Drugs Affecting Thyroid Gland

Question 1

TH SYNTHESIS AND SECRETION

Answer 1

1. Iodide uptake from blood to the follicle cell
   
   • Na+/I− symporter (NIS)
2. Iodide moved into the lumen
   
   • Pendrin1 (PDS), an I−/Cl− porter
3. Organification of iodide
   -.Oxidation of iodide and incorporation into thyroglobulin on tyrosine residues,
   
   • Catalysed by thyroperoxidase
4. ’ Coupling
    Monoiodotyrosine (MIT)
    Di-iodotyrosine (DIT)
    MIT combines with DIT to form T3
    Two DIT molecules combine to form T4
    Thyroperoxidase involved
5. Thyroglobulin molecule taken up into follicle cell by endocytosis
6. Endocytotic vesicles fuse with lysosomes
7. Proteolytic enzymes act on thyroglobulin
8. T 4 and T3 released and secreted into the plasma

Question 2

TH PHYSIOLOGICAL ACTION

Answer 2

1. Metabolic effects
2. Growth + development

Question 3

Metabolic Effects

Answer 3

• Increase and regulation of metabolism: proteins,
fats, carbohydrates
• Oxygen consumption increase and heat
production: increase basal metabolic rate
• Increased cardiac rate and output

Question 4

Growth & Development

Answer 4

• Directly • Indirectly via GH
production & potentiation • Skeletal development • Development of CNS

Question 5

TH REGULATION
[TRH+ TSH]

Answer 5

Thyrotrophin-releasing hormone (TRH)
 Released from hypothalamus
 Releases thyroid-stimulating hormone (TSH) from
anterior pituitary

TSH
 Trophic action on thyroid cells
 Controls TH synthesis & secretion
 Negative feedback control via TH on anterior
pituitary
 Somatostatin reduces TSH release

Question 6

TH REGULATION

Plasma iodide concentration

Answer 6

1. Reduced iodine intake
    Decrease TH production
    Increase TSH secretion
    Increase in gland vascularity and hypertrophy
2. Increased plasma iodide
    Size and vascularity of thyroid reduced
   ‘

Question 7

THYROID FUNCTION ABNORMALITIES

For Hyperthyroidism (thyrotoxicosis)

Answer 7

Hyperthyroidism (thyrotoxicosis)

1. Grave’s disease
   - Auto-antibodies against TSH receptor
   - Leads to activation
2. Toxic nodular goiter
   - Benign neoplasm or adenoma
3. Simple, non-toxic goiter
   
   • Iodine dietary deficiency
     • Rise in plasma TRH and eventually an increase in
     the size of the gland

Question 8

DRUGS USED TO TREAT HYPERTHYROIDISM

Answer 8

 Radio-iodine  Thioureylenes  Iodine  Adjunct

Question 9

RADIO-IODINE MoA

Answer 9

 Generally considered first-line treatment for
hyperthyroidism
 Isotope used is 131I
 Emits both β and γ radiation (so it’s cytotoxic to to cells)

Question 10

-RADIO-IODINE RoA

Answer 10

 Given orally
 Taken up and processed by thyroid
 Incorporated into thyroglobulin

[Β particles exert powerful cytotoxic action
- Restricted to cells of the thyroid follicles
- Significant destruction of tissue ]

Question 11

Radio-iodine max. effects+ AE

Answer 11

Effects seen after 1-2 months and maximal effects 2 months later

Hypothyroidism develops eventually
 Managed by replacement therapy with T 4

Question 12

RADIO-IODINE CI

Answer 12

Best avoided in children and pregnancy

Question 13

RADIO-IODINE Clinical use

Answer 13

Used diagnostically for thyroid function

Question 14

THIOUREYLENES exs.

