Endocrine

PROBLEM-BASED PHARMACOLOGY OF ENDOCRINE DISEASES Univ – Pécs, Medical School Department of Pharmacology and Pharmacotherapy Dr. Erika Pintér

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Endocrine

1st case • 31-year-old woman, she has a headache for some month

ago, has an irregular period and visual disturbances. • Laboratory parameters: high level of prolactin, functions of thyreoid glands are normal • MRI: tumor in the hypophysis, prolactinoma

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Endocrine

Which factors can elevate the level of prolactin beside the hypophyseal adenoma?

Which factors can elevate the level of prolactin beside the hypophyseal adenoma? • TRH, phenotiazines and butyrophenon antipsychotic

drugs , as well as metoclopamide stimulate the prolactin release • Lactotroph cells in the adenohypophysis are under the dopaminerg inhibiton of hypothalamus

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Endocrine

• Patient is worried by the brain surgery intervention, therefore

bromocriptine is subscribed in low dosage to prevent side effects. Then 2.5 mg, twice a day. • Prolactin level is decreasing but serious side effects are occuring which interfere with the patient’s job (librarian) • What are the side effects of bromocriptine?

What are the side effects of bromocriptine? Vomiting, vertigo, visual disturbances, distraction

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Endocrine

How does bromocriptine decrease the prolactine level?

How does bromocriptine decrease the prolactine level? • The dopamine agonist bromocriptine decreases the proliferation

of lactotroph cells and the prolactin release. • It is suitable to treat of microadenomas. • The prolactin release is not regulated by negative feedback because breast does not secrete hormones.

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Endocrine

• Ms. Y goes under trans-sphenoidal resectio. Operation is succesful.

After 2 days, she is always thirsty and continuously has to urinate. Her serum natrium level is high.

• What complication occured and how it can be

treated?

What complication occured and how it can be treated? • Excessive urination, hypernatraemia, thirsty: diabetes insipidus • Neurogenic DI is caused by ADH deficiency. During the resection

adenohypophysis can be damaged (16-30%). Most of the cases, it is transient. • Treatment: • Desmopressin: ADH analogue, stimulates the V2 receptors in the kidney • Nephrogenic DI (SIADH) is caused by the mutation of V2 receptors, cannot be

treated by ADH  demeclocyclin, lithium • Effects of high ADH level can be treated by ADH antagonist -> conivaptan

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2nd case • Diana is 45-year-old, always feels nervous, small things can

make her upset, worries a lot. She feels hot, set the room temperature low and her family feel cold. Her heart often beats very fast. • Medical diagnosis: thyroidal gland bigger than the average and exophthalmus • Laboratory parameters: high free (unbound) T3 and low TSH level. TSH receptor antibody is positive.

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Endocrine

Why T3 level is high and TSH level is low?

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Why T3 level is high and TSH level is low? • Negative feedback. In the Basedow-Grave’s disease, TSH

receptor antibodies are expressed, which bind to the TSH receptors and up-regulate the production of thyroid hormons. • Increased T3, T4 production, the T4 is being deiodinated on the periphery. • Peripheral hormons inhibit the TSH release.

• Basedow-disease has been diagnosed in Diana. She received

metimazol. After one month, symptomes are diminished, thyroidal hormon levels are normalized. • After one year, despite the metimazol treatment, symptomes occur again.

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Endocrine

How does metimazol act?

How does metimazol act? • The peroxidase enzyme is oxidizing iodide to reactive iodine

which is able to bind to tyrosine. Metimazol is peroxidase inhibitor. • Peroxidase also catalyze the forming of T3 and T4 from monoiodinetyrosine (MIT) and diiodinetyrosine (DIT). • Propylthiouracil is also peroxidase inhibitor and inhibits the deiodination, too.

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Endocrine

• Doctor suggested radioactive iodine therapy. Diana tolerated the

therapy very well, she had got normal thyroidal functions for 3 years. • How can radioactive iodine exert selective effect?

• How can radioactive iodine exert selective effect? • Thyroid gland accumulates iodide selectively. The radioactive I131

isotope is taken up selectively into the follicular cells and emits beta radiation which destructs the thyroid cells locally.

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Endocrine

• After 4 years, Diana had opposite symptomes. She felt always

tired and picked up 15 kg within half a year. Doctor diagnosed hypothyroidism. Prescribed thyroxine hormon. The condition of the patient improved. • Why did hypothyroidism develop?

