Quiz #6 Material Flashcards
(57 cards)
1
Q
Thyroid
A
- Composed of two lobes that flank the pharynx and esophagus
- Contains numerous follicles, composed of epithelial follicle cells and colloid
- Largest true endocrine gland
2
Q
Thyroid hormones control:
A
- The body’s basal metabolic rate
- The overall metabolism of protein, fat, and carbohydrates
- The sensitivity to catecholamines
3
Q
Thyroid Hormones
A
- Triiodothyronine (T3) and thyroxine (T4) are synthesized from thyroglobulin
- 660 kDa protein with ~120 tyrosines
- The major form of thyroid hormone in the blood is T4
- T4:T3 is ~20:1
- T4 has a longer half-life
- T3 is 5-10x more potent
- 25% of T4 is converted to T3 in peripheral tissues
- Mainly the liver and kidney
- Decarboxylation and deiodination of T3 and T4 produce thyronamine (T0a) and iodothyronamine (T1a)
- Their physiological roles are not completely understood
- Have generally opposing roles to T3 and T4
- May also function as neuromodulators
4
Q
Thyroid hormone synthesis
A
- The thyroid can store many weeks worth of thyroid hormone (cupled to thyroglobulin)
- If no dietary idoine is available for this period, thyroid hormone secretion will be maintained.
- Iodine ion comes into thyroid follicle cell via Na/I symporter and then leaves into follicle colloid via pendrin channel
- Thyroglobulin is made and then secreted via exocytosis into the follicle colloid
- Thyroid peroxidase (TPO) causes the oxidation of Iodine ion.
- Thyroglobulin is then iodinated and conjugated
- New molecule is taken into thyroid follicular cell via endocytosis
- Proteolysis causes molecule to split into T3 and T4, which is then secreted
5
Q
Thyroid stimulating hormone
A
- Acts directly on follicular cells
- Increases
- Iodide transport into follicular cells
- Production of thyroglobulin
- Iodination of thyroglobulin
- Endocytosis of iodinated thyroglobulin from the colloid into follicular cells
- Proteolysis of iodinated thyroglobulin
- Exocytosis into the capillaries
6
Q
Physiological roles of thyroid hormone (think heart and lungs)
A
- Cardiovascular system
- Increase heart rate
- Increase force of cardiac contractions
- Increase stroke volume
- Increase cardiac output
- Increase catecholamine receptors
- Respiratory system
- Inrease resting respiratory rate
- Increase minute ventilation
- Increase ventilatory response to hypercapnia and hypoxia
- Oxygen-carrying capacity
- Increase red blood cell mass
- Increase oxygen dissocation from hemoglobin
- Oxygen consumption
- Increase mitochondrial size, number and enzymes
- Increase plasma membrane Na-K ATPase activity
- Increase futile thermogenic energy cycles
- Decrease superoxide dismutase activity
7
Q
Physiological roles of thyroid hormone (others)
A
- Renal system
- Increase blood flow
- Increase glomerular filtration rate
- Reproductive system
- Required for normal follicular development and ovulation
- Required for normal maintenance of pregnancy
- Required for normal spermatogenesis
- Growth and tissue development
- Increases growth and maturation of bone
- Increases tooth development and eruption
- Increases growth and maturation of epidermis, hari follicles, and nails
- Increases rate and force of skeletal muscle contractions
- Nervous system
- Critical for central nervous system development
- Enhances wakefulness and alertness
- Enhances memory and learning capacity
- Increases speed and amplitude of peripheral nerve reflexes
8
Q
TR-RXR heterodimer action
A
- No ligand, no expression
- With ligand, activation of gene expression
9
Q
4 different thyroid hormone receptors
A
- Tα1 and Tα2 are splice variants of the THRA gene
- Tβ1 and Tβ2 are splice variants of the THRB gene
- Tα1, Tβ1 and Tβ2 generally activate transcription when T3 binds (except in pituatary, TRβ2 is a transcriptional activator until T3 binds then it inhibits)
- Tα2 does not bind T3/T4 and therefore inhibits
