ENDOCRINOLOGY Neurotransmitters - PowerPoint Presentation

1. ENDOCRINOLOGYNeurotransmitters Endocrine Hormones Neuroendocrine HormonesParacrinesAutocrinesCytokines1

2. ANATOMY OF GLANDS2

3. HYPOTHALAMUS TRH CRH GHRH GHIH ( somatostatin ) GnRH PIF. 3

4. ANTERIOR PITUITARY GH TSH ACTH PROLACTION FSH LH. 4

5. POSTERIOR PITUITARYANTIDIURETIC HORMONE ,also called VASOPRESSIN OXYTOCIN. THYROID TRI-IODOTHYRONINE (T3) THYROXINE (T4) CALCITONIN 5

6. ADRENAL CORTEX CORTISOL ALDOSTERON . ADRENAL MEDULLA NOREPINEPHRINE EPINEPHRINE. PANCREAS INSULIN (BETA cells )GLUCAGON (ALPHA cells )6

7. PARATHYROID PARATHYROID HORMONE ( PTH ) TESTES - Testosterone OVARIES – Estrogens Progesterone PLACENTA - Human chorionic gonadotropin Human somatomammotropin . KIDNNEY – Renin Dihydrroxycholecalciferol Erythropoietin.7

8. HEART –ANP STOMACH – gastric . SMALL INTESTINE –secretin , cholecystokinin .ADIPOCYTES - leptin8

9. CHEMICAL STRUCTURE & SYNTHESIS OF HORMONE PROTEINS & POLYPEPTIDES –Hormones secreted by anterior pituitary , posterior pituitary , pancreas & parathyroid gland. STEROIDS - Hormone secreted by adrenal cortex ,ovaries , testes & placenta . DERIVATIVES OF THE AMINO ACIDS -Thyroid & adrenal medulla .9

10. SYNTHESIS PROTEIN & POLYPEPTIDE hormones are synthesized on the rough end of the endoplasmic reticulum . STEROID hormones synthesized from cholesterol are not stored . They are lipid soluble & consists of three cyclohexyl rings & cylopentyl ring combined into a single structure . 10

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12. HORMONE SECRETION ONSET OF HORMONE SECRETION AFTER STIMULUS AND DURATION OF ACTION OF DIFFERENT HORMONES . CONCENTRATION OF HORMONES IN CIRCULATING BLOOD - 1 picogram in each mililiter of blood up to few micrograms per milliliter of blood . RATES OF SECRETION - measured in micrograms or milligrams per day . 12

13. FEEDBACK CONTROL OF HORMONE SECRETION NEGATIVE FEEDBACK PREVENTS OVERACTIVITY OF HORMONE SYSTEM . SURGES OF HORMONES CAN OCCUR WITH POSITIVE FEEDBACK .13

14. CLEARANCE OF HORMONES FROM THE BLOOD TWO FACTORS CAN INCREASE OR DECREASE THE CONCENTRATION OF HORMONES IN THE BLOOD 1. Rate of hormone secretion in to blood . 2. Rate removal of the hormone from the blood . METABOLIC CLEARANCE RATE .14

15. MECHANISMS OF ACTION OF HORMONES HORMONE RECEPTORS AND THEIR ACTIVATION Hormonal receptors are large proteins . THE LOCATIONS FOR THE DIFFERENT TYPES OF HORMONE RECEPTORS : 1. In or on the surface of the cell membrane - for protein , peptide & catecholamine .15

16. 2. In the cell cytoplasm - receptors for steroid hormones 3. In cell nucleus - receptors for the thyroid hormones . THE NUMBER & SENSITIVITY OF HORMONE RECEPTORS ARE REGULATED : Down regulation can occur as a result of 1. inactivation of some of the receptors 2. inactivation of some of the intracellular protein signaling molecules 3. temporary sequestration of the receptors 4. destruction of the receptors by lysosomes 5. decreased production of receptors .16

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22. MEASUREMENT OF HORMONE CONCENTRATIONS IN THE BLOOD RADIOIMMUNOASSAY . ENZYME- LINKED IMMUNOSORBENT ASSAY (ELISA )The ELISA method has become widely Used in clinical laboratories because1) it does not employ radioactive isotopes,2) cost is effective & accurate method for Assessing hormone levels. 22

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24. PITUITARY HORMONES & THEIR CONTROL BY THE HYPOTHALAMUS PITUITARY GLAND - TWO DISTINCT PARTS THE ANTERIOR & POSTERIOR PARTS . THE PITUITARY GLAND is a small gland , 1 cm in a diameter & 0.5 to 1 gm in wt lies in the sella turcica abony cavity at the base of the brain & is connected to hypothalamus by the pituitary or hypophysial stalk . Embriologically anterior pituitary originates from Rathke’s pouch & posterior pituitary from neural tissue outgrowth from the hypothalamus24

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27. ANTERIOR PITUITARY GLAND CONTAINS SEVERAL DIFFERENT CELL TYPES THAT SYNTHESIZED & SECRETE HORMONES Somatotropes – Human growth hormone Coricotropes – Adrenocorticotrpin Thyrotropes – Thyroid - stimulating hormone 4. Gonadotropes - Gonadotropic hormones 5. Lacto tropes – Prolactin27

28. About 30 to 40% - somatotropes 20% - corticotropes 3 to 5% - thyrotropes gonad tropes lacto tropesSomatotropes stain strongly with acid dyes & are called acidophils .Thus pituitary tumors that secrete large quantities of HGH are called acidophilic tumors. 28

29. CELLULAR STRUCTURE OF ANTERIOR PITUTARY GLAND29

30. Posterior pituitary hormones are synthesized by cell bodies in the hypothalamus. MAGNOCELLULAR NEURON’S SECRETE THE POSTERIOR PITUITARY HORMONES. 30

31. HYPOTHALAMUS CONTROLS PITUITARY SECRETION Secretion from posterior pituitary is controlled by nerve signals that originate in the hypothalamus & terminate in posterior pituitary Secretion by anterior pituitary is controlled By hormones secreted within hypothalamusItself & then conducted to the anterior pituitary through minute blood vessels Called HYPOTHALAMIC-HYPOPHYSIAL PORTAL VESSELS.31

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33. PHYSIOLOGICAL FUNCTIONS OF GROWTH HORMONE Growth hormone promotes growth of many body tissues . 2. Growth hormone has several Metabolic effects : Increased rate of protein synthesis in most cells of the body . Increased mobilization of fatty acids from adipose tissue ,increased free fatty acids in blood & increased use of fatty acids for energy .33

34. Decreased rate of glucose utilization throughout the body . 3. GROWTH HORMONE PROMOTES PROTEIN DEPOSITION IN TISSUES . -Enhancement of amino acids transport through the cell membranes. - Enhancement of RNA translation . -Increased nuclear transcription of DNA to form RNA . - Decreased catabolism of protein & amino acids . 34

35. Growth hormone enhances fat utilization for energy Growth hormone causing the release of fatty acids from adipose tissue & therefore,increasing the concentration of fatty acids in the body fluids.KETOGENIC EFFECT OF GROWTH HORMONE GROWTH HORMONE DECREASES CARBOHYDRATE UTILIZATION 35

36. GROWTH HORMONE STIMULATES CARTILAGE & BONE GROWTH Effects of growth hormone on bone 1) increased deposition of protein by the chondrocytic & osteogenic cells that cause bone growth.2) increased rate of reproduction of these cells.3) a specific effect of converting chondrocytes into osteogenic cells, causing deposition of new bone. 36

37. GROWTH HORMONE EXERTS MUCH OF ITS EFFECT THROUGH INTERMEDIATE SUBSTANCES CALLED ‘SOMATOMEDINS’(ALSO CALLED “ INSULIN – LIKE GROWTH FACTORS .” ) CONGENITAL INABILITY TO SYNTHESIZE SINGNIFICANT AMOUNTS OF SOMATOMEDIN C ( e.g. the LEVI – Lorain drawf )37

38. REGULATION OF GROWTH HORMONE SECRETION : FACTORS STIMULATING GROWTH HORMONE SECRETION : (1) Starvation (2) Hypoglycemia (3) Exercise (4) Excitement (5) Trauma .38

39. FACTORS INHIBITING GROWTH HORMONE SECRETION 1.Increased blood glucose 2.Increased blood free fatty acids3.Aging4.Obesity5.Growth hormone inhibitory hormone 39

40. APPLIED ASPECTS OF GH :PANHYPOPITUITARISM - Decreased secretion of all the anterior pituitary hormones . It may be congenital or may occur suddenly or slowly at any time during life. DWARFISM - TREATMENT WITH HUMAN GROWTH HORMONE .40

