Endocrine Pharmacology

Drugs used in Diabetes

2
 Drugs used in Diabetes
• The pancreas:
– Exocrine: digestive enzymes
– Endocrine: insulin, glucagon, and somatostatin

3
 Classification of DM
• ADA recognizes four clinical classifications of diabetes:

1) Type 1 diabetes (formerly, insulin-dependent diabetes

mellitus)
2) Type 2 diabetes (formerly, non-insulin-dependent
diabetes mellitus),
3) Gestational diabetes, and
4) Diabetes due to other causes (for example, genetic defects
or medications).

4
 Type 1 DM
– Absolute deficiency of insulin caused by massive β-cell
necrosis.
– Autoimmune-mediated processes directed against the β
cell.
– Shows classic symptoms of insulin deficiency (polydipsia,
polyphagia, polyuria, and weight loss)
– Rely on exogenous (injected) insulin to control
hyperglycemia.

5
 Type 2 DM
– Most diabetic patients have type 2 disease
– Type 2 diabetes is influenced by genetic factors, aging,
obesity, and peripheral insulin resistance, rather than by
autoimmune processes or viruses.
– Lack of sensitivity of target organs to either endogenous or
exogenous insulin.
– Weight reduction, exercise, and dietary modification
decrease insulin resistance.
– Oral glucose-lowering agents then, insulin therapy later.

6
 Criteria for the
diagnosis of diabetes

Clinical features of
diabetes at diagnosis

7
 Insulin

• Granules within the beta cells store the insulin in the form of crystals consisting of
two atoms of zinc and six molecules of insulin (hexamer).
• Pre pro insulin (108 AAs)-pro insulin (86AAs)-insulin (51AAs)
• C-peptide- indicter of insulin secretion
8
Insulin secretion

9
 Insulin preparations
– Human insulin is manufactured by bacterial
recombinant DNA technology.
– Insulin is indicated for individuals with type 1
diabetes as well as for those with type 2 diabetes
whose hyperglycemia does not respond to diet
therapy and other diabetes drugs.
– Human insulin is dispensed as either regular (R) or
Neutral Protamine Hagedorn (NPH) formulations.

10
Rapidly acting insulin analogs (Ultra short acting)

– Three insulin analogs (insulin lispro, insulin aspart,

and insulin glulisine) have rapid onsets & early
peaks of activity that permit control of postprandial
glucose levels.
– The 3 rapid-acting insulins have small alterations in
their primary amino acid sequences that speed their
entry into the circulation without affecting their
interaction with the insulin receptor.

11
Rapidly acting insulin analogs…

– The rapid-acting insulins are injected immediately

before a meal and are the preferred insulin for
continuous subcutaneous infusion devices.
– They also can be used for emergency treatment of
uncomplicated diabetic ketoacidosis

12
 Short-acting insulin preparations
Regular insulin
– IV regular insulin: particularly useful in the
treatment of diabetic ketoacidosis and during
the perioperative management of insulin-
requiring diabetics.
– Before the development of rapid-acting
insulins, it was the primary form of insulin
used for controlling postprandial glucose
concentrations, but it requires administration
1 h or more before a meal.
13
 Intermediate acting insulins
Neutral Protamine Hagedorn (NPH), or isophane
– is a combination of regular insulin and protamine that exhibits a
delayed onset and peak of action.
– The mixture has equivalent concentrations of protamine and
insulin, so that neither is in excess (isophane).
– NPH insulin is often combined with regular and rapid-acting
insulins.

14
Lente insulin (Insulin zinc suspension)

– Suspension of insulin in acetate buffer at neutral PH

– Physical state and crystal size influences the rate of

absorption from injection site
– mixture of 3 parts amorphous and 7 parts crystalline insulin zinc
suspension.

– Intermediate acting

15
 Long acting insulins
• are modified forms of human insulin that provide a peak
less basal insulin level lasting more than 20 h, which helps
control basal glucose levels without producing
hypoglycemia.
• Insulin glargine
– precipitate at the injection site that releases insulin over an
extended period.
– To maintain solubility, the formulation is unusually acidic
(pH 4.0), and insulin glargine should not be mixed with
other insulins.
16
 Long acting insulins…
• Insulin detemir
– the terminal threonine is dropped & has a fatty acid side chain
that enhances self aggregation & association to albumin.
– the affinity of insulin detemir is four- to five fold lower than that
of human soluble insulin unlike insulin glargine which has
similar affinity with native insulin.

