Transcript T 3
Thyroid and Antithyroid
Drugs
Dr Safaeian
Isfahan University of Medical
Sciences
Thyroid Physiology
Thyroid gland secretes:
Triiodothyronine (T3)
Tetraiodothyronine (T4, Thyroxine)
Calcitonin: important in regulation of calcium
metabolism
T3 and T4 → contain 59% and 65% (respectively)
of iodine as an essential part of the molecule.
They normalize growth and development, body
temperature, and energy levels.
Iodide Metabolism
Recommended daily adult iodide (I–) intake is 150
mcg (200 mcg during pregnancy).
Iodide, ingested from food, water, or medication, is
rapidly absorbed and enters an extracellular fluid pool.
Thyroid gland removes about 75 mcg a day from this
pool for hormone synthesis, and balance is excreted in
urine.
If iodide intake is increased, fractional iodine
uptake by thyroid is diminished.
Biosynthesis of Thyroid Hormones
1. Transport of iodide into thyroid gland by Na+/I-
symporter ► can be inhibited by anions as
thiocyanate (SCN–), pertechnetate (TcO4–), and
perchlorate (ClO4–).
At the apical cell
membrane a second
I– transport enzyme
called pendrin controls
flow of iodide
across membrane.
Biosynthesis of Thyroid Hormones
2. Oxidization of iodide by thyroidal peroxidase to
iodineis ► transiently blocked by high levels of
intrathyroidal iodide and blocked more persistently
by thioamide drugs.
3. Iodide organification:
iodinatation of tyrosine
residues within thyroglobulin
molecule → formation of
monoiodotyrosine (MIT) and
diiodotyrosine (DIT).
Biosynthesis of Thyroid Hormones
4. DIT + DIT → L-thyroxine (T4)
MIT + DIT →T3
5. Exocytosis: T4 and T3 are released from
thyroglobulin by proteolysis and exocytosis occurs ►
blocked by high levels of intrathyroidal iodide.
Ratio of T4 to T3 = 5:1
Most of T3 is derived from
peripheral metabolism of T4.
T3 is 4 times more
potent than T4.
Transport and Peripheral Metabolism
of Thyroid Hormones
T4 and T3 are bound to thyroxine-binding globulin (TBG) in
plasma . Only ~ 0.04% of total T4 and 0.4% of T3 exist in free
form.
T4 is deiodinized by 5´-deiodinase in outer ring to active
T3 and in inner ring to reverse T3 (rT3), which is
metabolically inactive.
5´-deiodinase is inhibited by:
- Amiodarone
- Iodinated contrast media
- β blockers
- Corticosteroids
- Severe illness or Starvation
Thyroid-Pituitary Relationships
Hypothalamus gland secretes
thyrotropin-releasing hormone (TRH).
TRH stimulates synthesis and release
of thyroid-stimulating hormone (TSH)
from pituitary gland.
TSH stimulates thyroid cells →
↑adenylyl cyclase activity →
↑synthesis and release of T4 and T3 .
Thyroid hormones block action
of TRH and TSH (negative feedback).
Autoregulation of Thyroid Gland
Thyroid gland also regulates its uptake of I- and
hormone synthesis by intrathyroidal
mechanisms that are independent of TSH and are
primarily related to level of I- in blood.
Large doses of iodine inhibit I- organification
(Wolff-Chaikoff block).
Hypothyroidism
Deficiency of thyroid hormones
Slowing down of all body functions
Can occur with or without thyroid enlargement
(goiter).
Most common cause: Hashimoto’s thyroiditis:
an autoimmune disorder → thyroid is destroyed by
antibodies.
Secondary hypothyroidism: Impaired
hypothalamus and pituitary function.
A diet insufficient in iodine causes
hypothyroidism.
Hypothyroidism
Myxedema coma: end state of untreated
hypothyroidism → progressive weakness, stupor,
hypothermia, hypoventilation, hypoglycemia,
hyponatremia, water intoxication, shock, and
death.
