Flashcards in Physiology Kanani IV Deck (45):
What are gastric secretions composed of?
These are both exocrine and endocrine in nature:
Ions: notably hydrochloric acid and bicarbonate
Pepsinogen: enzyme precursor for protein digestion
Intrinsic factor: for the absorption of vitamin B12
Hormones: gastrin is the main one, also histamine from regional mast cells
Which gastric cells are involved in these secretions?
Note that these cells are located within the gastric glands, the entrance to which is seen on the surface as gastric pits:
Parietal cells: secretion of HCl and intrinsic factor. Most frequently in the glands of the fundus
Chief cells: secreting pepsinogen, the precursor of pepsin
Mucous cells: most frequently found in the necks of the gastric glands of the pylorus
G-cells: found in the glands of the pylorus and they secrete the hormone gastrin
Why does the stomach secrete acid?
There are three main reasons:
HCl has some proteolytic activity
By reducing the gastric pH to 2, it provides the ideal environment for the gastric enzyme pepsin
Has antibacterial properties and prevents colonisation
What is the volume of gastric secretion daily?
1–1.5 L per day.
How is hydrochloric acid produced by the parietal cell?
There is the initial active transport of K and Cl into the cell
H that is generated from CO2 dissolving into the cytoplasm is actively exchanged with K at the H-K ATPase. The H enters the gastric lumen
The HCO3 generated through dissociation of H2CO3 diffuses back into the plasma in exchange for Cl
Chloride now enters the gastric lumen
How is the production of gastric acid controlled?
HCl secretion is stimulated by:
ACh: from parasympathetic vagal neurones that innervate the parietal cells directly
Gastrin: produced by pyloric G-cells
Histamine: produced by mast cells. This stimulates the parietal cells directly and also potentiates parietal cell stimulation by gastrin and neuronal stimulation
HCl secretion is inhibited by:
Somatostatin: from cells in the enteric nervous system
Secretin: produced by the duodenum and inhibits gastrin release
CCK: also inhibits gastrin release
Can you name some drugs that inhibit gastric acid
Omeprazole: one of the proton-pump (H-K ATPase) inhibitors
Cimetidine, ranitidine: anti histamines that prevent mast cell stimulation of parietal cells
Acetazolamide: inhibits the enzyme carbonic anhydrase, which catalyses the reaction that sees to HCO3 generation within the parietal cell
How does the stomach protect itself from autodigestion by the acid and pepsin that it produces?
There is copious production of mucus that forms a gel on the surface of the epithelium. Mixed within this is bicarbonate. Together, they ensure that the pH of the environment immediately adjacent to the epithelium is kept at neutral.
Describe the phases of gastric acid secretion.
Cephalic phase: initiated by the thought, smell and taste of food. Leads to vagal activation that stimulates HCl and gastrin secretion
Gastric phase: initiated by the presence of food in the stomach particularly protein rich food. There is, again, both an increase in the level of HCl and gastrin
Intestinal phase: initially, the presence of amino acid and food in the duodenum stimulate acid production. Later there is inhibition following the release of secretin and CCK
Summarise, then, the actions of gastrin.
Stimulates gastric acid secretion
Stimulates exocrine pancreatic secretions
Stimulates gastric motility
List the hormones which stimulate gastric emptying.
Gastrin: released from the gastric G-cells
CCK: from the duodenum
Secretin: also from the duodenum
Describe how metabolic alkalosis develops in pyloric stenosis.
Gastric secretions are rich in H and Cl, both of which are lost
There is a reduction of pancreatic exocrine secretions due to the reduced acid load at the duodenum. This therefore leads to retention of bicarbonate-rich pancreatic secretion, worsening the alkalosis already caused by loss of protons
Volume depletion maintains the alkalosis by leading to bicarbonate absorption over chloride
In order to maintain electrochemical neutrality, in response to loss of chloride, there is increased renal uptake of bicarbonate, further worsening the alkalosis
Describe some of the physiological effects of a total gastrectomy.
