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Year 2 - Endocrinology (DP) > Pharmacology > Flashcards

Flashcards in Pharmacology Deck (94):
1

What sort of glands are in the endocrine system?

Ductless

2

How is signal specificity achieved?

Chemically distinct hormones
Specific hormone receptors
Distinct receptor distribution

3

What are the features of amine hormones? (Synthesis, storage, release and transport)

Pre-synthesised:
- Formed by enzymes
Stored in vesicles
Released in response to calcium
Transported free in plasma (hydrophilic)

4

What are the features of peptide + protein hormones? (Synthesis, storage, release and transport)

Pre-synthesised:
- From longer precursor via proteolysis
Stored in vesicles
Calcium causes release
Transported free in plasma

5

What are the features of steroids hormones? (Synthesis, storage, release and transport)

Synthesised and secreted on demand
Stimuli increase:
- Cholesterol uptake
- Rate of conversion to pregnenolone (rate limiting)
Transport:
- 90% bound to plasma proteins (lipophilic)
- Free if biologically active

6

What hormones are insoluble?

Steroids
Thyroxine

7

What are the functions of carrier proteins?

Increase hormone transport in blood
Prevent renal filtration
Prevent rapid excretion

8

What does cortisol-binding globulin bind?

Cortisol
(+ aldosterone)

9

What does thyroxine-binding globulin bind?

T4 selectively
(+ some T3)

10

What does SHBG bind?

Testosterone
Oestradiol

11

What do albumin and transthryretin bind?

Albumin:
- Steroids
- T4
Transthyretin:
- T4
- Some steroids

12

What do carrier proteins act as?

Buffers and reservoirs:
- Main constant [Free hormone] in blood
- Keep bound and free hormones in equilibirum

13

What hormones can cross capillary walls?

Free hormones

14

What happens when free hormone is removed from the plasma?

Replaced by dissociation of bound protein

15

What is the primary determinant of hormone plasma concentration?

Rate of secretion

16

What does neuroendocrine release cause?

A sudden burst in secretion to meet a stimulus:
- eg. Stress -> Hypothalamus -> CRH -> ACTH -> Cortisol

17

How does diurnal rhythm release work?

Secretion fluctuates with time
Entrained to external cues (Night/Day)

18

What organs are the most important locations for elimination of hormones?

Liver
Kidney

19

What are the half lives of:
- Amine hormones
- Protein/Peptide hormones
- Steroids/T3 +T4

Amines -> Seconds
Proteins/Peptides -> Minutes
Steroids/T3+T4 -> Hours to days

20

What affects the half lives of hormones?

Protein binding

21

Where are G-protein coupled receptors found and what hormones activate them?

On cell surface
Activated by:
- Amines
- Some proteins/peptides

22

What do G-protein coupled receptors couple with?

Gs
Gi
Gq

23

Where are receptor kinases found and what hormones activate them?

On cell surface
Activated by some proteins and peptides

24

Where are nuclear receptors found and why are they found here?

Intracellularly:
- Ligands are lipophilic
> Can diffuse across cell membrane

25

What activates Class 1 Nuclear receptors? What happens when they are activated?

Many steroids:
- Migrate to nucleus on binding

26

What happens when Class 1 Nuclear Receptors are inactive?

Bound to inhibitory heat shock proteins in the cytoplasma

27

What activates Class 2 Nuclear receptors? Where are they found?

Mostly by lipids
In the nucelus

28

What activates the hybrid class nuclear receptors? What are they similar to?

T3 (+others)
Similar to Class 1

29

What happens when adrenaline, CRH or glucagon binds to a GPCR?

1. Gs subunit uncouples
2. Binds to adenylyl cyclase
3. Promotes ATP -> cAMP
4. cAMP activates Protein Kinase A
5. Target protein phosphorylation -> Effects

30

What happens when melatonin binds to a GPCR?

1. Gi subunit uncouples
2. Binds to adenylyl cyclase
3. Inhibits ATP -> cAMP
4. Less Protein Kinase A activation
5. Less target protein phosphorylation -> Inhibits effects

31

What happens when angiotensin ii, GRH or TRH binds to a GPCR?

