SM159 Pharm Flashcards
Desmopressin
ADH analog, long-acting
Vasopressin mechanism
Acts through GPCR
V1 receptors: couples to PLC, releases Ca++, causes vasoconstriction and CNS effects
V2 receptors: couples to AC to increase cAMP, increases water reabsorption in the collecting duct via insertion and stabilization of aquaporins, increases factor VIII and vWF
Is desmopressin or vasopressin more potent? Which as a longer half-life?
Desmo has a 4000x greater antidiurietic/pressor activity
Desmo also has a longer half-life
Vasopressin pharmacokinetics
Hepatic/renal metabolism
Reduction of disulfide bond
Vasopressin indications
Central DI (inadequate release of vasopressin) Stop esophageal varices bleeding Stop bleeding in hemophilia A and vW disease
Vasopressin adverse effects
Undesired vasoconstriction (like in patients with CAD) Nausea, cramps, headaches, allergic rxn
Nephrogenic DI: etiology, treatment
Impaired renal response to ADH
Treat with thiazides
SIADH: etiology, treatment
Malignancy, head injury, drugs
Conivaptan, tolvaptan: vasopression receptor antagonists
Oxytocin mechanism
Binds GPCR, releases Ca++ via PLC. Also causes release of prostaglandins and leukotrienes.
Actions: leads to smooth muscle contraction, stimulates uterine contraction, causes milk ejection.
Oxytocin indications
Induce labor when early vaginal delivery is indicated (eclampsia) or when labor is protracted or arrested
Postpartum to control uterine hemorrhage
Oxytocin adverse effects
Uterine rupture, fetal distress, activation of vasopressin receptors
GH analogs
Somatropin: identical
Somatrem: + methionine (extends half life)
GH regulation
Stimulated by GHRH
Inhibited by SS and dopamine
GH mechanism
Acts through TYK receptors, activates JAKs which activate STAT proteins. Stimulate release of IGF-1.
Actions: stimulates longitudinal growth of bone before plates close, increase muscle mass, decrease central fat, reduce sensitivity to insulin, increase glycolysis
GH indications
Replacement therapy for GH deficient kids
Other causes of short stature: Turner, Prader-Willi, chronic renal insufficiency
AIDS wasting
Abuse: antiaging, athletic enhancement
GH adverse effects
Joint and muscle pain, peripheral edema, carpal tunnel, insulin resistance, adrenal insufficiency due to inhibition of 11b-hydroxysteroid dehydrogenase
IGF-1 agonists
Sometimes GH response is inadequate, so use these
Mecasermin: recombinant form
Mecasermin rinfabate: contains IGF-1 and IGF-1 binding protein (IGFBP-3) that extends the half-life and stimulates uptake into cells
Mecasermin indications
Promote growth and normalize metabolism in cases of GH deficiency that are resistant to GH
Mecasermin adverse effects
Hypoglycemia, lipohypertrophy, slipped epiphyses, scoliosis
Contraindicated in people with cancer
Somatostatin analog
Octreotide
Somatostatin analogs indications
Acromegaly: abnormal growth of bone and cartilage
Octreotide adverse effects
Nausea and bloating, gall stones, bradycardia
Octreotide mechanism
Acts through SS receptors (GPCR), activates K+ channels and protein phosphotyrosine phosphotases
Actions: inhibits GH secretion, inhibits secretion of TSH, ACTH, glucagon, gastrin, and insulin
Pegvisomant mechanism
Allows receptor dimerization but blocks signaling in the JAK-STAT pathway
Pegvisomant adverse effects
Increase in liver transaminases, lipohypertrophy, compulsive behavior, GH-secreting adenomas
Bromocriptine and cabergoline mechanism
Selective dopamine D2 agonists, mimic effects of dopamine to inhibit GH production and secretion
Also inhibit prolactin
Bromocriptine and cabergoline adverse effects
Nausea, vomiting, headache, orthostatic hypotension
Generic names for thyroid hormones, other preparation used
T4 = levothyroxine T3 = liothyronine Liotrix = T4/T3 combination
Thyroid hormones mechanisms
Act as heterodimers through nuclear receptors to regulate genes. Receptors with no ligand bound acts as repressors.
