Pharmacology Flashcards
Describe the basic structure, synthesis,release and transport in Peptide hormones
Peptide hormones are formed from amino acid chains as long as 3 amini acids to complex hormones of 180 amino acids long.
They start with a gene which is transcribed into mRNAand translated into a protein in the ribosome. These are then attatched to a tubbular network that forms the Rough endoplasmic reticulum
The first structure formed is a preprohormone, this has a presignal that tells the molecule that it needs further processing. From here the signal peptide is cleaved and there is additional protein folding and disulfide bond formation.
This is then imported into the Golgi complex where furtherther processed as a prohormone to its final state. Bu the time it reaches the end of the Golgi complex, it is. packaged into secretory granules where it is stored until the arrival of an appropriate stimulus where they may leave via exocytosis.
Peptide hormones are hydrophilic, and because of this they simply dissolve in the aqueous environment so they do not need to be bound to the plasma proteins, but because of this they have a very short half-life of a few minutes as it is broken down by proteases
Describe and distinguish the basic structure, synthesis,release and transport, mechamism of hormone action in Steroid hormones
This is the formation of lipophilic substances. Cholesterol is taken as a basis and converted into a steroid hormone by a series of enzymatic reactions to give us a steroid. The hormone is lipophilic so it cannor be stored in an excretory granule as it would simply diffuse through the membrane.
As soon as it is synthesised, as it is lipophilic it will pass through the cell membrane via simple diffusion. In the blood it is not transported very well and so binds to carrier proteins. This is because the steroid hormones are highly lipophilic and the blood is an aqueous environment
The carrier proteins, protect the hormones from degradation and hence have a longer half-life of a few hours-days. We also need to bare in mind only the unbound or free hormone is biologically active
Explain the Physiological mechanisms involved in the regulation of hormone release including feedback control, the endocrine axis, neuroendocrine reflexes and diurnal rythms
Homeostasis is the maintenance of a constant internal environment and so is used as a mechanism to keep conditions in the body relatively constant.
One way this may occur is via feedback regulation
Another is via the endocrine axis where the Hypothalamus, peripheral endocrine glands are involved in the feedback regulation of hormone secretion.
Too high levels of peripheral hormone(The one that acts on targer cells) will have a direct and indirect inhibition via a negative feedback loop. The Hypothalamus is the indirect, the anterior pituitary is the direct inhibition
If levels are too low there is simply no inhibition on he anterior pituotary or hypothalamus
The diurnal ryhthm involces cortisol, Which is highest in the morning, supposedly after we wake up to make us alert for the day, so when this rhythm is disrupted
Describe the mechanisms by which endocrine disorders develop(Including autoimmune)
Endocrine disorders can be caused by Hypersecretion which can be as a result of a tumour or immunological factor such as Grave’s disease
Another reason for endocrine disorders is due to genetics,immunological attacks, destruction by disease or surgical removal.
Autoimmunity is where the body starts to attack itself which means we start to have the activation of the innate and adaptive immune systems. This OFTEN results in cellular damage, but not always like in the case of grave’s disease
There may also be a decrease in target-cell responsiveness at the level of receptor or even the downstreaming of the enzyme
The primary defect is release to the endocrine cell that makes the hormone, whereas the secondary defect could refer o the endocrine axis which regulates the endocrine gland
For example a defect at the Adrenal cortex would be primary but at the anterior pituitary would be regarded as a secondary defect.
Outline the types and ourposes of endocrine tests used in the invesigation of endocrine disorders
In order to investigate endocrine disorders there are a few methods we can use:
Single point baseline tests
Dynamic or provocative tests to check the integrity of the feedback control
Stumulation tests are used if we suspect hyposecretion. A failure to secrete indicates hormone insufficiency
Supression tests are used if we suspect Hypersecretion. Failure to supress indicates autonomous secretion, indicative of a tumour
Imaging is done as many endocrine disorders are due to the presence of a tumour
Summarise the principles of treatment of endocrine disorders
In the case of hormone defficiency, hormone reolacement is the general treatment method
In excess hormone producion, drugs which block production are used
If decreased target-cell responivesness - treat with drugs to enhance cellular respons to hormone.
If tumour - radoitherapy or surgery.
Desccribe the Mechanism of Hormone action in Peptide hormones
There are 2 receptors available for peptide hormones:
- G protein coupled receptors for hormones like glucagon
- Tyrosine Kinase receptors like insulin
These receptors are needed for proteins as they are hydrophillic syubstabces so they are required for the hormone to illicit Signal transduction which causes a physological response for example:
- Altered activity of enzymes or ion channels
- Alters expression of specific proteins
Desccribe the Mechanism of Hormone action in Steroid hormones
As steroid hormones are lipophilic when free, they can freely cross the lipid bilayer of the plasma membrane, as a result the majority of their action is via intracelluar receptors.
