Endocrine Drugs

By: - Belachew Boranto (B.Pharm, MSc)

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 Endocrine system

• Endocrine system is controlled by the pituitary &

hypothalamus

• The endocrine system releases hormones into the bloodstream,

– which carries these chemical messengers to target cells

throughout the body

• Hormones are key regulators of metabolism, growth, and

reproduction 2
The hypothalamic-pituitary endocrine system

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 Diabetes Mellitus (DM)

• DM- A chronic metabolic disorder characterized by a high

blood glucose concentration resulting from defects in insulin
secretion, insulin action, or both.
• It is diagnosed by;
– Fasting blood sugar (FBS) ≥ 126 (normal < 120mg/dl).
– 2-hours blood sugar after oral 75 g glucose ≥ 200 (normal <
140mg/dl).

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 Etiology and Classification of DM

• Types of Diabetes
– Type 1 DM

– Type 2 DM

– Type 3 DM: multiple other specific causes of elevated

blood glucose e.g. Genetic defects of β-cell function,
diseases of the exocrine pancreas, endocrinopathies, or drug
or chemical induced.
– Type 4 DM: Gestational diabetes mellitus
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Etiology and Classification of DM …

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Etiology and Classification of DM …

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 Etiology and Classification of DM …

• Type 4 DM (Gestational DM)

– Any abnormality in glucose level noted for the first time
during pregnancy
– During pregnancy, the placenta and placental hormones
create insulin resistance.
– Increased fetal growth resulting in weight exceeding 4 -
4.5kg
– 50% lifetime risk of developing Type II DM and the
Recurrence risk of GDM is 30 - 50% for the mother. 8
 Therapy
• Non Pharmacological therapy
– Diet therapy
Alcohol ingestion should be limited
Decrease cholesterol intake
Avoid simple sugars
– Exercise
– Weight reduction
– Maintain normal BMI of 18.5 and 24.9
• Pharmacologic therapy
– Insulin
– Oral hypoglycemic drugs
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Pharmacologic therapy

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 Insulin
• Insulin and Insulin Analogues
• Used in Type 1 Diabetes, Type 2 Diabetes (when oral agents
fail), and Gestational Diabetes.

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 Types of insulin

Figure: Extent and duration of action of various types of insulin 12

 Insulin …
• Mechanism of Action:
– Binds to insulin receptors → increases glucose uptake by

muscle and fat.

– Inhibits hepatic glucose production.
• Routes of administration: SC (for all), Intravenous (IV) in

emergencies (IV or IM only for regular insulin)

• Side Effects:
– Hypoglycemia, weight gain, lipodystrophy, insulin

resistance, allergic reactions. 13

 Oral Hypoglycemic Agents
• Used to treat patient with type 2 DM
• Fall into five groups:
1. Insulin Secretagogues (Increase Insulin Release)
– Sulphonylureas, Meglitinides
2. Insulin Sensitizers (Enhance Insulin Action)
– Biguanides, Thiazolidinediones
3. Alpha glucosidase inhibitors
4. DPP-4 Inhibitors
5. SGLT2 Inhibitors
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 Insulin Secretagogues

• Sulfonylureas (SUs)

– Examples: Glibenclamide, Glipizide, Gliclazide,

Glimepiride.

– MOA: Block K⁺ channels in β-cells → depolarization →

Ca²⁺ influx → insulin release.

– Side Effects: Hypoglycemia, weight gain, GI disturbances

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 Insulin Secretagogues

• Meglitinides (Glinides)
– Examples: Repaglinide, Nateglinide.
– MOA: Similar to SUs but shorter duration.
– Side Effects: Hypoglycemia (less than SUs), weight gain.

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 Insulin Sensitizers
• Biguanides
– Example: Metformin
– MOA: Decreases hepatic gluconeogenesis, increases
peripheral glucose uptake.
– Doesn't cause weight gain (first-line for Type 2 DM
especially in obese patients).
– Side Effects: GI upset (diarrhea, nausea), ↓appetite, lactic
acidosis (rare)
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 Insulin Sensitizers

• Thiazolidinediones (TZDs)

– Examples: Pioglitazone, Rosiglitazone.

– MOA: Activate Peroxisome proliferator-activated receptor

gamma (PPAR-γ) → increase insulin sensitivity.