1. Gq subunit uncouples
2. Binds to phospholipase C
3. Promotes PIP2 -> IP3
4. IP3 binds to IP3 receptor on endoplasmic reticulum
5. Calcium released
6. Cellular effects

32

What other effects does the hydrolysis of PIP2 to IP3 have?

1. Produces DAG
2. DAG activates Protein Kinase C (in membrane)
3. Target proteins are phosphorylated -> Effects

33

What happens when insulin binds to a receptor kinase?

1. Autophosphorylation of intracellular tryosine residues
2. Insulin receptor substrate proteins are phosphorylated
3. Cellular effects

34

How does signalling via Class 1 Nuclear Receptors work?

1. Steroid diffuses into cell
2. Binds to intracellular receptor + HSP dissociates
3. Moves to nucleus
4.Forms a dimer + binds to hormone response elements in DNA
5. Transactivation or Transrepression occurs
6. mRNA levels altered
7. Rate of protein synthesis changes
8. Protein levels altered

35

What drugs increase insulin secretion?

SUs
Incretin mimetics
Glinides
DPP-4 inhibitors (Gliptins)

36

What drugs reduce insulin resistance and reduce hepatic glucose output?

Biguanides
TZDs (Glitazones)

37

What drugs slow glucose absorption from the GI tract?

α-glucosidase inhibitors

38

What drugs increase glucose excretion in the kidneys?

SGLT2 inhibitors

39

Which drugs are insulin dependent and which are insulin independent?

Insulin-dependent:
- SUs
- Incretin mimetics
- Glinides
- DPP-4 inhibitors
- Biguanides
- TZDs
Insulin-independent:
- α-glucosidase inhibitors
- SGLT2 inhibitors

40

What is the physiology of insulin secretion?

1. Increased blood glucose
2. Increased glutamate diffusion into B-cell via GLUT2
3. Phosphorylation of glucose by glucokinase
4. Glycolysis of glucose-6-phosphate in mitochondria
5. Increased ATP/ADP ratio
6. ATP sensitive K+ channels close
7. Depolarisation
8. Voltage-gated calcium channels open
9. Increased intracellular [Calcium]
10. Insulin secretion

41

What is the structure of the Katp channel?

4 inward K+ rectifier 6.2 subunits (Kir6.2)
4 sulphonylurea receptor 1 subunits (SUR1)

42

What is the function of the Kir6.2 tetramer?

Selective K+ channel

43

What is the function of the SUR1 tetramer?

Regulates K+ channel activity

44

When does ATP bind to Kir6.2?

When [Glucose]e is high

45

When does ADP-Mg2+ bind to SUR1?

When [Glucose]e is low

46

What are some examples of SUs?

1st generation - Tolbutamide
2nd generation:
- Glibenclamide
- Glipizide

47

How do SUs work?

Displace ADP-Mg2+ from SUR1:
- Closes channel

48

What benefits do the 2nd generation SUs have over 1st generation?

More potent
Longer-acting

49

Who are at the greatest risk of hypos with SU use?

People using 2nd generation SUs
Elderly people
Patients with reduced hepatic/renal function

50

What can SUs be used with?

Metformin
TZDs

51

What effect do SUs have on weight?

They cause weight gain

52

How do glinides/meglitinides work?

Bind to SUR1 at benzamido site (close channel -> depolarization -> Insulin release)

53

What are some examples of glinides?

Repaglinide
Nateglinide

54

When are glinides taken? Why?

Before meals:
- Reduce post-prandial rise in blood glucose

55

What can glinides be used with?

Metformin
TZDs

56

When are GLP-1 and GIP released? From what cells are they released?

When food is ingested
Released from:
- L cells
- K cells

57

Where do GLP-1 and GIP enter?

Portal blood

58

What effects does GLP-1 have?

Increase insulin release from β-cells
Decrease gastric emptying

59

What effects does GIP have?

