Thyroid and antithyroid drugs. Hypothalamic and pituitary hormones

Question 1

Hyperthyreosis (symptoms and Causes)

Answer 1

1. Symptoms • Subjective symtoms: nervosity, anxiety, insomnia, tremor, palpitations, heat intolerance, increased GI motility • Objective symptoms: weight loss, increased glucose, tachiarrhythmias, hair loss, cholesterin reduced, wet and warm skin; in case of Basedow: exophtalmus, pretibial edemas 2. Causes Immunological (Graves’ disease) • TSH-receptor-antibodies stimulate the thyroid gland Multinodular goiter (Thyroid adenoma) • nodules grow up and secrete thyroid hormone autonomously Hypersecretion of thyroid stimulating hormone • pituitary adenoma, T3-resistent Thyroid cancer (rare)

Question 2

Tx of Hyperthyeosis

Answer 2

1. Thyrostatics -Thioamides : inhibitors of peroxidase enzyme - Inhibitors of iodine uptake - Iodine (high dose) : Inhibition of release of thyroid hormones 2. Surgery 3. Radioiodine

Question 3

2 Thioamides

Answer 3

Thiamazol (methimazol) (A12) Propylthiouracil (PTU) (A12)

Question 4

Thioamides Mode of action

Answer 4

-Blockade of Thyroid-Peroxidase (both functions) -onset - 1-4 weeks (first the previously synthesized hormones will be released)

Question 5

Thioamides Pharmacokinetics

Answer 5

– metabolism: oxidation and glucuronid conjugation – half life of thiamazol: 4-6 h, but duration of action: 24 h – half life of propylthiouracil: 2 h, - 6x daily – all cross the placenta, propylthiouracil has lower amount in breast milk

Question 6

Thioamides Adverse effect

Answer 6

• maculopapular pruritic rash, fever – agranulocytosis, (leukopenia) – usually first 2-6 weeks – allergy – hypothyreosis

Question 7

Iodine treatment in case of hypertyreosis

Answer 7

• Iodine in high dose (>5mg/d) inhibits the organification, the release of T4 and T3. (mechanism of action is not clear)
• onset: 24 h. max.: 10-15 d; after that gradual decrease in the effects • Radioiodine therapy • 131I – β emission
• selective uptake into the thyroid gland • treatment of Graves’ disease, adenomas and iodine storing cancers
• adverse effect: hypotyreosis (80%) • duration of the treatment: 5-14 d, onset: 10-12 weeks • contraindications: children, pregnancy

Question 8

Hypothyreosis (symptoms and Causes)

Answer 8

1. Causes Immuntyreoditis (Hashimoto), postoperative, drug-induced 2. Subjective symptoms disabilty, weakness, lethargy, devolution, fatigue, feeling cold, poor memory, constipation less frequently: mental depression, weight gain, cardiac problems, hair loss, poor appetite, joint pain 3. Objective symptoms dry skin, hoarseness, slow speech, dry and rough hair, bradycardia, delayed relaxation of tendon reflexes less frequently: swelling of the tongue, cardiomegaly, hypertension, myxedema

Question 9

Thyroid hormones used in case of hypothyroidism

Answer 9

Levothyroxine (T4) (A12) Liothyronine (T3) (Not in the list) Iodine (A12)

Question 10

Levothyroxine (T4) (A12)

Answer 10

• Oral, IV - Converted to T3 in target cells, liver, kidneys - Maximum effect is seen after 6-8 weeks of therapy - Hypothyroidism -Side effects: symptoms of thyroid excess

Question 11

Liothyronine (T3) (Not in the list)

Answer 11

• Oral, IV - 10X more potent than T4 - Hypothyroidism; used in case of deiodinase enzyme deficiency (T4 cannot be converted to T3) -Side effects: symptoms of thyroid excess

Question 12

Iodine (A12)

Answer 12

• Essential mineral nutrient, intake with diet - Daily requirement 150 μg - Iodine salt preparation (KI) for replacement therapy - Oral - Dietary iodine deficiency (endemic goiter) - Thyrotoxicosis crisis (high dose suppresses the gland) -Side effects: cutaneous and mucus membrane irritation, allergic reaction, hypo-/hyper- thyroiditis

