Thyroid drugs

thyroid

1. Thyroid hormone &
Thyroid inhibitors

2. Objectives
•List the clinical uses of thyroxine
•Outline the classification of thyroid inhibitors
•Describe the mechanism of action, pharmacokinetics, adverse effects
and clinical uses of antithyroid drugs
•Describe the mechanism of action, adverse effects and clinical uses
of iodine and iodides

3. Thyroid gland
•
Secretes three hormones
- Triiodothyronine (T
3
)
- Tetraiodothyronine (T
4
, thyroxine)
- Calcitonin

5. Biosynthesis of thyroid hormones

6. Steps in the synthesis
1.Iodide uptake
2.Oxidation and iodination
3.Coupling
4.Storage and release
5.Peripheral conversion of T4 to T3
6

7. Transport, Metabolism and Excretion
•Only about 0.03-0.08% of total T
4
& 0.2-0.5% of T
3
exist in the
free form.
•Binds with
-Thyroxine binding globulin
-Thyroxine binding prealbumin
-Albumin
Metabolic inactivation of T4 and T3 occurs by deiodination
and glucuronide/sulfate conjugation
Occurs mainly at liver
Excreted in bile and enters enterohepatic circulation
Finally excreted in urine
T1/2-
T4 6-7days, T3 1-2 days

8. Relation between T4 and T3
• Thyroid secretes more T4 than T3
• T4 is the major circulating hormone because
it is 15 times more tightly bound to plasma
proteins.
• T3 is 5 times more potent than T4 and acts
faster.
•Peak effect of T3 comes in 1–2 days while
that of T4 takes 6–8 days.
• T3 is more avidly bound to the nuclear receptor
than T4 and the T4-receptor complex is unable
to activate/derepress gene transcription.
• About 1/3 of T4 is converted to T3 in the
thyroid cells, liver and kidney by D1 type
of 5’deiodinase (5’DI) and released into
circulation.
**T3 is the active hormone, while T4 is mainly a transport form;
functions as a prohormone of T3.

9. Actions of thyroid hormone
•Metabolic function –
Lipid:
Enhance lipolysis
Plasma free FA levels elevated
Lipogenesis stimulated
Chol metabolism stimulated
Carbohydrate:
Met stimulated
Tissue sugar utilization increases
Compensatory glycogenolysis, gluconeogenesis and faster absorption of glucose in
intestine insulin resistance and hyperglycemia in hyperthyroidism
Protein :
Overall effect is catabolic
Protein as energy source
Negative nitrogen balance and wasting
Weight loss

10. Growth and development :
• Essential
•Exerted through the protein synthesis by translation of genetic code
•Cretinism in children and adults also impaired intelligence
•Affects nervous system
•On GIT:
•­ appetite & food intake.
•­ motility of GIT  diarrhea often result in hyperthyroidism
•On CVS:
•Direct action on contractile elements and upregulation of beta receptors
•Hyperdynamic circulation- due to demand and direct cardiac effect
•­cardiac output, HR, contractility
•Angina, AF, CHF, systolic BP increases
•On nervous system:
•excitable effect.
•Has role on development of brain in fetal & 1
st
few weeks of postnatal life
•Muscle weakness due to protein catabolism

11. •Haemopoiesis:
Anaemia in hypothyroidism
•Reproduction:
Indirect effect on reproduction

12. 12

13. 13
Thyroid drugs
PharmacokineticsPharmacokinetics
Levothyroxine bioavailability – 75%
Well absorbed orally
Should be taken empty stomach
Sucralfate, iron, calcium, PPI reduces absorption
Enzyme inducers- rifampicin, phenytoin, carbamazepine- accelerates
metabolism
DRUGSDRUGS
levothyroxine (L-T4)- oral + IV
liothyronine (T3)- IV used in myxedema coma

14. Liothyronine:
Faster onset
Shorter duration of action
Reserved for acute emergencies
Ex; myxedema coma
ADR:
Signs and symptoms of hyperthyroidism in overdose
Risk of angina pectoris, cardiac dysrhythmias and cardiac failure
Osteoporosis
Hypersensitivity reactions- rash, pruritus, oedema

15. Mechanism of action
Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR).
T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR—
Retinoid X receptor;
mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase

16. 16
Uses
-Mostly as replacement therapy
1.Cretinism : treat early as possible
8-12microgram/kg/day
2.Adult hypothyroidism:
start a low dose and increase every 2-3 wks and optimum 100-
200microgram/day
3. Myxoedema coma: emergency
IV T4 and low dose IV T3
4. Nontoxic goiter
5. Thyroid nodule- certain nodules only
if not size reduces in 6 months stop treatment
6. Papillary carcinoma of the thyroid
7. Empirical uses- refractory anaemia, mental depression, infertility,

