Endocrine and reproductive pharmac isology

Hormones produced by the Anterior pituitary gland

1. Growth hormone (GH)

2. Thyroid stimulating hormone (TSH)

3. Adenocorticotropic hormone (ACTH)

4. Follicle Stimulating hormone (FSH)

5. Luteinizing hormone (LH)

6. Prolactin

Hormone produced by the intermediary lobe of the pituitary gland

Melanocyte stimulating hormone (MSH)

Hormones produced by the posterior pituitary gland

1. Oxytocin

2. Anti Diuretic hormone (AD

Hormones produced by the thyroid gland

1. Thyroxine (T4)

2. Tri iodothyronine (T3)

3. Calcitonin

Hormone produced by the parathyroid gland

Parathyroid hormone (PTH)

Hormones produced by the adrenal cortex

1. Glucocorticoids

2. Mineralocorticoids like aldosterone

3. Sex corticoids called androgens

Hormones provided by the adrenal medulla

1. Epinephrine

2. Norepinephrine

Hormones produced by gonads

1. Androgens

2. Estrogens

3. Progestins

Hormones produced by the pancreas

1. Glucagon

2. Insulin

3. Somatostatin

Recombinant growth hormones

1. Somatrem

2. Somatropin

Uses of recombinant growth hormones

Somatropin and somatrem are used in the following

1. Treatment of pituitary dwarfism

2. Treatment of AIDs related wasting

3. Growth hormone deficiency in adults

4. Adult athletes to increase muscle mass

5. Growth failure in pediatric patients associated with :

   👉 Prader Willi syndrome ( Autosomal dominant genetic disease that is associated with growth failure, obesity and carbohydrate intolerance)

   👉 Turner’s syndrome (chromosomal anomaly in girls)

   👉 Chronic renal failure

These are given parenterally👌

Adverse effects of growth hormone

1. Creutzfeldt Jakob disease (is a brain damage)

2. Peripheral edema, myalgia , arthralgia, pancreatitis and gynecomastia in adults

3. Screening suggested for hypothyroidism and diabetes during GH treatment

Growth hormone releasing hormone (GHRH) analogues

1. Sermorelin

2. Hexarelin

   👉 These are recombinant GHRH analogues that are used for pituitary dwarfism

Mecasermin

👉 Is a complex of recombinant human IGF1 ( Insulin like growth factor 1 ) and IGF binding protein 3.

It is indicated for growth failure due to deficiency of IGF1 that is not responsive to GH.

It is administered subcutaneously

IGF binding protein if needed to maintain adequate half life of IGF1

Adverse effect of mecasermin

Hypoglycemia

Mechanism of action of growth hormone

💕Growth hormone binds to GH receptors increasing lipolysis and decreasing glucose uptake directly. It also acts indirectly by increasing production of IGF-1 which increases protein synthesis and bone and cartilage growth👊👊

Drugs of growth hormone

Somatrem

Somatropin

Pegvisomant

Growth hormone agonists

Somatrem

Somatropin

Growth hormone antagonist

pegvisomant👍

Mechanism of action of Somatrem and Somatropin

It acts through GH receptors to increase production of IGF-1 which restores normal growth and metabolic GH effects in GH deficient individuals. Increases final adult height in some children with short stature

Indications of growth hormone drugs

• Treatment of growth hormone deficiency

• Treatment of patients with short bowel syndrome who are dependent on total parenteral nutrition ( increases mucosal cell growth and villas height )

• Anti aging remedies

• Used in athletes to increase in muscle mass and athletic performance

• Treatment of Prader- Willi syndrome

• Treatment of Turners syndrome

• Adverse effects of growth hormone drugs

• Peripheral edema ( swelling of hands and legs, weight gain due to fluid retention)

• Increased risk of asphyxiation ( inadequate oxygen supply to the body especially the brain) in severe obese patients with Prader Willi syndrome

• Increased risk of otitis media in patients with turners syndrome while taking growth hormone

• Arthralgia (joint pain)

• Carpel tunnel syndrome ( median nerve compression)

• Muscle pain (myalgia)

• Hyperglycemia

• May precipitate or worsen diabetes

• Insulin resistance

• Pain and redness at injection sites

• Pancreatitis and gynecomastia

Pegvisomant

Is a GH receptor antagonist

It works by blocking the GH receptors, stops growth hormone action which prevents liver from making IGF , the hormone that causes growth effects. Adverse effects include increased liver enzymes, injection site reactions like pain , redness and swelling, headache and flue like symptoms, hypersensitivity , aggravates hypoglycemia , hypertension. 👨‍🎨👂

Detailed mechanism of action of growth hormone

1. Binds to growth hormone receptors

2. Receptor dimerization. One hormone molecule binds to two receptor molecules. This causes the receptors to come together ( dimerize) .

