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292 Chapter 11 Respiratory disease: asthma and COPD
14a) Name the main spasmogens released by mast cells. What is their effect in asthmatic airways?
14b) Antihistamines (H1 histamine receptor antagonists) are not used in the treatment of asthma to
reduce bronchospasm. Why is this?
15a) Prostaglandins and leukotrienes are mediators of inflammation involved in asthma. Complete the
diagram below to show the relationship between the two.
Membrane phospholipids
______________________
_____________ enzyme ______________ enzyme
______________________
______________________
15b) Use the diagram above to explain why aspirin may worsen asthma in some cases.
There are two main objectives in treating asthma:
1. Relievingthebronchospasmtoalleviatebreathlessness—theaimofrelievermedication.
2. Reductionofinammationinthelatephase,andprophylaxistoavoidfutureattacks—theaimof
preventer/controller medication.
16a) Which of Chris’s inhalers is the preventer medication? What type of drug is this?
16b) Describe the mechanism of action of this class of drug, and explain why it is the cornerstone of
asthma therapy.
Chris is started on a course of prednisolone. The pharmacist explains that this is a
corticosteroid, like the beclometasone she inhales. Prednisolone is given at high doses for a
short period to treat acute exacerbations by suppressing the inflammatory response.
17) Can a corticosteroid like prednisolone be used on its own to treat an asthma exacerbation? Explain
your answer.
18) Why can salbutamol be used as required, whilst beclometasone should be used regularly?
19) What other drugs are available for the treatment of asthma?
Chris remains in hospital for two more days, after which time her breathing has returned to
normal.
She is discharged with the following medication:
• usualinhalers(nochanges)
• prednisoloneforfourfurtherdays.
WORKBOOK 8 Chronic obstructive pulmonary disease and asthma 293
20) What are the dangers of abruptly stopping an oral corticosteroid? Is this a concern here? Explain
your answer.
Chris is seen by her respiratory consultant in the asthma clinic 4 weeks after her discharge. The
consultant suggests that Chris tries the SMART regime for controlling her asthma. This stands
for Symbicort® Maintenance and Reliever Therapy. By following this regime Chris will need just
one inhaler. She should use one puff of the Symbicort® regularly twice a day as preventer
medication, but can also use one puff of the same inhaler when required, as a reliever.
Symbicort® is a combination inhaler containing budesonide and formoterol. (Fostair® and DuoResp®
are alternatives with similar regimes.)
21a) Explain the role of the two components of Symbicort® in the treatment of asthma.
21b) What type of drug is formoterol? How does its action compare with salbutamol?
An appointment is made for Chris to return to the clinic in 3 months to be reviewed.
Chris’s children are very happy that she is healthy again, but they are disappointed that Felix
has to go!
Part 4
Gastrointestinal
and endocrine
disorders
296 Part 4 Gastrointestinal and endocrine disorders
In order to function normally, and to adapt to changes in the internal and external
environment, there must be communication between the various parts of the body. There
are two main systems enabling this interaction: the nervous system, which allows rapid
communication and fast responses, and the endocrine (or hormonal) system, which
produces widespread and more sustained responses. Part 4 of this book deals with the
treatment of some of the more common endocrine disorders, and how one aspect of the
endocrine system can be manipulated in order to prevent conception.
A number of hormones are secreted by cells within the gastrointestinal tract, which is
therefore considered as part of body’s endocrine system; the pharmacological treatment
of conditions arising from dysfunction of the digestive tract is also considered in Part 4.
In addition to its main function of digesting and absorbing nutrients and water, the
gastrointestinal tract plays a pivotal role in therapeutics as the site where most drugs are
administered and absorbed.
P4.1 Structure and function of the
gastrointestinal tract
The gastrointestinal tract describes the continuous structure, essentially a tube, running from
the mouth through to the anus. It is broadly divided into upper and lower sections (Figure P4.1).
The upper part starts at the mouth, from where ingested material is conducted, via the
pharynx, into the oesophagus and then into the stomach. The stomach contents are emptied
into the first section of the small intestine, the duodenum, which marks the start of the lower
gastrointestinal tract. From here, material passes sequentially through the remaining sections
of the small intestine (the jejunum and ileum) and into the large intestine (the cecum, colon,
and rectum). The continuous tract terminates at the anus, where solid wastes are eliminated.
The various sections perform specialized roles, which collectively enable the absorption of
nutrients, and the elimination of waste. The digestive process depends upon both motility
(mixing and propelling movements) and glandular secretions. These secretions are
produced by cells lining the gastrointestinal tract, and by accessory organs, the pancreas
and liver, which secrete their products into the lumen when signalled to do so. Digestive
motility and secretion are carefully coordinated so as to maximize absorption of nutrients,
controlled by both neuronal and hormonal networks.
