin a day get an increase risk of 1.5%
NSAIDs inhibit prostaglandin synthesis via COX pathway
COX-1 house keeping enzyme pathway protective prostaglandin eg GI mucosa
COX-2 inflammatory prostaglandins
Safer NSAIDs less inhibitory effect on COX-1
Celecoxib very little COX-1 activity
What are the signs and symptoms of PUD?
1-Gastric:
Pain on eating
Epigastric pain
2-Duodenal
Localised pain occurring between meals and at night
Relieved by eating (fatty food may aggravate)
Other symptoms for both:
*Bloating, nausea, anorexia, belching.
*Haematemesis and melaena present if bleeding occurs.
Summary
1-Gastritis inflammation of stomach lining caused mainly by H..Pylori
2-Gastric ulcer occur in stomach prolonged exposure to H.Pylori causes inflammation, gastric atrophy predisposes to this but also NSAIDs and their effects on reducing gastric cytoprotection implicated.
Stomach
Prolonged exposure to H.pylori causing inflammation and gastric atrophy
NSAIDs
3-Duodenal
Duodenum post stomach
Caused by genetic predisposition caused by Excessive acid secretion from stomach due to host factors h.pylori
Treatment?
GORD
5-10% of western world adults have symptomatic reflux.
Caused by gastric juice and occasionally duodenal contents in oesophagus
Defective lower oesophageal sphincter may be most important abnormality that causes GORD
Factors lowering pressure if the LOS:
Dietary factors
Fat
Chocolate
Caffeine
Alcohol
Cigarettes
Endocrine factors:
High level of oestrogen and progesterone
Pregnancy
HRT
COC contraceptives
Drugs
SSRI NSAIDs
AI:
Gastroesophageal reflux disease (GORD), also known as GERD (gastroesophageal reflux disease), is a chronic condition characterized by the reflux of gastric juice, and sometimes duodenal contents, into the esophagus. It is estimated that 5-10% of adults in the Western world experience symptomatic reflux associated with GORD.
The lower esophageal sphincter (LOS) is a muscular ring that acts as a barrier between the stomach and the esophagus. In individuals with GORD, the LOS is often defective and does not close properly, allowing the acidic stomach contents to flow back up into the esophagus. This can lead to symptoms such as heartburn, regurgitation, chest pain, and difficulty swallowing.
There are several factors that can contribute to a decrease in the pressure of the lower esophageal sphincter, making it more likely for reflux to occur. These factors include:
- Dietary factors: Certain foods can relax the LES and increase the risk of reflux. Examples include fatty foods, chocolate, caffeine (found in coffee, tea, and some sodas), alcohol, and cigarettes.
- Endocrine factors: Hormonal changes can affect the function of the LES. High levels of estrogen and progesterone, which can occur during pregnancy or when using hormone replacement therapy (HRT) or combined oral contraceptive (COC) pills, may contribute to the development or worsening of GORD symptoms.
- Drugs: Certain medications can weaken the LES or increase acid production, making reflux more likely. Examples include selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal anti-inflammatory drugs (NSAIDs).
The diagnosis of GORD is usually based on the presence of typical symptoms and response to treatment. However, in some cases, further diagnostic tests such as an upper gastrointestinal endoscopy or a pH monitoring test may be performed to assess the severity of the condition or rule out other possible causes.
Treatment for GORD aims to relieve symptoms, heal any esophageal damage, and prevent complications. Lifestyle modifications such as avoiding trigger foods, losing weight if overweight, elevating the head of the bed, and quitting smoking may be recommended. Medications such as antacids, H2 receptor antagonists, proton pump inhibitors (PPIs), and prokinetics may also be prescribed to reduce acid production, improve LES function, or promote faster emptying of the stomach.
In some cases, surgery may be considered if lifestyle modifications and medications do not provide sufficient relief. Surgical options for GORD include fundoplication, in which the upper part of the stomach is wrapped around the LES to strengthen it, and magnetic sphincter augmentation, where a magnetic device is implanted around the LES to help prevent reflux.
What is Hiatus Hernia?
Hiatus hernia occurs when part of the stomach is pushed up through the diaphragm due to weakness in the diaphragm wall or muscles and this prevents the LOS from closing properly allowing stomach content to escape into the oesophagus
Hiatus Hernia very prevalent
30-50% of population
Majority of patients asymptomatic
May present as GORD
What drugs lower the pressure of LOS?
It is important to investigate medication use when exploring symptoms of patients because many drugs lower the LOS pressure and this includes:
1-Anti-cholinergic
2-Beta-2 agonists
3-Calcium channel blockers
4-Diazepam
5-Nitrates
6-Alcohol
7-Progesterone
8-Oral contraceptives
9-Theophylline
What drugs cause oesophageal ulceration?
Drugs which can cause oesophageal ulcerations:
1-NSAIDs
2-Bisphosphonates
3-Clindamycin
4-Clotrimoxazole
5-Doxycycline
6-Potassium
7-Theophylline
8-Tetracycline
Antibiotics responsible for 50% of drug induced oesophagitis (especially Clindamycin in capsule form)
What are the complications of GORD?
In diagnosed patients, Motility of oesophagus may be abnormal in patients with GORD.
Gastric emptying delayed in 40% of patients with GORD
Main symptoms is heartburn dyspepsia.
May also suffer dysphagia or odynophagia (pain on swallowing)
Complications include Barrett’s oesophagus, haemorrhage, stricture. Barrett’s is a risk factor cancer., this is when lining of the oesophagus change so it resembles that of intestine.
Endoscopy only method of diagnosis.
Functional dyspepsia (NUD non ulcer dyspepsia)
Half of patients with chronic dyspepsia no evidence of organic disease
Could be due to hypersensitivity to gastric acid?
Four groups:
Ulcer like
Dysmotility like
Reflux like
Non-specific symptoms
Psychological factors stress anxiety Eradicate H.Pylori if present
Neutralise acid or prevent acid production (symptomatic relief)
Periodic monitoring safety netting as NUD can be precursor for more or a serious condition.
Symptoms summary (understand differences between NUD functional dyspepsia and GORD)
Heart burn= pain immediately with or after food if no organic disease means it is functional dyspepsia but upon investigation if diagnosis proves GORD then treatment is needed not just OTC
Epigastric pain check if pain is immediately with or after food could be functional dyspepsia but if diagnostic tests shows it’s gastritis or gastric ulcer
Epigastric pain if pain is between meals or at night or pain relieved by eating it could be functional dyspepsia so no organic disease but if diagnostic test shows it is gastritis or duodenal ulcer.
AI:
Non-ulcer dyspepsia (NUD) and functional dyspepsia are terms used to describe a condition characterized by recurring or chronic upper abdominal pain or discomfort without evidence of an underlying structural or organic cause. Gastroesophageal reflux disease (GERD) is a separate condition that involves the reflux of gastric acid into the esophagus. While there may be some overlap in symptoms, there are differences between these conditions:
- Symptoms:
- NUD/Functional dyspepsia: The main symptom is upper abdominal pain or discomfort that is not related to specific meal times and may be described as a burning, gnawing, or aching sensation. Other symptoms may include bloating, early satiety (feeling full soon after starting a meal), and nausea.
- GERD: The main symptom is heartburn, which is a burning sensation in the chest that may radiate to the throat. Regurgitation, the sensation of acid coming up into the throat or mouth, is also common. - Pathophysiology:
- NUD/Functional dyspepsia: The exact cause is not well understood, but it is believed to involve abnormalities in the way the gastrointestinal tract functions and processes sensory information. Factors such as altered gastric motility, abnormal sensitivity to stomach acid, and psychological factors may play a role.
- GERD: It is primarily caused by the reflux of stomach acid into the esophagus due to a weakened lower esophageal sphincter (LES) or increased pressure in the stomach. This can occur due to factors such as obesity, pregnancy, hiatal hernia, and certain medications. - Acid-related findings:
- NUD/Functional dyspepsia: There is no evidence of significant acid-related findings on diagnostic tests such as endoscopy or pH monitoring.
- GERD: Diagnostic tests may show evidence of esophageal inflammation, erosions, or strictures caused by the exposure to stomach acid. - Treatment:
- NUD/Functional dyspepsia: Treatment focuses on managing symptoms and may include lifestyle modifications (e.g., dietary changes, stress reduction), medications to reduce acid production or relieve symptoms (e.g., antacids, H2 receptor antagonists), and psychological interventions if stress or anxiety is contributing to the symptoms.
- GERD: Treatment aims to reduce acid reflux and relieve symptoms. Lifestyle modifications (e.g., dietary changes, weight loss, elevating the head of the bed), medications to reduce acid production (e.g., proton pump inhibitors, H2 receptor antagonists), and in some cases, surgical interventions may be recommended.
It’s important to note that these conditions can coexist in some individuals, and the symptoms can overlap. A thorough evaluation by a healthcare professional is necessary to differentiate between NUD/Functional dyspepsia and GERD and to develop an appropriate treatment plan.
Management of upper GI conditions
Stomach, peptic & duodenal ulcer
First of all identify organic cause of disease and treat it accordingly
Step-1 Identify and eradicate H.pylori
7 day triple therapy to treat H.Pylori PPI and two antibiotic’s amoxicillin and erythromycin.
Step-2 Stop inappropriate therapy like NSAIDs if use of NSAIDs is a must then ensure patient is on PPI for gastric protection
Step-3 Reduce acid production to reduce gastritis and enable mucosa to repair
Use drugs that will either block H2 or Proton Pump
Offer PPI or H2 for 8 weeks and once ulcer is healed test for H.Pylori and if H.Pylori is present then offer eradication therapy as well.
If we find patient doesn’t use NSAIDs or any other inappropriate medication and no presence of H.Pylori, then PPI or H2 will be prescribed for 4-8weeks
Sometimes patient ulcer won’t be healed even after taking the appropriate treatment steps
This could be due to their adherence as it is triple therapy, ahve they completed course, have they taken their medication appropriately, have they been able to stop the NSAIDs or are they taking NSAIDs over the counter or do they have crowns disease or malignancies.
If patient heals and symptoms reoccurs a low dose PPI should be given to control symptoms
How is GORD managed?
Remove causative agent
Anything which lowers the LOS pressure
Non-pharmacological advice
Use rafting product like gaviscon
Reduce acid production to enable recovery of oesophageal mucosa
State the non-pharmacological advice for the management of GORD
Diet:
Eat small meals
Avoid food which lowers the LOS pressure like caffeine chocolate alcohol
Avoid fatty foods- slow gastric motility
Avoid eating within 4hrs and drinking within 2hrs of going to bed
Avoid drugs which lower the LOS pressure
Avoid tight fitting clothes
Lose weight
Attention to posture
Avoid bending from the waist
Don’t lie down after eating increases exposure of food to oesophageal lining
Nocturnal heartburn symptoms raise the head of the bed 15-23com
Stop smoking
Reduce alcohol intake
What is the management of dyspepsia?
We can manage the initial presentation of these symptoms OTC if there are no alarm signs and symptoms present.
Symptomatic
Neutralise acid
Reduce flatulence
Prevent dislocation of acid
All treatment available over the counter
Upper GI treatment and referral
Aluminium, Magnesium, Sodium & Calcium salts.
