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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
Q

What is secondary hyperparathyroidism from?

A

Kidney disease

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26
Q

Minimal Ca intake

A

5 mmol/day
should be 1 gram/day

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27
Q

Net absorption of calcium + intake required

A

Net absorption above zero when intake above 5 mmol or 200 mg per day

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28
Q

Oral intake of calcium + absorption + age

A

Infants: 60%
15-20% adults lower with age

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29
Q

Optimal intake dose + Ca absorption

A

Absorption best with doses lower than 500 mg

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30
Q

Supplements vs dietary

A

Oral Ca supplements - therapy
Dietary Ca preferred

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31
Q

Most common Ca supplements

A

Calcium carbonate
Calcium citrate

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32
Q

Ca carbonate vs citrate

A

Calcium carbonate - cheapest, most absorbed with food, needs acidic environment
Calcium citrate- equally absorbed with and without food, absorbed with reduced stomach acid

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33
Q

Vitamin D and Ca+ absorption
Organ site
how influence each other

A

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

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34
Q

Factors influencing Ca excretion

A

PTH - regulates 10% renal reabsorption
Protein and Na levels increase calcium excretion
Thiazide diuretics – increase Ca reabsorption
Loop diuretics increase Ca excretion

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35
Q

Bone mineral density, how to prevent/treat

A

Ca and vitamin D
Biphosphonates
Denosumab
Parathyroid hormone
Romosozumab
Calcitonin

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36
Q

Prevalence of Age-related osteoporosis in Canada

A

1/4 woman >50 yrs
1/8 men > 50 yrs
Age-related bone loss, mineral and bone strength –> increased fracture risk

37
Q

Calcium and vitamin D supplementation on PM women

A

Vitamin D supplements reduced the incidence of vertebral fractures

38
Q

Antiresorptive example

A

Bisphosphonates

39
Q

Bisphosphonate function + drugs

A

Supply osteoclast apoptosis
Drug embedded in bone –> inhibits osteoclast activity–> apoptosis
Drugs: Alendronate, Zolendronate

40
Q

Bisphosphonate effect on bone mineral density
administration
pharmacokinetics

A

Injection iv or oral.
Rapid intake in bone mineral
Long-term depot

41
Q

Side effect of bisphosphonates

A

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
Q

Antiresorptive, but antibody

A

Denosumab

43
Q

Mechanism of Denosumab

A

Ab binds to RANKL, displacing RANK
RANK + RANKL usually bind osteoclast, promoting bone resorption
Now with mab, this is inhibited
Inhibited osteoclasts

44
Q

Denosumab, Dosing, Pharmacokinetics and side effects

A

Dosing: 60 mg shot/ 6 months
Rapid onset, reversible
Side effects: ONJ/rare
Long term atypical fractures

45
Q

PTH-Teriparatide mechanism of increasing BMD(2)

A

Anabolic - Intermittent low-dose PTH increases bone formation
However,
Continuous high-dose PTH increases osteoclast-mediated bone resorption

46
Q

What is this odd PTH mechanism called?

A

Use dependent mechanism

47
Q

Teriparatide name

A

Forteo

48
Q

Teriparatide: administration

A

20 mcg/day s.c. injection

49
Q

Teriparatide: PK and duration use

A

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
Q

Romosozumab mechanism of action

A

Anabolic
Wnt- stimulate osteoblast formation, cellular growth+differentiaion
Sclerostin - blocks Wnt signalling
Romosozumab - mab –> inhibits sclerostin

51
Q

Efficacy of anabolic Romosozumab

A

same efficacy as PTH - efficient

52
Q

Side effects of Romosozumab

A

Hypocalcemia - bone pain
CV- heart attack, stroke - incr risk

53
Q

Should use Romosozumab if CV issues

A

No; better to switch to PTH

54
Q

Calcitonin, organ + regulation

A

from thyroid gland, parafollicular cells
Increased synthesis + release when [Ca] and gastrin increase

55
Q

Calcitonin Effects + pathway

A

Binds to GPCR + Gs –> AC –> cAMP
Decrease Ca gut uptake
Increase kidney Ca excretion
Inhibit bone resorption via osteoclasts

