PHARM FINAL Flashcards
The hypothalamic - pituitary - adrenal Axis
Is our bodies response to stress (fight or flight)
Stimuli = stress
Leads to hippocampus activates the hypothalamus
Hypothalamus releases vasopressin and corticoid releasing factor
CRF travels to the pituitary gland which releases adrendocorticotropic hormone to the blood to the adrenal cortex
Adrenal cortex releases cortisol
Cortisol is a negative feedback to pituitary and hypothalamus to reduce further stimulation of the system
Discuss the anatomy of the adrenal glands
Most superficial
Zone glomerulosa = secretes aldosterone
Zone fasciculata = secretes cortisol and androgens
Zone reticularis = secretes cortisol and androgens
Adrenal medulla = secretes epinephrine and norepinephrine
Most deep
Why are there different expression of enzymes in different zones of the adrenal glands?
Most superficial
Zona Glomerulosa = CYP11B2 which lead to aldosterone
Zona Fasciculata / reticularis = CYP11B1 and CYP17 to lead to cortisol & corticosterone
Medulla = CYP17 to lead to DHEA & androstenedione
What is the Maastricht acute stress test for humans?
This test measures the levels of cortisol in humans that respond to stress when they did their hand in cold water and try to do arithmetic
-males have high release of stress and faster
-women have a slower and nit as high release
What is diurnal cycle of serum glucocorticoids?
-Is the lowest in the middle of the night, but peaks in the morning (probably;y have something to do with waking)
-maybe anti - inflammatory because melatonin is pro inflammatory
- there is no average difference between males and females, age puberty but there is a lot of variance in individual levels of glucocorticoids
Why does stress increase glucocorticoid release into the blood and what can this result in?
- there are big differences fro individual to individual
-inappropriate stress response can result in too much and too long which can lead to a weaker HPA axis response
What is habituation?
-Repeated stressor can lead to habituation
-Chronic stressors (server pains, hypoglycemia) can lead to NO habituation
-both cases a novel stress can cause HYPER response of the HPA axis
What do corticosteroids do?
-regulate energy metabolism
-increase short term memory
-maintain BP
-inhibit inflammation
-help with fetal lung development
What does it mean when you have corticosteroids deficiency?
Addison’s disease
-causes low blood sugar
-low BP
-weakness
-muscle and joint pain
-skin darkening or vitiligo
-salt craving (reduce salt, increase potassium)
-nausea/diarrhea
-depression
What does it mean when you have corticosteroid overload?
Cushing;s syndrome
-skin thinning
-depression/mood swings
-memory loss/learning disability
-muscle wasting
-poor wound healing / suppression immune system
-hypertension
-diabetes
-osteoporosis
-anovulation
What are clinical causes of Addison’s disease?
Adrenal glands not functioning leads to hypocortsiol and hypo aldosterone
Hypo cortisol leads to decrease liver function & creased stomach digestive enzymes -> low blood sugar & vomiting diarrhea -> brain coma & death
Hypo aldosterone - kidney and water sodium loss -> low fluid volume -> low p=blood pressure -> shock -> Brian coma & death
What are clinical causes Cushing’s syndrome?
Hyper tension,
Buffalo hump,
Skin ulcers from poor wound healing,
Thinking of skin, moon face,
Osteoporosis
What is cortisone?
Isolated in the 1940’s and used for rheumatoid arthritis for the first time in 1948 and quickly become a widely sued drug
Who are Hench, Kendall and Reichstien?
Received the Nobel price in 1950 for discoveries related to hormones of the adrenal cortex
What are therapeutic uses of corticosteroids?
Allergic reactions = asthma, angioedema
Inflammation of bones/joints = arthritis, bursitis
Skin diseases = atopic dermatitis
thyroid disease = malignant exophthalmos
Miscellaneous= hypercalcemia
List some therapeutic verse adverse effects of glucocorticoids use (Dose and length of treatment)
Therapeutic effects= anti inflammatory effect and immunosuppression will decrease pain, swelling, stiffness, and physical disability
Adverse = infections, myopathy, osteoporosis, weight gain, increase CDV risk
How do synthetic glucocorticoids compare to non synthetic glucocorticoids?
Synthetic glucocorticoids that are stronger anti-inflammatories and can be used topically. Most do not have the salt retention properties that cortisol dose. Although some (Dexamethansone) have dramatically longer half lives compared to hydrocortisone
How do glucocorticoids regulate the gene in your body?
-10-20% of the genes in your body regulate your genes by binding to glucocorticoids receptors (GR) inside cells - can be alpha (active) or beta (blocks alpha)
-Because they have great affinity to corticosteroid binding globulin (CBG) in plasma but not very well to albumin
-regulation of genes by the GR can either invites transaction of the target genes or transrespression (messes up other transcription factor)
How do glucocorticoids work in a cell?
Glucocorticoids bind to their receptor which cause dimerization, translocation to the nucleons and bind to DNA to regulate transcription of target genes
What is the net result of glucocorticoids regulating your genes in your body?
The net results in increase anti-inflammatory gene expression, decrease in pro-inflammatory gene
What do glucocorticoids do
Affect metabolism and immune function because secrete cortisol
-in blood and binds to CBG
what do mineral corticosteroids do?
