ENDOCRINE PHARMACOLOGY

THYROID HORMONES
Diseases Involving Thyroid Hormones
HYPOTHYROIDISM is characterized by a deficiency of thyroid hormone
• Signs of hypothyroidism include decreased coat and hair luster, weight gain, listlessness, intolerance to cold, and
reproductive failure
• Diagnosed by measuring serum total T4 and T3 or by a thyroid stimulation test or by the thyrotropin releasing
hormone response test
• Hypothyroid animals are treated with thyroid replacement therapy
– levothyroxine (T4)
– liothyronine (T3)
Thyroid Preparations:
1. L-Thyroxin (T4): The form most commonly used.
2. L-Thyroxin sodium : given by IV injection in case of (Myxoedema coma).
3. Liothyronine sodium(T3) : may be given IV in emergency (Myxoedema coma). It is more potent than
levothyroxin (4 times as potent). It has a quicker onset of action and shorter duration. T3 has the advantage
over T4 in that it is more readily absorbed by the GIT .
4. Liotrix: Is a preparation in tablet form containing a mixture of levothyroxin and liothyronine in the ratio 4: 1
Therapeutic Uses: Replacement therapy in :Hypothyroidism, Cretinism Myxoedema coma

HYPERTHYROIDISM (Thyrotoxicosis or Grave's disease) is characterized by an increased production of thyroid hormone

• Signs of hyperthyroidism include increased thirst, weight loss, increased stool production, restlessness, and
tachycardia
• Diagnosed by measuring serum total T4 and T3
• Hyperthyroid animals are treated with antithyroid drugs or surgical removal
– Radioactive isotopes of iodine (I-131) destroy the thyroid gland
– Methimazole: interferes with the incorporation of iodine in the molecules of T4 and T3
– Propylthiouracil (PTU): interferes with the conversion of T4 to T3

Preparations Used In Hyperthyroidism:

1. Iodides: e.g. potassium iodide and Lugol's solution
2. Thiourea derivatives (Thioamides): e.g. Propyl thiouracil, Carbimazole,Methimazole

3. Radioactive iodine: e.g. I 131and I 132.

IODIDES: Decreases I-trapping.; Decreases synthesis of thyroid hormones., Decreases release and decreases size and
vascularity of the thyroid gland.

THIOUREA DERIVATIVES (THIOAMIDES)

The main action of thiourea derivatives is to reduce the formation of thyroid hormone by inhibiting the (thyroid
peroxidase) catalyzed reactions; to block I2 organification i.e. inhibit the incorporation of I2 into organic form, iodotyrosine,
and by inhibiting the coupling of iodotyrosines to form T4 and T3 . Their onset of action ranges from 2-3 weeks.
RADIOIODINE (I131, I132)
They emit mainly P radiation (90%), which has destructive effect on thyroid cells and some Y radiation, The gamma
rays are useful for estimating the quantity of the radioactive material in the gland and can be detected by placing a Geiger
counter in front of the neck.
 HORMONES OF THE PANCREAS
The pancreas secretes two hormones that help regulate blood glucose
– Insulin responds to a rise in blood glucose and promotes the uptake and use of glucose for energy in cells
– Glucagon increases blood glucose levels by promoting the breakdown of glycogen into glucose

INSULIN
Insulin, a hormone produced by the pancreas, acts to maintain blood glucose levels within normal limits (60–120 mg/dL). This
is accomplished by the release of small amounts of insulin into the bloodstream throughout the day in response to changes in
blood glucose levels. Insulin is essential for the utilization of glucose in cellular metabolism and for the proper metabolism of
protein and fat.

Drugs That Increase the Hypoglycemic Effect of Insulin :

Alcohol, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic drugs, beta blocking drugs, calcium, clonidine,
disopyramide, , monoamine oxidase inhibitors (MAOIs), salicylates, sulfonamides, tetracycline
Drugs That Decrease the Hypoglycemic Effect of Insulin:
antivirals, albuterol, contraceptives, oral corticosteroids, diltiazem, diuretics, dobutamine, epinephrine,_ estrogens, lithium,
morphine sulfate, niacin, phenothiazines, thyroid hormones
Insulin Preparations:
Insulin preparations differ mainly in their rate of absorption following subcutaneous
FOUR main classes: based on onset of action and duration of action.
1. Ulra short acting 2. rapid-acting: with rapid onset of action. 3. Intermediate acting. And 4.Long
acting: with slow onset of action
Pharmacokinetic Aspects:
• Insulin is destroyed in the GIT therefore it is given by injection, usually SC.
• Intravenous and intraperitoneal infusion is also used in critical clinical situations. •Once in the blood, insulin has t 1/2 of
about 10 minutes.
• It is inactivated in the liver and kidney, and 10% is excreted unchanged.
Source of Insulin:
Most of the insulin used clinically is derived from either beef or pig. Recently, human-like insulin has been produced.
Insulin Products
1. Purified Animal Insulins (porcine, bovine)- purified by gel flitration, single peak purity, few contaminants
2. Recombinant human insulins (Humulin)- Extremely low-risk of insulin allergy
3. Designer Insulins” – biochemical modifications of human insulins altering their absorption profile, duration of action

