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Stage 3 Block 2 > Endocrine > Flashcards

Endocrine Flashcards

1
Q

Define diabetes mellitus

A

A persistent state of hyperglycaemia due to the body’s inability to properly utilise glucose

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2
Q

Compare the two different types of diabetes mellitus

A

T1DM - pancreas does not produce any insulin due to beta-cells in islets of Langerhans being destroyed

T2DM - relative insulin deficiency and/or resistance

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3
Q

What is T2DM commonly associated with?

A

Obesity, physical inactivity, HTN, dyslipidaemia, tendency to develop thrombosis

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4
Q

Explain the signs and symptoms of DM

A

Polyuria, nocturia, polydipsia - osmotic diuresis

Lethargy - inability to utilise glucose to provide energy

Weight loss - breakdown of body protein and fat as alternative energy sources as glucose is unavailable

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5
Q

Describe the different types of insulin available

A

Short acting
Intermediate
Long acting
Ultra long acting

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6
Q

When is short acting insulin used and why?

A

Mimics usual increases of insulin around meal times.
Soluble insulins are injected 15-30mins before meals, onset is 30-60m, peak action is 1-4h and duration is <9h.
Human insulin analogues are injected just before, with or just after a meal, onset is faster, peak action is 0-3h and duration is 2-5h.

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7
Q

What is the onset, peak action and duration of intermediate and long acting insulins?

A

Onset 1-2h, peak 3-12h, duration 11-24h.

Provide baseline

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8
Q

What ADRs are associated with insulin?

A

Local reactions at injection site
Hypoglycaemia
Hypersensitivity

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9
Q

What are the risk factors for gestational diabetes?

A

Obesity
Family history of DM
Unexplained stillbirth or death of a neonate in a previous pregnancy
Very large infant in a previous pregnancy
Previous history of gestational diabetes
Family origin south Asian, black Caribbean or middle eastern

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10
Q

What are the glucose targets?

A

Pre-prandial 4-7mmol/L

Post-prandial <9mmol/L

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11
Q

What are the symptoms of hypoglycaemia?

A 
Feeling shaky
Sweating
Hunger
Tiredness
Pallor
Blurred vision
Headaches
Irritability
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12
Q

What are the causes of hypoglycaemia?

A 
Too much insulin
Delayed/missed meal or snack
Not eating sufficient carbohydrates 
Excess physical activity 
Drinking large amounts of alcohol
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13
Q

What is the treatment for hypoglycaemia in a conscious patient?

A

15-20g fast acting carbohydrate
15-20g slower acting carbohydrate to prevent levels dropping low again
Blood glucose retested after 15-20mins and treatment repeated if levels <4mmol/L

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14
Q

What is the treatment for hypoglycaemia in an unconscious patient?

A

Recovery position
Glucagon injection
Ambulance

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15
Q

Define hyperglycaemia

A

Pre-prandial >7.5mmol/L

2h post-prandial >8.5mmol/L

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16
Q

What are the symptoms of hyperglycaemia?

A

Excessive thirst
Passing more urine than usual
Headaches
Tiredness/lethargy

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17
Q

What are the causes of hyperglycaemia?

A 
Missing doses of medication
Eating more carbohydrates than the body or medication can cope with
Stress
Concurrent infections
Over treating a hypoglycaemic episode
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18
Q

What is the main purpose of energy homeostasis in the fed state?

A

Store calories

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19
Q

What changes does insulin induce?

A

Glucose stored as glycogen in muscle and liver
Glucose used as fuel in muscle
Glucose carbons and calories sorted in fatty acids
Switched off glycogen degradation and gluconeogenesis

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20
Q

What effect does insulin have on lipid metabolism?

A

Glucose-> fatty acids

Fatty acid storage in adipose

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21
Q

Describe protein metabolism by the liver

A

Fed state - excess amino acids deaminated
Fasting - amino acids a major source of glucose (gluconeogenesis)
Glucagon => increased uptake, deamination and urea cycle activity

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22
Q

How is liver glycogen metabolism controlled?

A

Glycogen - stimulates PKA when blood glucose is scarce. FBPase2 is activated. Glycolysis is inhibited, and gluconeogenesis is stimulated.

High levels of fructose-6-phosphate stimulate phosphoprotein phosphatase. PFK2 is activated. Glycolysis is stimulated and gluconeogenesis is inhibited.