Question 13

Propylthiouracil (PTU) (A12)

Answer 13

• Oral - Duration of action 6-8 h’ - Requires 3-4 weeks for onset of activity (delayed action since the release of preformed thyroid hormones is not affected) - Hyperthyroidism - Used during pregnancy and lactation -Side effects: skin rash, nausea, vasculitis, agranulocytosis, liver dysfunction, hypothyroidism, drug-induced lupus

Question 14

Thiamazol (methimazol) (A12)

Answer 14

• Oral - Duration of action 24 h’ - Requires 3-4 weeks for onset of activity (delayed action since the release of preformed thyroid hormones is not affected) - No effect on deiodinase enzyme - Hyperthyroidism - Preferred generally (administered once per day) -Side effects: skin rash, nausea, vasculitis, agranulocytosis, liver dysfunction, hypothyroidism, drug-induced lupus, teratogenic

Question 15

Thyrotoxic crisis (thyroid storm)

Answer 15

Rare condition, presents as a life-threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. Mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment.

Thyrotoxic crisis is usually precipitated by acute illness (stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism.
Management:
- PTU or methimazole (IV bolus, high dose)
- Potassium-iodide solution (IV)
- β-blockers to control tachycardia and adrenergic symptoms (IV)
- Glucocorticoids to control ophthalmopathy (IV)

Question 16

Myxedema coma

Answer 16

Rare condition, life-threatening exacerbation of hypothyroidism.
Presentation:
- Hypothermia
- Hypoglycemia
- Hypotension
- Altered mental status
Management:
- Thyroid hormones (IV)
- Glucocorticoids (pituitary-adrenal axis is impaired in severe hypothyroidism)
- Supportive management
- Elimination of triggering event (if possible)

Question 17

Hormones releasing from Anterior pituitary

Answer 17

1. Growth hormone (GH)
   Controls growth and glucose metabolism
   Mediated via the somatomedins
2. ACTH
   Acts on the adrenal gland to stimulate the release of cortisol
3. Gonadotropins
   Luteinizing hormone ( ovulation, secretion of sex hormones
   Follicle stimulating hormone ( development of follicles
   and sperm cells
4. Prolactin stimulates breasts to develop milk
5. TSH
6. Melanocyte stimulating hormone
   Enhances synthesis of melanin

All the anterior pituitary hormones are under the control of a
hypothalamic hormone , and with the exception of prolactin

Question 18

Hormones releasing from Posterior pituitary

Answer 18

1. Antidiuretic hormone (vasopressin)
   Causes the retention of fluid in the urine
   Combats dehydration
2. Oxytocin
   •Causes lactation
   •Contractions during child birth

Question 19

2 Growth Hormone (GH) (not in the list)

Answer 19

1. Somatropin (somatotropin)

• Recombinant form of human GH
• • Subcutaneous injection
• • GH deficiency – dwarfism (genetic, developmental, acquired)
• Increased final adult height in children with conditions associated with short stature (Prader-Willi syndrome, Turner syndrome)
• Idiopathic short stature
• AIDS-associated wasting
• Malabsorption syndromes in patients who have undergone bowel intestinal resection
  Side effects: pseudotumor cerebri, slipped capital femoral epiphysis, edema, hyperglycemia, scoliosis, risk of asphyxia in severely obese patients with Prader-Willi syndrome and upper airway obstruction or sleep apnea

2. Asellacrin

• human GH, is available for parenteral use (IM).
• Side effects : diabetes, antibodies againts the drug

Question 20

2 GH antagonists (1 in the list)

Answer 20

Octreotide (A12) , Lanreotid (not in the list)

Inhibit the release of GH, insulin, glucagon, gastrin

• Parenteral administration
• Regular formulation – inject 2-4 times daily
• Slow-release formulation – inject every 4 w’

