Hypothalamic and Pituitary Pharmacology Flashcards
Control of anterior pituitary hormone release
a. Release of hypothalamic hormones (releasing factors) under CNS control via neurotransmitters (NE, DA, GABA, 5HT, ACh)
b. Release of anterior pituitary hormones (trophic hormones) is controlled by hypothalamic hormones (either releasing or inhibiting factors) that are synthesized in and released from peptidergic neurons.
i. They are then delivered via portal circulation to the pituitary gland for release into the systemic circulation where they act on endocrine glands to regulate production of hormones that perform ultimate regulatory functions
Control of posterior pituitary hormone release
a. Synthesized in peptidergic neurons in the hypothalamus and then transported to the neuronal terminal in the posterior lobe of pituitary
b. Neuronally released into the systemic circulation and act directly on target tissues to perform regulatory functions
Applications of Hypothalamic-Pituitary-Target Organ Hormones in Endocrine Pharmacology
a. Diagnostic tools: Testing for site of disorder along hypothalamic-pituitary-target organ axis in hypo- or hyperfunctional endocrine states. Often use hypothalamic releasing factors or pituitary trophic factors
b. Management of hypofunction: Hormone replacement (physiologic) therapy for deficiency states
c. Management of hyperfunction: Suppression of hormone synthesis or effect (nonhormonal agents)
d. Alteration of normal endocrine states: Interference with normal function in order to achieve desired state, e.g., oral contraceptives or anabolic steroids (supraphysiologic doses)
e. Control of nonendocrine disorders: Drug therapy for variety of diseases using pharmacologic doses of hormones, e.g., glucocorticoids for inflammatory diseases
Growth Hormone (aka GH, Somatropin)
Summary
a. Growth Hormone:
i. recombitant DNA creates: Somatropin, Somatrem
b. Pharmacodynamics
i. Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine
ii. Decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly
d. Uses: mostly for children with deficiency
i. Recombinant human growth hormone now available; until 1985 only source was human cadaver, use was discontinued due to possible prion contamination [Creutzfeldt-Jakob disease].
ii. Critical–> Replacement therapy in children with deficiency
- Given daily at bedtime via SC injection (more effective, mimics natural release pattern) or 3 times a week IM - SR preparations for weekly SC injection are in development
e. If growth hormone insensitive (receptor mutation - Laron dwarf) can treat with recombinant IGF-1 (Mecasermin-Increlex); concern with hypoglycemia, so carb intake prior to injection
Illicit use of Growth Hormone
a. Illicit: Use by athletes to increase muscle mass and improve performance despite lack of controlled studies and in violation of regulations (banned by IOC / MLB) and standard medical practice
i. NOTE: Many oral preparations containing “stacked” amino acids that reportedly stimulate GH release have been marketed as nutritional supplements.
ii. Again, validation in controlled trials is lacking, but they are part of multibillion dollar anti-aging and performance-enhancing programs.
b. Illicit: Use by healthy elderly for “anti-aging” effects
i. General consensus from limited studies suggests GH use is associated with small changes in body composition and increased rates of adverse events (edema, joint pain, muscle pain, carpal tunnel syndrome, skin numbness and tingling - may also increase growth of pre-existing malignant cells and increase the possibility of developing diabetes)
- Cannot be recommended
Growth Hormone Releasing Hormone (GHRH)
Summary
a. Pharmacology
i. Rapidly stimulates GH synthesis and secretion via binding to GPCR coupled to Gs —->increasing cAMP and Ca++ levels in somatotrophs - no receptor down-regulation with continuous stimulation
b. NOTE: Ghrelin is a 28 AA peptide that also stimulates GH release via a different GPCR.
i. It is secreted predominantly by endocrine cells in stomach and also stimulates appetite and increases food intake.
ii. Acts in complex manner to integrate functions of GI tract, hypothalamus, and pituitary.
c. Uses
i. Sermorelin -GHRH29 withdrawn from US market in 2008
ii. Diagnostic evaluation of patients with idiopathic GH deficiency
iii. Potential use in GH-deficient children (preserves feedback at pituitary level - smaller molecule than GH, less expensive); potentially fewer side effects. However, synthetic human growth hormone is now usually used for treatment of GH deficiency.