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23
Q

What occurs during the well-fed state?

A

Glucose and amino acids from food enter the blood stream and reach the liver via the portal vein.
Triacylglycerol from food is packed into chylomicrons and absorbed via the lymphatic system.
Insulin is secreted to stimulate the storage of fuels:
Glycogen synthesis occurs in the liver and muscles
Glycolysis occurs in the liver which generates acetyl-CoA for FA synthesis
Triglycerides are stored in adipose tissue

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24
Q

What effect does insulin have during the well-fed state?

A

Liver

  • switch off glycogenolysis and gluconeogenesis to reduce glucose output
  • switch on glycolysis - increased acetyl CoA to increase FA synthesis

Adipose
- switch off hormone sensitive lipase to reduce FA production and increase fat storage

Muscle
- increase GLUT4 expression - increased glucose uptake to increase use of glucose as fuel and decrease use of FAs

Brain
- decreased appetite

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25
Q

What changes occur between meals?

A

Blood glucose levels drop
Glucagon secreted
- glycogenolysis stimulated to release glucose - glucose taken up primarily by the brain
- FA released from adipose tissue increased, muscle uses FAs as primary fuel source
- gluconeogenesis stimulated

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26
Q

What changes occur during the fasting state?

A

Glucose no longer taken up by muscles - muscles use FAs and ketone bodies
Proteins broken down => atrophy - amino acids, lactate and glycerol all used to maintain a supply of glucose for the brain
Brain begins to rely more upon ketone bodies
Long-term starvation leads to brain malfunction

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27
Q

How does encephalopathy occur?

A

Reduced gluconeogenesis, glycogen storage - inadequate hepatic glucose production

Reduced fatty acid oxidation - inadequate ketone body production, inadequate energy for gluconeogenesis

Brain runs out of energy - toxic metabolites accumulate in brain cells => brain swelling and coma

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28
Q

How does T2DM occur?

A

Resistance to insulin, cannot raise insulin sufficiently to promote glucose uptake in muscle or control glucose production by the liver

Consequence of obesity
Normal increase in fructose 2,6-bisphosphate and down-regulation of phosphoenolpyruvate carboxylase does not occur
Translocation of GLUT4 to plasma membrane is decreased
Ketoacidosis rarely develops, observed increase in VLDL

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29
Q

How does T1DM occur?

A

Complete absence of insulin production by pancreas
Stuck in starved state
- liver is always gluconeogenic and glycogenolytic -> hyperglycaemia
- uncontrolled proteolysis-> muscle wasting and provides substrates for gluconeogenesis
- uncontrolled adipose tissue lipolysis increased plasma [FA] - liver ketone body production, uncontrolled by insulin leading to ketoacidosis

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30
Q

Describe normoglycaemia in endothelial cells

A

Glucose in via GLUT1 -> acetyl CoA -> ATP

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31
Q

What changes occur in endothelial cells during hyperglycaemia?

A

Glucose in via GLUT1 -> acetyl CoA -> ATP, no more ATP or acetyl CoA can be made, glucose takes other pathways:

Glucose -> sorbitol (reduced NADPH leads to oxidative stress, increased sorbitol leads to reduced vasoelasticity)

Glucose -> glycation (AGE) (increased protein stability, altered cellular interactions, altered extracellular matrix)

Glucose -> acetyl CoA -> FAs -> diacyl glycerol (DAG activates protein phosphorylation, altered cellular signalling, multiple effects on vascular cells)

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32
Q

Outline the major complications of T1DM

A

Chronic effects of hyperglycaemia
Hypoglycaemia
Diabetic ketoacidosis

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33
Q

How does diabetic ketoacidosis occur?

A

Uncontrolled lipolysis and beta-oxidation -> over-production of ketone bodies (strong acids) -> overwhelms the buffering capacity of the body -> acidosis -> coma and death

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34
Q

What causes insulin resistance?

A 
Genetics
Environment 
Ectopic lipid accumulation 
Cellular stress-response
Inflammation
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35
Q

What are the long-term complications of diabetes?

A

Microvascular damage => retinopathy, nephropahty, and neuropathy

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36
Q

How does diabetes cause peripheral neuropathies?