DIABETES MELLITUS

is a complicated, chronic disorder characterized by

 either insufficient insulin production by the beta cells of the pancreas or
 by cellular resistance to insulin.
 Insulin insufficiency results in elevated blood glucose levels, or hyperglycemia.
 As a result of the disease, individuals with diabetes are at greater risk for a number of disorders, including myocardial
infarction, cerebrovascular accident (stroke), blindness (retinopathy)s, kidney disease, and lower limb amputations.
 Insulin and the oral antidiabetic drugs, along with diet and exercise, are the cornerstones of treatment for diabetes
mellitus. They are used to prevent episodes of hypoglycemia and to normalize carbohydrate metabolism.
There are two major types of diabetes mellitus:
Type 1—Insulin-dependent diabetes mellitus (IDDM). Former names of this type of diabetes mellitus include Type 2—
Noninsulin-dependent diabetes mellitus (NIDDM). Former names of this type of diabetes mellitus include
Type 1 diabetes mellitus (Insulin Dependent Diabetes mellitus: (IDDM or type I)

Synonyms: Juvenile diabetes, juvenile-onset diabetes, and brittle diabetes

 produce insulin in insufficient amounts and therefore must have insulin supplementation to survive.
  Type 1 diabetes usually has a rapid onset, occurs before the age of 20 years, produces more severe symptoms than
type 2 diabetes, and is more difficult to control.
 Usually develops during childhood or puberty. There is no insulin release and with high tendency to ketoacidosis
 Major symptoms of type 1diabetes include hyperglycemia, polydipsia (increased thirst), polyphagia (increased
appetite), polyuria (increased urination), and weight loss.
 Treatment of type 1 diabetes is particularly difficult to control because of the lack of insulin production by the
pancreas.
 Treatment requires a strict regimen that typically includes a carefully calculated diet, planned physical activity, home
glucose testing several times a day, and multiple daily insulin injections.

Type 2 diabetes mellitus (Non Insulin Dependent Diabetes mellitus (NIDDM or Type II)

Synonyms ; maturity-onset diabetes, adultonset diabetes, and stable diabetes. (A third one recently recorded – Gestational
Diabetes)

 affects about 90% to 95% of individuals with diabetes.

 Develops later in life, usually over 40 years of age,especially in obese.it has strong genetic predisposition;with little or
no tendency to ketoacidosis
 Those with type 2 diabetes mellitus either have a decreased production of insulin by the beta cells of the pancreas or a
decreased sensitivity of the cells to insulin, making the cells insulin resistant.
 Although type 2 diabetes mellitus may occur at any age, the disorder occurs most often after the age of 40 years.
 The onset of type 2 diabetes is usually insidious, symptoms are less severe than in type 1 diabetes mellitus,
 Because it tends to be more stable, it is easier to control than type 1 diabetes

ORAL HYPOGLYCAEMIC AGENTS (ORAL ANTIDIABETIC DRUGS)

 The oral antidiabetic drugs are of value only in the treatment of patients with type 2 (NIDDM) diabetes mellitus
whose condition cannot be controlled by diet alone.
 These drugs may also be used with insulin in the management of some patients with diabetes mellitus. Use of an oral
antidiabetic drug with insulin may decrease the insulin dosage in some individuals.
 Two oral antidiabetic drugs (eg, a sulfonylurea and metformin) may also be used together when one antidiabetic drug
and diet do not control blood glucose levels in type 2 diabetes mellitus.
CLASSIFICATION
I. Sulfonylureas .
a) First generation: Acetohexamide , Chlorpropamide, Tolazamide,
Tolbutamide
b) Second generation: Glyburide(Glibenclamide), Glipizide , Glimepride,
gliclazide

II. Meglitinides: Repaglinide ,Nateglinide

III. Biguanides: Metformin , phenformin

IV. Alpha- Glucosidase inhibitors: Acarbose, Miglitol

V. Thiazolidinediones (Glitazones) : Pioglitazone , Rosiglitazone

SULFONYLUREAS

 These agents lower blood glucose by stimulating the beta cells of the pancreas to release insulin.
 Not effective if the beta cells of the pancreas are unable to release a sufficient amount of insulin to meet the
individual’s needs.
  The first generation sulfonylureas (eg, chlorpropamide, tolazamide, and tolbutamide) are not commonly used today
because they have a long duration of action and a higher incidence of adverse reactions, and are more likely to react
with other drugs.
 More commonly used sulfonylureas are the second generation drugs, such as glimepiride , glipizide , and glyburide