– Side Effects: Weight gain, fluid retention, heart failure

risk, osteoporosis.

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 α-Glucosidase Inhibitors

• Examples: Acarbose, Miglitol.

• MOA: Inhibit alpha-glucosidase enzymes in the small
intestine, delaying carbohydrate breakdown and glucose
absorption
• Side Effects: Flatulence, bloating, diarrhea.

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 SGLT2 Inhibitors

• Examples: Empagliflozin, Dapagliflozin, Canagliflozin

• MOA: Inhibit SGLT2 (Sodium-Glucose Cotransporter-2) in

the proximal renal tubule, increasing urinary glucose excretion

• Side Effects: UTIs, dehydration, ketoacidosis.

• Benefits: Cardioprotective, weight loss.

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 Incretin-Based Therapies

• Acts by enhancing Glucagon-Like Peptide-1 (GLP-1) Pathway

• GLP-1 Receptor Agonists (Injectable)

– Examples: Exenatide, Liraglutide, Semaglutide

– MOA: Mimic GLP-1, increasing insulin secretion,

suppressing glucagon, delaying gastric emptying, and

reducing appetite.
– Side Effects: Nausea, vomiting, pancreatitis, weight loss,

thyroid cancer risk.

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 Incretin-Based Therapies …

• DPP-4 Inhibitors (Gliptins)

– Examples: Sitagliptin, Vildagliptin, Linagliptin

– MOA: Inhibit DPP-4 enzyme, preventing GLP-1

degradation, thus enhancing insulin secretion and reducing

glucagon.
– Side Effects: Nasopharyngitis, headache, pancreatitis (rare).

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Thyroid Hormones

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 Synthesis of Thyroid hormone

Major pathways of thyroid hormone biosynthesis, storage as Regulation of thyroid

colloid, and release. hormone secretion 25
 Thyroid hormone (T3, T4) actions
• Have three principal actions:
1. Stimulation of energy use → Elevates BMR  in
• ↑ O2 consumption &
• ↑ Heat production
2. Stimulation of the heart 
• ↑ Heat rate
• ↑ Force of contraction → ↑ CO
3. Promotion of growth & development
• Brain & other components of the NS
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• Maturation of skeletal muscle
 Thyroid pathophysiology

• Hypothyroidism
– Adults - Mild →Hypothyroidism

- Severe → myxedema

– Infants → Cretinism

• Hyperthyroidism
– Grave’s diseases

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Thyroid & Antithyroid Drugs

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Drugs for Hypothyroidism and Hyperthyroidism

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β Adrenoceptor Blockers
• Propranolol or Nadolol
– Antagonize sympathetic overactivity in thyrotoxicosis
(cardioprotective).
– Inhibit conversion of T4 to T3 → divert T4 to the inactive rT3
• Indications
– Symptomatic: controls thyrotoxic symptoms until
antithyroid drugs or I131 work.
– Storm: Thyroid storm.
– Surgery: Preoperative medication for thyroidectomy.
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 Adrenocortical Steroids
• The adrenal cortex has three layers: the zona glomerulosa, the
zona fasciculata, and the zona reticularis
– From outside to inside: GFR, which makes hormones for
salt/sugar/sex
• The zona glomerulosa is stimulated by the renin-angiotensin
system to produce the mineralocorticoid aldosterone.
• The zona fasciculata and the zona reticularis are stimulated
by ACTH to produce glucocorticoids and sex hormones,
respectively 31
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 Adrenocortical Steroids …

• Hormones of the adrenal cortex affect multiple physiologic

processes, including:
– Maintenance of glucose availability,
– Regulation of water and electrolytes
– Development of sexual characteristics, and
– Life-preserving responses to stress

