Introduction to endocrine Pharmacology

THE PITUITARY GLAND IS DIVIDED INTO THE ANTERIOR, MID AND POSTERIOR LOBES.

GROWTH, FOLLICULAR STIMULATING, LEUTINIZING, THYROID STIMULATING, ADRENCORTICOTROPHIC HORMONES AND PROLACTIN.

THE MID LOBE SECRETES MELANOCYTE STIMULATING HORMONE,

POSTERIOR LOBE SECRETES ANTIDIURETIC HORMONE(VASOPRESIN) AND OXYTOCIN.

Secreted by somatotropes which account for 40% of hormone secreting cells of anterior pituitary.
GHRH(+ input ):enhances GH production.
GHRH PRODUCED FROM HYPOTHALAMUS
BINDS G PROTEIN COUPLED RECEPTORS ON SOMATOTROPES IN ANTERIOR PITUITARY
ELEVATES INTRACELLULAR C AMP AND CA2+.
GHRH ALSO STIMULATES PRODUCTION OF THYROTROPIN

SOMATOSTATIN(-INPUT): Inhibits GH production
FROM MORE WIDELY DISTRIBUTED NEURONES AND NEUROENDORINE CELLS IN GIT AND PANCREAS
BINDs TO AND ACTIVATES G COUPLED RECEPTORS(5 SUBTYPES IDENTIFIED).


INHIBITION OF C AMP ACCUMULATION`
K+ CHANNELS ACTIVATION
TYROSINE PHOSPHATASE ACTIVATION

B-ADRENERGIC REC AGONISTS, FFAs, INSULIN LIKE GROWTH FACTORS-1(IGF-1), GH, ORAL GLUCOSE IN OGTT

DOPAMINE, 5-HT, ALPHA-2 ADRENERGIC REC AGONISTS, HYPOGLYCAEMIA, EXERCISE, STRESS, EMOTIONAL EXCITEMENT, PROTEIN RICH FOODS

ARGININE, GLUCAGON, INSULIN INDUCED HYPOGLYCAEMIA, CLONIDINE, LEVODOPA. INCREASE GH IN 45-90 MINS.

GH BINDS GH RECEPTOR ON EXTRACELLULAR DOMAIN, THEN SIGNAL TRANSDUCTION OCCURS.
IGF-1AND IGF-2(insulin like growth factor)
GH INDUCES IGF-1 TO EXERT ITS ANABOLIC AND GROWTH PROMOTING ACTIONS INDIRECTLY.
GH ACTS ON ADIPOCYTES TO CAUSE LIPOLYSIS AND ON HEPATOCYTES TO CAUSE GLUCONEOGENESIS

DISEASES: RECEPTOR RESISTANCE DWARFISM(E.G. THE LARON SYNDROME OF GH RESISTANT DWARFISM), DECREASED GH PRODUCTION(USUALLY HYPOTHALAMIC), AIDS ASSOCIATED WASTING,GH EXCESS.

GH IS SPECIES-SPECIFIC, HUMANS NOT RESPOND TO NON PRIMATE SOURCES.
GH FROM CADAVA CAUSED FATAL CNS DISEASE
RECOMBINANT DNA TECHNOLOGY PREPS NOW USED

1. SOMATOSTATIN ANALOGS
OCTREOTIDE(SYNTHETIC DERIVATIVE OF SOMATOSTATIN) 100UG TID SC. SLOW RELEASE FORM GIVEN I/M ONCE EVERY 4 WEEKS 20-30 MG. GOAL IS TO DECREASE GH LEVELS TO LESS THAN 2Ug/liter FF AN OGTT AND TO BRING IGF-1 TO NORMAL RANGE FOR AGE AND SEX
LANREOTIDE30MG I/M 10- OR 14- DAY INTERVAL ADMINISTRATION

2.DOPAMIN REC AGONISTS
THESE PARADOXICALLY DECREASE GH SECRETION. CARBERGOLINE

3.GH ANTAGONISTS
BIND GH RECs BUT DO NOT CAUSE SIGNALLING.PEGVISOMANT

PROLACTIN IS SYNTHESIZED IN LACTOTROPES
SYNTHESIS AND SECRETION IN FOETAL PITUITARY STARTS FIRST FEW WEEKS OF GESTATION

INCREASE IN PROLACTIN SECRETIN(ALSO, GROWTH HORMONE SECRETION): DURING SLEEP, STRESS, HYPOGLYCAEMIA, EXERCISE& OESTROGEN

DOPAMINE SECRETED FROM TUBEROINFUNDIBULAR Neurones INTERACTS WITH D2 RECEPTORS ON LACTOTROPES TO INHIBIT PROLACTIN SECRETION