10
Q
Feedback control in the HPT axis
A
11
Q
Thyroid hormone circulation
A
- ~99.98% of T4 is bounds to 3 serum proteins
- 75% thyroid-binding globulin (TBG)
- 15-20% thyroid-binding prealbumin (TBPA or transthyretin)
- 5-10% albumin
- 0.02% of T4 in serum is free
- 0.4% of total T3 in serum is free
12
Q
Regulation of T4 metabolism
A
- Activation (β adrenergic)
- Deiodination (peripheral dehalogenases in liver/kidneys)
- T3
- Inactivation (glucocorticoids)
- Deiodination (peripheral dehalogenases in liver/kidneys)
- Reverse T3
- Inhibits T3 production
13
Q
Hypothyroidism
A
- Primary
- Cretinism
- Hypothyroidism during childhood
- Retarted growth, sluggish movements, mental deficiencies
- Myxedema
- Hypothyroidism during adulthood
- ~5% of the adult population
- Simple Goiter
- Iodine deficency
- High TSH causes thyroid hypertrophy
- Hashimoto’s syndrome
- Autoimmune
- Iatrogenic
- Often following treatment of hyperthyroidism
- Cretinism
- Secondary
- Pituitary disease
- Hypothalamic diease
14
Q
Hyperthyroidism
A
- Grave’s Disease
- Autoimmune
- Usually in 3rd decade, 8:1 women
- Diffuse thryoid enlargement, wide staring gaze, lid lag, protuberant eyes, hyperpigmentation, high body temp, jittery
- Excess endogenous thryoid hormone
- After treatment of hypothyroidism
- Thyroid cancers
- Produces excess thyroid hormone
- Acute hyperthyroidism
- Causes often unknown
- Muscle fatigue, weakness, weight loss, sweating, heat intolerance
15
Q
Hypothyrodisim treatment
A
- Iodine supplementation
- Synthetic T4 (Synthroid or equivalent)
- T3 is more active and acts faster but is more toxic
- T4 is less susceptible for feedback regulation
- Goal is to normalize TSH serum concentrations
- Always check for angina and perform an ECG
16
Q
Hyperthyroidism Treatments
A
- Thioamide drugs (TPO inhibitors)
- PTU, propylthiouracil
- MMI, methimazole (Tapazole)
-
Disadvantages
- Short half lives (1.5 hours for PTU)
- Can inhibit dehalogenase
- Slow acting
- Potential side effects; agranulocutosis, aplastic anemia, liver damage
-
131I
-
Advantages
- Short path length of radiation and local concentration makes it safe and effetive
- Excreted rapidly
-
Disadvantages
- Cannot be used long term (cancer risk)
- Can lead to delayed hypothyroidism
- Cannot be used during pregnancy
-
Advantages
- Surgery
- Partial (adenoma) or complete (Grave’s disease) thyroidectomy
- For patients allergic to thioamides or resistant to 131I treatment
17
Q
Multiple hormones influence eating
A
- Ghrelin
- Made in response to an empty stomach
- PYY
- Made in response to food entering the small intestine
- Insulin
- Made in response to rising blood glucose levels
- Leptin
- Made in response to increasing fat stores
18
Q
Cyclic secretion of apetite hormones
A
- Grehlin peaks at meals
- Insulin peaks post-prandial
19
Q
Leptin
A
- Discovered in 1994 as a gene mutated in obese mice that arose in Jackson Labs in the 50s
- Secreted by fats cells and circulating plasma levels of leptin correlate with fat stores
- Production depends on the number and size of adipocytes
- Obese people have high leptin levels
- Leptin levels do not appreciably rise after overfeeding
- Leptin levels do decrease rapidly with food restriction, suggesting it may be a signal to control fuel metabolism during fasting and starvation
- Adminstration of leptin during a fast prevents the starvation response (decreased thyroid and gonadal hormones, increased glucocorticcoids, decreased body temp, increased eating)
20
Q
Leptin Action
A
- Binds POMC neurons (anorexigenic neurons)
- Induces production of α-melanocyte-stimulating hormone (α-MSH)
- α-MSH suppresses appetite by signaling a “stop eating” signal
- Leptin binds NPY neurons (orexigenic neurons)
- Relieves inhibtion of POMC neurons
- Prevents triggering of “start eating” signal
21
Q
Leptin injection a treatment for obesity?