P4.1.1 Neuronal control of the gastrointestinal tract
The digestive system is regulated by two neuronal systems: the enteric nervous system
(intrinsic nerves) and the autonomic nervous system (extrinsic nerves). The enteric
nervous system is a vast system of nerves, lying entirely within the walls of the full length of
the gastrointestinal tract. It regulates all aspects of the digestive process, including motility,
blood flow, and secretions, and can act independently of the autonomic nervous system.
It comprises two major networks: the myenteric plexus, involved primarily with motility,
and the submucosal plexus, which regulates blood flow and secretions. The enteric
nervous system contains over 100 million neurons, about the same number as found in
the spinal cord.1 Within the enteric nervous system, sensory neurons (intrinsic primary
1 e enteric nervous system is sometimes referred to as the second brain.
P4.1 Structure and function of the gastrointestinal tract 297
Pharynx
Oral cavity
Tongue
Liver
Gallbladder
Common bile duct
Colon
Transverse colon
Ascending colon
Descending colon
Caecum
Appendix
Salivary glands
Parotid
Submandibular
Sublingual
Oesophagus
Stomach
Pancreas
Pancreatic
duct
Small intestine
Duodenum
Jejunum
Ileum
Upper gastrointestinal tract
Lower gastrointestinal tract
Rectum
Anus
Figure P4.1 Structures of the gastrointestinal tract.
Adapted from Pocock G, Richards C, The Human Body, 2009. By permission of Oxford University Press.
afferent neurons) respond to specific stimuli in the gastrointestinal tract. They
communicate, via interneurons, with intrinsic efferent neurons, and these innervate the
smooth muscle and secretory cells of the digestive system. The intrinsic nerve plexuses
directly coordinate local activity in the digestive tract, but overall function is influenced by
input from extrinsic nerves, and by endocrine and paracrine signals (see below).
Extrinsic nerves regulating digestive tract function are from both sympathetic and
parasympathetic branches of the autonomic nervous system. These nerves either act
directly to alter gut motility and secretions, or modulate the activity within the intrinsic
plexuses. The effects produced in response to parasympathetic (cholinergic) and
sympathetic (adrenergic) input are generally opposing, as described in Table P4.1.
298 Part 4 Gastrointestinal and endocrine disorders
Table P4.1 Effects of the sympathetic and parasympathetic nervous system on the
gastrointestinal tract
Parasympathetic Sympathetic
Salivary glands Increased secretion (thin/watery) Increased secretion (thick)
Smooth muscle Increased contractility leading to
increased motility
Sphincters Relaxation Contraction
Glands Increased secretion No effect
Blood flow No effect Decreased
P4.1.2 Hormonal controls in the gastrointestinal tract
In concert with neuronal control, gastric function is influenced by a number of substances
secreted by specialized epithelial cells within the lining of the gastrointestinal tract. These
can be broadly divided into two types (Figure P4.2).
1. Endocrine factors (classic hormones) are secreted into the bloodstream and travel to
their site of action, at a distance from the site of production. Important examples in the
gastrointestinal tract include gastrin, cholecystokinin, and secretin.
2. Paracrine factors are released by secretory cells and diffuse to their site of action. They
exert effects only on cells in the immediate vicinity of their release, and therefore act as
local messengers (or local hormones). Histamine is an example of a paracrine signal. It
is released from enterochromaffin-like cells in the gastric mucosa, and promotes
release of acid from nearby parietal cells (see Chapter 12).
Decreased contractility leading to
decreased motility
Secretory cells in gastric glands in the stomach lining produce three mediators: gastrin
and somatostatin2 (both endocrine factors), and histamine (a paracrine factor). These
factors regulate secretion of acid into the stomach, and are considered in detail in
Chapter 12, where some commonly encountered conditions arising from the
hypersecretion of gastric acid are examined.
These three factors act in concert with digestive enzymes and muscular mixing actions to
produce chyme. This thick liquid mixture enters the duodenum, the first part of the small
intestine. In the duodenum chyme is mixed with secretions from the absorptive epithelial
cells that line the intestines (enterocytes), and with exocrine secretions from the pancreas
and liver.
Two additional hormones generated in the duodenum itself regulate the digestive process:
1. Cholecystokinin (CCK): endocrine cells in the mucosal lining of the duodenum sense
the presence of fats and proteins, and in response they release CCK into the blood. It
travels to the pancreas where it stimulates the secretion of digestive enzymes into the
duodenum. CCK also promotes the release of bile by stimulating contraction of the
gallbladder, and by relaxing the sphincter of Oddi which guards the opening of the bile
2 Somatostatin has distinct roles elsewhere in the body. For instance it is produced in the hypothalamus and
inhibits the release of growth hormone from the anterior pituitary; see Box P4.1.
P4.1 Structure and function of the gastrointestinal tract 299
Parietal cell
Endocrine
cell
Hormone
Blood vessel
Endocrine signalling
Parietal cell
Paracrine
cell
Blood vessel
Paracrine signalling
Figure P4.2 Endocrine and paracrine signalling.
duct into the duodenum. CCK inhibits gastric motility and secretion to allow time for
nutrients already in the duodenum to be digested and absorbed.
