IMCP Exam 2 Study Guide PDF

1. Describe the basics of the hypothalamus-pituitary axis including the feedback mechanisms involved in regulating hormone release? Hypothalamus produces hormones/biomolecules to stimulate or inhibit the pituitary gland, which responds by synthesizing and releasing specific hormones...

1. Describe the basics of the hypothalamus-pituitary axis including the feedback mechanisms involved in regulating hormone release? Hypothalamus produces hormones/biomolecules to stimulate or inhibit the pituitary gland, which responds by synthesizing and releasing specific hormones that enter circulation. These hormones then act on specific endocrine glands/tissues that respond by producing a biological effect. 2. Compare and contrast the pituitary and hypothalamus hormones including where they are synthesized, target receptor type, and physiological effect(s)? The hypothalamus releases growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), thyroid-stimulating hormone (TSH), and dopamine. The anterior pituitary gland releases growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. The posterior pituitary gland releases the hormone anti-diuretic hormone (ADH) and oxytocin. The hormones released from the hypothalamus triggers the release of the subsequent anterior pituitary hormones and electrical signals stimulate the release of hormones from the posterior pituitary gland. 3. What drug(s) would you use in treating GH deficiency disease? Describe their specific MOAs: Somatropin: agonist at growth hormone (GH) receptors in tissue which leads to increase GH levels Mecasermin: agonist at IGF-1 receptors in liver, bone, etc. helps patients who are non-responsive to exogenous GH therapy. 4. What drug(s) would you use in treating Acromegaly or Gigantism and why are they effective? Somatostatin: binds SST receptors which prevents excessive GH release (acromegaly/gigantism) Octreotride/Lanreotide: agonist at SST receptors which helps prevent excessive GH release via mimicking somatostatin. Pegvisomant: competitive antagonist at GH receptors which blocks active site where GH binds to 5. What is IGF-1? Insulin-like growth factor 1, inhibits insulin secretion and hepatic glucose production 6. What is SST? Somatostatin, hormone that binds to SST receptors to prevent GH release 7. Describe the mechanism of action (MOA) for mecasermin: agonist at IGF-1 receptors in liver, bone, etc. helps patients who are non-responsive to exogenous GH therapy. 8. Which drugs that are used to treat hypothalamic/pituitary endocrine disorders can interfere with glycemic control? Which drug has the highest likelihood of causing hypoglycemia and why? Somatropin and mecasermin are both used to treat hypothalamic/pituitary endocrine disorders and can interfere with glycemic control because they stimulate IGF-1, which in turn inhibits insulin secretion and hepatic glucose production. Mecasermin is known to enhance the hypoglycemic effects of other diabetic agents due to the reasons stated above. 9. Which drug must be administered subQ due to the adverse effects it may cause if administered IV? Mecasermin 10. Which drug(s) are used to control prolactinemia and what is their mechanism of action? Bromocriptine: slightly selective D2 receptor agonist which is used to suppress pituitary secretion of prolactin Cabergoline: agonist that has higher D2 selectivity and can return the body to normal prolaction levels after dosage. 11. Of those drugs listed in Q\#10, which one has the longest half-life; and, which one is most likely to cause nausea, vomiting, and orthostatic hypotension? Cabergoline 12. Which drug, used to treat a hypothalamus/pituitary endocrine disorder, must be taken with a snack or small meal to avoid the patient having a hypoglycemic episode? Mecasermin 13. Compare and contrast goserelin, leuprolide, and degarelix in terms of their MOA, pharmacological benefits, and onset to effect: Goserelin and leuprolide are referred to as GnRH receptor super agonists and exert similar MOA, physiological effects, clinical indications, and side effects as endogenous GnRH. The main difference between Goserelin and leuprolide is that goserelin is contraindicated in pregnant patients whereas leuprolide is not. Degarelix is referred to as a GnRH receptor antagonist, and which reduces downstream endogenous production/secretion of LH & FSH and gonal steroids. 14. How does nafarelin differ from goserelin? Nafarelin and goserelin are both GnRH receptor super agonists, but nafarelin is typically administered as a nasal spray whereas goserelin is typically administered as a subcutaneous implant. 15. Which drugs covered in this section (hypothalamic -- pituitary endocrine pharmacology) are contraindicated during pregnancy; and why? Urofollitropin (Bravelle), follitropin alpha (Gonal-F), follitropin beta (Follistim), menotropins (Menopur, Repronex), choriogonadotropin alpha (Ovidrel), chorionic gonadotropin (Pregnyl, Profasi), GnRH super agonists like Gonadorelin (Factrel), Goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These drugs are all contraindicated in pregnancy due to their ability to yield high levels of FSH which indicates primary ovarian failure as well as the fact that ovarian hyperstimulation syndrome (OHSS) is a severe adverse drug event. 16. What is cabergoline and why is its useful as a pharmacological agent? Cabergoline (Dostenix) is a drug used for hyperprolactinemia that has increased selectivity for D2 dopamine receptors. 