3. Dimerization is essential because it activates the receptor

4. Activation of intracellular enzymes. Once the receptor is activated, it stimulates an enzyme called Janus kinase 2 ( JAK2) attached to the receptor inside the cell

5. JAK 2 becomes active and starts a signaling cascade😎😎

6. Activation of STAT proteins. Activated JAK2 phosphorylation signal transducer and activator of transcription proteins ( STATs)

7. Gene transcription in the nucleus. Phosphorylated STAT proteins move into the nucleus . Inside the nucleus they switch on specific genes responsible for growth

8. Production of insulin like growth factor . One of the most genes activated is the gene for insulin like growth factor 1 ( IGF-1) is mainly produced in th liver

9. Actions of IGF1 . Carries out most of the growth hormone effects 💪💪🫦

GHRH analogues

Sermorelin

Hexarelin

Tesamorelin

Mechanism of action of GHRH analogues

1. Bind to GHRH receptors on pituitary Somatropin ( cells in the pituitary gland that produce and secrete GH)

2. Activate Gs protein

3. Increase adenylate cyclase activity

4. Increase cyclic AMP

5. Stimulate synthesis and pulsatile release of growth hormone

6. Increase IGF-1 production

Indications of GHRH analogues💕💕

1. Are used in treatment of pituitary dwarfism🥰❤

2. Growth hormone deficiency

3. Short stature due to growth hormone deficiency ( in children)

4. Tesamorelin is specifically used for HIV lipodystrophy (abnormal distribution or loss of body fat or excess visceral fat) in HIV patients on ART

5. Evaluation of pituitary function. Used in GH stimulation tests 👁👁

Growth hormone stimulation tests 👌😇😇

1. This is the use of GHRH analogues to test whether the anterior pituitary ( Somatropin) is working properly and can release growth hormone e.g Sermorelin

2. These are used to diagnose adult GH deficiency and pituitary dysfunction

Doctors use it when they suspect adult growth hormone deficiency, pituitary damage (tumor, surgery, trauma, radiation) and in explained short stature in children

Adverse effects of GHRH analogues

• Pain, redness, itching and swelling at the injection site

• Peripheral edema

• Weight gain from fluid

• Joint stiffness or aching

• Arthralgia, myalgia and carpal tunnel like syndrome

• Insulin resistance

• Mild hyperglycemia

• May worsen diabetes in susceptible patients

• Headache due to fluid shifts or hormonal effects

• Tesamorelin commonly causes abdominal discomfort

Growth hormone inhibiting hormone (GHIH) / Somatostatin 👌👌👌

Somatostatin inhibits the release of the following hormones

• Growth hormone

• Thyroid stimulating hormone (TSH)

• Glucagon

• Insulin

• Gastrinoma

👉 Somatostatin analogues mimic the action of somatostatin

GHIH (Somatostatin) analogues

1. Ocreotide

2. Lancreotide

3. Vapreotide

4. Pasireotide

5. Seglitide

MOA of Somatostatin analogues

1. They bind to somatostatin receptors in target cells eg pituitary

2. Activate Gi protein

3. Decrease adenylate cyclase. Gi inhibits adenylate cyclase

4. Decrease cAMP production

5. Decrease protein kinase A . (cAMP is needed to activate PKA)

6. Decrease protein phosphorylation. PKA normally phosphorylates proteins that promote hormone secretion

7. Decreased phosphorylation of secretory machinery proteins

8. Decreased activation of transcription factors

9. Reduced gene expression and release machinery activity

Indications of somatostatin analogues🌕🌛🌚

1. Acromegaly

2. Growth hormone secreting pituitary tumors

3. Neuroendocrine tumors especially Carcinoid tumors, gastrinoma, VIPoma

4. Gastrointestinal hormone hypersecretion disorders . Used to reduce excessive GI secretions in conditions like VIPoma, gastrinoma ( zollinger Ellison syndrome, excess acid secretion), glucagonoma

