Download Thyroid and Anti thyroid Drugs

Thyroid and Antithyroid Drugs
By:
Bohlooli S, PhD
School of Medicine, Ardabil University of Medical
Sciences (ArUMS)
THYROID PHYSIOLOGY

Iodide Metabolism



The recommended daily adult iodide (I-)
intake is 150 mcg
Biosynthesis of Thyroid Hormones
Transport of Thyroid Hormones


thyroxine-binding globulin (TBG)
about 0.04% of total T4 and 0.4% of T3
exist in the free form.
Biosynthesis of thyroid hormones
Peripheral metabolism of thyroxine
Evaluation of Thyroid
Function



THYROID-PITUITARY RELATIONSHIPS
AUTOREGULATION OF THE THYROID
GLAND
ABNORMAL THYROID STIMULATORS
Typical values for thyroid function tests
Name of Test
Normal Value
1
Results in
Hypothyroidism
Results in
Hyperthyroidism
Total thyroxine by RIA (T4 [RIA])
5-12 mcg/dL (64-154 nmol/L)
Low
High
Total triiodothyronine by RIA (T3
[RIA])
70-132 ng/dL (1.1-2.0 nmol/L)
Normal or low
High
Free T4 (FT4)
0.7-1.86 mg/dL (9-24 pmol/L)
Low
High
Free T3 (FT3)
0.2-0.42 ng/dL (3-6.5 pmol/L)
Low
High
Thyrotropic hormone (TSH)
0.5-5.0 uIU/mL (0.5-5.0 mIU/L)
High
Low
5-35%
Low
High
Thyroglobulin autoantibodies (Tgab)
< 1 IU/mL
Often present
Usually present
Thyroid peroxidase antibodies
(TPA)
< 1 IU/mL
Often present
Usually present
Normal pattern
Test not indicated
Diffusely enlarged
gland
Fine-needle aspiration biopsy
(FNA)
Normal pattern
Test not indicated
Test not indicated
Serum thyroglobulin
< 56 ng/mL
Test not indicated
Test not indicated
Serum calcitonin
Male: < 8 ng/L (< 2.3 pmol/L);
female: < 4 ng/L (< 1.17
pmol/L)
Test not indicated
Test not indicated
TSH receptor-stimulating antibody
(thyroid stimulating imunoglobulin)
< 125%
Test not indicated
Elevated in Graves'
disease
123
I uptake at 24 hours
Isotope scan with
123
I or
99m
TcO4
2
The hypothalamic-pituitary
-thyroid axis
BASIC PHARMACOLOGY
THYROID HORMONES

Chemistry




Are levo (L) isomers
Dextro (D) isomer of thyroxine,
dextrothyroxine, has approximately 4% of
the biologic activity of the L isomer
Pharmacokinetics
Mechanism of Action
Summary of thyroid hormone kinetics.
Variable
T4
T3
Volume of distribution
10 L
40 L
Extrathyroidal pool
800 mcg
54 mcg
Daily production
75 mcg
25 mcg
Fractional turnover per day
10%
60%
Metabolic clearance per day
1.1 L
24 L
Half-life (biologic)
7 days
1 day
Serum levels
Total
5-12 mcg/dL (64-164 70-132 ng/dL (1.1nmol/L)
2.0 nmol/L)
Free
0.7-1.86 ng/dL (9-24
pmol/L)
0.23-0.42 ng/dL (3.56.47 pmol/L)
Amount bound
99.96%
99.6%
Biologic potency
1
4
Oral absorption
80%
95%
Model of the interaction of T3
with the T3 receptor
Effects of Thyroid
Hormones

The thyroid hormones are responsible
for :




