Pharmacology of Pituitary Agents PDF Fall 2024

PHRM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN For you created my inmost being; you knit me together in my mother’s womb. I praise you because I am fearfully and wonderfully made; your works are wonderful, I know that full well. Psalm 139:13-14  Abbreviation AC...

PHRM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN For you created my inmost being; you knit me together in my mother’s womb. I praise you because I am fearfully and wonderfully made; your works are wonderful, I know that full well. Psalm 139:13-14  Abbreviation ACTH- Adrenocorticotropic ▪ PTH – Para Thyroid Hormone Hormone TRH- Thyrotropin Releasing ADH – Antidiuretic Hormone Hormone FSH- Follicle Stimulating GR- glucocorticoid receptor Hormones LH - Luteinizing Hormone PR- progesterone receptor GH- Growth Hormone DI- diabetes insipidus GHRH- Growth Hormone DM- diabetes mellitus Releasing Hormone SHBG- sex hormone binding GnRH = LHRH – Gonadotropin / globulin Luteinizing Hormone Releasing HPA- hypothalamic pituitary Hormone adrenal axis  Somatostatin =Somatotropin  IGF – Insulin-like Growth releasing inhibiting factor Hormone  SSA- Somatostatin Analogues  PRL- Prolactin  SC - sub cutaneous  BG- blood glucose  IM - intramuscular  GC – glucocorticoids  TID - three times daily  CS- Cushing’s syndrome  DA – dopamine  MPA – medroxyprogesterone  d/c- discontinued At the end of this lecture and after studying the material, the student should be able to : 1. Identify drugs useful to treat acromegaly, their MOA and ADRs 2. Identify relationship between DA, GH, prolactin and acromegaly 3. Identify MOA, ADRs, DDI of recombinant human growth factor 4. State MOA, drug classes, ADRs, and DDI of drugs to treat Cushing syndrome 5. Identify MOA, use and ADRs of spironolactone 6. Identify drugs useful to treat Addison and how to take the drugs 7. Identify MOA, use of oxytocin and Atosiban 8. Identify drugs that can induce hyper-PRL 9. Identify ADRs of glucocorticosteroids Note: you are responsible to know drug names of every class and underlined ADR  Hyperfunction of glands ▪ Hyper-PRL (pituitary) ▪ Acromegaly (pituitary) ▪ Cushing syndrome (adrenal) ▪ Hyperaldosteronism (adrenal)  Hypofunction of glands ▪ Hypogonadism (pituitary) ▪ Hypo-PRL (pituitary) ▪ Short stature (pituitary) ▪ Addison’s (adrenal) ▪ 2nd adrenal insufficiency (adrenal) ▪ Hypoaldosteronism (adrenal) www.medem.com Hypothalamic hormones Anterior pituitary Target organ Organ hormone or hormones mediators GHRH (+ stimulate) GH Liver, muscle, bone, IGF-1 Somatostatin (- inhibit) (Somatropin) kidney TRH (+) TSH Thyroid T3, T4 LHRH (+) = GnRH FSH, LH Gonads E, P, T Dopamine (-) PRL Breast - CRH (+) ACTH Adrenal cortex Glucocorticoid, Mineralcorticoid, MSH (ACH and MSH Androgens from POMC)  All these hormones act through G protein coupled receptors in the pituitary, except GH and prolactine, which act through JAK/STAT receptors.  In the target organ, many act through superfamily of nuclear receptors. Katzung, Basic and Clinical Pharmacology, 2019  Amine hormones are derived from tyrosine or tryptophan Norepinephrine, Epinephrine, T4, T3, melatonin, dopamine  Polypeptide/protein hormones are chains of amino acids ADH, GH, insulin, oxytocin, glucagons, ACTH, PTH, LHRH  Glycoproteins hormones have peptide and oligosaccharide chains LH, FSH, TSH, EPO  Steroids are lipids derived from cholesterol Testosterone, estrogen, progesterone, glucocorticoids, mineralcorticoids, 1,25 dihydrocalciferol (vit D)  Acromegaly : GHA, SSA, DA agonist  Short stature: recombinant growth factor  Cushing syndrome: aminoglutethimide, metyrapone, ketoconazole, osilodrostat, mifepristone, cyproheptadine, mitotene  Addison’s disease: glucocorticoids, DHEA, mineralcorticoids  Aldosteronism: Spironolactone, eplerenone, amiloride  Hyperprolactin: bromocriptine, cabergoline  Oxytocin and oxytocin receptor antagonist  Due to: Increased production of GH and IGF-I during adulthood  Treatment Goals: Decrease Growth hormone (GH) and Insulin like growth hormone (IGF); Improve signs and symptoms; Decrease risk of complications associated with mortality Drugs: GH antagonists, somatostatin (SSA) analog, Dopamine agonist.  