GnRH Agonists & Antagonists

GnRH AGONISTS & ANTAGONISTS

GnRH AGONISTS & ANTAGONISTSPresented By: Dr. Manas Kr. Nath, PGT, Deptt. of Pharmacology, SMCH.Moderated By: Dr. Pinaki Chakravarty, Associate Professor, Deptt. of Pharmacology, SMCH.

Learning Objectives:Introduction.General Considerations.GnRH Agonists.Mechanism of Action.Pharmacokinetics.Pharmacodynamics.Individual Agents.Clinical Uses.GnRH Antagonists.Mechanism of Action.Individual Agents.Clinical Uses.

17-11-20162Deptt. of Pharmacology, SMCH.

Introduction:Agonadotropin releasing hormone analogue(GnRH analogue), also known as aluteinizing hormone releasing hormone agonist(LHRH agonist) orLHRH analogueis a syntheticpeptide drug (a decapeptide)modeled after the humanhypothalamic gonadotropin releasing hormone(GnRH). A GnRH analogue interacts with the GnRHreceptorand modify the release ofpituitary gonadotropins -Follicle Stimulating Hormone (FSH)andLuteinizing Hormone (LH) for therapeutic purposes.17-11-20163Deptt. of Pharmacology, SMCH.

Contd..A gonadotropin-releasing hormone agonist (GnRH agonist) is an analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH.These agents after their initial stimulating action eventually cause a paradoxical and sustained drop in gonadotropin secretion.This phase is reversible.17-11-2016Deptt. of Pharmacology, SMCH.4

Contd..A gonadotropin-releasing hormone antagonist (GnRH antagonist) is an analogue that blocks the GnRH receptor resulting in an immediate drop in gonadotropin (FSH, LH) secretion.This results in blockage of natural ovulation.17-11-2016Deptt. of Pharmacology, SMCH.5

General Considerations:Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotroph cells. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.17-11-2016Deptt. of Pharmacology, SMCH.6

Contd..This pulsatile secretion is governed by the feedback mechanisms from androgens and estrogens.Low-frequency GnRH pulses are required for FSH release, whereas high-frequency GnRH pulses stimulate LH pulses.In males, GnRH is secreted in pulses at a constant frequency while in females, the frequency of the pulses varies during the menstrual cycle, with a large surge of GnRH just before ovulation.Sustained non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism.

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Contd..17-11-2016Deptt. of Pharmacology, SMCH.8

Contd..17-11-2016Deptt. of Pharmacology, SMCH.9

Contd..During the reproductive years, pulsatile GnRH activity is crucial for successful reproductive function , which is controlled by the feedback mechanism.However, once pregnancy is established, GnRH activity is not required.Pulsatile activity can be disrupted by hypothalamic-pituitary disease.Increased levels of Prolactin decreases the GnRH activity while increase in Insulin levels increases its pulse activity.17-11-2016Deptt. of Pharmacology, SMCH.10

GnRH AGONISTS17-11-2016Deptt. of Pharmacology, SMCH.11

GnRH Agonists:Various GnRH Agonists available for clinical use are:Gonadorelin.Goserelin.Nafarelin.Triptorelin.Buserelin.Deslorelin (under trial).Histrelin.Leuprolide.17-11-2016Deptt. of Pharmacology, SMCH.12

Mechanism of Action:GnRH agonists binds to specific G-protein coupled receptors on the pituitary gonadotrophs.

Prolonged activation of GnRH receptors by GnRH agonists leads to desensitization and down regulation of GnRH receptors, thereby suppressing gonadotrophin (FSH & LH) secretion.17-11-2016Deptt. of Pharmacology, SMCH.13

Pharmacokinetics:Gonadorelin can be administered intravenously or subcutaneously.GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant.The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours.Duration of treatment depends on the clinical condition.17-11-2016Deptt. of Pharmacology, SMCH.14

Pharmacodynamics:Pulsatile GnRH release is responsible for stimulating LH and FSH production during the fetal and neonatal period.From the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary gland exhibits very low sensitivity to GnRH. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitivity to GnRH increases, which is due in part to the effect of increasing concentrations of gonadal steroids.17-11-2016Deptt. of Pharmacology, SMCH.15

Contd..In the menstrual cycle, highest amplitude of GnRH pulses occur during the luteal phase and the highest frequency occur late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion.Pulsatile intravenous administration of gonadorelin every 14 hours stimulates FSH and LH secretion.Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response.


Contd..During the first 710 days, an agonist effect results in increased concentrations of gonadal hormones in males and females (flare).Continued presence of GnRH results in an inhibitory action which manifests as a drop in the concentration of gonadotropins and gonadal steroids. This occurs due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH.17-11-2016Deptt. of Pharmacology, SMCH.17

GonadorelinGonadorelin is an acetate salt of synthetic human GnRH.Half life: Initial 2-10 min, Terminal 10-40 min.Metabolized to small peptides.Excreted via urine.Adverse Effects:Thrombophlebitis.Ovarian Hyperstimulation.


Goserelin

Half life: 2-4 hours.Poorly bound to plasma protein.Excreted through urine.Contraindicated in cases of Pregnancy, Lactation & undiagnosed abnormal vaginal bleeding.


Contd..Adverse effects:Hot flushes.Vaginitis.Reduced libido, erectile & sexual dysfunction.Mood Swings.Depression.Sweating.Acne.Diarrhoea.Breast Atrophy.Peripheral Oedema.UTI.Bone pain.Headache.17-11-2016Deptt. of Pharmacology, SMCH.20

Nafarelin

Highly protein bound.Metabolized by peptidase to small peptides.Excreted through urine (44%-55%) & feces (19%-44%).Half life: 3 hours.Contraindicated in cases of Pregnancy, Lactation & undiagnosed abnormal vaginal bleeding.


Contd..Adverse Effects:Acne.Hot flushes.Mood swings.Vaginal dryness.Decreased libido.Muscle pain.Aggravated sinusitis.17-11-2016Deptt. of Pharmacology, SMCH.22

TriptorelinHalf life: 3 hours.Not bound to plasma protein.Excreted through urine.Contraindicated in cases of females, children & hypersensitivity reactions.Adverse effects:Hot flushesSkeletal pain.17-11-2016Deptt. of Pharmacology, SMCH.23

BuserelinHalf life: 1-1.5 hours.Excreted mainly through urine.Contraindicated in cases of hypersensitivity reactions, undiagnosed abnormal vaginal bleeding, non-hormone dependent prostrate cancer.17-11-2016Deptt. of Pharmacology, SMCH.24

Contd..Adverse effects:Hot flushes..Reduced libido, sexual dysfunction.Mood Swings.Depression.Oedema.Breast pain.Headache.Hirsuitism.Myalgia.


HistrelinIt is a nonapeptide synthetic analogue of GnRH.Half life: 4-5 hours.highly bound to plasma protein.Excreted through urine.Contraindicated in cases of Pregnancy, Lactation & Children.


Contd..Adverse effects:Hot flushesRenal impairment (

GnRH Agonists & Antagonists

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