iv. Tesamorelin is a GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART) - reduces excess abdominal fat
Somatostatin (aka SST, Growth Hormone-Inhibiting Hormone, Somatotropin Release-Inhibiting Factor)
Summary
a. Pharmacology
i. Present in hypothalamus, nervous system, gut, endocrine and exocrine glands - function varies
ii. Critical*–> Inhibits Growth Hormone release via GPCR coupled to Gi decreasing cAMP levels and activating K+ channels
b. Physiology:
i. Decreases secretion of gastric enzymes and acid - decreased GI motility - suppresses release of serotonin and gastroenteropancreatic peptides
ii. Reduces insulin and glucagon release - complex effects on blood glucose
iii. Interferes with TRH ability to release TSH
c. Pharmacokinetics of Somatostatin and Analogs
i. Somatostatin: T1/2 following exogenous administration only 3-4 min limiting therapeutic usefulness - kidney has significant role in clearance
ii. Octreotide: plasma t1/2 is 90 min (duration is 12 hrs); given SC every 6-12 hours
iii. Octreotide: given intramuscularly every 4 weeks
iv. Lanreotide: given subcutaneously every 4 weeks
d. Uses of Somatostatin Analogs
Pituitary - excess of growth hormone
1. Acromegaly (adults - rare, most commonly due to pituitary somatotroph adenoma) and gigantism (children - extremely rare)
2. Surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery
3. Long-acting somatostatin analog is preferred pharmacotherapy - utilized after response seen to SC octreotide
e. Alternatives to Somatostatin
i. Dopamine agonists may inhibit GH secretion in some patients, but not as effective as SST analogs.
-Cabergoline is preferred agent for adjuvant management of acromegaly with advantage of oral administration
ii. GH receptor antagonist: Pegvisomant is a mutated GH molecule with polymers attached to extend its half-life. Binds to receptor, blocking GH access, but does activate signaling transduction. Single daily dose administered subcutaneously.
f. Non-Pituitary clinical use
i. Control of bleeding from esophageal varices and GI hemorrhage - direct action on vascular smooth muscle to constrict splanchnic arterioles. Fewer side effects than vasopressin.
Growth Hormone Physiological Effects
a. Produces anabolic and metabolic effects: Positive nitrogen balance, stimulation of lipolysis, increased free fatty acids and blood glucose
b. At pharmacologic doses GH works indirectly to stimulate synthesis of insulin-like growth factors (IGF-1, IGF-2 in growth plate cartilage and liver) promoting linear and skeletal muscle growth
Uses of Growth Hormone Releasing Hormone (GHRH)
a. Sermorelin- withdrawn from US market in 2008
b. Diagnostic evaluation of patients with idiopathic GH deficiency
c. Potential use in GH-deficient children (preserves feedback at pituitary level - smaller molecule than GH, less expensive); potentially fewer side effects.
i. However, synthetic human growth hormone is now usually used for treatment of GH deficiency.
d. Tesamorelin is a GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART) - reduces excess abdominal fat
Pharmacology and Physiology of Somatostatin
a. Pharmacology
i. Present in hypothalamus, nervous system, gut, endocrine and exocrine glands - function varies
ii. Critical*–> Inhibits Growth Hormone release via GPCR coupled to Gi decreasing cAMP levels and activating K+ channels
b. Physiology:
i. Decreases secretion of gastric enzymes and acid - decreased GI motility - suppresses release of serotonin and gastroenteropancreatic peptides
ii. Reduces insulin and glucagon release - complex effects on blood glucose
iii. Interferes with TRH ability to release TSH
Somatostatin pharmacokinetics and its Clinical Uses for Pituitary GH excess
a. Pharmacokinetics of Somatostatin and Analogs
i. Somatostatin: T1/2 following exogenous administration only 3-4 min limiting therapeutic usefulness - kidney has significant role in clearance
ii. Octreotide: plasma t1/2 is 90 min (duration is 12 hrs); given SC every 6-12 hours
iii. Octreotide: given intramuscularly every 4 weeks
iv. Lanreotide: given subcutaneously every 4 weeks
b. Uses of Somatostatin Analogs
Pituitary - excess of growth hormone
1. Acromegaly (adults - rare, most commonly due to pituitary somatotroph adenoma) and gigantism (children - extremely rare)
- Surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery
- Long-acting somatostatin analog is preferred pharmacotherapy - utilized after response seen to SC octreotide
c. Non-Pituitary clinical use
i. Control of bleeding from esophageal varices and GI hemorrhage - direct action on vascular smooth muscle to constrict splanchnic arterioles.
ii. Fewer side effects than vasopressin.