*Neutralise acid by combining with HCl, this gives relief and CO2 is released called Eructation
*Eructation
*Increase LOS pressure- by gastric alkalisation
*Mucosal protection via stimulation of prostaglandin synthesis
What affect do the two factors above have on gastric-release? its increased in response to increased pH after taking antacid, this results in an acid rebound. Although frequent high doses of these medications promote ulcer healing but they are only limited for short term use.
Drug form tablets and liquid break tablet or chew better
Liquids works quicker and have greater neutralising ability due to their smaller particle size but is shorter acting.
Best to use after 1 hour of meal when gastric emptying is slow so they remain the stomach for longer and they act up to 3hrs in comparison to 30mins before meal
Rapid relief of symptoms of heart burn and indigestion
As per NICE guidance Avoid long term, frequent, continuous use:
Only relieves symptoms in the short term, rather than prevention.
Rennies/settlers /tums.
What are the s/e of Antacids?
Side effects include constipation with aluminium based salts and diarrhoea with magnesium based salts?
These effects can be useful if patient has diarrhoea or constipation as these products can help or products can be used in combination to counteract s/e.
*Aluminium binds phosphate in the gut~~> osteoporosis
*Aluminium may be absorbed ~~~> neurotoxicity
Rebound gastric acid secretion with prolonged use
Sodium avoided in patients with hypertension and cardiac problems, use BNF to check for relative sodium content of indigestion products and avoid sodium products in patients with hypertension or cardiac issues.
Important drug interactions to consider, this is related to enteric coating of medications we can lose that protective effect of enteric coating and drug can be destroyed by stomach content so a lot of medication is not to be taken with indigestion products.
Reduced absorption we get binding with tetracycline and iron based tablets.
Generally safe in pregnancy but be mindful of sodium content as it can cause fluid retention. Low dose or no sodium product as heart burn indigestion is common in pregnancy,
Alginates & Dimethicone
Alginates formulated with antacid
Forms a high pH viscid is mass (Raft), trapping air bubbles and CO2 from the reaction of antacid with the stomach contents.
Floats to top of the stomach and protects oesophageal mucosa form the stomach contents
Dimeticone or Simeticone:
This is an anti-foaming agent
Reduces surface tension of intragastric air bubble.
Allows bubbles to escape- reduce bloating feeling.
What are the H2 receptor antagonists?
Cimetidine
Famotidine
Nizatidine
Ranitidine
H2 receptor antagonists have longer duration of action than antacids.
Competes for H2 receptor on parietal cells, H2 receptor antagonists effect is overridden by powerful stimulus such as large meal as this reverse block on H2 receptor.
PUD:
High healing rates, no reduction in relapse (has H.pylori been eradicated? As replaces suggests there is another underlying cause)
GORD
After 12 weeks 80-90% of patients with mild oesophagitis improved
Not effective in moderate to severe GORD.
What are the s/e of H2 antagonist?
1-7% of patients suffer from ADR:
*only headache and dizziness> placebo
*Cimetidine- gynaecomastia 0.2% impaired libido
*Nizatidine- swearing, abnormal dreams
*Confusional states in elderly with H2 antagonist use
Interactions
Cimetidine binds to P450 cytochrome P450 inhibitor increases drug effect.
Phenytoin, carbamazepine, theophylline, warfarin.
H2 antagonist OTC
Ranitidine (Zantac 75)
Symptomatic relief of heartburn, dyspepsia & hyperacidity.
6-days continuous treatment maximum
Maximum dose of 2 tablets in 24 in comparison to prescription only dose of 150mg BD or 300mg ON patient should only use it for 6days only.
Sub-therapeutic dosages
Patients use them prophylactically.
What are Proton pump inhibitors?
1-Omeprazole
2-Lansoprazole
3-Pantoprazole
4-Esomeprazole
Enteric coated preparations, absorbed in small intestine. PPIs take a day or 2 to reach their full effect so patients should be given antacid till PPI reach their full effect.
Blocks hydrogen-potassium ATPase enzyme.
Prolonged suppression of acid secretions.
20mg omeprazole causes 80% decrease in acid secretions for 24hours, 40mg 100%.
Heal ulcers more rapidly than H2 antagonists. Healing rate same at 8 weeks.
PPIs superior in the treatment of reflux/GORD.
PPI licensed for preventing acid aspiration in surgeries when patient undergoes general anaesthesia as it has prolonged acid suppression.
What are the s/e of PPI?
Short term side effects include nausea, diarrhoea, flatulence, Epigastric pain, dry mouth & headache.
Arthralgia and myalgia joint or muscle pain
Concerns about bacterial overgrowth
May increase risk of salmonella or helicobacter as acid in the stomach has antibacterial properties
Lanzoprazole take before food- food decrease its bioavailability
Rebound acid hyper-secretion may occur after stopping prolonged treatment with PPI. Therefore use lowest dose to control patients condition or use when needed.
PPI OTC
Omperazole 10mg and 20mg indicated for adults over 18
Swallow with plenty of water
20mg daily until symptoms improved then 10mg
Refer to GP
*If after 2 weeks still no relief
* If treatment required continuously for 4 weeks then refer
*Patient is over 45 and present with new or changed symptom.
What other drugs are used for upper GI?
1-Metoclopramide, Domperidoneis prescription only drug due to risk of CVD
*Increase gastric emptying and LOS tone.
2-Sucraflate
*Polymerise below pH-4 to form a sticky gel
*Protective barrier over ulcer (adheres strongly)
Physical protection and allows bicarbonate to restablish pH
3-Bismuth 2nd line for H.pylori regimes
May act similarly to sucralfate
Strong affinity for mucosa, especially in ulcer craters.
May blacken teeth and stools.
4-Misoprostol
Promotes ulcer healing by stimulating protective mechanisms-sometimes used with NSAIDs.
Draw a diagram showing where each drug acts on the GI to inhibit acid production.
Metoclopramide C
Increases LOS tone And increase gastric emptying
Alginates form a raft in the fundus that reduces reflux
Antacids act on the fundus wall stomach walls to neutralise acid
PPI and H2 antagonist block acid release from parietal cells act on lower part of the stomach pyloric antrum.
Which treatment-when?
Functional dyspepsia, gastritis or PUD
Removal of causative agents
Dietary changes
Symptomatic management
H2 antagonist or PPI
GORD
Lifestyle & dietary changes
Alginates products or PPI
Not H2 antagonist
When do we refer patients to GP?
Patients over 45 with new/changed symptoms of heartburn or dyspepsia
Continuous dyspepsia
Increasing severity
Weight loss, loss of appetite, sign of anaemia
Pain in exercise- cardiac origin?
Dysphagia (unexplainable pain on swallowing)
Blood in vomit or stools
Make sure you ask patients these questions so you can refer to GP or before giving them an OTC med.
Summary
Upper GI conditions common
Most symptoms can be treated by community pharmacist
Antacids and H2 antagonists
Rafting agents and PPIs
Refer:
When symptoms don’t improve
Symptoms present for first time over the age of 45
H2 antagonists medchem-1
What is the role of histamine?
Parietal cell can be stimulated by Histamine
Acetylcholine
Gastrin
Stimulation leads to formation of canaliculus invagination
H+ is pumped out into the canacliculus
Cl- flows through an ion channel
HCl passes into the lumen of the stomach.
When designing molecule to Intervene with response to stimulus by stopping natural ligands from binding to receptors on the parietal cells
We can target M2 or CCK2 but most successful target is to antagonise H2 receptor.
What is the structure of Histamine? Label and state functional groups
1-Histamine natural ligand unlike any other natural ligands due to it is imidazole ring structure. This means it can exist as 2 different tautomers.
Hydrogen can reside on either one of the nitrogens. Normal ratio is 1:4 showing favour to τ tautomer on the left. If you add a substitute to the ring you can change that ratio and make it in favour of π tautomer but this will make it have less of agonist action at H1 receptors.
2- At physiological pH histamine is charged, first charge occurs at aliphatic amine as it is most basic out of the other nitrogens. Overall the molecule is 99.6% ionised but of that 96% exist as mono-cation with charge on side chain and 3% exist as di-cation where the ring is charged.
Drug design process
Draw SAR of H1&2?
Drug design was based on natural ligand Histamine
SAR of both H1 and H2 to identify the similarities and differences for agonist binding.
Both H1&2 require a ring structure that is separated form a positively charged nitrogen via a two carbon spacer.
H1 receptor SAR for agonist is less specific with variation possible in heteroaromatic ring whereas H2 agonist the heteroaromatic ring has to contain this (amidine group)
Design process of the antagonist?
Standard approach for an antagonist is to take an agonist molecule and made it bigger and more hydrophobic.
Binds in the same way to agonist binding site.
Additional binding steps the receptor being switched on
Initial approaches unsuccessful but one agonist 4-methyl-histamine still an agonist selective for H2
Next step in design was to change the polar group NH3
N-alpha-guanylhistamine is partial agonist (postive charge of giants can be shared over 3nitrogens and can be further or closer to imidazole ring.
Does this mean antagonist binding involves a different binding region for the polar group?
It is proposed that the agonist binding site is closer to the ring binding site.
Histamine is too short to bind to the antagonist binding site.
N-alpha-guanylhistamine can access both sites acts as a poor agonist. Blocks the agonist and antagonist binding site.
Now the focus is to build pure antagonist not partial and this is down by focusing on charged part of molecule.
Thio derivative charge located at terminus (increased activity still as partial agonist)
Methylthio derivative where charge is not located at terminus (partial agonist reduced antagonist behaviour)
This gave rise to key model:
Good agonist behaviour comes from maximising binding interactions through 2 points of contact.
Increasing spacer length to maximise chelation interactions with a 3 carbon spacer chain and keep the same guanyl functional group. This forms a better antagonist. This activity was kept even if one of the nitrogen’s groups were replaced by another substituents. Example molecule is Isothiourea
A chelation type binding by hydrogen bonds rather than a charged binding interactions. Derivatives shouldn’t be charged as this means molecule would have better pharmacokinetics properties. Also removing charge could help on distinguishing between agonist and antagonist binding sites.
SKF-91581 important molecule as it was the first molecule to show pure antagonist behaviour. It so neutral at physiological pH and has same shape as guanyl grouo so it can do the same chelate binding. Further extension to carbon spacer and methylation gave Burimamide, has better activity and is selective but low bioavailability.
Imidazole ring and optimising it’s binding interactions by identifying which tautomer would be best for binding and finding a way to maximise the presence of that tautomer for histamine.
The pKa of the imidazole ring is 5.74 and at the physiological pH there is an an equilibrium between the two uncharged forms via charged intermediates. Tau form is predominant in histamine so it is involved Ik binding for both agonists and antagonists.
Majority of histamine is uncharged on the ring. However the pKa of the imidazole ring in burimamide is not the same as the pKa as in histamine, because it is side chain is electron donating this makes the nitrogen more electron rich and therefore more likely to act as a base and become protonated. This means 40% of burimamide will be double charged at physiological pH, charged on the side chain and charged on the imidazole and in histamine this is only 3%.
