- 2 - Rama Nada - Ensherah Mokhemar - Malik
When you see * refer to the index at the bottom of the page Quick revision: in the previous lecture we talked about: 1- Growth Hormone physiology 2- Growth Hormone deficiency and drugs which are used to treat it 3- Excessive Growth Hormone secretion and drugs which are used to treat it, we stopped here. In today s lecture we are going to discuss: 1- To continue our talking about excessive GH secretion medications 2- Prolactin hormone 3- We ll start talking about Thyroid hormones Let s go Excessive Growth hormone secretion in children causes Gigantism, while in adults it causes Acromegaly. In both cases we need to decrease the secretion or the effect of Growth hormone by one of these methods: How to antagonize GH? 1.Dopamine receptor agonists, ex: bromocriptine 2.Somatostatin analogs, ex: octreotide 3. GH receptor antagonists, ex: pegvisomant Inhibite the secretion of GH Now we ll discuss them: Inhibite the secretion of GH Inhibite the binding of GH to its receptors (antagonist) 1.Dopamine influences Growth hormone release, it inhibits the secretion of GH at the level of pituitary gland and hypothalamus. We give dopamine analogue as the half-life of dopamine is short. 2.Somatostatin is a 14 amino acid inhibitory peptide, it s secreted in the hypothalamus, CNS, pancreas, GIT. Somatostatin has an inhibitory effect on Growth hormone release in addition to inhibiting all the functions of
GIT starting from motility (Anti-diarrheal), secretion of gastrin and secretin, acid secretion and pancreatic secretions including glucagon and insulin. So, Somatostatin lack the specificity in its function on growth hormone (anti-git + inhibit GH release). Octreotide: its an analogue of somatostatin, more specific toward the brain, consequently more active on inhibiting GH secretion than its anti- GIT effect (but still have some activity on GIT). So, it won t inhibit the motility (won t cause constipation) or insulin secretion (won t cause hyperglycaemia) as much as somatostatin. (45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion, and that s what we want). - Its Half-life is around 80 min. - it s Given subcutaneously 3 times a day for treating acromegaly. Therapeutic uses: 1- Reduces symptoms caused by a variety of hormone-secreting tumors, especially for adenomas in the anterior pituitary which secrete growth hormone: acromegaly, carcinoid syndrome, gastrinoma, VIPoma, glucagonoma, insulinoma, and ACTHsecreting tumor. 2- Severe diarrhoea* induced by something, such as: secretory, HIV associated, diabetic, chemotherapy, or radiation induced. 3- Acute control of bleeding from oesophageal varices (portal hypertension). Adverse effect: 1- Hyperglycemia: as octreotide has inhibitory effect on insulin and glucagon secretion, rare and may be transient. 2- Pain at site of injection. 3- GIT effect (as it inhibits GIT functions): nausea, vomiting, abdominal cramps, flatulence, steatorrhea with bulky bowel movements. 4- Vitamin B12 deficiency with long-term use (reduced absorption). 5- The most important adverse effect is to induce Biliary sludge and gall stones (seen in 20-30% of patients after 6 months of use). *Note: mild to moderate diarrhoea is treated by suppurative therapy (water and salts), but if it was severe and induced by something you have to interevent, and sometimes to use strong drug such as octreotide.