•TRH, VASOACTIVE INTESTINAL PEPTIDE, PROLACTIN RELEASEING PEPTIDE, PITUITARY ADENYL CYCLASE-ACTIVATING PEPTIDE


ALSO, GH AND PLACENTAL LACTOGEN BIND PROLACTIN RECEPTORS AND ARE e cLACTOGENIC

HUMAN OESTROGEN, PROGETERONE, PLACENTAL LACTOGEN

PROLACTIN PLAYS AN IMPORTANT ROLE IN INDUCING GROWTH AND DIFFERENTIATION OF DUCTAL AND LOBULOALVEOLAR EPITHELIUM AND LACTATIONDOES NOT OCCUR IN THE ABSENCE OF PROLACTIN

THE HYPOTHALAMUS, LIVER, TESTES, OVARIES, PROSTATE, AND IMMUNE SYSTEM.

HYPERPROLACTINAEMIA SUPPRESSES THE HYPOTHALAMO-PITUITARY-GONADAL AXIS ? DUE TO INHIBITORY ACTION OF PROLACTIN ON HYPOTHALAMUS AND/OR GONADS
ELEVATED PROLACTIN IN BREASTFEEDING WOMEN SUPRESS THE NORMAL MENSTRUAL CYCLE AND PATHOLOGICAL HYPERPROLACTINAEMIA IS A CAUSE OF INFERTILITY IN WOMEN

MOST OFTEN HYPERPROLACTINAEMIA IS CAUSED BY PROLACTIN SECRETING- PUTUITARY ADENOMAS EITHER LESS THAN 1CM;MICROADENOMAS(<1CM) OR MACROADENOMAs (>CM)

MANIFESTATION IN WOMEN:GALACTORRHEA, AMENORREA, INFERTILITY

IN MEN: LOSS OF LIBIDO, IMPOTENCE, INFERTILITY

TRANSPHENOIDAL SURGRY, RADIATION AND D2 DOPAMINE RECEPTOR AGONISTS (BROMOCRIPTIN)

•BROMOCRIPTIN (PARLODEL): AN AGONIST AT D2 REC. ITS A SEMISYNTHETIC ERGOT ALKALOID
INHIBITS BOTH SPONTANEOUS AND THYROTROPIN –RELEASINGB HORMONE (TRH) INDUCED RELEASE OF PROLACTIN. TO A LESSER EXTENT IT ALSO ACTIVATES D1 REC

•BROMOCRIPTIN NORMALIZES PROLACTIN LEVEL IN 70-80% OF PATIENTS AND DECREASES TUMOUR SIZE IN > 50% OF PATIENTS(INCLUDING THOSE WITH MACROADENOMAS)
ADENOMA, HYPERPROLACTINAEMIA AND TUMOUR GROWTH RESUME AFTER CESATION OF THERAPY

•NAUSEA, VOMITING, HEADACHE, POSTURAL HYPERTENSION, PARTICULARLY ON INITIAL USE.

•LESS FREQUENTLY, NASAL CONGESTION, DIGITAL VASOSPASM, PSYCHOSIS, HALLUCINATIONS, NIGHTMARES, INSOMNIA

PERGOLIDE: ERGOT DERVATIVE. CHEAPEST DOPAMINE REC AGONIST, INDUCES MANY OF THE SAME SIDE EFFECTS AS BROMOCRIPTIN BUT GIVEN 0.025 MG AT BED TIME, INCREASED GRADUALLY TO MAX. DAILY OF 0.25MG

CARBERGOLINE: ALSO, ERGOT DERIVATIVE, T1/2 65HOURS. HIGHER AFFINITY, MORE SELECTIVE FOR D2 RECS THAN BROMOCRIPTIN(4X MORE POTENT). LESS GIT SYMPTOMS THOUGH MAY STILL CAUSE DIZZINESS AND HYPOTENSION. 0.25MG TWICE WEEKLY OR 0.5MG ONCE WEEKLY, MAY ICREASE TO 1.5MG TWICE OR 3X A WEEK AS TOLERATED. DOSE SHOULD NOT BE INCREASED MORE THAN EVERY 4 WEEKS.

QUINAGOLIDE: NONERGOT D2 DOPAMINE AGONIST, T1/2 22HOURS. ONCE DAILY AT 0.1 TO 0.5MG/DAY.
THESE DRUGS ALSO INDUCE OVULATION AND FIRST 3 DO NOT APPEAR TO BE DELITEROUS TO FOETAL WELLBEING.

THE 2 PITUITARY HORMONES, LUTEINIZING HORMONE, FOLLICULAR STIMULATING HORMONE AND PLACENTAL HORMONE CHORIONIC GONADOTROPIN (CG),

GnRH REGULATE SYNTHESIS AND SECRETION OF LH AND FSH BY PITUITARY GONADOTROPES.

