Thyroid drugs

Thyroid gland
 Located on each side of and anterior to the trachea
 Largest of the endocrine glands
 Hormones secreted:
 Thyroxine (T4)
 Triiodothyronine (T3)
 Calcitonin

 Increase the metabolic rate of the body

 Controlled by thyroid-stimulating hormone (TSH)

2
Regulation

3
Thyroid hormone synthesis
1. Uptake of Iodide (iodide trapping)
2. Iodide organification: oxidation and iodination
(iodide is oxidized by peroxidase to iodine which
iodinates tyrosine)
3. Coupling of MIT and DIT
4. Secretion of thyroid hormones
5. Conversion of T4 to T3, (Peripheral conversion)
Synthesis and Secretion

5
6
Transport
 Thyroid hormones: low water solubility, hence associated
with proteins
 Bound to plasma proteins
 Thyroxine-binding globulin (Main)~70% of hormone
 Thyroxine-binding pre-albumin (transthyretin) ~15%
 Albumin ~15%
 Released slowly to tissue cells
 Binding with plasma protein
 Stored and used slowly because of
 Binding with intracellular proteins
 Only about 0.04% of total T4 and 0.4% of T3 exist in the
free form (as FT4and FT3)
 Only free thyroid hormone (T3) is biologically available to
tissues
 Slow onset and long duration of action
7
 T4 Vs T3 As
T4 T3
Combination of two DIT T3 is a combination of one MIT
molecules and one DIT molecule

Less potent 4 times more potent than T4

75% protein bound
0.04% exists in free form
T4 is converted to T3 in the
peripheral tissues, liver and
kidneys
25% bound
0.4% exists in free form
T3 binds actively to
nuclear receptor(active form)
Mechanism of action

9
 Actions of thyroxine
 ↑ BMR, cellular metabolism
 ↑ Number and Activity of Mitochondria → ↑ rate of
formation of ATP
 ↑ amount of heat produced in the body
 Growth: bones in children, brain in fetal life and first few years of
postnatal life (Lack of thyroid hormone in fetal life – Cretinism)
 ↑ Respiration
 ↑ Gastrointestinal Motility
 Excitatory Effects on CNS
 ↑ rate of secretion of other endocrine glands: Eg GH
 Normal sexual function
Actions of thyroxine
 Effect of Thyroid Hormones on the Cardiovascular
System
 ↑ Blood Flow and Cardiac Output
 Rapid utilization of oxygen than normal and release of greater than
normal quantities of metabolic end products from the tissues, cause
vasodilation in most body tissues, thus increasing blood flow
 ↑ Heart Rate
 ↑ Heart force of contraction
 Normal Mean Arterial Pressure
 Increases the utilization of oxygen

11
Hypothyroidism
• Symptoms: Fatigue, cold intolerance, weight gain
despite lack of appetite, irregular menses,
nonpitting edema (myxedema), high blood
cholesterol, constipation, decreased deep tendon
reflex, dry skin
• Elderly dementia
• Etiology: Hashimoto’s thyroiditis (autoimmune),
drugs or radiation exposure, pituitary tumors
• Treatment options: Levothyroxine sodium
(consistent potency, long duration of action),
Liothyronine sodium
 Levothyroxine (T4)
• Indications:
• Hypothyroidism
• Prevention of mental retardation in newborns
with thyroid deficiency (infantile
hypothyroidism)
• TSH suppression therapy after treatment for
thyroid cancer, post- thyroidectemy
• PK: Oral administration (absorbed from small
intestine), hepatic metabolism, t ½ = 7 days
• Stable, safe, inexpensive, T4 levels in lab
• ADR: Tachycardia, heat intolerance, tremors
 Liothyronine sodium (T3)
• Indications: Reserved for the treatment of myxedema
coma (given along with T4)
• Myxedema coma: A medical emergency with
hypothermia, respiratory depression and loss of
consciousness
• T ½ = 24h
• ADR of liothyronine: Similar to levothyroxine but
MORE cardiotoxic
• Avoid use in heart disease
• It is not recommended for replacement: multiple
doses, high cost, difficulty to monitor, cardiotoxic
Hyperthyroidism (Thyrotoxicosis)
 Hyperthyroidism: serum levels of T4 or T3 that are excessive for
the individual
 Thyrotoxicosis: clinical manifestations associated with
hyperthyroidism