Alternatives to Somatostatin
For decreasing Growth Hormone excess
a. Dopamine agonists may inhibit GH secretion in some patients, but not as effective as SST analogs.
i. Cabergoline is preferred agent for adjuvant management of acromegaly with advantage of oral administration
b. GH receptor antagonist:
i. Pegvisomant is a mutated GH molecule with polymers attached to extend its half-life.
ii. Binds to receptor, blocking GH access, but does activate signaling transduction. Single daily dose administered subcutaneously.
Side Effects of Somatostatin
Side Effects
a. Transient deterioration in glucose tolerance (hyperglycemia) then subsequent improvement
i. *critical to know that it can cause hyperglycemia
b. Abdominal cramps, loose stools
c. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)
Prolactin
Summary
a. Pharmacodynamics
i. Prolactin release is under inhibitory control by hypothalamic dopamine at D2 receptors
ii. Main stimulus for release is suckling - causes 10-100-fold increase within 30 min
iii. Stimulates milk production if appropriate levels of insulin, estrogens, progestins, and corticosteroids are present
b. Uses
i. Hypoprolactinemia - No preparation available for prolactin deficiency
ii. Hyperprolactinemia (prolactinomas) - These pituitary adenomas are the most amenable to pharmacotherapy because of the availability of dopamine agonists that both decrease secretion and reduce tumor size.
- All available as oral preparations.
iii. Bromocriptine - prototype agent of long-standing use
- Ergot derivative that also activates D1 receptors
- Frequent side effects include nausea-vomiting, headache, and postural hypotension; less frequently can see psychosis or insomnia
iv. Cabergoline - has become preferred agent for hyperprolactinemia
- More selective for D2 receptor and more effective in reducing prolactin secretion
- Better tolerated, less nausea, but may cause hypotension and dizziness
- Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors)
Clinical TX involving Prolactin
a. Hypoprolactinemia - No preparation available for prolactin deficiency
i. No TX for this yet
b. Hyperprolactinemia (prolactinomas) - These pituitary adenomas are the most amenable to pharmacotherapy because of the availability of dopamine agonists that both decrease secretion and reduce tumor size.
i. All available as oral preparations.
ii. Use Bromocriptine or Cabergoline
c. Pharm Treatment for Hyperprolactinemia
- Bromocriptine - prototype agent of long-standing use
i. Ergot derivative that also activates D1 receptors
ii. Critical*–>Frequent side effects include nausea-vomiting, headache, and postural hypotension; less frequently can see psychosis or insomnia - Cabergoline - has become preferred agent for hyperprolactinemia
i. More selective for D2 receptor and more effective in reducing prolactin secretion
ii. Critical* Better tolerated, less nausea, but may cause hypotension and dizziness
iii. Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors)
Between Bromocriptine and Carbergoline, what is the better TX for Hyperprolactinemia
Cabergoline - has become preferred agent for hyperprolactinemia
i. More selective for D2 receptor and more effective in reducing prolactin secretion
ii. Critical* Better tolerated, less nausea, but may cause hypotension and dizziness
- more side effects from bromocriptine
iii. Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors)
Vasopressin (aka Antidiuretic Hormone, ADH)
Physiological/Pharm Summary
a. Structure / Pharmacokinetics
• Half-life about 20 min
• Must be administered parenterally (IV, IM, intranasally)
Desmopressin: ADH analog that is more stable to degradation, t1/2 is 1.5-2.5 hrs
b. Pharmacodynamics
• Critical role in control of water content throughout body via actions on cells in distal nephron and collecting tubules in kidney
• Released from supraoptic nuclei of hypothalamus
i. Main stimulus for release is rising blood osmolality
ii. Also released in response to a decrease in circulating blood volume
iii. Recall that release can be inhibited by alcohol
c. Physiological Actions
• Renal actions are mediated by V2 receptors (GPCRs coupled to Gs)
i. Main effect is to increase the rate of insertion of water channels (aquaporins) into luminal membrane–> increase water permeability—> leading to an antidiuretic effect
ii. Also activates urea transporters and increases Na+ transport in distal nephron
iii. Non-renal V2 actions include release of coagulation factor VIII and von Willebrand’s factor
• ADH-vasopressin actions at V1 receptors (GPCRs coupled to Gq)
i. Mediates vasoconstriction of vascular smooth muscle ii. BUT pressor responses occur in vivo only at much higher concentrations than those that produce maximal antidiuresis
Vasopressin (aka Antidiuretic Hormone, ADH)
Pharmacologic Therapy of Hypofunction
Hypofunction
a. Central Diabetes Insipidus - can result from head injury (trauma or surgery), pituitary tumors, cerebral aneurysm, or ischemia—> inadequate ADH secretion from posterior pituitary
1. Desmopressin is treatment of choice
i. Nasally 1-2/day individualized to response.
