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

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

Flashcards in ENDO; Lecture 3, 4 and 5 & Tutorial 2 - Neurohypophysial disorders, Hypothyroid disorders - treatment and Hyperthyroid disorders Deck (75)
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1
Q

What is the hypothalamo-neurohypophysial system?

A
2
Q

What are the effects of vasopressin?

A

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

3
Q

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

A

x

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)

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

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

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)

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)

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)

10
Q

What are the signs and symptoms of DI?

A
11
Q

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

A
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

13
Q

How does the cycle of osmolarity work in psychogenic polydipsia?

A

x

14
Q

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

A

NB: don’t worry about the actual numbers

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)

16
Q

What are the biochemical features of DI?

A

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

17
Q

What are the biochemical features of psychogenic polydipsia?

A

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

18
Q

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

A

V1 - terlipressin, V2 - desmopressin (DDAVP)

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

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

21
Q

What is SIADH?

A

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

22
Q

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

A

Euvolemic means have normal circulating volume

23
Q

What are the signs of SIADH?

A

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

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

25
Q

What are the causes of SIADH?

A
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)

27
Q

What are vaptans?

A

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

28
Q

How do vaptans function?

A

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

29
Q

What is aquaresis?

A

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

30
Q

Which hormones are secreted from the thyroid gland?

A

T4 and T3

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

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