A
- Obese patient show elevated blood leptin concentrations
- Leptin production is a function of fat cell abundance and size
- In most cases, leptin injections have no weight-reduing effects
- Obses patients have developed a resistance to the leptin signal
- Congential leptin deficency and leptin receptor dificency have been reported
- Leptin administration does help
22
Q
Adiponectin
A
- Secreted by adipocytes in response to high fat reserves
- Stimulates AMP-dependent protein kinase (AMPK)
- Increases fatty acid uptake by myocytes
- Increases the rate of fatty acid oxidation
- Slows fatty acid synthesis in the liver
- Slows gluconeogenesis in the liver
23
Q
Adiponectin and Type II Diabetes Drugs
A
- Obese of type II diabetes patients show reduced levels of adiponectin
- Thiazolidinediones used to treat type II diabetes elevate expression of adiponectin
- Thiazolidinedione bind PPAR: peroxisome proliferator-activated receptors
- These normally bind fatty acids or fatty acid derivatives
- Regulate genes involved in fatty acid metabolism including PEP carboxykinase, a regulated step in glyconeogenesis, and adiponectin
24
Q
Leptin and Insulin
A
- Insulin and leptin work in similar ways to regulate appetite
- Insulin brain levels reflect visceral fat
- Leptin levels reflect subutaneous fat
25
Ghrelin
* Discovered in 1999 as the first circulating hunger hormone
* Secreted by P/D1 cells of the stomach and epsilon cells of the pancreas
* Levels increase before meals and decrease after meals
* Ghrelin and synthetic ghrelin mimetics increase food intake and increase fat mass
* Ghrelin levels in obese individuals are lower than lean individuals, except in teh case of Prader-Willi syndrome-induced obesity
* Studies in 2004 found that ghrelin levels during the day were similar in lean and obese people, but during sleep were higher in thin people
* This suggests obese people may have a problem in the circadian regulation of ghrelin
* In normal people, shortened sleep cycles produce more ghrelin and less leptin, thus increasing appetite and food intake
26
Ghrelin Action
* Ghrelin binds NPY neurons
* Inhibits POMC neurons and production of α-MSH
* Increases appetite by sending the "start eating" signal
* Leptin and insulin sensitive
* NPY neurons also produce Agouti-related protein (AgRP)
* One of the most potent and long-lived appetite stimulators
* Blocks the "stop eating" signal
27
Other GI hormones induce satiety
* CCK (cholecystokinin)
* Released from the small intestine in response to nutrients
* Produces a satiety signal by stimulating vagal afferents to the brain
* PYY
* Released from the intestine in proportion to meal size
* A satiety signal
* GLP-1
* A satiety signal
* Obestatin
* Product of the ghrelin gene by differential peptide processing
* Decreases feeding
28
Serotonin and Satiety
* Serotonin increases short-term satiety signals associated with the consumption of a meal
* Decreases
* urge to eat high-calorie food
* consumption of fat
* intensity of hunger
* size of meals
* number of snacks
* bingeing
* Serotonin inhibits NPY/AgRP neurons and activated POMC neurons
29
Sibutramine (Reductil, Meridia)
* Mechanism: **inhibits serotonin reuptake in the CNS**
* Has **anorectic and thermogenic** effects
* Side effects: **insomnia, constipation, increase heart rate, slight hypertension**
* Effective in **causing ~5-10% weight loss**, increase HDL (good cholesterol) and decreased triglycerides