This led to this burimamide, inclusion of sulphur makes the side chain electron withdrawing, this reduces pKa of the ring so it is less likely to be charged. This gives better antagonist.
If charge matters then does tautomer matter and does it have to be tau tautomer?
In histamine the tau nitrogen is more basic because it is further away from the electron withdrawing side chain. This means it has bigger electron density and this is favoured.
We can have this effect by introducing an electron donating group on the ring because it is going to pass electrons I got he ring and that increase in the electron density will be more pronounced at the tau nitrogen than the pi nitrogen.
This gave rise a better molecule Metiamide was in clinical trial but got withdrawn as it cause a bad s/e of Agranulocytosis.
So how can we keep the activity and lose this bad s/e?
Research was done in range if substituted guanidines that were less likely to become charged at physiological pH. The cyano and the nitro derivatives were best for activity.
This led to the first H2 antagonist Cimetidine. Then ranitidine although it was not toxic but it had drug interactions.
Summary
H2 antagonist were designed with limited knowledge of the biological process.
The design is considered to be a classic in rational drug design gave rise to most important prescription drug Cimetidine.
H2 medchem-2
Draw structure of cimetidine?
Cimetidine is an inhibitor of many cytochrome P450 enzymes
Significant drug interactions
drugs from different classes
Effects levels of other drugs (decrease and increase)
Changed absorption of some drugs
How can the SAR of cimetidine be improved? Draw bidentate interaction and the what are the 4 forms of stereoisomers? Is bidentate theory right for the stereoisomers of cimetidine?
1-The side-chain guanidine substituent interacted through a bidentate interaction. This is a two way interaction between two amines and a single amino acid residue on just 1 binding site.
This hypothesis was revised because the structure of cimetidine can exist as one of 4 stereoisomers.
These stereoisomers are different depending on the orientation of the amine substituents relative to the double bond. Only 2 stereoisomers are active and exist in equilibrium as Z,E and E,Z form.
The E,E form you get a steric reaction between the methyl group and cimetidine.
The Z,Z form we get an interaction between the methyl group and the cyano group CN.
But if cimetidine only exists in the Z,E and E,Z form this means hypothesis can’t be right because the hydrogens are not pointing in the same direction meaning they can’t bind at the same binding site int he bidentate.
If the two hydrogens are not in the same position how do they bind? What is their new binding site?
The hypothesis was updated, there are still 2 points of interactions, but this is to two separate hydrogen binding sites (2 binding sites).
Evidence of this has been provided through the synthesis of molecules where conformation is fixed by including a ring structure, by putting the guanidine in a ring structure. The inclusion of isocytosine unit allowed additional hydrophobic derivatives and resulted in Oxmetidine drug.
What is the SAR of Ranitidine? include diagram
Ranitidine was fed through patent busting by finding original loop holes in cimetidine SAR. Thsi resulted in a better drug, fewer side effects and no drug interactions as ranitidine didn’t inhibit the P450.
Ranitidine has 2 major structural differences. It no longer has an Imidazole ring and the neutral polar group has been further modified further. As the imidazole ring is essential for an agonist but for an antagonist it’s not required. Also other nitrogen containing rings can be used and other hereto atoms rings.
Making changes on imidazole ring and new rings has very different effects. If we put a methyl group at the same position on the imidazole ring, it increases activity and on the furan methyl decreases activity. Thsi means binding isn’t occurring at the same place or receptor.
What modifications can be done on the guanidine group
Increased hydrophobicity, increases activity of molecule. This could be done by making the guanidine group less polar. How can we change the overall polarity of the guanidine group to make it more hydrophobic?
This is done by changing the polarity by making it less polar while still retaining the 2 amines for binding. This is form by changing the nitrogen to a carbon.
The addition of NO2 is essential as the electron withdrawing group then stabilises the desired tautomer where the 2 amines are available to do the binding interactions.
What is the SAR of ranitidine? List functional groups and their activity.
1-The structure activity relationship for ranitidine the ketoaminal group is optimal group binding.
2-If the sulphur is removed form the spacer chain activity will decrease. Activity also decreases if the sulphur position is moved.
3-If the ring is made more hydrophobic by making it a thiophene instead of the furan this would decrease activity.
4-The substitution pattern around the ring matters. Position is optimal at 2 & 5 position but we can change substituents, we can change the methylamino group significantly, so the actual properties of that group basicity and hydrophobicity are not crucial. Substitution can be varied without loss of activity, can be protonated.
Nizatidine and Famotidine are two derivatives of Ranitidine with slight changes this gave them advantage in activity.
PPIs medchem
How are H+ formed in parietal cells and what is their function?
Parietal cells can be stimulated by histamine, acetylcholine & gastrin.
Stimulation leads to formation of a canaliculus invagination, this is highly acidic (pH2).
The parietal cell is stimulated to generate acid via the action of histamine and this process can be stopped by H2 antagonists. H+ ions are produced in the parietal cells by the action of the enzyme carbonic anhydrase from the reaction of H2O and CO2. The H+ ions produced are pumped into the canaliculus and this occurs against conc gradient and at the same time K+ are into the parietal cell against the gradient. This step requires energy and that is provided by the hydrolysis of ATP (ATP~~~>ADP+Pi)
The 2 ion channels operate as well with Cl- ions and K+ ions flowing into the canaliculus with their gradient. The resulting HCl is passed in the canacliculus then into the lumen of the stomach.
What are the 4 PPIs? And how do they work?
Omperazole
Esomeprazole
Pantoprazole
Iansoprazole
Rabeprazole
PPIs taken orally and pass through into the systemic circulation, they’re able to do this because they’re lipophilic and neutral (weak bases pKa-4)
PPI reach the parietal cells and flow into the canaliculus. In the low pH of the canaliculus PPIs undergo a metabolic transformation and become charged molecules.
This enables a cascade reaction where PPIs can be transferred into an active species. This active species is able to form a disulphide bond with one or more of the 3 available cysteine m residues on the proton pump. This leads to irreversible inhibition.
Acid production restored if new proton pump is synthesised or by regeneration of inhibited cell through glutathione.
What is the mechanism of action of PPI? Draw the mechanism
1-PPI picks up a proton H+ and the benzimidazole ring become protonated.
2-Intramolecular reactions occurs. The nucleophilic pyridine nitrogen can now attack the carbon adjacent to the charged nitrogen and that gives a 5 membered ring. This arrangement of the molecule is known as Spiro derivative.
3- The benzimidazole ring is reformed and that results in the cleavage of the carbon sulphur bond and the formation of sulphinic acid derivatives.
4-this is highly reactive and a second intramolecular reaction occurs. This generates a cationic pyrimidine molecule and that is the active species that can interact with the protein.
5- a disulphide bond is formed from the thiol on the proton pump giving us the inhibited enzyme.
How were PPI molecules discovered?
Slide 10
So how were these molecules discovered? CMN 131 was the first molecule in the design process. As we’ve seen so many times before, this was not synthesised to interact with this biological system. It was designed as an antiviral. But testing against other disease models showed it to reduce acid secretion, but it’s too toxic for human use. And it was proposed that the problem with the molecule was the thioamide.
Thus research was undertaken to change that functionality and it resulted in H 77/67 where the thioamide is included within an aromatic ring structure. It keeps the same binding interactions, but it was a much less toxic molecule. It can be improved further by improving the hydrophobicity. So in the case of H 124/26, including another aromatic ring.
Slide 11
Analysis of how that molecule worked indicated that it was actually metabolised in the body to a sulfoxide, and that sulfoxide was much more active. So that molecule now called timoprazole was investigated as a drug itself. Unfortunately, it didn’t make it to market for two different reasons. Firstly, during clinical trials it was shown that it inhibited iodine uptake by the thyroid, but additionally it was also a known compound. It had been patented for the treatment of TB, which meant there was going to be no profit in it of taking this one to market. But the recognition of the importance of a sulfoxide group was a crucial step in developing the proton pump inhibitors we have today. The first real drug like molecule was picoprazole. So here the timoprazole structure has been slightly altered by the introduction of ring substituents. What’s really interesting about picoprazole is it maintained activity, but the toxicity was lost. Picoprazole was developed in 1976. We didn’t actually know what the target was, the proton pump, until 1977.
Slide 12
Further changes could be made to picoprazole and H159/69 was an important advance. Here it was shown that having electron donating groups on the pyridine ring enhanced activity. So here we have a methoxy group. It achieves this by increasing the nucleophilicity of the pyridine nitrogen. This allows the first step of our reaction to occur more easily. But unfortunately, the molecule proved to be too chemically sensitive and readily degraded. But by changing the ester on the benzimidazole ring to an ether, the activity could be kept and the molecule was more stable. And that led to omeprazole being the first successfully marketed proton pump inhibitor.
Slide 13
Omeprazole is a chiral molecule. Hang on. I’m pretty sure you don’t believe me about that. It’s a different sort of chirality to what you’ve seen before. And it’s to do with the sulphur being tetrahedral. You can think of the lone pair being equivalent to a bond. So our sulphur has four different substituents on it. It was shown that the S enantiomer is the better drug molecule, more potent and with better pharmacokinetics because it’s metabolised more slowly leading to a longer duration of action. The single enantiomer came onto the market in 2000.
Slide 14
So in summary, why are proton pump inhibitors so good? They have a highly specific mechanism. It works regardless of the stimuli for acid production. The drug is inactive at a normal body pH. The target is only available in the canaliculus. And the canaliculus is the only area of the body where the active drug can be formed. The local concentration of the drug is high as once it becomes protonated, it cannot diffuse back into the parietal cell, so it’s only activated once it’s at the site of action. It reacts quickly once it’s activated because of the cascade reaction. So overall, the proton pump inhibitors are excellent drug molecules.
If you want to find out more about this subject, you can read the relevant chapter in Patrick Medicinal Chemistry.
Constipation
What is the role of large intestine? how is faeces formed?
Chyme passes from small intestine and passes along caecum, colon and into rectum by peristalsis.
Chyme passes from the small intestine through the ileocecal valve and into the cecum of the large intestine. Any remaining nutrients and some water are absorbed as peristaltic waves move the chyme into the ascending and transverse colons. This dehydration, combined with peristaltic waves, helps compact the chyme.
Water and salts reabsorbed, resulting in drying of the stool, excess drying of the stool causes constipation.
Bacteria role in the intestine and white GI:
1-ferment non-digestible polysaccharides, some metabolites absorbed like cellulose.
2-produce vitamin K and biotin (B7), which can be reabsorbed.
3-produce gasses from undigested polysaccharide.
4-essential for development of caecum and lymphatics
Stool is stored in the rectum until urge for defection. Stools hard when stored in rectum for longer than normal so more water absorbed.
What is constipation?
Passage of hard stools faeces less frequently than patients own normal pattern. Constipation is a symptom not a disease. It’s characterised by difficulty in opening bowels.
*going to the toilet less than 3 times a week
*straining to open bowels more than 25% of occasions
*hard or pellet like stool on more than 25% of occasions
Chronic constipation- generally >12weeks in preceding 6months.