17
 Mixtures of insulins
– To control adequately both postprandial and basal
hyperglycemia.
– Stable premixed insulins (70% NPH and 30%
regular).
– Premixed preparations of rapidly acting insulin
analogs (lispro, aspart) and NPH are not stable
because of exchange of the rapidly acting insulin
analog for the human regular insulin in the
protamine complex.
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 Dosage regimen
• The total daily dose required is usually 0.5–1.0 unit/kg
(about 50 units).
• This is usually divided as 2⁄3 during the day and 1⁄3 at night
for minimum frequency regimens and 50/50 for basal-
bolus regimens.

19
Dosage regimen…

20
 Side effects of insulin regimens
• Hypoglycemia
– Tremor, palpitation, anxiety, sweating

– If severe, seizure & comma

• Weight gain
– insulin promotes fatty acid and protein synthesis

• Hypokalemia
• Lipodystrophy
21
 Oral antidiabetic Agents
– Anti-diabetic medications treat diabetes mellitus by
lowering glucose levels in the blood.
– With the exceptions of insulin, GLP-1 receptor
agonists, and pramlintide, all are administered orally
• thus also called oral hypoglycemic agents
– There are different classes & selection depends on:
• Nature of the diabetes
• Age, situation of the person & other factors

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 Classification

Insulin α-glucosidase
Insulin sensitizers New agents
secretagogues inhibitors
(GLP-1 Receptor
agonists, DPP4
inhibitors & others)
Sulfonylureas Biguanides

Meglitinide
Thiazolidinediones
analogue

23
 Metformin (Biguanide)
– classified as an insulin sensitizer
– requires insulin for its action, but it
does not promote insulin secretion.
– Therefore, the risk of hypoglycemia
is far less than that with
sulfonylureas.
– The main mechanism of action of
metformin is reduction of hepatic
gluconeogenesis.

24
  Metformin…
– Metformin activate AMPK by reducing mitochondrial
production of ATP and raising intracellular levels of AMP.
– AMPK increases the sensitivity of cells to insulin
Inhibit gluconeogenesis & enhancing glucose utilization
– Metformin increases lactate production (uncoupling
oxidative phosphorylation) & reduces lactate removal by
the liver by blocking gluconeogenesis.
Increases the risk of lactic acidosis in pts with renal disease

25
26
  Metformin…
 “Euglycemic,” ↓ postprandial glucose levels, but does not
cause hypoglycemia or weight gain.
 Weight loss may occur because metformin causes loss of
appetite.
Pharmacokinetics:

– Metformin is well absorbed orally

– is not bound to serum proteins
– It is not metabolized
– Excretion is via the urine as active compound
27
  Metformin clinical uses…
– first-line therapy for type 2 diabetes.
– because metformin is an insulin-sparing agent and
does not increase body weight or provoke
hypoglycemia
Preferred in these patients
– decreases the risk of macrovascular as well as
microvascular disease.
– reduces the risk of diabetes in high-risk patients.
– in the treatment of polycystic ovary syndrome
28
  Metformin…
 Adverse effects:
– These are largely gastrointestinal (NVD)
– It should be discontinued in cases of acute myocardial
infarction, exacerbation of heart failure, sepsis… (ARF)
– Long-term use may interfere with vitamin B12 absorption
– Lactic acidosis can sometimes occur with metformin
therapy.
 C/I: GFR < 50 mL/min, CHF, radiographic contrast studies,
seriously ill patients, acidosis.
29
 Sulfonylureas
Mechanism of Action
• The primary mechanism of the sulfonylureas is direct
stimulation of insulin release.
– In the presence of viable pancreatic B -cells,
sulfonylureas enhance the release of endogenous
insulin
• At higher doses, these drugs also decrease hepatic
glucose production.

30
Mode of action of sulfonylureas

31
 2nd -Generation Sulfonylureas

– higher specificity and affinity for the SUR

– more predictable PK in terms of time of onset and
duration of action.
– have fewer side effects & exert mild diuretic effects on
the kidney.
– are highly protein bound, primarily through nonionic
binding.

