181. Pituitary, Adrenal, Thyroid Pharmacology Flashcards
ADH
- structure, stimuli, fx
- name of analog
- mechanism of action
- kinetics
- uses
- SE
- post pit peptide, 9AA long
- stim by low BP, hypertonicity
- fx: increase BP, increase water reabsorption
Desmopressin: ADH synthetic analog, long acting
Mech: act thru GPCRs
V1R: coupled to Gq (PLC = more IP3/DAG) = vascular VC (IP3 = Ca release) and CNS bonding/depression
V2R: coupled to Gs (AC = more cAMP/PKA) = increase water reabsorption thru AQP trafficking and increase F.VII and vWF
Desmopressin: 4000x more anti-diuretic activity than native AVP b/c affinity for V2R»_space;> V1R
Kinetics: hepatic/renal metabolism, halflife (ADH = 15min; Desmopressin = 1.5-2.5hr), given ORAL and parenteral
USE: tx central DI, stop bleeding from esophageal varices, stop bleeding in hemophilia A and von Willebrand’s disease
SE: undesired VC (V1R) bad in CAD pts, nausea, abd cramps, headache, allergic reactions
Nephrogenic DI
- what is it
- cause
- tx
SIADH
- what is it
- cause
- tx
NDI: impaired renal response to ADH
cause: congenital or drug induced (Li)
Tx: thiazide diuretics (initially blocks distal Na reabsorption, increases urinary excretion; then low volume causes more proximal Na reabsorption, less distal Na delivery, decreased urine output)
SIADH: excess ADH secretion
cause: malignancy, head injury, drugs (psychotropics, SUs, alkaloids)
tx: AVP-receptor antagonists (Conivaptan and Tolvaptan = more selective for V2Rs and Orally effective, but higher risk for hepatotoxicity)
Oxytocin
- structure
- mechanism
- kinetics
- use
- SE
short 9AA peptide (2 AA different than ADH)
mech: activates GPCRs on smooth muscle (Gq = PLC = Ca = calmodulin = myosin) for contraction, promotes release of PGs and leukotrienes
kinetics: half life 4 min (shorter than ADH), hepatic/renal metabolism
Use: 1. induce labor under restricted conditions (early vaginal delivery indicated, labor is protracted/arrested)
2. control postpartum uterine hemorrhage
SE: uterine rupture, fetal distress (excessive contraction), activate AVP receptors at high doses (increase fluid retention and BP)
GH
- structure
- action, mechanism
- agonists
- kinetics
- uses
- SE
IGF-1 Agonists
- types
- use
- SE
- long 191AA peptide regulated by GHRH, SS, DA from hypothalamus
- action: stim longitudinal bone growth until epiphyseal closure, increase muscle mass, decrease central adiposity, reduces sensitivity to insulin
- mechanism: homodimeric RTKs activate JAK-STAT path, hepatic production of IGF-1 (negative feedback, can be stimulated by non-GH factors)
Agonists: Somatropin (recombinant peptide identical to native human GH), Somatrem (extra methionine to prolong half life)
Kinetics: SC ROUTE (not oral), half-life 20min but effects sustained (mimic pulsatile secretion for 1x/day dose)
Use: GH replacement (children w/ GH deficiency), other causes of short stature (Turner, Prader-Willi), AIDS wasting/malabsorption; ABUSED as anti-aging remedy (ineffective), performance enhancement (increase lean muscle mass)
SE: arthralgia, myalgia, peripheral edema, carpal tunnel, intracranial htn, insulin resistance (sometimes hypersensitivity due to loss of visceral fat)
IGF-1 Agonists:
Mescasermin - recombinant IGF1
Mescasermin rinfabate - IGF1 + IGFBP3 = prolong halflife
Use: promote growth and normalize metabolism in IGF1 deficiency resistant to GH
Hepatic/renal metabolism
SE: hypoglycemia, lipohypertrophy, intracranial htn, slipped epiphyses, scoliosis, contraindicated in cancer pts
Octreotide
- mechanism
- uses
- kinetics (vs. lantreotide)
- SE
Mech: SS analog (more potent than SS in inhibiting GH secretion) - acts through SS receptor (GPCR = Gi = activate K channels + protein phosphatases = inhibitory) [INHIBITS GH SECRETION - and blocks TSH, ACTH, glucagon, gastrin, insulin]
Use: acromegaly, other hormone-secreting tumors, secretory diarrhea from chemotherapy, “dumping syndrome” after gastric surgery
Kinetics: IV/SC ROUTE, short halflife (multiple doses per day) Lantreotide - long-acting analog
