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PCL469 > Parathyroid, Insulin > Flashcards

Parathyroid, Insulin Flashcards

1
Q

Normal range for serum calcium

A

2.1-2.5 mmol/ L

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2
Q

Diagram calcium ingested into gut

A

1000 mg
300 mg initially absorbed
125 excreted into gut again
175 mg into blood/ecf

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3
Q

from diet–> feces calcium

A

825 mg via gut 700 mg initially + 125 re-excreted from blood

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4
Q

Percentages of calcium in ECF

A

40% - protein bound
10 % - complexed
50% - ionized

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5
Q

How is calcium also excreted apart from feces

A

Urine from kidneys

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6
Q

ECF Calcium excretion

A

10 000 mg into kidney
but 175 into urine
9825 mg reabsorbed into blood

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7
Q

from ECF –> Bone

A

500 mg back and forth
regulated by PTH and calcitonin
kidneys

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8
Q

PTH/Teriparatide function + homeostasis

A

Stimulus: Falling blood Ca++
Release from PT glands
1. Stimulate Ca++ release from bones
2. Stimulates Ca++ uptake in kidneys + PO4 excretion
3. Kidney activates vitamin D –> increases Ca++ intestine uptake
Blood Ca++ rises to homeostasis

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9
Q

Calcitonin + Homeostasis

A

Stimulus: high Ca++ level
Thyroid gland: calcitonin
1. Reduce Ca++ uptake in kidneys - increase excretion
2. Stimulates Ca++ deposition in bones
Result: blood Ca++ levels decline

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10
Q

Calcitonin vs Teriparatide

A

antagonistic drugs

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11
Q

Calcium in blood with age + in norm?

A

Mostly above the norm 2.62 —> lowers then incr. with age

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12
Q

Parathyroid hormone significant AA

A

First 34 most active
Rest of peptide has subtle effects in signalling

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13
Q

Calcium regulation of PTH pathways

A

activate beta-arrestin
binds AP2
internalizes receptor to endosome
sustains signal for MAPK
also GPCRi–> increase MAPK + lower cAMP
Gq = increased calcium

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14
Q

PTH glands sensing calcium –> response speed/intensity

A

Narrow sensitivity to level of EC calcium to determine PTH release

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15
Q

Ca + vitamin D in regulating PTH/ negative feedback
when high [Ca]

A

Increase Ca –> decreased PTH release
Gq –> PLC –> Calcium inside increases –> ERK + MAPK –> SP1 –> vitamin D receptor transcription occurs

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16
Q

Calcium, vitamin D and PTH regulation
When increased vitamin D

A

Decreases PTH release
Vitamin D receptor + vit D –> into nucleus –> downregulates PTH transcription –> low PTH

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17
Q

Common denominator between Ca, vit D and regulation of PTH

A

When high Ca/vitamin D, levels of PTH decrease

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18
Q

Familial hypocalciuric hypercalcemia overall pathology. treatment

A
  • Autosomal dominant – inactivating mutation in calcium-sensor receptor gene
  • Parathyroid gland less sensitive to Ca, higher Ca+ needed to reduce PTH
  • Higher than normal blood Ca, low urinary Ca
  • Not treated
  • Chelator in emergencies
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19
Q

Autosomal dominant hypocalcemia
ADH type 1

A
  • Autosomal dominant activating mutations in Ca-sense-receptor
  • PT gland more sensitive to Ca, lower [Ca] required to reduce PTH
  • Lower [Ca], high PO4, higher urinary [Ca]
  • can cause seizures
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20
Q

Treating ADH

A
  1. Supplements - Ca + vit D
  2. Synthetic PTH –> increase Ca++ release and reuptake/kidney
  3. Calcilyitcs - CaSR antagonists – not approved in humans
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21
Q