These nuclear receptors or cytosolic receptors act as hormone-regulated transcription factors
This allows them to either increase or decrease gene expression which increases the protein which the DNA codes for and hence proportionally efefcts the biological action of that protein
Describe the composition of cells types wihin pancreatic islet and state their hormone products
In the pancreatic islets, the cells are:
Alpha cells(30-40%) - which make glucagon
Beta cells(50-60%) - which make insulin
Delta cells(5-10%) - Which make somatostatin
PP cells(1-5%) - which make pancreatic polypeptide
Epsilon cells(Less than 1%) - which make Ghrelin
Briefly describe the steps involved in the biosynthesis of insulin
Insulin is initially made as Prepro-insulin which has 86 amino acis and contains a signalling molecule which indicates that more processing needs to be done. It then goes to the RER for the cleavage of this signalling unit to produce proinsulin in microvesicles. This goes into the Golgi clomplex where the C peptide is produced to produce mature insulin
The cleavage renders insulin less water soluble, so it can precipitate out of with zinc ions to form a dense crystalloid core within the secretory granule in order to pack alot of insulin into a small space.
Outline the control of insulin and glucagon secretion - including effects of nutrients, autonomic innervation and intrapancreatic and paracrine effects
The main regulator of insulin release is glucose, though there are a number of nutrient stimuli like amino acids and fatty acids in addition which can lead to insulin secretion
Gut hormones known as incretins which are secreted from cells in the small intestine after eating can engance the nutrient-stimulated insulin release, it secretes insulin almost in anticipation from the raised blood glucose from eating
Another potential cause for insulin secretion is islet glucagon which is secreted by A cells, so we have paracrine communicationwhere it travels through interstitial fluid to influence neighbouring cells
Somatostatin secreted from the Delta islet cells inhibits both glucose and insulin secretion from their cells
The islets are also innervated by both branches of the nervous system
Describe the steps involved in glucose-indued insulin secretion
At low plasma glucose levels, There is low level of glucose metabolism, hense a low level of basal insulin sedretion due to low levels of calcium ions entering the cell through voltage gated calcium ion channels which would cause depolarisation of the membrane allowing for release of insulin via exocytosis
When levels go up by 5mM there is an increase in glucose metabolism which leads to an increased production of ATP from the phosphorylation of ADP. This increase in the ATP can cause the closing of ATP sensitive potassium ion channels, meaning more Potassium ions will stay in the cell, this reults in membrane depolarisation and so the opening of voltage gated Calcium channels which leads to exytosis of insulin
State the effects of insuslin on glucose uptake and glucose utilisation in key target tissues - state the anabolic effects of insulin
Insulin has effects in 3 differnt areas, The liver, adipose tissue and muscle. In the mucle, It promotes glucose uptake via GLUT-4 and protein synthesis, however decreases proetin breakdown
In the Adipose it promotes glucose uptake and lipogenesis, however decreases lipolysis
In the liiver it promotes Glycogen synthesis, and causes a decrease in glucose glycogen breakdown anf gluconeogenesis.
It has an overall effect of reducing blood glucose levels.
Briefly describe insulin receptor signalling - basic steps, five examples of adapter. proteins and signals
The binding of a hormone to the tyrosine receptor causes intrinsic Tyrosine phosphorylation in the inside of the cell which has a greater affinity for adaptor proteins that produce a number of signals including changes in gene expression
- The adaptor proteins in the insulin receptor are IRS and Shc.
- When IRS drawns near to the receptor it becomes phosphorylated which draws the enzyme PI-3 kinase towards which phosphorylates PIP 2 in the membrane to PIP 3 which activates a kinase PDK1/2 which activates protein kinase B which elicits a number of responses
- When Shc draws near to the phosphorylated receptor it interacts with Grb2 and SOS which causes the beginning of a growth signal
Describe The roles plated by insulin and the counter regulatory hormones in glucose homeostasis
Glucagon is a peptide hormone released in response to Low blood glucose Its release is inhibited by high blood glucose, insulin and somatostatin. They work by stimulating hepatic gluconeogenesis aswell as lipolysis to gibe free gatty acids and glycerol to be used in glucose prduction.