Reduce glucagon release from α-cells

60

Whet are the downstream effects of GLP-1 and GIP?

Enhanced glucose uptake + utilisation
Reduced glucose production

61

How do incretin analogues work?

Mimic GLP-1 action but are longer lasting

62

What is exenatide?

Synthetic extendin-4:
- A GLP-1 agonist
- Peptide in saliva of Gila monster

63

How does exenatide work?

Binds to GPCR GLP-1 receptors -> Increased [cAMP]i:
- Increased insulin secretion
- Reduced glucagon secretion
- Reduced gastric emptying
- Reduced appetite

64

What other effects do incretin mimetics have?

Modest weight loss
Reduced hepatic fat accumulation

65

How is exenatide administered?

S/C injection twice daily

66

How is liraglutide administered?

S/C injection once daily

67

What side effects can incretin mimetics have?

Nausea
Hypos
Pancreatitis (rare)

68

What does dipeptidyl peptidase-4 do?

Terminates GLP-1 and GIP action (in minutes)

69

What do DPP-4 inhibitors (gliptins) do?

Competitively inhibit DPP-4:
- Prolong GIP and GLP-1 actions

70

What are DPP-4 inhibitors usually used with?

TZDs
Metformin

71

What are some examples of DPP-4 inhibitors?

Sitagliptin
Saxigliptin
Vildagliptin

72

How often must DPP-4 inhibitors be administered?

Once daily PO

73

If used as monotherapy, can DPP-4 inhibitors cause hypos?

No

74

What effect do DPP-4 inhibitors have on weight?

They are weight neutral

75

What is α-glucosidase? What does it do?

A brush border enzyme:
- Starch and disaccharides -> Glucose

76

What does acarbose to?

Inhibits α-glucosidase and delays glucose absorption:
- Reduces post-prandial rise in blood glucose

77

When is acarbose used?

In T2DM is other drugs don't work

78

What are some side effects of acarbose?

Flatulence
Loose stools
Diarrhoea
Abdominal pain
Bloating

79

Does acarbose have any risk of hypos?

No

80

What is the only therapeutic biguanide?

Metformin

81

When is metformin the 1st line for T2DM?

In obese patients:
- With normal hepatic + renal function

82

What other effects does metformin have?

Reduces hepatic gluconeogenesis -> Stimulates AMPK
Increased glucose uptake and utilisation
Reduces carbohydrate absorption
Increased fatty acid oxidation

83

What effect does metformin have on weight?

Reduces it

84

What can metformin be combined with?

SUs
TZDs
Insulin

85

What are some side effects of metformin?

GI upset:
- Diarrhoea
- Nausea
- Anorexia
Lactic acidosis -> Avoid in hepatic/renal impairment

86

What do thiazolidinediones (glitazones) do?

Enhance action of insulin at target sites

87

How do TZDs work?

Exogenous agonists of peroxyisome proliferator-activated receptor-γ (PPARγ):
- Associated with retinoid receptor X (RXR)
- Largely confined to adipocytes

88

What does activated PPARγ-RXR act as?

Transcription factor:
- Binds to DNA
- Increases gene expression
- Increased protein encoding
> Insulin signalling
> Lipoprotein lipase, FFA transport + GLUT4

89

What are some desirable effects of TZDs?

Fatty acid uptake and storage in adipocytes
Reduce hepatic glucose output

90

What are some adverse effects of TZDs?

Increased weight due to adipocyte differentiation
Fluid retention due to increased Na+ reabsorption
Hepatotoxicity:
- Ciglitazone
- Troglitazone
Increased bone fractures

91

What TZD can be used with metformin and SUs?

Pioglitazone

92

How do SGLT2 inhibitors work?

Block reabsorption of glucose in PCT:
- Causes deliberate glycosuria

93

What effect do SGLT2 inhibitors have on weight?

Weight loss:
- Calorific loss -> Glucose voided
- Water loss -> Osmotic diuresis

94

What is the only licensed SGLT2 inhibitor?

Dapaglifozin