6- Sinus bradycardia* (25%) and conduction disturbances in the heart (10%), as a result of inhibiting GH secretion 3.Pegvisomant: it s a GH receptor antagonist (more specific, doesn t affect GIT functions). However, it doesn t replace octreotide and other drugs, but why? Look to the first point of the adverse effects below. - It doesn t affect GH release instead it affects GH binding to its receptors. - Useful for treatment of acromegaly. - Is a polyethylene glycol (PEG) derivative of a mutant GH (modified version of GH). - PEGylation reduces its clearance and improves its overall clinical effectiveness (several polyethylene glycol polymers have been covalently bound in order to slow clearance from blood). - It has increased affinity for one site of the GH receptor and reduced affinity at the second binding site. - This allows dimerization of the receptor but blocks the conformational changes required for signal transduction. - In acromegaly patients the level of both GH and IGF-1 are high when they are treated with Pegvisomant, it Normalizes IGF-1 levels, but does not inhibit GH secretion thus it will remain high. Adverse effect: 1- With long time of usage, it may lead to increased GH level and possible adenoma growth, this adverse effect is the crucial one which makes Pegvisomant doesn t replace other nonspecific GH secretion inhibitors. But why Pegvisomant causes adenomas growth? Because Pegvisomant interferes with GH binding to its receptor and doesn t affect the secretion. So, when it blocks the receptors the body still needs the activity of GH, so it will response through a positive feedback to increase the level of GH, in these patients the level of GH will be twice time as normal GH level, and this is bad as they have already high level of GH (acromegaly or giantism patients). So, continues stimulation and positive feedback response will cause adenoma growth. 2- Elevation of liver enzymes. * Note: growth hormone and somatomedin are known to increase cardiac contractility and heart strength, so inhibiting GH secretion causes bradycardia.
Prolactin We have finished talking about Growth hormone, now well discuss a related topic which is prolactin hormone. Prolactin is a 198 A.A peptide hormone that is also secreted by the anterior pituitary and similar in structure to growth hormone. Its primary function is to stimulate and maintain lactation (breast feeding) in the presence of estrogens, progestins, corticosteroids, and insulin. It s also important in men, high blood prolactin concentration interferes with the function of the testicles, the production of testosterone (the main male sex hormone), sperm production and cause infertility. Low testosterone causes decreased energy, sex drive, muscle mass and strength, and blood count (anemia). Estrogen stimulates prolactin secretion in the pituitary gland cells, that s why there is prolactin secretion during pregnancy. It s also stimulated by TRH. In pregnant women there is a relatively high level of prolactin, so why there is no milk production? Because estrogen inhibits prolactin receptors on milk producing cells Milk production starts in the third day after delivery, when the estrogen level decreases so it won t inhibit prolactin receptors consequently, milk production will occur. During breastfeeding there is a high level of prolactin produced by positive feedback, milk sucking will send neuronal stimulant to the anterior pituitary to release more prolactin thus more milk. Extra note mentioned by the Doctor: How mammary glands produces milk? After delivery when the placenta gets out from the body, estrogen level will return normal and prolactin will bind to its receptors to produce milk. Prolactin binding will activate JAK/STAT signalling pathway which increase the transcription and translation of several proteins, also it will open transporters in these glands to pick up minerals, IgG, IgM and other substances from mother s blood. For that reason, breastfeeding is sufficient to feed infants in the first 6 months even without give them water and it will give them a great immunity (read about this topic, it s very interesting).
Too much prolactin inhibits the release of GnRH from hypothalamus, so Hyperprolactinemia causes hypogonadism (FSH and LH) and this leads to: In women infertility, oligomenorrhea or amenorrhea, and galactorrhea in premenopausal women. In men loss of libido, erectile dysfunction and infertility - The prolactin-inhibiting hormone is dopamine. - Dopamine agonists are used to manage hyperprolactinemia. *If the nursing mother doesn t produce sufficient milk its not applicable to give her prolactin as prolactin half-life is short (However, it works in animals), instead we antagonize dopamine effect. * Hyperprolactinemia is the most common disorder of the anterior pituitary gland. How to antagonize Hyperprolactinemia? By giving dopamine* agonist As dopamine has negative activity on prolactin production. In reality we don t give dopamine as most of it is broken down in the periphery and doesn t reach CNS. So, instead we give dopamine agonist. The simplest one is Bromocriptine, it is given as one shot to inhibit lactation and suppress breastfeeding. Pharmacodynamics: 1- Suppress prolactin release effectively in patients with hyperprolactinemia. 2- GH release in acromegaly is suppressed but less effectively**. 3- Improve motor function and reduce levodopa requirements in Parkinson s disease. Note that Dopamine agonists differ from each other by the half-life and the dosage, as shown in the following table: Cabergoline 65 hours Twice weekly, or once daily with small dose Quinagolide 20 hours Once daily Bromocriptine 7 hours 3 times daily * Dopamine is also called prolactin inhibiting hormone PIH **if you forget it refer to page 2, point 1