32
 Glyburide (Glibenclamide)
2 -Generation Sulfonylureas…
nd

(5–10 mg/d)
– Glyburide is unique among sulfonylureas
• not only binds to SUR on membrane but
also becomes sequestered within the cell.
• prolonged biologic effect despite its
relatively short t1/2
– hepatic glucose production & exerts a mild
diuretic effect
– is completely metabolized in the liver to two
weakly active metabolites before excretion in
the urine.
– contraindicated in liver & renal disease

33
ADRs
– Adverse effects of the sulfonylureas include
hypoglycemia, hyperinsulinemia, and weight gain.
– They should be used with caution in hepatic or renal
insufficiency, since accumulation of sulfonylureas may
cause hypoglycemia.
– A decrease in alcohol tolerance also has been observed
in some patients taking sulfonylurea compounds
(chlorpropamide and glimepiride)
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 Incretins

• Gut hormones that amplify postprandial insulin secretion

– glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP).
– Oral glucose metabolized faster than IV glucose
• Therapeutic drugs in this class include
– GLP-1 receptor agonists
– Dipeptidyl peptidase 4 (DPP-4) inhibitors, which
increase levels of both GLP-1 and GIP.
35
 Incretins…

• When GLP-1 is infused in patients with type 2 diabetes,

– it stimulates insulin secretion and lowers glucose levels
– GLP-1 is rapidly proteolyzed & cleared rapidly by the
kidney.
– As a result, the half-life of GLP-1 is only 1 to 2 minutes
– The native peptide, therefore, cannot be used
therapeutically.

36
DPP-4 Inhibitors (orally)

• inhibition of the enzyme DPP-4

prolongs of the action of
endogenously released GLP-1 and
GIP
– Sitagliptin
– Saxagliptin (dosage adjustment in renal disese and
concurrent use of strong CYP3A4/5 inhibitors)
– Vildagliptin (rarely, it can cause hepatitis)
– Alogliptin (hypersensitivity reactions)
– Linagliptin (no dosage adjustment is in renal failure)

37
Thyroid & Antithyroid Drugs
Regulation of thyroid function

• Thyroid gland contains follicular cells

& parafollicular (C) cells.
• Follicular cells secrete T3 & T4 .
• Parafollicular cells secrete of
calcitonin.
 Thyroid hormones

- Thyroid hormones are required for the normal growth

and development.
- Deficiency of thyroid hormones leads to cretinism in
children and myxedema in adults.
- These are catabolic hormones and increase the
breakdown of fats (to FFA), carbohydrates (cause
hyperglycemia) and proteins (cause weight loss).
 Thyroid hormones…

- Thyroid hormones stimulate the heart (increase rate,

contractility and cardiac output).
- These are calorigenic and increase basal metabolic
rate.
- hyperthyroidism can result in anxiety, tremors,
nervousness, excitability & heat intolerance.
- Hypothyroidism results in mental retardation, cold
intolerance, lethargy & fatigue.
 Thyroid hormones…
- Main indication of thyroid hormones is hypothyroidism
(cretinism, myxedema and myxedema coma).
- Levo-thyroxine (T4) is preferred for all these indications due
to its long t1/2& requirement of less frequent dosing.
- Myxedema coma is an emergency situation, in which
liothyronine (only indication) can also be used (It should be
used cautiously in patients with heart diseases like AF).
 Thyroid hormones…

- Hypothyroidism in the adult is usually due to

malfunction of the thyroid itself.
- In iodine-sufficient countries, the principal cause is
chronic autoimmune thyroiditis (Hashimoto’s
thyroiditis).
Cretinism

• It is due to thyroid deficiency during development,

caused by congenital absence or incomplete
development of the thyroid, and is characterized by
gross retardation of growth and mental deficiency.

45
 Thyroid hormone preparations

- Levothyroxine sodium: a synthetic sodium salt of T4

- Liothyronine sodium: a synthetic sodium salt of T3.

- Liotrix: a 4:1 mixture of T4 and T3 preparations.

- Thyroid USP, which is prepared from dried and
defatted animal thyroid glands and contains a
mixture of T4, T3, MIT, and DIT.
 Levothyroxine (T4)
- is a synthetic preparation of thyroxine
- identical structure to that of the natural
hormone.
- is the drug of choice for most patients who
require thyroid hormone replacement.
- Absorption of oral levothyroxine is reduced
by food.
- should be taken on an empty stomach in the
morning, at least 30 to 60 minutes before
breakfast.
- can produce nearly normal levels of both T3
and T4.
 Levothyroxine (T4)…

- highly protein bound (about 99.97%) & has a prolonged

half-life (about 7 days).
- it takes about 1 month (four half-lives) for plasma levels
of levothyroxine to reach plateau (steady state).
- As a result, onset of full effects is delayed
- ADRs: tachycardia, angina, tremor, nervousness,
insomnia, hyperthermia, heat intolerance, and sweating.
- chronic overdosage is associated with accelerated bone
loss.
 Liothyronine (T3)

 Liothyronine differs from levothyroxine in three important ways:

