THYROID AND ANTITHYROID DRUGS Flashcards
What are the hormones secreted by the thyroid glands?
The organ secrete two hormones, thyroxine (T4) and 3,5,3’-triiodothyronine (T3).
Discuss the Biosynthesis of thyroid hormones
Biosynthesis of thyroid hormones:
Uptake of iodide ion into the gland by sodium iodide symporter (NIS).
Inhibited by pertechnate, thiocyanate, perchlorate.
Oxidation of iodide to iodine by peroxidase.
Iodination of tyrosine to form monoiodotyrosine and diiodotyrosine.
Coupling of iodotyrosine molecules.
Resorption of thyroglobulin.
Release of the hormones.
Peripheral and thyroidal conversion of T4 to T3
Discuss the pharmacokinetics of thyroid hormones
Pharmacokinetics:
Thyroid hormones are highly protein bound and only 0.03%-0.08% of T4 and 0.2-0.5% of T3 are in unbound form.
Binding is to TBG, Albumin and thyroxin binding prealbumin.
The hormones are metabolised by deiodination and glucuronide/sulphate conjugation mainly in the liver and excreted in bile.
A fraction of the conjugate is liberated and reabsorbed in the intestine.
Metabolism also occur in the kidneys and the salivary gland.
T4 is deiodinated to T3 or rT3 (3,3’,5’-triiodothyronine) which is metabolically inactive.
Normal circulating plasma levels of thyroxine range from 4.5 to 11μg/dl.
Normal circulating plasma levels of triiodothyronine range from 60 to 180ng/dl.
Actions of thyroid hormones
- Growth and development:
Important for normal growth and development.
Also essential for brain development. Deficiency within first 6 months of life leads to cretinism. - Calorigenic effects:
Increased BMR.
Increased rate of metabolism in brains, gonads, uterus, spleen.
Increased oxygen consumption.
Increased lipogenesis. - Metabolic effects:
Stimulation of carbohydrate metabolism with increased glycogenolysis and gluconeogenesis.
Stimulation of metabolism of cholesterol to bile acids.
Enhancement of lipolytic responses of fat cells to catecholamines and other hormones.
Catabolic effect on proteins with resultant negative nitrogen balance and tissue wasting with prolonged action. - Gastrointestinal system:
Enhances propulsive activity with dev. of diarrhoea in hyperthyroid states and constipation in hypothyroidism.
What is the mechanism of action of thyroid hormones?
The receptors are located in the nucleus and receptor (T3)/ hormone complex binds to TREs (thyrotropin releasing element) on DNA thereby leading to gene transcription and protein synthesis and specific effects.
T4 also bind to the receptor with less affinity and does not trigger gene expression.
What are the Effects of thyroid hyperfunction?
In what cases do we see this?
Heat intolerance.
Increased apetite.
Insomnia.
Restlessness.
Apprehension.
Anxiety
Increased bowel movements
Angina, arrythmias, heart failure
Tachycardia
Thyroid storm
Examples: grave’s disease and nodular goitre, thyroiditis
Symptoms of hypothyroidism includes:
Cretinism
Poor apetite
Constipation
Muscular weakness
Depression of deep tendon reflexes
Dry and cold skin
Husky, low-pitched voice
Mental dullness
Amenorrhoea
Excessive sleeping
Cold intolerance.
Thyroid hypofunction results from
- Iodide deficiency
Chronic autoimmune thyroiditis - High levels of circulating antibodies directed against thyroid peroxidase
- Presence of blocking antibodies against TSH receptor
- Thyroid destruction resulting from apoptotic cell death
Thyroid hormone preparations
- Levothyroxine sodium (L-T4, SYNTHROID, LEVOXYL, LEVOTHROID, UNITHROID.
- Liothyronine sodium (L-T3).
- Liotrix (THYROLAR)- mixture of thyroxine and triiodothyronine.
- Dessicated thyroid preparations from whole animal thyroids/ sheep thyroid hormone
Indications for thyroid hormone use are as replacement therapy in
Adult hypothyroidism
Cretinism
Nontoxic goitre
Myxoedema coma
Thyroid nodule
Ca thyroid
Discuss LEVOTHYROXIN SODIUM: use, where is it absorbed, what interferes with its absorption, where is it excreted and how is it administered?
Used for chronic thyroid hormone replacement therapy.
It is absorbed in the small intestine and absorption is better on empty stomach.
cholestryramine resin, iron and calcium supplements, aluminium hydroxide all interfere with its absorption.
Excretion is in the bile and this is increased by phenytoin, carbamazepine and rifampin.
Usually administered once daily orally but can be administered parenterally
Dose of LEVOTHYROXIN SODIUM
Average daily adult replacement dose of levothyroxine sodium is 112μg as a single dose.
Cumulative weekly dose can be given as a single weekly dose in noncompliant young adults.
Dose should be commenced at 20-25μg in individuals older than 60 years.
Dose of liothyronine sodium is 50-75μg daily in divided doses
Classes of drugs that interfere with thyroid hormone synthesis
Antithyroid drugs
Ionic inhibitors
Iodides
Radioactive iodine
Examples of Antithyroid drugs
Propylthiouracil
Methimazole
Carbimazole
Discuss Propylthiouracil
Prototype drug
Administered orally
Highly protein bound (meaning it is safer in pregnancy than methimazole)
Half life is 75 minutes
It is concentrated in the thyroid gland
Dosing is 3-4 times daily
It crosses the placenta
Excretion in urine
Discuss Methimazole
Oral administration.
Half life is 4-6 hours.
No protein binding (can cause fetal hypothyroidism therefore not safe in pregnancy )
Dosing is 1-2 times daily.