Therapeutic uses: 1- Hyperprolactinemia: Shrink pituitary prolactin-secreting tumors. Lower circulating prolactin levels. Restore ovulation in ~ 70% of women with microadenomas and ~ 30% of those with macroadenomas. 2- Suppression of physiologic lactation to prevent breast engorgement when breastfeeding was not desired. (discouraged use, as breastfeeding is desired for infants). Too much milk within the breast without sucking it by the baby will cause breast engorgement, this will increase the pressure and cause fever to the mother, so she need to go to hospital and suck the milk. 3- Acromegaly. 4- Parkinsonism Adverse effects: 1- Remember when we took anti-emetics in the GIS, we said that they work on dopamine or serotonin, so they are antidopaminergic, as dopamine and dopamine agonists cause Nausea, vomiting, headache, fatigue and light-headedness. 2- Orthostatic hypotension remember that dopamine has kidney dose, cardiac dose and vessels dose as it binds to alpha and beta receptors depending on the dose. The kidney dose dilates the vessels of the kidney thus increase the perfusion, so it decreases the pressure and causes Orthostatic hypotension. 3- Psychiatric manifestations even at lower doses and may take months to resolve (don t appear in all patients). Our life and personality are based on dopamine, serotonin and norepinephrine. Dopamine is responsible for excitement and movement*. Schizophrenia patients have hallucinations and positive thoughts, and this is due to excessive dopamine, so they are treated with dopamine antagonist. Consequently, patients who take dopamine agonists suffer from schizophrenia and psychiatric manifestations. * Dopamine controls movement, Parkinson patients have low dopamine level, so they are treated with dopamine or dopamine analogue.
4- Erythromelalgia (paroxysmal throbbing and burning pain in the skin, affecting one or both legs and feet, sometimes one or both hands). 5- Pulmonary infiltrates with chronic high dose therapy 6- No apparent increase in spontaneous abortion or congenital malformations if given during pregnancy for macroadenomas. 7- Stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation. Dr.Malik advice you to revise prolactin physiology We ve finished our talking about prolactin you deserve 15 minutes break Now let s continue Thyroid gland it s very important as thyroid gland disorders (hyper, hypo) are common among ladies (female: male 4:1). Thyroid gland physiology: pituitary gland is stimulated by TRH (Thyroid releasing hormone) from hypothalamus to release TSH (Thyroid stimulating hormone), which act on thyroid gland and stimulate it to release T3 and T4. Hypothalamus is stimulated to release TRH by cold (as thyroid hormone increases body temperature), acute psychosis*, circadian and pulsatile rhythms. Sever stress inhibits the release of thyroid hormones by acting on hypothalamus gland and inhibiting TRH secretion. T3 and T4 affect hypothalamus and pituitary gland by feedback inhibition to decrease the release of TRH and TSH. All these words are summarized in the following figure (see the next page): * it s a symptom of serious mental disorder, acute psychosis is caused by hypothyroidism, so it stimulates the hypothalamus to increase TRH level and consequently T3 and T4 level
Before we start pharmacology and learn how to treat hypo/hyperthyroidism we should revise the thyroid hormones (we took them in physiology if you remember : )). - Thyroid gland releases two hormones from follicular cells, they are T3 (triiodothyronine) and T4 (thyroxin). - Thyroid gland is a trapper for iodide (uptake iodide from all the body). - Thyroid gland has Co-transporter for iodide, when iodide enter the cell it s converted to organic iodine by peroxidase enzyme, then iodine binds to tyrosine residues within thyroglobulin molecule, if one iodine bind to one tyrosine the resulting molecule will be mono tyrosine and if two iodine molecules bind to one tyrosine residue the resulting molecule will be diiodotyrosine. - Then coupling occurs: Monoiodotyosine + Diiodotyrosine Triiodothyronine (T3) Diiodotyrosine + Diiodotyrosine Tetraiodothyronine (T4/Thyroxine) - Until now the products are present in the follicles, but how they are secreted? T3 and T4 within thyroglobulin molecule are back to the cells by pinocytosis, then thyroglobulin is cleaved by protease within the lysosomes to produce free T3 and T4 which are stored in the gland and then released to the blood upon stimulation.