* Casuses **a reduction in diabetes**, improved glycemic control
* As of 10/8/10, Abbot labs **withdrew sibutramine** from the US due to FDA concerns of efficacy couple with increased cardiovascular events and stroke
30
Lorcaserin (Belviq)
* Belviq was approved in June 2012
* Lorcaserin is a serotonin receptor agonist
* Thought to increase satiety signals
31
Orlistat (Xenical, Alli)
* MOA: specific gastric and pancreatic lipase inhibtor
* Prevents fat absorption
* Up to 30% of dietary fat will be excreted
* Drug is not absorbed
* To be used in conjunction with reduced-calorie diet
* Side effects: GI problems (only if excess fat in diet), slight reducing in fat-soluable vitamin levels
* Weight loss is modest, ~3% over placebo
* Total LDL and cholesterol decrease, glycemic control improved
32
Phentermine
* Phentermine is a component of the infamous Fen-Phen which is off the market because of cardiac toxcity-heart valve disease
* Norepinephrine and dopamine reuptake inhibitor
* Causes hypertension, insomnia
* Short term appetite suppression, but not very effective by itself
* Qsymia recenetly approved by FDA is a combination of phentermine and topiramate
33
Chronic GI disorders
* GERD
* Peptic ulcer disease (PUD)
* Inflammatory Bowel Diseases
* Crohn's
* Ulcerative coltitis
* Coeliac disease
34
Gastric acid secretion
* Acid production
* Stomach lumen in acididc
* pH 2-3
* Isotonic HCl solution
* Acid converts inactive pepsinogen to active pepsin
* Acid denatures proteins
* Mucus production
* Mucosal cells secrete mucus and bicarbonate
* pH gradient across the mucosa
* Alcohol affects the mucosa
35
GERD
* Backflow of acids into the esophagus
* Scarring can occur
* 10-20% population affected
* Triggers
* Food (fatty, alcohol, caffeine)
* Smoking
* Obesity
* Pregnancy
* Symptoms
* Heartburn, major
* Difficulty swallowing
* Chest pain
* Complications
* Esophogeal erosions
* Esophogeal ulcer
* Esophageal stricture
36
Barrett's Esophagus
* ~10% of patients, normal esophageal epithelium is replaced with abnormal (Barrett's) epithelium
* This is linked to cancer of the esophagus
* Needs monitoring to make sure it doesn't become malignant
37
Peptic Ulcer Disease (PUD)
* Benign
* Normal secretic of gastric acid
* Mucosal barrier is weak
* Malignant
* Excessive secretion of gastric acid
* Normal mucosal barrier is overwhelmed
* Causes
* H. pylori (85% of cases)
* Bacteria attach to epithelial cells
* Can't be washed out
* Damage mucosa be secreting enzymes/toxins
* Also elicit destructive immune response
* NSAIDs (10%) of cases
* Irritate stomach lining
* Inhibit prostaglandin synthesis
* Other (\<5% of cases)
* Benign pancreatic tumor secretions
* Unknown causes
38
Treatment goals for GERD and PUD
* Neutralize stomach pH
* Decrease gastric acid secretion
* Decrease H. pylori infection
* Provide mucosal protecion
* Promote mucosal healing
* Lifestyle changes
39
Treatments for GERD and PUD
* Antacids
* H2 Receptor blockers
* PPI
* Mucosal protection
* Anti-microbial agents
40
Regulation of Acid production
41
Antacids
* Weak bases
* Efficacy depends on
* Rate of dissolution
* Solubility in water
* Rate of reaction
* Often combined for better efficacy
* Treats symptoms, not underlying condition
* Typically taken 5-7 times per day
42
Histamine H2 receptor antagonists
* Histamine stimualtes acid production by parietal cells
* Activate histamine H2 receptors
* Increase proton pump activity
