Thyroid and antithyroid drugs

From Lippincotts Pharmacology 4th edition

(Thyroid hormones)



:

:


(Calcitonin)

T3 (triiodothyronine); T4 (thyroxine)
The ratio of T4 to T3 within thyroglobulin is 5:1,
the most of the hormones released is thyroxine
T4
T3
T3

Normal pooled
sera (NPS)

sodium/iodide
symporter
(NIS)

TG: Thyroglobulin

From Rang and Dales 6th edition

Expression of Pendrin and the Pendred
Syndrome (PDS) Gene in Human
Thyroid Tissues
Jean-Michel Bidart, Caterina Mian, Vladimir Lazar, Diego Russo, Sebastiano
Filetti, Bernard Caillou and Martin Schlumberger

The gene recently cloned that is responsible for the Pendred

syndrome (PDS), an autosomal recessive disease characterized by
goiter and congenital sensorineural deafness, is mainly expressed in
the thyroid gland. Its product, designated pendrin, was shown to
transport chloride and iodide.
In normal tissue, pendrin is localized at the apical pole of thyrocytes,
and this in contrast to the basolateral location of NIS (sodium/iodide
symporter).

Journal of Clinical Endocrinology & Metabolism

Vol. 85, No. 5 2028-2033, 2000
Iodination of tyrosyl residues by the
thyroperoxidase-H2O2 complex

From Rang and Dales 6th edition

Iodinated tyrosine residues

From Rang and Dales 6th edition

Peripheral metabolism of thyroxine

Amiodarone
-blockers
Corticosteroids
Severe illness or starvation

From Katzung 11th edition

Hypothalamic-pituitary-thyroid axis

+: stimulatory influence
-: inhibitory influence

From Katzung 11th edition

 T3 and T4
P-450

Phenytoin
rifampin
phenobarbital
P-450 enzyme

From Lippincotts Pharmacology 4th edition

 Pharmacokinetics
Thyroxine is absorbed best in the duodenum
and ileum
Oral bioavailability
Hyperthyroidism
Hypothyroidism
Pregnancyestrogensoral contraceptives
From Katzung 11th edition
Abnormalities of thyroid function
Hyperthyroidism
Diffuse toxic goiter (Graves disease or exophthalmic
goiter)
Toxic nodular goiter
Simple, non-toxic goiter
Hypothyroidism
A decreased activity of the thyroid function, and in
severe cases myxoedema
Hashimotos disease
Radioiodine
Cretinism ()

(Graves disease)
Autoimmune disease
(Goiter)
One of possible reasons: shortage of iodine
diet rise in plasma TRH

131I
(Thioamides )
Propylthiouracil (PTU)
Methimazole
Carbimazole (used in UK)
Anion inhibitors
Iodides
Adrenoceptor-blocking agents
Coticosteroids
 Radioactive iodine
Orally in solution as sodium 131I
It is rapidly absorbed, concentrated by the
thyroid, and incorporated into storage of
follicles.
rays and rays
Half-life: 8 days; 2 months
Not be administered to pregnant women,
nursing mothers and children
 Thioamides

Thiocarbamide
group

From Katzung 11th edition

 Propylthiouracil (PTU)
Pharmacokinetics
rapidly absorbed, reaching peak serum levels
after 1 hour
Bioavailability: 50-80% (first-pass effect in the
liver)
Distribution: approximates total body water
with accumulation in the thyroid gland
Excreted by the kidney within 24 hours
Plasma half-life: 1.5 hours
 Methimazole
Pharmacokinetics
Completely absorbed
Distribution: readily accumulated by the
thyroid gland and has a volume of distribution
similar to that of PTU
Excretion is slower than with PTU; 65-70% of
a dose is recovered in the urine in 48 hours
Plasma half-life: 6 hours
 PTU and methimazole
thyroglobulin
thyroglobulin
PTU methimazole

Pregnacy category D
Of the two, PTU is preferable in
pregnancy because it is more strongly
protein-bound
 Pharmacodynamics
Prevent hormone synthesis by inhibiting
the thyroid peroxidase-catalyzed
reactions and blocking iodine
organification
Blocking coupling of the iodotyrosines
PTU inhibit the peripheral T4 to T3
conversion
 I- Na+

SCN-, ClO4-

I- Na+
Extracellular
space Thioamides
TG Iodides(High)
Thyroid peroxidase
(organification) TG-MIT
TG-DIT
Thyroid peroxidase
(coupling)
T3 T4
Colloid
space
131I- TG

Iodides(High)
T3 T4
Follicular cell

Propylthiouracil (PTU)
T4
T3
 Toxicity of thioamides (I)
3-12% of treated patients
Nausea and GI distress (occur early)
An altered sense of taste or smell may occur
with methimazole
Most common: maculopapular pruritic rash (4-
6%)
Rare adverse effect: urticarial rash, vasculitis,
lupus-like etc.
Hepatitis (more common with PTU)
Cholestatic jaundice (more common with
methimazole)
 Toxicity of thioamides (II)
Agranulocytosis (most dangerous)
Granulocyte count < 500 cells/mm3
Older patients or high-dose methimazole
therapy (> 40 mg/day)
Cross-sensitivity between PTU and
methimazole is about 50%
switching drugs in patients with severe
reactions is not recommended
 Anion inhibitors
Perchiorate (ClO4-) pertechnetate (TcO4-)
thiocyanate (SCN-)
Action
blocking uptake of iodide transporter mechanism
Major clinical use
potassium perchlorate for iodide-induced
hyperthyroidism
Side effect: aplastic anemia
 Iodides
(I-)

H2O2


Propranolol
-adrenergic receptor antagonist

:
Guanethidine
Non-adrenergic-blocking agent (inhibits NE release)

Corticosteroids
T4 T3
Graves disease

Hyperthyroidism

NO NO
NO
Below Age 20
20-30 hypothyroidism
years old


YES YES
YES




YES
NO
NO

NO
PTU or YES
Methimazole

NO
NO YES

YES


6-12

T4
Thyroid storm (thyrotoxic crisis)
Thyroid storm

(nervous)
()
sinus tachycardiaatrium flutteratrial
fibrillation
pulmonary edema fatigue

convulsion
Treatments for thyroid storm (I)
Iodine-Lugol solution:
130 mg/ml (30)
Antithyroid drugPTU
-blockers
propranololmetoprolol
(beta1-blocker)
Treatments for thyroid storm (II)
Corticosteroids: 100 mg/q8h

fluid & electrolytedigitalis
thyroid storm
plasmapheresis
thyroid hormone & TSH
 (I)
Hypothyroidism is a syndrome resulting
from deficiency of thyroid hormones
Slowing down of all body functions

: low free thyroxine and

elevated serum TSH
From Katzung 11th edition
 (II)
Hashimotos thyroiditis ()-
immunologic disorder
: T4 (Levothyroxine) or T3
Levothyroxine
Toxicity of Levothyroxine





Take home message

From Principles of Pharmacology, 2nd Edition

From Katzung 11th edition
From Katzung 11th edition
 Other drugs affecting thyroid
hormone homeostasis
Salicylates
Displacement of T3 and T4 from TBG
Corticosteroids
Amiodarone
Antiarrhythmic drug (75 mg iodine/200 mg)
Hypothyroidism: contains a large
concentration of iodide (Wolff-Chaikoff effect)
Type I thyrotoxicosis and type II thyroditis
From Katzung 11th edition
Take Home Messages

From Katzung 10th edition

The End