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 Adrenal Cortex Hormones and Drugs
• Glucocorticoids
– Drugs: Hydrocortisone, Prednisone, Dexamethasone
– MOA: Bind to intracellular glucocorticoid receptors,
affecting gene transcription to reduce inflammation and
suppress the immune system.
– Uses: Inflammatory conditions, asthma, adrenal insufficiency
(Addison’s disease).
– Side Effects: Osteoporosis, Cushing’s syndrome,
hyperglycemia, hypertension.
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 Adrenal Cortex Hormones and Drugs …
• Mineralocorticoids
– Drug: Fludrocortisone
– MOA: Acts on aldosterone receptors to increase Na+ retention
and K+ excretion.
– Uses: Adrenal insufficiency, orthostatic hypotension.
– Side Effects: Edema, hypertension, hypokalemia.
• Aldosterone Antagonists: Spironolactone, Eplerenone
– MOA: Block aldosterone receptors.
– Uses: Heart failure, hypertension, hyperaldosteronism.
– Side Effects: Hyperkalemia, gynecomastia (spironolactone).
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Sex Hormones and Related Drugs

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 Biosynthetic pathways of Sex Hormones

Figure. The biosynthetic pathway for the androgens and oestrogens, with
sites of drug action
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Figure. Hormonal control of the female reproductive system. The
Graafan follicle (GF) is shown developing on the left, then
involuting to form the corpus luteum (CL) on the right, after the
ovum (•) has been released. FSH, follicle-stimulating hormone;
GnRH, gonadotrophin-releasing hormone; LH, luteinising hormone

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 Sex Hormones and Related Drugs …
• Estrogens and Progestins
– Estrogens (Ethinyl Estradiol, Estradiol):

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 Sex Hormones and Related Drugs …
• Estrogens and Progestins
– Progestins (Levonorgestrel, Medroxyprogesterone):

– Side Effects: Thrombosis, breast cancer risk.

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 Estrogen Antagonists
• Anastrozole:
– MOA: aromatase inhibitor →↓ estrogen synthesis
– Use: estrogen-dependent, postmenopausal breast cancer
– Side effects: headache, diarrhea, nausea, hot flushes, rash

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 Estrogen Antagonists …
• Clomiphene (fertility pill)
– MOA: ↓ feedback inhibition →↑ FSH and LH →↑
ovulation → pregnancy
– Use: fertility drug

– Side effect: ↑ multiple births, ovarian cancer (should

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not be used for more than six cycles )
Selective Estrogen-receptor Modulators (SERMs)

• Tamoxifen
– Variable actions depending on “target” tissue
Estrogen-receptor agonist (bone), antagonist (breast), and
partial agonist (endometrium)
– Possible ↑ risk of endometrial cancer
– Used in estrogen-dependent breast cancer and for
prophylaxis in high-risk patients

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 Selective Estrogen-receptor Modulators …
• Raloxifene
– Estrogen-receptor agonist (bone), antagonist breast and
uterus
– When used in menopause, there is no increased cancer risk
– Use: prophylaxis of postmenopausal osteoporosis, breast
cancer

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 Androgens

• Androgens include methyltestosterone and 17-alkyl derivatives

with increased anabolic actions, e.g., oxandrolone, nandrolone.

• Uses: Male hypogonadism and for anabolic actions →↑ muscle

mass, ↑ RBCs, ↓ nitrogen excretion, illicit use in athletics

• Side effects: excessive masculinization, premature closure of

epiphysis, cholestatic jaundice, aggression, dependence

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 Androgen Antagonists
• Flutamide:
– Androgen receptor blocker:
– Used for androgen-receptor– positive prostate cancer
• Leuprolide:
– GnRH analog:
– Repository form used for androgen-receptor– positive
prostate cancer, endometriosis, uterine fibroids, precocious
puberty
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 Androgen Antagonists …
• Finasteride
– MOA: 5α - reductase inhibitor, preventing conversion of
testosterone to dihydrotestosterone (DHT)
– DHT is responsible for hair loss and prostate enlargement
– Uses: BPH, male pattern baldness
– Caution: teratogenicity

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 Hormonal Contraceptives

• Hormonal contraceptives contain synthetic versions of

estrogen, progestin, or both.

• They work mainly by inhibiting ovulation, altering cervical

mucus, and affecting the endometrium

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Figure. Classification of hormonal contraceptives. aDepot medroxyprogesterone acetate;
b
Norethisterone enanthate 49
 Hormonal contraception

• The combined pills: estrogen + progestin

− Monophasic: fixed dose of estrogen & progestins for 21 days

− Biphasic: fixed dose of estrogen + 2 d/t doses of progestins

(7-10 & 11-14 days)

− Triphasic: fixed dose of estrogen + 3 d/t doses of progestins

(7/7/7 days)

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 The combined pill …
• Most commonly used

− Combines both estrogen & progestin

The combination is synergistic.