In simple terms, this leads to a complete loss of parietal cells leading to no gastric acid, together with no intrin- sic factor nor pepsin:
No IF: leads to vitamin B12 deficiency, manifest as a megaloblastic anaemia
Achlorhydria: promotes iron deficiency
Dumping syndrome: gastrectomy leads to the rapid transfer of hypertonic chyme into the small bowel. This leads to transfer of fluid from the extracellular space into the bowel. The immediate effect of this is abdominal distension, vomiting and diarrhoea. The fall in the circulating volume leads to the physiological shock response, with tachycardia, sweating and narrow pulse pressure
Hypokalaemia: Vomitus contains around 10 mmolL1 of potassium, which is lost. Further potassium is lost from the kidney as protons are exchanged for potassium. Also, the increased aldosterone secreted by the adrenal cortex in response to fluid loss exacerbates renal potassium loss
Where is saliva produced?
Parotid glands: produce a watery (serous) salivary secretion
Submandibular and sublingual glands: the saliva produced contains a higher concentration of protein, and so is more mucinous
Oral glands: smaller and spread diffusely
How is the secretion controlled?
This is under the control of the ANS.
Parasympathetic stimulation: produces a large volume of watery saliva that is low in protein
Sympathetic stimulation: causes a reduction of secretion, with high mucin content
What class of drug is atropine?
Atropine is a muscarinic cholinoceptor antagonist. It is a tertiary amine, so undergoes gut absorption, and CNS penetration.
Its effects may be understood in terms of parasympa- thetic inhibition:
Cardiovascular: although it produces tachycardia due to parasympathetic inhibition, a low dose may initially give rise to a bradycardia due to central vagal activation. Ultimately, the resulting tachycardia is only mild, since the cardiac parasympathetic tone is inhibited without any concurrent sympathetic stimulation
Gut: decreased gut motility, leading to constipation
Relaxation of other smooth muscles: such as in the
bronchi. May also lead to urinary retention due to
its effects on the bladder
Inhibition of glandular secretions: such as salivary and
Pupiliary dilatation (mydriasis) and failure of accommodation: leads to blurred vision and photophobia
CNS: causes excitation, restlessness and agitation
Why have agents in the same class as atropine been used for premedication prior to induction of anaesthesia?
Reduction of bronchial and salivary secretions prior to intubation reduces the risk of aspiration
Prevention of bronchospasm during intubation through relaxation of the bronchial smooth muscle
Inducing drowsiness preoperatively: hyoscine (unlike atropine) causes drowsiness and some amnesia
Antiemesis: especially hyoscine
Reduction of the unwanted effects of neostigmine (used for reversal of paralysis) – such as increased salivation and bradycardia
Counteraction of the hypotensive and bradycardic effects of some inhaled anaesthetic agents
Use of these agents
Premedication prior to anaesthesia, e.g.
Reversal of bradycardia, e.g. atropine for vaso-vagal
attacks or during cardio-pulmonary resuscitation
Anti-spasmodic for the gut, e.g. hyoscine
Anti-emesis, e.g. hyoscine for motion sickness
Mydriatic for eye examination, e.g. atropine, tropicamide
Organophosphate poisoning, e.g. atropine. These agents are potent anticholinesterases
From a pharmacological point of view, where are the two most important locations of nicotinic cholinoceptors?
Although found throughout the CNS, the two most clin- ically important areas for nicotinic cholinoceptors are at autonomic ganglia (serving both the SNS and PNS), and at the postsynaptic membrane of the NMJ.
Name some agents that block nicotinic cholinoceptors at the NMJ. What uses do they have?
Non-depolarising block Tubocurarine
It follows that these agents are used for producing muscular paralysis during induction and maintenance of anaesthesia. Note that the non- depolarising drugs are quaternary ammonium compounds, so are not absorbed by the gut
What is meant by a ‘depolarising’ and a ‘non- depolarising’ block?
Non-depolarising block is where there is competitive antagonism of ACh at the motor endplates. Thus, these agents act as a physical barrier to muscle fibre activation
Depolarising block is where there is an initial rapid and sustained activation of the postsynaptic membrane until finally there is loss of excitability and the block established
Therefore with a depolarising block, there is an initial muscular fasciculation until the block is established
Despite this, the depolarising agents produce a more rapid onset of block than the non- depolarising agents
Outline some of the unwanted effects associated with depolarising agents.
