pituitary hormons analogues

Pharmacology of

The Pituitary Gland

Basics

A. Exocrine gland– Ducts– Lumen and

surfaces

B. Endocrine gland

– Chemical messengers

– Blood stream

Hormones

• Chemical messenger

– Secreted by endocrine gland

– Specific to target– Activate cellular

change

4 Classes of Hormones

1. Peptide/ Protein

2. Steroid e.g. estradiol

3. Amine (single amino acid) e.g. Catecholamines (EPI, DA) from tyrosine

4. Eicosanoid (from arachidonic acid) e.g. prostaglandins.

Hormone + Receptor

Control of Endocrine Function

A. Positive

B. or Negative Feedback mechanisms

•. Self-regulating system

Hypothalamic-Pituitary Axis

• Most feedback loops run through this axis

• HPA mediates growth, metabolism, stress response, reproduction.

• is secondarily in charge of almost everything else.

STIMULUS

HypothalamusReleasing Hormone(Release-Inhibiting

Hormone)

PituitaryStimulating Hormone

GlandHormone

Target

Hypothalamic - pituitary endocrine system

ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopressin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

Anterior pituitary hormones

HORMONE TARGET FUNCTION

Thyroid (TSH) Stimulating

Thyroid gland TH synthesis &release

Growth (GH) Many tissues growth

Adrenocortico-Tropin (ACTH)

Adrenal cortex Cortisol release(androgens)

Prolactin (Prl) Breast Milk production

Follicle (FSH) Gonads Egg/sperm prod.

Luteinizing (LH) Gonads Sex hormones

ProlactinStructure: It is a single polypeptide chain composed of 198 amino acid residues.

It has three sulfide bonds.

Prolactin mechanism of action

Protein tyrosine kinase molecules (JAK)Transcription (STAT) molecules

Actions of Prolactin

Principal hormone of lactation [ with appropriate levels of coricosteroids, estrogen, progestins and insulin]

Abnormal prolactin secretion Deficiency:Pituitary deficency, Rare

Manifestations: Failure of lactation or a luteal phase defect.Treatment: no preparation available.

Increased secretion (Hyperprolactinaemia):• Hypothalamic destruction or• Prolactin-secreting adenomas

Manifestations: 1. Galactorrhea and amenorrhea in females – loss of libido and infertility in

males. [inhibition of GnRH]

2. Compression symptoms with large adenomas.

Treatment: Dopamine agonists

ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopressin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

Dopamine agonistsMechanisn of action:Agonist of G-protein coupled receptors.

Decrease prolactin and growth hormone.

Kinetics:Oral, vaginal or IM Ergot derivatives:Bromocriptine t½ 65 hand Cabergoline t½ 20 h

Non-ergot agent:Quinagolide t½ 7 h

Uses of dopamine agonists

1. Hyperprolactinaemia:Restore ovulation, decrease prolactin and decrease tumour size.

2. Physiological lactation:Rarely cause stroke or coronary thrombosis.

3. Acromegaly:In high doses with other treatments (radiation, surgery or octreotides)

Adverse effects of Dopamine agonist

At initiation of therapy: Nausea, headache, fatigue, postural hypotension and light-headness.

Long term:1. Erythromelalgia: consists of red, tender, painful, swollen feet and,

occasionally, hands, at times associated with arthralgia; symptoms and signs clear within a few days of withdrawal of the causal drug.

2. Psychiatric manifestations.3. Bleeding from peptic ulceration.4. Peripheral vasospasm.5. Pulmonary infiltrates.6. Local irritation.7. Dyskinesias.(extrapyramidal system)

Contraindications:1. Psychotic illness.2. Recent myocardial infarction. 3. Active peptic ulceration. 4. The ergot-derived agonists are best avoided in patients with peripheral

vascular disease.

Pregnancy: safe- Microadenoma → Discontinue (rare increase in tumour size)

- Macroadenomas → Continue

Adverse effects of Dopamine agonists cont.

Growth Hormone (GH)Structure: It is a single polypeptide chain composed of 191 amino acid residues.

It has two disulfide bonds.

GH mechanism of action

Protein tyrosine kinase molecules (JAK)Transcription (STAT) molecules

Actions of GHDirect:1. Anabolic effect on muscle (increase lean body mass).2. Catabolic effect on lipids (decrease adiposity).3. Decrease insulin sensitivity.

4. Produce IGF-I from LIVER, bone, cartilage, muscle and kidneys.

Indirect: through IGF-IInsulin like effect on glucose transport (↑glycogen and lipid synthesis) (↓ lipolysis , gluconeogenesis and proteolysis)

Uses of GHGrowth hormone deficiency:- Genetic or acquired (e.g. traumatic)Childhood: short stature, mild adiposity, hypoglycaemia Adulthood: generalized obesity, reduced muscle mass, asthenia and reduced cardiac output.