BIGUANIDES

 Acts by reducing hepatic glucose production and increasing insulin sensitivity in muscle and fat cells.
 The liver normally releases glucose by detecting the level of circulating insulin. When insulin levels are high, glucose is
available in the blood, and the liver produces little or no glucose. W
 hen insulin levels are low, there is little circulating glucose, so the liver produces more glucose.
 In type 2 diabetes, the liver may not detect levels of glucose in the blood and, instead of regulating glucose production,
releases glucose despite blood sugar levels.
 Metformin sensitizes the liver to circulating insulin levels and reduces hepatic glucose production

ALPHA -GLUCOSIDASE INHIBITORS:

 Lower blood sugar by delaying the digestion of carbohydrates and absorption of carbohydrates in the intestine
 primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from
the gastrointestinal tract.
 Act by competitively inhibiting α-glucosidases, a group of enzymes in the intestinal brush border epithelial cells that
includes glycoamylase, sucrase, maltase, and dextranase.
 The prolongation of the intestinal absorption of carbohydrates results in a blunted insulin response, keeping
postprandial hyperglycemia under control.
 To be effective, alpha glucosidase inhibitors must be taken before or with meals.

MEGLITINIDES:
 Like the sulfonylureas, the meglitinides act to lower blood glucose levels by stimulating the release of insulin from the
pancreas.
 Action is dependent on the ability of the beta cell in the pancreas to produce some insulin.
 However, the action is more rapid than that of the sulfonylureas and their duration of action much shorter. Because of
this they must be taken three times a day.
 Though structurally unrelated to sulfonylureas, the meglitinide class of hypoglycemic drugs bind to the same KATP
channel as do the sulfonylureas, but it is unclear whether they bind to the same SUR1 subunit within the KATP
complex.

THIAZOLIDINEDIONES(glitazones)
 Decrease insulin resistance and increase insulin sensitivity by modifying several processes, with the end result being
decreasing hepatic glucogenesis (formation of glucose from glycogen) and increasing insulindependent muscle glucose
uptake.
 They activate the nuclear peroxisome proliferator–activated receptor (PPAR) , a nuclear orphan receptor that is
predominantly expressed in adipose tissue and to a lesser extent in muscle, liver, and other tissues.
 The endogenous ligand for the PPAR- receptor is postulated to be prostaglandin J2, and it appears to work by
heterodimerizing with other nuclear receptors to modulate the expression of insulin-sensitive genes
 ZINC ACTION (IN HOURS)
SL ADDED CONTEN PEAK/ REACTIO
TYPE OF APPEARANC
NO NAME PROTEI T BUFFER MAX. DURATIO N
INSULIN E ONSET
N (MG/100 EFFEC N (pH)
IU) T
(h (hrs (hrs
r) ) )
I ULTRA SHORT INSULIN Clear Phosphat
ACTING None 0.02 0.25 0.5-1.5 2-5 Neutral
LISPRO e
1. REGULAR Clear
II SOLUBLE
INSULIN None 0.01-0.04 None 0.5-0.7 1.5-4 4-8 Acidic
SHORT
(CRYSTALLIN
ACTING
E)
2. NEUTRAL Clear
None 0.01-0.04 None 0.5 1-2 8 Neutral
INSULIN
II 1. NPH (Neutral Cloudy
I Protamine Hagedorn) Protamine
Phosphat
/ 0.016- 0.04 1-2 6-12 18-24 Neutral
INTERMEDIA ISOPHANE e
TE ACTING
INSULIN
2.LENTE Cloudy
None 0.2-0.25 Acetate 1-2 6-12 18-24 Neutral
INSULIN
1.PROTAMIN Cloudy
Phosphat
I E ZINC Protamine 0.2-0.25 4-6 14-20 36 Alkaline
e
V INSULIN (PZI)
LONG ACTING
2.ULTRALEN Cloudy
None 0.2-0.25 Acetate 4-6 16-18 36 Neutral
TE INSULIN
3.INSULIN Clear Non Non 2-5
0.03 5-24 18- 24 Acidic
GLARGINE e e
 ADRENAL CORTEX HORMONES: GLUCOCORTICOIDS
Mechanism of action
� Glucocorticoid receptors – : found in most cells
GRα and GRβ receptors – in the steroid superfamily
glucocorticoids bind to receptors in cytoplasm -form dimers - into nucleus - bind to DNA - induce transcription of
particular genes
� Gene repression
inhibition of transcription factors, e.g. AP-1, NF-κB
suppress expression of e.g. COX-2, NO synthase, etc.
� Gene induction
form specific mRNAs � direct protein synthesis
induce formation of annexin-1 (= lipocortin-1)
-ve feedback action on hypothalamus & anterior pituitary
» anti-inflammatory actions, by inhibiting PLA2