Constipation is very common and affects all ages:
1 in 7 people
1 in 5 older people
1 in 3 children
More common in women than men
Late pregnancy
Taking regular meds
10million prescriptions for laxities per year in England
What is the Aetiology of constipation?
Age elderly and young patients at higher risk.
1-Diet:
Low fibre, high animal fat, inadequate fluid intake, caffeine, alcohol both alcohol and caffeine are diuretics so less fluid in body and stool will be dry.
2-Poor bowel habits
*Ignoring urge to defecate
3-Imaginary constipation in elderly patients due to less food consumption which means less stool passage
4- Medications:
Antacids: Al and Ca salts
Antispasmodics because they contain anticholinergic API which reduces bowel motility.
Antidepressants: amitriptyline, doxepin because they have anticholinergic affect reduces bowel motility.
Iron tablets eg ferrous sulphate can bind up the bowel.
Diuretics thiazides, bendrofluazide, reduce patients hydration rate.
Opioid Painkillers: codeine, morphine
Ca channel blockers: diltiazem, verampail
ACE inhibitors eg enalapril, lisionpril
Anticholinergic eg hyoscine, tolterodine
Ulcer healing eg lansoprazole, Omperazole.
Antipsychotics eg haloperidol, olanzipine.
Laxative abuse.
AI:
The drugs mentioned can cause constipation due to various mechanisms:
- Antacids (Aluminum and Calcium salts): These antacids can cause constipation by reducing bowel motility and slowing down the movement of stool through the gastrointestinal tract.
- Antispasmodics (containing anticholinergic API): Antispasmodics that contain anticholinergic active pharmaceutical ingredients (API) can reduce bowel motility by blocking the action of acetylcholine, a neurotransmitter that promotes bowel movements.
- Antidepressants (such as amitriptyline, doxepin): Some antidepressants have anticholinergic effects, which can lead to reduced bowel motility and constipation.
- Iron tablets (e.g., ferrous sulfate): Iron tablets can bind up the bowel and cause constipation, especially when taken in high doses or for an extended period.
- Diuretics (such as thiazides, bendrofluazide): Diuretics can reduce the hydration rate of patients, which can lead to dehydration and subsequently result in constipation.
- Opioid painkillers (codeine, morphine): Opioid painkillers can cause constipation by slowing down the movement of stool through the gastrointestinal tract. They affect the smooth muscle contractions in the intestines, leading to decreased bowel motility.
- Calcium channel blockers (such as diltiazem, verapamil): Calcium channel blockers can affect the smooth muscle contractions in the intestines, leading to decreased bowel motility and constipation.
- ACE inhibitors (e.g., enalapril, lisinopril): ACE inhibitors are not typically associated with constipation. However, some individuals may experience constipation as a side effect, although it is relatively uncommon.
- Anticholinergic drugs (e.g., hyoscine, tolterodine): Anticholinergic drugs, as mentioned earlier, can reduce bowel motility and contribute to constipation.
- Ulcer healing medications (e.g., lansoprazole, omeprazole): Ulcer healing medications are not typically associated with constipation. However, some individuals may experience changes in bowel habits as a side effect.
- Antipsychotics (e.g., haloperidol, olanzapine): Antipsychotic medications can cause constipation as a side effect, possibly due to their anticholinergic effects.
- Laxative abuse: Overuse or abuse of laxatives can disrupt the natural bowel function and lead to dependence, making it difficult for the bowels to function properly without the use of laxatives.
It’s important to note that individual responses to medications can vary, and not everyone will experience constipation as a side effect. If constipation becomes persistent or bothersome while taking any medication, it’s best to consult with a healthcare professional for further evaluation and guidance.
Amitriptyline and doxepin are both tricyclic antidepressants that have been found to have anticholinergic effects. Anticholinergic effects refer to the ability of a drug to block the action of the neurotransmitter acetylcholine in the central and peripheral nervous systems.
Amitriptyline and doxepin, like many tricyclic antidepressants, have a chemical structure that allows them to bind to and block certain receptors for acetylcholine. By blocking these receptors, they interfere with the normal functioning of the cholinergic system.
Acetylcholine is involved in various physiological processes in the body, including regulation of muscle contractions, cognitive functions, and the autonomic nervous system. When the action of acetylcholine is blocked by drugs like amitriptyline and doxepin, it can lead to a range of anticholinergic effects, such as dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment.
It’s important to note that the anticholinergic effects of these medications can vary from person to person and may depend on factors such as dosage, individual sensitivity, and other medications being taken
There are several classes of drugs that have anticholinergic effects:
- Antidepressants: Tricyclic antidepressants (e.g., amitriptyline, doxepin), selective serotonin reuptake inhibitors (SSRIs) at higher doses (e.g., fluoxetine, paroxetine), and some monoamine oxidase inhibitors (MAOIs) can have anticholinergic effects.
- Antipsychotics: Some typical antipsychotics (e.g., haloperidol, chlorpromazine) and atypical antipsychotics (e.g., olanzapine, quetiapine) may have anticholinergic properties.
- Antihistamines: First-generation antihistamines (e.g., diphenhydramine, chlorpheniramine) often have significant anticholinergic effects. Some second-generation antihistamines (e.g., cetirizine, fexofenadine) have fewer anticholinergic properties.
- Antiparkinsonian medications: Certain medications used to treat Parkinson’s disease, such as trihexyphenidyl and benztropine, have anticholinergic effects to help reduce tremors.
- Antispasmodics/antimuscarinics: Medications like dicyclomine and oxybutynin, used to treat conditions like irritable bowel syndrome and overactive bladder, respectively, have anticholinergic effects.
- Motion sickness medications: Some medications used for motion sickness, such as scopolamine, have anticholinergic properties.
It’s important to note that different drugs within these classes may have varying degrees of anticholinergic effects. Additionally, individual sensitivity to these effects can also vary.
Anticholinergic drugs have several potential side effects due to their ability to block the action of acetylcholine in the body. These side effects can vary in severity and may depend on factors such as the specific drug, dosage, individual sensitivity, and duration of use. Some common side effects of anticholinergic drugs include:
- Dry mouth: Anticholinergic drugs can reduce saliva production, leading to a dry, sticky feeling in the mouth.
- Blurred vision: These drugs can cause blurred vision or difficulty focusing on nearby objects.
- Constipation: Anticholinergic medications can decrease bowel movements and lead to constipation.
- Urinary retention: These drugs may interfere with the normal bladder function, causing difficulty in urination or incomplete emptying of the bladder.
- Confusion or cognitive impairment: Anticholinergic drugs can affect cognitive function, leading to confusion, memory problems, or difficulty concentrating.
- Increased heart rate: Some anticholinergic drugs can cause an increase in heart rate.
- Dizziness or lightheadedness: These drugs can sometimes cause dizziness or a feeling of lightheadedness.
- Dry eyes: Anticholinergic medications can reduce tear production, resulting in dry and irritated eyes.
- Increased sensitivity to heat: Anticholinergic drugs can interfere with the body’s ability to regulate temperature, leading to increased sensitivity to heat and an increased risk of heat-related illnesses.
Anticholinergic drugs primarily act by blocking the action of acetylcholine, a neurotransmitter that plays a role in various physiological processes. These drugs bind to and inhibit specific receptors known as muscarinic receptors, which are predominantly found in the parasympathetic nervous system.
Muscarinic receptors are a subtype of cholinergic receptors, and there are five different subtypes (M1 to M5) that are distributed throughout the body. Anticholinergic drugs can bind to and block these receptors, preventing the binding of acetylcholine and inhibiting its effects.
By blocking muscarinic receptors, anticholinergic drugs can have various pharmacological effects, including:
- Decreased salivation: Anticholinergics reduce saliva production by blocking muscarinic receptors in salivary glands, leading to a dry mouth.
- Bronchodilation: By blocking muscarinic receptors in the airways, anticholinergics can relax smooth muscles and promote bronchodilation, which can be beneficial in the treatment of respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD).
- Reduced gastrointestinal motility: Anticholinergics can inhibit the activity of smooth muscles in the gastrointestinal tract, leading to decreased motility and potentially causing constipation.
- Decreased urinary frequency: By blocking muscarinic receptors in the bladder, anticholinergics can reduce bladder contractions and increase bladder capacity, resulting in decreased urinary frequency.
- Dilated pupils: Anticholinergic drugs can block muscarinic receptors in the iris muscles, causing dilation of the pupils (mydriasis).
- Reduced sweating: Anticholinergic drugs can inhibit sweat gland activity by blocking muscarinic receptors, leading to decreased sweating.
It’s important to note that different anticholinergic drugs may have different affinities for specific muscarinic receptor subtypes, which can contribute to variations in their pharmacological effects and side effect profiles.
Aetiology
IBS contributes to constipation but this condition alternates between constipation and diarrhoea.
Intestinal obstruction:
1-Scarring- from IBD, diverticulitis, or post surgery.
2-Adhesions
3-Intestinal cancers
4-Abdominal hernia
5-Gallstones wedged in intestine
6-Volvolus
7-Foreign bodies
8-Intussusception
9-Haemorrhoids
10-Fissures
Other disease can cause constipation:
Diabetic autonomic neuropathy
Spinal cord injury or tumours
Cerebro vascular accident
Multiple sclerosis
Parkinson’s disease
Connective tissue disorder
Hirschsprung’s disease
Mechanical problems of the anus and rectum
Eg rectal prolapse
*poor thyroid function cause main role of thyroid is to maintain regular bowel habit.
*lead poisoning
*pregnancy
*travel
*immobility
How is contipation diagnosed?
Medical history of patient?
History of symptoms:
What is the patients Normal pattern of defecation?
Do they have other symptoms
Frequency of their bowel habit and consistency of their stool.
Are they experiencing any faecal impaction or incontinence?
How long/ intense are the symptoms?
Impact on daily life?
Are they taking other medications
Changes in diet and life style.
New job?
Holiday?
Diet?
Constipation in
children?
Prevalent in 5-30% of children
Aetiology unknown for children but diet changes from milk to new food impacts their GI and milk is a laxative.
Symptoms:
Foul smelling wind and stools, irregular stool structure and excessive flatulence, abdominal pain, distension and discomfort.Soiling/overflow.
Constipation in older patient
Main causes
Age related decline in GI motility
Decreased mobility
Poor diet, low solid and liquid intake.
Wasting of pelvic floor muscles
Side effects of medicines
Faecal impaction may occur,
Summary
Constipation is a symptom not a disease
It affects a high percentage of the population
Many factors a cause constipation
When constipation has been confirmed appropriate steps need to be taken to manage the problem.
*lifestyle and dietary changes
*short course of laxatives
Constipation
Clinical considerations
1-Summarise the guidelines for managing constipation
-
Guidelines for Managing Constipation:
- Encourage increased fiber intake through diet or supplements.
- Promote adequate fluid intake.
- Encourage regular physical activity.
- Consider lifestyle changes such as establishing a regular bowel routine.
- Offer laxatives as appropriate if lifestyle changes are ineffective or if there’s an underlying cause of constipation.
2-Counsel a patient on appropriate lifestyle changes to help constipation symptoms.