Muscular pain: following the use of suxamethonium, patients often report generalised or localised muscle pain. This is related to the initial painful fasciculation produced by this agent as part of its depolarising block
Hyperkalaemia: due to loss of potassium from the muscle fibre. This occurs because of the increases in sodium uptake that occur during the depolarising block causes a net loss of potassium from the cell
Malignant hyperthermia: an autosomal dominant condition, leading to a rapid and uncontrolled hyperthermia following a depolarising block and fasciculation
Bradycardia in the case of suxamethonium due to a direct muscarinic stimulation
How may the block at the NMJ be reversed?
Non-depolarising agents may be reversed by the use of anticholinesterases.
As the name suggests, the AChEs prevent the hydrolysis of ACh at the synaptic cleft. The local increase in the concentration of ACh is enough to overcome the com- petitive block produced by the non-depolarising agents.
Name some of these agents. What uses do they have?
Examples of anticholinesterases include: neostigmine, physostigmine and edrophonium.
Apart from use in the reversal of non-depolarising muscle relaxants, they have also been used for the diag- nosis and palliation of myasthenia gravis. In this condi- tion, there is an immune-mediated destruction of ACh receptors, leading to progressive muscular weakness.
What is the danger of using anticholinesterase agents with depolarising neuromuscular blockers?
By causing a local increase of ACh, the anti- cholinesterase agents exacerbate the block produced by depolarising muscle relaxants.
What happens to the characteristics of the block caused by depolarising agents with continuous administration?
The initial depolarising block produced is also termed a ‘phase I block’. With repeated administration, a ‘phase II’ block is encountered, when a non-depolarising block occurs. This phenomenon of depolarising agents is also known as a DUAL BLOCK, and can lead to prolonged paralysis.
Therefore, given the change in the characteristics of the block, during phase II, the action of depolarising agents may be terminated with the use of anticholinesterases.
What is the basic histologic structure of the thyroid gland?
The thyroid is composed of numerous follicles that have a central fluid-filled cavity. They are lined with follicular cells that secrete the main hormones
Interspersed among the follicles are the para- follicular cells
Which hormones does the thyroid produce?
Tetra-iodothyronine (T4, thyroxine): the principle hormone of the thyroid gland
Tri-iodothyronine (T3): measure for measure, this is more potent than T4, however, has a shorter duration of action
Calcitonin: produced by the para-follicular cells. This is important in the regulation of serum calcium (see ‘Calcium balance’)
Name another source of T3 other than the thyroid.
This may also be produced by the conversion of T4 in the peripheral tissues. In fact, the thyroid accounts for only 20% of the extrathyroid pool of T3.
Which other hormone may be produced following the peripheral conversion of T4?
Reversed-T3 (r-T3). This is an inactive hormone acts as a point of peripheral thyroid hormone control.
Outline the steps involved in the production of T3 and T4.
Iodide trapping: dietary iodine is concentrated into the follicular cells by an active pump mechanism
Oxidation: of iodide to a reactive form by the enzyme peroxidase. This is located on the apical membrane
Organification: through binding with amino acids – mainly tyrosine. These form tyrosyl units
Thyroglobulin formation: tyrosyl units combine with a protein core to form thyroglobulin
Internal coupling: tyrosyl units combine on the thyroglobulin molecule to form T3 or T4 molecules still bound to the protein core
Storage: the thyroglobulin molecules are transferred to the colloid of the follicles for storage
Release: this occurs following stimulation by thyroid- stimulating hormone (TSH). The thyroglobulin molecule is taken up into the follicle by endocytosis, and following fusion with lysosomes, releases the T3 and T4 molecules
How are the molecules transported in the circulation?
T4: predominantly bound to thyroid-binding globulin, and a smaller proportion to thyroid- binding prealbumin. A small fraction is unbound
T3: bound mainly to thyroid-binding globulin. A higher proportion is found unbound
Outline the basic physiological roles of thyroid hormone.
