Transcript presentation source

Drugs and the Treatment of
Pituitary Disease
Joe Collier
Aims
• The session will describe:
– how drugs can modify pituitary function,
– how drugs can be used to treat patients with
abnormal circulating blood levels of:
• prolactin, growth hormone, testosterone, oestrogen
and vasopressin.
– Key pharmacodynamic and pharmacokinetic
properties of the drugs will be reviewed, as will
the main unwanted effects
• At the end of the session you should be able to
describe
– how drugs are used to treat patients with abnormal
circulating blood levels of: prolactin, growth hormone,
testosterone, oestrogen and vasopressin.
– the actions of dopamine agonists (bromocriptine),
growth hormone and its analogue (somatropin)
gonadorelin analogues (goserelin), somatostatin
analogues (octreotide), oestrogen receptor antagonists
(clomiphene) and carbamazepine and the vasopressin
analogues desmopressin, explaining, where possible,
the pharmacokinetics of these drugs.
– briefly their interactions and unwanted effects and the
principles of their use.
Effects of circulating prolactin
• Prolactin is a 198 amino acid single chain
polypeptide released from the anterior pituitary.
– normal (physiological) properties: initiation and
maintenance of lactation (effects on breast tissue
balanced by oestrogen)
– pathophysiological effects (as in hyperprolactinaemia):
• infertility (amenorrhoea, anovulatory cycles or sperm motility
problems, reduced semen volume)
• lack of libido
• galactorrhoea
• gynaecomastia
Control of Prolactin Release
• Primarily through an inhibitory (braking)
system whereby dopamine released by the
hypothalamus inhibits prolactin release
from the anterior pituitary.
• There is also probably a prolactin
releasing factor released by the
hypothalamus which promotes prolactin
release from the anterior pituitary.
Causes of hyperprolactinaemia
• Anything that reduces dopamine inhibition:
– (hypothalamic disease)
– (stalk section)
– inhibitors of dopamine production or release:
• methyl dopa
• reserpine
• inhibitors of dopamine receptors
– antipsychotics (haloperidol, chlorpromazine etc)
– metoclopramide
– (pituitary tumour)
Reducing Prolactin Levels
 Stop dopamine antagonist
 Give dopamine agonist such as bromocriptine (used
for inhibiting lactation in women not wishing to
breast feed). Unwanted effects are dose-dependent
eg nausea, vomiting, hypotension, stroke,
confusion, dyskinetic movements.
 Give stilboestrol to potentiate the negative
oestrogen effect (post partum). The drug must be
started straight after birth. The risks include
increased thromboembolism and uterine bleeding.
Pituitary Growth hormone (GH)
• 191 amino acid single chain polypeptide;
synthetic derivative known as somatropin.
• Control. GH release is regulated by
hypothalamic:
 Growth Hormone-Releasing Factor (GHRF;
synthetic derivative known as sermorelin)
 Growth Hormone-Release-Inhibiting Factor
(GHRIF or somatostatin; synthetic derivative
known as octreotide)
 Dopamine which inhibits release
Treating GH Deficiency
• This uses somatropin, produced by recombinant
DNA technology, with the same amino acid
sequence as naturally occurring GH, is given by
subcutaneous or im injection.
• Uses:
 Children; somatropin is given to those with pituitary
insufficiency and reduced growth
 In adults; somatropin is given to those with Turner
syndrome and (sometimes) those with GH- deficiency
syndromes (lassitude, muscle weakness, heart failure,
diminished bone density). The place of GH in adult
deficiency syndromes is not yet established.
Drug treatment of excess growth
hormone secretion
• Bromocriptine (orally up to four times daily,
which acts as a dopamine receptor stimulant
and so inhibits GH release. Doses higher
than used in suppression of lactation and
unwanted effects more pronounced;
tolerance to these develops with repeated
exposure.
Drug treatment of excess growth
hormone secretion
• Octreotide. This is a synthetic somatostatin
given by im or subcutaneous injection three
times daily (reserved for those in whom
surgery or bromocriptine are unsuccessful
or inappropriate). A new depot formulation
of octreotide for im injection (Sandostatin
LAR) needs to be given only monthly.
Treatment of low levels of testosterone
 Secondary to hypothalamic disease
 GnRH (gonadorelin) subcutaneuosly in pulsed doses
 Secondary to pituitary disease
 Human chorionic gonadotrophin (this has LH
activity).
 Primary testicular failure testosterone:




oral capsules (twice daily, unpredictable),
im injections (every three weeks),
subdermal implants (every 4-6 months)
skin patches (predicatable, once daily).
Treatment to lower testosterone
• Give synthetic GnRH (gonadorelin) such as
goserelin as a subcutaneous injection once
monthly. This initially stimulates LH release
from the pituitary, then after 2-3weeks,
inhibits LH release due to receptor
desensitisation. NB The initial LH release
gives a testosterone burst (flare) which
might need to be blocked by a testosterone
receptor antagonist such as flutamide.
Oestrogen
• Physiological control. Oestrogen is
synthesised in the ovary in response to
follicular stimulating hormone (FSH) and
luteinising hormone(LH) released from the
anterior pituitary. These are synthesised in
response to hypothalamic GonadotrophinReleasing Hormone (GnRH; gonadorelin).
Circulating oestrogen levels inhibit
gonadorelin release.
Oestrogen
 Raising the levels of LH and FSH so
stimulating ovulation
 Give a central oestrogen receptor blocker
such as the stilboestrol analogue
clomiphene (taken orally for 5 days).
Lowering the levels of oestrogens (as for
example in endometriosis or breast cancer).
Give a synthetic gonadorelin such as
goserelin.
Vasopressin (anti diuretic hormone
ADH)
• A nonapeptide synthesised in the hypothalamus
and subsequently secreted from the posterior
pituitary in response to increased blood osmotic
pressure.
• Pharmacological properties of vasopressin:
– increases permeability of the collecting ducts to water
so causing water retention (reabsorption).
– vasoconstriction (arteries, arterioles & venules).
– increases gut motility. Note that its effects on vessels
and tubule are about equal.
Diabetes insipidus treatment
• Desmopressin (desamino-8-D-arginine vasopressin
- ADH activity:vasoconstrictor activity 3000:1)
• Desmopressin is destroyed in the gut and has a
half-life of 75min. Give as nasal instillation, spray
or subcutaneous injection 2-3 times daily.
• Additional approaches: Chlorpropamide (increases
renal sensitivity to ADH), carbamazepine
(potentiates release of ADH from pituitary)
bendrofluazide (paradoxically effects renal tubules
to cause water retention).