ADRs: may cause nasal irritation
ii. Orally 2-3/day (bioavailability 5-10%), particularly useful in patients with sinusitis from nasal preps. ADRs: GI symptoms, asthenia, mild elevation of live enzymes
iii. ADRs: Headache, nausea, abdominal cramps, allergic reactions, water intoxication
- Chlorpropamide (1st generation sulfonylurea)
i. Potentiates action of small or residual amounts of ADH - mechanism not clear
ii. Option for patients intolerant (side effects-allergy) to desmopressin
b. Nephrogenic Diabetes Insipidus - can be congenital or drug-induced—> inadequate ADH actions
i. Congenital
• Diverse receptor and aquaporin mutations are known
ii. Drug-induced
• Lithium: reduces V2-receptor mediated stimulation of adenylyl cyclase. As many as 1/3 of patients treated with Li+ may develop nephrogenic diabetes insipidus
• Demeclocyline (tetracycline antibiotic): mechanism not completely understood but possibly acts via block of ADH binding to receptor
iii. Treatment–> The two treatments to know for nephrogenic diabetes insipidus is Thiazides and NSAIDS
• Low salt, low protein diet
• Thiazide diuretics: Paradoxically reduce the polyuria of patients with DI.
-Mechanism not completely understood but antidiuretic effect parallels ability to cause natriuresis - used in doses that mobilize edema fluid.
- NSAIDs: Since prostaglandins attenuate ADH-induced antidiuresis, inhibition of PG synthesis by indomethacin may relate to the antidiuretic response seen. Indomethacin has greatest efficacy among NSAIDs.
- Thiazides and indomethacin are also used as combined therapy
Central Diabetes Insipidus
a. Central Diabetes Insipidus - can result from head injury (trauma or surgery), pituitary tumors, cerebral aneurysm, or ischemia—> inadequate ADH secretion from posterior pituitary
Treatments
b. Desmopressin is treatment of choice
i. Nasally 1-2/day individualized to response.
ADRs: may cause nasal irritation
ii. Orally 2-3/day (bioavailability 5-10%), particularly useful in patients with sinusitis from nasal preps. ADRs: GI symptoms, asthenia, mild elevation of live enzymes
iii. ADRs: Headache, nausea, abdominal cramps, allergic reactions, water intoxication
c. Chlorpropamide (1st generation sulfonylurea)
i. Potentiates action of small or residual amounts of ADH - mechanism not clear
ii. Option for patients intolerant (side effects-allergy) to desmopressin
Nephrogenic Diabetes Insipidus
Summary to Treat
Nephrogenic Diabetes Insipidus - can be congenital or drug-induced—> inadequate ADH actions
a. Congenital Nephrogenic DI
i. Diverse receptor and aquaporin mutations are known
b. Drug-induced Nephrogenic DI
i. Lithium: reduces V2-receptor mediated stimulation of adenylyl cyclase. As many as 1/3 of patients treated with Li+ may develop nephrogenic diabetes insipidus
ii. Demeclocyline (tetracycline antibiotic): mechanism not completely understood but possibly acts via block of ADH binding to receptor
c. Treatment–> The two treatments to know for nephrogenic diabetes insipidus is Thiazides and NSAIDS
i. Non-pharm TX–> Low salt, low protein diet
- Thiazide diuretics: Paradoxically reduce the polyuria of patients with DI.
i. Mechanism not completely understood but antidiuretic effect parallels ability to cause natriuresis - used in doses that mobilize edema fluid.
ii. somehow stops the patient from loosing more water - NSAIDs: Since prostaglandins attenuate ADH-induced antidiuresis, inhibition of PG synthesis by indomethacin may relate to the antidiuretic response seen.
i. Critical*–> Indomethacin has greatest efficacy among NSAIDs.
