Pit pharm Flashcards
Somatropin
recombinant growth hormone
Sub cut. or IM
active levels persist 36 hrs
given at bedtime for children
children- Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency
Growth hormone deficiency in adults
Most commonly due to pituitary tumor or consequences of treatment - surgery and/or radiation)
Treatment of wasting or cachexia in AIDS patients
Patients with short bowel syndrome dependent on TPN
growth hormone deficient Tx
treat with recombinant IGF-1 (Mecasermin)
Adult-Onset Growth Hormone Deficiency (AoGHD)
GH replacement deficiency approved for use in Children-1985, Adults-1996
GH therapy-still somewhat controversial in adults regarding cost/benefit ratio
is off label usage of GH ok?
Increased rates of adverse events: edema, joint pain, muscle pain, carpal tunnel syndrome, skin numbness and tingling
hGH is exception among drugs in that off-label use has been deemed illegal - should not be recommended
Growth hormone releasing hormone deficiency Tx
Tesamorelin
Effective given intravenously, intranasally, subcutaneously
Adverse effects: rare, facial flushing (IV), antibody formation with continued use
Rapidly stimulates GH synthesis and secretion
Binds to GPCR coupled to Gs increasing cAMP and Ca++ levels in somatotrophs
what is the somatostatin like drug
Octreotide, Lanreotide
Excess of growth hormone - Acromegaly (adults) and gigantism (children)
Long-acting analog lanreotide is preferred drug therapy - used after response seen to SC octreotide
Dopamine agonists inhibit GH secretion in some patients
Not as effective as SST analogs - oral cabergoline is preferred agent for adjuvant management
GH receptor antagonist: Pegvisomant
(Mutated GH molecule - polymers attached to extend t1/2)
somatostatin adverse reactions
Adverse Reactions
Transient deterioration in glucose tolerance hyperglycemia then subsequent improvement
Abdominal cramps, loose stools
Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)
Regarding treatment of deficiencies and excesses of growth hormone:
- Risk of Creutzfeldt-Jacob disease must be considered when using currently available GH preparations
- Patients receiving cabergoline for acromegaly must be monitored for parkinsonian symptoms
- For patients who choose not to have surgery for acromegaly long-acting SST analogs are preferred over dopamine agonists
- Patients initiating GH replacement therapy should be monitored for hypoglycemia
- Use of GH for its antiaging properties is has approval by the FDA
- Somatostatin’s action to decrease GH release from somatotrophs is mediated via activation of Gi/o coupled receptors
- For patients who choose not to have surgery for acromegaly long-acting SST analogs are preferred over dopamine agonists
- Somatostatin’s action to decrease GH release from somatotrophs is mediated via activation of Gi/o coupled receptors
Hyperprolactinemia therapy
Dopamine agonists
Cabergoline - has become preferred agent
- More selective for D2 receptor and more effective in reducing prolactin secretion
- Better tolerated, less nausea, some hypotension and dizziness
- Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors)
Bromocriptine - prototype of long-standing use
- Ergot derivative that also activates D1 receptors
- Frequent side effects include n/v, HA, and postural hypotension - less frequently see psychosis or insomnia
Desmopressin (DDAVP):
ADH analog that is more stable to degradation
Renal actions are mediated by V2 receptors (GPCRs coupled to Gs)
MOA Increase the rate of insertion of water channels (aquaporins) into luminal membrane increase water permeability leading to an antidiuretic effect
Also activates urea transporters and increases Na+ transport in distal nephron
Non-renal V2 actions include release of coagulation factor VIII and von Willebrand’s factor
Pharmacodynamics
ADH-vasopressin actions at V1 receptors - GPCRs coupled to Gq ( Ca++)
Mediates vasoconstriction of vascular smooth muscle
Pressor responses occur only at much higher Cp than needed for maximal physiological antidiuresis
Recall that release of ADH can be inhibited by ethanol
what are uses of ddAVP
Central (Neurogenic) Diabetes Insipidus
Inadequate ADH secretion from posterior pituitary (head injury, pituitary tumors, cerebral aneurysm, or ischemia)
Chlorpropamide
central diabetes insipitus
(1st generation sulfonylurea)
Potentiates action of small or residual amounts of ADH - mechanism not clear
Option for patients intolerant to desmopressin (due to side effects or allergy)
Other drug options: carbamazepine, clofibrate (not in US), thiazides, NSAIDs
Nephrogenic Diabetes Insipidus
causes
Inadequate ADH actions congenital or drug-induced
Congenital causes
Diverse receptor and aquaporin mutations are known
Drug-induced causes (side effects useful in SIADH??)
Lithium: reduces V2-receptor stimulation of adenylyl cyclase - seen in 20-40% of bipolar patients on Li+
Demeclocyline (tetracycline antibiotic): mechanism not understood - ? block of ADH binding to receptor
Nephrogenic Diabetes Insipidus Tx
Fluids, low salt, low protein diet
Thiazide diuretics: Paradoxically reduces polyuria
Mechanism not completely understood but antidiuretic effect parallels ability to cause natriuresis
volume Na+-H2O at PCT H2O at CT
NSAIDs (indomethacin): PGs attenuate ADH-induced antidiuresis - inhibition of PG synthesis may relate to the enhanced antidiuretic response seen
Thiazides and indomethacin also used in combination
causes of SIADH
Incomplete suppression of ADH secretion under hypoosmolar conditions hyponatremia
Multitude of disorders: malignancies, pulmonary diseases, CNS trauma-infections-tumors
Drug classes most commonly implicated in SIADH
Psychotropic agents: SSRIs, haloperidol, tricyclic antidepressant
Sulfonylureas (chlorpropamide)
Vinca alkaloids chemotherapy
Methylenedioxymethamphetamine (MDMA)