Drugs are Categorized as

– Short-acting (duration of action < 12 hours)
• Cortisone and hydrocortisone
– Intermediate-acting (duration of action 12–36 hours)
• Prednisone, prednisolone, prednisolone sodium succinate, methylprednisolone, methylprednisolone
acetate, and triamcinolone
– Long-acting (duration of action > 36 hours)
• Dexamethasone, betamethasone, and fluocinolone

IMPORTANT AGENTS
• Injectable: Betametasone, Hydrocortisone , Dexamethasone, Methylprednisolone
– Prednisolone, Triamcinolone
• Oral: Betamethasone, Fludricortisone, Methylprednisolone, Prednisolone, Prednisone
 Topical: Betamethasone, Clobetasol, Flucinolone , Mometasone
• Inhalational: Beclomethasone , Budesonide, Flunisolide -

ROUTES OF ADMINISTRATION
� Topical administration:: inhalation – asthma, eye drops – conjunctivitis, nasal drops or spray – rhinitis, intra-articular
injection – arthritis, skin – ointments, creams – eczema, dermatitis, etc: minimal systemic side effects unless large amounts
� Systemic administration: oral, intramuscular, intravenous: side effects on prolonged therapy

BIOLOGICAL EFFECTS
 Metabolic and systemic effects
 carbohydrate metabolism
» decreased uptake and utilisation of glucose
» increase in gluconeogenesis
» changes lead to hyperglycaemia
 protein metabolism
» decreased protein synthesis
» increase in protein breakdown, esp. in muscle
 lipid metabolism
glucocorticoids - synthesis of a cAMP-dep kinase -lipase activation - fat edistribution if long period
 calcium metabolism
» Ca2+ absorption in GI tract and excretion by kidney, -ve calcium balance osteoporosis (+ gene effects)
 Anti-inflammatory and immunosuppressive effects
- ‘pharmacological’ actions of the glucocorticoids
 - lso physiological role: prevent overshoot of defence
- some effects mediated by annexin-1
- Decrease mediators of inflammatory and immune responses » e.g. prostanoids, ILs, LTs, NO, IgG,
histamine
- anti-inflammatory independent of the cause
- immunosuppression, e.g. to suppress graft rejection
GUIDELINES ABOUT/PRINCIPLES OF GLUCOCORTICOID THERAPY
 Dosing Schedules are designed to prevent suppression of HPA axis.
 • Short courses 7 days do not cause suppression and can be given for short term benefit-
 Large doses as pulse therapy especially useful in neoplastic and collagen disorders
 Glucocorticoids do not cure disease; They may help disseminate infectious microorganisms
 Use caution when giving high dosages of glucocorticoids to pregnant animals
 Whenever possible, use the topical form to avoid systemic imbalances
 Use alternate-day dosing at the lowest possible doses to prevent iatrogenic Cushing’s disease
 Taper animals off glucocorticoids to prevent iatrogenic Addison’s disease
 Do not use glucocorticoids in animals that have corneal ulcers
 Chronic or inappropriate use of corticosteroids cause life threatening hormonal and metabolic changes.
 Adverse effects due to corticosteroid treatment usually occur with long-term administration of the drug,
especially when high doses are used..
 As they suppress immune response. Animals receiving systemic corticosteroids may be more susceptible to
bacterial or viral infections. Systemic corticosteroids can mask signs of infection, such as an elevated
temperature.
 Polyuria, polydipsia, and muscle wasting can be seen with prolonged corticosteroid use.
 can cause or worsen gastric ulcers.
 Should be avoided or used very carefully in young animals both because of immune suppression and the risk
of GI ulcers.
 Have been implicated as a cause of laminitis in horses and ponies. Some corticosteroids are thought to be
more likely to cause laminitis than others and the dexamethasone drugs have not historically been
considered to be in the higher risk category.
 Should be avoided during pregnancy and lactation unless the benefits outweigh the risks. Large doses in
early pregnancy may be teratogenic. Corticosteroids can induce labor in cattle and has been used to
terminate pregnancy in bitches.
 With diuretics such as furosemide- an increased risk of electrolyte imbalances due to calcium and
potassium losses
 The risk of GI ulcers may be increased with GC
 should not be given intravenously with fluids containing calcium

Alternate day therapy: every other day treatments are used to maintain remission without side effects of daily or twice daily
administration such as HPA axis suppression.
Pulse therapy: is the parenteral administration of supra pharmacological doses of short acting steroids foe shorter periods of
time, usually reserved for immune mediated diseases

Short term therapy: ( <2weeks)