Progestins inhibit oestrogen-induced endometrial

proliferation ↓ risk of endometrial carcinoma.

• Estrogen: ethinyl estradiol, mestranol

• Progestin: norethindrone, levonorgestrel or desogestrel

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 Contraceptives: MOA

Figure: Mechanism of action of contraceptives.

• N.B;. For description of the numerals 1, 2, 3 and 4 shown in the figure

see the next slide 53
 Contraceptives: MOA

1. Both oestrogen and progestin inhibit the release of FSH and

LH (negative feedback inhibition)  prevent ovulation.

2. Cause tubal and uterine contractions that may interfere with

fertilization.

3. Make the endometrium less suitable for implantation.

4. Thick, viscid cervical mucus secretion prevents sperm

penetration (progestins).
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 Schedule for use of combined pill
• The combined pill is taken for 21 consecutive days followed
by 7 tablet free days or sometimes it has 7 tab of iron
preparation or placebo tablets

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 Schedule for use of combined pill

• What if a woman on combined oral contraceptive pills fails to

take a tablet?

− She should take two tablets the next day and continue rest

of the pills as prescribed

• If she misses more than two tablets,

− She should stop the treatment, use alternate method of

contraception and restart course of pills from next cycle

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 Adverse Effects and Contraindications
• Adverse Effects:
– Increased risk of thromboembolism (deep vein thrombosis,
stroke)
– Hypertension.
– Breast tenderness, nausea.
– Mood changes.
• Contraindications:
– Smokers over 35 years.
– History of thromboembolic disorders.
– Breast cancer, liver disease. 57
 Progestin-Only Contraceptives (POCs)

• Contain only progestin and are suitable for women who cannot
take estrogen.
• Include: norethindrone, levonorgestrel
• Mechanism of Action:
– Thickens cervical mucus.
– Inhibits ovulation (less consistently than combined
hormonal contraceptives).
– Alters endometrial receptivity.
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 Progestin only pills …
• Are less effective than the combination pills

• The pill is taken daily without interruption

Figure. Schedule for use of minipill

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 Progestin only pills …
• An advantage of progestin only pill can be taken after

parturition
− Unlike estrogen containing pills, it does not interfere with

lactation
• Indicated in case of estrogen contraindication as:

− Lactating mothers, diabetics, CVS diseases (MI, HTN,

stroke)
− Prior thromboembolism
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•
 Progestin only pills …
• Adverse Effects:
– Irregular menstrual bleeding.
– Weight gain.
– Mood changes, headache.
– ↑ risk of ectopic pregnancy
• Contraindications:
– History of breast cancer.
– Liver disease.
– Unexplained vaginal bleeding.
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 Emergency Contraceptives (EC)
• Used after unprotected intercourse to prevent pregnancy.
• Types:
– Levonorgestrel (0.75mg) (Plan B)
A single or two-dose progestin pill taken within 72 hrs
Delays ovulation.
– Ulipristal Acetate (Ella)
Selective progesterone receptor modulator (SPRM).
Effective up to 5 days post-intercourse.
– Mifepristone
Used to terminate early pregnancy (used with PGs)
Also interferes with implantation 62
 Side effects

• Nausea or vomiting - 40%

− Administered with antiemetics

• Headache

• Dizziness

• Breast tenderness

• Abdominal and leg cramp

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 Parenteral Contraceptives
• Injectable Contraceptives
− Depot medroxyprogesterone acetate (DMPA): 150 mg deep
i.m. once in 3 months.
− Norethindrone enanthate (NET-EN): 200 mg i.m. once in 2
months.
• Advantages
− Regular oral medication is avoided, so patient compliance is
better.
− Can be used safely during lactation.
− ↓ risk of endometrial cancer on prolonged administration64
 Parenteral Contraceptives …
• Side effects of injectable
− Menstrual irregularities & amenorrhea: common
− Infertility may persist for many months after cessation (6–8
months)
− Headache
− Mood changes,
− Weight gain
− Osteoporosis
− ↓HDL and ↑LDL levels.
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 Parenteral Contraceptives …
• Implants
− Norplant: six silastic capsules each containing 36mg of
levonorgestrel is implanted in the left upper arm under local
anesthesia, effective up to 5yrs

