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by: Charles Kohler


Charles Kohler
GPA 3.94

W. Stickle

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W. Stickle
Class Notes
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This 70 page Class Notes was uploaded by Charles Kohler on Tuesday October 13, 2015. The Class Notes belongs to BIOL 2160 at Louisiana State University taught by W. Stickle in Fall. Since its upload, it has received 12 views. For similar materials see /class/222829/biol-2160-louisiana-state-university in Biological Sciences at Louisiana State University.

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Date Created: 10/13/15
Control of Homeostatic Functions of the Body Nervous System controls rapid activities of the body Endocrine System Principally regulates the metabolic functions of the body Definition of a hormone Chemical Classification of Hormones Mechanism of Hormone Action Use second messengers Activate gene transcription Specific Endocrine Glands and Cells and Their Physiology Glands 0 Cells Cytokines Prostaglandins The Endocrine System Controls metabolic functions of the body Rates of chemical reactions Transport of substances across cell membranes Growth and secretion Hormone a chemical substance that is secreted into body fluids by one cell or a group of cells that exert a physiological control effect on other cells of the body Chemical Classification of Hormones Amines derived from the amino acids tyrosine and tryptophan epinephrine thyroxine Polypeptides and proteins Polypeptides generally contain lt 100 amino acids antidiuretic hormone Protein gt 100 amino acids growth hormone Glycoproteins consist of a protein bound to one or more carbohydrate groups FSH LH Steroids Derived from cholesterol testosterone estradiol etc See Table 111 112 p 299300 Mechanisms of Hormone Action Hydrophilic hormones use a second messenger system that activates existing enzymes Adenylate cyclase CAMP system Phospholipase CCa system Tyrosine Kinase system Amplification see slide Hydrophobic hormones use nuclear receptor proteins that activate genes Steroid Hormones Thyroxine and triiodothyronine Adenylate CyclasecAMP Mediates effects of many polypeptide amp glycoprotein hormones Hormone binds to receptor causing dissociation of a Gprotein subunit u anpyngmah 39 Inc 39 display I 7 2 H 739 r 7 j quoti 4 Phospho Actiyation of speci c enzymes proteins Inactivation of specific enzymes 11 25 Adenylate CyclasecAMP Gprotein subunit binds to amp activates adenylate cyclase Which converts ATP into cAMP cAMP attaches to inhibitory subunit of protein kinase Phospho I f proteins Activation Of lna ctivation of specmc enzymes specific enzymes 11 26 Adenylate CyclasecAMP Inhibitory subunit dissociates activating protein kinase Which phosphorylates enzymes that produce hormone s effects cAMP inactivated by phosphodiesterase cupyughl a quot Phospho proteins Activation of Inactivation of speCIfIc enzymes specific enzymes 11 27 PhospholipaseCCa2 Serves as 2nd messenger system for some hormones Hormone binds to surface receptor activates G protein which activates phospholipase C eproteins Ca2 Cazquot H Endoplasmic reticulum 11 28 PhospholipaseCCa2 Phospholipase C splits a membrane phospholipid into 2nd messengers E3 amp DAG o IP3 diffuses through cytoplasm to ER Causing Ca2 channels to open an ilIllhg Dow 0o I 439 n alumniw h 39 my jitllyi i 5 1quot Gprotelns Ca2 poi s Endoplasmic 39 reticulum 11 29 PhospholipaseCCa2 Ca2 diffuses into cytoplasm amp binds to amp activates calmodulin Ca2Camoduin activates protein kinases which phosphorylate enzymes that produce hormone39s effects 11 30 Copynghl Ele IchrnuHlal Companms Inc Pum Liver cell Iuinn mainland for pmdumber or Him 591339 7 denyi5i39 E dfenerg c cyclase Active Eff 810f ATP retain epineph mi 7 7 7 mass Ca2 Glycogen xquot W xixf Alpha 7 Active protein A adrenergic kmnfse effect of Gluca e1 TV g epinephrine phosphate L m CE2 Glucose 6 Free glucosea r phosphata 1131 Tyrosine Kinase 2nd Messenger System ls used by insulin amp many growth factors to cause cellular effects Surface receptor is tyrosine kinase Consists of 2 units that form active dimer when insulin Binuling to Dimerization receptor binds proteins Cytoplasm 11 32 Tyrosine Kinase 2nd Messenger System Activated tyrosine kinase phosphorylates signaling molecules that induce hormonegrowth factor effects l H 394 dl Phosphorylation Phospvhnrylation of at receptur signal molecules Tyrosine Cascade of effects 339 0W Glucose uptake and acuve anabolic reactions 11 33 1 Amplification I through G OSFmo A 39fi Adenylate cyclase 2 Amplification MDT 0 CAMP I T l 3 Protein kinase A 4 Ampli cation 39 a Phosphorylase kinase 5 Amplificaiion Phosphorylasea 6 Amplification Glucose 1 