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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
What changes occur between meals?
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
26
What changes occur during the fasting state?
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
27
How does encephalopathy occur?
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
28
How does T2DM occur?
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
29
How does T1DM occur?
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
30
Describe normoglycaemia in endothelial cells
Glucose in via GLUT1 -> acetyl CoA -> ATP
31
What changes occur in endothelial cells during hyperglycaemia?
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)
32
Outline the major complications of T1DM
Chronic effects of hyperglycaemia Hypoglycaemia Diabetic ketoacidosis
33
How does diabetic ketoacidosis occur?
Uncontrolled lipolysis and beta-oxidation -> over-production of ketone bodies (strong acids) -> overwhelms the buffering capacity of the body -> acidosis -> coma and death
34
What causes insulin resistance?
``` Genetics Environment Ectopic lipid accumulation Cellular stress-response Inflammation ```
35
What are the long-term complications of diabetes?
Microvascular damage => retinopathy, nephropahty, and neuropathy
36
How does diabetes cause peripheral neuropathies?
Endothelial damage -> wall thickening -> ischaemia and neural death
37
Compare the different types of diabetic peripheral neuropathies
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)
38
What are the risk factors for diabetic nephropathy?
``` Genetic and familial predisposition Elevated BP Poor glycaemic control Smoking Hyperlipidaemia Microalbuminuria ```
39
What are the risk factors for diabetic retinopathy?
Poor glycaemic control Elevated BP Hyperlipidaemia
40
Describe the pathogenesis for diabetic retinopathy
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
41
What class of drug is metformin?
A biguanide
42
Describe the mechanism of action of metformin
``` Becomes concentrated in hepatocytes Inhibit mitochondrial respiratory chain complex I Alters ATP:AMP Activates AMPK Decreased glucose output ```
43
What ADRs are associated with metformin?
Lactic acidosis | Hypoglycaemia
44
What cautions surround the use of metformin?
Patients receiving radiological contrast agent may suffer temporary renal impairment - withdraw metform for 48h
45
What are the contraindications for the use of metformin?
Renal insufficiency - risk of lactic acidosis
46
What interactions are associated with metformin?
Drugs which impair renal function e.g. NSAIDs (risk of lactic acidosis)
47
Give examples of sulfonylureas
Gliclazide, glibenclamide, glipizide, glimepiride, tolbutamide
48
Describe the mechanism of action of sulfonylureas
``` Bind SUR1 ATP-sensitive potassium channel closes Membrane depolarises Voltage-gated calcium channel opens Insulin secretion and synthesis triggered ```
49
What ADRs are associated with sulfonylureas?
``` Hypoglycaemia Weight gain Nausea Vomiting Diarrhoea Constipation ```
50
What cautions surround the use of sulfonylureas?
Elderly, debilitated and malnourished patients are at greater risk of hypoglycaemia Hepatic impairment - increased risk of hypoglycaemia
51
What are the contraindications for the use of sulfonylureas?
Acute porphyria | Ketoacidosis
52
What interactions are associated with sulfonylureas?
Corticosteroids (increase expression of enzymes involved in gluconeogenesis) Thiazides (hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion) Meglitinides
53
Give examples of meglitinides
Nateglinide and repaglinide
54
Describe the mechanism of action of meglitindes
Close potassium channels Membrane depolarises Calcium channels open Insulin synthesis and secretion triggered
55
What ADRs are associated with meglitinides?
``` Hypoglycaemia Weight gain Nausea Vomiting Diarrhoea Constipation ```
56
What cautions surround the use of meglitinides?
Elderly, debilitated and malnourished at greater risk of hypoglycaemia Hepatic impairment - increased risk of hypoglycaemia
57
What interactions are associated with meglitinides?
Corticosteroids - increase expression of enzymes involved in gluconeogenesis Thiazides - hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion Sulfonylureas
58
What effect does GLP-1 have on insulin secretion?
Potentiates glucose-stimulated insulin secretion - increases secretory machinery - increases insulin biosynthesis - increases calcium channel activity
59
What is the mechanism of action of DPP-4 inhibitors?
Increases GLP-1 concentration - increases secretory machinery - increases insulin biosynthesis - increases calcium channel activity
60
Give examples of GLP-1 agonists
``` Liraglutide Lixisenatide Exenatide Albiglutide Dulaglutide ```
61
Give examples of DPP-4 inhibitors
``` Alogliptin Linagliptin Saxaglitpin Sitagliptin Vildaglitpin ```
62
What ADRs are associated with GLP-1 agonists?
Nausea and vomiting Significant weight loss Pancreatitis and kidney failure
63
What ADRs are associated with DPP-4 inhibitors?
Pancreatitis and kidney failure | Some GI ADRs
64
What class of drug is pioglitazone?
Thiazolidinedione
65
Describe the mechanism of action of pioglitazone
Ligand for transcription factor PPAR-gamma Decrease ectopic fat storage Improving insulin resistance
66
What cautions surround the use of pioglitazone?
HF | Increased risk of bladder cancer
67
What are the contraindications for the use of pioglitazone?
Hepatic insufficiency History of HF Active bladder cancer History of bladder cancer or uninvestigated haematuria
68
What interactions are associated with pioglitazone?
