HP axis Flashcards
Somatropin, Somatrem
Somatropin = recombinant GH Somatrem = GH analog
Pharmacokinetics
• Active blood levels = persist for ~ 36 h
• Given subcutaneously 3-7 times a week
SE's Children • Generally well tolerated • Hypothyroidism • Intracranial hypertension (rare) • Scoliosis (during rapid growth) • Otitis media (increased risk for Turner Syndrome patients) • Pancreatitis, gynecomastia & nevus growth • Diabetic syndrome (chronic use)
Adults
• Peripheral edema, myalgias & arthralgias (hands & wrists especially)
• Carpal tunnel syndrome
• Proliferative retinopathy (rare)
Contraindications
• Cytochrome P450 inducer
• Patients with a known malignancy
Sermorelin
• GHRH analog
• FDA approved for treatment of GH deficiency
• Generally well tolerated and less expensive than
somatropin (BUT less effective)
• Will not work in patients whose GH deficiency results from defects in anterior pituitary
Adverse Effects
• Same as recombinant GH
Mecasermin
- IGF-1 analog. Complex of recombinant human IGF-1 and recombinant human IGF-binding protein-3. Small number of children with growth failure have IGF-1 deficiency
- Causes: mutations in gene that encodes for GH receptor & development of neutralizing antibodies to GH
SE
• Hypoglycemia (eat 20 min before or after admin.) • Intracranial hypertension (rare)
• Asymptomatic elevation of liver enzymes (rare)
Pegvisomant
• GH rec antagonist. Prevents dimerization of GH recs -> no JAK signaling -> no GH signaling
Octreotide
• SST analog. Inhibits release of GH, glucagon, insulin, and gastrin
Clinical Applications
• Reduces symptoms caused by hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, nesidioblastosis, watery diarrhea, hypokalemia, achlorhydria syndrome & diabetic diarrhea.
• Localizing neuroendocrine tumors
• Acute control of bleeding from esophageal varices
PK
• 45 x more potent than somatostatin
• 2 x more potent in reducing insulin secretion
• t 1⁄2 = ~ 80 min (30 x somatostatin)
• Octreotide acetate long-acting suspension can be given at 4 week intervals
SE
• Nausea, vomiting, abdominal cramps, flatulence, steatorrhea (with bulky bowel movements)
• Constipation
• Biliary sludge & gallstones (20-30% patients after 6 month use)
• Sinus bradycardia (25%) & conduction disturbances (10%)
• Vitamin B12 deficiency (may occur with long-term use)
• Pain at injection site = common (esp. with long-acting)
Bromocriptine, Cabergoline
Pharmacokinetics
• Oral or as vaginal inserts
• Bromocriptine t1/2 = ~7 h
• Cabergoline t1/2 = ~65 h
Clinical Applications
• Hyperprolactinemia. Standard treatment. Dopamine agonists shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in ~70% women with microadenomas & ~30% with macroadenomas
• Acromegaly. Alone or in addition to surgery, radiation or octreotide admin.
SE
• Nausea (bromocriptine>cabergoline), headache, light-headedness, orthostatic hypotension, fatigue
• Psychiatric manifestations occasionally occur
• High doses = cold-induced peripheral digital vasospasm
• Chronic high-dosage therapy = pulmonary infiltrates
Gonadotropin
Menotropins or human menopausal gonadotropins (hMG):
- Purified extract of FSH and LH
Purified FSH :
- Follitropin a and follitropin B (rFSH): recombinant FSH
- Urofollitropin (uFSH): purified human FSH extract
hCG
• Extracted and purified from urine (given IM)
• Choriogonadotropin a (rhCG): recombinant form (given SC)
Pharmacokinetics
• SC or IM injection (usually daily)
Women
• Ovarian hyperstimulation syndrome (ovarian enlargement, ascites, hydrothorax, and hypovolemia. Hemoperitoneum, fever & arterial thromboembolism can occur)
• Multiple pregnancies (15-20%)
• Headache, depression, edema, precocious puberty
Men
• Gynecomastia
GnRH and analogs
• Gonadorelin = gonadotropin-releasing hormone
• Goserelin, leuprolide, nafarelin = gonadotropin- releasing hormone analogs
• GnRH binds to GPCRs on gonadotroph cell membranes
• Pulsatile GnRH secretion is required to stimulate release of LH and FSH
• Sustained nonpulsatile admin. of GnRH inhibits FSH and LH release (men & women) leading to hypogonadism
