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Y2 LCRS 1 - Pharm, Endo, Reproduction > ENDO; Lecture 3, 4 and 5 & Tutorial 2 - Neurohypophysial disorders, Hypothyroid disorders - treatment and Hyperthyroid disorders > Flashcards

ENDO; Lecture 3, 4 and 5 & Tutorial 2 - Neurohypophysial disorders, Hypothyroid disorders - treatment and Hyperthyroid disorders Flashcards

1
Q

What is the hypothalamo-neurohypophysial system?

A
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2
Q

What are the effects of vasopressin?

A

Anti-diuretic -> acts on renal cortical and medullary collecting ducts via V2 receptors

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3
Q

What is the mechanism of action of VP on the collecting duct cell to cause AQP2, 3 and 4 insertion?

A

x

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4
Q

Where is VP release regulated?

A

Osmoreceptors are located in the Organum vasculosum -> projecting to hypothalamic PVN (paraventricular nucleus) and SON (supraoptic nucleus)

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5
Q

How do the osmoreceptors react to changes in osmolality?

A

Osmoreceptors are very sensitive to changes in EC osmolarity, so if increase in EC Na, osmoreceptor shrinks stimulating osmoreceptor firing, causing release from hypothalamic PVN and SON

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6
Q

What is the normal response to water deprivation?

A

Retaining water at the kidneys means that urine volume decreases and serum osmolality is maintained

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7
Q

What are the 2 forms of diabetes insipidus?

A

Absence/lack of circulating VP (cranial/central) OR end-organ (kidneys) resistance to VP (nephrogenic)

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8
Q

How is cranial diabetes insipidus caused and what are the 2 types?

A

Acquired: Damage to neurohypophysial system due to traumatic brain injury, pit surgery, pit tumours, craniopharyngiomas, metastasis to pit gland, granulomatous infiltration of median eminence (TB, sarcoidosis). Congenital (rare)

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9
Q

How is nephrogenic diabetes insipidus caused?

A

Congenital (rare -> mutation in gene encoding V2 receptor, AQP2) OR acquired (drugs -> lithium: used for bipolar disorder but can cause primary hypoparathyroidism as well)

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10
Q

What are the signs and symptoms of DI?

A
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11
Q

How does the DI thirst loop differ if no water is given?

A
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12
Q

What is psychogenic polydipsia?

A

Seen in psych patients due to ‘dry mouth’ -> could be in patients told to drink plenty; leading to polydipsia and polyuria without DI as VP secretion is preserved

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13
Q

How does the cycle of osmolarity work in psychogenic polydipsia?

A

x

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14
Q

How does the plasma osmolarity differ between DI, normal and psychogenic polydypsia?

A

NB: don’t worry about the actual numbers

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15
Q

How does the urine osmolarity differ between DI, normal and psychogenic polydipsia during a water deprivation test?

A

First part of test is to differentiate between psychogenic polydipsia and DI -> measure concentration and volume of urime made and osmolality of circulating blood (also weigh them frequently) Second part is to differentiate between nephrogenic and cranial DI with a synthetic VP analogue (central is due to not enough VP so giving them VP improves their function but nephrogenic can’t respond to VP so isn’t going to help the patient)

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16
Q

What are the biochemical features of DI?

A

Hypernatraemia, raised urea, increased plasma osmolarity, hypo-osmolar urine (dilute)

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17
Q

What are the biochemical features of psychogenic polydipsia?

A

Mild hyponatraemia (excess water intake), low plasma osmolality, Hypo-osmolar urine (dilute)

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18
Q

What examples of selective VP receptor peptidergic agonists exist for V1 and V2?

A

V1 - terlipressin, V2 - desmopressin (DDAVP)

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19
Q

What is desmopressin - administration, use and care?

A

Admin - nasally, orally, SC; Use - reduction in urine volume and concentration in cranial DI; Care - tell patient to NOT drink large amounts of fluid, risk of hyponatraemia

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20
Q

How do you treat nephrogenic diabetes insipidus and what is the mechanism?

A

Thiazides (bendroflumethiazide) -> Inhibits Na/Cl transport in DCT, volume depletion, compensatory increase in Na reabsorption from PCT, increase proximal water reabsorption, decreased fluid reaching collecting duct, reduced urine volume

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21
Q

What is SIADH?

A

Syndrome of inappropriate ADH -> plasma VP concentration is inappropriately high for existing plasma osmolality

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22
Q

What happens when VP is increased (hyponatraemia and euvolaemia)?

A

Euvolemic means have normal circulating volume

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23
Q

What are the signs of SIADH?

A

Raised urine osmolality, decreased urine volume, hyponatraemia due to increased water reabsorption

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24
Q

What are the symptoms of SIADH?