Possible Etiologies: ▪ GH-secreting pituitary adenoma ▪ Ectopic GH-secreting adenoma ▪ Excess GHRH secretion 1. GH antagonist (GHA) MOA: binds to GH receptors in liver and inhibits IGF. ✓ Does not inhibit GH production, but block the physiologic effects of GH on the target tissues. Drug: Pegvisomant (Somavert®) ADR: hepatoxicity, LFT , nausea, diarrhea, pain at injection site. Need dose adjustment in hepatic impairment (see additional slide)  2. Somatostatin analogues (SSA) MOA: inhibit GH and IGF1 45 times more potent than endogenous somatostatin Also inhibit gastrin, insulin and glucagon- monitor can cause hypoglycemia or hyperglycemia Drugs: Octreotide, Lanreotide ADRs: nausea, flatulence, gallstones, bradycardia, deficient in vitamin B12, chest pain, hyperglycemia in type II DM, severe hypoglycemia in type I DM, malaise, fever, diarrhea/abdominaldiscomfort ( happen in75% , but  after 10- 14 days) t½ - 80 mins, endogenous t 1/2 3 mins (see additional slides ) 3. Dopamine MOA:  GH,  IGF,  PRL A. Bromocriptine (Parlodel®) Duration is shorter for treatment of acromegaly, longer for hyperprolactinemia. Prefer for pt desiring to be pregnant ADRs: nausea, HA, ortostatic hypotension, fatigue, abdominal pain B. Cabergoline  Drug of choice to treat micro- or macro-prolactinemia.  Useful in patients with pituitary tumor that secrete excess PRL and/or GH, or resistant to bromocriptine.  Long acting drug (t1/2 is 65 hr) and have high selectivity  ADRs: same like bromocriptine, but less ADR (see other slide) Class Available Agents Advantages Disadvantages Somatostatin Octreotide Rapid decrease in GH & GI ADRs (75% of patients) Analogues (SC TID, IM q 4 wks) IGF-I (50-70% of pts) Risk of gallstones (SSA) Once-monthly injection Lanreotide expensive, difficult to (IM q 2 wks) reconstitute GH Antagonist Pegvisomant Effective in normalizing Increased risk of hepatotoxicity (GHA) (SC daily) IGF-I in > 90% of pts when combined SSA Dopamine Cabergoline PO administration Less effective in decreasing GH & Agonists (PO weekly) Less costly IGF-I Useful for patients with Bromocriptine increased PRL (PO daily) For treatment of: Hyperprolactinemia, Parkinson’s disease Acromegaly In normal adults, using dopamine agonist can cause  GH production. In acromegaly have paradoxical effect →  GH production 1. Bromocriptine is _____ agonist that _____ release of prolactin 2. Cabergoline is NOT us in pregnant women, but have advantages over bromocriptine as ___________, ________________, _______, ______________ 3. Disorders of pituitary include ___________, __________, __________________ 4. Disorders of adrenal are ______________, __________________,__________  Definition: height > 2 standard definitions below population mean and < 3rd percentile for height in age group  Possible etiologies: ▪ Congenital: GH deficiency ▪ Acquired: GH insufficiency ▪ Idiopathic: Non-GH related causes ✓ Secretion is stimulated by GHRH from hypothalamus, inhibited by somatostatin ✓ The growth promoting effect of GH are mediated by IGF-1 and IGF-2  IGF = somatomedin C  Liver produces and secretes IGF-1 in response to GH ▪JAK-Janus Kinase ▪Stat- Signal Transducer and Activator of Transcription Recombinant human growth factor (rhGH) Drugs: Somatropin ® (many preparations) ADR: usually tolerated well. Intracranial HTN: vision, HA, nausea, edema. Hypothyroidism, pancreatitis, gynecomastia, myalgia, fluid imbalance, pain at injection,  ALT and AST ▪ Pregnancy B/C depending on the manufacture DDI: glucocorticoid may inhibit GH effect. GH may induce insulin resistance in DM or cause hyperglycemia Use: ▪ Treat growth failure in pediatric due to inadequate endogenous GH secretion ▪ Treat GH deficiency in adult due to deficiency of GH or other hormones (hypopituitarism), or due to lean body wasting Corticosteroids Primary Function 24-Hr Plasma Secretion Concentration Glucocorticoid Regulates protein, 8-25 mg 0-25 mcg/dL Cortisol carbohydrate, and fat metabolism Mineralcorticoid Maintains electrolyte and 0.15 mg 2-9 ng/dL Aldosterone volume homeostasis by (supine promoting Na+ position, reabsorption and K+ normal sodium excretion diet) Agent Glucocorticoid t1/2 (hrs) Equivalent oral dose (mg) Mineralcorticoid Short-medium acting glucocorticoids -Hydrocortisone 1 8 20 1 -Cortisone 0.8 8, IM 18 25 0.8 -Prednisone 4 16-36 5 0.25 -Prednisolone 5 16-36 5 0.25 -Methylprednisolone 5 18-40 4 < 0.01 Intermediate acting glucocorticoids -Triamcinolone 5 12-36 4 < 0.01 - Fluprednisolone 15 1.5 < 0.01 Long acting glucocorticoids -Betamethasone 25-40 36-54 0.6 < 0.01 -Dexamethasone 30 36-54 0.75 < 0.01 Mineralcorticoid -Fludrocortisone 10 3.5 250 Hydrocortisone = cortisol Fludrocortisone for treatment of insufficiency in mineralcosticosteroids ( adrenal dysfunction) ✓The salt (form) of glucocorticoid does not effect the duration of action when the drug is given orally ▪ Natural cortisol have t 1/2 60-90 minutes in normal condition ▪ Increase level of glucocorticoids in the body during stress ▪ Normal level of glucocorticoids are 10-120 mg secreted daily ▪ Synthetic hydrocortisone – t1/2 depend on the structure of the drug ▪ Prolonged used can cause systemic ADRs ▪ 90% bound to CBG or albumin. 10% free ▪ Prolonged effect seen when given intramuscularly versus oral ▪ Absorb from GI and synovial rapidly, but absorb by skin very slowly ▪ Metabolism mostly by glucuronidation in the liver, and in renal ▪ Administer with meals to avoid GI problems. Increase diet with source for K+, B6, Ca2+, vit. C, Vit D and protein. ▪ Pregnancy: C, except budesonide (B) ▪ DDI: strong inhibitor of CYP34A; avoid alcohol (see next slides) ▪ Monitor: blood glucose, blood pressure, electrolytes ▪ ADRs- many (see next slides) Oral bioavailability: Triamcinolone Flunisolide Beclomethasone Budesonide Fluticasone ▪ Prednisone is prodrug of prednisolone. ▪ Prednisone and prednisolone are the most commonly used oral glucocorticoids ▪ If use oral for more than 2 weeks, can cause systemic ADRs to occur ▪ Need to taper off gradually before discontinuation, to prevent undesirable effects 1. Adrenal suppression ❖ If dose is reduced too fast, symptoms of disease may reappear and intensify ❖It take 2-12 mo for HPAaxis to return to normal, and cortisol level may not return to normal for another 6-9 mo 2. Hyperglycemia ▪ Causing lipolysis → free fatty acids formation ▪ Stimulate gluconeogenesis in the liver. Serum glucose, inhibit reuptake of glucose by muscle  3. Hypertension and hypokalemia ▪  Na+ and water retention, secretion of K+. ▪ Also  vasopressin release →  ability to excrete water load → causing HTN 4. Increased risk of infection (16-18%) ▪ Normal glucocorticoid level is needed to maintain glucose levels to provide energy for body to fight stress due to trauma, infection. ▪ Cortisol cause  lymphocytes → body ability to fight infection ▪ Oropharyngeal candidiasis (need to rinse mouth after each use of inhaler)  5. Osteoporosis ▪ Glucocorticoid alter bone mineral homeostasis: by antagonizing Vit D-stimulated Ca 2+ transport, by stimulating renal Ca 2+ excretion ( resorption