Most common cause of hypercalcemia

A

Primary Hyperparathyoridism

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22
Q

Causes of primary hyperparathyroidism

A

Parathyroid:
hyperplasia, adenoma, carcinoma

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23
Q

Solution of primary hyperparathyroidism

A

Surgical removal
CaSR regulators

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24
Q

What are calcimimetics for

A
  • Increase CaSR sensitivity to serum calcium
  • Inhibit PTH release –> reduce [Ca] reuptake
  • Treat primary + secondary hyperparathyroidism
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25
What is secondary hyperparathyroidism from?
Kidney disease
26
Minimal Ca intake
5 mmol/day should be 1 gram/day
27
Net absorption of calcium + intake required
Net absorption above zero when intake above 5 mmol or 200 mg per day
28
Oral intake of calcium + absorption + age
Infants: 60% 15-20% adults lower with age
29
Optimal intake dose + Ca absorption
Absorption best with doses lower than 500 mg
30
Supplements vs dietary
Oral Ca supplements - therapy Dietary Ca preferred
31
Most common Ca supplements
Calcium carbonate Calcium citrate
32
Ca carbonate vs citrate
Calcium carbonate - cheapest, most absorbed with food, needs acidic environment Calcium citrate- equally absorbed with and without food, absorbed with reduced stomach acid
33
Vitamin D and Ca+ absorption Organ site how influence each other
Calcium absorption primarily --> duodenum and jejunum Vitamin D increases Ca binding protein - increase Ca uptake, cytoplasmic transport and basolateral membrane transfer Vitamin D deficiency results in decreased Ca absorption
34
Factors influencing Ca excretion
PTH - regulates 10% renal reabsorption Protein and Na levels increase calcium excretion Thiazide diuretics -- increase Ca reabsorption Loop diuretics increase Ca excretion
35
Bone mineral density, how to prevent/treat
Ca and vitamin D Biphosphonates Denosumab Parathyroid hormone Romosozumab Calcitonin
36
Prevalence of Age-related osteoporosis in Canada
1/4 woman >50 yrs 1/8 men > 50 yrs Age-related bone loss, mineral and bone strength --> increased fracture risk
37
Calcium and vitamin D supplementation on PM women
Vitamin D supplements reduced the incidence of vertebral fractures
38
Antiresorptive example
Bisphosphonates
39
Bisphosphonate function + drugs
Supply osteoclast apoptosis Drug embedded in bone --> inhibits osteoclast activity--> apoptosis Drugs: Alendronate, Zolendronate
40
Bisphosphonate effect on bone mineral density administration pharmacokinetics
Injection iv or oral. Rapid intake in bone mineral Long-term depot
41
Side effect of bisphosphonates
Oral administration GI issues need to be taken on empty stomach, upright for an hour Long-term use, atypical fractures Osteonecrosis of the jaw, rare, due to dental work
42
Antiresorptive, but antibody
Denosumab
43
Mechanism of Denosumab
Ab binds to RANKL, displacing RANK RANK + RANKL usually bind osteoclast, promoting bone resorption Now with mab, this is inhibited Inhibited osteoclasts
44
Denosumab, Dosing, Pharmacokinetics and side effects
Dosing: 60 mg shot/ 6 months Rapid onset, reversible Side effects: ONJ/rare Long term atypical fractures
45
PTH-Teriparatide mechanism of increasing BMD(2)
Anabolic - Intermittent low-dose PTH increases bone formation However, Continuous high-dose PTH increases osteoclast-mediated bone resorption
46
What is this odd PTH mechanism called?
Use dependent mechanism
47
Teriparatide name
Forteo
48
Teriparatide: administration
20 mcg/day s.c. injection
49
Teriparatide: PK and duration use
95% bioavailability from s.c. injection half-life 5 mins B-c metabolism non-spcific enzyme degradation Excretion: renal Duration: restricted to 2 years - potential osteosarcoma
50
Romosozumab mechanism of action
Anabolic Wnt- stimulate osteoblast formation, cellular growth+differentiaion Sclerostin - blocks Wnt signalling Romosozumab - mab --> inhibits sclerostin
51
Efficacy of anabolic Romosozumab
same efficacy as PTH - efficient
52
Side effects of Romosozumab
Hypocalcemia - bone pain CV- heart attack, stroke - incr risk
53
Should use Romosozumab if CV issues
No; better to switch to PTH
54
Calcitonin, organ + regulation
from thyroid gland, parafollicular cells Increased synthesis + release when [Ca] and gastrin increase
55
Calcitonin Effects + pathway