• Why did hypothyroidism develop? • The radioactive iodine killed the follicular cells. • The Wolff-Chaikoff effect, when high inorganic iodine

concentration inhibits the synthesis of hormons. It is reversible (Plummer method, Lugol solution).

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Endocrine

Levothyroxine (T4) is used for subtitution. What is this therapy like?

What is this therapy like? This is the L-isomere of the T4. Elimination half-life is 6 days. Decreases the TSH production by negative feedback. TSH level is need to be checked during therapy. Interactions: (increase the tyroxine breakdown) – inductors – rifampicin, fenitoin, phenobarbital Side effect: palpitation (beta blockers are needed)

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Endocrine

3rd case • 72-year-old female patient saved by ambulance in January. Her

neighbours had noticed that she did not take her newspaper. Ambulance persons found Mrs P. in confused state in her bed. In the apartment there were pitching and stool remains. There was cold in the room. Mrs. P. is confused but she can tell that she’s got heart disease, got high blood pressure and hypothyroidism. She received antibiotics for her cystitis 2 weeks ago, but she got diarrhea and vomited. She could not have been eating , drinking or taking her medication since 10 days.

• Examination: patient is dehydrated, temperature is 35 Celsius,

heart rate: 58/min, breath rate: 8/min, RR: 86/52 Hgmm, dry mucosas, swollen stomach, reduced bowel sounds, oedematic, swollen, pale skin • EKG: bradycardia, elongated QT, non-specific ST changes • RTG: cardiomegalia, aspirational pneumonia in the right lower lobe.

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Endocrine

What could be Mrs. P. laboratory finding?

What could be Mrs. P. laboratory finding? • Mixoedema, life threatening hypothiroidism • High TSH, low T3, T4 • Factors predisposing to mixoedema: • GIT bleeding, cold exposition, infection, cerebrovascular disease, trauma, medications (barbiturates, lithium, narcotics, phenotiazines, phenitoin)

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Endocrine

• Mrs. P. received i.v. volume replacement, broad spectrum

antibiotic and heating blanket. • What else therapy is needed?

• What else therapy is needed? • I.v. thyroxine (T4) • I.v. corticosteroid, corticoid hormon levels are monitored

(parallel adrenal cortex insufficiency could be exist) • Beta blockers are needed against the side effects

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Endocrine

Why beta blockers are utilized?

Why beta blockers are utilized? • Beta blockers reduce the sympathomimetic symptomes caused

by tyroxine (tachycardia, tremor, anxiety). • Also reduce the conversion of T4 to T3 on the periphery.

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Endocrine

Many drugs alter the thyroidal functions. Which are they?

Many drugs alter the thyroidal functions. Which are they? • Amiodarone: can cause hypothyroidism, because iodine can be

• • • •

free from it. Plasma iodine concentration is increasing. Because the negative feedback, the thyroidal hormon synthesis is decreased (Wolff-Chaikoff effect). Inhibits the T4-T3 conversion. Amiodarone can cause hyperthyroidism as well, becasue iodine can increase the hormon production. Rifampicine can induce the CYP450 enzymes. Tyroxine metabolism is augmented. Metimazol: inhibits the peroxidase, hormon production decreases Corticosteroids: inhibits T4-T3 conversion Bile acid sequestrants: inhibit the adsorption

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4th case • Johnny, 8 year old boy, has breathing difficulties, especially for

physical exercise. Other antiasthmatic agents do not alleviate fully the symptomes therefore oral prednisolone is administered. • After a few weeks asthmatic attacks are ceased. • Doctor follows Johnny’s growing.

Why prednisolone can be utilized for treatment of asthma?

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Endocrine

Why prednisolone can be utilized for treatment of asthma? • Cortisol decreases the airway inflammation, inhibits the cytokine

release and production of prostaglandins.

Why did the doctor check Johnny’s growing?

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Endocrine

• Why did the doctor check Johnny’s growing? • Long term glucocorticoid treatment decreases the longitudinal

bone growth and can cause shortness. • Glucocorticoids inhibits the vitamin D mediated Ca-absorption. This cause the compensatory increase of PTH, which inhibits the calcification of bones and releases the Ca from the bones. • Glucocorticoids also inhibit the osteoblasts and cause osteoporosis.

• After 2 weeks, doctor decides that switch to inhalation

glucocorticoid and oral prednisolone is suspended. • After 3 days, airway infection is developed and the child is admitted to hospital with fever and low blood pressure. He receives i.v hydrocortisone and saline infusion.

Why did this serious condition develope after the suspending the oral prednisolone?