SE: Nausea, bloating, gallstones, bradycardia
Pegvisomant
- mechanism
- use
- SE
GH receptor antagonist - modified mutant form of GH
Mech: allows receptor dimerization but blocks subsequent signaling (no JAK-STAT activation = low IGF1)
Use: acromegaly
SE: elevated liver transaminases, lipohypertrophy, possible loss of negative feedback (growth of GH adenomas), increased compulsive behavior
Bromocriptine + Cabergoline
- structure
- mechanism
- use
- kinetics
- SE
Structure: semisynthetic ergot alkaloids
Mech: selective D2 receptor agonists - mimic DA to inhibit GH production/secretion at ant pit, even more effective at blocking pit
Use: acromegaly, hyperPRL/galactorrhea from injuries, tumors, drugs
Kinetics: ORAL, carbergoline more potent longer half life
SE: N/V, headache, orthostatic hypotension, rare psychoses/nightmares/hallucinations, cabergoline less GI SE but more assoc with valvular heart disease
Thyroid Hormones
- names
- mechanism/areas of action
- developmental/non-developmental actions
- target genes
T4 (levothyroxine) and T3 (liothyronine)
Mech: act thru nuclear receptors to directly regulate gene transcription in liver (B1>A), heart (A1>B1), hypothalamus (B2 - negative fb), (A2 inactive nonbinding), receptors interact with response elements as heterodimers (RXR-TR)
Actions: critical for development of CNS + skeleton (fetus - 6 mo old) [prenatal deficiency = mental impairment, learning disability, skeletal defects]
Metabolic - optimize energy metabolism, reproductive fx
Cardiac - increase HR/contractility, potentiate Beta ANS effects
Hepatic - increase chol metabolism, may cause ins resistance
Skeletal - promote osteoporosis
Genes: Myelin basic protein (brain development), Ca-ATPase in skeletal muscle (calorigenic effect), Ion channel protein in cardiac pacemaker (chronotrophic effect), B-adrenergic receptor (cardiac effect), IGF-1 stimulation (bone formation)
Thyroid Hormones
- kinetics (T3 vs T4)
- use, effects
- SE
- caveat in use
T3 - 10x more potent than T4, better absorption, lower protein-binding, faster clearance
T4 - preparation of choice due to longer half life and lower risk (T3 very potent)
Dosing - oral effective, higher dose in pregnancy, lower dose in older pts or with heart disease
Use: hypothyroidism replacement for Hashimoto’s, synthetic enzyme defects, destruction of thyroid
potentially lower chol (need to only stim TRbeta and avoid TRalpha to prevent cardiac stim SE)
SE: high thyroid fx (weight loss, sweating, diarrhea, anxiety, headache), high beta SNS (palpitations, angina, coronary/cerebral thromboses), chronic excess (muscle weakness, infertility, anemia, cardiac failure, bone loss, ins resistance)
Caveat: many signs only mimic hypothyroid (lethargy, fatigue, weight gain, infertility) - leads to inappropriately excessive use of thyroid hormones
Hyperthyroidism
- sx
- tx (list the options)
- targets of tx
Sx: high thyroid fx (weight loss, sweating, diarrhea, anxiety, headaches), high beta SNS (palpitations, angina, thromboses), chronic excess (muscle weakness, infertility, anemia, cardiac failure, bone loss, ins resistance)
Tx: surgery (resect hyperplastic glands)
radioactive Iodine (131-I)
thioureylene/thionamide anti-thyroid drugs
sympatholytic agents (B-blockers)
potassium iodide (KI)
Targets:
- Oxidation (converting I- to I in colloid via follicular cells)
- Coupling/Iodination (adding I to tyrosine to make MIT/DIT via thyroid peroxidase enzyme)
- Proteolysis/Secretion of T3 + T4 previously bound to TG
Isotope Therapy (131-I)
- kinetics
- mechanism
- use
Methimazole + PTU
- mechanisms
- kinetics
- SE
131-I: emits gamma and beta particles
- oral admin, rapid absorption, half life 8 days (long)
- mech: released beta-particles cause necrosis of follicular cells = hyperthyroid sx abate over weeks-months (need to drain hormone stores)
- need to block synthesis of thyroid hormone so no radioactive hormones + precursors are released!!
- NOT used in pregnant/nursing women!