osteoclast, and by blocking bone formation (osteoblast precursor) ▪ The imbalance between osteoclast and osteoblast →osteoporosis 6. Catabolic effect ▪ Glucocorticoids causing protein synthesis in liver, but causing  protein breakdown in muscle, fat, skin ▪ Myopathy (weakness of proximal limb muscles) ▪ Excessive protein catabolism and protein wasting ▪ Bruising, thinning of skin 7. Behavioral changes: depression ,insomnia,psychosis, hypomania ▪ Direct effect on the brain (neurosteroids). Effect mood, neuron→ excitability behavior. ▪ Withdrawal of glucocorticoids causing depression, hypomania 8. Peptic ulcer ▪ Stimulates over production of gastric acid and pepsin in stomach →exacerbate ulcer. ▪ Suppress local immune response against H pylori → H pylori become active  9. Weight gain ▪ Stimulate Lipolysis → f.a. ,  fat deposition ▪ Serum glucose, inhibit reuptake of glucose by muscle. appetite 10. Glaucoma, cataracts ▪  Intraocular pressure of the eye 11. Iatrogenic Cushing syndrome ▪ Fat distribution in back (buffalo), neck, face (moon face). Metabolic changes can become serious: myopathy, diversion of amino acids to glucose production, hyperglycemia, osteoporosis, and others. 12. Retard growth ▪ During skeletal growth phase, activity of osteoblast predominates. Glucocorticoids decrease osteoblast precursors ▪ Natural glucococorticoids have less growth suppressing potency than synthetic, even at the “at equivalent doses” Cushing syndrome and how to avoid ( 1 of 11) Drug induced: 1. Glucocorticoids 1. Administer lowest possible dose that will manage the disease (primarily oral therapy) 2. Continue therapy for shortest duration possible 3. Utilize administration routes with least systemic 2. Medroxy absorption ( inhalation, dermal routes) progesterone acetate 4. Administer every other day in the morning 5. Avoid concurrent medications that inhibit glucocorticoid metabolism 6. Gradually decrease dose per day 3.OTC /herbals: 7. Continue to taper dose down until equivalent physiologic Topical hydrocortisone, dose is reached (e.g. 5-7.5 mg/day of prednisone or equivalent magnolia bark, adrenal dose of another glucocorticoid). At this point, may d/c cortex extracts 8. Full recovery of HPA axis may take up to 1 year after d/c. During this time GC supplementation may be necessary during periods of acute stress.  Definition: pathophysiologic changes linked to exposure to high cortisol concentrations (hypercorticolism)  Possible Etiologies: ▪ Exogenous: Drug-induced ▪ ACTH-independent: Primary adrenal adenoma or carcinoma ▪ Endogenous: ACTH-dependent ▪ Pituitary adenoma (Cushing’s disease) ▪ Ectopic ACTH-secreting adenoma  Acne  Buffalo hump  Central obesity  Cutaneous striae  Glucose intolerance  Hirsutism  Hypertension  Menstrual irregularities  Moon face  Myopathy/muscular weakness  Osteoporosis  Psychiatric changes  Virilization Osidrostat Kester M et al. 2007 1. Aminoglutethimide (Cytadren ®) : MOA: - inhibit cholesterol desmolase (1st step) Also inhibits aromatase, but not specific. When the drug is given too long, blocks the ability of the adrenal glands to produce steroids. Has been used with hydrocortisone to eliminate E and T production in breast carcinoma. Absorbed in the gut, excreted unchanged in the urine. ADRs: sedation, nausea, skin rash, anorexia (administer q 6 hr) DDI:  warfarin effect ✓  efficacy and less ADRs when used with metyrapone. Can use lesser dose of aminoglutethamide 2. Metyrapone (Metopirone ®): MOA: inhibit the last step of cholesterol synthesis Steroidogenesis inhibitor Use: test ACTH production (HPA function) ADRs: nausea, sedation, hypertension, hirsutism, acne ( androgen), salt and water retention Administer every 6 hr with foods Only can be obtained through Novartis (for compassionate