41. PANHYPOPITUITARISM IN THE ADULT : TWO TUMOROUS CONDITIONS : Craniopharyngiomas or Chromophobe tumors. Thrombosis of the pituitary blood vessels .The general effects of adult panhypopituitarism areHypothyroidism Depressed production of glucocorticoids by the adrenal glandsSuppressed secretion of the gonadotropic hormones so that sexual functions are lost. 41

42. GIGANTISM Acidophilic tumors occur in the gland.All body tissues grow rapidly,including bones.If the condition occurs before adolescence the person become giantTREATNENT- FURTHER EFFECTS CAN BLOCKED BY MICROSURGICAL REMOVAL OF THE TUMOR OR BY IRRADIATION OF THE PITUITARY GLAND. 42

43. ACROMEGALYACIDOPHILIC TUMOR OCCURS AFTER ADOLESCENCE-i.e. after the epiphyses of the long bones have fused with the shaft,the person cannot grow taller,but the bones can become thicker & soft tissues can continue to grow. 43

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45. POSTERIOR PITUITARY GLAND & RELATIONS TO THE HYPOTHALAMUS: Posterior pituitary gland is composed mainly of glial –like cells called pituicytes.CHEMICAL STRUCTURES OF ADH & OXYTOCIN :Both are polypeptides 45

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47. PHYSIOLOGICAL FUNCTIONS OF ADHIN THE ABSENCE OF ADH-Loss of water into the urineIN THE PRESENCE OF ADH-Concentrated urineHIGHLY WATER PERMEABLE PORES CALLED AQUAPORINS. 47

48. REGULATION OF ADH PRODUCTIONOSMOTIC REGULATION-Near the hypothalamus neuron receptors called osmoreceptors.ECF becomes too concentrated,fluid is pulled by osmosis out of the osmoreceptors cell cause additional ADH secretion.OSMORECEPTORS are located in the organum vasculosum. 48

49. Minute concentrations of ADH cause increased water conservation by kidneys .Higher concentrations of ADH have potent effect of constricting the arterioles throughout the body & therefore increasing the arterial BP.49

50. ATRIA EXCITATION SIGNALS TO THE BRAIN TO INHIBIT ADH SECRETION OXYTOCIN – Causes contraction of the pregnant uterus & aids in milk ejection by the breast .50

51. THYROID METABOLIC HORMONE:The thyroid gland , located immediately below the larynx . Wt . 15 to 20 gms in adults . Secrete two hormones –T3 & T4 93% hormone secreted by thyroid is T4 & 7 % is T3 . Functions of these hormones are same ,but they differ in rapidity & intensity of action .51

52. PHYSIOLOGICAL ANATOMY OF THYROID GLAND52

53. IODINE IS REQUIRED FOR FORMATION OF THYROXINEAbout 50mg of ingested iodine in the form of iodides are required each year, or about 1mg/week. To prevent iodine deficiency,common table salt is iodized with about 1 part sodium iodide to every 100,000parts sodium chloride. 53

54. FATE OF INGESTED IODIDES Most of the iodides are rapidly excreted by the kidneys, but only after about one fifth are selectively removed from the circulating blood by the cells of the thyroid gland & used for synthesis of the thyroid hormones. 54

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56. IODIDE PUMP (Iodide Trapping ) The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to interior of the cell . This is called Iodide trapping . THYROGLOBULIN & CHEMISTRY OF T4 & T3 FORMATION :The endoplasmic reticulum & Golgi apparatus Synthesize & secrete into follicles a large glycoprotein molecule called thyroglobulin .56

57. EACH MOLECULE OF THYROGLOBULIN CONTAINS ABOUT 70 TYROSINE AMINO ACIDS,& THAT COMBINE WITH IODINE TO FORM THE THYROID HORMONES.OXIDATION OF THE IODIDE ION.ORGANIFICATION OF THE THYROGLOBULIN STORAGE OF THYROGLOBULIN.RELEASE OF T4 & T3 FROM THYROID GLAND 57

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59. DAILY RATE OF SECRETION OF T4 & T3ABOUT 93% OF THE THYROID HORMONE RELEASED FROM THE THYROID GLAND IS T4 & 7% IS T3.59

60. TRANSPORT OF THYROXINE & TRI-IODOTHYRONINE TO TISSUES : T3 & T4 ARE BOUND TO PLASMA PROTEIN T3 & T4 ARE RELEASESD SLOWLY TO TISSUE THYROID HORMONES HAVE SLOW ONSET & LONG DURATION OF ACTION .60

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62. PHYSIOLOGIC FUNCTIONS OF THE THYROID HORMONES: 1. Thyroid hormones increase the transcription of large numbers of Genes . - Thyroid hormones activate nuclear receptor 2. Thyroid hormones increase cellular metabolic activity . 3. Thyroid hormones increase the number & activity of mitochondria.62

63. THYROID HORMONE INCREASE ACTIVE TRANSPORT OF IONS THROUGH CELL MEMBRANENa-K ATPase that increases its activity in response to thyroid hormones.EFFECT OF THYROID HORMONE ON GROWTHEFFECTS OF THYROID HORMONE ON SPECIFIC BODILY MECHANISMS 63

64. STIMULATION OF CARBOHYDRATE METABOLISM.STIMULATION OF FAT METABOLISMEFFECT ON PLASMA & LIVER FATS.Increased thyroid hormone decreases the concentrations of cholesterol, phospholipids,& triglycerides in the plasma,even though it increases the free fatty acids. 64

65. INCREASED REQUIREMENT FOR VITAMINS.INCREASED BASAL METABOLIC RATE.DECREASED BODY WEIGHT65

66. EFFECT OF THYROID HORMONES ON THE CARDIOVASCULAR SYSTEMIncreased blood flow and cardiac output.Increased heart rate.Increased heart strength.Normal arterial pressure.Increased respiration.Increased gastrointestinal motility. 66

67. EXCITATORY EFFECTS ON THE CENTRAL NERVOUS SYSTEM.EFFECT ON THE FUNCTION OF THE MUSCLES.MUSCLE TREMOR.EFFECT ON SLEEP.EFFECT ON OTHER ENDOCRINE GLANDS.EFFECT ON SEXUAL FUNCTION. 67

68. REGULATION OF THYROID HORMONE SECRETION TSH INCREASES THYROID SECRETION TSH also known as thyrotropin , it is glycoprotein with MW 28000. ITS SPECIFIC EFFECT ON THE THYROID GLAND are as follows 1. Increases proteolysis of the thyroglobulin 2. Increases activity of the iodide pump 3. Increases iodination of tyrosine to form the thyroid hormones .68

69. 4.Increased size & increased secretory activity of the thyroid cells.Increased number of thyroid cells CYCLIC ADENOSINE MONOPHOSPHATE MEDIATES THE STIMULATORY EFFECT OF TSH.69

70. ANTERIOR PITUITARY SECRETION OF TSH IS REGULATED BY THYROTROPIN-RELEASING HORMONE FROM THE HYPOTHALAMUS EFFECT OF COLD & OTHER NEUROGENIC STIMULI ON TRH & TSH SECRETION 70

71. FEEDBACK EFFECT OF THYROID HORMONE TO INCREASE ANTERIOR PITUITARY SECRETION OF TSH 71

72. ANTITHYROID SUBSTANCES-THIOCYANATE, PROPYLTHIOURACIL,& high concentrations of inorganic iodides . THIOCYNATE IONS DECREASE IODIDE TRAPPING.PROPYLTHIOURACIL DECREASES THYROID HORMONE FORMATION IODIDES IN HIGH CONCENTRATIONS DECREASE THYROID ACTIVITY & THYROID GLAND SIZE.72

73. DISEASES OF THE THYROID HYPERTHYROIDISM .CAUSES OF HYPERTHYROIDISM –- ( TOXIC GOITER , THYROTOXICOSIS, GRAVE’S DISEASE.)73

74. Symptoms of hyperthyroidism(1) a high state of excitability (2) intolerance to heat (3) increased sweating (4) mild to extreme weight loss (5) diarrhea (6) muscle weakness (7) psychic disorders (8) fatigue (9) tremor of the hands.74

75. EXOPTHALAMOS THE PROTRUSION OF EYEBALLS .SOMETIMES IN SEVERE CONDITIONS EYEBALL PROTRUSION STRETCHES THE OPTIC NERVE TO DAMAGE VISION.CAUSE- EDEMATOUS SWEELLING OF THE RETRO-ORBITAL TISSUES & DEGENERATIVE CHANGES IN THE EXTRAOCULAR MUSCLES. 75