A

Can be symptomless, but if p[Na] < 120mM: generalised weakness, poor mental function, nausea and if p[Na] <110mM, confusion leading to coma and ultimately DEATH

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25
Q

What are the causes of SIADH?

A
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26
Q

What is the treatment for SIADH?

A

Appropriate -> surgery for tumour; reducing immediate concern -> fluid restriction (immediate) and then use drugs preventing VP action in kidneys (long-term), inducing nephrogenic DI (reducing renal water reabsorption (demeclocyline - V2 receptor antagonists)

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27
Q

What are vaptans?

A

V2 receptor antagonists (Non-competitive) -> very expensive and licensed in UK to treat hyponatraemia associated with SIADH

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28
Q

How do vaptans function?

A

Inhibit AQP2 synthesis and transport to collecting duct apical membrane preventing renal water reabsorption

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29
Q

What is aquaresis?

A

Solute sparing renal excretion of water, contrasting with diuretics which produce simultaneous electrolyte loss

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30
Q

Which hormones are secreted from the thyroid gland?

A

T4 and T3

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31
Q

What is T4?

A

Tetraiodothyronine, a prohormone which is converted by deiodinase enzyme activity into T3

32
Q

How much of circulating T3 is formed from deiodination of T4 and how much from the thyroid directly?

A

80% from T4 and 20% from Thyroid

33
Q

How do T3 and T4 act on the cell?

A

T3 binds to RXR heterodimer which binds to TRE which results in gene transcription

34
Q

What are the substances used in thyroid hormone replacement therapy?

A

Levothyroxine sodium -> thyroxine sodium, thyroxine, T4; Liothyronine sodium -> T3 (less commonly used)

35
Q

What are the clinical uses of levothyroxine sodium (synthetic T4)?

A

AI 1ry hypothyroidism; iatrogenic 1ry hypothyroidism (post-thyroidectomy, post-radioactive iodine); secondary hypothyroidism (pit. tumour, post-pit surgery/radiotherapy)

36
Q

How is levothyroxine sodium administered for primary hypothyroidism?

A

Orally and TSH is used as a guidance for thyroxine dose -> aims to suppress TSH into reference range

37
Q

How is levothyroxine sodium administered for secondary hypothyroidism?

A

Orally and TSH is low due to ant. pit. failure so can’t use TSH as a guide to dose so need to aim for fT4 middle of reference range

38
Q

What is the clinical use of Liothyronine?

A

Myxoedema coma - very rare complication of hypothyroidism because you want to very quickly increase their T3 levels

39
Q

How is liothyronine administered?

A

IV initially then oral when possible (onset of action is faster than T4)

40
Q

What is the combined thyroid hormone replacement?

A

Combined T3/4 improved some well-being - they feel better (no data to support)

41
Q

What are some complications about the combined thyroid hormone replacement?

A

Symptoms of ‘toxicity’ due to potency of T3 -> palpitations, tremors, anxiety - often combination treatment suppresses TSH

42
Q

What are some adverse effects of thyroid hormone over-replacement?

A

Associated with low/suppressed TSH -> Skeletal: increased bone turnover, reduction in bone mineral density with risk of osteoporosis; cardiac: tachycardia, risk of dysrhythmia, particularly atrial fibrillation; metabolism: increased energy expanditure, weight loss; increased beta-adrenergic sensitivity: tremor, nervousness

43
Q

What are the pharmacokinetics of Levothyroxine and liothyronine - administration, half life, extracellular binding, T4 c.f. T3, clearance?

A

Both active orally with long t1/2 -> T4 = 6 days and T3 = 2.5 days; 99.97% T4 and 99.7% T3 are bound to plasma proteins (TBG) -> only free hormone is available to tissues; 10x more T4 in plasma than T3; free and unconjugated hormone secreted in bile and urine, T3 cleared in hrs, T4 in 6 days.

44
Q

When do plasma binding proteins change concentrations?

A

Pregnancy/prolonged treatment with oestrogens and phenothiazines -> increases; TBG falls with malnutrition, liver disease, certain drug treatments; certain co-admin drugs compete for protein binding sites (phenytoin, salicylates)

45
Q

What are the responses to exogenous VP?

A

X

46
Q

What are the symptoms of hypothyroidism?

A

Depression, cold intolerance, tiredness, weight gain, constipation, bradycardia, deepening voice

47
Q

What is hyperthyroidism and what are the three types?

A

Too much thyroxine made -> Graves’ disease, Nodular goitre (plummer’s disease) and thyroiditis

48
Q

What is Graves’ disease?

A

Autoimmune by the antibodies binding to and stimulating TSH receptor in the thyroid

49
Q

What are the classes of drugs used in treatment of hyperthyroidism?

A

Thionamides, (propylthiouracil, carbimazole), potassium iodide, radioiodine, beta-blockers

50
Q

What is the main function of the thionamides, potassium iodide and radioiodine?