Cretinism: thyroid deprivation in early
life → mental retardation and dwarfism.
Signs and Symptoms of Hypothyroidism
Skin and appendages: Pale,
cool Skin, dry and brittle
hair, brittle nails, sensitivity to cold
Eyes, face: Drooping of
eyelids; periorbital edema; loss of
temporal aspects of eyebrows; puffy facies; large tongue
Cardiovascular system:
↑PVR; ↓HR, ↓stroke volume,
↓cardiac output, ↓pulse pressure; bradycardia, prolonged
PR interval, flat T wave; pericardial effusion
Respiratory system: Pleural effusions; hypoventilation
GI system:↓Appetite;
CNS:
↓bowel movements; ascites
Lethargy; slowing of mental processes; neuropathies
Signs and Symptoms of Hypothyroidism
Musculoskeletal system:
Stiffness, Muscle fatigue, ↓deep
tendon reflexes; ↑alkaline phosphatase, ↑LDH
Renal system:
Impaired water excretion; ↓renal blood
flow; ↓GFR
Hematopoietic system:
Reproductive system:
↓Erythropoiesis, Anemia
Hypermenorrhea; infertility;
↓libido; impotence; oligospermia; ↓steroid metabolism
Metabolic system: ↓Basal
metabolic rate, ↑Cholesterol,
↑TG, ↓hormone and drug metabolism
Treatment for Hypothyroidism
Hormone replacement therapy:
Synthetic:
Levothyroxine Sodium (T4) (Tab, Cap
50, 75, 100 mcg)
Liothyronine Sodium (T3) (Tab 25 mcg)
Liotrix (4:1 ratio of T4: T3)
Animal origin: desiccated thyroid
Thyroid Hormones: Pharmacokinetics
T4 absorption is modified by intraluminal factors
such as food, drugs, and intestinal flora.
Oral bioavailability: T4 = 80% , T3 = 95%
Levothyroxine doses should be administered on an
empty stomach in the morning 30–60 minutes
before breakfast or at bedtime 4 hours after the last
meal.
Thyroid Hormones: Pharmacokinetics
Interference with T4 absorption:
Cholestyramine, colestipol, ciprofloxacin,
proton pump inhibitors, sucralfate,
aluminum hydroxide, ferrous sulfate,
calcium carbonate, bran, soy, coffee
Thyroid Hormones: Mechanism of Action
Free T4 and T3 enter the cell by active transport.
Within the cell, T4 is converted to T3 .
T3 enters the nucleus → binds to a specific T3 receptor
protein →↑formation of RNA and protein synthesis.
Large numbers of TR are found in the most
hormone-responsive tissues (pituitary, liver,
kidney, heart, skeletal muscle, lung, and intestine)
Few receptor sites occur in hormone-unresponsive
tissues (spleen, testes).
Brain lacks an anabolic response to T3 , contains an
intermediate number of receptors.
Affinity of receptor site for T4 is about 10 times lower
than T3
Effects of Thyroid Hormones
Responsible for optimal growth, development,
function, and maintenance of all body tissues
Critical for nervous, skeletal, and reproductive
tissues
Its effects depend on protein synthesis as well as
potentiation of secretion and action of GH
Widespread influence on metabolism of drugs
as well as carbohydrates, fats, proteins, and
vitamins.
Effects of Thyroid Hormones
Affect secretion and degradation rates of
other hormones (catecholamines, cortisol,
estrogens, testosterone, insulin)
Thyroid hyperactivity resemble sympathetic
nervous system overactivity→ ↑numbers and
signal of β receptors (especially in cardiovascular
system)
Other clinical symptoms indicative excessive
epinephrine activity (tremor, excessive
sweating, anxiety, nervousness)
Thyroid Preparations
Choice: Synthetic levothyroxine, because of:
Its stability, content uniformity, low cost, lack of
allergenic foreign protein, easy laboratory
measurement of serum levels, and long half-life (7
days) → once-daily administration
Liothyronine: greater hormone activity and
consequent greater risk of cardiotoxicity, best used
for short-term suppression of TSH.
