BIOL2048/2049 Endocrine Pharmacology PDF

BIOL2048/2049 Endocrine Pharmacology Dr Mogib Khedr Adapted from Professor Lindy Holden-Dye [email protected] 85/3044  Content 1.Overview of the endocrine system; the role of the hypothalamic pituitary...

BIOL2048/2049 Endocrine Pharmacology Dr Mogib Khedr Adapted from Professor Lindy Holden-Dye [email protected] 85/3044  Content 1.Overview of the endocrine system; the role of the hypothalamic pituitary axis 2. Corticotrophin and adrenal steroids 3.The female reproductive system and contraceptive drugs 4.The endocrine pancreas and the control of blood glucose  Learning outcomes You should have knowledge of the pharmacology of endocrine systems and be able to, 1. Describe the role of the hypothalamic pituitary axis 2. Describe the role of corticotrophin and adrenal steroids; 3. Describe the female reproductive system and contraceptive drugs; 4. Describe the endocrine pancreas and the control of blood glucose REVIEW of hypothalamic- pituitary axis and hormonal control systems 1. REVIEW of hypothalamic- pituitary axis and hormonal control systems HOW DOES THE HYPOTHALAMUS SIGNAL TO THE ANTERIOR PITUITAR Y? Signalling between the hypothalamus and the anterior pituitary Releasing Factors n.b. control of hormones from posterior pituitary does not involve releasing factors  Hypothalamic-Anterior pituitary Releasing FACTORS are Hypothalamic HORMONES (Most are NEUROPEPTIDES- the clue to their role is in the name…!) Growth hormone- Corticotrophin- Gonadotropin- Thyrotrophin- Growth hormone releasing factor releasing factor releasing hormone releasing hormone release-inhibiting factor Hypothalamus GHRF CRF GnRH TRH Dopamine Somatostatin X X Anterior GH ACTH FSH+LH TSH Prolactin GH Pituitary growth cortisol sex hormones thyroid DOPAMINE – this is a catecholamine- it inhibits prolactin release  Cells of the Anterior Pituitary….. …get their name from their function: Lactotrophs Somatrophs Corticotrophs Gonadotrophs What do you think the TSH releasing cells are called? HOW DOES THE HYPOTHALAMUS SIGNAL TO THE POSTERIOR PITUITAR Y? Hypothalamus signaling via the posterior pituitary hypothalamus hormone synthesis hormone transport neurone pituitary (hypophysis) hormone release capillaries anterior pituitary posterior pituitary (adenohypophysis) (neurohypophysis)  Posterior Pituitary Hormones Posterior Pituitary Major functions Hormone Oxytocin Uterine smooth muscle (paraventricular nucleus) contraction Breast myoepithelial contraction Vasopressin Antidiuretic Hormone (ADH) Water retention by kidney (supraoptic nucleus) Summary of Pituitary Hormones Posterior Anterior Disorders of the hypothalamic pituitary axis- and treatment Growth hormone Thyroid hormone Diabetes insipidus  Growth hormone GH = Anabolic hormone Stimulates amino acid/protein uptake into muscle. Stimulates IGF-1 (insulin-like growth factor-1) release from liver. IGF-1 is a somatomedin. IGF-1 especially important in growth of skeleton and cartilage (GH inhibits glucose uptake)  GH excess In childhood: Altered growth/stature In adulthood: ↑GH Acromegaly Growth of soft tissues Mild hyperglycaemia GH excess; Acromegaly treatment Somatostatin receptor agonists; These are selective for somatostatin receptor subtypes expressed in GH-secreting tumours and have a longer half-life than somatostatin  GH insufficiency; Pituitary dwarfism treatment 1. Injection human recombinant GH (Somatropin) 2. Injection of human recombinant IGF-1 (Mecasermin) –abnormal GH receptor Laron’s dwarfism 3. Sermorelin is a GHRF analogue- used a diagnostic and also to increase growth in children  Thyroid hormone Key role in metabolism and development Increases lipid, carbohydrate and protein metabolism oxygen consumption heat production basal metabolic rate  Thyroid hormones 1. Thyroid glands produce: Thyroxine (T4= prohormone) & Triiodothyronine (T3). Both are tyrosine-based hormones. 2. Production requires IODINE 3. Target cells contain thyroid hormone nuclear receptor (TR). Non-toxic Goitre; lack of iodine in diet Non-toxic goitre (= Derbyshire neck) Hyperplasia from lack of thyroid hormones Simple treatment Childhood iodine deficiency = cretinism  Hypothyroidism Myxoedema Hashimoto’s disease/ Hashimoto’s thyroiditis most common =autoimmune disease Symptoms: fatigue/depression/weight gain/cold intolerance  Hyperthyroidism Graves’ disease (diffuse toxic goitre) –often autoimmune Symptoms: anxiety/ hyperactivity/Weight loss/goitre/bulging eyes/ tachycardia/sweating Hyperthyroidism: Pharmacological interventions Thioureylenes (-S=C-N-) Eg carbimazole, methimazole. Inhibit iodination of tyrosine. Protirelin- synthetic TRH, used diagnostically to test functionality of anterior pituitary to produce thyrotrophin/TSH Thioureylenes inhibit thyroperoxidase -S=C-N-  Disorders of the hypothalamic POSTERIOR pituitary axis- and treatment Antidiuretic hormone/Vasopressin (involved in blood volume and osmolarity control) ↓ADH Diabetes insipidus; treatments with hormone analogues  Learning outcomes checklist Describe the role of the hypothalamic-pituitary axis We have covered - how hormones are released from the pituitary gland- giving specific examples. - conditions associated with pituitary hormone imbalance and what interventions are possible.  