-
Counselling a Patient on Lifestyle Changes:
- Increase dietary fiber intake by consuming fruits, vegetables, and whole grains.
- Ensure adequate hydration by drinking plenty of fluids, especially water.
- Engage in regular physical activity, such as walking or jogging, to promote bowel movement.
- Establish a consistent bowel routine by attempting to defecate at the same time each day.
3-Discuss the differences in the guidelines for particular patient groups
-
Differences in Guidelines for Specific Patient Groups:
- For elderly patients or those with mobility issues, additional emphasis may be placed on maintaining hydration and physical activity.
- Pregnant women may require tailored advice regarding fiber intake and suitable laxatives.
- Patients with comorbidities may need careful consideration of medication interactions and contraindications.
4-Distinguish the key features of each laxative
-
Key Features of Laxatives:
- Bulk-forming laxatives: Increase stool bulk and promote bowel movement.
- Osmotic laxatives: Draw water into the bowel to soften stools and stimulate bowel movements.
- Stimulant laxatives: Directly stimulate the bowel muscles to encourage movement.
- Stool softeners: Soften stools by adding moisture to them, making them easier to pass.
5-Describe why one laxative is chosen over another
-
Choosing Laxatives:
- Selection depends on factors such as the severity of constipation, patient preference, and any underlying medical conditions.
- Bulk-forming laxatives are often recommended as first-line treatment due to their safety profile and effectiveness.
- Osmotic laxatives may be preferred in cases of more severe constipation or when rapid relief is needed.
- Stimulant laxatives are usually reserved for short-term use or when other treatments have failed due to the risk of dependency and side effects.
What are the goals of constipation management?
1-To achieve an individuals normal frequency of defecation
2-Establishing regular, comfortable defecation.
3-Preventing laxatives dependence
4-Relieving discomfort
Bristol stool chart
Type 1-7
Characterise stool
Type 1 separate hard lumps
Type-7 watery no solid stool
Type -1 The longer the transit time the longer it takes food and waste products to make it is way through the GI system
The greater opportunity body had to absorb water from the stool so stool is harder to pass and constipation occur. Type-7 less transit time so body hasn’t absorbed water from stool which means diarrhoea will occur
Type 3-4 normal stool.
List the medications used to treat constipation
1-Bulking agents:
Ispaghula husk, methyl cellulose
2-Stimulant laxatives:
Bisacodyl (oral and rectal)
Senna
Dantron (in co-danthrathmer or co-danthrusate)
Sodium picosulphate
3-Faecal softeners:
Docusate (oral and rectal)
Glycerol (suppository)
Arachis oil (enema)
4-Osmotic laxatives:
Lactulose
Macrogols (inert polymers of ethylene glycol)
Magnesium hydroxide and magnesium sulphate
Phosphate (suppository and enema)
Sodium citrate (microenema)
BOSS
- Bulking Agents (B): Ispaghula husk and methyl cellulose.
- Stimulant Laxatives (S): Bisacodyl, Senna, Dantron, Sodium picosulphate.
- Faecal Softeners (S): Docusate, Glycerol, Arachis oil.
- Osmotic Laxatives (O): Lactulose, Macrogols, Magnesium hydroxide, Magnesium sulphate, Phosphate, Sodium citrate.
What are NICE guidelines for adults?
For both acute and chronic:
1-Lifestyle advice and manage any underlying cause. Fluid intake, exercise, diet high fibre fruit&veg. Medical history, medications eg opioids.
2-Bulk forming eg. Ispaghula husk gives some response within 1-3 days then add osmotic laxatives but if bulk forming laxative doesn’t yield benefit the use osmotic laxative alone.
3- (+/or) Osmotic: Macrogol use osmotic laxative for 1-3 days if not effective use stimulant eg. senna.
4-stimulant
6- Gradually titrate the laxative doses up or down aiming to produce soft, formed stool without straining at least 3 times per week.
In acute step 5:
Gradually reduce and stop after producing a soft, formed stool without straining at least 3 times per week.
In terms of stopping these laxatives it must be done gradually over a period of months, starting with the stimulant laxatives first you may need to simultaneously increase dose of osmotic laxatives to off set this affect.
In chronic step 5:
if stimulant laxatives fails
Next step is to use prucalopride (pro-kinetic serotonin agonist) stimulates GI motility (Prucalopride is a medication used to treat chronic constipation in adults who have not responded to at least two classes of other laxatives at maximum and recommended dose for at least 6 months and where symptoms are severe and when invasive treatment is used like suppository or enema or removal of stool. It works by increasing the movement of the gut, helping stools to pass more easily.)
What are the guidelines for faecal loading or impaction?
Faecal loading is a generalised term to describe build up of faecal matter within the colon whereas impaction occurs when that matter has been present for a long period of time where body has reabsorbed water from stools. Impaction is characterised by dry hard matter that patient can’t evacuate from the bowel.
Hard stools is seen in faecal impaction and soft stool is a symptom of faecal loading.
The guidance for faecal impaction/hard stool states first step in treatment is high dose of oral macrgol like laxado or movacol. Aim to draw water into the stool via osmosis to make stool softer and easier to pass.
If unsuccessful after 48hrs maximum.
The next step is to treat with stimulant laxatives like senna or bisacodyl aim to get movement of the bowel working about 12hrs.
if still unsuccessful at this stage or response is slow or inadequate. The next step is to consider using glycerols suppository either on it is own or suppository plus bisacodyl suppository gives quick bowel movement of 30mins to an hour should notice improvement in the patient symptoms. If this step fails, consider a sodium phosphate enema or a Arachis oil retention enema. Sodium phosphate is one of the strongest osmotic laxatives of previous measure fail we need to use more potent laxatives.
If we got soft stools a symptom of faecal loading:
First step in the pathway is to use stimulant pathway senna or bisacodyl reason for this unlike for hard stools we try to use osmotic laxative to soften stool, here the stool is already soft so there is limited benefit of osmotic laxatives.
First step to use stimulant laxative if unsuccessful, next step consider Docusate which is a stool softener which also got stimulant effects or a sodium citrate mini enema and this is an osmotic laxative.
If unsuccessful with both treatment then move to next step in the pathway is to use a sodium phosphate enema or Arachis oil enema.
How is Opioid induced constipation treated?
Avoid bulk forming laxatives
Because their mechanism of action is that they increase faecal mass this causes the colon to be distended and that stimulates peristalsis but opioids reduce bowel contractions and this means reduction in peristalsis, have antagonist effects here. Avoid bulk forming laxatives like fybogel ispaghula husk.
Use osmotic laxative movcol, laxdor or (Docusate) stool softener got mild stimulant activity as first line in treating opioid induced constipation.
Second line is stimulant laxatives like senna or bisacodyl because stimulants work directly on the bowel in order to stimulate peristalsis. They are having an exact opposite effect on the bowel as the opioids, this helps the bowel to overcome inhibition of peristalsis. Osmotic and stimulant ideal combination soften and increases peristalsis combined effect.
If this fails next step in the guidance is to use peripherally acting μ-opioid opioid receptor antagonist PAMORA.
Peripheral means medication is not acting centrally
Opioids are agonists at the opioid receptors in the brain I.e having central affect. The side effect of constipation is a peripheral side effect taking place in a location outside of the brain blocking of μ-opioid receptors in the GI tract and this is resulting in the constipation of the patient.
The mechanism of action of PAMORA is blocking the the μ-opioid receptors in the GI tract without blocking the central effects, thus protecting the analgesic effects for the patient and relieving constipation.
1-Naloxegol:
Peripherally acting μ-opioid receptor antagonist (PAMORA)
Given orally
When patient hasn’t responded to laxatives
PAMORAs don’t antagonise the important opioid receptors.
2-Methylnaltrexone
PAMORA
Subcutaneous
No evidence submitted to NICE not recommend by NICE
3-Naldemedine (NICE TA651) Sept 2020
PAMORA
Oral
A new option.
Lifestyle advice
High fibre diet:
30g fibre/day with sufficient fluid (most only get 18g)
Caution when increasing fibre intake due to obstructive symptoms or faecal impaction.
Increasing fibre intake is Ineffective in slow transit constipation or defecatory disorders.
Switch from white to whole meal
Limit evidence but also recommend:
Increased physical activity
2L of water per day
Be cautious with increasing the fibre intake, take care if there’s any obstructive symptoms or faecal impaction. also increasing the fibre intake is ineffective in slow transit Constipation or in patients who have got defecatory disorders so patients who are not going to benefit from having the high fibre diet will be people with these obstructive symptoms that we mentioned which can be caused by conditions like Crohn’s diverticulitis cancer perhaps even having a foreign body within within the GI system and also then faecal impaction, this is when faeces have built up
obstructive symptoms that’s where the patient would experience abdominal pain nausea vomiting cramping and flatulence caused by the intestinal obstruction and some patients might have that as adhesion’s after surgery possibly also after a hernia.
the issue with fibre being ineffective and slow transit Constipation, this goes back to the Bristol stool chart so slow transit Constipation is where the food and waste products are moving through the GI system quite slowly or relatively slowly now if that is the case then increasing the fibre has no benefit for those patients because what we’re looking to do is bulk up the contents of their stool but if they’ve already got slow transit Constipation that actually increasing the content of the colon is certainly not going to help the situation now likewise if the patient’s has a defecatory disorder for example something like Hirschsprung’s disease which is a nerve conduction problem with the bowel again in this particular case because the patient has gotten anatomical issue actually increasing the content of the colon is not going to bring about an improvement for that patient, for everybody else for whom they will benefit from a high fibre diet a simple switch they can make is to move from white foods for wholemeal foods so if we take the examples of rice bread pasta if we’re moving from white versions of foods to wholemeal versions of those products they’re going to have a much higher fibre content so that’s an easy change that people can make
there is limited evidence for some of the further interventions that we can make however all of the interventions that we will discuss are good lifestyle advice and things that we would be recommending people for as part of their overall health picture OK so we firstly would advise people to increase their physical activity for the simple reason that we know that patients who are predominantly bedbound are at much greater risk of developing Constipation OK so it stands to reason that we should increase our physical activity in order to ensure regular bowel movements and the patients also need to be advised to ensure they’re getting an adequate fluid intake so minimum of two litres of water per day obviously if they’re having increased physical activity or it’s a particularly hot climate and that figure needs to go up accordingly
What are obstructive symptoms and why do obstruction occurs in the GI?
Obstructive symptoms refer to a set of symptoms that occur when there is a blockage or obstruction in the gastrointestinal (GI) tract, hindering the normal passage of food, fluids, or waste material. These symptoms can manifest in various ways and may include:
- Abdominal pain: Often described as cramping or sharp pain, abdominal discomfort is a common symptom of GI obstruction.
- Nausea: Feeling queasy or the urge to vomit is another typical symptom of obstruction.
- Vomiting: In severe cases, vomiting may occur due to the body’s attempt to expel the blockage or because of the build-up of gastric contents.
- Cramping: Spasms or cramps in the abdomen may accompany obstruction, reflecting the body’s attempt to move material past the blockage.
- Flatulence: Excessive gas production and bloating can occur due to the obstruction, leading to discomfort and distention of the abdomen.