Thyroid hormones are not effective and can be
harmful in management of obesity, abnormal
vaginal bleeding, or depression if thyroid
hormone levels are normal.
Hyperthyroidism (Thyrotoxicosis)
Over production of thyroid hormones.
Most common form: Graves' disease, or diffuse
toxic goiter: autoimmune disorder with antibodies
against TSH receptor in thyroid cell membrane with
capacity to stimulate growth and biosynthetic activity
of thyroid cell (with much longer duration of effect)
Thyroid storm (Thyrotoxic crisis): sudden
acute exacerbation of thyrotoxicosis
and a life-threatening syndrome.
Signs and Symptoms of Hyperthyroidism
Skin and appendages: Warm, moist
skin, sweating, heat
intolerance; fine, thin hair, Plummer nail
Eyes, face: periorbital edema; exophthalmos
Cardiovascular system:
↓PVR; ↑HR, ↑stroke volume,
↑cardiac output, ↑pulse pressure; arrhythmias; angina
Respiratory system: Dyspnea;
GI system:
CNS:
↓vital capacity
↑Appetite; ↑bowel movements
Nervousness; hyperkinesia; emotional lability
Signs and Symptoms of Hyperthyroidism
Musculoskeletal system:
Weakness, Muscle fatigue,
↑deep tendon reflexes; hypercalcemia; osteoporosis
Renal system:
Mild polyuria; ↑renal blood flow; ↑GFR
Hematopoietic system:
Reproductive system:
↑Erythropoiesis, Anemia
Menstrual irregularities; ↓fertility;
↑gonadal steroid metabolism
Metabolic system: ↑Basal
metabolic rate, hyperglycemia;
↓Cholesterol, ↓TG, ↑hormone and drug metabolism
Treatment for Hyperthyroidism
Anti-thyroid Therapy
Radioactive Iodine
Thyroidectomy
Three main therapies, each was equally effective in
normalizing serum thyroid hormone concentrations
within 6 weeks.
ANTITHYROID AGENTS
1. Thioamides
2. Anion Inhibitors
3. Iodides
4. Iodinated Contrast Media
5. Radioactive Iodine
Thioamides
Propylthiouracil (PTU)
Methimazole
Carbimazole (converted to
methimazole)
Methimazole: 10 times more
potent than PTU.
Thioamides: Pharmacokinetics
PTU: bioavailability of 50–80% due to incomplete
absorption or a large first-pass effect, half-life=1.5 hrs
Methimazole: completely absorbed , half-life=6 hrs
Excreted by kidney
Accumulated by thyroid gland.
Methimazole is preferred because of its longer
duration of action, allowing for once daily dosing,
more rapid efficacy, and lower incidence of side
effects.
Thioamides in pregnancy
PTU is preferred during the first trimester of
because of more strongly protein-bound and crosses
the placenta less readily.
In the second trimester ► switching from PTU to
an equivalent dose of Methimazole because of risk
of hepatitis with PTU.
Both are secreted in low concentrations in breast
milk but are considered safe for nursing infant.
Thioamides: Pharmacodynamics
Prevent hormone synthesis by:
Inhibiting thyroid peroxidase
Blocking iodine organification
Block coupling of the iodotyrosines
Inhibiting peripheral deiodination of T4 to T3
Since synthesis rather than release of
hormones is affected, onset of action is slow
→ requiring 3–4 weeks before stores of T4
are depleted.
Thioamides: Toxicity
Nausea, GI distress
Altered sense of taste or smell with
methimazole
Maculopapular pruritic rash
accompanied by systemic signs
such as fever
Rare: Hepatitis and cholestatic jaundice
Most dangerous: Agranulocytosis
Thioamides: Recommendations
Monitoring ► periodic clinical assessment and
measurements of serum T4
Since hyperthyroidism results in negative Ca balance,
↓bone density, and ↑fracture risk ► advise to ingest
1200 to 1500 mg elemental Ca daily.
