ENDOCRINOLOGY PART 1

BPT LECTURE SERIES

DR. SAYAN CHATTERJEE: MD PGT DEPT. OF

PHARMACOLOGY
 OUTLINE OF PRESENTATION

• INTRODUCTION
• ANTERIOR PITUITARY HORMONES
• THYROID HORMONES
• INSULIN, ORAL AND INJECTABLE
ANTIDIABETICS,GLUCAGON
 INTRODUCTION
• GLAND: An organ which secretes particular chemical substances for use in the
body or for discharge into the surroundings

• 3 TYPES: Exocrine, Endocrine, Heterocrine

ENDOCRINE
EXOCRINE HETEROCRINE
Secretes into
Secretions directly bloodstream rather Both exocrine and
into the ducts than ducts endocrine functions
e.g. sweat gland,
salivary gland e.g. pancreas, e.g. pancreas
thyroid
 INTRODUCTION
• HYPOTHALAMIC PITUITARY ENDOCRINE AXIS
• Discrete sets of hypothalamic neurons produce different releasing and inhibiting
hormones
stimulation

Secretion of hypothalamic hormones into the hypothalamic-

adenophyseal portal veins connecting anterior pituitary

POSITIVE FEEDBACK
Anterior pituitary

NEGATIVE FEEDBACK
Target endocrine organs and
exertion of specific functions
Anterior pituitary hormones
GROWTH HORMONE( GH )
Action of growth hormone
Stimulating of growth of bones, cartilage and connective tissue:
 Somatomedins are synthesized in the liver, in response to
stimulation by GH

 The effects of GH on skeletal growth are mediated by

somatomedins
Effect on Protein and Mineral Metabolism:
 On protein metabolism: GH is protein anabolic hormone.
 On mineral metabolism:
a) Increase calcium absorption from GIT
b) Decrease sodium, potassium, calcium and phosphorous
excretion from kidney
Effect on carbohydrate and fat metabolism:
 On carbohydrate-
GH is diabetogenic, because it produce hyperglycemia
 On fat metabolism-
GH has catabolic effect i.e. Increases mobilization of fats from
adipose tissues
The release of GH is primary under the control of two hypothalamic hormones:
 GH releasing hormone
a) Stimuli increases GH
b) Secretions by stimulating GHRH release. e.g. during exercise and stress
 GH inhibiting hormone
Stimuli decrease GH secretion by release of GHIH also called Somatostatin

DISEASES RELATED TO GROWTH HORMONE

• GIGANTISM: overproduction of GH
during adolescence
• DWARFISM: deficiency of GH
• ACROMEGALY: overproduction of
GH during adulthood
PROLACTIN( PRL )
Prolactin plays an important role in the development of the mammary gland and in milk
synthesis
Prolactin suppresses hypothalamo-pituitary gonadal axis by inhibiting GnRH release.
Continuous high level of prolactin during breastfeeding is responsible for lactational amenorrhoea,
inhibition of ovulation and infertility for several months postpartum

Prolactin is under predominant inhibitory control of hypothalamus through PRIH which is dopamine that
acts on pituitary lactotrope D2 receptor

Prolactin inhibitors
• Bromocriptine: potent D2 agonist, used in hyperprolactemia, acromegaly, parkinsonism, diabetes mellitus

• Cabergoline:
 newer D2 agonist; more potent; more selective for pituitary lactotrope D2 receptors, and
longer acting than bromocriptine

 Used in the treatment of small pituitary tumor induced acromegaly

GONADOTROPINS: FSH & LH
FOLLICLE STIMULATING HORMONE(FSH):

• In females it induces follicular growth, development of ovum and secretion of oestrogens.

• In males it supports spermatogenesis and has a trophic influence on seminiferous tubules.
• Ovarian and testicular atrophy occurs in the absence of FSH.

LUTEINIZING HORMONE(LH):
• In females maintenance of corpus luteum pregnancy. Progesterone secretion occurs only
under the influence of LH
• In males stimulates testosterone secretion by the interstitial cells

A single releasing factor, GnRH produced by the hypothalamusstimulates synthesis and release of
both FSH and LH from pituitary.
THYROID STIMULATING HORMONE(TSH)
• TSH stimulates thyroid to synthesize and secrete thyroxine
(T4) and tri iodothyronine (T3)
• Synthesis and release of TSH by pituitary is controlled by
hypothalamus primarily through TRH, while somatostatin
inhibits TSH secretion.

ADRENOCORTICOTROPIC HORMONE(ACTH)
• ACTH promotes steroidogenesis in adrenal cortex
• Hypothalamus regulates ACTH release from pituitary through corticotropin-releasing
hormone (CRH).
• Excess production of ACTH from basophil pituitary tumours is responsible for some
cases of Cushing's syndrome
Thyroid hormones
 Insulin, oral and injectable antidiabetics,glucagon
DIABETES MELLITUS
Insulin was discovered in 1921 by Banting and Best