5. Acute varicella bleeding ( Reduces portal blood flow, helps control bleeding in liver cirrhosis patients)

6. Secretory diarrhea

7. Oesophageal varices

8. Ocreotide is used in TSH secreting adenoma and overdose of sulfonyl ureas

9. Ocreotide is used in diarrhea associated with diabetes🌹💐🥀🌻🌞

Adverse effects of somatostatin analogues🙂🙂

1. Abdominal pain, nausea, vomiting , diarrhea and steatorrhea( fatty stools) since they reduce GI secretions and slow intestinal motility

2. Gallstones ( cholethiasis)

3. Hyperglycemia due to decreased insulin and glucagon secretion raising blood glucose

4. Pain, redness, swelling and local irritation at the injection site

5. Malabsorption/ fat digestion problems. Reduced pancreatic enzyme secretion, fatty stools ( steatorrhea)

6. Reduced TSH leading to mild hypothyroid like symptoms 😍😍🌹

Prolactin👏👏👏👏

• It causes growth and development of breast during pregnancy

• It induces milk secretion after delivery

• It inhibits hypothalamic pituitary- gonadal axis

• Hypothalamus secretes prolactin release inhibitoy hormone (same as dopamine )

• Thus dopamine agonists like bromocriptine possess inhibitory actions on prolactin and D2 blockers like antipsychotics and metoclopramide can cause hyperprolactinemia

• High prolactin suppresses GnRH from hypothalamus

• Hence decreasing LH and FSH from pituitary

• Finally preventing ovulation

Effects of excess prolactin

1. Amenorrhea (lactational). Temporary absence of menstruation after child birth during breast feeding

2. Inhibition of ovulation and fertility

3. Galactorrhoea in females ( abnormal production and discharge of breast milk in people who are not breastfeeding or pregnant)

4. Infertility in males 😳😳

Major drugs used for treatment of excess prolactin production

Dopamine agonists

Examples of dopamine agonists

• Bromocriptine

• Cabergoline

• Quinagolide

Bromocriptine: Is a dopamine agonists useful in the treatment of hyperprolactinemia. Can also be used in treatment of acromegaly although less effective than Ocreotide.

Also used in suppression of lactation

Cabergolide : is a longest acting dopamine agonists (ergot derivative) that is better tolerated than bromocriptine

Quinagolide: is a non ergot dopamine agonists having less adverse effects

Mechanism of action of dopamine agonists

1. Bind to D2 (dopamine)receptors located on lactotroph cells in the anterior pituitary gland

2. D2 receptor is coupled to Gi inhibitoy protein so it’s activated

3. This leads to reduced adenylate cyclase activity which decreases cAMP

4. Lower cAMP leads to reduced protein kinase A activity

5. This decreases cellular activity of lactotrophs

6. Reduced prolactin gene expression

7. Decreased prolactin exocytosis from pituitary

8. Chronic stimulation leads to shrinkage of prolactin secreting adenomas ( prolactinomas). This leads to reduced tumor size especially with cabergoline 👍👍

Indications of dopamine agonists

1. Hyperprolactinemia

2. Prolactin-secreting pituitary tumors ( prolactinomas)

3. Infertility due to hyperprolactinemia

4. Galactorrhea

5. Hypogonadism due to high prolactin

6. Adjunct in some acromegaly cases

Adverse effects of dopamine agonists

1. Nausea and vomiting

2. Headache and dizziness

3. Postural hypotension

4. Hallucinations/ confusion

5. Nasal congestion

6. GI upset

7. Mood changes

Drugs used in treatment of acromegaly

1. Dopamine agonists e.g cabergolide

2. Somatostatin analogues e.g Ocreotide

3. GH receptor antagonist e.g pegvisomant

4. Tamoxifen

Gonadotropins

• These include FSH and LH

• Secretion of theses hormones is controlled by GnRH that si secreted in a pulsatile manner