phosphata ades greatly amplify hormone action In the pathway ofhor cading afamplifying steps in the form of r lll Km 11 ll39l Lipophilic Hormones Activate Genes Steroid Hormones Thyroxine Hormones That Bind to Nuclear Receptor Proteins Lipid hormones travel in blood attached to carrier proteins They dissociate from carriers to pass thru plasma membrane of target Receptors are called nuclear hormone receptors Fig 114 Copyrigmb39 In 39 A 39 my i l mRNA Receptor l 3 M protein Protelnx synthesis f 1 g a Steron 0 hormq 6 response K iTa r e t cell Blood 11 18 Nuclear Hormone Receptors Serve as transcription factors when bound to hormone ligands Activate transcription Constitute a quotsuperfamilyquot composed of steroid family amp thyroid hormone family which includes vitamin D amp retinoic acid 11 19 Metabolic Pathways for Hormone Synthesis gamma thwmwmnm um w lawman aquot 7 Corpus HZOH secreted lluteum 0 co 4 ycorpus A Ho OH I teum of g ovaries Cortisol hydrocortisone Secretedgy adrenal cortex Follicles in CH3 Fig 112 Mx39 C 0 HOP7 1 o l Pegnenolone Cholesterol H3 Adrenal rogesteggl 390 0 cortex w 39 vary 3 a Androstenedione 0H 0 Ti Secreted by Leydlg ells 0 E5393 r Spermatic lnterstitial cord I I L Secret d by follicles of 0v Q Teg is sem39quot iferous 39 tubules estoslerone Ovary Ho MVE N w 1 01 O Aldosterone is a lipidsoluble hormone and can easily diffuse through the plasma membrane Aldosterone once inside of the cell binds with an aldosterone receptor molecule in the cytoplasm The aldosterone receptor complex moves into the nucleus and binds to DNA The binding of the aldosteronereceptor complex to DNA stimulates the synthesis of messenger RNA mRNA which codes for specific proteins The mRNA leaves the nucleus passes into the cytoplasm of the cell and binds to ribosomes where it directs the synthesis of the specific proteins The proteins synthesized on the ribosomes produce the response of the cell to aldosterone 39Plasma membrane Aldosterone I Aldosterone Aldosterone receptor Nuclear membrane Proteins produce a response Chemical Classification of Hormones d Steroid amp thyroid hormones are lipids Can diffuse into target cells The 2 major thyroid hormones are shown in Fig 113 I I NH2 0 7 HO O CHgCHC OH I I Thyroxine or tetraiodothyronine T4 I I NH 2 O l H0 0 CH2CHC OH I Triiodothyronine T3 11 9 Mechanism of Thyroid Hormone Action Thyroid secretes 90 T4 thyroxine amp 10 T3 9996 of T4 in blood is bound to carrier protein thyroid binding globulin TBG Only free can enter cells so bound is reservoir T4 converted to T3 inside cell T3 binds to receptor protein located in nucleus 1122 Mechanism of Thyroid Hormone Action ea T3 amp receptor bind tc Rm 39 t TR 1 half Slte I I qsr freci tor Other halfSite binds r3336 triiodothymmne retinoic acid Two partners form heterodimer that Dimeriza on activates HRE 9cis R t Stimulates eaggIc D E Tmodothyronlne transcription of target gene JENKI 1 t Hormone Genetic response transcription element LmRNA Fig 117 1123 Specific Endocrine Glands Pituitary or hypophysis Thyroid Parathyroids Thymus Adrenals Pancreas Gastrointestinal tract cells Gonads Placental Hormones Endocrine Glands Are ductless amp secrete hormones into i pituitary bloodstream g39and Hormones go to target quot cells that contain receptor proteins for it Neurohormones are Adm 339 9mquotd secreted into blood by Pancreas specialized neurons Ovary Hormones affect Fig 111 metabolism of targets a 3 Te 11 4 The Pituitary Gland Master gland hormones mainly influence other endocrine glands physiology and secretion Anatomy and embryology Neural source downgrowth of the floor of the thalamus called the infundibulum neurohypophysis or the posterior lobe Ectoderm of the primitive oral cavity anterior and intermediate lobe fetus only adenohypophysis and pars intermedia Blood supply of the anterior and intermediate lobe is independent of that of the brain proper hypothalamic hypophyseal portal system Releasing factors are released from cells of the hypothalamus and travel in the hypothalamichypophyseal portal system to control release of hormones from the adenohypophysis Cells from the former intermediate lobe pars intermedia mingle with those of the anterior lobe and secrete melanocyte stimulating hormone insignificant amounts in man Pituitary Gland Pituitary gland is located beneath hypothalamus at base of forebrain Hypotnalamus Pi tuitar gland y 11 35 Pituitary Gland ls structurally amp functionally divided into anterior amp posterior lobes Hangs below hypothalamus by infundibulum Anterior produces own Optic chiasma hormones frateriolrlobeh Controlled b a quot Vp p 539 hypothalam gs Pars tuberalis lnfund39bumm Pars distalis PosterIor stores amp releases hormones made in hypothalamus Posterior lobe neurohypophysis