- (1) T3 has a shorter t1/2 (1 day) & shorter duration of action

- (2) liothyronine has a more rapid onset, and

- (3) liothyronine is more expensive.
 Because of its high price and relatively brief duration of action,
liothyronine is less desirable than levothyroxine for long-term use.
 However, because its effects develop quickly, liothyronine may be
superior to levothyroxine in situations that require speedy results,
especially myxedema coma.
Antithyroid drugs
 Hyperthyroidism

- There are two major forms of hyperthyroidism: Graves’

disease and toxic nodular goiter (also known as
Plummer’s disease).
- Of the two disorders, Graves’ disease is more common.
- Signs and symptoms of both disorders are similar.
- The principal difference is that Graves’ disease may
cause exophthalmos, whereas toxic nodular goiter does
not.
…

52
 Treatment
 Treatment modality
- (1) surgical removal of thyroid tissue, (2) destruction of
thyroid tissue with radioactive iodine, and (3)
suppression of thyroid hormone synthesis with an
antithyroid drug (methimazole or propylthiouracil).
- Radiation is the preferred treatment for adults, whereas
antithyroid drugs are preferred for younger patients.
- Beta-blockers & non-radioactive iodine may be used as
adjunctive therapy.
Synthesis of thyroid hormone & effects
of antithyroid Agents
 Thioamides

- Thyroid peroxidase enzyme catalyzes three reactions

(oxidation, organification and coupling).
- Carbimazole, methimazole and propylthiouracil act
by inhibiting this enzyme.
- They do not affect T3/T4 already within the thyroid
- Thus, a lag period of 1-3 weeks is present.
- Carbimazole is a prodrug and acts after conversion to
methimazole.
 Thioamides…
 Methimazole
- is a first-line drug for hyperthyroidism.
- safer and more convenient than PTU,
and hence is preferred for most
patients—except women who are
pregnant or breast-feeding.
- it may take 3 to 12 weeks to produce a
euthyroid state.
- ADRs: Agranulocytosis,
hypothyroidism, avoid during the first
trimester.
 Thioamides…

 PTU is much like methimazole, but with four

significant differences:
- PTU can cause severe liver injury, whereas
methimazole does not.
- PTU has a shorter half-life than
methimazole
- PTU crosses the placenta less readily than
does methimazole.
- PTU blocks conversion of T4 to T3 in the
periphery, whereas methimazole does not.
PK of methimazole & PTU
 Thioamides…

 There are three groups for whom PTU is preferred:

- Pregnant women, but only during the first trimester.
(Methimazole is preferred during the second and
third trimesters).
- Patients experiencing thyroid storm (Because PTU
can block conversion of T4 to T3, it may be more
effective than methimazole).
- Patients who are intolerant of methimazole.
 Thioamides…

 Adverse Effects of PTU

- The most common undesired effect is rash.
- Liver Injury (Liver toxicity is unrelated to dosage or
duration of treatment)
- Agranulocytosis
- PTU may also cause nausea, arthralgia, headache,
dizziness, and paresthesias.
 Radioactive Iodine (131I)

- Iodine-131 is a radioactive isotope of stable iodine that

emits a combination of beta particles and gamma rays.
- Radioactive decay of 131I takes place rapidly, with a half-
life of 8 days.
- Hence, after 56 days (seven half-lives), less than 1% of
the radioactivity in a dose of 131I remains.
- Iodine-131 can be used to destroy thyroid tissue in
patients with hyperthyroidism.
 Radioactive Iodine ( I)… 131

- The objective is to produce clinical remission

without causing complete destruction of the
gland.
- Unfortunately, delayed hypothyroidism, due
to excessive thyroid damage, is a frequent
complication.
- Like stable iodine, 131I is concentrated in the
thyroid gland.
- Destruction of thyroid tissue is produced
primarily by emission of beta particles.
 Iodide Salts and Iodine
 Sodium iodide, potassium iodide and Lugol’s
solution
- inhibit iodination of tyrosine and thyroid hormone
release
their onset of action occurs rapidly, within 2–7 d

- these salts also decrease the size and

vascularity of the hyperplastic thyroid gland.
- However, the effects are transient; the
thyroid gland “escapes” from the iodide
block after several weeks of treatment.
 Iodide Salts and Iodine..
- are used in the management of thyroid storm and to
prepare patients for surgical resection of a hyperactive
thyroid.
• Adverse effects
 acute reaction consisting of swelling of lips, angioedema,
fever, joint pain and petechial hemorrhages can occur
 chronic overdose of iodides is called iodism.
 Major symptoms are inflamed mucus membranes, increase
in secretions (salivation, lacrimation and rhinorrhoea),
headache, rashes and gastrointestinal distress.
 Adjuvant drugs
- BBs antagonize the sympathetic effects of
thyrotoxicosis like tremors, tachycardia, palpitations
and anxiety.
- Propranolol also inhibits the peripheral conversion of
T4 to T3.
- Calcium channel blockers like diltiazem can also be
used for this purpose.
Corticosteroids
The outer zona glomerulosa produces
mineralocorticoids (for example, aldosterone)