2. Secretin is released in response to the presence of acid in the duodenum. This
endocrine factor promotes pancreatic secretion of bicarbonate-rich alkaline fluid. The
acid-neutralizing effect has two roles: it reduces the damaging effects of the acid, and it
provides the optimal pH for the activity of the pancreatic enzymes. Like CCK, secretin
also inhibits gastric motility and secretion.
These hormones act in concert with neuronal inputs to exert fine control over the rate of
movement of ingested material through the digestive tract, thereby optimizing absorption
of nutrients; disturbances to the rate of transit through the gut can lead to diarrhoea and
constipation (see Chapter 13).
300 Part 4 Gastrointestinal and endocrine disorders
The interplay between neuronal and endocrine systems is illustrated when considering the
physiological response to the anticipation of food (the cephalic phase of gastric secretion).
The sight or smell of food acts via the parasympathetic nervous system to increase gastric
acid secretion by the parietal cells of the stomach (see Chapter 12, Box 12.1). This results
both from direct vagal stimulation of G-cells in the stomach, increasing secretion of the
endocrine factor gastrin, and from the activation of intrinsic nerves, which stimulate the
parietal cells.
P4.2 Structure and function of the endocrine
system
The key structures involved in the endocrine system are the hypothalamus, pituitary
gland, thyroid gland, adrenal gland, pancreas, and gonads (ovaries and testes). At the
centre is the hypothalamus, located at the base of the brain. Located within the central
nervous system, the hypothalamus provides the essential link between the nervous and
endocrine systems, and receives input from both the internal and external environments.
The hypothalamus produces a range of hormones, most of which promote or inhibit the
release of hormones from the pituitary gland (see Box P4.1). In humans, the pituitary
gland is a marble-sized gland that is connected to the hypothalamus by a series of blood
vessels, and by a group of nerves called the hypothalamo-hypophyseal tract. The gland is
composed of two lobes: the larger is the anterior pituitary, and the smaller is the posterior
pituitary. The posterior region secretes two hormones: antidiuretic hormone (also called
vasopressin) and oxytocin. Antidiuretic hormone is involved in controlling the osmolarity of
the blood (a measure of the concentration of solutes such as ions (e.g. Na+, Cl−) and other
substances such as glucose). It is released following stimulation of osmoreceptors in the
hypothalamus, which sense increases in the osmolarity of the blood. Antidiuretic hormone
then signals an increase in the permeability of the kidney distal and collecting tubules, to
allow greater reabsorption of water, with the result that a more concentrated urine is
produced.
The second posterior pituitary hormone, oxytocin, is involved in the contraction of the
uterus and the ejection of milk during lactation.
The hormones of the anterior pituitary control an extremely broad range of functions,
acting on many tissues and glands including the adrenal and thyroid glands, liver, gonads,
muscles, and bone (see Box P4.1). Their secretion is regulated by hormones, mostly
peptides, released from the hypothalamus.
Thyroid stimulating hormone released from the anterior pituitary regulates the function of
the thyroid gland which determines the body’s basal metabolic rate, as well as having
important roles in growth and development; thyroid disorders are the subject of Chapter 15,
Section 15.2. Two further hormones from the anterior pituitary, luteinizing hormone and
follicle stimulating hormone, and their roles in the female reproductive cycle, are
considered in Chapter 15, Section 15.4, in the context of pharmacological contraception.
Adrenocorticotropic hormone is responsible for the production of the ‘stress hormone’
cortisol by the adrenal cortex. This glucocorticosteroid hormone is involved in protecting the
body from various stresses, including trauma and severe infections; the anti-inflammatory
actions of drugs acting at receptors for cortisol have been discussed in detail in Chapter 9.
Box P4.1
Major elements of the endocrine system
HYPOTHALAMUS
CRH
GnRH
ANTERIOR PITUITARY
TRH
GHRH
Somatostatin
Dopamine
ACTH
Adrenal gland Gonads Thyroid
Cortisol
Controls
carbohydrate,
protein and fat
metabolism;
protects against
stress
Figure a
ACTH, adrenocorticotropic hormone; CRH, corticotrophin-releasing hormone; FSH, follicle stimulating hormone; GH, growth
hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinizing hormone;
MSH, melanocyte stimulating hormone; TRH, thyrotrophin-releasing hormone; TSH, thyroid stimulating hormone; T4,
tetraiodothyronine (thyroxine); T3, triiodothyronine; ⊖, inhibits release; ⊕, promotes release.
FSH
LH
Oestrogen
Progesterone
(females)
Testosterone
(males)
Promotes development and
function of female and male
reproductive organs;
required for pregnancy
and lactation
TSH
T4 & T
Increase
metabolism in
most tissues
Prolactin
3
Promotes milk
production
GH
Targets the liver, bones,
and muscles. Controls
the body’s growth
and development