Chemical Structure
• Gonadorelin = acetate salt of synthetic human GnRH
• Analogs = D-amino acids at position 6 and (apart from nafarelin) have ethylamide substituted for glycine at position 10
• All analogs are more potent & longer-lasting than GnRH / gonadorelin
PK • Gonadorelin = IV or SC • Analogs = SC, IM, nasal spray (nafarelin) or as SC implant • Gonadorelin t1/2 = 4 min Analog t1/2’s = ~3 h
Administration
Continuous administration gives biphasic response:
• First 7 days = agonist response ‘flare’,
• Chronic effects (> 1 week) = inhibitory action (due to receptor down-regulation & changes in signaling pathways)
GnRH and analogs clinical applications
Stimulation
• Female infertility: Use is uncommon (inconvenient & costly)
• Male infertility: In men with hypothalamic hypogonadotropic hypogonadism (pulsatile gonadorelin)
• Diagnosis of LH responsiveness: Whether delayed puberty is due to constitutional delay or hypogonadotropic hypogonadism
Suppression
Agents are more commonly used for suppression of gonadotropin release
• Controlled ovarian hyperstimulation (leuprolide, nafarelin): Critical to suppress endogenous LH surge that could prematurely trigger ovulation
• Endometriosis (leuprolide, goserelin, nafarelin): Pain often decreased by abolishing exposure to cyclical changes in estrogen & progesterone concentrations during menstrual cycle. Treatment limited to 6 months
• Uterine Leiomyomata (fibroids) (leuprolide, goserelin, nafarelin): Can reduce fibroid size and combined with supplemental iron can improve anemia
• Prostate Cancer (leuprolide, goserelin): Combined therapy with continuous GnRH agonist and an androgen receptor antagonist is effective as castration in reducing serum testosterone
• Central Precocious Puberty (leuprolide, nafarelin): Must confirm diagnosis before treatment begins
• Advanced Breast & Ovarian Cancer
• Treatment of Amenorrhea & Infertility in women with Polycystic Ovary Disease
• Thinning of Endometrial lining: Preparation for endometrial ablation procedure in women with dysfunctional uterine bleeding
Gonadorelin SE
- Headache, light-headedness, nausea, flushing
- Swelling at SC injection site
- Generalized hypersensitivity dermatitis (long-term admin.)
- Rare acute hypersensitivity reactions
- Sudden pituitary apoplexy & blindness (reported in patients with a gonadotropin-secreting pituitary tumor)
GnRH analogs - SEs in continuous treatment
Women
• Menopausal symptoms (hot flushes, sweats, headaches)
• Depression, diminished libido, generalized pain, vaginal dryness & breast atrophy can occur
• Ovarian cysts (generally resolve)
• Reduced bone density & osteoporosis (long treatment)
Contraindications
• Pregnant and breast-feeding women
Men
• Hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, & injection site reactions
Certrorelix, Ganirelix
• Competitive antagonists of GnRH recs
Clinical Applications
• Suppression of Gonadotropin Production: Prevent LH surge during controlled ovarian hyperstimulation
Corticotropin, Syntropin
• ACTH analogs
• Limited utility as a therapeutic agents (less predictable and convenient than corticosteroid therapy)
• Act via MC2R (GPCR -> increased cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralocorticoids & androgen precursor
• ACTH normally released from pituitary in pulses with highest concentration at ~ 6am and lowest in evening. Secretion also stimulated by stress
• Cortisol suppresses its release (-ve feedback)
Clinical Applications
• Diagnostic tool for differentiating between primary adrenal insufficiency (Addison’s disease) and secondary adrenal insufficiency (inadequate ACTH secretion)
• Infantile spasm (West Syndrome) treatment
Adverse Effects
• Similar to glucocorticoids
Oxytocin
- Acts on GPCRs -> stimulates release of prostaglandins & leukotrienes that augment uterine contraction
- Small doses increase force & frequency of contractions
- Higher doses evoke sustained contractions. Weak antidiuretic & pressor activity (vasopressin R activation)