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Endocrine

Why did this serious condition develope after the suspending the oral prednisolone? • Johnny developes acute adrenal cortical insufficiency. • Oral prednisolone therapy lead to the decrease of ACTH

secretion which caused adrenal cortex atrophy. Adrenal cortex did not work efficiently in the stress situation caused by infection and sepsis occured. • Exogenous glucocorticoid therapy can be suspended ONLY slowly, during months.

• Johnny recovered and oral prednisolone was switched to

inhalation glucocorticoid. This was efficient for his asthma. • Why inhalation glucocorticoid is safer than oral in the chronic treatment of asthma?

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Endocrine

• Why inhalation glucocorticoid is safer than oral in the

chronic treatment of asthma? • In case of local treatment, glucocorticoids act on the surface of bronchial mucosa. Inhibit the inflammation in the lung. Small amount is absorbed and side • effects are less. The oropharingeal candidiasis is a potential complication due to the immunsuppressive effect.

5th case • 36-year-old man suffers from Addison disease, treated with

exogenous corticosteroids therapy for many years. • Severe backache exists, lumbosacral fusion is suggested by ortthopedic sugeons. Operation is dangerous because of the cortical insufficiency (1955 JAMA, John Kennedy).

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Endocrine

Which physiological functions are under the control of cortisol?

Which physiological functions are under the control of cortisol? • Cortisol has metabolic and antiinflammatory effects: • During starving mobilizes amino acids to maintain glucose level.

Gluconeogenesis. • Antagonising the insulin effect, increases the free fatty acid concentration. In stress situation, these substances maintain the homeostasis. • Patients with Addison disease cannot maintain the energy balance during stress.

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• Patient with Addison disease was operated. There were some

postoperative complications but Addison crisis did not develope. Patient was „brown” for one year. • Which symptomes do go along with hypoaldosteronism?

• Which symptomes do go along with hypoaldosteronism? • Hypotension. Since aldosteron increases sodium and water

reabsorption. If aldosteron is low, sodium loss and hyperkalaemia developes.

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Why does Addison disease cause hyperpigmentation?

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Why does Addison disease cause hyperpigmentation? • High level of ACTH and MSH stimulate the MSH receptors in the

skin. Melanogenesis increases. • Because cortisol is low  CRH production is high in the hypothalamus and ACTH production in the hypophysis. • CRH stimulates the POMC production which is precursor of the ACTH and MSH production.

• What is the mechanism of action of spironolactone?

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Endocrine

• What is the mechanism of action of spironolactone? • Competitive antagonist on the mineralocorticoid receptors.

Potassium-sparing diuretic.

• What patients with secunder adrenal insufficiency need to

be treated with?

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Endocrine

• What patients with secunder adrenal insufficiency need to

be treated with? • They have to be treated with hydrocortison (glucocorticoid) substitution. • These patients have low ACTH level, that’s why cortisol and sex hormon levels are also low, but aldosterone level is normal. • Aldosterone level is regulated by the RAAS system and serum potassium level.

6th case • Amy noticed hair loss in her teenage especially at forehead area.

However facial hair growing also occured. She saw her doctor at age 24 with complains of hirsutism and irregular period. The longest period was half year, the shortest was 22 days. Bleedings were painful and longer than 5 days. She picked up a lot of weight during the college in spite of she was doing sport very actively. • Laboratory findings: free and total testosterone moderately increased, LH/FSH ratio is high. • Diagnosis: polycystic ovarial syndrome (PCOS)

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Endocrine

What is the connection between excessive hair growth and infertility in PCOS?

What is the connection between excessive hair growth and infertility in PCOS? • The increased LH and androgen hormon levels inhibit the

ovulation and high androgen hormon level cause hirsutism. • The high level of LH produced by the hypophysis stimulates the thecal cells of ovarium, which produce testosterone in high amount • The high LH and androgen hormon levels are inhibiting the ovulation and oestrogen secretion. • Lack of oestrogen leads to lack of mature follicules, there is no LH peak and ovulation

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Hormonal changes in PCOS are caused by the following: 1. Primer increasing of LH release 2. Effect of increased insuline secretion on sex hormones (obesity-dependent resistency) 3. Primer disorder of sex hormon synthesis in thecal cells

• The aromatase enzyme converts androgens to estrogen in

ovarium, fat tissue, hypophyseal neurons and muscles • Activity of aromatase is regulated by FSH • In males, LH stimulates the androgen secretion of Leydig cells in testicles.