• Deficiency of gonadotropins can lead to

Anovulatory infertility in females

Oligozoospermia

Infertility in males ( hypogonadotropic hypogonadism)

• Excessive secretion of those hormones is associated with

  Precocious puberty

  Endometriosis

  Prostatic carcinoma

  Fibroids

  Polycystic ovarian syndrome ( PCOS)

FSH analogues

1. Follitropin Alfa

2. Follitropin beta

3. Urofollitropin

4. Menotropins (hMG)

About FSH analogues

1. Follitropin alpha and follitropin beta are recombinant forms of FSH

2. Urofollitropin is purified FSH obtained from urine of post menopausal women

3. Menotropins : Extract of the urine of post menopausal women and it contains both FSH and LH activity

LH analogues

1. Lutropin Alfa

2. Human chorionic gonadotropin

3. Choriogonadotropin alfa

About LH analogues

1. Lutropin Alfa is a recombinant (synthetic) form of LH

2. Hcg acts like LH because it binds to LH receptors l

3. Choriogonadotropin Alfa is a recombinant form of hcg with LH like activity

Mechanism of action of FSH analogues

1. Bind to FSH receptors on ovarian granulosa cells in females and Sertoli cells in males. These receptors are G- protein coupledreceptors (GPCRs)

2. Binding activates Gs protein increasing adenylate cyclase activity and increasing cAMP

3. This leads to activation of protein kinase A

4. In females it leads to stimulation of growth and maturation of ovarian follicles, promotion of estrogen production and increases aroma taste activity which converts androgens to estrogen

5. In males, acts on Sertoli cells promoting spermatogenesis, increased production of androgen binding protein and support maturation of sperm cells

• Indications of FSH analogues

• Female infertility

• Ovulation induction

• PCOS

• Male hypogonadotropic hypogonadism

• Delayed puberty

• Male infertility to stimulate spermatogenesis

Adverse effects of FSH

• Ovarian hyper stimulation syndrome (OHSS)

• Multiple pregnancy (twins, triplets)

• Abdominal pain

• Ovarian enlargement

• Headache

• Breast tenderness

• Injection site reactions (pain, redness, swelling)

• Gynecomastia in men

• Depression (mood changes)

• Edema in both sexes

MOA of LH agonists

Bind to LH receptors on ovarian theca and granulosa cells in femalesand leydig cells in testes of males

Activation of Gs protein and continuous pathway

In females : Triggers final maturation of follicles, causes ovulation (LH surge effect), promotes corpus luteum formation and increases progesterone secretion.

In males, it stimulates leydig cells increasing testosterone synthesis

Indications of Luteinizing hormone agonists

Ovulation triggering in assisted reproduction (IVF/ART)

Female infertility

Luteal phase support

Delayed puberty in males

Ovarian follicle development in women with hypogonadotropic hypogonadism

Male hypogonadotropic hypogonadism

Adverse effects of LH agonists

• Ovarian hyper stimulation syndrome

• Multiple pregnancies in women

• Gynecomastia in men

• Headache

• Depression ( mood changes)

• Edema in both sexes.

Edema happens because these hormones increase sex steroid production especially estrogen which causes sodium and water retention. It’s usually mild such as ankle swelling, weight gain from fluid 👌👌

GnRH

• GnRH is secreted by neurons in the hypothalamus which goes to the pituitary gland where it stimulates the release of FSH and LH

• Pulsatile GnRH is required to stimulate the gonadotropin cells to release FSH and LH.

• Sustained nonpulsatile administration of GnRH or GnRH analogues inhibits the release of FSH and LH by the pituitary gland in both men and women resulting in to hypogonadism