The two insulin and glucose have complementary action. When the level of blood glucose is altered the cells in the islets will stimulate or inhibit appropriate hormone secretion in response to bring blood glucose levels back to normal
Define Diabetes Mellitus and distinguish between T1DM and T2DM he causes, prevalence and key features
Diabetes melitus is a chronic metabolic disorder characterised by hyperglycaemia, the most comon forms are T1DM and T2DM
Type one Diebetes is characterised by a total insulin deficiency whereas Type 2 there is impaired B-islet functions and/or a loss of insulin sensitivity or insulin resistance. In this diabetes, at the start to compensate for insulin resistance in the body, there may be an increased secretion of Insulin which will ultimately offset the insulin resisance, and so overtime when the okasma insulin level may fall with decreased beta cell function to to the earlier proliferation, there may will be a fall in insulin with high plasma glucose levels aswell.
They accounf for 90% of diabetes cases
Outline the secondary causes of diabetes, briefly describe the processes that lead to the presentation of common signs and symptoms of diabetes
One of the symptoms which appear in diabetic patients is glycosuria, which is the prevelance of glucose in the urine. When Plasma glucose exceeds certain levels, It exceeds the renal reabsorbtive capacity which means that glucsoe is no longer reabsorbed back into the blood and thus appears in urine. This occurs as the glucose transporters in the kidney reach their saturation point
As glucose is an Osmotically active substance, as it is drawn into the urine, it also causes an increase in urinary osmotic pressure and hence the urnie retains water which is known as osmotic diuresis and causes excessive urinary production. This presents the symptoms of dehydration aswell as polyuria
Other common symrotoms are Fatigue and malaise due to lack of insulin action in the body. as well as blurred vision.
T1DM selectivey may present symptoms of weight loss and DKA(Nausea and vomiting)
T2DM may selectively present altered mental status
Secondary causes of DM include Endocerine diseases such as Cushing’s syndrome which may present excess Cortisol, Acrimegaly which presents Excess growth hormone and Excessive secretion of Adrenaline.
There is also drug induced DM from Steroids, Beta-blovkers, Diuretics
Outline the principle methods of treatment of T1DM and describe the techniques available for assessing the degree of glycaemic control achieved
- Normal
- Fasting Greater than 7mM
- Random Greater than 11.1mM
- If patients present with signs/symptoms ad their plasma glucose levels are as below in any of the categories then a diagnosis of DM can be made
- Fasting should be less than 7mM
- Random should be less than 11.1mM
- Plasma glucose conc is over or equal to 11mM if performed with an oral glucose tolerance test
- HbA1c is a test of glycated haemoglobin - glucose molecules attaching to haemoglobin, it is an indicator of glycaemic control during the previous 2-3 months. A value greater than 48 mmol/mol is a diagnosis of diabetes
- If the patient presents asymptomatic then 2 glucose tests will be required to present the diagnosis of diabetes
The main treatment options are insulin regular exercise and healthy diet
Outline the principle methods of treatment of T2DM and descrube the techniques available for assessing the degree of glycaemic control achieved
Around 10-20% of patients rely on diet and 80-90% by drugs
It is intially managed with diet and lifestyle interventions following diagnosis for the first 3 months, if the patient does not respond well, there is a stepwise management with drug treatment.
The firstline drug is metformin, though there is caution in patients with renal failure, with possible alternatives DPP-4 inhibitors, SGLT2 inhibitors.
If a patient develops CHF/CVD or has a Qrisk score of 10% higher, SGLT2 inhibitors are prescribed alongside Metformin
Define Hypoglycaemia, how might this develop in a patient with diabetes and state the physical signs and symoroms associaed wih a hypo- discuss its management
Hypoglycaemia is a low blood glucose level of less than 4 mM. We may see this occur in patients with T1DM who may have an insulin overdose, excessive exercise or inadequte CHO intake relative to ther insulin dose.
Signs and symptoms include dizziness, hunger, iritability, headache etc. This may progress further into palpatation, Tremors, sweating and anxiety
If Blood glucose is nont restored to normallevels we may see a glucose difficiency in the brain which may lead to a loss of consciousness and seizure.
Treatment options are sugary drink and good
What is DKA
DKA is often presented in patients with undiagnosed DKA
This could be due to the omission or reduction in an insulin dose and it results in a wide range of side effects.
