Endocrine Pharmacology

• For the thyroid system, thyrotrophin releasing hormone (TRH) from the hypothalamus releases thyroid stimulating hormone (TSH) from the anterior pituitary which in turn releases thyroxine (T4) from the thyroid gland. Thyroxine, like many peripheral hormones however, as shown in the right-hand diagram, also exerts a negative feedback response on both the hypothalamus and the anterior pituitary to inhibit its own release.

  
• Anterior pituitary hormones are the central component of a 3-step pathway. They are released into the circulation by hypothalamic releasing hormones to act on peripheral endocrine glands

  
• Hypothyroidism

  goitre,

   weight gain,

  cold intolerance, myxedema

  TSH

  Primary ↑

  Secondary ↓

  
• The major symptoms of hypothyroidism include goitre, an enlarged thyroid, weight gain, cold intolerance and myxedema, which is the deposition of sugar residues in connective tissue resulting in a puffy face.

  
• If the primary defect is in the thyroid gland itself, the decrease in thyroxine will reduce its negative effect on the anterior pituitary, increasing the release of TSH. However, if the cause of hypothyroidism is a secondary effect on the pituitary itself, TSH levels will fall together with the fall in thyroxine.

  
• Thyroid Drugs

  Levothyroxine

  •Oral tablet 50-100µg/day

  •Half - life prolonged by binding to TBG

  •Prodrug - T4 converted to T3 in cell to act on a nuclear receptor
• Thyroid Drugs

  Liothyronine

  •Intravenous injection - emergency use

          (faster onset, but shorter duration of action)

  •Oral tablet 10-20μg/day useful in patients with deiodinase deficiency

          (inability to convert T4 to T3)
• Thyroxine (chemically known as tetra-iodothyronine) is frequently called T4 because each molecule contains 4 atoms of iodine
• The drug treatment of hypothyroidism consists of replacement therapy with oral thyroxine using the levo-isomer, levothyroxine. However, levothyroxine is in fact a form of tissue prodrug which is converted into triiodothyronine (T3) within peripheral cells of the body. There is no T4 receptor as such but a nuclear receptor for T3.
• The drug form of T3 is called liothyronine which is available in intravenous form for emergency use since, it doesn’t require metabolic conversion into an active form. An oral form of liothyronine is also available for patients lacking the deiodinase enzymes required to convert T4 into T3.
• levothyroxine is a prodrug, metabolised to triiodothyronine (T3) by iodinase enzymes in the cell membrane.
• The receptor for T3, thyroid hormone receptor (TR), is present in the cell nucleus. This receptor has two binding domains, a ligand binding domain (LBD) for T3 and a DNA binding domain (DBD). The receptor is kept quiescent by combination with co-repressor proteins and activated by co-activator proteins when T3 binds to the ligand binding domain. For T3 to stimulate protein transcription, the activation of a retinoic acid receptor is also required.

  
• Levothyroxine has effects on nearly every cell in the body. For example, levothyroxine increases cardiac muscle contractility, gut motility, red cell maturation and bone turnover. One important effect of pharmacological interest is the increased sensitivity to catecholamines such as adrenaline or sympathetic nerve stimulation, which is particularly important in treating the cardiac effects of hyperthyroidism.
• Levothyroxine : Pharmacological Effects

  •Increased O2 consumption and heat production

  •Increased cardiac muscle contractility

  •Increased sensitivity to catecholamines

  •Maintenance of hypoxic and hypercapnic drive in respiratory centre

  •Increased gut motility

  •Increased erythropoiesis

  •Increased bone turnover

  •Increased protein turnover and loss of muscle tissue

  •Increased cholesterol degradation

  •Increased metabolic turnover of many hormones and drugs
• Thyroxine : Adverse Effects

  Excessive Dose

   

  diarrhoea, 

  sweating,

  nervousness, 

  tachycardia,

  increased appetite, 

  loss of weight.
• Thyroxine : Adverse Effects

  May Precipitate 

  heart failure,

  angina, 

  arrhythmia,

  osteoporosis

  (long term).
• from 2017 where levothyroxine was the second most widely prescribed drug in primary care. Liothyronine, in contrast, is used in about 0.2% of hypothyroid patients but is some 50 times more expensive than levothyroxine
• Hyperthyroidism

    

  exophthalamos,

   weight loss,

  heat intolerance,

  CVS­

  TSH

  Primary↓

  Secondary↑
• Hyperthyroidism is associated with weight loss, heat intolerance, an activated cardiovascular system and exophthalamos, a condition of bulging eyes due to the deposition of abnormal connective tissue in the orbit of the eye.
• Primary hyperthyroidism in the thyroid will stimulate a negative feedback response on the anterior pituitary, decreasing TSH release. However, If the defect causing hyperthyroidism is secondary, in the pituitary, TSH will also be elevated. Unlike hypothyroidism, the target for drugs to treat hyperthyroidism is the thyroid gland itself.
• Thyroid hormones, in particular thyroxine, are synthesised in the thyroid gland. Iodide is transported into the thyroid follicle by a sodium/iodide symporter and attached to tyrosine amino acids contained within the protein, thyroglobulin. This combination is activated by the enzyme thyroperoxidase at the border of the lumen of the thyroid follicle.

  
• Tyrosine can be iodinated once, to produce mono-idotyrosine and twice to produce di-iodotyrosine. Endocytosis of the thyroglobulin back into the follicle wall allows lysosomal enzymes to metabolise the iodinated thyroglobulin, releasing their amino acid content to allow the synthesis of new thyroglobulin protein releasing new thyroid hormones to diffuse back into the circulation. It is important to remember that thyroxine is stored in both the thyroid and in the circulation, where it is highly bound to plasma protein.