Indications

• Acromegaly (pituitary adenoma), gigantism
• Endocrine tumors (carcinoid, gastrinoma, glucagonoma, insulinoma, VIPoma)
• Control of bleeding from esophageal varices
  Side effects: GI disturbances, steatorrhea (due to impaired pancreatic secretion), gall stone, cardiac conduction abnormalities

Question 21

2 Hyperprolactinemia treatment drugs

Answer 21

Bromocriptin (A12) , Cabergoline (not in the list)

Dopamine D2 receptor agonist

• Suppresses pituitary secretion of prolactin and GH (to lesser extent)
• Oral
• Indications : hyperprolactinemia , Parkinson disease, stop of lactation
• Acromegaly (effective only in high doses)
  Side effects : nausea, vomiting, dizziness, neuropsychiatric symptoms

Question 22

Adrenocorticotrop hormone (ACTH, corticotropin)

-Main actions

Answer 22

1. mineralocorticoids, glucocorticoids , androgen
2. Cortisol changes according to circadian rhythms
3. Side effects: allergy, salt and water retention

Question 23

corticotrophin (ACTH) analogue

Answer 23

Tetracosactrin (Not in the list)

-synthetic, less allergy, long term application, cortisol
effects

-Diagnostic purpose: differentiation of Cushing syndrome and increased
ACTH synthesis
-Parenteral administration

Question 24

Follicle Stimulating Hormone: (FSH)

Mode of Action

Answer 24

1. Interacts with specific receptors (present in the
   plasma membrane of ovaries and testes).
2. Released during the follicular phase of the menstrual
   cycle and is required for the proper development of
   the ovarian follicles.
3. In males is responsible for the maturation of the
   germinal elements of the testis and stimulates
   spermatogenesis

Question 25

Luteinizing Hormone : (LH)

Mode of Action

Answer 25

1. In females, LH is required to stimulate oestrogen
   production and for the production of progesterone by
   the corpus luteum of the ovary and is essential for
   ovulation
2. Very similar to hCG produced in placanta
3. In males, more precisely called interstitial cell
   stimulating hormone Leydig cells stimulates
   testosterone biosynthesis

Question 26

hMG (Gestyl)

Answer 26

Human menopausal gonadotropin (HMG) is isolated from the urine of
postmenopausal women. It is rich in LH and FSH.

• Uses: Used to treat infertility in women who fail to ovulate despite the

presence of potentially functional ovaries.

• -Dose: 75 IU is given parenterally for 9 -12 consecutive days to stimulate

ovarian follicular growth and to prime the ovaries to ensure responsiveness
to the subsequent administration of Human Chorionic Gonadotrophin

• (hCG) which exhibit biological activity similar to that of hCG

Question 27

hCG (Pregnyl)

Answer 27

HCG is a hormone produced by human placenta and excreted in the urine of
pregnant women.

Uses:

1. For the induction of ovulation when injected after priming of ovaries with
   HMG.
2. To stimulate descent of the testis in male patients with cryptorchidism in
   whom no anatomical obstruction.
3. Hypogonadism that is secondary to pituitary failure.

Question 28

Oxytocin (A12)

Answer 28

Oxytocin receptor agonist
- IV

• Induction and augmentation of labor
• Control of uterine hemorrhage after delivery
  Side effects: fetal distress, placental abruption, uterine rupture, fluid retention, hypotension

Question 29

Desmopressin (A12)

Answer 29

–V 1 Gq ) VSMC → vasoconstriction
–V 2 Gs ) renal tubule → ↑ water resorbtion

• Synthetic analogue of ADH (peptide)
• Prolonged half-life and duration of action compared to endogenous ADH
• IV, intranasal, oral, subcutaneous
• Central diabetic insipidus
• Hemophilia A – factor VIII deficiency
• Von-Willebrand disease
  Side effects: GI disturbances, headache, hyponatremia, allergic reaction

Question 30

Drugs affecting ADH hormone antagonists

Answer 30

1. Lithium (A31)
2. Tolvaptan (B23)
   competitive vasopressin receptor 2
   (V2) antagonist

Indications:
Hyponatremia
Syndrome of in appropiate ADH
secretion