The middle zona fasciculata synthesizes

glucocorticoids (for example, cortisol)

The inner zona reticularis secretes adrenal

androgens (dehydroepiandrosterone (DHEA))

CRH = corticotropin-releasing hormone

ACTH = adrenocorticotropic hormone

67
 Corticosteroids

- The corticosteroids are steroid hormones produced

by the adrenal cortex.
- 2 major physiologic and pharmacologic groups:
1. Glucocorticoids, which have important effects on
metabolism (catabolism), immune responses &
inflammation.
2. Mineralocorticoids, which regulate Na and K
reabsorption in the collecting tubules of the kidney.
Effects of glucocorticoids
Effects of glucocorticoids…
 Cortisol

- The major natural glucocorticoid is cortisol

(hydrocortisone).
- The physiologic secretion of cortisol is regulated by
ACTH and varies during the day (circadian rhythm).
- The peak occurs in the morning & the trough occurs
about midnight.
- Cortisol is 95% bound to CBG in plasma.
- well absorbed, but has short duration (cleared by
liver).
 Cortisol..

- Although it diffuses poorly across normal skin,

cortisol is readily absorbed across inflamed skin and
mucous membranes.
- The cortisol molecule also has a small but significant
salt-retaining (mineralocorticoid) effect.
- This is an important cause of hypertension in
patients with a cortisol-secreting adrenal tumor or a
pituitary ACTH-secreting tumor (cushing’s
syndrome).
 Synthetic glucocorticoids

- The mechanism of action of these agents is identical with

that of cortisol.
- A large number of synthetic glucocorticoids are available
for use; prednisone and its active metabolite,
prednisolone, dexamethasone, and triamcinolone are
representative.
- Their properties (compared with cortisol) include longer
half-life and duration of action, reduced salt-retaining
effect, and better penetration of lipid barriers for topical
activity.
 Synthetic glucocorticoids…

- Special glucocorticoids have been developed for use

in asthma and other conditions in which good surface
activity on mucous membranes or skin is needed and
systemic effects are to be avoided.
- Beclomethasone and budesonide readily penetrate
the airway mucosa but have very short half-lives after
they enter the blood, so that systemic effects and
toxicity are greatly reduced.
PK properties
 Uses of Corticosteroids

- Acute adrenal insufficiency: iv hydrocortisone

- Chronic adrenal insufficiency (Addison’s disease):
• Oral hydrocortisone & fludrocortisone may also be required.

- Congenital adrenal hyperplasia (CAH): feedback

inhibition
- Adrenal insufficiency states (infection, shock, trauma)
- Premature delivery to prevent respiratory distress
syndrome: Betamethasone to accelerate the fetal lung
maturation.
 Uses of Corticosteroids…

 Anti-inflammatory uses:
- rheumatoid arthritis, osteoarthritis (intra-articular)
and acute gouty arthritis
- inflammatory conditions of eye like conjunctivitis,
iritis, iridocyclitis and keratitis (C/I in herpes simplex
keratitis).
 Anti-allergic uses: respiratory & dermatological
- Asthma, urticaria, angioedema and skin conditions
like pemphigus vulgaris, exfoliative dermatitis and
 Uses of Corticosteroids…

 Immunosuppressive uses:
- to prevent graft rejection
- Autoimmune diseases (e.g. myasthenia gravis,
hemolytic anemia) and collagen vascular diseases
(like SLE, polyarteritis nodosa and nephrotic
syndrome).
- in patients with ulcerative colitis and Crohn’s disease
who are not responding to 5-aminosalicylic acid.
 Uses of Corticosteroids….

 Anti-cancer uses
- Due to prominent lympholytic action in malignant cells
- essential component of the combination therapy of ALL
and lymphomas (both Hodgkin as well as non-
Hodgkin).
- are also useful in the breast carcinoma.
- These can also be used with anti-neoplastic agents to
decrease nausea and vomiting
Diagnostic use: dexamethasone suppression test
 Glucocorticoids..