A

Endothelial damage -> wall thickening -> ischaemia and neural death

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37
Q

Compare the different types of diabetic peripheral neuropathies

A

Somatic - parasethesias; impaired pain, temperature, light touch, two-point discrimination and vibratory sensation

Autonomic - vasomotor function (postural hypotension), gastrointestinal function (postprandial and nocturnal diarrhoea), genitourinary function (impotence), cranial nerve (impaired pupillary responses)

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38
Q

What are the risk factors for diabetic nephropathy?

A 
Genetic and familial predisposition
Elevated BP
Poor glycaemic control
Smoking
Hyperlipidaemia
Microalbuminuria
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39
Q

What are the risk factors for diabetic retinopathy?

A

Poor glycaemic control
Elevated BP
Hyperlipidaemia

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40
Q

Describe the pathogenesis for diabetic retinopathy

A

Endothelial change of vascular wall

  • microaneurysms -> burst -> scarring, damage to cellular environment, macular oedema
  • ischaemia -> fragile new blood vessels, more prone to aneurysms and bursting
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41
Q

What class of drug is metformin?

A

A biguanide

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42
Q

Describe the mechanism of action of metformin

A 
Becomes concentrated in hepatocytes
Inhibit mitochondrial respiratory chain complex I
Alters ATP:AMP
Activates AMPK
Decreased glucose output
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43
Q

What ADRs are associated with metformin?

A

Lactic acidosis

Hypoglycaemia

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44
Q

What cautions surround the use of metformin?

A

Patients receiving radiological contrast agent may suffer temporary renal impairment - withdraw metform for 48h

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45
Q

What are the contraindications for the use of metformin?

A

Renal insufficiency - risk of lactic acidosis

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46
Q

What interactions are associated with metformin?

A

Drugs which impair renal function e.g. NSAIDs (risk of lactic acidosis)

47
Q

Give examples of sulfonylureas

A

Gliclazide, glibenclamide, glipizide, glimepiride, tolbutamide

48
Q

Describe the mechanism of action of sulfonylureas

A 
Bind SUR1
ATP-sensitive potassium channel closes
Membrane depolarises 
Voltage-gated calcium channel opens
Insulin secretion and synthesis triggered
49
Q

What ADRs are associated with sulfonylureas?

A 
Hypoglycaemia
Weight gain
Nausea
Vomiting
Diarrhoea
Constipation
50
Q

What cautions surround the use of sulfonylureas?

A

Elderly, debilitated and malnourished patients are at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia

51
Q

What are the contraindications for the use of sulfonylureas?

A

Acute porphyria

Ketoacidosis

52
Q

What interactions are associated with sulfonylureas?

A

Corticosteroids (increase expression of enzymes involved in gluconeogenesis)
Thiazides (hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion)
Meglitinides

53
Q

Give examples of meglitinides

A

Nateglinide and repaglinide

54
Q

Describe the mechanism of action of meglitindes

A

Close potassium channels
Membrane depolarises
Calcium channels open
Insulin synthesis and secretion triggered

55
Q

What ADRs are associated with meglitinides?

A 
Hypoglycaemia
Weight gain
Nausea
Vomiting
Diarrhoea
Constipation
56
Q

What cautions surround the use of meglitinides?

A

Elderly, debilitated and malnourished at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia

57
Q

What interactions are associated with meglitinides?

A

Corticosteroids - increase expression of enzymes involved in gluconeogenesis
Thiazides - hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion
Sulfonylureas

58
Q

What effect does GLP-1 have on insulin secretion?

A

Potentiates glucose-stimulated insulin secretion

  • increases secretory machinery
  • increases insulin biosynthesis
  • increases calcium channel activity
59
Q

What is the mechanism of action of DPP-4 inhibitors?

A

Increases GLP-1 concentration

  • increases secretory machinery
  • increases insulin biosynthesis
  • increases calcium channel activity
60
Q

Give examples of GLP-1 agonists

A 
Liraglutide
Lixisenatide
Exenatide
Albiglutide
Dulaglutide
61
Q

Give examples of DPP-4 inhibitors

A 
Alogliptin
Linagliptin
Saxaglitpin
Sitagliptin
Vildaglitpin
62
Q

What ADRs are associated with GLP-1 agonists?

A

Nausea and vomiting
Significant weight loss
Pancreatitis and kidney failure

63
Q

What ADRs are associated with DPP-4 inhibitors?

A

Pancreatitis and kidney failure

Some GI ADRs

64
Q

What class of drug is pioglitazone?