use) 3. Ketoconazole (Nizoral ®) MOA: inhibit steroidogenesis (at very high dose). ▪ Potent, but not selective inhibitor of gonadal or adrenal synthesis. ▪ It can  E and T ratio by unknown mechanism (can cause gynecomastia) ▪ Anti fungal drugs ADRs:  T,  libido, hepatic enzyme, gynecomastia, nausea, vomiting DDI: many serious interaction Administer with food Highly effective 4. Osilodrostat (Isturisa ®) MOA: inhibitor of 11-beta-hydroxylase enzyme crucial for the cortisol biosynthesis Steroidogenesis Inhibitor Use: For Cushing who can’t undergo pituitary gland surgery or have undergone the surgery but still have the disease ADRs: adrenal insufficiency, fatigue, nausea, headache, edema Monitor: QT prolongation DDI: Cyp3A4 inducer and inhibitor, CYP2D6 inducer 5. Mifepristone (Korlym, Mifeprex ®) MOA: anti progesterone, but also work as glucocorticoid receptors antagonist ✓ Block the binding of steroid hormones to its receptors. Potential agent to block excessive glucocorticoids. Use: termination of early pregnancy /first trimester, emergency contraceptives, treatment of endometriosis, Cushing syndrome, breast ADRs: vomiting, diarrhea, pain, excessive vaginal bleeding, abdominal and uterine cramping, nausea, hypokalemia Restricted use - need prescriber agreement, licensed pharmacies 5. Cyproheptadine (Periactin®)  MOA: central neuromodulators by ACTH release  Reserve for patient who failed other therapy. Response is 3-4 gm of sodium per day ▪ DDI: Diuretics, acetazolamide, CYP enzyme inducers, NSAIDs, some antidepressants, some antibiotics. Use cautiously/avoid  Disease Renin aldosterone BP 1 aldosteron low high high 2 aldosteron high high N Malignant HTN high high high Congenital low low high hyperplasia Cushing Low- N Low-N high Liddle sydndrome low low high Licorise ingestion low high Low-N Low renin HTN low Low-N high  Dipiro JT et al. 2014 http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/Cardio/Cardio_cases/Images/Angiotensin_fig1.jpg  Based on MOA, divided into 2 groups: 1. Na+ channel inhibitors: - amiloride (Midamor®) 2. Mineralcorticosteroids or aldosterone receptor antagonist): - spironolactone, - eplerenone ▪Brenner GM and Stevens CW. Pharmacology 3rd ed, 2010 1. Spironolactone MOA: block mineralcortoid receptors (MR)→prevent formation of aldosterone- induced proteins (AIPs) → indirectly ↓ Na+ channel permeability→ ↓Na+ reabsorption, K+ retention, inhibit aldosterone action. Also inhibit androgen production ▪ Needs several days before full effect is seen. ▪ 40-fold more potent than eplerenone in blocking aldosterone activation of MR Use: ✓ Cushing syndrome (for symptomatic relief of HTN and hypokalemia), ✓ Aldosteronism( inhibit aldosterone biosynthesis in adrenal gland,  HTN) ✓ Diagnosis tool to detect aldosteronism, ✓ Treatment of hirsutism in women, Heart failure ADRs: hyperkalemia, metabolic acidosis, gynecomastia, GI discomfort, fatigue, menstrual irregular, hypotension 2. Eplerenone (Inspra®) ▪ More selective and less ADRs than spironolactone. Role in treatment of hyperaldosteronism has not been proved. ▪ ADRs: hyperkalemia, hypotension, headache 3. Amiloride (Midamor ®) ▪ Less effective than spironolactone ▪ ADRs: hyperkalemia, nausea, vomit, diarrhea, headache ▪ Structure like GH Hypothalamus does not produce hormone that stimulates PRL production (PRL is not regulated by negative feedback) Principles hormone for lactation after childbirth. Release is influenced by E, P, cortisol, and insulin Over production of PRL (due to adenoma or impaired transport of DA) can cause  E Hyperprolactinemia can be due to: ▪ antipsychotic (don’t d/c psychoactive drugs), ▪ DA antagonist, metoclopramide, ▪ TCA, MAOI, SSRI, H2 blocker, ▪ verapamil, methyldopa  Females: acne, amenorrhea, Decreased