Graves Disease-Most common

Toxic Multinodular Goiter

Thyroid Adenomas

Subacute, Postpartum, and Silent Thyroiditis

Medication-Induced Hyperthyroidism

Pregnancy and hCG-Secreting trophoblastic Tumors

15
Symptoms
 Excitability
 Intolerance to heat
 Increased sweating
 Mild to extreme weight loss
 Varying degrees of diarrhea
 Muscle weakness
 Nervousness or other psychic disorders
 Extreme fatigue but inability to sleep
 Tremor of the hands

16
 Symptoms
Exophthalmos
 Protrusion of the eyeball:
 Due to edematous
swelling of the retro-
orbital tissues
 Degenerative changes in
the extraocular muscles
 Ulceration of cornea:
 Eyelids do not close
completely when the
person blinks or is asleep,
epithelial surfaces of the
eyes become dry and
irritated
 Stretches the optic nerve to
damage vision 17
 Differentiation of thyroid diseases
TSH Free T3 FT4 RAI Disease
Graves

Sub acute
thyroiditis
Exogenous T3 or
or T4
normal
normal normal normal normal But total T4
Pregnancy TBG
Primary
hypothyroidism
TSH: 0.4-4 mIU/L, T3: 100-200ng/dl; T4 4.5-11.2 ug/dl
FT3: 2.3-4.2pg/ml, FT4: 0.8-1.8 ng/L 19
Radioactive iodine uptake scan (RAI)
15-25% 24 hours (I123)

20
Thyroid Inhibitors

Anti-thyroid drugs Ionic inhibitors

Thyroid
inhibitors
Radioactive
Iodides
iodine

21
Thyroid inhibitors
Anti-Thyroid Drugs
Thioamides: Propylthiouracil (PTU), Methimazole,
Carbimazole (Prodrug)

Anti-thyroid drugs MOA

Propylthiouracil
additionally

Inhibit peroxidase enzyme

(iodination, coupling)

Inhibits peripheral
Inhibit formation of thyroid deiodination of T4
hormones to T3
23
Mechanism of action

24
PK of Anti-thyroid Drugs
Propylthiouracil Methimazole
Plasma protein binding 75% Nil
Plasma t1/2 75 min 4-6 hrs
Volume of distribution 20 L 40 L
Severe liver disease Normal Low
Severe kidney disease Normal Normal
Trans placental passage Low Low
Levels in breast milk Low Low
Dosing frequency 1-4 times daily 1-2 times daily

25
Adverse Reactions
 Urticarial papular rash
 Common
 Subsides spontaneously
 Agranulocytosis
 Most serious
 Sore throat or fever
 Discontinuation of the drug
 Administration of recombinant human GCSF

26
Adverse Reactions
 Methimazole: Cholestatic dysfunction
• Propylthiouracil: Liver failure
• Close monitoring of liver function
• Should not be used in children except in the case of
methimazole allergy

 Pregnancy: both PTU and Methimazole are teratogenic

 PTU is safer* and preferred in first trimester because of it’s
extensive protein binding
 Methimazole is used in the 2nd and 3rd trimester of
pregnancy to avoid PTU liver toxicity in latter trimesters
 If surgery considered: Mid trimester thyroidectomy

27
* Safety data in this case, obtained from data of PTU use over time
Uses
1. Graves' disease, toxic nodular goitre
2. Conjunction with radioactive iodine
3. Preoperative preparation of thyroid gland
4. Thyrotoxic crisis

Response to treatment
Improves Euthyroidism Anti-thyroid
within 1 within 3 drug can be
month months reduced

Examination Follow-up
and TFT every every 4
2 months months

28
Ionic Inhibitors
Competitively inhibiting the NIS
 Thiocyanate
Inhibit the organification of iodine
 Perchlorate
 10 times x thiocyanate
 Fatal aplastic anemia
 Fluoroborate= Perchlorate
 Use: To Rx Graves’ disease and Amiodarone-induced
thyrotoxicosis