•Thiazides and indomethacin are also used as combined therapy
Vasopressin (aka Antidiuretic Hormone, ADH)
Pharmacological Therapy of Hyperfunction (overproduction of ADH)
a. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) - incomplete suppression of ADH secretion under hypoosmolar conditions
i. Produced by multitude of disorders including malignancies, pulmonary diseases, CNS trauma-infections-tumors
ii. Certain Drug classes also cause SIADH
b. Treatment
i. Restriction of free water intake is initial conservative approach
ii. Demeclocyline inhibits ADH effect on distal tubule and has been preferred drug in patients with inadequate response to conservative measures
c. V2 receptor antagonist - potential therapeutic advance for hyponatremia (also tried in HF)
1. Tolvaptan - oral route, but use limited by cost, increase in thirst
2. Conivaptan - IV infusion (useful in hospitalized SIADH patients) - if severe symptomatic hyponatremia present, conivaptan can be given with hypertonic saline (3%), permitting a more rapid initial correction
d. BUT: Warning against too rapid correction of hyponatremia—> cerebellar pontine myelinolysis—> serious consequences and fatalities
i. Both are eliminated by CYP3A4 and associated with variety of drug-drug interactions
Additional Therapeutic Applications
a. V1 Receptor-Mediated [Vasopressin]
i. Attenuates pressure and bleeding in esophageal varices via vasoconstriction of splanchnic arterioles - octreotide better tolerated and now preferred if drug used +- endoscopy
ii. Used as a vasopressor for treatment of patients with severe septic shock
iii. Alternative to epinephrine in ACLS protocol for shock-refractory ventricular tachycardia / fibrillation (long duration of action may have adverse effects on survival)
b. V2 Receptor-Mediated
i. Option in nocturnal enuresis - oral desmopressin [DDAVP]: 30% of children are full responders and 40% have a partial response
ii. Von Willebrand’s disease (elevates von Willebrand factor) and moderate hemophilia A (elevates factor VIII) - IV desmopressin
Growth Hormone (aka Somatropin)
Pharmacokinetics
a. Structure / Pharmacokinetics
i. 191 amino acid peptide with 2 sulfhydryl bridges
ii. Produced with recombinant DNA technology
b. Native GH AA sequence: Drug to know–>Somatropin
c. Can be given SC or IM
i. subcutaneous
d. Circulating t1/2 of 25 min; peak levels in 2-4 hrs, active levels persist 36 hrs
* know its active levels
Growth Hormone (aka Somatropin)
Pharmacodynamics
a. Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine (and Ghrelin)
b. Release decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly
c. Growth Hormone works indirectly
i. Stimulate synthesis of IGF-1in growth plate cartilage and liver—> linear and skeletal muscle growth
d. Coupled to receptors of cytokine superfamily
e. Produces anabolic and metabolic effects—> positive nitrogen balance, increase lipolysis—> increase FFA and glucose
Growth Hormone (aka Somatropin)
Stuff to know
a. Structure / Pharmacokinetics
1. Can be given SC or IM
i. subcutaneous
2. Circulating t1/2 of 25 min
3. active levels persist 36 hrs
b. Mechanism:
1. Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine (and Ghrelin)
- Release decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly
- Growth Hormone works indirectly
i. Stimulate synthesis of IGF-1in growth plate cartilage and liver—> linear and skeletal muscle growth - Coupled to receptors of cytokine superfamily
- Produces anabolic and metabolic effects—> positive nitrogen balance, increase lipolysis—> increase FFA and glucose
Clinical Use:
- GH deficiency - replacement therapy in children
i. Given daily at bedtime via SC injection - more effective than 3 times a week IM (mimics natural release pattern)
ii. Sustained release preparations for weekly SC injection are in development
iii. Yearly cost $10,000-50,000 based on patient’s weight - GH insensitive deficiency
i. GH receptor mutation - Laron dwarf
ii. Treat with recombinant IGF-1 (mecasermin) - concern with hypoglycemia, so carb intake prior to SC injection - Use in children with idiopathic short stature controversial
i. Response to GH is highly variable - responders showing only modest growth increase