Crosses the placenta.
Excretion in urine
Mechanism of action uses and side effects of antithyroid drugs
Doses of antithyroid drugs
Mechanism of action of anti thyroid drugs.
Inhibition of iodine into tyrosyl residues.
Inhibition of coupling of iodotyrosyl residues.
Propylthiouracil partially inhibits conversion of T4 to T3.
Side effects
Rash
Joint pain and stiffness
Paraesthesia
Nausea
Skin pigmentation
Agranulocytosis (manifests as a sore throat)
Uses
Treatment of Grave’s disease
Pre-thyroidectomy.
Used in conjunction with radioactive iodide.
Carbimazole on absorption is conveyed to methimazole
Starting dose for propylthiouracil is 100mg 8hrly or 150mg 12hrly.
Dose of methimazole is 30-40mg once daily.
Dose of the antithyroid drugs are reduced once euthyroid state is achieved.
Discuss Ionic Inhibitors
These are monovalent anions similar in size to iodide.
Inhibit the uptake of iodide
They are thiocyanate, pertechnate, perchlorate.
They act by inhibiting NIS.
Most active is perchlorate.
They are used in managing Grave’s disease and amiodarone-iodine-induced thyrotoxicosis.
Highly toxic
Unpredictable effect therefore not used so much
Discuss Iodide
Earliest agents for managing thyrotoxicosis.
Act by inhibiting transport of iodine into the cells.
Inhibit the synthesis of thyroid hormones.
Inhibit release of thyroid hormones.
Rapid but transient effect.
Effects of Iodide
Rapid and striking response.
Rapid drop in basal metabolic rate.
Reduced vascularity of the thyroid gland.
Increased firmness of the thyroid gland.
Maximal effect in 10-15 days of continous therapy.
Beneficial effects disappear after some time.
Uses of Iodide
What preparation of iodide is commonly used?
Uses
-Preoperatively in preparation for thyroidectomy.
-Protection of the thyroid during radioactive accident.
Preparations:
-Lugol’s solution (5% iodine and 10% potassium iodide) yields dose of 6.3mg iodine per drop.
-Saturated solution of potassium iodide (SSKI), 38mg iodine per drop.
Doses: 3-5 drops of Lugol’s solution or 1-3 drops of SSKI 3 times daily.
Side effects of Iodide
-Hypersensitivity which may include angioedema, laryngeal edema, serum sickness, TTP.
-Chronic intoxication (iodism): rashes, conjunctivitis, rhinorrhea, metallic taste, mucositis, pulmonary edema, enlargement of maxillary and submandibular glands, anaphylaxis.
Discuss Radioactive iodine I131
Destroy thyroid tissue, get concentrated in thyroid gland and then emit β and γ rays.
β and γ rays.
Oral administration.
T1/2 0f 8 days.
Acts by destroying the thyroid gland.
Slow and gradual effect.
Used in managing hyperthyroidism and thyroid carcinoma or adenoma
Main side effect is hypothyroidism.
Major contraindication is pregnancy
Treatment of myxoedema coma
Treat associated conditions
All medications should be administered iv
Tx is with loading dose of levothyroxine 300-400mcg iv followed by 50-100mcg daily
Iv triiodothronine can also be used but with caution
Dose of levothyroxine should be increased by 30-50% in pregnant hypothyroid women.
Causes of hypothyroidism
Congenital: absence, ectopic, iodine deficiency, TSH receptor blocking drugs
Hashimoto’s thyroiditis:
-antibodies against thyroid peroxidase and thyroglobulin
-Blocking antibodies against TSH receptors
Drugs: iodides, lithium, amiodarone, cytokines, fluorides, thionamides, ionic inhibitors
Radiation: I131, x-ray
Thyroidectomy
Secondary: pituitary or hypothalamic disease
Treatment of hypothyroidism
Withdrawal of offending drugs
Replacement therapy with levothyroxine.
-Administration should be on an empty stomach 30 minutes before or 1hr after meals
-Restlessness, insomnia, accelerated bone maturation and growth may indicate toxicity in children
-Adults may experience increased nervousness, heat intolerance, palpitation, tachycardia, unexplained weight loss
Other agents used as adjuvants in managing hyperthyroidism include
Beta antagonists
E.g propranolol which is an inhibitor of deiodinase enzyme inhibiting the conversion of T4-T3
Calcium channel blockers
Myxoedema coma
End state of untreated hypothyroidism
There is weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, shock, death
Medical emergency
Causes of hyperthyroidism
-Grave’s disease
-Toxic nodular goitre
-Exogenous ingestion of thyroid hormones
What is thyroid storm and what causes it?
A manifestation of severe hyperthyroidism
Acute exacerbation of all the symptoms of thyrotoxicosis
Causes include:
-Abrupt cessation of antithyroid medications
-Infections
-Thyroidectomy
-Other types of surgeries
-Trauma
-Acute illnesses eg DKA, heart failure, drug reaction
-Child birth
-stroke
Treatment of thyroid storm
-
Propranolol, 1-2mg iv slowly or 40-80mg orally every 6 hrs (to prevent the conversion of T4-T3)
- Diltiazem (where propranolol is contraindicated eg. in asthmatics) to control the cardiovascular manifestations
- SSKI is given at a dose of 10 drops or iodinated contrast media 1g orally daily to inhibit release of thyroid hormones and block conversion of T4 to T3
-PTU at 250mg 6hrly to block hormone synthesis
-Hydrocortisone 50mg iv 6hrly to protect against shock and also block conversion of T4 to T3
-Supportive treatment to control fever, heart failure and any underlying illness that may have precipitated the storm