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Endocrine

• Amy received combined estrogen-progestin oral contraceptive to

regularize her cycle and spironolactone to reduce her problems with excessive hair growth and balding. How do act combined oral anticontraceptives?

• How do act combined oral anticontraceptives? • Estrogen-gestagen anticontraceptives decrease the GnRH, LH,

FSH release, inhibit the maturing of follicules and ovulation. Besides this, they are reducing the peristalsis of oviduct, preventing the inplantation of blastocyst into endometrium. Increasing the viscosity of cervical fluid, inhibiting the transport of spermiums • Side effects: bile-stone, thromboemboly (over 35 years, smoking females)

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Endocrine

• Why spironolactone was prescribed for Amy?

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• Why spironolactone was prescribed for Amy? • Spironolactone is an androgen receptor antagonist • It inhibits the binding of endogenous androgen to its receptors

competetively. • Reduces hair growth. • Aldosterone receptor antagonist, potassium-sparing diuretic drug

7th case • 26-year-old male amateur bodybuilder, (110 kg, 175 cm) •

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suddenly collapses in the gym. Incontinent of urine, develop agonal respirations, cardiopulmonary arrest. Despite advanced cardiac life support measures, patient expired at the hospital. Autopsy report: gynecomastia, testicular atrophy, acneiform rash over the face and torso Mildly atherosclerotic coronary arteries, hearth weight is 515 g (normally it is 250 g), concentric left ventricular hypertrophy Patient had just completed a 3-month cycle of anabolic androgenic steroids: methenolone (dihiydrotestosterone derivative and veterinarian-grade testosterone enanthate

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Endocrine

Why gynecomastia and testicular atrophy are developed to the administration of exogenous testosterone?

Why gynecomastia and testicular atrophy are developed to the administration of exogenous testosterone? • Exogenous testosterone suppresses the GnRH release from

hypothalamus and the FSH and LH release from the hypophysis. Functions of Sertolli and Leydig cells are also inhibited. Azospermia, testicular atrophy are developed. Testosterone converted to estrogen by aromatase and induces gynecomastia. • Other side effects: erythrocytosis, acne, hyperlipidaemia, muscle hypertrophy, hypertension, arrythmias, myocardial ischemia. Death is caused by the cardiovascular complications. That’s why androgen steroids are controled substances (schedule III)

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Endocrine

At elderly ages hypogonadism and low testosterone level can be treated with androgen therapy. How is it performed?

How is it performed? • Can be administered intramuscular way on every 2-4 weeks,

transdermal patches, buccal tablets or topical gel. Gel can produce physiological hormon level within 1 month. • Oral testosterone less effective due to the high first pass effect. • Must not be administered in case of prostatic carcinoma.

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• Finasteride is used for treatment of benign prostatic hyperplasia. • By what mechanism does finasteride reduce the rate of

prostatic enlargement?

• By what mechanism does finasteride reduce the rate of

prostatic enlargement? • Dihydrotestosterone (DHT) is the most active androgen, binds

to he receptor ten times higher affinity than testosterone. • Finasteride inhibits the type II 5-alpha-reductase conversion of testosterone to DHT in prostatic cells slowing their growth.

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• Leuprolin, goserelin (GnRH agonists) block the LH secretion

and testicular testosterone production. Suitable for androgendependent prostatic cancer treatment. • Flutamide is direct competitive antagonist on androgen receptors • Anastrozole, letrozole, formestane are aromatase inhibitors, they block the androgen-estrogen conversion. They are used in case of estrogen-dependent breast tumors.

• Selective estrogen receptor modulators (SERMs) inhibit

estrogenic effects in some tissues while promoting estrogenic effects in others. • How do they act?

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Endocrine

• How do they act? • Some SERMs are mixed agonist, antagonist in a tissue specific way • Tamoxifen is estrogen antagonist in breast tissues but agonist in

endometrial tissues. Prevents estrogen-dependent breast cancer but can cause endometrial tumors. • Raloxifen is antagonist in the breast and endometrium but antagonist in bones. Used for preventing breast cancer in high risk patients. Also inhibits osteoporosis. • Clomiphene is estrogen antagonist in hypothalamus and hypophysis, agonist in the ovarium. Increases the FSH, Lh secretion, can be used for induction of ovulation.

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What are the side effects of estrogen substitution therapy?

What are the side effects of estrogen substitution therapy? • Estrogen substitution may cause thromboembolic complications.

Clinical trials showed that estrogen treatment does not increase the risk of coronary diseases and breast cancer but increases the risk of stroke and thromboembolic disease. • Prevents osteoporosis.

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