Obstructive symptoms can result from various conditions affecting the GI tract, including:
- Mechanical obstruction: Physical blockages caused by conditions such as tumors, strictures (narrowing of the intestine), adhesions (scar tissue), or foreign bodies can impede the normal flow of contents through the GI tract.
- Functional obstruction: In some cases, the muscles of the GI tract may fail to contract properly, leading to a functional obstruction. Conditions like intestinal pseudo-obstruction or Hirschsprung’s disease can cause this type of obstruction.
- Inflammatory conditions: Inflammatory bowel diseases like Crohn’s disease or diverticulitis can cause inflammation and swelling, leading to partial or complete obstruction of the intestine.
- Volvolus: This occurs when a loop of the intestine twists around itself, causing a mechanical obstruction.
Overall, obstructive symptoms in the GI tract can be caused by a wide range of conditions, each requiring specific diagnostic and treatment approaches to alleviate symptoms and address the underlying cause.
What is faecal impaction?
Faecal impaction occurs when a large, hardened mass of stool becomes stuck in the rectum or colon and cannot be passed naturally. This condition typically develops over time due to chronic constipation or prolonged periods of not having a bowel movement. As fecal matter accumulates and becomes compacted, it becomes increasingly difficult and painful to pass.
Symptoms of fecal impaction may include:
- Severe constipation
- Abdominal pain or discomfort
- Rectal pain or pressure
- Difficulty or inability to pass stool
- Nausea or vomiting
- Bloating or abdominal distention
- Loss of appetite
- Leakage of stool or liquid stool around the impacted mass
Fecal impaction requires medical attention to address and resolve. Treatment may involve a combination of methods, such as manual disimpaction (physical removal of the impacted stool), laxatives or stool softeners to help soften and loosen the stool, enemas or suppositories to stimulate bowel movements, and dietary changes or fiber supplements to promote regular bowel movements and prevent recurrence. In severe cases, hospitalization may be necessary for more intensive treatment and monitoring. It’s essential to seek medical care promptly if symptoms of fecal impaction develop to prevent complications such as bowel obstruction or perforation.
What is slow transit constipation?
Slow transit constipation is a type of chronic constipation characterized by delayed movement of stool through the colon (large intestine) and rectum. In individuals with this condition, the muscles of the digestive tract may not contract properly, leading to sluggish or ineffective movement of fecal matter. As a result, stools move through the colon at a slower-than-normal pace, causing difficulty in passing stools and infrequent bowel movements.
Symptoms of slow transit constipation may include:
- Infrequent bowel movements (typically fewer than three times per week)
- Difficulty passing stools
- Straining during bowel movements
- Feeling of incomplete evacuation after bowel movements
- Abdominal discomfort or bloating
- Rectal pain or pressure
- Excessive gas or flatulence
- Abdominal distention
The exact cause of slow transit constipation is not always clear, but it may be related to dysfunction of the nerves or muscles that control bowel movements. Risk factors for developing this condition include a sedentary lifestyle, inadequate dietary fiber intake, certain medications (such as opioids or anticholinergic drugs), neurological disorders, and hormonal imbalances.
Diagnosis of slow transit constipation often involves a thorough medical history, physical examination, and diagnostic tests such as colonic transit studies, anorectal manometry, and defecography. Treatment typically focuses on relieving symptoms and may include dietary modifications (such as increasing fiber intake), lifestyle changes (such as regular exercise), laxatives or stool softeners, biofeedback therapy, and in severe cases, surgical options such as colonic resection or placement of a colonic stimulator.
Overall, slow transit constipation can significantly impact an individual’s quality of life, but with appropriate management and treatment, symptoms can often be effectively controlled and managed. It’s important for individuals experiencing chronic constipation to consult with a healthcare professional for proper evaluation and management.
Constipation in pregnancy and breastfeeding?
First step is to offer bulk forming laxative.
Add or switch to an osmotic laxative.
Can also consider a short course of a stimulant such a senna but it can’t be given OTC must be prescribed as stimulant laxatives can induce labour contractions. Never supply stimulant laxatives in a pharmacy setting in pregnancy or pregnant patients.
Consider glycerol suppository
38% of pregnant women suffer from constipation as a result of increased progesterone and this causes the bowel smooth muscle to become relaxed and this reduces motility.
Compression of the bowel from the uterus this will reduce motility.
Many pregnant women take iron supplements this will cause constipation too. Check for haemorrhoids as it is common in pregnancy.
Breastfeeding:
Offer bulk forming laxatives
Add or switch to an osmotic laxative
Can consider a short course of a stimulant laxatives such as bisacodyl or senna.
Glycerol suppository
Laxatives in breastfeeding
Constipation in children
Children may not go to the toilet as frequent and delaying stool passage causes excess drying of the stool and thus constipation, anal fissures, anal spasms. This leads to learnt behaviour of avoiding defecation.
1st line treatment- Macrogols paediatric version of movacol laxdor paediatric or cosmocol and negotiated and nonpunitive behavioural interventions suited to persons stage of development.
2nd line- add stimulant laxatives like senna
Or if 1st line Macrogol was not tolerated or not beneficial change to stimulant laxatives
3rd line add lactulose or other softening laxatives like Docusate if Macrogol was not tolerated continue at maintenance dose (which may be for several months)
Some paediatric Macrogol products are not licensed for children under 2 (such as Cosmocol paediatric) informed and documented verbal consent recommended for prescriber)
Each product has different licensing age even though they contain macrogol before prescribing make sure and tell parents about unlicensed indication is known.
NICE recommends Suppositories and enemas but not recommended for routine use in primary care. Parents pick glycerol suppository from pharmacy but complexity use is not recommended oral is much more convenient for children.
Laxatives may be needed for several months to (overcome the learned behaviour)
Bulk forming laxatives
1-Ispaghula husk: e.g. fybogel 3.5g/sachet
*Hi-fibre brand is the same as the original!
*1 sachet BD for children 12yrs and over
*Sachets which you pour into full glass of water and take straight away.
*Preferably after meals but not just before bed.
*Take 1/2 to 1 hour before or after other medications
*Remains effective despite long term use as they don’t act directly on the bowel itself
2-Methylcellulose e.g. Celevac
*500mg tablets
*3-6 tablets BD with at least 300ml of liquid
*break tablets in the mouth before swallowing because this aids water absorption
*Don’t take just before bed because these meds swell when in contact with water and the aim is to absorb fluid and this bulks up stool and this distends the colon which stimulates a bowel contraction. At night patient won’t have peristalsis as this slows down in sleep, don’t take before bed as this is against natural peristalsis in the body.
*Ensure good fluid intake is maintained as these meds absorb water and if patient is dehydrated this reduces the effectiveness of the medication. If patient doesn’t have enough fluid or excess fluid, this can cause constipation for some patients
*2-3 days for effect to be seen
Osmotic laxatives and faecal softeners
- In these types of laxatives adequate water intake is essential*
1-Macrogol: e.g. Movicol, Cosmocol, Laxido
1-3 sachets daily, in divided doses
Sachets to dissolve in 125ml of water
Can be high in sodium so it’s contraindicated n hypertension, heart disease and renal impairment.
Do not take other oral medicines 1 hour before or after dose because this affects absorption.
Different flavours available- can mix with diluting squash if desired
1-3 days for effect.
2- Lactulose
15-45ml daily (single dose or in divided doses)
Very sweet tasting liquid- sticky sweet
can cause if intolerant to lactose.
No issue for diabetic patients as Lactulose is not absorbed through gut wall.
Up to 2 days for effect.
3-Magnesium hydroxide: e.g. Milk of Magnesia liquid
Mainly seen as liquid: 30-45ml PRN
Dose to be given at bedtime
Can be abused as it is very purgative (strong effect)
Old fashioned remedy - caution in elderly due to its purgative effect it can affect elderly more than younger patients. Can cause a strong laxative effect such as diarrhoea this can affect elderly worse than younger patients.
Commonly seen as OTC (max 3days use)
Research weak no RCT
3-6 hours for effect.
4- Docusate: e.g. DulcoEase, Dioctyl
Up to 500mg daily in divided doses
12-72 hours for effect of tablets, suppositories 15min
Softening agent with a stimulant effect
May be useful alternative for people who find it hard to increase their fluid intake
Generally well tolerated.
How to use suppositories and enemas?
As pharmacist have to instruct patient on use of both enema and suppositories.
1-Suppositories:
Position yourself comfortably. Lying on your left side with feet level or slightly elevated is the best position when in inserting a suppository
When ready, take the suppository out of the package and hold it in between your thumb and middle finger. Be careful not to drop it
Use water soluble lubricant to coat the blunt end of the suppository
Be sure that the blunt shape is pointing toward the anus not the tip. Insert suppository directly into the anus.
Insert it enough to avoid suppository from coming out. (Usually to the depth of your finger is sufficient)
Lie still and hold suppository inside the back passage for 10-15 minutes.
2-Enemas:
1. Once you have warmed the enema in a bowl or sink of warm water, pull the lid off the nozzle. Hold the bottle upright so the contents do not spill.
2. The nozzle is already lubricated, but you can put on more lubricating jelly if you like.
3. Lie on your left hand side, on the towel, with your knees bent up toward your chest as far as comfortable.
4. Gently push the nozzle about 7cm (in) into your anus.
5. Slowly squirt the contents in. Remove the nozzle once you have finished and stay lying down.
6. Try to hold the liquid in your bottom for as long as you can - five minutes, if possible.
Go to the toilet when you can no longer hold it and you really feel like emptying your bowels
8. Stay near the toilet for the next hour
9. Some people have stomach cramos for a short time after using the enema
10. Occasionally, you can feel faint or dizzy. If this happens, lie down until you feel better
*both products have a quick onset of action, given when prescriber wants urgent solution or a quick acting method more than oral tablets. Used before hospitalisation to undergo procedure for bowel evacuation.
These products licensed for constipation not faecal impaction. Arachis oil only exception given for faecal impaction but be aware of peanut allergy, warn patient.
Stimulant laxatives
Short term use
1-Senna/senokot
Tablets and syrup
7.5mg daily max per dose 30mg daily
Onset of action 8-13hours advice patient to take before bed at 6pm or 8pm and they should get bowel movement next morning.
Syrup is unpalatable.
2-Dantron/ co-danthramer or co-danthrusate
Co-danthramer includes PEG (Macrogol)
Co-danthrusate includes Docusate
Colours urine red but I harmful side effect.
Avoid prolonged contact with skin as it can cause skin irritation advice patients who wear nappies to be cautious and to change nappy frequently
Only used in terminally ill patients due to potential risk of ( potential carcinogen)
Oral solution
Onset of action 6-12 hours.
Sodium picosulphate/ Dulcolax
5-10mg once daily
Tablets and syrup
Syrup is palatable
Onset of action 10-14hours
Bisacodyl: Duclolax
Acts on small intestine
5-10mg once daily: increased if necessary up to 20mg OD
Tablets act in 10-12hrs
Suppositories act in 20-60mins but it can cause local inflammation
What is prucalopride (Resolor)?
