PHARMACOLOGY: THYROID DRUGS BY DR.

FIRMALINO
THYROID DRUGS
3. cardiovascular effect - tachycardia with increase force of heart
Thyroid Gland
contraction and increased cardiac output due to increase in number
Anatomy
of myocardial beta adrenergic receptors
a ductless endocrine gland
4. metabolic effect - increased metabolism of cholesterol and bile
located in anterior neck over the trachea below the thyroid
acids increased lipolysis, increased ultilization of carbohydrates
cartilage
5. Inhibition of secretion of TSH by the pituitary - Thru negative
weight = 15-20 grams
feedback to pituitary by decreased secretion of TSH
Physiology
thyroid hormones = essentiaI for growth and development
Relation of iodine to thyroid functions
regulation of energy metabolism
Iodine is necessary for thyroid hormone synthesis
If iodine intake is decreased
Synthesis of thyroid hormone
hormone production is decreased (hypothyroid state)
dependent on dietary iodine (from food, drugs, water)
TSH is increased (negative feedback from pituitary)
o
rec.
daily req. = 150-200 ug
thyroid gland hypertrophies (endemic goiter)
vascularity increased
Iodide concentrating mechanism increased
Major steps in thyroid hormone production
production of normal amount of hormone
1. Iodine trapping
2. Oxidation of iodine and Iodination of Tyrosine
3. Formation of T3 and T4 by coupling
Sources of iodine
4. Secretion
marine life sea fish / shells = as much as
200 -1000 ug/kg
5. Peripheral conversion of T4 to T3
whereas 5 kg of vegetables / fruits or 3 kg of meat or fresh water
fish provides only 100 ug iodine
1. Iodide trapping
to provide enough Iodine - other regions inject iodized oil
Is the active transport of iodide from circulation to colloid of
most practical = addition of iodide or iodate to table salt
thyroid gland
1 gram iodized salt = 100 ug iodine
iodide pump
stimulated by thyrotropin (TSH)
Clinical Diagnosis
inhibited by thiocyanate and perchlorate
1.
Hypothyroidism
autoregulated - decrease thyroid iodine will enhance uptake
2.
Hyperthyroidism
Hypothyroidism
2. Oxidation/lodination
deficiency in thyroid hormone due to iodine deficiency (endemic
Iodide is oxidized to iodine by thyroid peroxidase
goiter)
Followed by iodination of tyrosine in the thyroglobulin
congenital cretinism in children
Result =
absent or atrophic thyroid gland
o
mono iodo tyrosyl (MIT)
post thyroidectomy
o
diiodotyrosyl (DIT)
post radioactive Iodine therapy
This is blocked by PTU
myxedema when severe
3. Coupling reaction
Signs & symptoms of Hypothyroidism
Formation of T3 and T4
Cretinism, Short extremities, Mental retardation
MIT + DIT = T3 or Triiodothyronine
inactive, uncomplaining. expressionless, drowsy
DIT + DIT = T4 or Thyroxine
Puffy face, thickened lips, half open mouth, enlarged tongue
T3 is 3-5x more active than T4
Doughy, yellowish scaly skin, cool and dry to touch
Coarse, sparse, brittle hair, Thick, brittle nails
4. Secretion of thyroid hormone
Thick subcutaneous tissue, Low pitch, husky voice
T3 and T4 are synthesized and stored in the thyroglobulin
Cold intolerance, Cardiomegaly, decreased heart rate
Secretion is initiated by endocytosis of colloid from the follicular
lumen
Hyperthyroidism
The ingested thyroglobulin fuse with lysosomes containing the
resemble sympathetic hyperactivity even though epinephrine is
proteolytic enzyme resulting to release of thyroid hormone which
not elevated, Tachycardia, full pulse
then exit the cell by exocytosis
Palpitation, Lid lag/retraction, Tremor, excessive sweating,
activated by TSH by increasing activity of the lysosomal
anxiety, nervousness
enzymes
Heat intolerance, warm skin, Muscle weakness
Increased appetite, increased energy expenditure, weight loss,
5. Peripheral conversion T4 and T3
wasting
80% of T3 comes from conversion of T4 in peripheral tissues
Insomnia, restlessness, Increased bowel movement
5 deiodinase enzyme involved
this enzyme a lnhibited by PTU
2 forms
1. Diffuse toxic goiter (Grave dis.)
Transport of thyroid hormone in the blood
T3 and T4 = bound in Thyroxin binding globulin (TBG)
2. Nodular toxic goiter (Plummers dis)
Only 0.03% of total Thyroxine (T4) is free
Free T3 is 0.2-0.5%
T3 is less firmly bound
Diffuse toxic goiter (Grave dis.)
Only free form is active
Exopthalmos, Pretibial myxedema ( non pitting)
Pregnancy or estrogen administration causes increase TBG with
Young middle aged woman
increase binding, thus decrease in free form
Auto immune
Thyroid stimulating Ig G antibodies binds to TSH receptor &
Degradation and excretion
triggers increase in T4 & T3
T3 has a half life of 2 days or less
T4 half life 6-7 days
Nodular toxic goiter (Plummers dis)
in hyperthyroidism - decreased to 3-4 days
Older patients, 60 y/o above, female
in hypothyroidism - increased to 9-10 days
Arise from long standing non toxic nodular goiter
Degradation = liver
Excretion - kidney mainly, stool = 20 - 40%
TREATMENT
Actions of thyroid hormone
Thyroid Hormone
1. regulation of growth and development - increased protein
Synthethic
synthesis by controlling DNA transcription
Levothyroxine
2. calorigenic effect - increased basal metabolic rate by increasing
Liothyronine
oxygen consumption
Liotrix