GnRH agonists

1. Gonadorelin

2. Goserelin

3. Histrelin

4. Leuprolide

5. Nafarelin

6. Triptorelin

7. Buserelin

MOA of GnRH agonists

1. GnRH initially stimulate GnRH receptors in the anterior pituitary gland

2. This causes increased release of LH and FSH

3. Resulting into temporary sex hormone production

   Increased testosterone in males

   Increased estrogen/progesterone in females

4. When given continuously ( not in pulses), the pituitary receptors become desensitized and downregulated

5. This leads to

Decreased LH secretion

Decreased FSH secretion

6. Therefore

Reduced testosterone in males

Reduced estrogen in females

This creates a reversible hypogonadal state

Indications of GnRH agonists when given in a pulsatile manner

1. Anovulattory infertility (induction of ovulation, fertility treatment)

2. Hypogonadotropic hypogonadism

3. Delayed puberty

4. GnRH deficiency related infertility

5. Cryptorchidism (a condition where one or both testes fail to descend into the scrotum

6. Induction of ovulation (fertility treatment)

7. Induction of spermatogenesis in selected male infertility cases

Indications of GnRH agonists when given in continuous manner

1. Precocious puberty ( puberty that comes early)

2. Endometriosis

3. Prostatic carcinoma

4. Polycystic Ovarian Syndrome (PCOS)

5. Uterine fibroids

6. Hormone sensitive breast cancer

7. Assisted reproductive techniques (ART) to prevent LH surge in IVF

8. Used in Gender affirming hormone suppression therapy

9. Central precocious puberty

Adverse effects of GnRH agonists when given in pulsatile manner (stimulation)

• Ovarian hyper stimulation syndrome in females

• Multiple ovulation (multiple pregnancy risk)

• Ovarian cyst formation

• Breast tenderness

• Bloating (pelvic discomfort )

• Mood changes

• Acne, libido changes in men due to changes in testosterone

Adverse effects of GnRH agonists when given in a continuous manner( causing deprivation)

• Hot flashes

• Decreased libido

• Fatigue

• Mood depression

• Osteoporosis

• Weight gain

• Initial tumor flare that worsens symptoms of prostatic carcinoma

• Amenorrhea

• Vaginal dryness

• Reduced estrogen effects

Facts about GnRH analogues 👌👌👌👌

1. Initially after administration of GnRH analogues during 7 to 10 days, an agonist effect results in increased concentrations of gonadal hormones. This initial phase is referred to as a flare. 💕💕

2. After this period (2 weeks), the continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropics and gonadal steroids 🌹🌹🌹

3. This inhibitory action is due to down regulation of GnRH receptors due to their prolonged occupation by GnRH and the signaling pathways activated by GnRH👁👁

Advantages of GnRH antagonists over GnRH agonists

1. Quick onset of action (act immediately)

2. Lower risk of ovarian hyper stimulation syndrome

3. Do not cause initial flare up reaction

4. Used when rapid control is needed while agonists are used when long term suppression is needed

GnRH antagonists

1. Ganirelix

2. Cetrorelix

3. Degarelix

4. Abarelix

MOA of GnRH antagonists

1. Completely block GnRH receptors in the anterior pituitary gland which reduces endogenous production of FSH and LH decreasing estrogen in females and testosterone in males

2. Are administered subcutaneously

3. In males: It decreases testosterone level; useful in advanced prostatic cancer

4. In females: Suppresses LH surge during controlled ovarian hyper stimulation in ART

Indications of GnRH antagonists

1. Uterine fibroids

2. Endometriosis: Reduces estrogen production hence shrinks endometrial tissue

3. Controlled ovarian stimulation in in vitro fertilization. In this process, recombinant FSH is given to prepare the ova for ovulation induction. Constant monitoring of serum estradiol is done and when sufficient levels are reached, GnRH antagonists are given to prevent premature spontaneous ovulation (granirelix and cetrorelix)

4. Advanced prostrate cancer (degarelix)

5. Assisted reproduction (IVF) . Prevent premature LH surge (ovulation)

Adverse effects of GnRH antagonists

1. Hot flashes

2. Reduced libido

3. Osteoporosis

4. Mood changes

Synthesis of thyroxine hormone

1. Iodine trapping

2. Oxidation and iodinating

3. Coupling

Detailed synthesis of thyroid hormones

SYNTHESIS OF THYROID HORMONES

1.Iodide trapping: Active transport of iodide ions into follicular cells of thyroid gland. It takes place by a basement membrane pro- tein called sodium/iodide symporter.

2. Oxidation and iodination: The iodide ion is oxidized to iodine by peroxidase enzyme. Iodine combines with tyrosine residues of thyroglobulin molecule and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).