Increased BMR: this leads to increased oxygen consumption and increased heat production
Protein metabolism: this has implications for growth and development. Both protein formation and degradation are enhanced. During hormone excesses, degradation is increased over synthesis
Carbohydrate metabolism: all aspects of metabolism are increased-cellular uptake of glucose, glycolysis, gluconeogenesis and glycogenolysis
Fat metabolism: lead to lipolysis with a concomitant increase in the plasma FFA concentration. At the same time increases the cellular oxidation of these fatty acids
Others systems: increases the CO, in part through increasing the BMR and by enhancing the effects of other hormones. Also important for CNS development and increasing cortical arousal
Potentiation of other hormones: enhances the actions of catacholamines and insulin, among others
What is their mechanism of action?
Like steroid hormones, the thyroid hormones act through an intracellular mechanism. They penetrate the cytoplasm with ease and act on intracellular receptors to active various genes in the cell’s nucleus.
How is hormone production regulated?
The anterior pituitary hormone TSH controls release of hormone. It enhances all of the steps of thyroid hor- mone production outlined above. Various other hor- mones stimulate release, such as estrogens.
Other than a goitre, what other physical signs may you expect to find when examining a patient with Grave’s disease?
Generally, may have features of recent weight loss
Patient may be flushed, suggesting heat intolerance
Other features of sympathetic stimulation: peripheral tremor, presence of atrial fibrillation
Extrathyroid manifestations: eye signs, thyroid acropachy (a form of pseudo-clubbing of the fingers) and pretibial myxoedema
What are the eye signs?
Lid retraction and lid lag: due to increased sympathetic activation of the levator palpebrae superiorus
Exophthalmos/proptosis: due to oedema of the retro- orbital fat
Diplopia: due to combinations of the above
a wave is due to atrial contraction
x wave follows the end of atrial systole
c wave is produced by bulging of the tricuspid valve into the atrium at the start of ventricular systole
v wave occurs due to progressive venous return to the atrium. It indicates the timing of ventricular systole, but is not directly caused by it
y descent occurs following opening of the tricuspid valve
What is the normal range for the CVP?
Which factors determine the venous return to the heart, and hence the CVP?
Circulating blood volume: it follows that the greater the blood volume, the greater the venous pressure
Venous tone: sympathetic stimulation in various peripheral and visceral venous beds causes venoconstriction, leading to increased venous return and venous pressure. This is an important compensatory mechanism in hypovolaemia that maintains the stroke volume and CO
Posture: supine posture or leg elevation increases the venous return
Skeletal muscle pump: the calf pump system is particularly important in increasing the venous return during exercise, when muscle contraction compresses the deep soleus plexus of veins
Respiratory cycle and intrathoracic pressure: during inspiration, the intrathoracic pressure falls (i.e. becomes more negative) increasing the venous return gradient to the heart. The opposite occurs during expiration
How do ventilation and perfusion vary in different parts of the lung?
The lower parts of the lung are better perfused than the higher parts
The lower parts are also relatively better ventilated. (The lower portions of the lung lie on a steeper portion of the compliance curve than the apex)
However, in terms of the ratio of the two variables, the V/Q falls going from the apex to the base of the lung
You have stated that adequate oxygenation depends on an even matching of ventilation and perfusion in the various lung units. How is the ratio kept as even as possible?
There are two main mechanisms by which mismatching of ventilation and perfusion is kept to the minimum in lung units:
Hypoxic vasoconstriction: a fall in the PaO2 that accompanies a fall in the V/Q leads to reflex vasoconstriction of pulmonary arterioles. This evens out the V/Q, improving oxygenation. Conversely, if the V/Q is high, there is pulmonary vasodilatation, again matching the V/Q
Changes in bronchial smooth muscle tone: this is also sensitive to hypoxaemia, altering the calibre of the airways and therefore ventilation of lung units
Give some causes for hypoxaemia due to a V/Q mismatch.
Congenital cardiac defects mentioned above
Pulmonary oedema, e.g due to cardiac failure and ARDS
Note that this produces a Type I respiratory failure. Hyperventilation does not increase the PaO2 due to the large shunt, but it blows off the CO2. Thus, there is hypoxaemia, with a low or normal PaCO2.