GnRH RELEASE IS INTERMITTENT AND GOVERNED BY A NEURAL PULSE GENERATOR WHICH IS ACTIVE BY LATE FOETAL LIFE UP TO 1 YEAR AFTER BIRTH BUT CONSEQUENTLY SUPPRESSED TILL JUST BEFORE PUBERTY. ITS PRODUCTION IS THEN INCREASED TILL THE ADULT LEVELS OF FSH AND LH ARE ATTAINED.

LH ACTS ON TESTICULAR LEYDIG CELLS TO STIMULATE DE NOVO SYNTHESIS OF ANDROGENS, PRIMARILY TESTOSTERONE.

•TESTOSTERONE NEEDED FOR GAMETOGENESIS WITHIN SEMINIFEROUS TUBules,
•MAINTAINANCE OF LIBIDO AND SECONDARY SEXUAL CHARACTERISTICS

FSH ACTS ON SERTOLI CELLS:

PRODUCTION OF PROTEINS AND NUTRIENTS FOR SPERM MATURATION, THEREFORE INDIRECTLY SUPPORTING GERM CELL MATURATION

•FSH STIMULATES GROWTH OF DEVELOPING OVARIAN FOLLICLES AND
• INDUCES EXPRESSION OF LH RECs ON THECA AND GRANULOSA CELLS
•FSH REGULATES ACTIVITY OF AROMATASE IN GRANULOMA CELLS ,THEREBY STIMULATING PRODUCTION 17β-ESTRADIOLLH

LH ACTS ON THECA CELLS TO STIMULATE SYNTHESIS OF ANDROSTENEDIONE, THE MAJOR PRECURSOR OF OVARIAN 17β-ESTRADIOL IN PREMENOPAUSAL WOMEN

•LH REQUIRED FOR RUPTURE OF THE DOMINANT FOLLICLE DURING OVULATION
• FOR SYNTHESIS OF BPROGESTERONE BY THE CORPEUS LUTEUM
•LH AND LH RECs IN WOMEN INDUCE EXPRESSION OF FSH RECs BY GRANULOSA CELLS; LH THUS PLAYS A PERMISIVE ROLE IN FSH ACTION

1. SYNTHETIC GnRH(gonadorelin)

GnRH ANALOGUES WITH ENHANCED POTENCY AND PROLONGED DURATION OF ACTION( CF WITH GnRH t1/2 2-4MINS).

GnRH ANTAGONISTS WHICH DO NOT CAUSE INITIAL INCREASE IN GONADOTROPIN SECRETION SEEN WITH LONG-ACTING GnRH AGONIST SUPRESS LH SURGE IN OVARIAN STIMULATION PROTOCOLS DURING ASSSTED REPRODUCTION TECHNIQUES, THIS WILL DECREASE THE DURATION OF IN-VITERO FERTIRLIZATION .

Arginine vasoPressin VARIES FROM OXYTICIN by ONLY 2 AA RESIDUES, ISOLEUCIN AND LEUCIN.

•INCREASE IN PLASMA OSMOLALITY
•SEVERE HYPOVOLEMIA/HYPOTENSION
•PAIN
•NAUSEA
•HYPOXIA
•ACh via nicotinic receptors
•GLUTAMINE,ASPARTATE, CHOLECYSTOKININ, NEUROPEPTIDE Y, SUBSTANCE P, VASOACTIVE INTESTINAL POLYPEPTIDE, PROSTAGLANDINS, ANGIOTENSIN II
•Histamine(via H1 REC)
•DOPAMINE (D1 &D2)
•VINCRISTINE, CYCLOPHOSPHAMIDE, TRICYCLIC ANTIDEPRESSANTS, NICOTIN, EPINEPHRINE, HIGH DOSES OF MORPHINE, LITHIUM(BUT IT INHIBITS ITS RENAL EFFECTS)
 

•Decreased plasma osmolality
•Ethanol
•phenytoin
•low doses of morphine
•Glucocorticoids
•HALOPERIDOL
•FLUPHENAZIN
•CARBAMAZEPIN VIA A CENTRAL ACTION(BUT IT PRODUCES ANTIDIURESIS THROUGH ITS RENAL EFFECTS), CHLOPROPAMIDE, ARTRIAL NATURETIC PEPTIDE, GABA, OPIODS, NSAIDS
•PROMETHAZINE
•BUTORPHANOL
•OXILORPHAN

ADH ACTS THROUGH V1a, V1b AND V2 RECEPTORS.