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77. DIAGNOSTIC TESTS FOR HYPERTHYROIDISM DIRECT MEASUREMENT OF THE CONCENTRATION OF FREE T4 (& SOMETIMES T3) IN THE PLASMA . TREATMENT IN HYPERTHYROIDISM -SURGICAL REMOVAL OF MOST OF THE THYROID GLAND TREATMENT OF THE HYPERPLASTIC THYROID GLAND WITH RADIOACTIVE IODINE 77

78. HYPOTHYROIDISMTHYROID GOITER ENDEMIC COLLOID GOITER –caused by dietary iodine deficiency.IDIOPATHIC NONTOXIC COLLOID GOITER-Deficient iodide-trapping mechanism Deficient peroxidase systemDeficient coupling of iodinated tyrosinesin the thyroglobulin molecule Deficient of the deiodinase enzyme78

79. PHYSIOLOGICAL CHARACTERISTICS OF THE HYPOTHYROIDISM fatigue ,extreme muscular sluggishness, slowed heart rate ,decrease cardiac output, decreased blood volume, increased body weight ,constipation ,depressed growth of the hair & scalinessof the skin development of the froglikehusky voice &in severe cases development of the edematous appearance throughout the body 79

80. MYXEDEMA- total lack of thyroid hormone ATHEROSCLEROSIS IN HYPOTHYROIDISM DIAGNOSTIC TESTS IN HYPOTHYROIDISM .TREATEMENT OF HYPOTHYROIDISM. -THYROXINE80

81. CRETINISM EXTREME HYPOTHYROIDISM During fetal life ,infancy ,or childhood . 1. CONGENITAL CRETINISM –CNGENITAL LACK OF A THYROID GLAND 2. ENDEMIC CRETINISM - IODINE LACK IN DIET81

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83. THYROID FUNCTION TESTS A.BASED ON METABOLIC EFFECTS OF T41.BMR i.e. O2 consumption of the subject under physical & mental rest.NORMAL: +20% or -20%2. BLOOD SUGAR 3.SERUM CHOLESTEROL4.SERUM CREATININE 83

84. B.BASED ON HANDLING OF IODINE1.Protein bound iodine normal 3.5-7.5 microgm%PBI decreases in hypothyroidism,pregnancy & acute thyroiditis & increases in hyperthyroidism & patients on oral contraceptives.2.BUTANOL EXTRACTABLE IODINE NORMAL: 3-5 microgm% increases in hyperthyroidism & decreases in hypothyroidism. 84

85. 3.RADIOACTIVE IODINE UPTAKE 4.T3 SUPPRESSION TESTuseful in suspected cases of thyrotoxicosis5.SERUM THYROID HORMONE & TSH LEVELS.C. OTHER INVESTIGATIONS1.Radiography2.Indirect Lyrangoscopy3.Biopsy4.Urinary calcium loss. 85

86. ADRENOCORTICAL HORMONES THE TWO ADRENAL GLANDS ,WT 4gms ,lie at the superior poles of the two kidney EACH GLAND COMPOSED OF TWO DISTINCT PARTS –ADRENAL MEDULLA ADRENAL CORTEX .86

87. SYNTHESIS & SECRETION OF ADRENALCORTICAL HORMONES THE ADRENAL CORTEX HAS THREE LAYERS .1. THE ZONA GLOMERULOSA 2. THE ZONA FASCICULATA 3. THE ZONA RETICULARIS 87

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89. ADRENOCORTICAL HORMONES ARE STEROIDS DERIVED FROM CHOLESTEROL. Although the cells of the adrenal cortex can synthesize de novo small amounts of cholesterol from acetate ,approximately 80 % of the cholesterol used for steroid synthesis is provided by (LDL)in the circulating plasma . 89

90. PATHWAYS FOR SYNTHESIS OF STEROID HORMONES BY THE ADRENAL CORTEX CHOLESTESROL PREGNENOLONE PROGESTERONE 11-DEOXCORTICOSTERONE CORTICOSTERONE ALDOSTERONE 90

91. PREGNENOLONE 17-HYDROXYPREGNENOLONE 11-HYROXYPROGESTERONE 11-DEOXYCORTISOL CORTISOL91

92. PROGESTERONE 17-HYDROXYPROGESTERONE ANDROSTENEDIONE 92

93. PREGNENOLONE 17-HYDROXYPREGNENOLONE DEHYDROEPIANDROSTERONE ANDROSTENEDIONE93

94. MINERALOCORTICOIDS ALDOSTERONEDESOXYCORTICOSTERONE CORTICOSTERONE9alpha –FLUOROCORTISOLCORTISOL CORTISONE 94

95. GLUCOCORTICOIDS CORTISOL CORTOCOSTERONE CORTISONE PREDNISONEMETHYLPREDNISONEDEXAMETHASONE95

96. 90 to 95% of the cortisol in plasma binds plasma proteins ,especially a globulin called crtisol binding globulin or transcortin. Cortisol has a long half life of 60 to 90 minutes .Aldosterone has a short half life of about 20 minutes. 96

97. ADRENOCORTICAL HORMONES ARE METABOLISED IN THE LIVERThe adrenal steroids are degraded mainly in the liver & conjugated especially to Glucuronic acid & , to a lesser extent , sulfates .About 25 % of these conjugates are excreted The remaining conjugates formed by the liver Enter the circulation but are not bound to plasma proteins , are highly soluble in the plasma, & are therefore filtered readily by the kidneys & excreted in the urine.97

98. THE NORMAL CONCENTRATION OF ALDOSTERONE IN THE BLOOD IS ABOUT 6 NANOGRAMS PER 100ml & THE AVERAGE SECRETORY RATE IS 150 microgram / day .THE CONCENTRATION OF CORTISOL IN THE BLOOD IS 12 microgram / 100 ml & THE SECRETORY RATE AVERAGES 15 to 20 mg/day 98

99. FUNCTIONS OF THE MINERALOCORTICOIDS –ALDOSTERONE Mineralocorticoids deficiency causes severe renal sodium chloride wasting & hyperkalemia Aldosterone increases renal tubularreabsorption of sodium & secretion of potassium. 99

100. Excess aldosterone increases extrcellular fluid volume & arterial pressure but has only a small effect on plasma sodium concentration .Excess aldosterone causes hypokalemia & muscle weakness ; Too little aldosterone causes hyprekalemia & cardiac toxicity. 100

101. Excess aldosterone increases tubular hydrogen ion secretion ,& causes mild alkalosis.Aldosterone stimulates sodium & potassium transport in sweat glands, salivary glands,& intestinal epithelial cells. 101

102. Cellular mechanism of aldosterone action The basic action of aldosterone on the tubular cells to increase transport of sodium1. Because of its lipid solubility in the cellular Membranes, aldosterone diffuses readily to the interior of the tubular epithelial cells.2. In the cytoplasm of the tubular cells , aldosterone combines with a highly specific cytoplasmic receptor protein.102

103. 3. Aldosteron-receptor complex, 4. Formation of protein 103

104. NONGENOMIC ACTIONS OF ALDOSTERONEINCREASE FORMATION OF c AMP .STIMULATE THE PHOSPHATIDYLINOSITOL SECOND MESSENGER SYSTEM. 104

105. REGULATION OF ALDOSTERONE SECRETION 1. Increased potassium ion concentration in the ECF increases aldosterone secretion .Increased activity of the renin- angiotensin system increases aldosterone secretion . 3. Increased sodium ion concentration in the ECF decreases aldosterone secretion .ACTH is necessary for aldosterone secretion but has little effect in controlling the rate of secretion . 105

106. FUNCTIONS OF THE GLUCOCORTICOIDS EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISMStimulation of gluconeogenesis 1. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells .2. Cortisol causes mobilization of amino acids from the extrahepatic tisssues Mainly from muscle. 106

107. Decreased glucose utilization by cells .ADRENAL DIABETES 107

108. EFFECTS OF CORTISOL ON PROTEIN METABOLISM REDUCTION IN CELLULAR PROTEIN. CORTISOL INCREASES LIVER & PLASMA PROTEINS .CORTISOL DEMINISHED TRANSPORT OF AMINO ACIDS INTO EXTRAHEPATIC CELLS , & ENHANCED TRANSPORT INTO HEPATIC CELLS .108

109. EFFECTS OF CORTISOL ON FAT METABOLISM MOBILIZATION OF FATTY ACIDS .OBESITY CAUSED BY EXCESS CORTISOL.109

110. STRESS INCREASES CRTISOL SECRETION 1. TRAUMA 2. INFECTION 3. INTENCE HEAT OR COLD 4. INJECTION OF NOREPINEPHRINE & OTHER SYMPATHOMIMETIC DRUGS. 5. SURGERY 6. INJECTION OF NECROTIZING SUBTANCES BENEATH THE SKIN 7. RESTRAINING AN SANIMAL SO THAT IT CANNOT MOVE 8. ANY DEBILITING DISEASE110