PHARMACOLOGY: THYROID DRUGS BY DR. FIRMALINO

Both PTU & Methimazole can cross the placental barrier and
concentrate in fetal thyroid causing fetal hypothyroidism
But PTU is preferred for pregnant women since it is strongly
bound to protein carrier and therefore cross the placenta less
Levothyroxine
readily and is not secreted in breast milk in sufficient quantity.
Preparation of choice for replacement therapy for
hypothyroidism & suppression therapy
mechanism of action of thionamide
Characteristics Stabilily, Content uniformity, Low cost, Lack of
major action - prevents hormone synthesis by inhibiting the
allergenic foreign protein, Easy lab interpretation for monitoring
thyroid peroxidase
Long half life = 7 days
catalyzed reactions to block iodine organifications
allows once daily administration
blocks coupling or iodotyrosine
Preparation - Synthroid or Levothroid, Eltroxin (available locally
does not block iodide uptake by the gland
in the Phil), 50 or 100 ug/tab
PTU inhibits peripheral deiodination of T4 to T3 by inhibiting
deiodinase, but not Methimazole
Liothyronine
slow onset 3-4 weeks lapses before T4 is depleted
3-4X more active
short half life = 24 hours
Side effects
must be given in multiple daily doses
most common - maculopapular rash, fever
not ideal for routine replacement
Late vasculitis, hepatitis, arthralgia, lymphadenopathy, a
higher cost
lupus Iike reaction, polyserositis
difficult to monitor thru lab test
most dangerous (infrequent = 3-6%) - agranulocytosis more cardiotoxic
reversible if drug is stopped, sign = sore throat with high fever
best used as a diagnostic test in T3 suppression and short term
suppression of TSH
Anion Inhibitors
Preparation - Tertroxin , 20 ug/tab
blocks uptake of iodine by the gland thru competitive inhibition of
iodide transport
Liotrix
Agents
A mixture of levothyroxine and iodothyronine in a ratio of 4:1
1. Perchlorate - may produce aplastic anemia, mainly used as rocket
Preparation Euthyroid,
Thyrolar
fuel
2. Pertechnetate Technetium scan of thyroid
Natural Thyroid
3. Thiocyanate present in cabbage, brocolli, cauliflower considered
Fine powder from dessicated pig thyroid
as anticancer, but incidentally is also a goitrogen inhibiting thyroid
Preparation - Armour or Thyrar,
hormone causing goiter
1 grain (60 mg), or 325 mg/tab
Very toxic
used only for diagnostic purposes
Natural Thyroglobulin
Purified pig extract
Preparation - Proloid, 32.5 and 65 mg/tab
Thiocyanate in large amount may even block organification of iodine
Dose - 60-300 mg/day
this chemical is produced by enzymatic hydrolysis of certain plant
glycosides like cabbage
Antithyroid Agents
mainly used for hyperthyroidism
Iodides
4 categories
Inhibits organification (step 2)
1.Thionamides or Thiourylenes - interfere directly with thyroid
inhibits hormone release thru inhibition of thyroglobulin decreased
hormone synthesis
the size and vascularity of the gland (step 4)
2. Ionic inhibitors - block the iodide transport mechanism
Dose
3. Iodide - suppression of thyroid hormone synthesis when given in
>6 mg/day (or 6000 ug), daily req is only 150 to 200 ug
high doses
rapid improvement in thyrotoxic symptoms within 2-7 days
4. Radioactive iodine - damages and destroy the gland by ionizing
radiation
Iodides
disadvantages
Thionamides
increased lntraglandular stores of iodine which delay onset of
2 groups
thionamide therapy
1.Propylthioracil (PTU)
prevent use of radioactive iodine therapy for several weeks
2.Methimazole
should not be used alone because the gland will escape from the
iodide block in 2-8 weeks
withdrawals may produce severe exacerbation of thyrotoxicosis on
Propylthiouracil (PTU)
iodine enriched gland
rapidly absorbed
cross the placenta and cause fetal goiter
peak serum level after 1 hour
mostly excreted in the kidneys as the inactive glucoronide within
Toxicity of Iodides are reversible
24 hours
drug fever
Dosage - 100 mg every 6 hours will inhibit 60% of iodine
acneiform rash
organification for 7 hours
metallic taste
swollen salivary gland
Methimazole (Tapazole 5 mg/tab)
bleeding disorders
10x more active that PTU