Essentially the loss of insulin in the skeletal muscle causes an increase in the breakdown of amino acids and datty acids and glycerol to aid in gluconeogenesis.The break down of the fatty acids simulates the formaion of acetoacetate which goes on to form the acidic B-hydroxybutyrate and acetone which lower the pH of the blood due to its acidity leading to metabolic acidoseis leading to CNS depression, peripheral circulatory failure and eventulally deatb
What are the microvascular Complications of Diabetes
Damage of small vessels like capillaries as a result of hyperglycaemia as well as its metabolites associated with the condition and glycation of proteins which can lead to advance glycated endproducts and hence impaired protein function
Retinoathy - Back of eye disease
Nephropathy - kidney disease
Neuropathy - alteration in nerve functiondue to impaited capillary supply to the nerves
Wha are the macrovascular complications of diabetes
These are conditions which tend to affect nmedium to large blood vesels and includes:
CV disease - ischaemic heart disease
CVD - stroke
Peripheral Vascular disease
- Very much associated with Accelerated atherosclerosis
- IHD develops prematurely and is the leading cause of death in diabetes
- There is an increased risk of complications after MI in these patients as well
- Requires vigorous management of risk factors such as hypercholesterolaemia and hypertension in DM patients
- With Cerebral vascular disease in stroke, there is a 10-fold increase in younger patients and it is more likely to be fatal with the less damaging TIAs less likely. Hypertension control is needed
- Peripheral Vascular disease focuses on the larger vasculature in the periphery
- Intermittent cramping is to do with the blood supply to the calves, ulceration
- Risk of gangrene(Tissue necrosis)/amputation
- Risk of other vascular events like embolisms for example
- Diabetic foot ulcers arise with poor blood supply as well as neuropathy which results in poor sensation and poor healing. There is also an increased susceptibility to infection
Why do T2DM patients not undergo DKA
This is because T2DM still produce insulin which inhibits this process, therefore there would be no ketones in the urine
MoA of metformin?
The MoA is not clear but it is thought to activate AMP kinase which is an enzyme that plays an important role in insulin Signalling and the metabolism of proteins and fats.
Doing so increases glucoseutilisation and decreases glucoseneuogenesis. AMP kinase plays an important tole in inhibiting hepatic gluconeogenesis as well as increasing peripheral insulin sensitivity.
MoA of sulphonylurea
These like gliclazide act on binding sites of a potassium channel and stimulate insulin secretion by blocking the potassium channel from opening which leads to membrane depolarisation -> extracellular calcium inlux -> increased insulin release
MoA of pioglitazone
The Pioglitazone are thiazolidinedione which is also known PPAR gamma agonist or insulin sensitiser. These PPAR receptors are on adipose tissue and promotes the maturation of fat cells and ultimately reduces circulating fat leveles hence a reduction in insulin resistance and so an improvement in insulin sensitivity in the body
MoA of GLP-2 mimetics
These can also be classified as incretin mimetics. These are gut hormores which lower blood glucose level by stimulateinf glucose-induced insulin release as well as inhibition of glucagon release
DPP-4 degrades the incretins very quickly so the use of GLP-2 mimmetics can be used which are resistent to the DPP-4 Action
Describe The vascular and nervous connections between the hypothalamus and the pituitary gland
The posterior piruitary is essemtialy a continuation or extention of the hypothalamus - a downgrowth from the brain which gives it a much more neural appearence , whereas the anterior pituitary is much more vasculatisaed which is common for endocrine cells
There are cell bodies within the Hypothalamus that secrete hypotahlamic releasing-factors into thecapilary bed of the pituitary stalk, these go down portal vessels to reach the capillary bed in the anterior pituitary which is made up of a range of endocrine cells leading to the secretion of hormones in the anterior pituitary
The connectio with the Posterior pituitary as stated is a more neural connection with long acons that spread to the posterior pituitary from the hypothalamus. Cell bodies of the PVN and SON as well as the nuerones carrying oxytocin and Vasopressin are transported dow the aons to the hypophyseal tract to be stored at the axon termini of the Neuroendocirne cells of the posterior putuitary where they are secreted into the small capillary netweork to trael around the body
Briefly review The consequences of a pituitary tumour, in relation to structures which are anaomically related to the pituitary in terms of hormone production
The pituitary sits close to the Optic Chiasm, the nerves and bloos supply of the eyes, therefore a pituitary Tumour will impact the optic chiasm where the nerves and blood supply may potentially cross over to present potential signs and symotoms such as a headache for examoke due to increasing cranial pressure
Desribe what is meant by endocrine Axis and outline control of secretion of the Anterior pituitary hormones and respective hypothalamic releasing hormones
The endocrine axis is a representation of the interactions between the Hypothalamus, the pituitary and peripheral endocrine glands.