− Side effects
Irregular menstrual bleeding
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Headache or visual disturbance
 Parenteral Contraceptives …
• Implants …
– Implanon. It is a subdermal single rod containing 68 mg of
desogestrel.
− The contraceptive effect lasts for 3 years

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 Devices
• Intrauterine devices:
− Levonorgestrel device:
It is a ‘T’-shaped device inserted into the uterine cavity
and the contraceptive effect lasts for 5 years.
− Progestasert:
Intrauterine device containing progestogen; can be
inserted into the uterine cavity.
The efficacy is low and the device has to be replaced
yearly
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 Uterine Stimulants (Oxytocics, Abortifacients)
• These drugs increase uterine motility, especially at term.
– Posterior pituitary hormone
 Oxytocin
– Ergot alkaloids
 Ergometrine (Ergonovine), Methylergometrine
– Prostaglandins
 PGE2, PGF2α, 15-methyl PGF2α, Misoprostol
– Miscellaneous
 Ethacridine, Quinine. 69
 Oxytocin
• Oxytocin is a nonapeptide secreted by the posterior pituitary
along with vasopressin (ADH).

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 Oxytocin …
• Physiologic and pharmacologic effects

– Uterine stimulation፡ Increased force, frequency, and

duration of uterine contractions

– Milk ejection፡ Milk produced by glandular tissue of breast

is transferred into large sinuses through milk-ejection reflex

– Water retention፡ Similar to ADH, so promotes renal water

retention

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 Oxytocin …
• Stimuli for oxytocin release include sensory stimuli from the:
– Cervix and vagina as well as suckling from the breast.
• Oxytocin Receptors
– Promote influx of calcium into the cell
– Activation of the oxytocin receptor also stimulates PG

synthesis
– Oxytocin in small doses increases both the frequency and

force of uterine contractions.

– Contractions resemble the normal physiological contractions
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 Oxytocin …
• Therapeutic uses

– Induction of labor

– Augmentation of labor,

– Postpartum use to control bleeding,

– Milk ejection,

• Adverse effects: Water intoxication (ADH like action)

• Precautions and contraindications: Improper use can be

hazardous (uterine rupture) 73

 Ergometrine, Methylergometrine
• Ergometrine (ergonovine), methylergometrine (Methergine)
• Both have similar pharmacological property,
• Actions
– Uterus: stimulate contraction involving both upper and

lower segments
methylergometrine has more potent effect on uterus than

ergometrine
– CVS: weak vasoconstriction
– GIT: Peristalsis increases in high doses 74
 Ergometrine, Methylergometrine …
• Therapeutic uses
– Prevention and treatment of postpartum hemorrhage
– Prevention of uterine atony
– To hasten involution of uterus
• Adverse effects
– Less toxic than ergotamine
– Nausea, vomiting
– Angina, hypertension, headache
– Inhibition of prolactin release (dopaminergic action).
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– Ergotism – cramps, spasm, hallucination, severe GI upset
 Prostaglandins
• Endogenous produced from endometrium and myometrium in

the proliferative stage of menstrual cycle.

• PGE and PGF – contracts the non pregnant and pregnant uterus,

relaxes cervix
• Uterine muscles - more sensitive to progesterone during

pregnancy
• PGF2α - implicated in the ischemic necrosis of the endometrium

that precedes menstruation

• Vasodilators – PGE2 and PGF2 76
 Prostaglandins …
• Also play a part in two of the main disorders of menstruation –

– Dysmenorrhea (painful menstruation) and menorrhagia

(excessive blood loss)

• Dysmenorrhea – increased production of PGE2 and PGF2α

• Menorrhagia - increased vasodilation and reduced

haemostasis

– Due to PGE2 and PGI2 increase compared to PGF2α

• Cox inhibitors are useful in managing these conditions

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 Prostaglandins …
• Exogenous Prostaglandins
– Dinoprostone - PGF2α

– Carboprost – 15 –methyl PGF2α

– Misoprostol - PGE1 analogue

• Adverse effects: uterine pain, nausea and vomiting
• Clinical uses
– Abortifacient
– Induction of labor
– Postpartum hemorrhage 78
Thanks!!
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