A

Thiazolidinedione

65
Q

Describe the mechanism of action of pioglitazone

A

Ligand for transcription factor PPAR-gamma
Decrease ectopic fat storage
Improving insulin resistance

66
Q

What cautions surround the use of pioglitazone?

A

HF

Increased risk of bladder cancer

67
Q

What are the contraindications for the use of pioglitazone?

A

Hepatic insufficiency
History of HF
Active bladder cancer
History of bladder cancer or uninvestigated haematuria

68
Q

What interactions are associated with pioglitazone?

A

Clopidogrel

Oral contraceptives

69
Q

Give examples of SGLT-2 inhibitors

A

Dapagliflozin
Canagliflozin
Empagliflozin

70
Q

Describe the mechanism of action of SGLT-2 inhibitors

A

Inhibit SGLT-2 leading to reduced reabsorption and increased loss of glucose in urine

71
Q

What ADRs are associated with SGLT-2 inhibitors?

A

Increased risk of UTIs
Increased risk of breast and bladder cancer
Minor risk of euglycaemia diabetic ketoacidosis

72
Q

What cautions surround the use of SGLT-2 inhibitors?

A

Increased urination -> increased risk of hypovolaemia or hypotension
Reduced efficacy in patients with impaired renal function

73
Q

What are the contraindications for the use of SGLT-2 inhibitors?

A

Hepatic insufficiency

Impaired left ventricular function

74
Q

What interactions are associated with SGLT-2 inhibitors?

A

Diuretics

75
Q

Describe the action of oestrogen

A

Oestrogen act as signalling molecules by interacting with specific target cells
- include tissues of the breast, uterus, brain, heart, liver and bone
- ER modulation used in contraception
ER undergoes dimerisation in order for it to have increased affinity for EREs and regulate gene expression

76
Q

What are the targets and uses of progestins?

A

Physiological target - reproductive tract

  • decreases oestrogen-driven endometrial proliferation
  • establishment and maintenance of pregnancy

Uses

  • oral contraceptives
  • HRT
  • Uterine bleeding disorders
  • premature labour
77
Q

Name a progesterone antagonist

A

Mifepristone

78
Q

What is mifepristone used for?

A

Termination of pregnancy

Induction of labour after foetal death

79
Q

Describe the pituitary hormone effects that occur in the early follicular phase

A

FSH stimulates several follicles to grow, and stimulates estradiol secretion

80
Q

Describe the ovarian hormone effects that occur during the early follicular phase

A

Follicles produce low levels of estradiol which:

  • causes endometrial arteries to constrict, resulting in menstruation
  • inhibits LH secretion
  • stimulates FSH secretion
81
Q

Describe the pituitary hormone effects that occur during the late follicular phase/ovulation

A

FSH stimulates one follicle to further develop

LH surge stimulates ovulation from that follicle

82
Q

Describe the ovarian hormone effects that occur during the late follicular phase/ovulation

A

Follicles produce increasing levels of estradiol which:

  • stimulates GnRH secretion by hypothalamus
  • with GnRH drives LH levels to spike, causing ovulation
  • causes the endometrium to further develop
83
Q

Describe the pituitary hormone effects of the luteal phase

A

LH stimulates development of a corpus lute up left behind after ovulation

84
Q

Describe the ovarian hormone effects that occur during the luteal phase

A

The corpus luteum secretes progesterone and estradiol which:

  • blocks GnRH secretion by the hypothalamus and LH and FSH secretion by the pituitary
  • causes the endometrium to further develop
85
Q

Describe the pituitary hormone effects that occur during menstruation

A

Low GnRH, LH, FSH

86
Q

Describe the ovarian hormone effects that occur during menstruation

A

Progesterone and estradiol levels fall:

- causes endometrial arteries to constrict, resulting in menstruation

87
Q

What changes occur to the menstrual cycle during pregnancy?

A

Implantation - blastocyst produces hCG which supports continued secretion of progesterone by corpus luteum until placenta takes over
Progesterone:
- maintains decidua (lining of uterus)
- promotes blood vessel growth

88
Q

What changes occur to the menstrual cycle during the menopause?

A

All follicles depleted

Decreased oestrogen and inhibin -> LH, FSH

89
Q

What are the two types of method of contraception?

A

Mechanical

  • condoms, diaphragms, intrauterine devices
  • some can be combined with chemical spermicide - essential with a diaphragm, nonoxynol 9 (surfactant)

Hormonal
- p.o, depot formulation for i.m. Injection, transdermal patch, vaginal ring, intrauterine devices

90
Q

What oestrogens are used in hormonal contraception?