- The free forms of thyroid hormones, T4 and T3, dissociate from thyroid-binding proteins, enter the cell by the active transporters. - Within the cell T4 is converted to T3 by 5'deiodinase. - T3 enters the nucleus where it binds to a specific T3 receptor protein. - The T3 receptor exists in two forms, α and β. Notes: T4 is secreted in larger amount but the active form is T3 (the potency is 4 for T3 and 1 for T4), so T4 is converted to T3 inside the cell by deiodinase. There are drugs prevent the conversion of T4 to T3, and others inhibit the secretion of T3 and T4 (we ll discuss them in detail Inshallah). - Activation of nuclear receptor leads to increased formation of mrna and subsequent protein synthesis (delay in onset of action hours-days). - Affinity of the receptor for T4 is about 10 times lower than T3. - The number of nuclear receptors may be altered to preserve body homeostasis. Remember: We studied that there are 4 types of receptors; G protein coupled receptors, enzyme linked receptors, channels ligand and intracellular receptors, thyroid hormone receptors are example on intracellular receptors the main feature of intracellular receptors is delayed function (it may take days), as they are work on nucleus, genes transcription and proteins translation. - The receptors of thyroid hormones are distributed in all the cells of the body, so their function and effect will be distributed. - Thyroid hormones Normalize growth and development, body temperature, and energy levels, aslo they are used as thyroid replacement therapy in hypothyroidism. - The half-life of T4 is 7 days while it s only 1 day for T3, there is a huge difference between them. Both T3 and T4 are bound to a carrier protein in the blood, some of them are free to do their activities*. *remember from physiology we said that the majority of these hormones are bound to carrier protein while only little amount are free to be functional).
This figure summarizes the previous steps. But in case of hypothyroidism what we ll give the patient T3 or T4 and why? In most cases we give T4 due to its long half-life compared to T3, but in some cases when we need rapid action we give T3 (severe hypothyroidism) to save that patient from lethal coma. From slides: T4 & T3 are available for replacement therapy as levothyroxine and liothyronine, respectively. T3 is not recommended for routine replacement therapy because of its shorter half-life (24 hours), requiring multiple daily doses, and difficulty in its monitoring by conventional laboratory tests. It is also more cardiotoxic. T3 and T4 increase the basal metabolic rate in the body, the temperature and cardiac output. If there is hypersecretion the patient will present tachycardia and arrythmia, so don t give T3 except for the sever cases which need rapid action other wise there is a likelihood to develop hyperthyroidism manifestations especially tachycardia and arrythmia, as T3 is difficult to be monitored.
Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy 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), which permits once-daily to weekly administration. How to diagnose your patient with hyper/hypothyroidism? By TSH level (not T3 and T4). In hypothyroidism T3 and T4 may be normal or low but TSH will be high, while in hyperthyroidism T3 and T4 maybe normal or high but TSH will be low. Finally, we reach the pharmacology part How to treat hyperthyroidism? BY Antithyroid drugs: 1- Thionamides Propylthiouracil (PTU) Methimazole Carbimazole (pro-drug converted to methimazole 2- Iodides, it is dose dependent; too much iodide will inhibit the production of T3 and T4, but in low amount it will decrease the production of T3 and T4 (will be discussed later Inshallah). 3- Radioactive iodine (I 131 instead of I 128); radioactive iodine will kill the surrounding cells by radiation. 4- Iodinated Contrast Media 5- β-adrenergic Blockers; they don t affect the thyroid gland, they work in peripheral tissue by inhibiting the conversion of T4 to T3, this will decrease the activity of thyroid hormones. Now we will talk about each type in detail 1- Thionamides They are the most commonly used drug for hyperthyroidism. Pharmacodynamics (the mechanism of action): 1. Prevention of thyroid hormone synthesis by inhibiting thyroid peroxidase and blockade of iodine organification.