17. What other drug has the same clinical usefulness as cabergoline? Bromocriptine (Parlodel) 18. What is the MOA and PK for cabergoline; what DDIs are associated with this drug? The MOA for cabergoline is that it is an agonist drug that has heightened selectivity for dopamine D2 receptors; dopamine inhibits prolactin release via these receptors on lactotropes. The PK for this drug is that it does not undergo CYP metabolism, but rather extensive hepatic hydrolysis which and has a half-life of approximately 65 hours. The DDIs associated with this drug are alpha receptor agonists like clonidine, beta receptor agonists like albuterol, and anti-psychotics like aripiprazole. 19. Describe MOA(s) for desmopressin and conivaptan; and how do they exert their pharmacological effects: The MOA for desmopressin (DDAVP) is that it is a relatively selective agonist at V2 vasopressin receptors. The MOA for conivaptan (Vaprisol) is that it is an antagonist at V1a and V2 vasopressin receptors. Desmopressin decreases water excretion in the renal collecting duct cells and stimulates V2 receptors to increase Factor 8 and von-Willebrand factors outside of the kidneys. The physiological effect of conivaptan is that it increases renal excretion of water in the collecting duct. 20. Explain the clinical usefulness/conditions when you would use the two drugs listed above, and what different type of patients would they help? Desmopressin and conivaptan are useful clinically because they both regulate water balance in the body but do so in opposite ways. Desmopressin is used to reduce urination and would help someone suffering from diabetes insipidus, because they are producing too little ADH and are dehydrated due to excessive urination. Conivaptan is used to stimulate urination and could help someone suffering from SIADH because they are producing too much ADH and are retaining too much water. 21. What drug(s) covered in this section would help with diabetes insipidus and how does it help the patient? Desmopressin would help someone suffering from diabetes insipidus, because they are producing too little ADH and are dehydrated due to excessive urination. 22. What type of drugs are octreotide and lanreotide, and what is their MOA? Octreotide and lanreotide are somatostatin (SST) analogs and their MOA is that they both are agonists at SST receptors. Octreotide is an agonist at SST receptors 1-5 and lanreotide is an agonist at SST receptor 2 and 5 only. 23. What drug is used to treat a patient with hyponatremia? How does the drug correct the sodium levels? Conivaptan is used to treat a patient with hyponatremia because it helps reduce the inappropriate water retention of an individuals suffering from SIADH or edema secondary to heart failure. 24. List three (3) major (significant) adverse effects associated with octreotide and lanreotide? Bradycardia, inappropriate blood sugar levels (hypoglycemia or hyperglycemia can occur), and impaired thyroid function (generally hypothyroidism). 25. What side effects are associated with FSH analogs? Which one is specific to males? Side effects that happen in both sexes include headache, depression, and edema. A side effect that is specific to just males is gynecomastia. 26. How is TSH similar and different from LSH and FH? (compare & contrast) TSH, FSH, and LH are all released from the anterior pituitary gland, however TSH release is regulated by thyrotropin-releasing hormone (TRH) whereas the release of LH and FSH are stimulated by gonadotropin-releasing hormone (GnRH). 27. Briefly describe the 5 key steps in biosynthesis of the thyroid hormones: 1) Uptake of iodine I^-^ by the gland via NIS (Na^+^/I^-^ symporter) 2) Oxidation of iodide; iodination of tyrosyl groups on thyroglobulin 3) coupling of iodotyrosine residues by ether linkage -\> iodothyronines 4) resorption of thyroglobulin colloid from lumen into the cell 5) recycling & reuse of I^-^ in thyroid cells via de-iodination of MITs/DITs 6) proteolysis of thyroglobulin; release of thyroxine (T~4~) and triiodothyronine (T~3~) into circulation 7) conversion of T4 to T3 in peripheral tissues and thyroid gland. 28. List the drugs and biomolecules that can interfere in the biosynthesis of T3/T4 and where in the process they interfere: Propylthiouracil and methimazole both block the biosynthesis of T3/T4. Propylthiouracil inhibits thyroidal peroxidase (TPO) as well as 5' deiodination activity, whereas methimazole only inhibits TPO but is 10x more potent than PTU. 29. Compare and contrast the thyroid hormones (TSH, T3, T4, rT3) including endogenous ligand, receptor type, potency, half-life, and physiological effect(s)? TSH: TSH itself is the ligand, its receptor type is a G protein-coupled receptor (GPCR) on the thyroid gland, its potency indirectly affects T3 and T4 production, its half-life is approximately 1 hour, its physiological effects are that it stimulates the thyroid gland to produce and release T3 and T4. Triiodothyronine (T3): T3 itself is the ligand, its receptor type is a nuclear receptor, it is the most potent thyroid hormone (5x more potent than T4), its half-life is approximately 1 day, its physiological effects are that it increases basic metabolic rate and affects protein synthesis as well as influences growth and development. Thyroxine (T4): T4 itself is the ligand, its receptor type is converted to T3 and binds to nuclear receptors, its potency is less potent than T3, its half-life is approximately 7 days, its physiological effects are that it serves as a precursor to T3 which regulates metabolism and energy balance. Reverse triiodothyronine (rT3): rT3 itself is the ligand, its receptor type does not bind effectively to thyroid hormone receptors, its potency is that it is biologically inactive, its half-life is approximately 0.2 days, and its physiological effects are that it is considered an inactive form of T3 so it acts as a regulatory mechanism to decrease T3 activity. 