 Toxicity
- Long term use (for more than 2 weeks) can lead to
HPA axis suppression. Steroids should not be
withdrawn abruptly because it may precipitate
acute adrenal insufficiency.
- Methods for minimizing these toxicities include local
application (eg, aerosols for asthma), alternate-day
therapy (to reduce pituitary suppression), and
tapering the dose soon after achieving a therapeutic
The pharmacology of
Drugs Acting on Uterus
oxytocics and
tocolytics

81
 Drugs acting on uterus

 Drugs acting on uterus can primarily affect the

endometrium or the myometrium.
 The responsiveness of myometrium to drugs is
markedly affected by the hormonal and gestational
status.

82
 Uterine stimulants (oxytocics, abortifacients)

 These drugs increase uterine motility, especially at term.

1. Posterior pituitary hormone: Oxytocin, Desamino oxytocin

2. Ergot alkaloids: Ergometrine (Ergonovine), Methylergometrine

3. Prostaglandins: PGE2, PGF2α, 15-methyl PGF2α,

Misoprostol
4. Miscellaneous Ethacridine, Quinine

83
 Oxytocin
 Oxytocin is a 9-amino-acid peptide secreted by the posterior
pituitary along with vasopressin (ADH).
 Synthesized within the nerve cell bodies in supraoptic and
paraventricular nuclei of hypothalamus.
 Released by stimuli i.e. coitus, parturition, suckling

84
 Actions of oxytocin
1. Uterus
 Increases the force and frequency of uterine contractions
 basal tone increases only with high doses
 With low doses, full relaxation occurs in between
contractions
 Estrogens sensitize the uterus to oxytocin
 increase oxytocin receptors (GPCRs)
 Progestins decrease the sensitivity, not marked in vivo.
85
 Actions…
 Nonpregnant uterus and that during early pregnancy is
rather resistant to oxytocin.
 Sensitivity increases progressively in the third trimester;
 a sharpnear term and quick fall during puerperium
 At term the increased contractility is restricted to the
fundus and body
 lower segment is not contracted; may even be
relaxed
86
87
 Mechanism of action
 Independent of innervation
 Rather, through specific G-protein coupled oxytocin receptors
 The number of oxytocin receptors increases markedly during
later part of pregnancy.
 Oxytocin also increases PG synthesis and release by the
endometrium which may contribute to the contractile
response.

88
 Actions…
2. Breast: Milk ejection
3. CVS
 Conventional doses used in obstetrics have no effect on BP, but
higher doses cause vasodilatation, fall in BP, reflex tachycardia
and flushing.
4. Kidney
 Oxytocin in high doses exerts ADH-like action: urine output 
 Pulmonary edema can occur if large amounts of i.v. fluids and
oxytocin are infused together.
89
 Pharmacokinetics
 Being a peptide, oxytocin is inactive orally
 Generally administered by i.m. or i.v. routes
 Rarely by intranasal spray
 It is rapidly degraded in liver and kidney
 Plasma t½ 6-12 min, and is still shortened at term
 Pregnant uterus and placenta elaborate a specific
aminopeptidase called oxytocinase—which can be
detected in maternal plasma. 90
 Oxytocin indications
 Induction of labour & Uterine inertia/augmentation
 Postpartum haemorrhage
• When ergometrine is contraindicated in HTN & Sepsis.
• It acts by forcefully contracting the uterine muscle
which compresses the blood vessels passing through its
mesh work.
 Breast engorgement: due to inefficient milk ejection
reflex
91
 Adverse effects
i. Injudicious use of oxytocin during labour can produce too
strong uterine contractions forcing the presenting part
through incompletely dilated birth canal, causing maternal
and foetal soft tissue injury, rupture of uterus, foetal
asphyxia and death.
ii. Water intoxication: This occurs due to ADH like action of
large doses given along with i.v. fluids, especially in
toxaemia of pregnancy and renal insufficiency. It is a
serious (may be fatal) complication. 92
Ergometrine & Methylergometrine
1. Uterus
 force, frequency and duration of uterine
contractions
 At low doses, relaxation occur in between
contractions
 Gravid uterus is more sensitive, especially at
term and in early puerperium.
 Their stimulant action involves the lower
segment also.
 The uterotonic action is believed to result
from partial agonistic action on 5-HT2 and α
adrenergic receptors. 93
 Actions…

2. CVS
 Both are much weaker vasoconstrictors than ergotamine
 have low propensity to cause endothelial damage
 Though they can raise BP, this is not significant at doses
used in obstetrics.
3. CNS: at high dose complex actions (not at usual dose)