56
Q

Calcitonin + for what + drug

A

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
Q

Endocrine – pancreas and hormones

A

Alpha cells - glucagon, breakdown of glycogen
Beta cells - insulin, glucose uptake-utilization
Delta cells - somatostatin - inhibit insulin/glucagon release

58
Q

Type 1 diabetes

A

Early life onset
Autoimmune destruction of pancreatic beta cells
Loss of insulin
Replacement therapy required

59
Q

Type 2 diabetes

A

Later life onset
Assoc with obesity
insulin resistance in target tissue
Feedback increases insulin secretion
eventual hyperglycemia

60
Q

Why diabetes is deadly

A

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
Q

Who has increased risk of diabetes

A

Asian indian
Lowest risk - europeans
Also BMI factor

62
Q

Contributing factors in T2D

A

Energy expenditure
Caloric intake
Dietary nutrients
Microbiome
Epigenetics
Age
^^^ all environmental factors for obesity

63
Q

What other than environment affect obesity –> what is result for both

A

Adiposity genes
result: beta-cell dysfunction
Type 2 diabetes

64
Q

Diagnosis of diabetes

A

TBG - fasting blood glucose
HbA1c- glycosylated hemoglobin
OGTT - glucose tolerance test

65
Q

FPG normal vs diabetic

A

<5.5 mmol/L
>7.0mmol/L

66
Q

OGTT peak glucose normal vs diabetic

A

<7.8 mmol/L
>11.1 mmol/L

67
Q

Treatment options for T2D

A

Lifestyle change
Insulin secretagogues
Insulin sensitizers

68
Q

What are biguanides?

A

Insulin sensitizers
Metformin

69
Q

Metformin mechanisms

A

Antihyperglycemic
Lower elevated hepatic gluc outpu
Inhibit gluconeogenesis
Inhibit glucose 6 phosphatase activity–> glycogen sparing
Lower insulin resistance

70
Q

Mechanism of metformin

A

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
Q

Thiazolidinediones - site of action + effect

A

PPAR
Nuclear hormone receptor
Expressed in fat–> adipocyte differentiation
Glitazones activate PPAR
Effect:
increase adipose tissues
increase storage
decreased bone density
weight gain

72
Q

Example glitazone

A

Rosiglitazone

73
Q

Newer T2D drugs

A

Pramlintide
Colesevelam
Liraglutide
Sitagliptin
Dapagliflozin, Canagliflozin

74
Q

Pramlintide - site of action, effects

A

GI tract
Amylin analogue
Amylin release from beta cells with insulin, multiple effects
Inject before each meal subcutaneous

75
Q

Pramlintide - mechanism

A

Brain –hunger inhibits
Slows gastric emptying - slower carb uptake
Inhibit glucagon release
Result : lower plasma glucose, body weight loss

76
Q

Colesevelam effect

A

Bile acid binding resin - lower cholesterol
Inhibit gluconeogenesis
Improve plasma glucose

77
Q

Colesevelam mechanism

A

May be attributed on affecting incretins release from gut

78
Q

What are incretins

A

Group of hormones gut-released after eating
Regulate insulin amount released
Maintain beta cells

79
Q

2 Regulators of incretin and receptors

A

Liraglutide
Sitagliptin

80
Q

Liraglutide mechanism

A

GLP-1 receptor agonist

81
Q

Sitagliptin mechanism

A

DPP-4 dipeptidyl peptidase-4 inhibitor - blocks GLP-1 degradation

82
Q

Liraglutide effect

A

Duration of action 24 hours
Increase insulin, glucose dependent
Improve beta cells
Slow gastric emptying
Weight loss
Inhibit glucagon secretion

83
Q

Liraglutide administration

A

Subcutaneous injection 1x/d
Thigh, stomach, upper arm

84
Q

What is SGLT 2

A

Na-glucose reuptake transporter
In proximal convoluted tubule of nephron
Reabsorption of glucose usually

85
Q

SGLT inhibitor

A

Dapagliflozin, Canagliflozin

86
Q

Positive and negative effects fo D and C- flozin

A

+ - 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
Q

Combination therapies

A

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
Q

Which comb. treatment is safest + effective

A

SGLT2 inhibitor and DPP4 inhibitor

PCL469 (6 decks)

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