111. CORTISOL PREVENTS THE DEVELOPMENT OF INFLAMMATION BY STABILIZING LYSOSOMES & BY OTHER EFFECTS.1.Cortisol stabilizes the lysosomal membranes.2. Cortisol decreases the permeability of the capillaries .3. Cortisol decreases both migration of WBCS into the inflammed area & phagocytosis of the damaged cells.4. Cortisol suppresses the immune system 111

112. Causing lymphocyte reproduction to decrease markedly .5. Cortisol attenuates fever mainly because it reduces the release of interleukin-1 from the white blood cells . 112

113. CORTISOL CAUSES RESOLUTION OF INFLAMMATION .OTHER EFFECTS OF CORTISOL - Cortisol blocks the inflammatory response to allergic reactions.- Effects on blood cells & on immunity in infectious diseases. 113

114. Cortisol inhibits prostaglandins synthesis, leukotriene synthesis.Role of lipocortinEffects of cortisol on muscle,skeleton and connective tissues.Effects of on CNS114

115. CELLULAR MECHANISM OF CORTISOL ACTION115

116. REGULATION OF CORTISOL SECRETION ACTH STIMULATES CORTISOL SECRETION ACTH SECRETION IS CONTROLLED BY CRF FROM THE HYPOTHALAMUS ACTH ACTIVATES ADRENOCORTICAL CELLS TO PRODUCE STEROIDS BY INCREASING cAMP .116

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118. Circadian rhythm of glucocorticoid secretionROLE OF MSH, LIPOTROPIN,& ENDORPHIN118

119. ADRENAL ANDROGEN 119

120. ABNORMALITIES OF ADRENOCORTICAL SECRETION HYPOADRENALISM HYPERADRENALISM 120

121. ADDISSON’S DISEASEFailure of the adrenal cortices to produce adrenocortical hormones caused by primary atrophy of the adrenal cortices .80% of the cases , the atrophy is caused By autoimmunity against the cortices .Mineralocorticoid & glucocorticoid deficiency. 121

122. Melanin pegmentation TREATMENT OF ADDISON’S DISEASE - minaralocorticoids & glucocorticoids ADDISONIAN CRISIS 122

123. CUSHING’S SYNDROME HYPERSECRETION OF ACTH CAUSES – 1) adenomas of the anterior pituitary 2) abnormal function of the hypothalamus 3) ectopic secretion of ACTH4) adenomas of the adrenal cortex .CAUSHING SYNDROME CAN ALSO OCCUR WHEN LARGE AMOUNTS OF GLUCOCORTICOIDS ARE ADMINISTERED.123

124. CHARACTERISTIC OF CUSHING’S SYNDROME Extra deposition of fat in the thoracic & upper abdominal regions .Edematous appearance of the face Increased blood glucose concentration level Decreased tissue proteins. 124

125. TREATEMENT OF CUSHING’S SYNDROME Removing an adrenal tumor .Drugs that block steroidogenesis , such as METYRAPONE , KETOCONAZOLE, &AMINOGLUTETHIMIDE.Drugs that inihibit ACTH secretion SEROTININ ANTAGONIST & GABA –TRANSAMINASE INIHIBITORS .125

126. PRIMARY ALDOSTERONISM (CONN’S SYNDROME) Tumor of the zona glomerulosa cells .EFFECTS - Hypokalemia , muscle paralysis TREATMENT - surgical removal of the tumor or of most of the adrenal tissue when hyperplasia is the cause .126

127. ADRENOGENITAL SYNDROME ADRENOCORTICAL TUMOR SECRETES EXCESSIVE QUANTITES OF ADROGENS IN FEMALE –Virile characteristics, growth of a beard,depper voice deposition of proteins 127

128. ADRENAL MEDULLASTRUCTURE AND FUNCTION OF MEDULLARY HORMONES Ctaecholamines-NOREPINEPHRINE,EPINEPHRINE,& DOPAMINE ARE SECRETED BY THE ADRENAL MEDULLA.NOREPINEPHRINE is formed by hydroxylation & decarboxylation of tyrosine,& EPINEPHRINE by methylation of norepinephrine. 128

129. Phenylethanolamine-N-methyltransferase(PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in brain & the adrenal medulla.In plasma, about 95% of the dopamine & 70% of norepinephrine & epinephrine are conjugated to sulphate. 129

130. The epinephrine found in tissues other than the adrenal medulla and the brain is for the most part absorbed from blood stream .The plasma free dopamine level is about 35 pg/ml, and appreciable quantities of dopamine are present in the urine.The catecholamines have half-life of about 2min in the circulation. 130

131. OTHER SUBSTANCES SECRETED BY THE ADRENAL MEDULLA SECRETION IS INITIATED BY ACETYLCHOLINE RELEASED FROM THE PREGANGLIONIC NEURONS THAT INNERVATE THE SECRETORY CELLS. 131

132. EFFECTS BY ACTIONS ON TWO CLASSES OF RECEPTORS ALPHA & BETA 132

133. EFFECTS OF EPINEPHRINE & NOREPINEPHRINE 1. METABOLIC EFFECTS2.STIMULATION OF METABOLIC RATE.3.INCREASE FORCE & RATE OF CONTRACTION OF ISOLATED HEART.4.INCREASE MYOCARDIAL EXCITABILITYEPINEPHRINE & NOREPINEPHRINE BOTH CAUSE GLYCOGENOLYSIS. ADIPOSE TISSUE LIPOLYSIS.MENTAL ALTERTNESS OF THE FIGHT OR FLIGHT.133

134. ADRENAL MEDULLARY TUMOURS ALSO CALLED PHEOCHROMOCYTOMAS PRODUCE SUSTAINED HYPERTENSION .EFFECTS OF DOPAMINE RENAL VASODILATION,IT ALSO PRODUCES VASODILATION IN MESENTERY.MODERATE DOSES OF DOPAMINE IS AN INCREASE IN SBP & NO CHANGE IN DBP .DOPAMINE CAUSES NATRIURESIS & MAY EXERT THIS EFFECT BY INHIBITING RENAL NA-KATPase 134

135. REGULATION OF ADRENAL MEDULLARY SECRETION NEURAL CONTROL SELECTIVE CONTROL135

136. INSULIN & GLUCAGON PHYSIOLOGICAL ANATOMY OF THE PANCREASThe pancreas is composed of two major Types of tissues 1. The acini 2. The islets of langerhans 136

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138. THE ISLETS CONTAIN THREE MAJOR TYPES OF CELLS , ALPHA ,BETA & DELTA CELLS THE BETA CELLS CONSTITUING ABOUT 60% OF ALL THE CELLS OF THE ISLETS & SECRETE INSULIN & AMYLIN .THE ALPHA CELLS ABOUT 25% OF THE TOTAL , SECRETE GLUCAGON .THE DELTA CELLS , ABOUT 10% OF THE TOTAL , SECRETE SOMATOSTATIN . 138

139. THE PP CELLS ,IS PRESENT IN SMALL NUMBERS IN THE ISLETS & SECRETES A HORMONE OF UNCERTAIN FUNCTION CALLED PANCREATIC POLYPEPTIDE . 139

140. INSULIN & ITS METABOLIC EFFECTS Insulin is first isolated from the pancreas In 1922 by Banting & Best .Insulin is a small protein ; human insulin Has a MW of 5808 . It is composed of two amino acids chains.140

141. BIOSYNTHESIS OF INSULIN 141

142. HUMAN INSULINTARGET ORGAN FOR INSULIN ACTION 1.LIVER2.MUSCLE3.ADIPOSE TISSUE 142

143. 143

144. 144

145. GLUT1 Placenta.BBB.brain,red cells,kidney,colonGLUT2 – liver, intestine,kidneyGLUT3- brain,placenta,kidneysGLUT4- skeletal,cardiac muuscle,adipose tissueGLUT5 – FRUCTOSE TRANSPORT IN JEJUNUM,SPERM 145

146. GLUT6 – NONE GLUT7- glucose6-phosphate transporter in ER IN LIVER,OTHER TISSUES. 146

147. EFFECTS OF INSULIN ON CARBOHYDRATE METABOLISM INSULIN PROMOTES MUSCLE GLUCOSE UPTAKE & METABOLISM Under two conditions the muscles do use Large amounts of glucose .1. During moderate or heavy exercise. 2. During the few hours after a meal.147