  
• Inhibitors of Thyroperoxidase

  Competitive inhibitors for substrate binding site on thyroperoxidase.

  Inhibit the iodination of tyrosyl residues in thyroglobulin
• Inhibitors of Thyroperoxidase

  Carbimazole

  Oral liver prodrug (active metabolite methimazole) - rapid inhibition of enzyme (12h). However, effect on thyroxine takes 2-4 weeks – depletion of thyroid and plasma stores of T4 required. Potential for block and replace therapy.
• Inhibitors of Thyroperoxidase

  Propylthiouracil

  Additional mechanism - reduces the deiodination of T4 to T3 in peripheral tissues may work more quickly. Preferred in thyroid storm.
• Inhibitors of Thyroperoxidase

  Adverse Effects

  Rash, headache, joint pain. Neutropenia and agranulocytosis (c1%) symptom, sore throat – blood count required.
• Hyperthyroidism is treated by competitive inhibitors for the substrate binding site on thyroperoxidase to inhibit the iodination of tyrosyl residues in thyroglobulin.  Two agents are available carbimazole and propylthiouracil
• Carbimazole is a liver prodrug which generates an active metabolite methimazole which rapidly inhibits thyroxine synthesis but, due to the presence of thyroxine stores in both the thyroid and the circulation, it takes some 2-4 weeks to lower thyroxine levels to normal.
• However, a graded reduction in thyroxine levels in hyperthyroidism can be difficult to achieve, so a system called ‘block and replace’ may be used where thyroxine synthesis is firstly inhibited completely, followed by the re-introduction of levothyroxine administered orally to maintain normal levels. Therefore paradoxically, patients with either hypothroidismy or hyperthyroidism may be taking levothyroxine.
• Propylthiouracil has an additional property of inhibiting the de-iodination of thyroxine at the cellular level and therefore may work more quickly than carbimazole, an advantage in patients showing symptoms of a thyroid storm
• Please take care with inhibitors of thyroperoxidase as some 1% of patients suffer from neutropenia and agranulocytosis, the symptoms of which may start with a sore throat but include rash, headache and joint pain.
• Permissive Hormone Action - T3 and the heart

  b-adrenoceptor­ increase

  post receptor signalling­ increase

  muscle protein ­increase

  Na/K ATP-ase­ increase

  Ca ATP-ase ­increase

  chronotrope, inotrope

  Hyperthyroid

   tachycardia/arrhythmia

  b -Blockers propranolol

  
• due to the increase in sensitivity to catecholamines, symptoms of hyperthyroidism may include tachycardia and arrhythmia due to stimulation of the sympathetic nervous system. This synergism is shown

  with epinephrine (adrenaline) by stimulating the release of fatty acids in cells treated with thyroxine. It is important to understand that the acute cardiac effects of hyperthyroidism are treated with beta-adrenoceptor antagonists (beta-blockers) such as propranolol, not antithyroid drugs. It is important that such acute cardiac effects are treated as soon as possible.

  
• antithyroid drugs (like methimazole or propylthiouracil) work by reducing the production of thyroid hormones (thyroxine and triiodothyronine), which ultimately addresses the underlying cause of hyperthyroidism. However, they do not directly affect the immediate cardiac symptoms. Since beta-blockers specifically target the sympathetic nervous system's overstimulation, they are more effective at providing quick relief from the heart-related symptoms of hyperthyroidism, while antithyroid drugs take time to lower thyroid hormone levels and may not provide immediate symptom control.
• Beta-blockers are used to treat the acute cardiac effects of hyperthyroidism, such as tachycardia and arrhythmias, because they directly address the symptoms caused by the overstimulation of the sympathetic nervous system. Hyperthyroidism increases the sensitivity of the body to catecholamines (like adrenaline), which can lead to a rapid heart rate, high blood pressure, and irregular heart rhythms. Beta-blockers, such as propranolol, work by blocking beta-adrenergic receptors in the heart, which prevents the action of adrenaline and thus helps to slow the heart rate and stabilize the rhythm
• beta-blockers are used for acute symptom management, especially for heart-related issues, while antithyroid drugs address the root cause of the disorder.
• Anterior pituitary hormones represent the central component of a 3-step pathway. Corticotrophin releasing hormone (CRH) releases ACTH from the anterior pituitary into the circulation to stimulate the release of cortisol, the major glucocorticoid, from the adrenal cortex. As with thyroid hormones, cortisol can then exert a negative feedback on the pituitary to inhibit ACTH release. The release of the major mineralocorticoid, aldosterone, from the adrenal cortex is however largely under peripheral control of angiotensin II and potassium in the circulation.

  
• The adrenal gland lies on the top of the kidney and consists of two major layers the cortex and the medulla. The cortex is then further divided into 3 layers, which include the outer layer (zona glomerulosa) which syntheses aldosterone, a mineralocorticoid, and a middle layer (zona fasiculata) which syntheses cortisol and androgens. The adrenal medulla is which generates adrenaline (epinephrine) and to a lessor extent noradrenaline (norepinephrine).

  
• Adrenaline Medulla

  Therapeutic Uses

  (blood vessels, heart, bronchial smooth muscle)

  Epinephrine

  1. Cardiac arrest

  2. Anaphylaxis, angioedema – acute hypersensitivity (Epipen)

  3. Vasoconstrictor – local anaesthetics

  Norepinephrine – vasoconstrictor in shock

  * β-blockade - reduced response, hypertension, bradycardia
• Drugs which interact with adrenoceptors or the neuronal release and uptake of noradrenaline include the major drug groups of alpha and beta-adrenoceptor antagonists, the beta-adrenoceptor agonists used in asthma and the antidepressants used to in the treatment of anxiety and depression.