- Contraction of myoepithelial cells surrounding mammary alveoli -> milk ejection
Pharmacokinetics
• IV used for initiation & augmentation of labor
• IM used for control of postpartum bleeding
• t1/2 = 5 min
Clinical applications
• Labor Induction: When early vaginal delivery is required (Rh problems, maternal diabetes, preeclampsia, ruptured membranes)
• Augment Normal Labor: When labor is protracted or displays arrest disorder
• Control of uterine hemorrhage
SE
• Severe toxicity is rare
• Excessive stimulation of uterine contractions: Fetal distress, placental abruption, uterine rupture
• Inadvertent activation of vasopressin receptors: Excessive fluid retention, water intoxication -> hyponatremia, heart failure, seizures, death
• Bolus injections can lead to hypotension: Administer IV as dilute solution at a controlled rate
CI • Fetal distress • Prematurity • Abnormal fetal presentation • Cephalopelvic disproportion • Uterine rupture predisposition
Atosiban
• Oxytocin antagonist. Used for treatment of preterm labor (NOT in US)
Vasopressin, Desmopressin
Desmopressin
• Long-acting synthetic analog of vasopressin
• Minimal V1 activity (as opposed to vasopressin) -> little vasopressor activity
• Antidiuretic-to-vasopressor ratio 4000 x vasopressin
Pharmacodynamics
• 2 GPCRs activated
• V1R = vascular smooth muscle -> vasoconstriction
• V2R = renal tubule cells -> increased water permeability & water reabsorption
Pharmacokinetics
• Vasopressin: IV, IM (t1/2 = ~15 min)
• Desmopressin: IV, SC, intranasally or orally (t1/2 = 1.5-2.5 h)
Clinical applications
• Drugs of choice for Diabetes Insipidus
• Vasopressin: Esophageal variceal bleeding & colonic diverticular bleeding
• Desmopressin: Coagulopathy treatment in Hemophilia A and von Willebrand’s disease
SE
• Headache, nausea, abdominal cramps, allergic reactions
• Overdosage = hyponatremia & seizures
Conivaptan
• Vasopressin antagonist. Approved for use in patients with hyponatremia (due to elevated vasopressin)
• Conivaptan has high affinity for V1 & V2 R’s
Cortisol (Hydrocortisone) metabolic effects
Metabolic Effects
• Stimulates and is required for gluconeogenesis & glycogen synthesis (which maintains hepatic glycogen availability) in fasting state
-> increase serum glucose levels (thus leading to stimulation of insulin release) & inhibiting uptake by muscle cells
• Stimulates lipolysis (leading to fat deposition and redistribution & increased release of fatty acids & glycerol)
• Stimulates protein catabolism & release of amino acids
Net Result: Maintenance of an adequate glucose supply to brain (most apparent in fasting state)
Catabolic Effects
• In addition to protein catabolism, cortisol also has effects in lymphoid and connective tissue, muscle, peripheral fat and skin (wasting occurs at high concentrations)
• Catabolic effects on bone = osteoporosis
• In children = growth retardation
Both are major limitations in long-term treatment with glucocorticoids.
Cortisol (Hydrocortisone) other effects
Immunosuppressive Effects
• Effects on leukocytes
• Increased neutrophils (increased influx into blood & decreased migration from blood vessels)
• Decreased lymphocytes (T and B cells), monocytes, eosinophils and basophils (movement from vascular bed to lymphoid tissue)
• Vasoconstriction due possibly to suppression of mast cell degranulation
• Decreased histamine release and capillary permeability
Anti-inflammatory Effects
• Inhibition of phospholipase A2 (through induction & activation of annexin I) which blocks arachidonic acid release (major precursor of prostaglandins).
• Cyclooxygenase-2 synthesis is reduced (through inhibition of NF-kB).
• Induction of MAPK phosphatase I (inhibits MAPK activated proinflammatory signaling pathways).
Other Effects
• CNS: behavioural changes (insomnia, euphoria leading to depression)
• Increased intracranial pressure: large doses
• Suppression of release of ACTH, growth hormone, thyroid-stimulating hormone & luteinizing hormone: chronic use
• Peptic Ulcers: Stimulation of gastric acid. Suppression of immune response to H.pylori?