 Use short acting steroids
 Administer in divide doses ,BID
 Used till the condition is controlled (4-7days)
 Discontinue therapy once the condition is controlled
Long term therapy:
 Starting as above for 2 weeks, then bring the dosage to the lowest possible single dose per day.
 Double the dose and give every other day
 Giving other adjubnctive therapy like antihistaminics, NSAIDS to keep steroid dose as low as possible.
 Gradual withdrawl by tapering the dose, in order to avoid iatrogenic hypoadrenocortisism.
INDICATIONS FOR GLUCOCORTICOID THERAPY:
 Allergic Disorders: Seasonal allergies, bee stings, drug allergies, allergic skin diseases , ranasal administration in
allergic rhinitis.- Budesonide
Flunisonide
 For replacement therapy in primary and secondary adrenal insufficiency, such as Addison’s disease.
 For their anti-inflammatory effects in arthritis, asthma, and inflammatory bowel disease.
 In organ transplant patients and those with autoimmune disorders (Rheumatic disorders, SLE, Vasculitic disorders,
Haemolytic anaemia ) corticosteroids are used for their immunosuppressive effects. , Combined with other
immunosuppressants Cyclosporin, azathioprine
 Metabolic disorders: iatrogenic hypoadrenocorticotropism, primary hyperparathyroidism, ketosis
 Noeplasia: lymphoma, mast cel tumour , As a component of most combination
regimens for malignancies
 Ocular Diseases : Important drug therapy for suppressing inflammation in eye and preservation of sight. • Topical
steroids are use for conditions of the anterior chamber • Systemic steroids for posterior chamber.; •.
 Hepatic disease: autoimmune chronic active hepatitis, Alcoholic liver disease
 Cerebral oedema/ inflammation due to CNS neoplasms/ parasites, Sarcoidosis, Spinal cord injury
 Antiemetic , Acute mountain sickness
 Chronic Obstructive Pulmonary Disease(COPD)
 Asthma
Contraindications:
 Infectious diseases , Ocular- - viral infections, fulminant bacterial infections, fungal infections, injuries and glaucoma
 GIT/ Peptic and corneal ulcer s
 Diabtes mellitus
 Demodicosis
 Osteoporosis
 Epilepsy
 CHF
 Renal failure
 Latepregnancy
 Recent major surgery
 hypertension
 Ulcerative colitis , pancreatitis

ADRENAL CORTEX DYSFUNCTIONS: / DISEASES OF ADRENAL CORTEX HORMONES

1.Hypoadrenalism – Addison’s Disease
• Adrenocortical insufficiency (Addison’s disease) is a progressive condition associated with adrenal atrophy, adrenal
cortex produces inadequate amounts of hormones, caused by autoimmunity against cortices 80%
• also caused by tuberculosis, drugs, cancer
• plasma sodium decreases and may lead to circulatory collapse
– Result is a deficient production of corticosteroids and mineralocorticoids
• Signs of this disease include lethargy, weakness, anorexia, vomiting, diarrhea, and PU/PDDiagnosed by the ACTH
stimulation test
• Treatment involves a long-acting mineralocorticoid and corticosteroids
– Desoxycorticosterone (DOCP): mineralocorticoid
– Corticosteroids
– Fludrocortisone: both glucocorticoid and mineralocorticoid activity

Hyperadrenalism – Cushing’s Syndrome

• Hyperadrenocorticism (Cushing’s disease) is characterized by excessive glucocorticoid production due to prolonged
administration of adrenocortical hormones, adrenocortical tumors, or pituitary disorders, exogenous glucocorticoids
and by tumours (adrenal or pituitary)

• Signs: PU/PD, hair loss, pendulous abdomen

• Diagnosed by the ACTH stimulation test or low-dose dexamethosone suppression test
Treatment involves
• Removal of adrenal tumor if this is the cause
• Partial or total adrenalectomy followed by administration of adrenal steroids to compensate insufficiencies that
develop
• Destroying part of the adrenal cortex by admionistering
– Mitotane (o, p’-DDD)
– Ketoconazole: antifungal that blocks the enzymes needed to produce steroid compounds
– Metyrapone
– Selegiline: monoamine oxidase inhibitor
 HYPOTHALAMIC HORMONES

Clinical uses of Hypothalamic hormones

Hypothalamic Hormone Clinical Uses
Growth hormone-releasing Used rarely as a diagnostic test for GH responsiveness
hormone (GHRH)

Thyrotropin-releasing Used rarely to diagnose hyper- or hypothyroidism

hormone (TRH, protirelin)

Corticotropin-releasing Used rarely to distinguish Cushing's disease from ectopic ACTH secretion
hormone (CRH)

Gonadotropin-releasing Used rarely in pulses to treat infertility caused by hypothalamic dysfunction

hormone (GnRH)
Analogs used in long-acting formulations to inhibit gonadal function in men with prostate cancer
and women undergoing assisted reproductive technology (ART) or women who require ovarian
suppression for a gynecological disorder

Dopamine Analogs used for treatment of hyperprolactinemia

 PITUITARY HORMONES

ADH (Vasopressin)
 Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus.
 A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with
hyponatremia or acute heart failure which is often associated with elevated concentrations of vasopressin. Eg:
Conivaptan and. Tolvaptan