A child with short stature: improve growthChronic renal insufficiencyTurner syndrome, Prader-Willi syndrome, Noonan syndrome, Idiopathic short stature

Other uses:Short bowel syndrome (improve GIT function)HIV infectionAnti-agingIncrease muscle mass (athletes)

Toxicity of GHChildren : rare1. Intracranial hypertension.2. Scoliosis during rapid growth, slipped capital femoral epiphysis and

edema. 3. Patients with Prader-Willi syndrome have an increased risk of otitis

media. Hypothyroidism.4. Pancreatitis, gynecomastia, and nevus growth.

Adults:5. Peripheral edema, myalgias, and arthralgias (especially in the hands

and wrists). Carpal tunnel syndrome. 6. Proliferative retinopathy may rarely occur. 7. Increase mortality critically ill patients.

Contraindicated in a patient with a known malignancy!! (No increase incidence).

Increases the activity of cytochrome P450 isoforms.

IGF-I AgonistsIndication:Failure of response to GH

Mecasermin (rhIGF-I)Mecasermin rinfabate (rhIGF-I + rhIFG-I BP-3) ↑ t1/2

Adverse effects:1. HYPOGLYCAEMIA2. Increased intracranial tension3. Elevation of liver enzymes

GH AntagonistsSomatostatin Hypothalamus, pancreasInhibit release of GH, TSH, glucagon, insulin and gastrin.Drawbacks: t½ 1-3 minutes and multiple effects.

Somatostatin Analogs:Octreotide: LanreotideUses: acromegaly, hormone secreted tumur and control of bleeding oesophageal varices.

Adverse effects: 1. Nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with

bulky bowel movements. Biliary sludge and gallstones. 2. Sinus bradycardia and conduction disturbances. 3. Pain at the site of injection is common, especially with the long-acting

octreotide suspension. 4. Vitamin B12 deficiency may occur with long-term use of octreotide.

GH Receptor Antagonists

Pegvisomant: Mutant form of GH which allows dimerization of the receptor but blocks the conformational changes required for signal transduction.

Uses: Acromegaly

Adverse effects: elevated liver enzymes

FSH and LHDynamics: G-protein coupled receptors

Preparations:Menotropins (from urine of menupausal women) (FSH and LH)FSH ONLY: Urofollitropin, follitropin alfa and betaLH ONLY: Lutropin alfa

Uses:Ovulation inductionMale infertility.

Adverse effects: 1. Ovarian hyperstimulation [ovarian enlargment, ascites, hydrothorax,

hypovolaemia and shock] (Hemoperitoneum, fever and thromboembolism amy occur)

2. Multiple pregnancies.

Posterior pituitary hormones

OxytocinStructure:

A 9-amino acid peptide.

Oxytocin mechanism of actionG protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle.

Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction.

Actions of Oxytocin

On uterine muscles:1. In small doses: increases both the frequency and the force of uterine

contractions. 2. At higher doses: it produces sustained contraction.

Lactation:Contraction of myoepithelial cells surrounding mammary alveoli,which leads to milk ejection.

Antidiuretic and pressor activity: weakAt high concentrations, due to activation of vasopressin receptors.

Oxytocin Kinetics Administration:I.V.: for initiation and augmentation of labour. I.M.: for control of postpartum bleeding.

Oxytocin is not bound to plasma proteins.

Elimination: By the kidneys and liver, with t½ 5 minutes.

1. Induction of labour.2. Post partum haemorrhage.3. Uterine inertia.

Uses of Oxytocin

Adverse effects of OxytocinExcessive stimulation of uterine contractions before delivery:Fetal distress, placental abruption, or uterine rupture.

Activation of vasopressin receptors:Fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death.

Hypotension: Bolus injections.

Contraindications:Fetal distress, prematurity, abnormal fetal Presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.

VASOPRESSIN (ANTIDIURETIC HORMONE, ADH)Structure:

A 9-amino acid peptide. released in response to rising

plasma tonicity or falling blood pressure.

ADH mechanism of actionG protein-coupled receptors

ADH Kinetics Adminstration:Vasopressin I.V. or I.M. Elimination: By the kidneys and liver, with t½ 15 minutes.

Desmopressin:[long acting synthetic analog with minimal pressor effect]I.V., I.M., intranasally, or orally

1. Pituitary diabetes insipidus.2. Control of bleeding of oesophageal varices.3. Paralytic ileus.4. Before radiography.

Uses of ADH

Adverse effects of ADH1. Nausea, abdominal cramps, agitation.2. Allergic reactions.3. Overdosage: hyponatremia and seizures.4. Vasoconstriction: vasopressin only.