29
 Iodides
 Lugol's solution
 5% iodine and 10% potassium iodide
 8 mg of iodine per drop
 Saturated solution of potassium iodide (KISS)
 50 mg per drop
Inhibition of
 Potassium iodide synthesis of
Limit its own
iodotyrosine
transport
& iodo-
thyronines
MoA
Inhibition of
the release Reduces
of thyroid vascularity
hormone
30
Uses
 Preoperative preparation of thyroid gland
 Thyrotoxic crisis
 Radioactive iodine fallout
 Response to treatment: Rapid within 2-7 days
 Maximal effect is attained in 10-15 days, after which,
there is thyroid “escape” (Iodides should not be used
alone)
 Vascularity is reduced
 Gland becomes much firmer, cells become smaller
 Colloid re-accumulates
 Bound iodine increases

31
Adverse reaction
Marked sensitivity to iodide
 Angioedema
 Laryngeal edema
 Serum-sickness type of hypersensitivity
 Thrombotic thrombocytopenic purpura
 Fatal periarteritis nodosa
 IODISM: Chronic intoxication with iodide
 Brassy taste and burning in the mouth and throat
 ↑ salivation, coryza, sneezing, and irritation of the eyes
 Parotid and submaxillary glands enlarged and tender
 Pulmonary edema

32
 Radioactive Iodine
123I 131I
Emits γ rays Emits both γ rays and β particles
t1/2 : 13 hours t1/2 : 5 days
Diagnostic studies Therapeutic –thyroid destruction

MoA: Trapped by the thyroid gland

Incorporated into the iodoamino acids

Deposited in the colloid

β particles act on parenchymal cells of thyroid

(penetration 2mm) ablates thyroid tissue permanently

No damage to surrounding tissue

33
 Uses
 Graves disease
 Older patients *
 Patients with heart disease (after making euthyroid)
 Recurrence after subtotal thyroidectomy
 Anti-thyroid drugs has not led to remission
 Toxic nodular goiter
 Response to treatment
 Symptoms ↓2 months
 Cure:
 80%: Single dose
 20%: Two doses

34
Contraindications
 Pregnancy
 Fetal thyroid will concentrate the isotope and thus suffer
damage
 Neoplastic changes in the thyroid gland
 Graves ophthalmopathy
 Worsening

Advantages Disadvantages
No risks of surgery ↑Delayed hypothyroidism
Cost ↓ ↑Stomach, kidney, breast cancer
↑Radiation thyroiditis

35
Dosage
 Sodium iodide 131I : solution or capsules
 Expressed in terms of microcuries taken up per gram of
thyroid tissue
 80-150 mCi
 Antithyroid drugs should be discontinued 1 week before
and resumed 3 days after 131I therapy
 ↓efficacy

36
 Why use anti-thyroid drugs before RAI/surgery?
Explanation:
 Damage to the thyroid gland/ surgical handling –causes outpouring of
stored colloidal thyroxine –worsening of thyrotoxicosis symptoms –
cardiotoxic –dangerous
 Using anti-thyroid drugs, many weeks prior to procedure, decreases
production of thyroxine, less chance of hormone-induced thyrotoxicosis
 At the same time, anti-thyroid drugs inhibit thyroxine production itself
by inhibiting peroxidase
 Drugs which make use of the peroxidase enzyme to get incorporated
into the colloid and produce their action (RAI) will have reduced efficacy
 Hence Anti-thyroid drugs should be discontinued 1 week prior to therapy
 Why restarted after therapy?
 After RAI starts working –release of stored hormones –toxicity –to stop
thyrotoxicosis symptoms, restart the anti-thyroid until all issues resolved
Adjuvant Therapy
 β Adrenergic receptor antagonists -Propranolol
 Antagonizing the sympathetic effects of thyrotoxicosis

 Ca2+ channel blockers

 To control tachycardia and ↓ supraventricular
tachyarrhythmias
 Diltiazem

38
 Beta blocker
• Beta blockers without intrinsic sympathomimetic activity (ISA)
• Propranolol inhibits T4 conversion to T3 (in very high dose
160mg/d, usual dose is 30mg/d)
• Atenolol, alprenolol, metoprolol reduce conversion, but sotalol
and nadolol do not (atenolol can not enter CNS)
• Propranolol preferred due to its lipid solubility -enters CNS
• Combined with thioamides until euthyroid
B blockers with ISA are contraindicated in hyperthyroidism