Methimazole and PTU: inhibit thyroid peroxidase (blocks iodination and coupling); PTU also inhibits peripheral conversion of T4 to T3
Kinetics: good orally, accumulate in thyroid, slow onset of effect (3-4 weeks) b/c need to drain hormone stores
SE: pruritic rash, arthralgia, rare agranulocytosis, PTU = fulminant hepatitis, MMI = avoid/decrease dose in pregnancy to prevent fetal hypothyroid
Hyperthyroidism Tx:
- Sympatholytic Tx
- types, mechanism, effect - Potassium Iodide (KI)
- mechanism
- kinetics
- SE
B-Block: atenolol, propranolol
- control tachycardia, htn, afib during acute phase
- chronic bp control
- propranolol: weak inhibitor of peripheral T4-T3 conversion
KI: inhibit TG proteolysis and hormone release (later steps in path)
kinetics: give at HIGH DOSE (rapid absorption, rapid onset)
SE: crosses placenta = fetal hypothyroidism (not used in pregnancy), not used in long-term tx
Adrenal Steroids
- mechanism of action
- effects of GCs (metabolic and non-metabolic)
Mech: interact with cytoplasmic receptors = release hsp90 = exposes DNA-binding domain of receptor + translocation to nucleus, receptors bind as homodimers and interact with HREs = regulate gene transcription
Metabolic:
Liver - conserve glu: more glycogen synthesis, more gluconeogenesis
C.T. - decrease protein synthesis, increase protein breakdown (catabolic) [muscle wasting, skin thinning, osteoporosis]
Adipose - fat redistribution, central obesity
Nonmetabolic:
Kidney - increase Ca excretion, Na retention, K/H excretion (MC)
Immunosuppressant - less Ab production, less lymphocytes, cytokines, PGs
GI - mucus thinning, more acid/pepsin secretion, less Ca absorption
CNS - euphoria, depression, sleep disturbance
Stress - increase CO, increase GFR
Use:
- Addison’s disease (lose adrenal cortical fx: muscle weakness, low BP = replace GCs/MCs)
- Acute loss adrenal fx: replace GCs with Na/H2O (no MCs)
- CAH: only cortisol mediates -fb = will have adrenal hyperplasia (high ACTH) without cortisol; 21-H deficiency (replace GC and MC); 11-H Deficiency (replace GC only)
Adrenal Hyperfunction: list primary and secondary causes
- tx types (mechanisms of mifepristone/RU-486, metyrapone, ketoconazole, aminoglutethimide, mitotane, octreotide)
What are the 3 pit-adrenal fx tests?
Primary: adrenal adenoma or ca
Secondary: high ACTH (pit adenoma, ectopic ACTH)
Tx: surgery or irradiation or meds
Mifepristone/RU-486: GC receptor antagonist
Metyraponse: 11-Hydroxylase inhibitor
Ketoconazole: blocks multiple steps in GC synthesis
Aminoglutethimide: blocks chol side chain cleavage (1st step steroid synthesis)
Mitotane: most toxic, used for ca
Octreotide: ss analog, suppress elevated ACTH (if secondary hyperfx issue)
- ACTH test: determines etiology of hypofx
- Pit insufficiency: adrenal secretion with exogenous ACTH
- primary adrenal hypofx: no adrenal secretion - Metyrapone test: determines etiology of hypofx
- block 11-hydroxylase = lower GC production = raise ACTH
- used to evaluate pit function (ability to raise ACTH) - Dexamethasone test: etiology of hyperfx
- synthetic GC to suppress response (usually suppresses pit adenomas but not ectopic ACTH)
Hyperphysiologic Doses of GCs: effect
GC kinetics, SE
How does steroid withdrawal occur? How do you prevent it?
Anti-inflammatory, immunosuppressant (lower PG synthesis, cytokines, lymphocytes, monocytes, Ab production)
Anti-cancer (lower lymphocytes, increase cancer cell differentiation)
Undesired effects: more GC mediated MC effects (Na retention, HTN)
Kinetics: ORAL, injected, topical, inhaled
halflife: 60-90 min
90% bound to CBG (binding protein)
most inactivated/metabolized in liver
SE: hypokalemic alkalosis (K/H wasting), glycosuria, susceptibility/masking infection, ulcers, myopathy, osteoporosis, hypercoagulability, glaucoma, reproductive disturbance, adrenal insufficiency on withdrawal
Withdrawal: when tx abruptly discontinued, loss of high negative feedback - no ACTH control = adrenal insufficiency (low cortisol due to low ACTH)
prevention: taper GC dose down