Clopidogrel | Oral contraceptives
69
Give examples of SGLT-2 inhibitors
Dapagliflozin Canagliflozin Empagliflozin
70
Describe the mechanism of action of SGLT-2 inhibitors
Inhibit SGLT-2 leading to reduced reabsorption and increased loss of glucose in urine
71
What ADRs are associated with SGLT-2 inhibitors?
Increased risk of UTIs Increased risk of breast and bladder cancer Minor risk of euglycaemia diabetic ketoacidosis
72
What cautions surround the use of SGLT-2 inhibitors?
Increased urination -> increased risk of hypovolaemia or hypotension Reduced efficacy in patients with impaired renal function
73
What are the contraindications for the use of SGLT-2 inhibitors?
Hepatic insufficiency | Impaired left ventricular function
74
What interactions are associated with SGLT-2 inhibitors?
Diuretics
75
Describe the action of oestrogen
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
What are the targets and uses of progestins?
Physiological target - reproductive tract - decreases oestrogen-driven endometrial proliferation - establishment and maintenance of pregnancy Uses - oral contraceptives - HRT - Uterine bleeding disorders - premature labour
77
Name a progesterone antagonist
Mifepristone
78
What is mifepristone used for?
Termination of pregnancy | Induction of labour after foetal death
79
Describe the pituitary hormone effects that occur in the early follicular phase
FSH stimulates several follicles to grow, and stimulates estradiol secretion
80
Describe the ovarian hormone effects that occur during the early follicular phase
Follicles produce low levels of estradiol which: - causes endometrial arteries to constrict, resulting in menstruation - inhibits LH secretion - stimulates FSH secretion
81
Describe the pituitary hormone effects that occur during the late follicular phase/ovulation
FSH stimulates one follicle to further develop | LH surge stimulates ovulation from that follicle
82
Describe the ovarian hormone effects that occur during the late follicular phase/ovulation
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
Describe the pituitary hormone effects of the luteal phase
LH stimulates development of a corpus lute up left behind after ovulation
84
Describe the ovarian hormone effects that occur during the luteal phase
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
Describe the pituitary hormone effects that occur during menstruation
Low GnRH, LH, FSH
86
Describe the ovarian hormone effects that occur during menstruation
Progesterone and estradiol levels fall: | - causes endometrial arteries to constrict, resulting in menstruation
87
What changes occur to the menstrual cycle during pregnancy?
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
What changes occur to the menstrual cycle during the menopause?
All follicles depleted | Decreased oestrogen and inhibin -> LH, FSH
89
What are the two types of method of contraception?
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
What oestrogens are used in hormonal contraception?
Ethinyl estradiol or mestranol
91
What progestins are used in hormonal contraception?
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
What is the mechanism of action of COCs?
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
What effects do oestrogen only contraceptives have?
Promote endometrial growth => Endometrial cancer
94
Outline the PK of COCs
Phase 1 - extensive first pass by CYP3A4 | Phase 2 - sulfation and glucuronidation followed by biliary secretion
95
Compare monophasic and multiphasic COCs
Monophasic - dose of oestrogen and progestin doesn’t vary Multiphasic - biphasic - progestin dose varies - triphasic - 3 different dose combinations
96
What ADRs are associated with oestrogens?
Fluid retention HTN Increased risk of endometrial cancer
97
What ADRs are associated with progestogen?
Headache Nausea Vomiting Lower back pain
98
What ADRs are associated with COCs?
HTN Thromboembolism Cancer
99
What are the contraindications for the use of COCs?
Risk of CV, thromboembolic or malignant disease | Pregnancy
100
What interactions are associated with COCs?
CYP3A4 inducers => contraceptive failure - rifampicin - phenytoin - phenobarbital - st john’ wort
101
What is the mechanism of action of POPs?
Inhibit GnRH release | No menstruation
102
What ADRs are associated with POPs?
Breakthrough bleeding
103
What progestogen only depot injections are available?
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
What progestogen only subdermal implants are available?
Levonorgestrel - fertility restored on removal - irregular and prolong bleeding can occur
105
What progestogen only intrauterine devices are available?
Levonorgestrel - prevents endometrial thickening - fertility restored on removal - irregular and prolonged bleeding can occur - dysmenorrhoea less than with copper IUD
106
How do copper IUDs work?
Release copper to prevent fertilisation
107
What EHCs are available?
Levonorgestrel - high single dose - blocks LH surge - useful for up to 72h after intercourse Ulipristal - useful for up to 120h after intercourse
108
How does tamoxifen work?
ER antagonist in breast tissue (inhibits oestrogen-dependent growth of breast cancer) Partial ER agonist in endometrium and bone
109
How do SERMs work?
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
Outline the properties of an ideal SERM
``` Strengthen bones Lower LDL Raise HDL Relieve hot flushes Reduce breast cancer risk Reduce uterine cancer risk ```
111
Outline the good effects of real oxide effects
``` Strengthens bones Lowers LDL Reduces risk for invasive breast cancer Fewer uterine cancers than tamoxifen Fewer blood clots than tamoxifen ```
112
Outline the bad effects of raloxfiene
Hot flushes Blood clots Leg cramps Teratogenic
113
What are the effects of raloxifene?
Antagonist in breast and endometrium | Agonist in bone

Stage 3 Block 2 (8 decks)

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