Answer 14

Carbimazole, methimazole (active metabolite of
carbimazole), propylthiouracil PTU

Question 15

THIOUREYLENES MoA

Answer 15

Clinical response may take several weeks

Mechanism of action: decrease the output of
thyroid hormones from the gland

- May competitively inhibit the thyroperoxidase- Clinical response may take several weeks catalysed oxidation reactions :
       • Oxidation of iodine and thyroglobulin 
       • Organification of iodine 
       • Coupling

Question 16

Methimazole CI

Answer 16

Methimazole is the preferred antithyroid
medication except in the first trimester of
pregnancy

Question 17

PTU advantage

Answer 17

(Give to preg in 1st trimester)
 Additional effect of reducing the deiodination of T
T 3 in peripheral tissues (5’ deiodinase inhibition)
 May act more rapidly
 Concerns over hepatotoxicity
 Safer in pregnancy
- Methimazole is a possible teratogen (aplasia cutis)

Question 18

Methimazole AE

Answer 18

Methimazole is a possible teratogen (aplasia cutis)

Question 19

ADVERSE EFFECTS of THIOUREYLENES

Answer 19

 Rashes  Headache  Nausea  Jaundice
 Neutropenia and agranulocytosis (if infxns present)
 Incidence of 0.1–1.2%
 Reversible on cessation of treatment

Question 20

IODINE/ Lugols iodine

Answer 20

Converted to iodide (I-) in vivo
 Temporarily inhibits release of thyroid
hormones
 Marked reduction of vascularity and size of
gland

Question 21

Iodine max effects reached

Answer 21

Maximum effects reached by 10-15 days, then
effects decrease

Question 22

Iodine MoA

Answer 22

MOA not well-understood
May inhibit iodination of thyroglobulin, possibly by reducing H2O2 generation
May temporarily inhibit proteolytic release of T 3
/T4 from thyroglobulin

Question 23

IODINE/IODIDE
Clinical uses

Answer 23

 Preparation of hyperthyroid subjects for surgical
resection
 As part of the treatment of severe thyrotoxic crisis
(thyroid storm)

Question 24

IODINE/IODIDE
AE

Answer 24

Adverse effects
 Allergic reactions
 Lacrimation
 Conjunctivitis
 Pain in the salivary glands
 Cold-like syndrome

Question 25

Adjunct drugs for Hyperthyroidism

Answer 25

1. β blocker 2. + for Exophthalmos

Question 26

Beta-blockers Clinical uses

Answer 26

 Useful for decreasing signs and symptoms of hyperthyroidism: tachycardia, dysrhythmias, tremor, agitation initially  Preparation of thyrotoxic patients for surgery  Acute hyperthyroid crisis

Answer 27

Exophtalmos:  Guanethidine eye drops - Noradrenergic-blocking agent - Relaxes smooth muscle that causes eyelid retraction  Glucocorticoids: Hydrocortisone useful in thyroid storm treatment  Surgery

Question 28

ABNORMALITIES OF THYROID FUNCTION For HYPOthyroidism + causes

Answer 28

Hypothyroidism - Decreased activity of the thyroid  Causes -Therapy with radioiodine - Immunological •Hashimoto’s thyroiditis

Question 29

''HYPOTHYROIDISM TREATMENT

Answer 29

1. Iodine deficiency 2. Thyroid Replacement therapy

Question 30

Iodine deficiency tx

Answer 30

Iodine deficiency  Treated with iodide

Question 31

Thyroid replacement therapy (T4+ T3)

Answer 31

Off-label use as weight loss supplements , Synthetic T4 (official name: levothyroxine) - Synthetic T3 (official name: liothyronine)

Question 32

Synthetic T4 (RoA+ MoA)

Answer 32

 First-line treatment  Oral formulation  Converted in vivo to T3

Question 33

Synthetic T3 RoA + clinical uses+ axn durn

Answer 33

 Faster-onset  Shorter duration of action  Generally given for acute emergencies  IV route

Question 34

AE of Replacement therapy

Answer 34

 Hyperthyroidism  Tremors  Heat intolerance  Angina pectoris  Cardiac dysrhythmias  Cardiac failure  Increased bone resorption: Osteoporosis (watch out : elders)

Question 35

Other drugs for Hypothyroidism

Answer 35

1. Amiodarone 2. Iodine-containing radiocontrast agents drugs 3. Sulfonamides 4. Lithium

Question 36

Amiodarone

Answer 36

 Rich in iodine  Can cause hyperthyroidism or hypothyroidism

Question 37

Iodine-containing radiocontrast agents drugs

Answer 37

 Iopanoic acid  for Hypothyroidism

Question 38

Sulfonamides ex+ clinical use

Answer 38

 E.g. sulfonyureas  Hypothyroidism

Question 39

Lithium

Answer 39

 for Hypothyroidism