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
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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
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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.
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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
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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