148. STORAGE OF GLYCOGEN IN MUSCLE.INSULIN PROMOTES LIVER UPTAKE,STORAGE,& USE OF GLUCOSE 1.Insulin inactivates liver phosphorylase,the enzyme that causes liver glycogen to split into glucose.2.Insulin causes enhanced uptake of glucose from the blood by the liver cells.Itdoes this by increasing the activity of the enzyme glucokinase.3.Insulin increases the activities of the enzymes that promote glycogen synthesis, including glycogen synthase,which is responsible for polymerization of the monosaccharide units to form glycogen molecule 148

149. GLUCOSE IS RELEASED FROM THE LIVER BETWEEN MEALS.1.The decreasing blood glucose causes the pancreas to decrease its insulin secretion.2.The lack of insulin stopping further synthesis of glycogen in the liver& preventing further uptake of glucose by the liver from the blood .3.The lack of insulin activates the enzyme phosphorylase,which causes the splitting of glycogen into glucose phosphate. 149

150. 4.Insulin lack activates the enzyme glucose phosphatase & cause the phosphate radicle to split away from the glucose ;this allows the free glucose to diffuse back into blood . 150

151. THE BRAIN CELLS USE ONLY GLUCOSE FOR ENERGY151

152. INSULIN PROMOTES CONVERSION OF EXCESS GLUCOSE INTO FATTY ACIDS & INHIBITS GLUCONEOGENESISIN THE LIVER. EFFECT OF INSULI ON CARBOHYDRATE METABOLISM IN OTHER CELLS EFFECT OF INSULIN ON FAT METABOLISM Insulin promotes fat synthesis & storage-Insulin increases the transport of glucose into the liver cells .-An excess of citrate & isocitrate ions is formed by the citric acid when excess amounts of glucose are being used for energy. -Most of the fatty acids are synthesized withinthe liver itself & used to form triglycerides. 152

153. ROLE OF INSULIN IN STORAGE OF FAT IN THE ADIPOSE CELLS.1. INSULIN INHIBITS THE ACTION OF HORMONE SENSITIVE LIPASE. 2. INSULIN PROMOTES GLUCOSE TRANSPORT THROUGH THE CELLS MEMBRANE INTO THE FAT CELLS .INSULIN DEFICIENCY INCREASES USE OF FAT FOR ENERGYINSULIN DEFICIENCY CAUSES LIPOLYSIS OF STORAGE FAT & RELEASE OF FREE FATTY ACIDS. 153

154. INSULIN DEFICIENCY INCREASES PLASMA CHOLESTEROL & PHOSPHOLIPID CONCENTRATIONS.EXCESS USAGE OF FATS DURING INSULIN LACK CAUSES KETOSIS AND ACIDOSIS.154

155. EFFECT OF INSULIN ON PROTEIN METABOLISMINSULIN PROMOTES PROTEIN SYNTHESIS & STORAGE.1.Insulin stimulates transport of many of the amino acids into the cells.2.Insulin increases,the translation of messenger RNA.3.Over a longer period of time,insulin also increases the rate of trancription of selected DNA genetic sequences in cell nuclei.4.Insulin inhibits the catabolism of proteins.5.In the liver,insulin depresses the rate of gluconeogenesis. 155

156. INSULIN LACK CAUSES PROTEIN DEPLETION & INCREASED PLASMA AMINO ACIDS.INSULIN & GROWTH HORMONE INTERACT SYNERGISTICALLY TO PROMOTE GROWTH. 156

157. MECHANISM OF INSULIN SECRETIONBASIC MECHANISMS OF GLUCOSE STIMULATION OF INSULIN SECRETION BY BETA CELLS OF THE PANCREASE. GLUT, GLUCOSE TRANSPORTER. 157

158. 158

159. Factors and conditions that increases or decreases insulin secretion INCREASE INSULIN SECRETION 1.Increase blood glucose 2.Increase blood free fatty acids3.Increase blood amino acids4.Gastrointestinal hormones5.Glucagon,growth hormone,cortisol6.Parasympathetic stimulation7.Beta-adrenergic stimulation8.Insulin resistance;obesity9.Sulfonylurea drugs. 159

160. DECREASE INSULIN SECRETION 1.Decrease blood glucose 2.Fasting3.Somatostatin4.Alpha-adrenergic activity5.Leptin 160

161. CONTROL OF INSULIN SECRETION FEEDBACK RELATION BETWEEN BLOOD GLUCOSE CONCENTRATION & INSULIN SECRETION RATE 161

162. OTHER FACTORS THAT STIMULATE INSULIN SECRETIONAMINO ACIDS GASTROINTESTINAL HORMONESOTHER HORMONES 162

163. GLUCAGON AND ITS FUNCTIONS GLUCAGON IS A LARGE POLYPEPTIDE.IT HAS A MW 3485 & IS COMPOSED OF A CHAIN OF 29AMINO ACIDS.GLUCAGON IS ALSO CALLED THE HYPERGLYCEMIC HORMONE 163

164. EFFECT OF GLUCAGON ON GLUCOSE METABOLISM1.Breakdown of liver glycogen.2.Increased gluconeogenesis in the liver.-Glucagon activates adenylyl cyclase inthe hepatic cell membrane, formation of cyclic adenosine monophosphateActivation of protein kinase regulator protein164

165. Activation of protein kinase Activation of phosphorylase b protein Converts phosphorylase b into phosphorylase a Degradation of glycogen into glucose-1- phosphate Dephosphorylization & glucose is releasedFrom the liver cells 165

166. OTHER EFFECTS OF GLUCAGON Glucagon activates adipose cell lipaseGlucagon inhibits the storage of triglycerides in the liverGlucagon in high concentrationsenhances the strength of the heartincreases blood flow in some tissues,especially the kidneys; 166

167. enhances bile secretion & inhibits gastric acid secretion. 167

168. REGULATION OF GLUCAGON SECRETIONINCREASD BLOOD GLUCOSE INHIBITS GLUCAGON SECRETION INCREASED BLOOD AMINO ACIDS STIMULATES GLUCAGON SECRETIONEXERCISE STIMULATES GLUCAGON SECRETION 168

169. SOMATOSTATIN POLYPEPTIDE CONTAINING 14 AMINO ACIDSFACTORS STIMULATING SOMATOSTATINSECRETION 1.Increased blood glucose 2.Increased amino acids 3.Increased fatty acids 4.Increased concentration of several of the GIT hormones released from the upper GIT in response to food intake 169

170. Somatostatin has multiple inhibitory effects 1.IT DEPRESS THE SECRETION OF BOTH INSULIN & GLUCAGON2.IT DECREASES THE MOTILITY OF THE STOMACH3. SOMATOSTATIN DECREASES BOTH SECRETION AND ABSORPTIONIN THE GASTROINTESTINAL TRACT. 170

171. PANCREATIC POLYPEPTIDEREDUCES APPETITE AND PREVENTS OBESITY 171

172. BLOOD GLUCOSE CONCENTRATION NOT RISE TOO HIGH FOR FOUR REASONS1.GLUCOSE CAN EXERT A LARGE AMOUNT OF OSMOTIC PRESSURE IN ECF2.HIGH LEVEL OF BLOOD GLUCOSE CAUSES LOSS OF GLUCOSE IN THE URINE3.CAUSES OSMOTIC DIURESIS BY THE KIDNEYS4.INCREASE BLOOD GLUCOSE MAY CAUSE DAMAGE TO MANY TISSUES,BLOOD VESSELS 172

173. DIABETES MELLITUSDiabetes mellitus is a syndrome ofimpaired carbohydrate,fat,& proteinmetabolism caused by either lack ofinsulin secretion or decreased sensitivity of the tissues to insulin. 173

174. TYPE I DIABETES –LACK OF INSULIN PRODUCTION BY BETA CELLS OF THE PANCREASEInjury to the beta cells of the pancrease or diseases that impair insulin production can lead to type I diabetes.Viral infections or autoimmune disorders may be involved in the destruction of the beta cells.s 174

175. TYPES OF DIABETES MELLITUS1.TYPE I DIABETES,ALSO CALLED INSULIN DEPENDENT DIABETES MELLITUS (IDDM), CAUSED BY LACK OF INSULIN SECRETION.2. TYPE II DIABETES, ALSO CALLED NON INSULIN DEPENDENT DIABETES MELLITUS (NIDDM), CAUSED BY DECREASED SENSITIVITY OF TARGET TISSUES TO THE MATABOLIC EFFECT OF INSULIN. THIS REDUCED SENSITIVITY TO INSULIN IS OFTEN CALLED INSULIN RESISTANCE. 175