Optimal growth
Development
Function
Maintenance of all body tissues
Manifestations of thyrotoxicosis and hypothyroidism (1)
System
Thyrotoxicosis
Hypothyroidism
Skin and appendages
Warm, moist skin; sweating; heat
intolerance; fine, thin hair;
Plummer's nails; pretibial
dermopathy (Graves' disease)
Pale, cool, puffy skin; dry and
brittle hair; brittle nails
Eyes, face
Retraction of upper lid with wide
stare; periorbital edema;
exophthalmos; diplopia
(Graves' disease)
Drooping of eyelids; periorbital
edema; loss of temporal aspects
of eyebrows; puffy, nonpitting
facies; large tongue
Cardiovascular
system
Decreased peripheral vascular
resistance, increased heart rate,
stroke volume, cardiac output,
pulse pressure; high-output
heart failure; increased
inotropic and chronotropic
effects; arrhythmias; angina
Increased peripheral vascular
resistance; decreased heart rate,
stroke volume, cardiac output,
pulse pressure; low-output heart
failure; ECG: bradycardia,
prolonged PR interval, flat T
wave, low voltage; pericardial
effusion
Respiratory system
Dyspnea; decreased vital capacity
Pleural effusions; hypoventilation
and CO2 retention
Manifestations of thyrotoxicosis and hypothyroidism (2)
System
Thyrotoxicosis
Hypothyroidism
Gastrointestinal
system
Increased appetite; increased
frequency of bowel
movements; hypoproteinemia
Decreased appetite; decreased
frequency of bowel
movements; ascites
Central nervous
system
Nervousness; hyperkinesia;
emotional lability
Lethargy; general slowing of
mental processes; neuropathies
Musculoskeletal
system
Weakness and muscle fatigue;
increased deep tendon
reflexes; hypercalcemia;
osteoporosis
Stiffness and muscle fatigue;
decreased deep tendon reflexes;
increased alkaline phosphatase,
LDH, AST
Renal system
Mild polyuria; increased renal
blood flow; increased
glomerular filtration rate
Impaired water excretion;
decreased renal blood flow;
decreased glomerular filtration
rate
Hematopoietic
system
Increased erythropoiesis; anemia1
Decreased erythropoiesis; anemia1
Reproductive system
Menstrual irregularities; decreased
fertility; increased gonadal
steroid metabolism
Hypermenorrhea; infertility;
decreased libido; impotence;
oligospermia; decreased
gonadal steroid metabolism
Manifestations of thyrotoxicosis and hypothyroidism (3)
System
Metabolic system
Thyrotoxicosis
Hypothyroidism
Increased basal metabolic
Decreased basal metabolic
rate; negative nitrogen
rate; slight positive
balance; hyperglycemia;
nitrogen balance; delayed
increased free fatty acids;
degradation of insulin, with
decreased cholesterol and
increased sensitivity;
triglycerides; increased
increased cholesterol and
hormone degradation;
triglycerides; decreased
increased requirements for
hormone degradation;
fat- and water-soluble
decreased requirements for
vitamins; increased drug
fat- and water-soluble
metabolism
vitamins; decreased drug
metabolism
Thyroid Preparations

Synthetic:


levothyroxine, liothyronine, liotrix
Animal origin

desiccated thyroid
ANTITHYROID AGENTS




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
Thioamides
Anion Inhibitors
Iodides
Iodinated Contrast Media
Radioactive Iodine
Adrenoceptor-Blocking Agents
Thioamides
Thioamides

Pharmacokinetics



Propylthiouracil is rapidly absorbed and the
bioavailability is 50-80%
Methimazole is completely absorbed
Both thioamides cross the placental barrier
Thioamides;
Pharmacodynamics




Act by multiple mechanisms
Prevent hormone synthesis by inhibiting
the thyroid peroxidase
Inhibiting the peripheral deiodination of
T4 and T3
The onset of these agents is slow, often
requiring 3-4 weeks
Thioamides: Toxicity:




Occur in 3-12% of treated patients
Nausea and gastrointestinal distress
The most common adverse effect is a maculopapular
pruritic rash (4-6%)
Rare adverse effects include:



an urticarial rash, vasculitis, a lupus-like reaction,
lymphadenopathy, hypoprothrombinemia, exfoliative
dermatitis, polyserositis, and acute arthralgia.
Hepatitis can be fatal
The most dangerous complication is agranulocytosis
Anion Inhibitors



Perchlorate (ClO4-)
Pertechnetate (TcO4-)
Thiocyanate (SCN-)
Iodides



Inhibit organification
Hormone release
Decrease the size and vascularity of the
hyperplastic gland
Iodinated Contrast Media




diatrizoate
iohexol
inhibit the conversion of T4 to T3
inhibition of hormone release
Radioactive Iodine
I is the only isotope used for
treatment of thyrotoxicosis
therapeutic effect depends on emission
of  rays
 131

Adrenoceptor-Blocking
Agents

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Metoprolol
Propranolol
Atenolol
effective therapeutic adjuncts in the
management of thyrotoxicosis
CLINICAL PHARMACOLOGY
OF THYROID &
ANTITHYROID DRUGS
HYPOTHYROIDISM
HYPERTHYROIDISM
Thyroid Storm
Ophthalmopathy
Dermopathy
Etiology and pathogenesis of hypothyroidism
Cause
Pathogenesis
Goiter
Degree of
Hypothyroidi
sm
Hashimoto's
thyroiditis
Autoimmune destruction of
thyroid
Present
early,
absent
later
Drug-induced1
Blocked hormone formation2
Present
Dyshormonogenesis
Impaired synthesis of T4 due to
Present
enzyme deficiency
Mild to severe
Radiation, 131I, x-ray,
thyroidectomy
Destruction or removal of
gland
Absent
Severe
Congenital
(cretinism)
Athyreosis or ectopic thyroid,
iodine deficiency; TSH
receptor-blocking
antibodies
Absent or
present
Severe
Secondary (TSH
deficit)
Pituitary or hypothalamic
disease
Absent
Mild
Mild to severe
Mild to moderate