Prucalopride is a selective serotonin 5HT4- receptor agonist with pro kinetic properties. Prucalopride is a medication that is used to treat constipation. It works by specifically targeting and activating serotonin 5HT4 receptors in the gut. By doing so, it enhances the natural movement of the digestive system, known as peristalsis, which helps to facilitate the passage of stools through the intestines. This prokinetic effect of prucalopride helps to relieve constipation and improve bowel movements.
Should only be prescribed by clinicians experienced in treating chronic constipation after careful review.
2mg tablets OD, review treatment if no response after 4 weeks (reduced dose in elderly)
S/E
Headache and GI disturbance
Increased doses will not improve response
1-2 weeks for effect
*Linaclotide for use for constipation in patients with IBS.
μ-opioid antagonist PAMORA
Peripherally acting μ-opioid antagonist PAMORA
*Naloxegol e.g. moventig tablets and syrup
*25mg OD to be taken in the morning
Counsel on the risk of opioid withdrawal (shouldn’t occur but cases have been reported)
Tablets can be crushed mixed with 120ml of water and taken immediately mixture can be administered via nasogastric tube if required.
Take on empty stomach
When naloxegol therapy is initiated it is recommended that all currently used maintenance laxative therapy should be halted until clinical effect if naloxegol is determined.
Works within 12-72 hours
*Naldemedine e.g. Rizmoic
200mcg tablets OD
Counsel on risk of opioid withdrawal
What is the pharmacology of Bulk forming laxatives?
Mostly of plant origin, including non digestible polysaccharides *cellulose and other components
Mechanism of action depends on type:
•typically polysaccharides increase osmolality in the gut when broken down, causing water retention.
•Retention of water in the GIT, so expanding and softening the stool.
•Bulkier stool distends the colon
•Promotion of peristalsis via stimulating colonic mucosal receptors/stretch receptors
•This leads to acetylcholine release which increases parasympathetic drive.
ACh activates muscarinic acetylcholine receptors mostly M2 and M3 subtypes, this increases peristalsis.
Also creates mucus layer in the intestinal lining, facilitating defecation.
What is the pharmacology of osmotic laxatives?
*Poorly absorbed so they act as osmotic agents and that increases water retention in the gut lumen.
*because they are hyperosmolar agents, they are absorbed into stools by osmosis, making it softer
*Softer stools are easier to pass.
*Many osmotic laxatives also contain Mg2+
*Mg2+ triggers release of cholecystokinin CCK
*CCK increases intestinal secreations and colonic motility
*Decreases transit time through gut.
AI:
Osmotic laxatives work by drawing water into the intestines, which helps soften the stool and promote bowel movements. They do this by increasing the osmotic pressure in the intestines, which prevents water from being absorbed and instead encourages water to be retained in the bowel. This increased water content in the intestines helps to stimulate bowel movements and relieve constipation. Osmotic laxatives can be helpful for short-term relief of constipation, but they should be used with caution and under the guidance of a healthcare professional.
What is the pharmacology of stimulant laxatives?
*Stimulate local reflexes of myenteric nerve plexus of the gut.
*Irritate nerve endings in wall of intestine
- Motor effect on gut wall increases propulsion
*Increases secretion of water into bowel
*Increases gut motility and decreased transit time
AI:
The pharmacology of stimulant laxatives involves several mechanisms that promote bowel movements and relieve constipation:
- Stimulation of Myenteric Nerve Plexus: Stimulant laxatives directly stimulate the local reflexes of the myenteric nerve plexus in the gut. This stimulation triggers rhythmic contractions (peristalsis) of the intestinal muscles, leading to increased propulsion of fecal matter through the intestines.
- Irritation of Nerve Endings: Stimulant laxatives also irritate the nerve endings in the wall of the intestine. This irritation enhances the sensitivity of the intestinal muscles to nerve signals, further promoting muscle contractions and bowel movements.
- Motor Effect on Gut Wall: The stimulation of the myenteric nerve plexus and the irritation of nerve endings in the intestine result in a motor effect on the gut wall. This effect increases the propulsive movements of the intestinal muscles, facilitating the movement of fecal matter towards the rectum.
- Increased Secretion of Water: Some stimulant laxatives, such as bisacodyl and senna, also increase the secretion of water into the bowel. This additional fluid softens the stool, making it easier to pass, and helps to prevent constipation by promoting regular bowel movements.
- Increased Gut Motility and Decreased Transit Time: Overall, the pharmacological actions of stimulant laxatives lead to increased gut motility and decreased transit time of fecal matter through the intestines. This accelerates intestinal transit, softens the stool, and promotes more frequent and easier bowel movements.
By targeting multiple mechanisms involved in bowel function, stimulant laxatives effectively relieve constipation and promote regular bowel function. However, it’s important to use them judiciously and under the guidance of a healthcare professional to minimize the risk of adverse effects and ensure optimal therapeutic outcomes.
What is the pharmacology of Senna?
Senna is an Anthraquinone laxatives, it combines with sugars to form glycosides.
Glycosides are molecules where the sugar is attached to a functional group via glycosidic bond.
Glycosides bond hydrolysed by colonic bacteria to release irritant anthracene glycoside derivatives, specifically sennosides A&B are absorbed and have direct action on myenteric nerve plexus, increasing smooth muscle activity.
They also increase PGE2 secretion (which increases gut motility).
Also reduces colonic water absorption.
Also
What’s the pharmacology of stool softeners?
Stool softener is known as emollient laxatives. Some work as surface wetting agents/surfactants (e.g. Docusate)
Reduced surface tension allows water/fats to penetrate stool.
This softens the stool, making it easier to pass.
Docusate has stimulant activity too
Arachis oil and paraffin creates a barrier between stool and intestinal wall. This eases passage of stool through intestine.
Paraffin no longer popular due to concerns over carcinogenicities.
What’s pharmacology of PAMORAs?
PAMORAs are competitive antagonist at mu-opioid receptors.
Prevent opioid activation of intestinal receptors. Targeting underlying opioid induced side effects ie reduced GI motility, hypertonicity, increased fluid absorption. This results in normal propulsion and peristalsis.
What’s the pharmacology of prucalopride?
Prucalopride is a 5HT4 receptor agonist:
5HT4 receptors are present on GI tract , especially myenteric plexus.
5HT4 activation leads to increased release of ACh this increases rest and digest parasympathetic drive and peristalsis and propulsion.
What are the alarm symptoms in community pharmacy and when is referral required?
Red flags:
1-Pain on defecation- causing suppression of reflex.
2-Patient over 40 years with sudden changes in bowel habits (no obvious cause)
3-Greater than 14days duration (no obvious cause)
4-Associated fatigue
5-Presence of blood in stool
6-Repeated failure of laxatives
7-Suspected laxative abuse
Children although there are laxatives licensed for children OTC, they require initial referral to a GP to have physical examination.
Macrogols is 1st line laxdor
Paediatric dose Macrogol is a POM, adult Macrogol is P med.
How does benign prostrate enlargement cause constipation?
70% of men over 70 have some degree of prostate enlargement.
Prostate is located above the rectum, enlargement of prostate puts pressure on rectum causes rectum to narrow affecting stool passage.
These patients must use stimulant laxatives for long time POM only.
Refer repeat requests and unexplained constipation in the over 40s but refer for prostate check too.
What’s Diarrhoea?
A change in normal bowel habit resulting in increased frequency of bowel movements and the passage of soft or watery stools.
May be accompanied by colicky pain due to increased contraction of smooth muscle with additional production of gases.
It is a symptom of different conditions but not a disease.
What’s acute and chronic diarrhoea?
*Acute diarrhoea:
Abrupt onset of >3 loose stools/day and lasts no longer than 14 days.
Dietary insults like alcohol or spicy food
Bacterial/viral infections
Majority of cases resolve within 2-3 days without specific treatment.
Use rehydration salt
*Chronic diarrhoea:
Pathological cause
Lasts >14 days
Possibly flare up of previously diagnosed condition eg IBS, UC, Crohn’s disease.
Needs further investigation to get to underlying cause.
How common is diarrhoea?
Difficult to quantify or determine as many cases are self limiting and not reported.
Common in children under 5:
Acute gastroenteritis most common
Between 1-3 cases per year due to underdeveloped GI system makes them more prone.
Adults:
Just under 1 episode/yr
22% food related
Travellers diarrhoea
Mortality & Morbidity of diarrhoea?
Mortality from acute diarrhoea declining globally.
Second highest cause of childhood mortality
Age and nutritional status are most important host factors in determining severity and duration.
The younger the child, the higher risk for severe, life threatening dehydration
What is the Pathophysiology of diarrhoea?
Change in the balance between the absorption and secretion of water and electrolytes due to:
Osmotic force that drives water into the gut lumen, eg after ingestion of nonabsorbable sugars
Proportional to the intake and responsive to fasting.
Or
Enterocytes actively secreting fluid eg enterotoxin-induced diarrhoea.
Not responsive to fasting
Ion transport activated by bacteria resulting in pathogens invading enterocytes or producing enterotoxins which damage cells or inducing cytokine secretion to produce PGE which stimulates secretion.
The passage is explaining the changes in the balance between the absorption and secretion of water and electrolytes that occur in the pathophysiology of diarrhea. There are two main mechanisms mentioned:
- Osmotic Force: This refers to the presence of substances in the gut lumen that cannot be absorbed by the body, such as nonabsorbable sugars. These substances create an osmotic gradient that draws water into the gut, leading to diarrhea. The amount of water that enters the gut is proportional to the intake of these substances and can also be influenced by fasting.
- Enterocyte Secretion: Enterocytes are cells lining the intestines that are responsible for absorbing nutrients and fluids. In some cases, these enterocytes can become overactive and start actively secreting fluid instead of absorbing it. This can be induced by enterotoxins, which are toxins produced by certain bacteria that specifically target the enterocytes. This type of diarrhea is not responsive to fasting.
Additionally, the passage mentions that ion transport, which involves the movement of electrolytes across the intestinal lining, can be activated by bacteria. This can occur when certain pathogens invade the enterocytes or produce enterotoxins that damage the cells. The activation of ion transport can also be triggered by the production of cytokines, which are inflammatory molecules, leading to the secretion of prostaglandins. Prostaglandins further stimulate fluid secretion in the intestines, contributing to diarrhea.
In summary, the passage explains that diarrhea can occur due to a change in the balance between the absorption and secretion of water and electrolytes in the intestines. This can be caused by the osmotic force created by nonabsorbable substances or by the active secretion of fluid by enterocytes, which can be induced by enterotoxins or bacterial invasion.
•AI:
Diarrhea is a condition characterized by the frequent passing of loose, watery stools. The pathophysiology of diarrhea involves disruption in the normal functioning of the gastrointestinal tract, leading to increased fluid secretion, decreased fluid absorption, or both.
There are several mechanisms that can contribute to the development of diarrhea:
- Increased Fluid Secretion: Certain infections, such as those caused by bacteria or viruses, can stimulate the release of toxins that activate chloride channels in the intestinal lining. This leads to increased secretion of chloride and water into the intestinal lumen, resulting in watery diarrhea.