176. SECONDARY DIABETES SOME CASES OF DIABETES ARE DUO TO OTHER DISEASES OR CONDITIONS SUCH AS CHRONIC PANCREATITIS, TOTAL PANCREATECTOMY,CUSHING’S SYNDROME& ACROMEGALY. THESE MAKE UP 5% OF THE TOTAL CASES & ARE SOMETIMES CLASSIFIED AS SECONDARY DIABETES 176

177. Type I DIABETES-LACK OF INSULIN PRODUCTION BY BETA CELLS OF THE PANCREASINJURY TO THE BETA CELLS OF THE PANCREAS OR DISEASES THAT IMPAIR INSULIN PRODUCTION CAN LEAD TO TYPE I DIABETES. 177

178. VIRAL INFECTIONS OR AUTOIMMUNE DISORDERS MAY BE INVOLVED IN THE DESTRUCTION OF BETA CELLS IN MANY PATIENTS WITH TYPE I DIABETES,ALTHOUGH HEREDITY ALSO PLAYS A MAJOR ROLE IN DETERMINING THE SUSEPTIBILITY OF THE BETA CELLS TO DESTRUCTION. 178

179. THE USUAL ONSET OF TYPE I DIABETES OCCURS AT ABOUT 14 YEARS OF AGE & FOR THIS REASON IT IS OFTEN CALLED AS JUVENILE DIABETS MELLITUS.TYPE I DIABETES MAY DEVELOP VERY ABRUPTLY,OVER A PERIOD OF A FEW DAYS OR WEEKS, WITH THREE PRINCIPLE SEQUELAE: 179

180. (1) INCREASED BLOOD GLUCOSE (2) INCREASED UTILIZATION OF FATS FOR ENERGY & FOR FORMATION OF CHOLESTEROL BY THE LIVER,& (3) DEPLETION OF THE BODY’S PROTEINS. 180

181. THE LACK OF INSULIN DECREASES THE EFFICIENCY OF PERIPHERAL GLUCOSE UTILIZATION & AUGMENTS GLUCOSE PRODUCTION,RAISING PLASMA GLUCOSE TO 300 TO 1200 mg/ 100 ml. THE INCREASED PLASMA GLUCOSE THEN HAS MULTIPLE EFFECTS THROUGHOUT THE BODY. 181

182. INCREASED BLOOD GLUCOSE CAUSES LOSS OF GLUCOSE IN THE URINE.INCREASED BLOOD GLUCOSE CAUSES DEHYDRATION.CHRONIC HIGH GLUCOSE CONCENTRATION CAUSES TISSUE INJURY. 182

183. DIABETES MELLITUS CAUSES INCREASED UTILIZATION OF FATS & METABOLIC ACIDOSIS.The shift from carbohydrate to fat metabolism in diabetes increases the release of keto acids, such as acetoacetic acids & beta hydroxybutyric acids, into the plasma more rapidly than they can be taken up & oxidized by the tissue cells.As a result , the patient develops severe metabolic acidosis from the excess ketoacids, Which , in association with dehydration duo to the excessive urine formation, can cause severe acidosis.This leads rapidly to diabetic coma .183

184. DIABETES CAUSES DEPLETION OF THE BODY’S PROTEINS.Failure to use glucose for energy leads to increased utilization & decreased storage of proteins as well as fat.therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss & asthenia. asthenia.184

185. TYPE II DIABETES-RESISTANCE TO THE METABOLIC EFFECTS OF INSULIN In most cases, the onset of type II diabetes occurs after age of 30 years, often between the age of 50 & 60 years and the disease develops gradually. Therefore this syndrome is often called as adult-onset diabetes. TYPE II DIABETES IS ASSOCIATED WITH INCREASED PLASMA INSULIN CONCENTRATION ( Hyperinsulinemia) .185

186. INSULIN RESISTANCE IS A PART OF A CASCADE OF DISORDERS THAT IS OFTEN CALLED THE ‘METABOLIC SYNDROME’1) OBESITY 2) INSULIN RESISTANCE3) FASTING HYPERGLYCEMIA 4) LIPID ABNORMALITIES5) HYPERTENSIO N186

187. OTHER FACTORS THAT CAN CAUSE INSULIN RASISTANCE & TYPE II DIABETES MELLITUS POLYCYSTIC OVARY SYNDROME EXCESS FORMATION OF GLUCOCORTICOIDS(CUSHING’S SYNDROME)OR GROWTH HORMONE (ACROMEGALY) 187

188. DRUGS THAT INCREASE INSULIN SENSETIVITY, SUCH AS THIAZOLIDINEDIONES & METFORMINOR DRUGS THAT CAUSE ADDITIONAL RELEASE OF INSULIN SUCH AS SULFONYLUREAS MAY BE USED. 188

189. PHYSIOLOGY OF DIAGNOSIS OF DIBETES MELLITUS URINARY GLUCOSE FASTING BLOOD GLUCOSE & INSULIN LEVELS.The fasting blood glucose level is normally 80 to 100 mg/100ml & GLUCOSE TOLERANCE TEST.ACETONE BREATH. 189

190. TREATMENT OF DIABETES TYPE I DIABETES –ADMINISTRATION OF ENOUGH INSULIN SO THAT THE PATIENTWILL HAVE CARBOHYDRATE, FAT & PROTEIN METABOLISM THAT IS AS NORMAL AS POSSIBLE.REGULAR INSULIN HAS A DURATION OF ACTION THAT LASTS FROM 3 to 8 HOURS. 190

191. OTHER FORMS OF INSULIN(Precipitatedwith zinc or with various protein derivatives) are absorbed slowly from the injection site & therefore have effects that last as long as 10 to 48 hours. TYPE II DIABETES –DIETING & EXERCISEIn the past, the insulin used for treatment was derived from animal pancreata.191

192. INSULIN SHOCK AND HYPOGLYCEMIAIf high levels of insulin cause blood glucose to fall to low values,the metabolism of the CNSbecomes depressed.As the blood glucose level falls into the range of 50 to 70mg/100mlthe CNS usually becomes quite excitable,because this degree of hypoglycemia sensitizes neuronal activity. 192

193. TREATMENT FOR HYPOGLYCEMIC SHOCK OR COMAIMMEDIATE ADMINISTRATION OF LARGEQUANTITIES OF GLUCOSE.ADMINISTRATION OF GLUCAGON. 193

194. CALCIUM AND PHOSPHATE METABOLISMCALCIUM PLAYS A KEY ROLE IN MANY PHYSIOLOGICAL PROCESSES INCLUDING CONTRACTION OF SKELETAL ,CARDIAC AND SMOOTH MUSCLES ; BLOOD CLOTTING& TRANSMISSION OF NERVE IMPULSES,HYPERCALCEMIA CAUSE PROGRESSIVEDEPRESSION OF THE NERVOUS SYSTEMHYPOCALCEMIA CAUSE NERVOUS SYSTEM TO BECOME EXCITABLE.194

195. 0.1% OF THE TOTAL BODY CALCIUM IS IN THE ECF, ABOUT 1% IS IN THE CELLS & REST IS STOREED IN BONES.85 % OF THE BODY’S PHOSPHATE IS STORED IN BONES, 14 TO 15 % IS IN THE CELLS, & LESS THAN 1% IS IN THE ECF. 195

196. CALCIUM IN THE PLASMA & INTERSTITIAL FLUID 41% of the calcium is combined with plasma proteins & in this form is nondiffusible through the capillary membrane.9% of the calcium is diffusible through the capillary membrane but is combined with anionic substances of the plasma & interstitial fluids in such manner that it is not ionized.196

197. 3.The remaining 50 % of the calcium in the plasma is both diffusible through the capillary membrane & ionized.197

198. HYPOCALCEMIA CAUSES NERVOUS SYSTEM EXCITEMENT AND TATANYTETANY OCCURS WHEN BLOOD CONCENTRATION OF CA FALLS FROM ITS NORMAL LEVEL OF 9.4mg/dl to about 6 mg/dl.HYPERCALCEMIA DEPRESSES NERVOUS SYSTEM & MUSCLE ACTIVITY. 198

199. ABSORPTION & EXCRETION OF CALCIUM & PHOSPHATEINTESTINAL ABSORPTION & FECAL EXCRETION OF CALCIUM & PHOSPHATE.RENAL EXCRETION OF CALCIUM & PHOSPHATE 199

200. 200

201. BONE AND ITS RELATION TO EXTRACELLULAR CALCIUM AND PHOSPHATEBONE IS COMPOSED OF A TOUGHORGANIC MATRIX THAT IS GREATLY STRENGTHENED BY DEPOSITS OF CALCIUM SALTS.201

202. Average compact bone contains by weight about 30% matrix & 70% salts.Newly formed bone may have a considerably higher percentage of matrix in relation to salts. 202