4 major types: a1, a2, b1, b2
Thyroid hormone tissue differences
b1 > a1 in liver
b2 in hypothalamus
a2 is a non-binding inactive form
Thyroid hormones role in development
Critical for CNS development (inadequacy gives you cretinism) both during gestation and postpartum
Critical for skeleton development
Thyroid hormones non-development effects
Metabolic: important for optimal energy metabolism and reproductive function
Cardiac: inotropic and chronotropic effects; potentiate effects of sympathomimetic amines
Hepatic: increase cholesterol metabolism; effects on glucose metabolism cause insulin resistance
Skeletal: excess thyroid hormone can promote osteoporosis, especially in adults
Target genes for thyroid hormones
Myelin basic protein Ca++ ATPase in skeletal muscle Ion channel protein in pacemaker b-adrenergic receptors IGF-1
T4 to T3 conversion
5’-deiodination in the periphery (blocked by beta-blockers)
T3 or T4: which is more potent, better cleared, binds less proteins, and cleared faster? Which one is most commonly used and why?
T3 is better in each category
T4 is more commonly used: more convenient dosage and lower risk
Thyroid hormone indications
Hypothyroidism: Hashimoto’s, destruction by medical treatment, secondary
Thyroid hormone adverse effects
Weight loss, sweating, diarrhea, anxiety, headaches
Palpitations, angina, thrombosis (due to beta-adrenergic signaling)
Chronic: weakness, anemia, infertility, HF, bone loss, insulin resistance
T3/T4 production mechanism
Iodide is transported into the follicular cells, peroxidase oxidizes iodide and couples it to thyroglobulin to produce MIT and DIT (target of antithyroid drugs), two DIT get put together and then proteolysis gives you T4
T4 is turned into T3 in the periphery
Radioactive iodide (131 I) mechanism
Gamma and beta emitter
131 I gets trapped, incorporated, and deposited into the colloid
Released beta particles cause necrosis of follicular cells without damaging nearby cells
Methimazole and propylthioruacil mechanism
Thionamides: used for hyperthyroidism
Inhibit thyroid peroxidase (PTU also blocks T4 to T3 conversion in the periphery)
Thionamide adverse effects
Pruritic rash, arthralgia
Agranulocytosis is rare but fatal
Give PTU in pregnancy
Role of sympatholytics in hyperthyroidism (beta-blockers)
Controls tachycardia, HTN, A Fib
KI mechanism
Inhibits hormone release, antagonizes TSH, inhibits peroxidase
KI indications
Prior to thyroid surgery Radiation emergencies (block uptake of 131 I)
KI adverse effects
Rashes, swollen salivary glands, headache
Can cross placenta and cause hypothyroidism
Glucocorticoids mechanism
Interacts with receptors in cytoplasm, resulting in release of hsp90. This exposes the DNA binding domain and allows translocation to the nucleus, where they bind as homodimers.
Mineralocorticoids mechanism
Act at the distal convoluted tubule and collecting duct, induce the synthesis of proteins that promote transepithelial Na transport
Increases the lumen-negative transepithelial voltage that drive K and H into the urine
Net result: Na retention and K/H excretion
Adrenal steroid indications
Replacement therapy: Addison’s disease, ACTH deficiency, acute loss of adrenal function, congenital adrenal hyperplasia (CAH - hydroxylases essential for steroid synthesis are deficient resulting in hypersecretion of either mineralocorticoids or androgens occurs)
21-hydroxylase deficiency
Low glucocorticoids and mineralocorticoids, high ACTH, high androgens
11-hydroxylase deficiency
Low glucocorticoids, high ACTH, high mineralocorticoids and androgens
Adrenal excess treatments: what suppresses ACTH, what suppresses synthesis, what is a receptor antagonist?
SS analogs (suppress ACTH), glucocorticoid synthesis inhibitors (metyrapone and ketoconazole), receptor antagonist (mifepristone RU-486)
ACTH test for adrenal hypofunction
Exogenous ACTH will stimulate secretion if problem is secondary but not primary
Metyrapone test for adrenal hypofunction
Metyrapone blocks 11-hydroxylase, leading to less glucocorticoids, which leads to less negative feedback, which should lead to more ACTH secretion
Dexamethasone test for adrenal hyperfunction
Test whether the adrenal response is suppressible. Pituitary adenomas are suppressible with high levels, ectopic ACTH and cortisol-producing tumors are not suppressible.
Antiinflammatory mechanism of glucocorticoids
Decrease synthesis of prostaglandins and inflammatory cytokines, decrease lymphocytes/monocytes/eosinophils/basoils, decrease antibody production and antigen processing, decrease scar formation
Chemotherapeutic mechanism of glucocorticoids
Decreases lymphocytes, especially good for hematologic malignancies
Pegvisomant
GH receptor antagonist
Bromocriptine/cabergoline
Ergots, dopamine agonists
Suppress GH and PRL