2. Adrenal gland hormones Hypothalamus GHRH CRH GnRH TRH Anterior Pituitary GH ACTH FSH+LH TSH growth cortisol sex hormones thyroid  Adrenal glands 1. Hormones produced by adrenal glands Adrenal cortex: - Aldosterone -Androgens - Cortisol 2. Diseases of adrenal function 3. Corticosteroids Adrenal steroids: synthesis of aldosterone and hydrocortisone  Mechanism of action of the glucocorticoid receptor Figure 46–5 Intracellular mechanism of action of the GR. The figure shows the molecular pathway by which cortisol (labeled S) enters cells and interacts with the GR to change GR conformation (indicated by the change in shape of the GR), induce GR nuclear translocation, and activate transcription of target genes. Glucocorticoids also inhibit the expression of certain genes, including POMC expression by corticotropes. Here, GRE indicates the GREs in the DNA that are bound by GR, thus providing specificity to induction of gene transcription by glucocorticoids. Within the gene are introns (gray) and exons (red); transcription and mRNA processing leads to splicing and removal of introns and assembly of exons into mRNA.  ALDOSTERONE It is body’s major MINERALOCORTICOID* hormone Acts on kidney nephrons (distal tubule & collecting duct) Na+ retention K+ excretion * Regulates water and electrolyte balance….important!  Regulation of Aldosterone Secretion  ↓ extracellular fluid  Activates kidney release of renin  Renin convert Angiotensin to Ang I then  ACE converts to AngII  Ang II acts on adrenal cortex to stimulate  ALDOSTERONE Aldosterone Extracellular fluid release More Na+ volume retention Blood pressure Cardiac output  Functions of Cortisol The body’s major GLUCOCORTICOID hormone A) metabolic actions oppose those of insulin skeletal protein synthesis muscle protein degradation adipose liver glucose uptake lipid mobilisation gluconeogenesis } catabolic blood glucose glycogen storage B) actions on tissues and organs muscle -contractility bone -decreases bone formation CNS- modulates perception, helps wakefulness C) Anti-inflammatory and immune responses inhibits body response to tissue injury cortisol lipocortin phospholipase A2 arachidonic prostaglandins acids Cortisol and Aldosterone are both steroid hormones 1. All steroid hormones made from Cholesterol 2. Conversion of Cholesterol into Pregnenolone first step in STEROIDOGENESIS 3. ACTH and Angiotensin II increase Pregnenolone production. 4. From Pregnenolone both Aldesterone and Cortisol (and the Sex Steroids) are made. 5. 17a-hydroxylase converts aldosterone precursors into cortisol precursors. 6. Aldosterone production from Corticosterone stimulated by Angiotensin II. 7. 11-b-hydoxylase is final enzyme in synthesis of Cortisol  Diseases of adrenal glands Cushing’s syndrome Addison’s disease (↑glucocorticoids) adrenal insufficiency  Diseases of adrenal glands Cushing’s Syndrome = signs and symptoms associated with cortisol excess Often caused by excessive steroid medication Cushing’s disease (type of Cushing’s Syndrome) caused by CRH or ACTH excess Leads to excessive cortisol secretion Symptoms of Cushing Disease You could predict these symptoms from functions of cortisol  Treatment of Cushing’s disease Aminoglutethimide: decreases synthesis of all steroid hormones (blocks actions of P450scc) Metyrapone : 11-b-hydroxylase inhibitor Treatment; Surgical removal of tumour (dexamethasone suppression test and ACTH blood levels for diagnosis)  Diseases of adrenal glands Addison’s Disease (1:100 000) Often autoimmune: destroys adrenal cortex glucocorticoid + mineralocorticoid deficient glucocorticoids lethargy, weakness, weight loss mineralocorticoids hypotension (due increased Na excretion and so lowered ECF, leads to increased thirst, salt craving)  Corticosteroids- clinical uses Used as an Anti-Inflammatory or Immunosuppressant Rheumatoid arthritis Asthma Chronic Obstructive Pulmonary disease (COPD) Lupus Allergic rhinitis (hay fever) Ulcerative colitis Eczema Psoriasis Multiple sclerosis Often used in cancer therapy- various reasons…. Replacement therapy for AD- Cushing’s syndrome MC –like side effects Corticosteroid medications  Corticosteroid medications prednisolone prednisone cortisol cortisone  Corticosteroid medications cortisol fludrocortisone dexathemasone  Learning outcomes checklist 1. Be able to describe the actions of cortisol and aldosterone. 2. Be able to describe how steroid hormones are made from cholesterol. 3. Be able to describe what Addison’s disease and Cushing’s Syndrome are. 4. Be able to describe why cortisol and corticosteroids can have unwanted actions. 