30. What biomolecules / drugs inhibit the synthesis / release of TSH from the anterior pituitary, you should be able to list at least 5 examples? T3/T4, somatostatin, dopamine, glucocorticoids and retinoids can all inhibit the release of TSH. 31. What transporter is used by T3/T4 for uptake into peripheral tissue/cells? Monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide (OATP1C1). 32. What drugs decrease peripheral levels of both T3 and T4? Drugs that induce hepatic microsomal enzymes such as rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, and HIV protease inhibitors increase the metabolism of both T3 and T4. 33. What drugs lower T3 but raise rT3 levels and why? Drugs such as amiodarone, iodinated contrast media, beta blockers, and corticosteroids inhibit the 5'-deiodinase necessary to mediate the conversion of T4 to T3, which results in low T3 and high rT3 levels in the serum. 34. What drug(s) would you use in treating hyperthyroidism? Drugs that inhibit hormone synthesis (propylthiouracil, methimazole, carbimazole), iodides (KI, NaI, iodinated contrast media), anion inhibitors (perchlorates, thiocynates), and beta blockers (propranolol). 35. What drug(s) would you use in treating hypothyroidism and how are they different? Levothyroxine (Levothyroid or Synthroid), liothyronine (Cytomel), or liotrix (Thyrolar) are all "synthetic" T3/T3 hormones. Thyroid (Armour Thyroid) is what is known as a "desiccated" thyroid supplement. 36. Describe the mechanism of action (MOA) for thioamides and what drugs fall in this drug class? The major action of thioamides is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. They also block coupling of iodotyrosines. Methimazole, propylthiouracil, and carbimazole fall under this drug class. 37. What DDIs occur with propylthiouracil? Consider those where propylthiouracil impact the effectiveness of the other drug as well as those drugs that impact the effectiveness of propylthiouracil. Amiodarone and iodide reduce the effect of propylthiouracil (PTU). Warfarin effects are also decreased due to inhibited T3/T4 levels as a result of PTU usage. 38. Compare and contrast levothyroxine, liothyronine, and liotrix in terms of their composition, pharmacological benefit and their MOA: Levothyroxine: 100% synthetic T4 hormone, precursor to T3 that is a ligand and is an agonist for TR, the pharmacological benefit is to treat hypothyroidism. Liothyronine: 100% synthetic T3 hormone, agonist at nuclear T3 receptors (with higher binding affinity than T4), the pharmacological benefit is to treat hypothyroidism. Liotrix: 20% T3 and 80% T4 synthetic hormone, agonist at T3 receptors (transcription/translation genes), the pharmacological benefit is to treat hypothyroidism. 39. What adverse effects and DDIs are associated with these drugs? Adverse effects experienced from taking thyroid supplements include fatigue, heat intolerance, palpitations, increased blood pressure, or headache, GI upset, and osteoporosis from chronic use. The drug-drug interactions associated with taking thyroid supplements are that they increase anti-coagulant responses, decrease insulin/oral hypoglycemic effectiveness, as well as decrease digoxin levels due to T4 expression of the sodium/potassium pump. 40. Compare and contrast propylthiouracil, methimazole, and potassium iodide in terms of their structure, pharmacological benefit, pharmacokinetic parameters and their MOA: Propylthiouracil inhibits thyroidal peroxidase (TPO) and 5' deiodinase and has 1/10^th^ the potency of methimazole. It is highly protein bound and readily absorbed with a half-life of 75 minutes. Methimazole inhibits TPO only because it lacks 5' deiodinase inhibitory activity. It has a high bioavailability (approximately 80-95%) and has a half-life of 4-6 hours. Potassium iodide competitively inhibits iodide transport via the NIS (Na^+^/I^-^ symporter). It has clinical uses of treating thyroid storming and is often used as for pre-operative preparation for surgical treatment. 41. What is the purpose of using beta-blockers in patients with thyroid disorders and when is it appropriate to use them? Beta blockers cause clinical improvement of hyperthyroid symptoms such as an increased heart rate, and are typically given to hypothyroid patients starting thyroid supplement therapy to prevent rebound tachycardia. Is it appropriate to use any beta-blocker or which ones are most appropriate? When would esmolol be used? You must use beta blockers without intrinsic sympathomimetic activity such as metoprolol, propranolol, and atenolol. Propranolol is generally viewed as the best option because it can also prevent the conversion of T4 to T3. Esmolol would be used in a critical care setting for something like a thyroid storm because it allows for rapid titration and control of the heart rate due to its very short half-life. 42. What would you use as an alternative to a patient who has cardiac problems that does not respond to beta-blockers? Calcium channel blockers could be a good alternative.