libido, hirsutism, infertility, galactorrhea, osteoporosis  Males: decreased libido, erectile dysfunction, galactorrhea, gynecomastia, infertility, loss of muscle mass Adapted from Clinical Endocrinology (2006); 65:265-273  Dopamine Advantages Disadvantages Bromocriptine Less costly Less effective in decreasing PRL levels and tumor size Preferred for patients Requires administration of multiple tabs 2-3 x daily desiring pregnancy HA, dizziness, GI discomfort, postural hypotension Cabergoline More effective in More costly decreasing PRL and tumor Efficacy not established beyond 2 years size and restoring gonadal function Increased tolerability Administered 1-2 x per wk Minimum 1 year of therapy. Monitor: serum PRL q 6-12 months once s/sx have resolved. If normal PRL levels and decrease in tumor size were maintained for ≥ 2 years, consider withdrawing agent to determine if patient has achieved remission 1. Drugs that cause increase PRL are _______, _________, _______________, _________, ___________, ___________ 2. Spironolactone are useful to treat __________, _________, ___________, _____ 3. Symptoms of Addison are___ Corticosteroids, ___mineralocorticoids, ___ sex steroids. Showing as _____, _____, ______,_________, ________ 4. Derivative of cholesterol compounds are ____________, _____________, __________________ 1. ADRs of corticosteroids are ______________, _________________, ________________, ______________, _______________, _________________ 2.Supplementation with ___________, ______________, _______________, ____________, ___________ are important when taking corticosteroids 3. Growth hormone related agents are _________,__________,___________, _______. NOT _______ ADR of GH ______________, ___________, ________________ MOA: act through G protein →to contract the uterus to induce labor ❖ Contract mammary gland to cause “milk let down” ❖ E induce oxytocin receptor synthesis  Drug: Oxytocin, IV.  Inactivated in liver and kidney by circulating placental enzyme.  ADRs: excessive stimulation can cause fetal distress, uterine rapture, fluid retention in the mother, hyponatremia, heart failure, hypotension (oxytocin has vasodilator effect). MOA: oxytocin antagonist that prevent uterine contraction, prevent preterm labor ▪ Drug: Atoxiban®  Can  neonatal mortality if used before 28 weeks of gestation  Given as IV, can prolonged the pregnancy for up to 7 days to halt premature labor Drugs useful to treat Cushing syndrome are: A. Steroidogenesis inhibitors _______, _________, ______________, ________ B. Adrenolytic :________________. MOA: ________, ____________, _________ C. _________________, neuromodulator preventing ACTH release D. Korlym ® ___________________, ___________ All these drugs are aiming to _______ corticosteroids ✓ Katzung. Basic and Clinical Pharmacology, 15th ed, 2021 ✓ Various internet as cited ✓ Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition Editors: Brunton, Hilal-Dandan, Knollmann. Publisher: McGraw-Hill, 2023 TSH Class Long-term Outcomes Monitoring Somatostatin Analogues Improvement in sx and serious GH, IGF-I, ultrasonography complications of gallstones if symptoms Decrease in tumor size in only present, BG, GH, HR, EKG, 30-50% of patients vit B12, thyroid function, and ADRs GH-Antagonist Effects on tumor size and LFTs monthly x 6 months, systemic complications unknown MRI yearly, IGF-I, ADRs Dopamine Agonist Possible decrease in tumor size GH, IGF-I, ADRs with cabergoline  Surgery is preferred treatment ▪ 50-9 % efficacy ▪ Alleviates tumor-related neurologic problems ▪ Alleviates co-morbidities associated with active disease ▪ Improves pituitary function and restores hormone deficits Adapted from AACE Acromegaly Guidelines, EndocrPract. 2004; 10(3) Adapted from http:/www.anselm.edu/