203. ORGANIC MATRIX OF BONE The organic matrix of bone is 90-95% collagen fibers,& remainder is a homogeneous gelatinous medium called ground substance.The ground substance is composed of ECF pulse proteoglycans,especially chondroitin sulfate & hyaluronic acid. 203

204. BONE SALTSCRYSTALLINE SALTS DEPOSITED IN THE ORGANIC MATRIX OF BONE & COMPOSED OF CA & PH.Mg ,Na,K,& CARBONATE IONS ARE ALSO PRESENT AMONG THE BONE SALTS. 204

205. TENSILE & COMPRESSIONAL STRENGTH OF BONE.The collagen fibers of bone, like those of tendons, have great tensile strength, where as the ca salts have great compressional strength. 205

206. PRECIPITATION AND ABSORPTION OF CA AND PHOSPHATE IN BONE –EQUILIBRIUM WITH THE ECFHYDROXYAPATITE DOES NOT PRECIPITATE IN ECF DESPITE SUPERSATURATION OF CA AND PH IONS. 206

207. MECHANISM OF BONE CALCIFICATIONCollagen molecules (collagen monomers) & ground substance (proteoglycans) by osteoblasts.Precipitation of ca in nonosseous tissues under abnormal conditions.207

208. CALCIUM EXCHANGE BETWEEN BONE & ECF BUFFERING MECHANISM OF CALCIUM 208

209. DEPOSITION & ABOSORPTION OF BONE-REMODELING OF BONEDeposition of bone by the osteoblasts. Absorption of bone- function of the osteoclasts.209

210. 210

211. 211

212. VITAMIN DHas a potent effect to increase caabsorption from the intestinal tract,also has important effects on both bone deposition & bone absorption. 212

213. 213

214. THE TERM VITAMIN D IS USED TO REFER TO A GROUP OF CLOSELY RELATED STEROLS PRODUCED BY THE ACTION OF UV LIGHT ON CERTAIN PROVITAMINS. 214

215. ACTIONS OF VITAMIN DThe active form of vit.D 1,25-dihydroxycholecalciferol,has several effects on the intestines,kidneys,& bones that increase absorption of ca & phosphate into ECF & contribute to feedback regulation of these substances. 215

216. HORMONAL EFFECTS OF VITAMIN D TO PROMOTE INTESTINAL CA ABSORPTIONOTHER EFFECTS OF 1,25-DIHYDROXYCHOLECALCEFEROL 1.FORMATION OF CA STIMULATED ATPase IN THE BRUSH BORDER OF THE EPITHELIAL CELLS.2.ALKALINE PHOSPHATASE IN THE EPITHELIAL CELLS. 216

217. VITAMIN D PROMOTES PHOSPHATE ABSORPTION BY THE INTESTINE 217

218. VITAMIN D DECREASES RENAL CALCIUM AND PHOSPHATE EXCRETION.218

219. EFFECT OF VITAMIN D ON BONE & ITS RELATION TO PTH ACTIVITYVITAMIN D PLAYS IMPORTANT ROLES IN BOTH BONE ABSORPTION & BONE DEPOSITION.VITAMIN D IN SMALL QUANTITIES PROMOTES BONE CALCIFICATION. 219

220. PARATHYROID HORMONEParathyroid hormone provides a powerful mechanism for controlling extracellular calcium & phosphate concentrations by regulating intestinal reabsorption,renal excretion,& exchange between the extracellular fluid & bone of these ions. 220

221. Excess activity of the parathyroid gland causes rapid absorption of calcium salts from the bones, with resultant hypercalcemia in the extracellular fluid; coversely, hypofunction of the parathyroid glands causes hypocalcemia, often with resultant tetany. 221

222. PHYSIOLOGICAL ANATOMY OF THE PARATHYROID GLANDSFOUR PARATHYROID GLANDS IN HUMANS.LOCATED IMMEDIATELY BEHIND THE THYROID GLAND-ONE BEHIND EACH OF THE UPPER & EACH OF THE LOWER POLES OF THE THYROID . 222

223. 223

224. CHEMISTRY OF PARATHYROID HORMONEIT IS SYNTHESIZED ON THE RIBOSOMES IN THE FORM OF A PREPROHORMONE.This is cleaved first to a prohormone then to the hormone itself with 84 amino acids by the endoplasmic reticulum & golgi apparatus,& finally packaged in secretory granules in the cytoplasm of the cells. 224

225. Effect of PTH on calcium & phosphate concentrations in the ECFThe rise in calcium concentrations is caused by two effects:(1) an effect of PTH to increase ca & phosphate absorption from the bone & (2) a rapid effect of PTH to decrease the excretion of ca by the kidneys. 225

226. PTH INCREASES CA & PHOSPHATE ABSORPTION FROM THE BONE PTH HAS TWO EFFECTS1.ACTIVATION OF OSTEOCYTES2. PROLIFERATION OF THE OSTEOCLASTSRAPID PHASE OF CA & PHOSPHATE ABSORPTION – OSTEOLYSISSLOW PHASE OF BONE ABSORPTION & CALCIUM PHOSPHATE RELEASE- ACTIVATION OF THE OSTEOCLASTS. 226

227. ACTIVATION OF THE OSTEOCLASTIC SYSTEM OCCURS IN TWO STAGES: 1) IMMEDIATE ACTIVATION OF THE OSTEOCLASTS THAT ARE ALREADY FORMED & 2)FORMATION OF NEW OSTEOCLASTSPTH DECREASES CALCIUM EXCRETION & INCREASES PHOSPHATE EXCRETION BY THE KIDNEYS. PTH INCREASES INTETINAL ABSORPTION OF CALCIUM & PHOSPHATE227

228. Cyclic adenosine monophosphate mediates the effects of parathyroid hormone .Camp responsile for osteoclastic secretion of enzymes & acids to cause bone resorption & formation of 1,25-dihydroxycholecalciferol in the kidneys. 228

229. CONTROL OF PARATHYROID SECRETION BY CALCIUM ION CONCENTRATIONEven the slightest decrease in ca ion concentration in ECF causes the parathyroid glands to increase their rate of secretion within minutes;if the decreased ca concentration persists, the glands will hypertrophy. 229

230. Conditions that increase the ca ion concentration above the normal cause decreased activity & reduced size of the parathyroid glands1) excess quantities of ca in the diet2) increased vit D in the diet & 3) bone absorption caused by factors other than PTH230

231. CALCITONINIS A PEPTIDE HORMONE SECRETED BY THE THYROID GLAND.Synthesis & secretion of calcitonin occur in The parafollicular cells, or C cells, lying in the interstital fluid between the folliclesOf the thyroid gland. Calcitonin is 32 amino acids peptide with MW 3400.231

232. CALCITONIN GENE RELATED PEPTIDE IS VASODILATOR AS WELL AS IT INCREASES CARDIAC CONTRACTILITY. 232

233. CALCITONIN LOWERS THE PLASMA CA CONCENTRATION BY APPOSING THE EFFECTS OF PTH IN THE BONES. 233

234. INCREASED PLASMA CA CONCENTRATION STIMULATES CALCITONIN SECRETION.CALCITONIN DECREASES PLASMA CA CONCENTRATION 1. The immediate effect is to decrease the absorptive activities of the osteoclasts & possibly the osteolytic effect of the osteocytic membrane throughout the bone. 234

235. 2.More prolonged effect of calcitonin is to decrease the formation of new osteoclasts.CALCITONIN HAS MINOR EFFECTS ON CALCIUM HANDLING IN THE KIDNEY TUBULES & THE INTESTINES. 235

236. CALCITONIN HAS A WEAK EFFECT ON PLASMA CALCIUM CONCENTRATION IN THE ADULT HUMANAny initial reduction of the ca ion concentration caused by calcitonin leads within hours to a powerful stimulation of PTH secretion,which almost overrides the calcitonin effect.In the adult,daily rates of absorption & deposition of ca are small 236

237. CONTROL OF CALCIUM ION CONCENTRATION Buffer function of the exchangeable calcium in bones - the first line of defence.Hormonal control of calcium ion concentration – the second line of defence.237

238. CALCITONIN IS USEFUL IN THE TREATMENT OF PAGET’S DISEASE 238

239. PATHOPHYSIOLOGY OF PARATHYROID HORMONE, VITAMINE D,& BONE DISEASEHypoparathyroidismWhen parathyroid glands do not secrete sufficient PTH, the osteocytic reabsorption of exchangeable calcium decreases & the osteoclasts become totally inactive.. 239

240. When parathyroid glands are suddenly removed, the ca level in the blood falls from the normal of 9.4 mg/dl to 6 to 7 mg/dl within 2 to 3 days.The usual signs of tetany develop. 240