OXYTOCIN:
mediates contractility of the endometrium which has been prestimulated with estradiol. It stimulates contractility of the
myoepithelial cells that surround mammary alveoli. Oxytocin facilitates some milk let-down without having galactopoietic
ability. It is mildly antidiuretic.
  Inappropriate use of oxytocin can lead to uterine rupture, anaphylactoid and other allergic reactions, and possibly
maternal death. Prolonged stimulation of uterine contractions can result in the following fetal adverse reactions:
persistent uteroplacental insufficiency, sinus bradycardia, premature ventricular contractions, other arrhythmias, and
fetal death.
 Oxytocin may be given by intravenous infusion (e.g., labor induction), intramuscular injection (e.g., control of
postpartum bleeding),
 To promote contraction of uterine smooth muscle to assist vaginal birth, to induce uterine evacuation in metritis and
to assist uterine contraction following reduction of uterine prolapse.
 To promote milk let-down in bitches with adequate milk production.
 Doses recommended have ranged from 0.25–4 IU or 1–5 IU per bitch to 5–20 IU per bitch, repeated up to three times.
In the queen, 2 IU maximum per queen and per injection IM or by IV infusion.
 It is important to use calcium gluconate 10% solution (1 mL/5.5 kg SC q.4–6 h) minimum 15 min before oxytocin even
in eucalcemic bitches. If one treatment of oxytocin for dystocia is unsuccessful, repeated use must be questioned,
given the likelihood of inducing tetanic uterine contraction and fetal death
Contraindications and precautions:
 Obstructive dystocia.;
 Any contraindication for vaginal delivery (e.g.relative or absolute oversize);
 Maternal toxemia.;
 Underlying causes of dystocia (e.g. hypocalcemia) should be treated before use of oxytocin.
Adverse effects
 Use in obstructive dystocia can cause uterine rupture.; Overdose, either single large doses or multiple doses, will
cause spastic, hypertonic or tetanic uterine muscle contraction with lack of orchestration of contractions. This may
induce placental separation or damage without delivery, fetal distress or death and uterine rupture.
 Incompatible with fibrinolysin, noradrenaline (norepinephrine) bitartrate, prochlorperazine edisylate and warfarin
sodium. If used with sympathomimetic agents, can result in postpartum hypertension.
Dose: Cattle: uterine inertia, agalactia due to failure of ‘let down’, to promote uterine involution: 10–40 units SC.IM;, 2.5–10.0
units of diluted solution slow IV; Mastitis: initial dose 80 units, SC.IM before stripping out and initial intramammary
treatment, then 20 units, SC,IM before each stripping out and concurrent intramammary treatment Uterine prolapse:, 2.5–10
units,IM. Sheep, goats, pigs, dogs: uterine inertia, agalactia due to failure of ‘let down’, to promote uterine involution: 2–10
units, SC,IM; 0.5–2.5 units of diluted solution slow IV; Cats: uterine inertia, agalactia due to failure of ‘let down’ to promote
uterine involution, 2–5 units SC,IM; , 0.5–1.25 units, slow IV.

Atosiban is an antagonist of the oxytocin receptor that has been approved outside the USA as a treatment for preterm labor
(tocolysis). Atosiban is a modified form of oxytocin that is administered by IV infusion for 2-48 hoursppears to be as effective as
b-adrenoceptor-agonist tocolytics and to produce fewer adverse effects.

GROWTH HORMONE (SOMATOTROPIN)

Its effects are primarily mediated via insulin-like growth factor 1 (IGF-1, somatomedin C) and to a lesser extent both directly
and through insulin-like growth factor 2 (IGF-2). Individuals with congenital or acquired deficiency in GH during childhood or
adolescence fail to reach their predicted adult height and have disproportionately increased body fat and decreased muscle
mass.
Two types of recombinant human growth hormone (rhGH) are approved for clinical use.
 Somatropin has a 191-amino-acid sequence that is identical with the predominant native form of human growth
hormone.
 Somatrem has 192 amino acids consisting of the 191 amino acids of GH plus an extra methionine residue at the amino
terminal end. The two preparations appear to be equipotent.
Uses of Growth Hormone

GROWTH HORMONE ANTAGONISTS

The need for antagonists of GH stems from the tendency of GH-producing cells (somatotrophs) in the anterior pituitary
to form secreting tumors. Pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas cause
acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle,
heart, liver, and the gastrointestinal tract. Acromegaly adversely affects the skeletal, muscular, cardiovascular, respiratory, and
metabolic systems.
 When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to the rare condition, gigantism.
Small GH-secreting adenomas can be treated with GH antagonists.
 Somatostatin is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites
in the gastrointestinal tract. It inhibits the release of GH, glucagon, insulin, and gastrin.
It has limited therapeutic usefulness because of its short duration of action and its multiple effects in many secretory
systems.
 Octreotide, an analog of somatostatin is 45 times more potent than somatostatin in inhibiting GH release but only
twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic B cells,
hyperglycemia rarely occurs during treatment. The plasma elimination half-life of octreotide is about 80 minutes, 30
times longer in humans than that of somatostatin