94
 Pharmacokinetics

 rapidly and nearly completely absorbed from the

oral route.
 The onset of uterine action is: Oral—15 min; i.m.—
5 min; i.v.—almost immediate.
 They are partly metabolized in liver and excreted
in urine.
 Plasma t½ is 1–2 hours.
95
 Effects of a single dose last 3–4 hours.
 Ergometrine indications

I. To control and prevent postpartum haemorrhage

(PPH)
 methylergometrine is more potent oxytocic and is
preferred for this indication
II. After caesarean section/instrumental delivery —to
prevent uterine atony.
III. To ensure normal involution
IV. Diagnosis of variant angina 96
 Adverse effects
 Ergometrine & methylergometrine: less toxic than
ergotamine.
 When correctly used in obstetrics—hardly any
complications arise.
 Nausea, vomiting and rise in BP occur occasionally.
 They can decrease milk secretion if higher doses are
used for many days postpartum; this is due to
inhibition of prolactin release (dopaminergic action).
97
 Ergometrine should be avoided in—
 patients with vascular disease, hypertension,
toxaemia.
 presence of sepsis—may cause gangrene.
 liver and kidney disease
 They are contraindicated during pregnancy and
before 3rd stage of labour.

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 Prostaglandins

 PGE2, PGF2 α and 15-methyl PGF2 α are potent uterine

stimulants, especially in the later part of pregnancy and
cause ripening of cervix.
 Since misoprostol (a PG analogue used for peptic ulcer)
produces less side effects, it is being used for obstetric
indications as well

99
 Prostaglandins…

 Advantages of administration of PGE2 for

cervical ripening
 Enhances cervical inducebility
 Decreased need for oxytocin for induction
 Decrease oxytocin induction time and dosage
 Decreased C/S rate related to failed induction
 Dosage forms: Suppository (vaginal), 20mg; tablet
(vaginal), 3mg
100
 Uterine relaxants (tocolytics)
 These are drugs which decrease uterine motility
 They have been used to
 delay or postpone labour
 arrest threatened abortion and
 in dysmenorrhoea

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 Adrenergic agonists
 Ritodrine, the β2 selective agonist
 approved to suppress premature labour and to delay
delivery in case of some exigency or acute foetal distress.
 Use of ritodrine to arrest labour has been found to
increase maternal morbidity.
 Salbutamol and terbutaline can be used as alternatives to
ritodrine

102
 Calcium channel blockers
 Nifedipine
 Reduce the tone of myometrium and oppose contractions.
 Can postpone labour if used early enough
 Efficacy comparable to β2 adrenergic agonists has been
demonstrated and side effects are fewer.

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 Magnesium sulphate
 It is mainly used to control convulsions in eclampsia.
 It also possesses tocolytic activity by inhibiting Ca entry
in to cells.
 It is preferred over β2 agonists in patients with cardiac
problems, diabetes, hyperthyroidism and hypertension.

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 Oxytocin antagonist
 Atosiban
 is a peptide analogue of oxytocin that acts as antagonist at
the oxytocin receptors.
 It is available for inhibition of labour between 24–33 weeks
of gestation, and may offer better benefit risk ratio than
other tocolytics.

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 Prostaglandin synthesis inhibitors

• The depletion of prostaglandins prevents stimulation of

uterus

NSAID,s e.g. Aspirin

Indomethacin
Ibuprofen

Adverse effects
• ulceration
• premature closure of ductus arteriosus.

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Contraceptives

107
 Contraceptives

 Contraceptives may be
 Hormonal (estrogen & progestin containing) or
 Non-hormonal (for example, condom,
diaphragm, contraceptive sponge, and copper
intrauterine device).

108
 Contraception…

ÞExogenously administered estrogen in contraceptives

provides negative feedback which blunts release of
FSH by the pituitary gland and progestin inhibits LH
secretion, thus preventing ovulation.
ÞProgestin also thickens the cervical mucus, thus
hampering the transport of sperm.
ÞWithdrawal of the progestin stimulates menstrual
bleeding during the placebo week.
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Combination oral contraceptives
 A combination of estrogen and progestin is the most
common type of oral contraceptive.
 The most common estrogen in combination pills is
ethinyl estradiol & mestranol.
 The most common progestins are norethindrone,
levonorgestrel, desogestrel, norgestimate, and
drospirenone.
Þhighly effective in achieving contraception
110
Combination oral contraceptives…
 Combined OCPs may be
 Monophasic: Content of estrogen and
progesterone remain same in all the pills
(for 21 days).
 Biphasic: Content of progesterone is
different in pills for first 10 days and that for
11-21 days
 Triphasic: Content of progesterone is
gradually increased.
 It is lowest in first phase (1-6 days),
moderate in second phase (7-11 days) and
further increased in third phase (12-21 days).
111
Combination oral contraceptives…