39
 Clinical Uses
Class/Drug HTN Angina Arrhy MI CHF Comments

Non-selective β1/β2
carteolol X ISA; long acting; also used for glaucoma
carvedilol X X α-blocking activity
labetalol X X ISA; α-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
ISA cannot be used in hyperthyroidism
pindolol X X ISA; MSA
propranolol X X X X MSA; prototypical beta-blocker
sotalol X several other significant mechanisms
timolol X X X X primarily used for glaucoma
β1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA
bisoprolol X X X
esmolol X X ultra short acting; intra or postoperative HTN
metoprolol X X X X X MSA
relatively selective in most patients; vasodilating (NO
nebivolol X
release)
40
Adjuvant Therapy
 Dexamethasone
 Inhibit the peripheral conversion of T4 to T3
 Iopanoic acid & Sodium ipodate
 Inhibit the peripheral conversion of T4 to T3
 Cholestyramine
 Block the enterohepatic circulation of the
iodothyronines
 Rituximab
 Prolongs remission of Graves' disease

41
 Thyroid Storm
 Life-threatening complication of thyrotoxicosis
 Precipitating factors
 Stress, trauma, surgery, radioactive iodine treatment
 Infections, diabetic ketoacidosis, heart disease, Labor
 Clinical features = thyrotoxicosis but exaggerated
 Supportive measures
 Intravenous fluids, antipyretics, cooling blankets, and sedation
 Anti-thyroid drugs: Propylthiouracil > methimazole
 Impairs peripheral conversion of T4 to T3
 -adrenergic blockers: treat hypertension and HR
 Hydrocortisone: prevents shock, inhibits peripheral conversion of T4-T3
 Oral iodides :Iopanoic acid, sodium ipodate
 Treatment of underlying precipitating illness
42
 Summary
Subclass, Drug MoA and Effects Indications PK, Toxicities, Interactions
Thyroid hormone Preparations
• Levothyroxine (T4) Activation of nuclear Hypothyroidism maximum effect seen after 6–8
• Liothyronine (T3) receptors results in weeks of therapy
gene expression with
RNA formation and
protein synthesis
Antithyroid Agents
THIOAMIDES
• Methimazole Inhibit thyroid Hyperthyroidism Oral • duration of action: 24 h
• Propylthiouracil (PTU) peroxidase reactions • (methimazole), 6–8 h (PTU) •
block iodine delayed onset of action
organification • inhibit • Toxicity: Nausea,
peripheral deiodination gastrointestinal distress, rash,
of T4 and T3 (primarily agranulocytosis, hepatitis (PTU
PTU) black box), hypothyroidism
IODIDES
• Lugol’s solution Inhibit organification Preparation for surgical Oral • acute onset within 2–7
• Potassium iodide and hormone release • thyroidectomy days • Toxicity: Rare
reduce the size and
vascularity of the gland
 PK, Toxicities,
Subclass, Drug MoA and Effects Indications
Interactions
BETA BLOCKERS
• Propranolol, other Inhibition of β Hyperthyroidism, Onset within hours •
β blockers lacking adrenoreceptors • especially thyroid duration of 4–6 h
partial agonist inhibit T4 to storm • adjunct to (oral propranolol)
activity T3 conversion (only control tachycardia, • Toxicity: Asthma,
propranolol) hypertension, and AV blockade,
atrial fibrillation hypotension,
bradycardia
131
RADIOACTIVE IODINE I (RAI)
Radiation destruction Hyperthyroidism • Oral • half-life 5 days
of thyroid patients should be • onset in 6–12
parenchyma euthyroid or on β weeks • maximum
blockers before RAI • effect in 3–6 months
avoid in pregnancy • Toxicity: Sore
and in nursing throat, sialitis,
mothers hypothyroidism
 Questions
• What are the symptoms of hypothyroidism?
• How do you treat hypothyroidism? What is the side effect of this drug?
• What are the symptoms of hyperthyroidism?
• How do you differentiate hypo- or hyper- thyroidism in lab?
• How is T3 synthesized?
• How does propylthiouracil inhibit T3?
• What are the differences between propylthiouracil and methimazole?
• Why do you need to check WBC while taking methimazole?
• When do you use iodide?
• What is the most important side effect of I131 treatment?
• How do you diagnose thyroid storm?
• How do you treat thyroid storm?
• How do you diagnose myxedema coma?
• How do you treat myxedema coma?
• Which B blockers are contraindicated in hyperthyroidism?
45