GONADOTROPINS
Chemistry: Glycoproteins ; 92 amino acid a subunit (identical to that of TSH) ß subunits which confer biological specificity:
a) Pituitary Gonadotropins : Luteinizing hormone ( LH) - 115 aa; Follicle stimulating hormone (f FSH)- 115 aa. Both can be
obtained in semipurified form, but expensive. Porcine FSH(pFSH) and recombinant derived FSH are used to induce
superovulation in donor cows for embryo transfer.
b) Non Pituitary Gonadotropins: human Chorionic gonadotropin (hCG)- 145 aa_ ; Pregnant mare serum gonadotrophin
(PMSG/eCG)

Gonadotropins used clinically

LH activity: Human chorionic gonadotropin (hCG)
Equivalent LH and FSH activity: Human menopausal gonadotropin (hMG; menotropin)
FSH activity: Urofollitropin (uFSH) Pregnant mare serum gonadotrophin (PMSG/equine chorionic gonadotrophin;eCG),
Menotropin with LH component removed Recombinant human FSH (rFSH)

Actions:
In the female: FSH:stimulates development of ovarian follicles,
LH stimulates production of estrogen and progesterone, induces ovulation
In the male: FSH stimulates production of androgen-binding globulin
maintains high testosterone levels in the seminiferous tubules required for spermatogenesis, LH stimulates production of
testosterone

INDICATIONS OF FSH ( PMSG)

 Superovulation in donor cows for embryo transfer
 Impaired spermatogenesis in bulls
 Induce oestrous in physiological anoestrus in bitches
 In association with hCG to stimulate onset of cyclical activity after fasrrowing in pigs.
 In association woith intravaginal progestogen sponges to advance the onset of breeding season in sheep and goats
 Dose: 1500- 300IU, SC or IM(cattle); 500-800IU, SC or IM(sheep and goat); 50-200IU, SC or IM(dog); 1000I U, SC or
IM(pig)

INDICATIONS OF LH (hCG)
 Delayed ovulation and anovulation, ovarian cysts, luteal deficiency, improving conception rate, improving libido in
cattle , pigs, sheeps, goat andf horses
 To induce ovulation in cats, to curtail prolonged or persistent prooestrus/oestrus in bitches.
 Dose: 1500- 300IU, IV or IM(cattle and horse); 100- 500 IU, SC or IM(sheep and goat); 100-500 IU, SC or IM(dog);
500-1000I U, IV or IM(pig), 100-200 IU (cat)

GnRH AND ANALOGS

Secretion by the hypothalamus is driven by a pulse generator that is regulated by negative feedback of the gonadal
hormones
 Biologic preparation very costly, hence synthetic GnRH analogs are used.
Hormone preparations used clinically: are Synthetic GnRH (gonadorelin hydrochloride) peptide analogues:
Used for pulsatile administration examples: Long-acting synthetic agonists- Buserelin acetate, Leuprolide acetate,
Histrelin acetate ,Nafarelin acetate, Goserelin acetate, fertyilerin, deslorelin
Indications:
 Follicular cysts
 Delayed ovulation, anovulation
 Acyclicity- anoestrus, suboestrus,
 Improved conception rate after insemination, In oestrus synchronisation

Dose: Buserelin; cow. 10-20µg; horse, 40 µg, IM, IV, SC; gonadorelin: cow, 0.5mg, IM,SC,IV, Fertilerin, cow, 100 µg,IM

GnRH Antagonists:
Ganirelix acetate, Cetorelix acetate are GnRH analogs, itive antagonists of the GnRH receptor  LH secretion > than FSH
Used to inhibit premature LH surges during the early to mid-follicular phase in women undergoing controlled ovarian
stimulation for treatment of infertility
DRUGS AFFECTING REPRODUCTION
ANDROGENS
Testosterone:
• Examples:
– Testosterone cypionate in oil
– Testosterone enanthate in oil
– Testosterone propionate in oil
– Danazol
– Methyl testosterone
• Used to treat conditions such as infertility and hypogonadism, produce estrus detectors, and for
testosterone-responsive urinary incontinence in dogs. Also used to treat debilitated aniumals because
of their anabolic effects, used to postpone oestrus in bithches, to overcome behavioural problems
associated wioth pseudopregnancy. And reverse feminization associated with sertoli cell tumour.
– Mibolerone:
• Blocks the release of LH from the anterior pituitary gland; therefore the follicle does not fully develop
• Used to prevent estrus in adult female dogs and the treatment of false pregnancies

ANTIANDROGENS:
 These are progestogens, are used to counteract the behavioural actions of endogenous androgens.
 Indicated to control hypersexuality in male dogs, and to treat prostatic hyperplasia and proststis in dogs
 Eg: Delemidinone acetate, danazol, flutamide, bicalutamide, cyproterone acetate
Finasteride( 5-alpha reductase inhibitor; not a specific antiandrogen)