A

Reduce thyroid hormone synthesis

51
Q

What is the main function of beta-blockers?

A

Help with symptoms of hyperthyroidism

52
Q

What are the clinical uses of thionamides?

A

Daily treatment of hyperthyroid conditions (Graves’ and toxic thyroid nodule/toxic multinodular goitre); treatment prior to surgery; reduction of symptoms while waiting for radioactive iodine to act

53
Q

How is thyroid hormone synthesised?

A
54
Q

What are the mechanisms of action of thionamides on the synthesis of thyroid hormone?

A

Inhibition of thyroperoxidase so T3/4 synthesis and excretion - affects T3/4 that will be made not the ones already out there; may suppress antibody production in Graves’ disease; reduces conversion of T4 to T3 in peripheral tissues

55
Q

What are the unwanted actions of thionamides?

A

Agranulocytosis/granulocytopoenia (reduction/absence of granular leukocytes) is rare (can cause neutropenic sepsis) and reversible on wihdrawal of drug; rashes (common)

56
Q

What are the pharmacokinetics of thionamides - admin, biochemistry, t1/2, excretion, metabolised?

A

Admin - orally active; Biochem - Carbimazole is a prodrug converted into methimazole; Plasma t1/2 is 6-15h; Crosses placenta and is secreted in breastmilk (PTU>CBZ); Metabolised in liver and secreted in urine

57
Q

How do you follow up the patient with hyperthyroidism and on thionamides?

A

Aim to stop anti-thyroid drug treatment after 18 months; review patient periodically including thyroid function tests for remission/relapse

58
Q

What is the role of beta-blockers in thyrotoxicosis?

A

Several weeks for ATDs to have clinical effects (reduced tremor, slower heart rate, less anxiety); non-selective beta blocker (propanolol) achieves effects in interim (less so with selective B1 blockers - atenolol, as the adrenaline effects need b2 receptors to be blocked)

59
Q

What is the use of KI?

A

Preparation of hyperthyroid patients for surgery and for severe thyrotoxic crisis (thyroid storm)

60
Q

What is the mechanism of action of KI?

A

Inhibits iodination of thyroglobulin, inhibits H2O2 generation

61
Q

What are the unwanted actions of KI?

A

Allergic reactions (rashes, fever, angio-oedema)

62
Q

What is the pharmacokinetics of KI?

A

Orally (lugol’s solution), max effects after 10 days continuous admin

63
Q

What is the use of radioiodine (131 I)?

A

Treats hyperthyroidism (medium dose) and thyroid cancers (high dose)

64
Q

What is the mechanism of action of radioiodine?

A

Accumulates in colloid; emits beta particles and destroys follicular cells

65
Q

What is the pharmacokinetics of radioiodine?

A

Discontinue anti-thyroid drugs 7-10 days prior to radioiodine treatment so that the thyroid becomes a bit more active and can suck up a larger amount; admin as single oral dose (graves = 500; thyroid cancer = 3000MBq); radioactive t1/2=8d; radioactivity negligible after 2 months

66
Q

What cautions are needed for radioiodine?

A

Avoid close contact with small children for several weeks after receiving RI; cantra-indicated in pregnancy and breast feeding

67
Q

What tests are used for thyroid gland pathology -> toxic nodule, thyroiditis vs Graves’?

A

Administer IV radioiodine (v. low, tracer doses) with negligible cytotoxicity

68
Q

What is Plummer’s disease?

A

Toxic nodular goitre, not AI, benign adenoma that is overactive

69
Q

What are the effects of thyroxine on the SNS?

A

Sensitises beta adrenoceptors to ambient levels of adrenaline and NA so apparent sympathetic activation

70
Q

What are the symptoms of Plummer’s disease?

A

Tachycardia, palpitations, tremor in hands, lid lag (extra adrenaline effects the eye, keeping it open for a little bit)

71
Q

What are the symptoms of hyperthyroidism?

A

Breathlessness, heat intolerance, diarrhoea, increased appetite, weight loss, tachycardia, sweating, lid lag and other sympathetic symptoms

72
Q

What is a thyroid storm?

A

Medical emergency (50% mortality) - hyperpyrexia >41C, accelerated tachycardia/arrhythmia, cardiac failure, jaundice/ hepatocellular dysfunction, delirium/frank psychosis

73
Q

What is the Wolff-Chaikoff effect?

A

Presumed autoregulatory effect - iodide shuts down production of thyroxine

74
Q

What are the symptoms of Viral Thyroiditis?

A

Painful dysphagia, hyperthyroidism, pyrexia, raised ESR

75
Q

How does viral thyroiditis work?

A

Virus attacks thyroid gland causing pain and tenderness with the thyroid making very little thyroxine

Y2 LCRS 1 - Pharm, Endo, Reproduction (19 decks)

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