Binds to GPCR + Gs --> AC --> cAMP Decrease Ca gut uptake Increase kidney Ca excretion Inhibit bone resorption via osteoclasts
56
Calcitonin + for what + drug
Calcitonin has been used to treat osteoporosis Salmon calcitonin is used as a nasal spray Removed from Canadian and US markets for lack of evidence of efficacy in osteoporosis and potential risk of increased cancer incidence
57
Endocrine -- pancreas and hormones
Alpha cells - glucagon, breakdown of glycogen Beta cells - insulin, glucose uptake-utilization Delta cells - somatostatin - inhibit insulin/glucagon release
58
Type 1 diabetes
Early life onset Autoimmune destruction of pancreatic beta cells Loss of insulin Replacement therapy required
59
Type 2 diabetes
Later life onset Assoc with obesity insulin resistance in target tissue Feedback increases insulin secretion eventual hyperglycemia
60
Why diabetes is deadly
Not able to produce insulin in late stage then insulin dependent Up regulation of PKC signalling Increase in inflammatory cytokines CV disease Renal disease Blindness Heart attack, stroke
61
Who has increased risk of diabetes
Asian indian Lowest risk - europeans Also BMI factor
62
Contributing factors in T2D
Energy expenditure Caloric intake Dietary nutrients Microbiome Epigenetics Age ^^^ all environmental factors for obesity
63
What other than environment affect obesity --> what is result for both
Adiposity genes result: beta-cell dysfunction Type 2 diabetes
64
Diagnosis of diabetes
TBG - fasting blood glucose HbA1c- glycosylated hemoglobin OGTT - glucose tolerance test
65
FPG normal vs diabetic
<5.5 mmol/L >7.0mmol/L
66
OGTT peak glucose normal vs diabetic
<7.8 mmol/L >11.1 mmol/L
67
Treatment options for T2D
Lifestyle change Insulin secretagogues Insulin sensitizers
68
What are biguanides?
Insulin sensitizers Metformin
69
Metformin mechanisms
Antihyperglycemic Lower elevated hepatic gluc outpu Inhibit gluconeogenesis Inhibit glucose 6 phosphatase activity--> glycogen sparing Lower insulin resistance
70
Mechanism of metformin
Activation of 5 amp activated protein kinase AMPK in hepatocytes and muscles Do not increase insulin secretion, therefore not hypoglycemic, even at high doses
71
Thiazolidinediones - site of action + effect
PPAR Nuclear hormone receptor Expressed in fat--> adipocyte differentiation Glitazones activate PPAR Effect: increase adipose tissues increase storage decreased bone density weight gain
72
Example glitazone
Rosiglitazone
73
Newer T2D drugs
Pramlintide Colesevelam Liraglutide Sitagliptin Dapagliflozin, Canagliflozin
74
Pramlintide - site of action, effects
GI tract Amylin analogue Amylin release from beta cells with insulin, multiple effects Inject before each meal subcutaneous
75
Pramlintide - mechanism
Brain --hunger inhibits Slows gastric emptying - slower carb uptake Inhibit glucagon release Result : lower plasma glucose, body weight loss
76
Colesevelam effect
Bile acid binding resin - lower cholesterol Inhibit gluconeogenesis Improve plasma glucose
77
Colesevelam mechanism
May be attributed on affecting incretins release from gut
78
What are incretins
Group of hormones gut-released after eating Regulate insulin amount released Maintain beta cells
79
2 Regulators of incretin and receptors
Liraglutide Sitagliptin
80
Liraglutide mechanism
GLP-1 receptor agonist
81
Sitagliptin mechanism
DPP-4 dipeptidyl peptidase-4 inhibitor - blocks GLP-1 degradation
82
Liraglutide effect
Duration of action 24 hours Increase insulin, glucose dependent Improve beta cells Slow gastric emptying Weight loss Inhibit glucagon secretion
83
Liraglutide administration
Subcutaneous injection 1x/d Thigh, stomach, upper arm
84
What is SGLT 2
Na-glucose reuptake transporter In proximal convoluted tubule of nephron Reabsorption of glucose usually
85
SGLT inhibitor
Dapagliflozin, Canagliflozin
86
Positive and negative effects fo D and C- flozin
+ - decreases plasma [glu] decrease weight and BP Diuretic Decrease heart failure CV system - tive 5x mycotic infection in urinary tract due to glucose in urine-bacteria?
87
Combination therapies
Multisensitizers: Metformin + Rosiglitazone Insulin secretagog+ sensitizer: Glumepriride + Rosiglitazone Insulin sensitizer and DPP4 inhibitor: Metformin + Sitaglimptin/linagliptin/saxagliptin SGLT2 inhibitor + DPP4 inhibitor: Empagliflozin and Linagliptin
88
Which comb. treatment is safest + effective
SGLT2 inhibitor and DPP4 inhibitor

PCL469 (6 decks)

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