FEMALE HORMONES
Estrogen:
• Promotes female sex characteristics and stimulates and maintains the reproductive tract
• Synthetic estrogens are used in dogs to prevent implantation of fertilized ova and to correct urinary
incontinence, vaginitis, and dermatitis
• Synthetic estrogens are used in cattle to treat persistent corpus luteum, aid in expulsion of retained
placentas and mummified feti, and to promote weight gain
• Synthetic estrogens are used in horses to induce estrus in the nonbreeding season
• Examples:
• Natural : estradiol, estrone, estriol
• Semisynthetic: ethinyl oestradiol, esters like estradiol benzoate, cypionate, propionate, valerate,
ethenate., diethyl stilbestrol.
• Synthetic: mestranol, tibolone, hexestrol, dienestrol, diphenyl ethylene(stilbene)etc.

Indications:
 Endometritis treatment in cattle(contraindicated in acute toxic metritis), to tone atonic uterus
 Prevention of unplanned pregnancy / mismating in bithches, urinary incontinence in spayed bitches,
 prostatic hyperplasia and adenoma in male dog, to depress hypersexuality in male dog.
 Ripening of cervix before oxytoin induced foaling in horse
 To induce artificial lactation in cattle

ANTIOESTROGENS (NONSTEROIDAL) :
Clomiphene citrate, tamoxifen citrate, centchroman
 Primarily indicated in conditions of anovulatory oestrus, low sperm counts in males, breast cancer in females
 Raloxifene is another partial estrogen agonist-antagonist (Selective Estrogen Receptor Modulator(SERM) at some but
not all target tissues. has been approved in the USA for the prevention of postmenopausal osteoporosis.
 Anastrozole, ( and Letrozole) a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen
synthesis,), is effective in some women whose breast tumors have become resistant to tamoxifen
 Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrazole and letrozole, it is approved
for use in women with advanced breast cancer
PROGESTOGENS: (PROGESTINS)
Progestational Compounds Used in Veterinary Medicine
Medroxyprogesterone acetate, Megestrol acetate and Proligestone , delmadinone acetate, chlormadinone acetate, and
norethisterone acetate

Indications:
 Threatende abortion/ habitual abortions
 Prolonged postponement / Temporary Postponement / Suppression
(proestrus administration)
 (anestrus administration (anestrus administration) ,
 Uterine Hemorrhage,
 Pregnancy Failure,
 Pseudopregnancy,
 Lactation, Nymphomania
Dosages: Medroxyprogesterone Acetate- 2.5 - 3.0 mg/kg IM every 5 months, while it is 2.0 mg/kg IM every 5 months for the
feline]. Megestrol Acetate-In 2.5 mg/cat/day.
PRID: ( Progesterone releasing intravaginal device): device containing progesterone an d estradiol ester, used for
synchronization of oestrous/ ovulation in cows and heifers , in combination with PGF 2 α. The device is is inserted in to vagina
nd kept insitu for 12 days, PGF2 α is administered 24 hours before removal to improve the effectiveness of the
synchronization. Oetrus occurs after 2-5 days of withdrawl.

ANTIPROGESTINS
Antiprogestins are synthetic steroids which bind with great affinity to progesterone receptors without any of the effects of
progesterone.
 In bitches, two antiprogestins have been studied: mifepristone (RU 486) and aglepristone (RU 534) .
 Mifepristone is a progesterone and glucocorticoid antagonist. It is more potent as an anti-progestin than as an anti-
corticoid.
 To improve its efficacy, mifepristone is currently used in combination with low doses of prostaglandin analogs such as
misoprostol.
Mifepristone- In pregnant bitches, mifepristone was effective if administered after day 30 of gestation . 2.5 mg/kg, PO.bid, or
4 to 5 days. Pregnancy was terminated without side effects within 3 to 4 days after treatment.

PROSTAGLANDINS AND PG ANALOGUES:

Natural PGF2 α ( dinoprost, carboprost ) and its synthetic analogs( Cloprostenol, luprostiol, , tiaprost ) are potent luteolytic
agents, except in bitch and cat.
Indications:
Cattle:, Horse, sheep and goats
 Oetsrus synchronization in cow and heifers
 Treatmwent of silent heat/ nonobserved oestrus.
 Induction of parturition /foaling/farrowing
 Induction of abortion and expulsion of mummified fetus
 Treatment of pyometra and Endometritis
 Treatment of luteal cysts
 Pseudopregnancy in goats
 Bitches: treatment of open pyometra and termination of pregnancy / mismating in combination with Antiprogestin.

Dose: Dinoprost, 25-35mg( 5ml, IM)), cattle; 5mg horse, 10mg, pig; 0.25-0.5mg/kg-bitch, all IM.
Cloprostenol -250-500µg,IM, 125-250µg, pig, IM; luprostiol- 15mg, cattle, IM