5. Appreciate the drug choices available for corticosteroids  3. Female reproductive system and contraceptive drugs Fig. 36.1 Hormonal control of the female reproductive system. The Graafian 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. Hormonal control of the female reproductive system  Key points FSH stimulates growth of ovarian follicles (each follicle contains one oocyte). 17b oestradiol is produced by growing follicles. 17b oestradiol negative feedback prevent excessive FSH production. In humans only one follicle fully matures (Graafian Follicle- GF) 17b oestradiol triggers release of Luteinising Hormone Ovulation triggered by a LH rise Corpus Luteum and Progesterone  Key points GF forms corpus luteum (CL) after ovulation. CL produces hormone progesterone (and some 17b oestradiol) Progesterone stimulates uterus for embryo implantation Progesterone prevents formation of new CL by inhibiting FSH release. Progesterone= hormone of pregnancy Progesterone stimulate cervix to produce a mucous that prevents sperm entry  Oestrogens List of major functions (17b-oestradiol, oestrone, oestriol in pregnancy) Puberty Pregnancy functions (breast development, childbirth) Maintain menstrual cycle Sexual desire (some species) Prevent bone resorption Increase blood coagulation (increase blood factors) Decrease blood platelet aggregation Increase Blood High-density Lipoprotein (HDL) Decrease Blood Low-Density Lipoprotein (LDL) Decrease plasma cholesterol  Major uses of oestrogen drugs Primary hypogonadism: stimulates development of secondary sexual characteristics and accelerates growth in children. Primary amenorrhoea (no periods): induces an artificial menstrual cycle in adults. Contraception: as an oral contraception in women. Given with a progestogen. Hormone Replacement Therapy (HRT). Given to women at or after the menopause. HRT helps physical symptoms of menopause and bone loss (osteoporosis).  Oral contraceptives Combination of estrogens and progestins estrogen: ethinyl estradiol progestin: norethindrone Adminstered orally, daily Day 5 - 21 of ovarian cycle Three types of formulation: monophasic, biphasic and triphasic Act by providing negative feedback to the pituitary and shut down secretion of LH and FSH Adverse effects: Abnormal menstrual bleeding Hypertension Increased appetite, weight gain Nausea, oedema, breast tenderness  Uses of Antiprogestogens Antiprogestogens Medical termination of pregnancy (arbortifacient): mifepristone (RU-486). Emergency ‘Contraception’. Endometrial shedding and embryo loss from site of implantation; cervix softening.  Antioestrogens 1. Oestrogens bind nuclear receptors in target cells 2. Oestrogen receptors are: Estrogen Receptor α (ERα) or Estrogen Receptor β (ERβ). 3. There are multiple forms of ERα and ERβ. 4. A tissue can have just one type of ER (e.g brain regions) or both (eg prostate). 5. Due to variety of ER’s, actions of anti-oestrogens can be varied and tissue specific.  Antioestrogens Clomiphene – induces ovulation by reducing negative feedback inhibition of oestrogen on hypothalamus and anterior pituitary gland. Clomiphene - non-steroidal oestrogen antagonist Used in fertility treatment for anovulation. Antioestrogens- Clomiphene Clomiphene allows FSH and LH level to rise= no negative feedback inhibition of oestrogen Raised FSH allows more follicles to grow Raised LH eventually triggers ovulation  Antioestrogens -SERMs Oestrogens bind nuclear receptors in target cells (ERα or ERβ) modification of gene transcription. SERMS (Selective oEstrogen Receptor Modulators) = competitive antagonists or partial agonists of oestrogen- ER binding SERM- Tamoxifen is used in oestrogen-dependent breast cancer. SERM- Raloxifene is used to treat postmenopausal bone loss.  Learning outcomes checklist 1. Be able to describe the hormonal control of sperm production in the testis. 2. Be able to describe the synthesis relationship between oestrogen and testosterone. 3. Be able to describe the hormonal control of ovulation and pregnancy. 4. Be able to describe what is meant by progestins, oestrogens, and antiestrogens (including SERMs) 4. The endocrine pancreas & control of blood glucose Factors regulating insulin secretion  Disorders of glucose homeostasis Diabetes- Type 1 and Type 2 Treatments: Insulin replacement Oral hypoglycaemics: – Sulfonylureas – Biguanides – Alpha-glucosidase inhibitors – Thiazolidinediones  Summary You should have an overview of the disorders of the endocrine system and therapeutic drugs Sample short answer questions: 1. Outline one endocrine disorder that results from abnormal function of the hypothalamic-pituitary axis. What are the symptoms and how can they be treated? 2. Name a clinical condition that can be treated with glucocorticoids. Include in your answer a description of the side- effects of drug treatment and how they arise. 3. Write short notes on oral hypoglycaemic drugs.