 Biphasic and triphasic pills permit reduction in

progesterone content without compromising efficacy.
 attempt to mimic the natural female cycle
 These pills decrease the risk of breakthrough bleeding.
 Combined OCPs are started on first day of menstrual
cycle and given for 21 days.
 To allow withdrawal bleeding, iron tablets are given
(without hormones) for next seven days.
112
Combination oral contraceptives…
Monophasic combination ESTROGEN PROGESTIN
(μg) (mg)
Ethinyl estradiol/desogestrel 30 0.15
Ethinyl estradiol/drospirenone 30 3
Ethinyl estradiol/levonorgestrel 20 0.1
30 0.3
Ethinyl estradiol/norgestrel 50 0.5
Ethinyl estradiol/norgestimate 35 0.25
Mestranol/norethindrone 50 1
20 1
Ethinyl estradiol/norethindrone 30 1.5
35 0.4
50 1
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Combination oral contraceptives…
Biphasic combination ESTROGEN PROGESTIN
(μg) (mg)
35 0.5 (10 tabs)
Ethinyl estradiol/norethindrone 35 1(11 tabs)
Triphasic combination
30 0.05 (6 tabs)
Ethinyl estradiol/levonorgestrel 30 0.075 (5 tabs)
30 0.125 (10 tabs)
25 or 35 0.18 (7 tabs)
Ethinyl estradiol/norgestimate 25 or 35 0.215 (7 tabs)
25 or 35 0.25 (7 tabs)

114
 Progestin-only pills (minipills)
 Norethindrone (0.35mg), Norgestrel (0.75mg)
 These contain low dose of progestin without any estrogen.
 These are less effective than combined OCPs.
 Minipills are preferred in women where estrogen is contra-
indicated e.g.
Smokers
>35 years of age
Risk factors of thromboembolism

115
 Progestin-only pills (minipills)…
 Minipills are oral contraceptives of choice for
Lactating women
Sickle cell anemia
Seizure disorder
 Progesterone only pills are given daily without any break.
 Thickening of cervical mucus is major mechanism of
minipills.
 Breakthrough bleeding is as high as 25%.
116
 Parenteral contraceptives
 These can be used in females with contra-indication to
estrogens.
 Major problem with these methods is prolonged
infertility after their use.
 Most common adverse effects of parenteral
contraceptives is irregular bleeding.

117
 Injectable progestin
 Medroxyprogesterone acetate (im/sc): every 3
months.
 provides high sustained levels of progestin, and causes
amenorrhea
 return to fertility may be delayed for several months
 Weight gain is a common adverse effect.
 may contribute to bone loss and predispose patients to
osteoporosis and/or fractures.
 Therefore, the drug should not be continued for more
118
than 2 years unless the patient is unable to tolerate
 Implanon
 Subdermal placement in the upper arm (contraception for 3
years)
 Contain etonogestrel (metabolite of desogestrel)
 The implant is as reliable as sterilization, and the
contraceptive effect is reversible when removed.
 Progestin implants and intrauterine devices are known as
long-acting reversible contraceptives (LARC).
 Adverse effects: irregular menstrual bleeding and
headaches. 119
Parenteral contraceptives

120
 Adverse effects
 The most common adverse effects with estrogens are
 breast fullness, fluid retention, headache, and nausea.
 Increased blood pressure may also occur.
 Progestins may be associated with depression, changes in
libido, hirsutism, weight gain and acne.
 Desogestrel and norgestimate cause less weight gain.
 Acne and hirsutism may worsen by progestins
containing androgenic properties.
121
 Adverse effects…
 Migraine is made worse with the use of OCPs.
 Breakthrough bleeding is common problem (progesterone).
 Failure of withdrawal bleeding can also occur
 Risk of venous thromboembolism (estrogen) with OCP use.
 breast and cervical carcinoma ; whereas endometrial and
ovarian carcinomas  by OCP use.
 Progesterone is responsible for decreasing the risks
  Cholestatic jaundice, gall bladder disease & hepatic adenomas

122
 Postcoital contraception
 Postcoital or emergency contraception reduces the probability of

pregnancy after intercourse without effective contraception to between

0.2% and 3%.
 Levonorgestrel (1.5 mg single dose) ---Plan B approach
 better tolerated & most common method
 should be taken as soon as possible after unprotected

intercourse and preferably within 72 hours.

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 The End

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