3. Coupling: This is the final step in the synthesis of thyroid hormones and is catalysed by thyroid peroxidase. Two molecules of DIT couple to form thyroxine (T4) and one molecule of MIT with one molecule of DIT forms triiodothyronine (T3).

4. Hormone release: Release of thyroid hormones takes place under the control of TSH. The process involves endocytosis and proteolysis of iodinated thyroglobulin and results in release of T4, T3, MIT and DIT.

5. Peripheral conversion of T4 to T3: Most of the hormone released from thyroid is T4, which is less potent than T3. Conversion of T4 to T3 occurs mainly in liver and kidney. Peripheral conversion of T4 to T3 is inhibited by propylthiouracil, iopanoic acid, propranolol and glucocorticoids

Characteristics of T3 ( Triiodothyronine

1. T3 is formed by DIT and MIT

2. Relatively rapid onset of action

3. Short duration of action , half life is 1 day

4. More potent than T4

5. Useful to treat myxedema coma

Characteristics of T4 ( thyroxine)

1. Formed by DIT and another molecule of DIT

2. Slower onset of action

3. Long duration of action, half life 7 days

4. Less potent

5. Used to treat myxedema coma and for regular treatment of myxedema

MOA of thyroid hormones

Thyroxine needs to be converted into T3 inside the cell for binding to nuclear receptor

1. T4 (major circulating form) enters target cells via transport proteins.

2. Inside the cell, T4 is converted into the more active T3 by deiodinase enzymes

3. T3 enters the nucleus and binds to thyroid hormone receptors

4. These receptors are already attached to DNA at thyroid response elements

5. Activation of different genes

6. Synthesis of various proteins

7. Diverse effects

Indications of thyroid hormones

1. Hypothyroidism

2. Myxoedema (adult hypothyroidism); occurs in adults due to severe or long standing hypothyroidism.

3. Congenital hypothyroidism (cretinism)

4. Myxoedema coma (Is a medical emergency and usually common in long standing untreated Myxoedema cases)

5. Simple goiter

6. TSH suppression in thyroid cancer

Thyroid hormone agonists facts

Are substances or drugs that mimic the action of thyroid hormones by activating thyroid hormone receptors

1. They increase basal metabolic rate

2. Increase growth and development

3. Increase heat production

4. Increase protein synthesis

5. CNS development in children

6. Increased carbohydrate and fat metabolism

7. Increased oxygen consumption

Thyroid hormone agonists

1. Levothyroxine (synthetic form of T4)

2. Liothyronine (synthetic form of T3)

3. Liotrix (combination of (T3 and T4). Less commonly used

Levothyroxine

• Synthetic form of T4

• Most commonly used thyroid hormone replacement

• Long half life (7 days)

• Converted to T3 in tissues

• Tablets and parenteral formulation

Best for long term treatment of

1. Hypothyroidism

2. Cretinism

3. Myxoedema

   Thyroid hormone replacement therapy

Due to long half life, stable blood levels and safer for chronic use. Limitation is that it acts slowly, so it is not ideal when a rapid effect is needed

Liothyronine

1. Oral tablets

2. Synthetic form of T3

3. Faster onset

4. More potent than T4

5. Shorter duration of action

6. Can treat situations needing rapid action that T4 may not manage quickly enough

Used in treatment of Myxoedema coma, a severe form of hypothyroidism

Diagnostic suppression tests also

Adverse effects of thyroid hormone agonists

Their common side effects are mainly due to excess thyroid hormone effects ( hyperthyroidism/ thyrotoxicosis)

1. Tachycardia

2. Palpitations

3. Arrhythmias

4. Increased blood pressure

5. Nervousness

6. Anxiety

7. Tremors

8. Weight loss

9. Heat intolerance

10. Excess sweating

11. Increased metabolism

12. Diarrhea

13. Abdominal cramps

14. Muscle weakness

Thyroid hormone antagonists

1. Thyroid hormone synthesis inhibitors (thyroid peroxidase inhibitors)

2. Thyroid hormone release inhibitors

3. Inhibitors of iodine trapping (inhibitors of Na-I symporter) or anion inhibitors

4. Thyroid tissue destroying agent, radioactive iodine

5. Others, propranolol, atenolol, diltiazem, dexamethasone

Thyroid hormone synthesis Inhibitors / thyroid peroxidase inhibitors/ thiomide or thiourea derivatives

Carbimazole

Methimazole

Propylthiouracil

Moa of thyroid hormone synthesis inhibitors

These drugs inhibit thyroid peroxidase enzyme which is responsible for oxidation, iodination of tyrosine residues in thyroglobulin and coupling

However their action manifests only when already stored pool of T3 and T4 is utilized, thus a lag period of 1-3 weeks is present.

