Pharmacology II Exam 1

somatotrophic hormones

• growth hormone

• prolactin

glycoprotein hormones

• luteinizing hormone

• follicle stimulating hormone

• thyroid stimulating hormone

growth hormone effects are mediated by

IGF-1

why are IGF-1 levels a better diagnostic tool than growth hormone for disease states

GH has a short half life, IGF-1 has a long half life

GH release from the anterior pituitary is mediated by

• sleep

• nutrition

• GHRH

• sex hormones

• ghrelin

GH release from the anterior pituitary is inhibited by

• somatostatin

• IGF-1

• GH

GHRH analogues

• sermorelin

• tesamorelin

GH analogue

somatotrophin

recombinant IGF-1

mecasermin

GH deficiency most commonly originates from

defective hypothalamic release of GHRH

anterior pituitary adenoma prior to epiphyses closure/puberty results in

gigantism

anterior pituitary adenoma after epiphyses closure/puberty results in

acromegaly

somatostatin receptor ligands

• octreotide

• lanreotide

• pasireotide

downside to using somatostatin receptor ligands for treatment of GH excess

somatostatin receptors are widely distributed so the medications can have many adverse effects

GH receptor antagonist

pegvisomant

pegvisomant

• GH analog that binds to GH receptor and prevents dimerization

• competitive antagonist

• multiple PEG residues increases half-life and allows for once daily dosing

• reduces IGF-1 release, ends up promoting GH release by eliminating inhibitory pathway

prolactinoma

benign prolactin-producing pituitary tumor

dopamine agonists

• cabergoline

• bromocriptine

first line therapy for prolactinomas

• dopamine agonists

• cabergoline is preferred over bromocriptine, more selective and less adverse effects

prolactin release is stimulated by

TRH/estrogen

prolactin release is inhibited by

dopamine

prolactin

stimulates breast tissue to produce milk

due to hypothalamic-mediated inhibition, patients taking dopamine antagonists may exhibit

increased prolactin levels

bromocriptine

• dopamine receptor agonist

• less selective, more adverse effects

• CYP3A4 interactions

cabergoline

• long acting

• selective D2 receptor agonist

• less adverse effects

• CYP3A4 interactions

hormones released form posterior pituitary

• oxytocin

• vasopressin

vasopressin effect at liver

glycogenolysis

vasopressin effect at vascular smooth muscle

vasoconstriction

vasopressin effect at endothelial cells

vWF release

vasopressin effect at platelets

aggregation

vasopressin/ADH release factors

• hyperosmolarity/hypovolemia

• shock

• ang II

• sympathetic activity

vasopressin receptors

• V1: vessels

• V2: kidney

diabetes insipidus

• nephrogenic: ADH resistance

• neurogenic: insufficient ADH

renal effects of ADH

• V2 receptor expressed on basolateral membranes of collecting duct cells activated via GPCR Ga-s cascade

• increased aquaporin production on apical membrane

• increased H₂O reabsorption

treatment of neurogenic diabetes insipidus

• ADH replacement

• desmopressin

treatment pf nephrogenic diabetes insipidus

• reduce osmotic load

• thiazide diuretics

• prostaglandin inhibitor

SIADH

• excess secretion of ADH

• high blood volume and pressure

• hypo-osmolarity

diabetes insipidus

decreased secretion or unresponsiveness to ADH

ADH receptor antagonists

• conivaptan (V1a and V2)

• tolvaptan (V2)

treatments for SIADH

• fluid restriction

• ADH receptor antagonists

• demeclocycline

• lithium

conivaptan

• ADH receptor antagonist

• high affinity for both V1 and V2

• metabolized by CYP3A4 - interacts with ketoconazole, protease inhibitors, macrolide antibiotics

tolvaptan

• higher affinity for V2 - more renal specific effects, less risk of vasoconstriction