A

Ethinyl estradiol or mestranol

91
Q

What progestins are used in hormonal contraception?

A

Norethisterone (1st gen)
Norgestrel/levonorgestrel (2nd gen) - agonists at AR
Desogestrel/gestodene/norgestimate (3rd gen) - less androgen activity
Drospirenone (4th gen) - anti-androgenic and anti-mineralocorticoid

92
Q

What is the mechanism of action of COCs?

A

Suppress GnRH, LH, and FSH release at hypothalamic and pituitary level
Progestin inhibits oestrogen-induced LH “surge” and inhibits ovulation
- oestrogen up-regulates PGR, increasing negative feedback by the progestogen

93
Q

What effects do oestrogen only contraceptives have?

A

Promote endometrial growth => Endometrial cancer

94
Q

Outline the PK of COCs

A

Phase 1 - extensive first pass by CYP3A4

Phase 2 - sulfation and glucuronidation followed by biliary secretion

95
Q

Compare monophasic and multiphasic COCs

A

Monophasic - dose of oestrogen and progestin doesn’t vary

Multiphasic

  • biphasic - progestin dose varies
  • triphasic - 3 different dose combinations
96
Q

What ADRs are associated with oestrogens?

A

Fluid retention
HTN
Increased risk of endometrial cancer

97
Q

What ADRs are associated with progestogen?

A

Headache
Nausea
Vomiting
Lower back pain

98
Q

What ADRs are associated with COCs?

A

HTN
Thromboembolism
Cancer

99
Q

What are the contraindications for the use of COCs?

A

Risk of CV, thromboembolic or malignant disease

Pregnancy

100
Q

What interactions are associated with COCs?

A

CYP3A4 inducers => contraceptive failure

  • rifampicin
  • phenytoin
  • phenobarbital
  • st john’ wort
101
Q

What is the mechanism of action of POPs?

A

Inhibit GnRH release

No menstruation

102
Q

What ADRs are associated with POPs?

A

Breakthrough bleeding

103
Q

What progestogen only depot injections are available?

A

Medroxyprogesterone

  • t1/2~30h
  • aqueous depot formulation for i.m injection every ~12weeks

Norethisterone

  • oil depot formulation used for short term contraception
  • also used to treat heavy periods
104
Q

What progestogen only subdermal implants are available?

A

Levonorgestrel

  • fertility restored on removal
  • irregular and prolong bleeding can occur
105
Q

What progestogen only intrauterine devices are available?

A

Levonorgestrel

  • prevents endometrial thickening
  • fertility restored on removal
  • irregular and prolonged bleeding can occur
  • dysmenorrhoea less than with copper IUD
106
Q

How do copper IUDs work?

A

Release copper to prevent fertilisation

107
Q

What EHCs are available?

A

Levonorgestrel

  • high single dose
  • blocks LH surge
  • useful for up to 72h after intercourse

Ulipristal
- useful for up to 120h after intercourse

108
Q

How does tamoxifen work?

A

ER antagonist in breast tissue (inhibits oestrogen-dependent growth of breast cancer)
Partial ER agonist in endometrium and bone

109
Q

How do SERMs work?

A

Tissue-specific patterns of oestrogen receptors

Tissue-specific pattern of co-regulator expression

  • pattern of genes activated by ER activation regulated by the expression of co-regulator proteins
  • co-regulator repertoire varies from tissue to tissue
  • co-regulator recruitment may be ligand-dependent, thus a ligand may recruit co-activators specific to one tissue but co-repressors specific to another

Effects on ER stability and degradation

110
Q

Outline the properties of an ideal SERM

A 
Strengthen bones
Lower LDL
Raise HDL
Relieve hot flushes
Reduce breast cancer risk
Reduce uterine cancer risk
111
Q

Outline the good effects of real oxide effects

A 
Strengthens bones
Lowers LDL
Reduces risk for invasive breast cancer
Fewer uterine cancers than tamoxifen
Fewer blood clots than tamoxifen
112
Q

Outline the bad effects of raloxfiene

A

Hot flushes
Blood clots
Leg cramps
Teratogenic

113
Q

What are the effects of raloxifene?

A

Antagonist in breast and endometrium

Agonist in bone

Stage 3 Block 2 (8 decks)

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