2. Block coupling of iodotyrosines. 3. PTU (Propylthiouracil) also blocks the peripheral conversion of T4 into T3 by 5'-deiodinase (similar to β-adrenergic Blockers). This drug reduces the synthesis of T3 and T4 The effect is slow requiring 3-4 weeks before stores of T4 are depleted; in other words, the half-life of T4 is 7 days, remember from pharmacokinetics we need 5 half-life to eliminate it totally from the body, so it takes 3-4 weeks to deplete all T4 stores in the thyroid gland. To make sure that you get the idea: Summary: A middle age female patient with hyperthyroidism clinical features come to your clinic, after testing TSH level and find it low you confirm the diagnosis, then you decide to treat her with thionamides as they are the most commonly used drug, when the patient start to take the drug the synthesis of T3 and T4 will be stopped, T3 will be eliminated rapidly from the body as its half-life is short, while T4 will need 3-4 weeks as its half-life is longer. The key words are marked with pink The members of Thionamides family: Methimazole is ~ 10x more potent than propylthiouracil and is the drug of choice in adults and children, except pregnant women. Propylthiouracil should be reserved for use during the first trimester of pregnancy, in thyroid storm, and in those experiencing adverse reactions to methimazole (other than agranulocytosis or hepatitis). Both drugs can cross placenta and accumulate in fetal thyroid and cause hypothyroidism. This is a disaster for the baby as if he/she doesn t be treated rapidly before 6 month of post-uterine life he/she will be mentally retarded (in most countries including Jordan the level of TSH, T3 and T4 MUST be tested in newborn babies). Note that She is written in bold because it is more common in females. But PTU less readily so because of high protein binding, actually 99% of PTU will be bound to a protein and only little amount will be free to
function so it isn t secreted in breast milk or cross the placenta in sufficient quantities, this is the only case at which we prefer to use PTU instead of methimazole. The end result: always the drug of choice is methimazole except for pregnant women we use PTU due to the reason mentioned above. We don t like to use PTU in other cases as it is a bad drug and has adverse effects; the most dangerous one is Severe may be fatal hepatitis, so it s a contraindicated drug and you need a reason to prescribe it and the only reasons are pregnancy or in case of thyroid storm (Thyrotoxicosis). The others adverse effects will be continued in the next lecture Inshallah The last thing to talk about is the half-life: The half-life of PTU is 1.5 hours and given every 6-8 hours, while the half-life of methimazole is 6 hours and given once daily, you may think how this occurs. the answer is that there are two half-life for these drugs one in the plasma and the other in the thyroid gland itself, in the thyroid gland they will act longer (4 times more than the normal half-life), remember that the shorter half-life is associated with more rapid action, so PTU will go to thyroid gland rapidly as it has shorter half-life in plasma (1.5 h), but on the other hand you only need to give it every 6-8 hours (remember it is given in thyroid storm when there is very high production of T3 and T4)that is because it s half-life in the thyroid gland itself is longer, while methimazole will go to thyroid gland slower than PTU as it has longer half-life (6 hours) and you give it only once daily also because it has longer half-life in the thyroid gland. Again, to catch the idea read the mind map in the sheet index (the following page :p) Best of luck And Sorry for any mistake
Sheet index: you have a patient with hyperthyroidism, what you will do? Hyperthyroidism patient Surgery Subtotal thyroidectomy, the surgeon removes all the thyroid gland except 5% to avoid hypothyroidism, it s a difficult surgery and not preferable so go toward treatment Treatment Is she pregnant? / or is this a case of thyrotoxicosis? PTU yes NO methimazole