241. TREATMENT OF HYPOPARATHYROIDISM PTH is occasionally used for treating hypoparathyroidism.Vit D 100,000 units per day, along with intake of 1 to 2 gms of ca.1,25-dihydroxycholecalcifrrol instead of the nonactivated form of vit D because of its much more potent & rapid action. 241

242. PRIMARY HYPERPARATHYROIDISMEXCESS PTH SECRETION CAUSE-TUMOR BONE DISEASE –multiple fractures of the weakened bones can result from only slight trauma.The cystic bone disease of hyperparathyroidism is called osteitis fibrosa cystica. 242

243. EFFECTS OF HYPERCALCEMIADepression of the CNS & PNS,muscle weakness, constipation, abdominal pain, peptic ulcer,lack of appetite,& depressed relaxation of the heart during diastole. 243

244. PARATHYROID POISONING & METASTATIC CALCIFICATION FORMATION OF KIDNEY STONES IN HYPERPARATHYROIDISM 244

245. SECONDARY HYPERPARATHYROIDISMHigh levels of PTH occur as a compensation for hypocalcemia rather than as a primary abnormality of the parathyroid glands.Secondary hyperparathyroidism can be caused by vitamin D deficiency or chronic renal disease in which the damaged kidneys are unable to produce sufficient amounts of the 245

246. Active form of vitamin D,1,25-dihydroxycholecalciferol.THE PLASMA CA LEVEL IS LOW IN CHRONIC RENAL DISEASE .TROUSSEAU’S SIGN246

247. FAMILIAL HYPOCALCIMIA & HYPERCALCIMIAMUTATION IN THE GENE FOR THE CA RECEPTORS CAUSE PERDICTABLE LONG TERM CHANGES IN PLASMA CALCIUM. 247

248. HYPERCALCIMIA OF MALIGNANCY248

249. RICKETS-VITAMIN D DEFICIENCYRickets occurs in children.CALCIUM & PHOSPHORUS DEFICENCY IN THE ECF,CAUSED BY LACK OF VITAMIN DIF THE CHILD IS EXPOSED TO SUNLIGHT, 7-DEHYDROCHOLESTEROL IN THE SKIN BECOMES ACTIVATED BY THE ULTRAVIOLET RAYS & FORMS VITAMIN D3RICKETS WEAKENS THE BONES. 249

250. TETANY IN RICKETS AS THE BLOOD CALCIUM LEVEL FALLS BELOW 7 mg/dl, THE USUAL SIGNS OF TETANY DEVELOP.TREATMENT-ADEQUATE CA & PHOSPHATE IN THE DIET & ADMINISTRATION OF LARGE AMOUNTS OF VITAMIN D. 250

251. OSTEOMALACIA- ADULT RICKETSDEFICIENCY OF BOTH VITAMIN D & CA OCCASIONALLY OCCUR AS A RESULT OF STEATORRHEA.OSTEOMALACIA & RICKETS CAUSED BY RENAL DISEASE CONGENITAL HYPOPHOSPHATEMIA-VITAMIN D-RESISTANT RICKETS. 251

252. OSTEOPOROSIS- decreased bone matrixTHE OSTEOBLASTIC ACTIVITY IN THE BONE IS LESS THAN NORMAL,THE RATE OF BONE OSTEOID DEPOSITION IS DEPRESSED.CAUSES 1) lack of physical stress on the bones because of inactivity;2) malnutrition 3) lack of vitamin c 4) postmenopausal lack of estrogen secretion 5) old age 6)cushing’s syndrome. 252

253. 1Receptors for protein hormones are presents(a)in the cell nucleus(b)in the cell cytoplasm(c)in or on the surface of the cell membrane(d) all of the above 253

254. 2. Chemical substances produced by endocrine glands having their effect on distant target organs are called(a)hormones (b)vitamins (c)enzymes(c)lipids 254

255. 3.Parafollicular cells of the thyroid produce(a)T4 hormone (b) T3 hormone (C) Calcitonin (d) calcium4.Thyroperoxidase enzymes facilitates(a) Iodide trapping(b)Iodide binding(c)oxidation of iodide(d) Iodide coupling 255

256. 5.Myxedema means thyroid deficiency at(a)any age (b)childhood (c)young age (d) adults6.Serum calcium concentration normally is(a)5-10 mg% (b)9-11mg% (c)10-15mg% (d)1-4mg% 256

257. 7.Tetany develops when there is (a)decrease serum ca level(b)decrease protein bound serum ca level(c)increase serum ca level(d)increase serum phosphate level8.Hypercalcemia causes(a)CNS depession(b)CNS excitation(c)CNS irritable(d) all of the above 257

258. 9.Aldosterone is secreted by the (a)zona glomerulosa(b)zona reticularis(c)zona fasciculata(d)leydig cell10.cortisol(a)raises blood sugar level(b)lowers blood sugar level(c)has no effects on blood sugar level(d)all of the above 258

259. 11.Beta cells of islet of langerhans secret(a)insulin (b)glucagon (C)pancreatic polypeptide(d)somatomedin12.NIDDM means(a)lack of insulin is there(b)insulin resistance is there(c)increase insulin level(d)all of the above 259

260. 13.Which of the following is not essential for normal biosynthesis of thyroid hormone(a)ferritin (b)iodine (c)thyroglobulin(d)TSH14.Increasing intracellular iodideduo to the action of sodium-iodidesymporter is an example of(a)endocytosis (b)secondary active transport (c)passive diffusion(D) primary active transport 260

261. 15 insulin increases the entry of glucose into(a)renal tubular cells (b)the mucosa of the small intestine(C)most neurons in the cerebral cortex(d)skeletal muscle 261

262. 16.Thyroglobulin is a(a) glycoprotein (b)steroid(C)carbohydrate (d) glycolipidDecreased secretion of growth hormone(a)cretinism (b) dwarfism (c)acromegaly (d)gigantism 262

263. 18.Diabetes insipidus occurs duo to deficiency of (a)growth hormone (b) insulin (c)ADH (D)thyroxineIncreased secretion of growth hormone before puberty(a)cretinism (b) dwrfism (c)acromegaly (d)gigantism 263

264. 20. Hormones which have effect on the adjacent cells are called(a) classical hormones(b)neurohormones(c)paracrine hormones(d)autocrine hormones 264

265. ASSESMENT OF CARDIOVASCULAR AUTONOMIC FUNCTION TESTS IN HYPERTENSIVE PATIENTS BY DR. VAISHALI PATIL ASST.PROF DEPT OF PHYSIOLOGYRURAL MEDICAL COLLEGE, LONI 265

266. INRODUCTION Hypertension is a very common abnormality in humans. It can be produced by many diseases. It causes a number of serious disorders. Autonomic neuropathy affects 10 -40% of hypertensive patients . A Strong association found in cardiovascular autonomic dysfunction in hypertensive patients.266

267. AIMS & OBJECTIVESThe present study is aimed to diagnose & identify the autonomic dysfunction in the patients of hypertension with duration of 10 -15 yrs with or without complications.Cardiovascular autonomic function tests for sympathetic nervous system1. Pulse rate 2. postural hypotension3. sustained handgrip267

268. MATERIALS AND METHODSFor the present study 30 patients will be selected. Study period will be from jan 20010 to Aug 20010.The following parameters will be noted in each patients.Pulse by palpatory method for one minute.Blood pressure will be recorded by computerised CANWIN instrument (Genesis of medical system Pvt.Ltd. Hydrabad) Windows based cardiac Autonomic Neuropathy Analyser. 268

269. ANALYSIS The parameters of autonomic functions will be studied & compared with duration of hypertension. 269

270. OBSERVATIONS & RESULTSAll the observations obtained will be presented in tabular forms & analysis of data will be done by applying suitable statistical test to obtain the result. 270

271. REFERENCES1.Ewing DJ (1978): cardiovascular reflexes & autonomic neuropathy. Clin.sci.Mol.Med.,55,321-327.2.Lloyd Mostyn RH & Watkins PJ (1975) : Defective innervation of heart in autonomic neuropathy.Br.Med.J.,3,15-17.3.Friedberg C.k.,(1966): The heart in hypertension & renal diseases. In diseases of the heart.3rd Edn.Publisher W.B.Saunders Co. 1968; pp.1474-1527271

272. 4.Verrir R. L.Hagested E.L. Role of the autonomic nervous system in sudden death .In cardiovascular clinics,15/3 sudden cardiac death.Ed.Josephson M.E. publisher F.A.Davis company 1985;pp.41-64.5.Ziegler M.G.;Posyural hypotension. In annual review of medicine 1980; 31:239-245. 272

273. THANK YOU273