mucous ulcer
completely absorbed and accumulated in the thyroid gland

anaphylaxis
slower excretion than PTU (65-70% is recovered in the urine in

conjunctivitis
48 hours)

rhinorrhea
Dosage - 15-30 mg exerts antithyroid effect for >24 hours
given single dose daily for mild to moderate hyperthyroidism

lodinated Contrast Media

for severe cases - increase dose to 60 mg/day

lpodate, lopanoic acid

may also be given in 3 divided doses every 8 hrs

Valuable in treatment of hyperthyroidism (through it is not

maintenance = 5-15 mg/day
approved by the FDA)
Pedia = 0.4 mg/kg/day w/ maintenance of 1/2 of initial dose

Rapidly inhibit the conversion of T4 and T3 in liver, kidney,

pituitary gland and brain (step s)
Carbimazole

Also inhibition of hormone release due to iodine release (step

NeoMercazole 5 mg/tab), mother drug, converted to methimazole in
4)
vivo

Relatively non-toxic - similar to iodide

15-60 mg/day initially

Useful adjunct to thyroid storm

maintenance = 15 mg/day
natural (animal origin - pigs)
desiccated thyroid
thyroglobulin

PHARMACOLOGY: THYROID DRUGS BY DR. FIRMALINO

important alternative if iodides and thionamides are

RAI
contraindicated

Advantages - easy administration, effectiveness, low expense,

May not interfere with 131 I retention as much as iodides
absence of pain

Disadvantag es - genetic damage, leukemia,

- neoplasia
Radioactive Iodine

restrict use only to patient 35 years old above

131 iodine is the only Isotope used for thyrotoxicosis

Contraindications
orally - in solution as Na 131 iodine

pregnancy - crosses the placenta,

rapidly absorbed

nursing mothers - goes out with milk

concentrated by thyroid and incorporated into storage follicles

Adrenoreceptor Blocking Agents

RAI

many signs and symptoms of thyrotoxicosis mimic those

therapeutic effect Is dependent on emission of Beta rays with
associated with sympathetic stimulation, thus agents that
an effective half life of 5 days and penetration range of 400deplete catecholamines(reserpineand guanithidine) or agents
2000 um.
like beta
Destruction or thyroid parenchyma follows within a few weeks.
evidence of thyroid destruction

blockers are useful because they impair tissue response at the

receptor site.
epithelial swelling and necrosis

Choice Propanolol
follicular disruption

end
edema
leukocytic infiltration