1 Hypothalamus & Pituitary Drugs Flashcards
Growth hormone
- 191 aa peptide from somatotrophs
- tyrosine kinase GH receptor
- adipocyte: lipolysis
- induce production of IGFs & somatomedins from liver
- anabolic effect on skeletal muscles & on cartilage at epiphyses of long bone -> longitudinal growth
Treatment of GH Deficiency
- lack of GH releasing hormone
- pituitary disorders
- failure of IGF generation
- children: pituitary dwarfism, normal proportion of body is maintained
- adult: obesity, reduced muscle mass, lack of strength, reduced cardiac output & impaired psychological well-being
- use Somatropin & Somatrem
- use Sermorelin
- use Mecasermin
Somatropin (identical sequence as GH) & Somatrem (an extra methionine at N-terminal)
Recombinant Growth Hormone
*for Treatment of GH Deficiency
Mechanism & Effects:
- tyrosine kinase GH receptor
- inc lean body mass & bone density
- dec fat mass
- inc exercise tolerance
- drug interaction P450 induction, anti-insulin effect
- cleared by liver
Clinical Use: - short stature (epiphyseal plate unsealed) - Turner's syndrome - AIDS-related wasting/cachlexia - GH deficiency/insufficiency in children - GH deficiency in adults; inc lean body mass & bone density inc exercise tolerance improved sense of well-being dec fat mass - s.c. in evening
Side Effect:
- children; well tolerated
- children; rarely intracranial hypertension w/ vision changes, headache, nausea & vomit
- adult; peripheral edema, carpal tunnel syndrome, arthralgia & myalgia
- adult; more frequent in older & obese patients
Sermorelin*
Synthetic Human GHRH
*for Treatment of GH Deficiency
Mechanism & Effects:
- G-protein coupled GHRH receptor in somatotrophs
- inc cAMP & Ca2+
- synthesis & secretion of GH (induced in mins)
- full biological activity of GHRH
Clinical Use:
- first diagnosis of pituitary GH secretory capacity
- treat idiopathic GH deficiency not due to ant pit defect
- s.c. or i.v. at bedtime, GH induced in minutes
Side Effect:
- pain, redness or swell at injection site
- itching, trouble swallowing, dizzy, flushing, headache, sleepiness & hypereactivity
Mecasermin*
Synthetic Human IGF-1
*for Treatment of GH Deficiency
Mechanism & Effects:
* complex of rhIGF-1 +rhIGFBP-3 to maintain an adequate t-1/2
Clinical Use:
- long term treatment of growth failure in children w/ severe primary IGF-1 deficiency
- s.c. 20 mins before/after meal, twice daily
Side Effect:
* hypoglycemia
Treatment of GH Excess
- benign pituitary tumor
- inc GH & IGF-1 level
- Gigantism in children
- Acromegaly in adult
enlargement of facial structures & limbs
inc mortality due to cardiovascular disease, upper airway obstruction & GI malignancies - use Octreotide
- use Pegvisomant
- use Bromocriptine, Cabergoline, Pergolide, Quinagolide (non-ergot)
Octreotide*
Somatostatin analogue
*for Treatment of GH Excess
Mechanism & Effects:
- G-protein coupled somatostatin (SST) receptor
- inhibit AC & voltage gated Ca2+ channel
- 40x more potent than somatostatin in inhibiting GH release
- affect timing & amplitude of GH release
- synthesis of GH not affected, reduce GH levels
- reduce GH levels & hence symptoms of acromegaly
- no rebound GH hypersecretion after cessation
Clinical Use:
- dec symptoms of acromegaly
- dec symptoms of gastroentero-pancreatic endocrine tumor
potent inhibitory effect on release of peptides of gastroentero-pancreatic endocrine system
- control bleeding of esophageal varices
*drug of choice
inhibition of vasodilatory hormones (e.g. glucagon) indirectly causes splanchnic vasoconstriction & dec portal blood flow
- resistant to enzymatic degradation
- s.c. (mins) or i.m. (weeks)
Side Effect:
- pain & swell at injection site
- anorexia, nausea, vomit, abdominal pain, loose stools, steatorrhea
- increased incidence of gallstones
Pegvisomant
GH receptor antagonist
*for Treatment of GH Excess
Mechanism & Effects:
- polyethylene glycol (PEG) derivation of genetically modified hGH
- bind to GH receptor & prevent dimerization
- potent ability to achieve & sustain normalization of IGF-1 level after s.c.