17. •Used to lower the functional capacity of the hyperactive thyroid gland
Thyrotoxicosis-
Two main causes
1.grave’s disease
2.Toxic nodular goiter
17
Thyroid inhibitors

18. Classification of drugs:
1.Inhibit hormone synthesis-
PTU, Methimazole, Carbimazole
2. Inhiit iodide trapping/ ionic inhibitors
thiocyanates, perchlorates, nitrates
3. Inhibit hormone release
iodine, iodides of Na&K, organic iodide
4. Destroy thyroid tissue
Radioactive iodine I-131,125,123

19. Thioamides/ antithyroid drugs
•Prevent hormone synthesis by inhibiting the thyroid
peroxidase-catalyzed reactions and blocking iodide/
iodotyrosyl oxidation
1.Inhibit iodination of tyrosine in thyroglobulin
2.Inhibit coupling of iodotyrosine residues to form T3
and T4
•Thyroid colloid depleted over the time
•Do not interfere with trapping of iodide and not
modify the action of T3 and T4
•Do not affect the release of T3/T4
•PTU inhibits peripheral conversion of T4 to T3

21. PK
•Well absorbed orally
•Widely distributed
•Enter milk and cross placenta
•Metabolized in liver and excreted in urine
•Concentrated in thyroid and thyroid t1/2 is longer
•Carbimazole converted to methimazole

22. Adverse reactions
•Intolerance
•Skin rashes and joint pain
•Hypothyroidism and goiter due to over treatment
•An altered sense of taste
•Liver damage
•The most dangerous – agranulocytosis (granulocyte count <
500 cells/mm
2
)- rare

23. Use
•Control thyrotoxicosis
•Clinical improvement by 1-2 wks or more
•Maintenance doses titrated with clinical status of the patient
1. Definitive therapy-
Grave’s disease: remission by 1-2 yrs or reinstitute if recur
Toxic nodular goiter: surgery/ I-131/ permanent maintenance therapy
with antithyroid drugs
2. preoperatively
3. Along with I-131

24. Benefit& disadvantages of antithyroid
drugs Vs Surgery/radio iodine
Benefit
•No surgical risk
•If hypothyroidism occur- reversible
•Can be used in children and adults
Disadvantages
•Prolonged/ life long treatment
•Difficult in uncooperative ptn
•Drug toxicity

25. Which one to prescribe during
pregnancy?

26. Ionic inhibitors
•Monovalent anions inhibit iodide trapping into thyroid
•Toxic and not clinically used now
•Ex: perchlorates, thiocyanates

27. Iodine and Iodides
•Fastest acting thyroid inhibitor
•Thyroid status starts to return normal
•Complete stoppage of hormone release from the gland
•Thyroid gland involutes and colloid restored
•Response to iodine and iodide is identical
•Peak effects in 10-15 days
•Thyroid escape occur following- again thyrotoxicosis
•Main action- inhibition of hormone release
•Wolff-Chaikoff effect: excess ioidide rapidly and briefly interferes
with iodination of tyrosil and thyronil residues of thyroglobulin
resulting in reduced T3/T4 synthesis
Ex:Lugol’s solution

28. Cont’d
•Uses:
1.Preoperative preparation
2.Thyroid storm
3.Prophylaxis of endemic goiter
4.Antiseptic
•Adverse effect:
•Acute reaction : swelling of lip, eye lid, face, angineurotic edema of larynx, fever,
joint pain, lymphadenopathy, thrombocytopenia
•Chronic overdose : inflammation of mucous membrane , salivation, lacrimation,
burning sensation in the mouth, rhinorrhoea, GI intolerance

29. Radioactive iodine
•
131
I
is
- used for treatment of thyrotoxisis
•Administered orally in solution as sodium
131
I, it is rapidly
absorbed
•concentrated by the thyroid, & incorporated into storage
follicles  emits β particles & X rays  β particles
damage the thyroid cells  thyroid tissue destroyed by
pyknosis and necrosis replaced by fibrosis
•Use
•Diagnostic purpose  25-100μ curies in thyroid function test
•Therapeutic use  3-6 milli curies in toxic nodular goiter, graves disease.

30. •Advantage :
•Easy administration
•Effectiveness
•Low expense
•Absence of pain
•In patient who have indication of operation but want to avoid operation
•Once treated no chance of recurrence
•Disadvantage :
•Hypothyroidism
•Latent period of getting response (8-12 weeks)
•Contraindicated in pregnancy
•Not suitable for young patients