1. carbimazole is a prodrug and acts after conversion to methimazole👌. It has longer duration of action (12-24) hrs

Special facts about propylthiouracil compared to Carbimazole

1. Has high plasma protein binding

2. Can be used in pregnancy ( due to less transfer across the placenta due to high PBP

3. Less potent

4. Has shorter plasma half life, so requires multiple daily dosing ( duration of action 4-8 hrs)

5. Also inhibits peripheral conversation of T4 to T3 👌💕

Indications of thyroid hormone synthesis inhibitors

1. Control of thyrotoxicosis in patients with Graves’ disease and toxic modular goiter where surgery where surgery is not feasible and radioactive iodine is contradicted

2. Used to make patient euthyroid before application of radioactive iodine

3. Propylthiouracil is drug of choice for hyperthyroidism in first trimester pregnancy and lactation

4. Used along with radioactive iodine because it has a slow onset of action hence Carbimazole is also administered for initial control of hyperthyroidism in most patients treated with radioactive iodine

5. For treatment of thyrotoxic crisis Propylthiouracil is used along with iodide and propranolol

Adverse effects of thyroid hormone synthesis inhibitors

1. Propylthiouracil is hepatotoxic. Should be avoided except in first trimester of pregnancy and lactation

2. Maculopapular pruritic rash (skin rash)

3. Agranulocytosis (dangerous but rare involves sore throat and or fever)

4. Hypothyroidism may occur but it’s reversible

5. Joint pain, fever, hepatitis, nephritis.

Pharmacokinetics of thyroid hormone synthesis inhibitors

1. Thionamides are well absorbed orally

2. Propylthiouracil is most rapidly absorbed

3. Carbimazole is converted to methimazole after absorption

4. They are widely distributed but get accumulated in thyroid gland

5. Propylthiouracil has a short half life and needs to be given 6-8 hours

6. They are excreted in urine

7. They cross placenta barrier and can cause fetal hypothyroidism

Inhibitors of Na-I symporter (anion inhibitors)

Iodine is trapped in the follicular cells with Na-I symporter. Examples of anion inhibitors include

1. Thiocyanate

2. Fluoborate

3. Perchlorate

4. Pertechtenate

5. Nitrates

These drugs inhibit this transporter and thus thyroid hormone synthesis

These drugs are very toxic and no longer used

Inhibitors of thyroid hormone release

1. Sodium iodide

2. Potassium iodide

3. Lugols solution (5 percent iodine in 10 percent solution of potassium chloride)

Moa of thyroid hormone release inhibitors

They act as thyroid constipating agents by inhibiting the release of T3 and T4

These drugs are the fastest acting anti thyroid drugs

They make the thyroid shrink in size and decrease the vascularity

These properties are utilized in pre operative preparation of thyroid gland

High level of intracellular iodine inhibits iodination of tyrosine residues and hormone synthesis which is transient, later thyroid escape occurs.

Indications of thyroid hormone release inhibitors

1. Thyroid storm ( thyrotoxic crisis). Used after Thiomides eg methimazole to block release of stored hormone

2. Pre operative preparation for thyroidectomy

3. Pre treatment in hyperthyroidism before radio iodine therapy

Adverse effects of thyroid hormone release inhibitors

1. Hypersensitivity which presents as swelling of lips, angioedema, fever, joint pain and petechial hemorrhage, eosinophilia, lymphadenopathy

2. Chronic overdose with iodine results in iodism ( inflamed mucus membranes, irritation of eyes, sneezing, salivation, pulmonary edema)

3. Hypothyroidism may also occur

4. Use of iodides during pregnancy may cause fetal goiter

5. May also cause flagging up of acne in adolescents