* Histamine H2 receptor antagonists
* Drugs of choice during 70-90's
* Modifications of histamine structure
* Cimedtidine, Famotidine, Ranitidine, Nizatidine
43
Histamine H2 Receptor Antagonists: Details
* Highly selective
* No effects at histamine H1, H3, or H4 receptors
* Long acting
* 6-12 hours of duration, 1-2 times per day
* Inhibit 60-70% of gastric acid secretion in 24 hour period
* Rank order of potency
* famotidine\>nizatidine=ranitidine\>cimetidine
* Side effects (\<3% of patients)
* Diarrhea
* Fatigue
* Headache
* Myalgias
44
PPI
* Irreversible inhibit the PP in parietal cells
* Inactive at neutral pH, but activated in the acidic stomach
* Omeprazole, Lansopraxole, Esomeprazole, Rabeprazole
45
PPI: details
* Long acting
* Acid production reduced for 24-48 hours
* Once a day
* Inhibit 90-98% of gastric acid secretion in 24 hours period
* Similar efficacies across compounds
* Effective in 80-90% of patients
* Minimal side effects (\<5% of patients)
* Diarrhea
* Headache
* Abdominal pain
* Reduced vitamin B12, Ca2+, iron, zinc absorption
* Current drug of choice
46
Mucosal protective agents
* Potentiate endogenous mucosal repair and defense mechanisms
* Misoprostol
* Prostaglandin E1 analog
* **Endogenous PGs stimulate mucus and bicarbonate production**
* Activates PGE3 and PGE4 receptors on parietal cells
* Counters histamine effects
* **Often used with NSAIDS that inhibit endogenous PG synthesis**
* Suralfate (Carafate)
* Sucrose sulfate-aluminum salt
* Requires an acid pH to activate
* Forms complex gels with mucus to improve the mucosal barrier
* Not absorbed, local and effective
* Can bind with drugs and interfere with absorption
* Generally free of side effects
47
Peptic Ulcer therapies; Antibiotics
* Disrupt the cell wall of H. pylori
* Bismuth
* Amoxicillin
* Disrupt protein synthesis in H. pylori
* Clarithromycin
* Tetracycline
* Disrupt nucleic acid synthesis in H. pylori
* Metronidazole
* Often used due to bacterial resistance or intolerance to amoxicillin and tetracycline
* Standard treatment regimen is often a combination therapy
* Omprazole, bismuth, tetracycline, and metronidazole
48
Inflammatory Bowel Disease
* Crohn's Disease
* Patchy inflammation
* May affect any part of GI tract
* Symptoms:
* Abdominal pain
* Diarrhea
* Weight loss
* Intestinal obstruction
* Ulcerative colitis
* Diffuse inflammation
* Limited to the colon
* Symptoms:
* Abdominal pain
* Diarrhea
* Weight loss
* Intestinal obstruction
49
Causes of IBD
* Gut microbiota is altered in affected individuals
* 30-50% reduced biodiversity in commensalism bacteria
* More likely to have been prescribed antibiotics 2-5 years before onset
* Genetics may be a factor
* 163 IBD susceptibility loci have been identified
* Many genes involved in cytokine production, lymphocyte activation, response to bacterial infection
* Account for an 8-13% variance in Crohn's disease
* Account for a 4-7% variance in ulcerative colitis
50
Coeliac Disease
* Autoimmune disease
* ~1 in 140 are affected in US
* Reaction to gliadin (a gluten protein)
* Symptoms:
* Pain and GI discomfort
* Weight loss
* Anemia
* Fatigue
* Genetic cause
* Nearly all patients have a mutant allele in HLA-DQ1 or HLA-DQ8
* HLA-DQ is part of the MHC class II antigen-presenting receptor
* Mutant forms bind gliadin peptides more tightly
* Increased activation of lymphocytes and heightened immune reaction
* Treatment
* Lifelong GF diet
51
IBD Treatements
* Treatment