Assessment of thyroid function at 4 to 6 week intervals
until stabilized on maintenance thionamide therapy.
Persistently low serum TSH concentrations after more
than 6 months of therapy with thionamide ► unlikely
to have a remission when the drug is stopped.
Anion Inhibitors
Perchlorate (ClO4–)
Pertechnetate (TcO4–)
Thiocyanate (SCN–)
Block uptake of iodide by gland through
competitive inhibition of iodide transport.
Rarely used clinically because of association
with aplastic anemia.
Iodides: Saturated Solution of
Potassium Iodide (SSKI; Lugol's solution)
Mechanism of Action:
Inhibit organification
Inhibit hormone release (inhibition of thyroglobulin
proteolysis)
↓Size and vascularity of hyperplastic gland
Preoperative preparation for surgery
Rarely used as sole therapy.
Iodine elixirs, up to 10 drops of SSKI, 50 mg iodide
per drop [0.05 mL]) daily, can be used to ameliorate
very mild hyperthyroidism.
Iodides: Disadvantages
Increase in intraglandular stores of iodine→ delay
onset of thioamide therapy or prevent use of
radioactive iodine therapy.
Should not be used alone → gland will escape
from iodide block in 2–8 weeks, and its
withdrawal→ severe exacerbation of
thyrotoxicosis
Chronic use in pregnancy should be avoided→
cross placenta and can cause fetal goiter.
Iodides
Adverse Effects:
Acne, swollen salivary glands, mucous
membrane ulcerations, conjunctivitis,
rhinorrhea, drug fever, metallic taste, bleeding
disorders and, rarely anaphylactoid reactions.
Iodinated Contrast Media
Diatrizoate (orally)
Iohexol (orally or IV)
Rapidly inhibit conversion of T4 to T3
Adjunctive therapy in the treatment of thyroid
storm
Toxicity is similar to that of iodides.
Patients who have severe hyperthyroidism or
are allergic to thionamides may benefit from
Iodinated contrast agents and iodine therapies.
Radioactive Iodine: 131I
Administered orally in solution as sodium
131I
Concentrated by thyroid.
Therapeutic effect: emission of β rays →
destruction of thyroid parenchyma.
Advantages: easy administration, effectiveness,
low expense, and absence of pain.
Should not be administered to pregnant women or
nursing mothers or women desiring to become
pregnant in the near future.
Avoid close contact with young children for several
days after radioiodine administration.
Adjuncts to antithyroid therapy:
β-Blockers
Diltiazem (control of tachycardia in patients in whom β
blockers are contraindicated, eg, those with asthma)
Vitamin supplements
Barbiturates (accelerate T4 breakdown by hepatic
enzyme induction and may be helpful as sedatives)
Bile acid sequestrants (rapidly lower T4 levels by
increasing the fecal excretion of T4)
Adrenoceptor-Blocking Agents
Beta blockers without intrinsic sympathomimetic
activity (eg, metoprolol, propranolol, atenolol)
Effective therapeutic adjuncts in management of
thyrotoxicosis
Ameliorate symptoms of hyperthyroidism due to
↑beta-adrenergic tone (palpitations, tachycardia,
tremulousness, anxiety, heat intolerance).
Beta-blocker should be started in most patients as
soon as diagnosis of hyperthyroidism.
Effect of thyroid function on drug effects
Anticoagulation: Lower doses of warfarin required
in hyperthyroidism, higher doses in hypothyroidism
Glucose control: ↑hepatic glucose production and
glucose intolerance in hyperthyroidism; impaired
insulin action and glucose disposal in hypothyroidism
Cardiac drugs: Higher doses of digoxin required in
hyperthyroidism; lower doses in hypothyroidism
Sedatives; Analgesics: ↑sedative and respiratory
depressant effects from sedatives and opioids in
hypothyroidism; converse in hyperthyroidism