- Decreased Fluid Absorption: Inflammation or damage to the intestinal lining can impair the absorption of fluid from the gut. Conditions like inflammatory bowel disease, celiac disease, or radiation enteritis can disrupt the normal absorption process, leading to diarrhea.
- Altered Intestinal Motility: Normal bowel movements rely on coordinated contractions of the intestinal muscles. Any disruption in this motility can affect the transit time of stool through the intestines. Conditions like irritable bowel syndrome or certain medications can cause abnormal motility patterns, leading to diarrhea.
- Malabsorption: Some digestive disorders, such as lactose intolerance or pancreatic insufficiency, can interfere with the normal absorption of nutrients and water from the intestines. This can result in osmotic diarrhea, where undigested substances draw excess water into the intestinal lumen.
- Microbial Imbalance: The balance of normal intestinal bacteria, known as the gut microbiota, plays a crucial role in maintaining gut health. Disruption of this balance, such as through the use of antibiotics, can lead to an overgrowth of harmful bacteria or yeast, causing diarrhea.
It’s important to note that the specific pathophysiology of diarrhea can vary depending on the underlying cause. Effective management of diarrhea involves identifying and addressing the underlying cause, as well as addressing fluid and electrolyte imbalances to prevent complications.
How do bacteria cause diarrhoea?
•Invasive bacteria causing diarrhoea: specific types of microorganisms can directly attack mucosal cells which cause diarrhoea. Stools will contain blood and pus. Patient will have fever, typical examples shigella, salmonella, yersinia, enteroinvasive E-coli.
•Non invasive: don’t directly damage the gut, bacteria produce enterotoxins that disrupt secretion of water and electrolytes. Patient will present with watery diarrhoea, examples include:
Staphylococcus aureus, B cereus, C perfingens, enterotoxigenic E. coli.
•Virally induced diarrhoea:
Mechanism not fully understood
Enterocytes become secretory resulting in watery diarrhoea.
How is diarrhoea diagnosed?
•Symptoms:
Accompanying symptoms; temp, fever, blood in stool.
Rapid onset
Absence of stool formation
•Trigger factors:
Bad/unusual food, alcohol, drugs, contaminated water.
Time/intensity:
Dehydration in major risk groups, dehydration serious risk in elderly patients.
Fecal studies and tests to identify pathogen. If bacterial infection it can be treated with antibiotics.
Serum albumin
Fecal alpha 1 anti-trypsin
Both tests can identify protein loss as this suggests damage in GI tract, not specific test but aids in diagnosis.
Intestinal biopsy used in severe diarrhoea.
What are the common causes of diarrhoea?
Infants: infectious gastroenteritis, toddlers diarrhoea, food intolerance, coeliac disease.
School age children:
Infectious gastroenteritis, drugs (antibiotics)
Adults: Infectious gastroenteritis, IBS, IBD, drugs, XS alcohol and spicy food, coeliac disease.
Older people:
Infectious gastroenteritis, large bowel cancer, faecal impaction (pseudo-diarrhoea) drugs, ischaemic colitis.
Typical causing organisms causing diarrhoea:
Children < 5: rotavirus most common and onset 12-48hrs.
Adults: campylobacter (onset 2-5days) most common, followed by rotavirus.
Other causes:
E.coli 1-6days, salmonella 12-24hrs, shigella 1-7days, clostridium difficile (usually starts during AB therapy), clostridium perfringens (12-18hrs), bacillus cereus (1-16hours), staphylococcus aureus (1-7hours).
What drugs induce diarrhoea?
Antibiotics-most common-broad spectrum.
Laxatives
Metformin
Ferrous sulphate (iron)
NSAIDs
Colestyramine
Antacids-Mg Salts
Beta blockers
Digoxin
Misoprostol
How to prevent diarrhoea?
Good hygiene: wash hands
After visiting the toilet
Before touching food
After gardening
After playing with pets
Between handling raw and cooked food
SUMMARY:
Diarrhoea is a change in normal bowel habit resulting in increased frequency and soft or watery stools.
Considerations in treatment include:
Age, frequency, duration
Assess dehydration risk
Anti-motility drugs have a role in the management of diarrhoea.
Diarrhoea clinical considerations
•List treatment options for different patients groups
•Describe the pharmacology of the treatment options
•Describe how to apply the guidance to over counter requests
•List appropriate non-pharmaceutical advice
•Identify and give details on the signs of dehydration
•Describe the cause, symptoms and treatment of Clostridioides Difficile infection (C.Diff)
What’s the treatment of acute diarrhoea in adults?
Treatment aims:
*prevention and reversal of fluid and electrolyte depletion
*Management of dehydration if present
•Most settle spontaneously at around 3 days
•Oral rehydration therapy ORT dioralyte rehydration salt.
•Rapid control of symptoms required?
Consider using Loperamide or branded Imodium peripheral opioid agonist (Loperamide acts as a potent opiate agonist in the intestine and reduces intestinal motility, causing a slowing of intestinal transport and increased resorption of water and electrolytes, actions that are helpful in treating diarrhea.)
Difference between prescribed dose and OTC med GSL and P med.
•Prescribed dose >12years: initially 4mg, followed by 2mg after each loose stool (for up to 5days max) usual dose 6-8mg daily; maximum16mg per day (8 caps).
•GSL/P dose >12 years: initially 4mg, followed by 2mg after each loose stool (for up to 48hours max); usual dose 6-8mg daily; maximum 12mg per day (6 caps).
Eat as soon as able bland food like soups, bread, pasta, rice, potatoes.
Avoid caffeine, alcohol, carbonated drinks. All of these drinks are diuretics.
Avoid anti-motility drugs in severe gastroenteritis or dysentery. These are more serious forms of diarrhoea due to blood/mucus in stools, fever. The concern is that loperamide can prolong the infection.
Prevention and treatment of fluid and electrolyte depletion is primary importance.
Oral rehydration therapy
Dioralyte >2 (if under 2 years only under medical supervision)
Mainstay of treatment for acute diarrhoea, to prevent or correct dehydration.
Advise patient to Maintain appropriate fluid intake once rehydration established.
Mix sachet with 200ml water.
Dioralyte relief: contains rice starch (bulks when in contact with water, this helps retain water int he colon to bulk up stools and help patients lose leas water)
Severe cases of diarrhoea require hospitalisation for IV fluids.
If under 1 year old-only under doctor supervision and supply:
Prescription doses For child 1-11months: 1-1.5 times usual feed volume to be given
For child 1-11years
200ml, to be given after every loose motion
For child 12-17 years
200-400ml to be given every loose motion, dose according to fluid loss.
For adult
200-400ml to be given after every loose motion, dose according to fluid loss.
How is chronic diarrhoea treated?
1-Determine underlying cause and treat as appropriate.
•underplaying pathological cause like crohns or IBS.
•foreign travel
•laxative abuse
•medications-PPIs or antibiotics
•immunocompromised
•family history of IBS/coeliac disease
•lactose intolerance (if worsened by diary), excess caffeine/sorbitol
•Refer for specialist investigation
Oral rehydration therapy and loperamide must be given while ongoing investigations to identify cause.
Testament in pregnancy and breastfeeding?
Loperamide manufacturers advice to avoid in pregnancy (no info available)
Weigh up risks to both baby and mum (if severe refer to professional)
Loperamide appears in breast milk
Amount probably too small to be harmful but it is still not licensed for OTC use in pregnancy or breast feeding.
Give patient ORT and fluid essentials- avoid dehydration
If symptoms warrant loperamide, refer in both instances from community pharmacy.
Treatment in children?
Feeding babies, continue with normal milk feeds. Breast milk has antibodies to fight infection or pathogen causing diarrhoea.
Children: encourage plenty of fluids
Use ORT
Anti-diarrhoeals not recommended by NICE ( BNF states doses for children but not licensed in <12 year olds for most products, so never sell from community pharmacy. For <12 need prescription.
Preventing spread of diarrohea
Careful washing and drying of hands after using toilet, nappy changing and before meals.
Don’t share towels
48hour exclusion from school following cessation of symptoms
Avoid swimming for 2 weeks following last episode of diarrhoea.
List the meds used to treat diarrhoea?
1-Co-phentrope
•atropine and diphenoxylate (anticholinergic and opioid)
•licensed as adjunct to rehydration in acute diarrohea
•Initially 4 tablets followed by 2 tablets every 6 hours until diarrhoea controlled.
2-Kaoline and Morphine
•Not evidence based such small amount of morphine
No evidence for kaolin in acute diarrhoea
Historical use elderly patient
Potential for abuse
3-Bismuth sub-salicylate
PeptoBismol (never in less than 16yrs old due to Reye’s syndrome)
Limited evidence not recommended by BNF or NICE
Inhibits intestinal fluid secretion
Suppresses intestinal inflammation
Bactericidal action.
4-Probiotics
•live bacteria
•compete for available nutrients with pathogen
•insufficient evidence for use on NHS
What’s the pharmacology of loperamide?
Synthetic opioid analogue-pethidine congener which doesn’t readily pass BBB.
Binds to mu-opioid receptors in gut wall, this inhibits Acetylcholine and Prostaglandin release.
ACh is the main excitatory neurotransmitter in the GI tract
ACh binds to muscarinic/ nicotinic ACh receptors, increasing parasympathetic activity.
ACh inhibition leads to:
Decreased propulsive peristalsis
Decreased sensitivity to rectal distension
Increased sphincter tone of the ileocaecal valve and anal sphincter.
•prostaglandin inhibiton leads to:
Reduced gut secreations
Reduced gut motility both mainly via inhibition of PGE2
Increased intestinal transit time (enhancing water and electrolyte reabsorption)
Morphine/codeine are also sometimes used to treat diarrohea
As opioids, they share this mechanism of action
Problems with abuse/dependence.
What’s the pharmacology of Co-phenotrope?
100 parts diphenoxylate HCl to 1 part atropine sulphate.
1-Diphenoxylate
•synthetic opioid- pethidine congener; doesn’t readily pass BBB.
•Does not usually have CNS activity; large doses lead to typical opioid effects.
•Insoluble salts mean that there is no potential for misuse by injectors.
2-Atropine
•Muscarinic ACh receptors antagonist.
•Reduction in ACh reduces parasympathetic drive PNS.
•GI motility is inhibited.
•Effect not marked as several as several excitatory transmitters, including ACh are important in the function.
AI:
Co-phenotrope is a combination medication that contains 100 parts of diphenoxylate HCl and 1 part of atropine sulphate. Here is the pharmacology of each component:
- Diphenoxylate:
- It is a synthetic opioid and a congener of pethidine.
- Diphenoxylate does not readily pass the blood-brain barrier (BBB).
- Typically, diphenoxylate does not have central nervous system (CNS) activity. However, at high doses, it can produce typical opioid effects.
- The presence of insoluble salts in diphenoxylate reduces the potential for misuse by injectors. - Atropine:
- Atropine is an antagonist of muscarinic acetylcholine (ACh) receptors.
- By blocking the action of ACh, atropine reduces parasympathetic drive from the peripheral nervous system (PNS).
- Inhibition of GI motility is one of the effects of atropine.
- However, the effect of atropine on GI function is not as pronounced as several excitatory transmitters, including ACh, play a role in GI function.