* Current goal is to resolve acute episodes and prolong remission
* Individualized to each patient
* Drug choice and administration route depends on many factors
* Type, distribution, and severity of the patient's disease
* Patient history
* Patient preferences
* Therapies
* Aminosalicylates
* Corticosteroids
* Thiopurines
* Methotrexate
* Cyclosporin
* Infliximab or adalimumab
* Surgery to remove a protion of the intestine
* Fecal transplant
52
Aminosalicylates treatment of IBD
* Derivative of salicylic acid
* Anti-inflammatory
* Poorly absorbed so acts locally in the GI
* Oral and rectal preparations
* Used in active disease
* Used to maintain remission
* Aminosalicylates
* Mesalazine (5-aminosalycilic acid, 5-ASA)
* Sulfasalazine (a sulfapyridine form of 5-ASA)
* Balsalazide (prodrug from of 5-ASA)
* Olsalazine (5-ASA dimer cleaved in colon)
* Adverse effects
* 10-45% patients can have nausea, headache, epigastric pain, diarrhea, pancreatitis, blood disorder, lung disorder, and myo/pericarditis
* Caution with renal impairment, pregnancy and breast feeding
53
Corticosteroid treatment of IBD
* Used for moderate to severe relapses
* Prednisone is typically used
* Adverse effects (typical for corticosteroids)
* Acne
* Moon face
* Sleep disturbances
* Dyspepsia
* Glucose intolerance
* Osteoporosis
* Myopathy
* Glaucoma and cataract formation
54
IBD treatments: Thiopurines
* Mode of action
* Inhibitors of ribonucleotide synthesis
* Can induce T-cell apoptosis
* Used to manage active and chronic disease
* Allows discontinuation of steroids (steroid sparing)
* Thiopurines
* Thioguanine
* Mercaptopurine
* Azathioprine
* Adverse effects
* Leukopenia
* Flu-like symptoms after 2-3 weeks
* Liver and pancreas toxicity
* ~30% of patients do not respond properly to treatment
* Genetic variation in thiopurine S-methyltransferase (TPMT) is associated with adverse effects if standard doses are used
55
IBD treatments: methotrexate
* MOA:
* Inhibits dihydrofolate reductase: converts dihydrofolate into tetrahydrofolate
* Tetrahydrofolate is essential for purine and thymidylate synthesis
* Important for cell proliferation and cell growth
* Likely prevents cytokine and eicosanoid production
* Used in active or relapsing disease that is refractory/intolerant to thiopurines
* Adverse effects
* Blood in urine or stools
* Nausea or vomiting
* Diarrhea
* Hair loss
* Hepatotoxicity
* Skin complications (acne, rash, itching)
56
IBD treatments: Cyclosporin
* MOA:
* Binds to cyclophilin
* This inhibits calcineurin function
* Calcineruin is important for production of IL-2 and cytokines
* Used to manage active and chronic disease
* Steroid sparing
* Adverse effects
* Gingical hyperplasia
* Convulsions
* Peptic ulcers
* Pancreatitis
* Fever
* Vomiting
* Diarrhea
* High blood pressure
* Nephrotoxicity
* Hepatotoxcity
57
IBD treatments: infliximab adalimumab
* MOA
* Monoclonal Ab against tumor necrosis factor alpha (TNF-α)
* TNF-α is a cytokine involved in systemic inflammation
* Very potent anti-inflammatory effects
* Must be given as an IV infusion
* Used for severe disease refractory/intolerant to steroids or immunosuppressive agents
* Remicade (infliximab), Humira (adalimumab)
* Adverse effects
* Infusion reactions
* Sepsis
* Serious blood disorders that can become fatal
* Increased risk of infection
* Increased risk of acquiring or reactivating tuberculosis
* Psoriasis
* Liver injury
* Lymphoma and solid tissue cancers