Salt retaking from secreting aldosterone
-causes sodium reabsportion in distal renal tubule, sweat glands, salivary glands and GI
-when it binds to mineralcorticoid receptor it increases the expression of sodium / postassium ATPase and epithelial sodium channel in the collecting duct in kidneys
What is insulin and where is it produced?
Insulin is a peptide h romaine produced by the beta cells of the pancreas and is central for regulating carbohydrate and fat metabolism
What is glycogen and where is it produced?
Glycogen is a polysaccharide and is produced in the liver and ,uncles
What is glucagon and where is it produced?
Glucagon is a peptide hormone and is produced by the alpha cells of the pancreases
What is glucose and where is it produced?
Glucose is a small molecule that and is produced by the liver when it turned glycogen into glucose
What role does the pancreas play in glucose metabolism and what pancreatic cells are involved?
Homeostasis blood glucose @ 90 mg/100mL
Stimulus when blood glucose rises -> detected by the BETA cells of the pancreas to release insulin ->insulin travels in the blood stream to the liver and body cells and tells it to uptake glucose from the blood and stores it as glycogen -> lower glucose levels
Stimulus when blood glucose decrease -> detected by ALPHA cells of the pancreas to release glucagon -> glucagon travels to the liver and tells it to break down glycogen and release glucose into the blood stream -> raises blood glucose levels
What are the different types of glucose transporters and where are they expressed?
GLUT 1 = all tissues especially red cells, brain
GLUT 2 = (FIRST to deal with blood glucose) beta cells of pancreas, liver, kidney, gut
GLUT 3 = brain, placenta
GLUT 4 = muscle, adipose tissue
GLUT 5 = gut, kidney
What is the effect of insulin on muscle
Increase glycogen synthesis
Increase glucose transport
Increase glycogen synthase and inhibits phosphorylase
Increase protein synthesis
Increase amino acid transport
Increase ribosomal protein synthesis
What is the effect of insulin on liver?
Anabolic action
Promotes glucose storage as glycogen increases triglyceride synthesis and VDL lipoprotein
Reversal of catabolic features of insulin deficiency
Inhibits glycogenolysis
Inhibits conversion of fatty acids to keto acid
Inhibits conversion of amino acid to glucose or keto acid
What is the effect of insulin on adipose tissue?
Increases triglyceride storage
What does it mean to be insulin resistant?
When cells in your muscles, fat and liver do not respond well to insulin and cannot use glucose from your blood as storage
What is diabetes mellitus?
Elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without impairment of insulin action
What are they four different types of diabetes?
Type 1: insulin -dependent diabetes, selective beta cells destruction, insulin deficiency
Type 2: non insulin dependent, tissue resistance to insulin, relative deficiency of insulin
Type 3: other, such as pancreatectomy, pancreatitis, drug therapy
Type 4: gestational diabetes mellitus, placental hormones cause insulin resistance
What is the root cause and symptoms of type 2 diabetes?
-too much food with too much animal fat
-not enough exercise
-genetics
-overweight
-insulin resistance
-fat deposits in pancreas
What are the activities of diabetes drug biguanides?
Metformin, it activates AMPKinase and reduces liver glucose production
Metformin = inhibits production in the liver by activation of 5’ Adenosine monophosphate - activated protein kinase (AMP)
What are the activities of diabetes drug sulfonylureas?
Causes insulin secretion from beta cells by closing K+ channels
What are the activities of diabetes drug GLP-1 receptor agonists?
EX: Exenatide (from Gila monster venom). Bind to glucagon-like polypeptide receptors (GLP-1, a gut hormone) to increase insulin release, lower glucagon, reduce appetite
What does A1C measure ?
Hemoglobin A1C that measures average blood sugar over the past 3 months
-6.5 % higher = diabetes
-5.7% - 6.4% = prediabetes
-5.7% and below = good
What are DPP-4 inhibitors?
Block degradation of GLP-1, raise circulating GLP-1 levels. Increase insulin release, lowers glucagon levels, reduce appetite
What are alpha cells?
20% and secretes glucagon
What are beta cells?
75% secretes insulin, C-peptide, amylin
What are delta cells?
3-5% secretes somatostatin
What are G cells?
1% and secretes Gastrin
What are F cells?
1% and secrete pancreatic polypeptide
Therapeutic insulin
Different half lives and drives glucose uptake
What is Exenatide?
GLP-1 receptor agonist made from Gila monster Venom
What is pramlintide?
Binds amylin receptors to decrease appetite
What is octreotide?
Mimics somatostatin, blocks growth hormone, glucagon, and insulin
How is function insulin and C peptide created?
cleavage of pro - insulin by proprotein convertase to create functional insulin and its by product C - peptide
What can all increases blood glucose ?
Flood, glucagon, and glucocorticoids
Fasting versus prandial state
Fasting = most glucose goes to the brain
Prandial = (after eating) goes to brain, liver, and muscle
Basic metabolic differences between non diabetic and diabetic people
Metabolic effects of diabetic people- no stimulation of glucose transport and metabolism
Non diabetic - stimulation of glucose transport and metabolism
Stimulation of glycogen synthesis
Stimulation of lipogenesis
Inhabitation of lipolysis