Insulin is a two chain polypeptide having 51 amino

acids and MW about 6000. The A-chain has 21
while B-chain has 30 amino acids

The overall effects of insulin are to dispose meal

derived glucose, amino acids, fatty acids and
favour storage of fuel. It is a major anabolic
hormone: promotes synthesis of gylcogen, lipids
and protein
Sulfonylureas
 Insulin secretagogue
 Requires at least 30% functional β
cells
• Glibenclamide, Glicazide, Glipizide,
Glimepiride
• MOA: ↑ insulin secretion by acting on
sulfonylurea receptor at ATP sensitive K+
channel
• Acts by blocking the K+ ATP channel that
reduces influx of rectifying K+ ion current &
causes partial depolarization of pancreatic
beta-cells increased influx of Ca++ ions as
well as release of Ca++ from intracellular
stores & promotes exocytotic release of
insulin.
• Chronic use: sensitize the target tissue to
the action of insulin
• Slow hepatic degradation of insulin
• Reduces glucagon secretion
Sulfonylureas

Pharmacokinetics:
• Well absorbed orally
• High plasma protein bound (90%)
• Single daily dose is sufficient
Adverse Effects:
• Hypoglycaemia
• Non specific Side effects: weight gain, nausea, vomiting, flatulence, diarrhoea,
constipation, headache, paresthesia
• Hypersensitivity: Rashes, photosensitivity, purpura, transient leukopenia, rarely
agranulocytosis
• SU + alcohol: flushing, disulfiram-like reaction
MEGLITINIDE/PHENYLALANINE ANALOGUES

Mechanism of Action:
• K+ ATP channel blockers; quick and short lasting
action
• Normalises meal time glucose levels

Repaglinide and Nateglinide:

• Quickly absorbed and rapidly metabolised
• Administered before each major meal, omit if
meal missed.
• Lower incidence of hypoglycaemia
Indication:
• Type 2 DM with pronounced postprandial
hyperglycaemia
• Along with Metformin/long acting insulin
S/E: Mild headache, dyspepsia, arthralgia weight
gain
Avoid in liver disease!
GLUCAGON-LIKE PEPTIDE-1 (GLP) RECEPTOR AGONISTS

MOA: GLP-1 is an important incretin released from the

gut in response to ingested glucose. It induces insulin
release from pancreatic β cells, inhibits glucagon
release from α cells, slows gastric emptying and
suppresses appetite.

Exenatide:
•Synthetic dipeptidyl peptidase-4 (DPP-4)
enzyme resistant analogue.
• Activates GLP receptors
• Cannot be given orally
• Used as an add-on drug to metformin/SU/Pioglitazone
•Lowers postprandial as well as fasting blood glucose,
HbA1c and body weight
S/E: nausea/vomiting, tolerance develops later

Liraglutide:
• Highly bound to plasma proteins: longer duration of
action
 DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

DPP-4 enzyme causes rapid degradation of endogenous GLP- 1, thus

orally active inhibitors of this enzyme have been developed as indirectly
acting insulin secretagogues.

Sitagliptin:
• MOA: Acts as competitive and selective DPP-4 inhibitor & potentiates
the action of GLP-1 and GIP.
• Boosts postprandial release, decreases glucagon secretion and lowers
meal time as well as fasting blood glucose in Type 2DM
• Body weight neutral, low risk of hypoglycaemia
• Well absorbed orally, little metabolised, largely excreted unchanged
in urine
• Dose reduction needed in renal dysfunction
• S/E: nausea, loose stools, headaches, rashes, allergic reactions,
edema
BIGUANIDES (METFORMIN)
Biguanides do not causeinsulin release,but presenceof insulin is essential for their
action.
MOA: Metformin causes activation of AMPK, leading to:
• Suppression of hepatic gluconeogenesis
•Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat
•Interferes with mitochondrial respiratory chain and promotes peripheral glucose
utilization
•Retards glucose absorption of glucose, hexose, amino acids, Vit B12 Adverse Effects:
Hypoglycaemia in overdose, Lactic acidosis, Vitamin B12 deficiency
Contraindicated in hypotensive states, heart failure, severe respiratory, hepatic
and renal disease, alcoholics

Advantages: nonhypoglycaemic, weightloss, complications, prolongs beta cell life

Limiting feature: gastrointestinal intolerance
THIAZOLIDINEDIONES (PPARγ ACTIVATOR)

MOA: Pioglitazone is selective agonist for the nuclear peroxisome

proliferator-activated receptor γ (PPARγ) expressed mainly in fat cells,
and in muscle cells. It enhances transcription of insulin responsive genes
& tends to reverse insulin resistance by enhancing GLUT4 receptor
expression and translocation.
• Suppresses hepatic gluconeogenesis
• Additionally, lowers serum triglyceride, raises HDL
• Well tolerated
S/E: plasma volume expansion, edema, weight gain, headache, myalgia,
mild anaemia, increased risk of fracture esp. in elderly women
Contraindicated in liver disease and in CHF
α GLUCOSIDASE INHIBITORS

Acarbose:
MOA: Inhibits α-glucosidases (enzyme responsible for digestion of carbohydrates in
the brush border of small intestine mucosa) slow down and decrease digestion and
absorption of polysaccharides and sucrose. Dose 50–100 mg TDS is taken at the
beginning of each major meal. Additionally it promotes GLP-1 release.
S/E: Flatulence, abdominal discomfort, loose stool; Poor patient acceptability
Miglitol: It has a smaller molecule than acarbose, and it is a stronger inhibitor of
sucrase. Potency for other α-glucosidases is equivalent to acarbose. Dose: 25–100
mg TDS at beginning of each meal.
Voglibose: It has properties, use and side effects similar to that of acarbose. Dose:
0.2–0.3 mg TDS just before meals.