- unexplained & contraindicated for rare elevation in liver function tests
Clinical Use:
- no effect in reducing tumor size
Bromocriptine
Cabergoline*
Pergolide*
Quinagolide (non-ergot)
Dopamine receptor agonist
Mechanism & Effects:
- selective agonist for D2 receptor
- coupled to Gi -> dec AC activity
- inhibit GH release from tumor cells
- reduce GH levels, hence acromegaly symptoms
- higher doses when treating GH excess than prolactinoma
Clinical Use:
- GH excess to tumor (best on tumors secreting GH & prolactin)
- reduce symptoms of acromegaly
- reduce prolactinoma size & serum prolactin level
- oral
- bromocriptine & cabergoline for intravaginal too
Side Effect:
- nausea, dizzy, postural hypotension & fatigue
- peripheral digital vasospasm & neuropsychological symptoms at high dose
Treatment of Hyperprolactinaemia
- excess prolactin secretion
pituitary lactotroph adenomas - galactorrhea, amenorrhea, gynaecomastia, infertility & hypogonadism
- dopamine = prolactin inhibiting factor
- drug of choice regardless of etiology or sex
- reduction in prolactinoma size & serum prolactin level
Vasopressin*
Vasopressin
Mechanism & Effects:
- V1 receptor on VSM: PLC
- V2 receptor on renal tubule cells: AC
- V3 receptor in ant pit: PLC
- vasoconstriction (V1)
- ADH action (V2) on renal tubules
- release coagulation factor VIII (V2)
- promote release of corticotrophin (V3)
Clinical Use:
- cranial diabetes insipidus
- i.v. or s.c.; given parenterally (mins)
Side Effect:
- spasm of coronary artery
Treatment of Diabetes Insipidus (DI)
- continous production of copious amounts of hypotonic urine
- neurohypophyseal DI: reduced ADH release
- nephrogenic DI; impaired response of nephrons to normal ADH levels
- use vasopressin (i.v. or s.c.)
- use desmopressin (long acting)
Desmopressin*
Vasopressin (analogue)
Mechanism & Effects:
- V2 selective agonist
- diuretic action
- small vasopressor action
- inc plasma factor VIII levels at high dose
- long duration
Clinical Use: - cranial diabetes insipidus - mild hemophilia & von Willebrand's disease - prepare minor surgery inc plasma factor VIII at high dose given as slow i.v. or intranasal - does NOT work w/ severe clotting factor deficiency - does NOT stop hemorrhage - s.c. / oral / intranasal
Side Effect:
- headache, nausea, abdominal cramp, agitation & hypersensitivity reactions
Terlipressin*
Vasopressin (analogue)
Mechanism & Effects:
- V1 selective agonist
- directly constrict mesenteric arterioles & dec portal blood flow
- triglycyl derivative of lysine vasopressin
- converted to lysine vasopressin after i.v. injection
Clinical Use:
- dec portal pressure & control variceal bleeding episodes
Side Effect:
- inc mortality rate due to vasoconstriction (better tgt w/ nitroglycerin)
- concomitant nitroglycerin alleviates some vasoconstriction & better than vasopressin alone
Oxytocin
diagnosis of fetal well-being:
- oxytocin -> uterine contraction -> dec fetal blood supply -> inc fetal HR -> normal
Clinical Use:
- induction of labor (slow i.v.)
- augmentation of dysfunctional labor (slow i.v.)
- management of incomplete, missed or inevitable abortion
- control of post-partum bleeding (fast i.v.)
Side Effect:
- at high dose; transient but severe hypotension w/ tachycardia
- water retention -> water intoxication
- sustained uterine contraction & interfere placental blood flow
damage to fetus or mother