•LITHIUM INHIBITES THE ANTIDIURETC ACTION OF ADH AND CAN CAUSE POLYURIA
•DEMECLOCYCLINE ATTENUATES THE ANTIDIURTIC EFFECTS OF VASOPRESSIN

IT IS A NUROTRANSMITTER IN THE CNS, THROUGH V2 RECEPTORS IT INCREASES CIRCULATORY LEVELS OF PROCOAGULANT FACTORS VIII AND OF VON WILLIBRAND FACTOR, DESMOPRESSIN HAS BEEN USED TO STOP NASAL BLEEDING.

CAUSES VASOCONSTRICTION IN SMOOTH MUSCLE OF THE CVS, GIT, SKIN, UTERUS

•CENTRAL OR CRANIAL DUE TO INADEQUATE SECRETION OF ADH.
• NEPHROGENIC DUE TO INSUFFICIENT RESPONSE. ( could be acquired or genetic)

HEAD INJURY , INFECTIONS, ANUERYSM, TUMOURS, POST OPERATIVE, CEREBRAL ISCHAEMIA, VASOPRESSINASE .

VASOPRESSINASE IN PREGNANCY MAY CAUSE ENOURMOUS METABOLISM OF VASOPRESSIN WITH RESULTANT DIURESIS, IT MAY ALSO CAUSE REDUCED SENSITIVITY TO ADH
CENTRAL DI IS EITHER FAMILIAL OR IDIOPATHIC

•ANTIDIURETIC PEPTIDES; DESMOPRESSIN
•CHLORPROPAMIDE+ OR- THIAZIDE DIURETIC WHICH POTENTIATES THE ACTION OF THE SMALL AMOUNTS OF ADH AVAILABLE
CARBAMAZEPINE AND CLOFIBRATE THOUGH NOT APPROPRIATE FOR LONG TERM USE B/C OF ADRS

HYPERCALCAEMIA, HYPOKALAEMIA , POST OBSTRUCTIVE RENAL FAILURE, LITHIUM, DEMECLOCYCLINE

ASSURANCE OF ADEQUATE FLUID INTAKE, AMILORIDE BLOCKS UPTAKE OF LITHIUM, HENCE IS APPROPRIATE FOR LITHIUM INDUCED.
THIAZIDE DIURETICS ARE GENERALLY USEFUL

INHIBITORS OF TESTOSTERONE SYNTHESIS.

GnRH ANTAGONISTS BLOCK THE ACTION OF ENDOGENOUS GnRH AT THE GONADOTROPH CELL’S GnRH REC

INHIBITORS OF ANDROGEN ACTION
THESE ACT BY INHIBITING THE BINDING OF ANDROGEN TO THE ANDROGEN REC OR BY INHIBITING 5-ALPHA REDUCTASE

FLUTAMIDE AND BICATULAMIDE. THESE ARE RELATIVELY POTENT AT THE REC SITE BUT LIMITED IN ACTION B/C INCREASED LH STIMULATES HIGHER SERUM TESTOSTERONE CONCENTRATIONS. THEY ARE USED WITH GnRH ANALOG IN THE TREATMENT OF METASTATIC PROSTATE CANCER, THEY THEREFORE BLOCK THE ACTION OF ADRENAL ANDROGENS WHICH ARE NOT INHIBITD BY GnRH ANALOGS. BICATULAMIDE IS PREFERED B/C IT IS TAKEN ONCE DAILY (FLUTAMIDE TID) AND LESS HEPATOTOXIC .
FLUTAMIDE USED FOR HIRSUTISM IN WOMEN BUT CAUTION B/C IT IS HEPATOTOXIC

FINASTERIDE ANTAGONISES ESPECIALLY THE TYPE II, SO IT BLOCKS THE CONVERSION OF TESTOSTERONE TO DIHYDROTESTOSTERONE ESPECIALLY IN THE MALE EXTERNAL GENITALIA.

•USFUL FOR BPH REDUCING OBSTRUCTION TO URINARY OUTFLOW,
•USEFUL FOR TREATMENT OF MALE BALDNESS ALTHOUGH TYPE I ENZYMES ARE INVOLVED IN BALDNESS.

Ketotiphen
Mitotane
Aminogluthetimide
Ketoconazole
SPIRONOLACTONE

THE THYROID GLAND PRODUCES THYROID HORMONE; TETRAIODOTYRONINE T4, TRI-IODOTYRONINE T3, DI-IODOTYRONINE T2, MONO-IODOTYRONINE.

•Calorigenic effect(In:ionotropy&chronothropy)
• Metabolic effect
• Cardiovascular effect

ANTITHYROID DRUGS
Propylthiouracil, Methimazole and Carbimazole(converted to methimazole after absorption)

ADRs: Low, propylthiouracil=3%, methimazole=7% .Most serious reaction is agranulocytosis,which occurs during the first few weeks, months or later. Agranulocytosis in methimazole is dose related but not so for propyltiouracil.Treatment= withdraw drug, administration of recombinant human granulocyte colony-stimulating factor.