All the hypothalamic-releasing hormones are tropic, meaning they only act on the Anterior pituitary . Many of the anterior pituitary hormones are also tropic
Growth hormone is predominantly stimulated by Growth hormone-releasing hormone, a small element is mediated by the inhibitory somatostatin
Describe the actions of Growth hormone and prolactin
Prolactin may not be considered as a tropic hormone as i doesnt act on another endocrine gland but instead on the breast tissue instead.
High levels of prolactin can inhibit GnRH which can cause a decerase in the release ofsex-hormones which is often associated with post-partum women, It stimulates mammary glands to produce milk as well as the growth and development of breasts. Excess prolactin is caused by Hyperprolactammia which has symptoms of loss of fertility, libido and also breast development in mean, The treatment is mainly dopamine recepotor antagonists whcih would inhibit prolactin secretion and shrink tumouts. The main Cause is prolactinoma
Growth hormone has a major role in growth, particulatly in linear growth. It also has effects on metabolism
- GH helps to build up protein/muscle by increasing amino acid uptake and protein synthesis
- It causes an increase in lipolysis, where the free fatty acids and glycerol are used in gluconeogenesis in the liver
- There is also a decrease in glucose uptake in fat tissue and muscle
- There is an overall increase in blood glucose as there is increased synthesis and decreased uptake by muscle and fats. this therefore means patients with Growth hormone can develop secondary diabetes, and has an indirect ability in providing growth
- It stimulates growth factors such as IGF-I and IGF-II from liver and other cell types
- These are known as somatomedins
- By doing so we promote the growth of soft tissue by increasing cell size and cell number(Hyperplasia)
- as well as promoting skeletal growth in both the length and thickness of bone
Outline regulation of posterioir pituitary hormones, arginine Vasopressin and oxytocin and summarise heir actions
cell bodies of the PVN and SON nuclei and the neurones carry oxytocin and AVP to the posterior pituitary, where they are stored/released.
AVP/ADH release is stimulated by increase in body fluid Osmolality which is regulated by osmotic control as well as falls in blood volume or pressure which is regulated by Haemodynamic control.
AVP essentially causes Vasoconstriction of blood vessels via V1 recepors a higher AVP concentrations and it causes an increased permeability og water and hence reabbsotbtion of such via V2 receptors in the DCT and Collecting Duct
Oxytocin is released by sucjking and by cervical stimulation whuch triggers sensory nerves to stimulate an impule to the hypothalamus down the long axon of the Posterior pituitary which releases oxytocin that stimulates he expression of breast milk as well as smooth muscle contraction.
Describe the main features of pituitary diseases of hormone deficiency and excess and the principle of treatment of these disorders
A growth homone deficiency in childten may cause stundeted growth aka pituitary drwarfism, as well as a defficiency later in adulthood, whereas an excess would cause Accelerated growth in children and Acromegaly in adulthood.
In adults there are a variety of non spacific symproms such as osteoporosis and adipose tissue gain around the waist. Acromegaly may result in headaches, sleep apnoea, hypertension and more with a treatment possibly having to get rid of GH-secreting tumours meaning radio therapy or possibly somatostatin analogues which will decrease levels.
State the various hormones produced by the adrenal gland
The Cortex(Outer layer of adrenal gland) make the adrenal steroids such as glucocorticoids like Cortisol, Mineralocorticoids like aldosterone, and weakandrigens like DHEA.
The medulla is where the Catecholamines are made such as adrenaline and noradrenaline
Regarding aldosterone and adrenal androgens, briefly describe the control of hormone release and their actions in the body
Describe the hyothalamic-pituitary-adrenal axis
When the hypothalamus releases CRH, it acts on t he anterioir pituitary to release ACTH which acts on the arenal cortex release the Cortisol, aldosterone and weak androgens, However it is importan to note that interms of negative feedback control, only Cortisol is involved.
Cotisol is a stress horone which has a big impluse in acute stress. High levels of cortisol enable us to get up and about or day once woken up. Fot this reason administration of steroids in the night ay cause for patients to not be able to get adequate sleep as their body clock may get confused.
Review the metabolic actions of cortisol on target tissues, and its immunosupressive effects
Discuss the role of cortisol in the bodys stress response
Increases Glucose levels in the body by increases fat breakdown and protein breakdown in the muscle for gluconeogenesis.
Decreases Glucose uprake and lipogenesis in the liver.
It also stores excess glucose as glycogen
Describe the mechanisms underlying the main disorders of the adrenal cortex including Cushings, addisons and Conns disease. Describe Signs and symptoms associated with these conditions and the principles of treatment of these disorders