• use limited to 30 days due to hepatotoxicity

oxytocin

• stimulates uterine muscle contraction - childbirth

• stimulates milk release during lactation

tocolytic therapy

• management of pre-term labor by suppressing uterine contractions

• oxytocin receptor antagonists

oxytocin receptor antagonist

atosiban

tocolytics

• terbutaline

• nifedipine

hypothalamic-pituitary-adrenal axis

• hypothalamus releases corticotropin-releasing hormone (CRH)

• CRH tells anterior pituitary to release adrenocorticotropic hormone (ACTH)

• ACTH tells adrenal glands to release cortisol

• high cortisol levels inhibits the release of CRH and ACTH

synthesizing ACTH

• the pituitary splits proopiomelanocortin (POMC) into pieces to make ACTH

• this process also makes melanocyte-releasing hormone (MSH), lipoprotein, and beta-endorphin

purpose of cortisol

• vascular tone

• electrolyte balance

• glucose homeostasis

excess cortisol results in

Cushing’s syndrome

when do cortisol levels peak

early morning

HPA axis is controlled by

circadian rhythm

what contributes to regional production of hormones within the adrenal cortex

expression of different CYP450s

zona glomerulosa of the adrenal cortex secretes

aldosterone

zona fasciculata/reticularis of the adrenal cortex secretes

cortisol/androgens

glucocorticoids are synthesized from

cholesterol

characteristics of peptide hormones

• hydrophilic - cell surface receptors

• small

• Ca⁺² dependent exocytosis

• freely circulating

• short duration

characteristics of steroid hormones

• lipophilic - intracellular/nuclear receptors

• immediate/constitutive secretion

• bound to plasma proteins

• long duration

how do plasma binding proteins regulate cortisol activity

only unbound cortisol is bioavailable

plasma binding protein affinity for cortisol

• corticosteroid binding globulin (CBG): high affinity, low capacity

• albumin: low affinity, high capacity

how much circulating cortisol is bound by plasma binding proteins

90%

how does Mitotane inhibit adrenal steroidogenic pathways

inhibits all pathways

how does Aminoglutethimide inhibit adrenal steroidogenic pathways

inhibits all pathways, also inhibits aromatase in ovary

how does Ketoconazole inhibit adrenal steroidogenic pathways

• high levels inhibits all pathways

• low levels only inhibit the synthesis of androgens

how does Metyrapone inhibit adrenal steroidogenic pathways

inhibits cortisol and aldosterone synthesis

how does Trilostane inhibit adrenal steroidogenic pathways

inhibits all pathways, primarily cortisone and aldosterone

P450c21 affects the production of ___ in adrenal cortex

aldosterone and cortisol

P450c11 affects the production of ___ in adrenal cortex

aldosterone and cortisol

P450c17 affects the production of ___ in adrenal cortex

cortisol and androgens

Aminogluethemide

• prevents cholesterol conversion to pregnenolone

• inhibits synthesis of cortisol, aldosterone, androgens

Ketoconazole

• many non-specific CYP enzyme inhibition

• blocks several steps in adrenal steroidogenic pathways

• inhibits synthesis of cortisol, aldosterone, and androgens

Metyrapone

• inhibits CYP11B1 conversion of progesterone to corticosterone

• inhibits 17-a hydroxypregnenolone conversion to cortisol

• inhibits synthesis of aldosterone and cortisol

• dosed multiple times a day due to short half life

Etomidate

• inhibits CYP11B1 conversion of progesterone to corticosterone

• inhibits synthesis of aldosterone

• requires ICU monitoring

Trilostane

• inhibits all adrenal steroidogenic pathways, primarily cortisone and aldosterone

• no longer used in humans, only veterinary medicine

physiological functions of glucocorticoids

• breakdown of skeletal muscle protein

• breakdown of adipose tissue

• breakdown of bone

• suppression of immune system

• gluconeogenesis

• anti-inflammatory

glucocorticoid effects at cellular level

• after dimerization, the receptor-GC hormone complex recruits coactivator proteins