• Increase platelets & RBCs
• Renal function: is impaired with cortisol deficiency
• Development of fetal lungs
PK • Relatively short duration of action • Diffuses poorly across skin (unless inflamed) • Diffuses well across mucous membranes • Some salt-retaining effects
Synthetic glucocorticoids
- Prednisone, Methylprednisolone, Dexamethasone, Beclomethasone, Triamcinolone
- Rapidly and completely absorbed orally
- Selected compounds can also be given IV, IM, topically, intra-articularly & by aerosol
- Long t1/2’s
- Reduced salt-retaining effects
- Prednisone = prodrug (rapidly converted to active prednisolone)
- Beclomethasone = short t1/2 & penetrates airway mucosa (low systemic toxicity)
Fludrocortisone
• Synthetic mineralocorticoid. Most commonly prescribed salt-retaining hormone
Clinical applications of synthetic corticosteroids
Adrenocortical Insufficiency
a. Chronic (Addison’s disease)
• Characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, inability to maintain blood glucose levels during fasting
Treatment
• Daily hydrocortisone (increase dose during stress) + mineralocorticoid (fludrocortisone)
• DO NOT administer long-acting glucocorticoids or ones lacking salt-retaining effects
Adrenocortical Insufficiency
b. Acute
• Associated with life-threatening shock, infection or trauma
Treatment
• Start treatment immediately
• Large amounts of parenteral hydrocortisone + correction of fluid & electrolyte abnormalities
• Can administer salt-retaining hormone once hydrocortisone levels are reduced (~ 5 days)
Adrenocortical hypo- and hyperfunction
a. Congenital Adrenal Hyperplasia
• Caused by defects in cortisol synthesis (either in CRH production by hypothalamus or in corticotropin production by pituitary)
• Decreased steroid levels lead to an increase in ACTH production and hyperplasia of adrenal gland
-> increased amounts of cortisol precursors that are diverted to the androgen pathway
Treatment
• Glucocorticoid admin. leads to suppression of ACTH
• Treat initially as an acute adrenal crisis
• Once stabilized: oral hydrocortisone or prednisone + fludrocortisone
• Fetus can be protected in high-risk pregnancies by dexamethasone admin. to mother
b. Cushings Syndrome
• Usually result of bilateral adrenal hyperplasia secondary to an ACTH-secreting pituitary adenoma
• Manifestations associated with chronic presence of excessive glucocorticoids
Treatment
• Surgical removal of tumor, irradiation of pituitary tumor, or resection of one or both adrenals
• Patients must receive high doses of cortisol before and after surgery
• Dose has to be slowly decreased to prevent withdrawal
Adrenocortical hypo- and hyperfunction
c. Aldosteronism
• Primary aldosteronism usually results from excessive production by adrenal adenoma (can be from malignant tumor)
Symptoms: result from renal loss of K+ (hypokalemia, alkalosis & elevation of serum Na+)
Diagnosis and Treatment
Spironolactone
Diagnostic Purposes
Dexamethasone Suppression Test
• Cushing’s syndrome: dexamethasone suppresses cortisol release in individuals with pituitary- dependent Cushing’s syndrome (not released from adrenal tumors)
• Depressive psychiatric states
Stimulation of Lung Maturation in Fetus
• Fetal lung maturation is regulated by cortisol secretion
• If premature delivery is expected, treatment of the mother with large doses of glucocorticoids reduces incidence of respiratory distress syndrome
• IM steroids are used (usually dexamethasone)
Non-Adrenal Disorders
• Numerous immunological inflammatory conditions: asthma, collagen vascular disorders (Rheumatoid arthritis), ocular diseases (uveitis, optic neuritis, exopthalmos),
• Allergic reactions (contact dermatitis, urticaria etc) • Hodgkin’s lymphoma (prednisone)
• Cerebal Edema (dexamethasone)
• Chemotherapy-induced vomiting
- Hematologic disorders (anemia, leukemia etc)
- Organ transplants (prevention of rejection)
- Renal disorders (nephrotic syndrome)
- Hypercalcemia
- Mountain Sickness
- Inflammatory bowel disease etc.
Corticosteroid SEs, CIs
• Peptic ulcers
• Clinical findings of certain disorders (particularly bacterial & mycotic infections) may be masked by steroid use
• Myopathy (part. with long-acting steroids)
• Nausea, dizziness, weight loss
• CNS (euphoria, psychosis, depression)
• Increased intraocular pressure (glaucoma)
• Posterior subcapsular cataracts
• Sodium & fluid retention, loss of potassium
• Growth retardation (children)
• Adrenal suppression
Use with caution in patients with: • Peptic ulcers • Heart disease or hypertension with heart failure • TB, varicella zoster infections • Psychoses • Diabetes • Osteoporosis • Glaucoma
Spironolactone
• Acts by competing with aldosterone for its receptor (decreasing its effect peripherally)
Clinical Applications:
• Aldosteronism (diagnosis & treatment)
• Hirsutism in women (acts as androgen antag.)
• Diuretic
SE
• Hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, GI disturbances, skin rashes