• this complex is transported to the nucleus where it attaches to gene promoter elements

• the complex acts as a transcription factor to turn genes on or off depending on the tissue

• chaperone release following receptor-GC hormone complex formation can trigger non-genomic rapid responses

immune-adrenal axis

• when macrophages encounter infection or immune stimulus they release inflammatory cytokines

  • tells thermoregulatory centers in the brain to trigger fever

  • tells the hypothalamus to release corticotropin-releasing hormone (CRH)

• CRH tells the pituitary to release ACTH, which tell the adrenal cortex to release cortisol

  • cortisol stimulates anti-inflammatory factors, mediators of inflammation, and stops inflammatory cytokines from being released

  • cortisol inhibits more CRH and ACTH from being released

systemic adverse effects of glucocorticoids

• early manifestations: insomnia, enhanced appetite, weight gain, leukocytosis, hyperglycemia

• sustained therapy: cushingoid habitus, HPA suppression, infection, osteoporosis, impaired wound healing

glucocorticoid duration of action depends on

• fraction of drug bound to plasma proteins

• affinity of the drug for 11B-HSD2

• lipophilicity of the drug

• receptor affinity

cortisol peripheral metabolism

• liver: 11B-HSD 1 catalyzes conversion of cortisone (inactive) to cortisol (active)

• kidney: 11B-HSD 2 catalyzes conversion of cortisol (active to cortisone (inactive)

inhaled glucocorticoids

• primarily halogenated versions of cortisol

• almost complete first-pass metabolism, any swallowed compound is inactivated

• concentrated local delivery to target tissues - avoids systemic affects

• caution when switching form systemic to inhaled corticosteroids to avoid triggering acute adrenal insufficiency

• oropharyngeal candidiasis risk - must rinse mouth after use

examples of inhaled glucocorticoids

• beclomethasone dipropionate

• fluticasone propionate

• budesonide

• mometasone furoate

• ciclesonide

• triamcinolone

• flunisolide

examples of systemic glucocorticoids

• hydrocortisone

• prednisolone

• methylprednisolone

• dexamethasone

Cushing’s syndrome

• increased cortisol production

• tumor induced:

  • ectopic: small cell lung carcinomas

  • pituitary adenomas

  • adrenal cortex adenomas/carcinomas

• GC therapy induced: iatrogenic Cushing’s

pharmacological targets in treating Cushing’s disease

• glucocorticoid receptor antagonist (mifepristone)

• inhibit steroidogenesis

• inhibit ACTH release (2’ hypersecretion)

• surgical resection/ablation of adrenal gland (1’ hypersecretion)

Mifepristone

• glucocorticoid receptor antagonist

• stabilizes GR-hsp90 co-repressor interaction

  • displaces helix 12 from agonist position, enlarging the coregulator binding site and enabling binding of NCoR

• contraindicated in pregnancy

• CYP3A4 interactions

• ADR: endogenous ACTH, cortisol, hypokalemia, hypertension, nausea, fatigue, peripheral edema

Pasireotide

• somatostatin analog used to treat Cushing’s disease

• inhibits anterior pituitary ACTH secretion

• mimics cyclic structure of endogenous somatostatin

• ADR: GI side effects, hyperglycemia

Cabergoline

• dopamine agonist used to treat Cushing’s disease

• inhibits anterior pituitary ACTH secretion

• ergot alkaloid, also used in hyperprolactinemia

Cabergoline is a

dopamine agonist

Pasireotide is a

somatostatin analog

Mitotane

• used for cytotoxic ablation in Cushing’s disease

• gross destruction of the zona fasciculata and reticularis but not zona glomerulosa

• ADR: diarrhea, nausea, vomiting, depression, somnolence, skin rash

• withdrawn from US market

• lipophilic/long half life

• CYP3A4 inhibitor

• teratogenic