Fig 1112 1136 Hormones of the Posterior Pituitary Releases two neurohormones which are produced in the hypothalamus and released from axonal ends in the posterior lobe Sup39raoptic nucleus gt antidiuretic hormone ADH arginine vasopressin Promotes the reabsorption of water from the collecting ducts by 39 D inserting aquaporln channels in the C High doses vasoconstriction of vascular beds Paraventricular nucleus gtOxytocin 5 stimulates uterine contractions during labor childbirth s postpartum stimulates contractions of the mammary gland alveoli and ducts which results in the milk ejection reflex in lactating women 839s rise in secretion at the time of ejaculation significance Release is controlled by neuroendocrine reflexes ADH Release stimulated by osmoreceptor neurons in hypothalamus Inhibited release by stretch receptors in left atrium Oxytocin Released by suckling reflex Hypothalamic Control of Posterior Pituitary Supraoptic nucleiof hypothalamus produce ADH Paraventricular nuclei produce oxytocin Both transported along hypothalamo hypophyseal tract to posterior pituitary Release controlled in hypothalamus by neuroendocrine reflexes Fig1113 Paraventricular nucleus Supraoptic nucleus Optic chiasma lnfundibulum Hypothalamo hypophyseal tract Anterior Posterior pituitary pituitary 11 44 Anterior Pituitary Release of anterior pituitary hormones is controlled by hypothalamic releasing amp inhibitinq factors Table 117 amp by feedback from levels of target gland hormones 1139 Anterior Pituitary Releasing ampinhibiting hormones from hypothalamus are released from axon Axonstoprmary endings into capillary caPi39larieS bed in median i eminence Primary ma capillaries Carried by hypothalamo hVDOthsealponal system directly to Secondary another capillary bed in capillaries 39 A Pit Anterior Diffuse into A Pit amp P39m39mry regulate secretion of its hormones Fig 1115 Cell body Posterior pituitary 11 40 Anterior Pituitary Secretes 6 trophic hormones that maintain size of targets High blood levels cause target to hypertrophy Low levels cause atrophy Copynghlb quotquot 39 JnLquot 39 39 39 mu 7 display Paraventricular nucleus Supraoptic nucleus Median eminence Hypothalamus Portal system A Anterior pituitary J IOMh l mane II F n Gonado tropins M l Ad 1137 Feedback Control of Anterior Pituitary Involves short feedback oog in which retrograde flow of blood amp hormones from A Pit to hypothalamus inhibits secretion of releasing hormone Involves negative feedback of target gland hormones amp during menstrual cycle estrogen stimulates LH surge by positive feedback Wmquot 39 39 rm quotquotquotquot quot Hypothalamus Fig 1117 I Gona39 atropin releasing hormone iNegative Gn H feedback 1 Anterior 9 l P39tu39tary Negative 1 1 feedback Gonadotro ins 39 Inhibits FSH and H 39quoth39b39ts secretion respontsteness Of GinRH Gonads GnFlH L Sex steroid 3 hormones estrogens and androgens 11 41 Higher Brain Function amp Anterior Pituitary Secretion Hypothalamus receives input from higher brain centers that can affect anterior pituitary secretion Eg psychological stress affects circadian rhythms menstrual cycle amp adrenal hormones 11 42 Pineal Gland s located in I basal forebrain Flg 1132 near thalamus Secretes melatonin in Day 1 response to Inhibition activity of suprachiasmatic Night 39 balm i39 St I t oi i Su erior cerVIcal nUCIGUS Of lmual g tgagglion Suprachias atic nucleus hypothalamus the quotbiological clock 11 66 Pineal Gland SCN is primary timing center for circadian rhythms Reset by daily lightdark changes Melatonin is involved in aligning physiology with sleepwake cycle amp seasons Secreted at night amp is inhibited by light Inhibits GnRH antigonadotropic in many animals 1167 The Thyroid Gland Located in the neck near the junction of the larynx and trachea Structural unit alveolus or follicle filled with colloid store for thyroxine or triiodothyronine in combination with thyroglobulin Primary calorigenic action Release controlled by the circulating level of TSH Abnormalities Hyperthyroidism Hypothyroidism goiter Thyroid Gland ls located just below the larynx Secretes T4 amp T3 which set BMR amp are needed for growth development Fig 1121 Cricoid cartilage of larynx Thyroid gland a 11 52 Production of Thyroid Hormones Iodide l39 in blood is actively transported into follicles amp secreted into colloid Where it is oxidized to iodine l2 amp attached to tyrosines of W A large storage molecule for T4 amp T3 TSH stimulates hydrolysis of T4 amp T35 from thyroglobulin amp then secretion Blood plasma I m Thyroid follicle Iodide in plasm Thyroid uptake of iodide Plasma 139 carria protein Thyroid hormone secretion lm h Fig 1123 11 54 Diseases of the Thyroid Goiter In absence of sufficient dietary iodide T4 amp T3 cannot be made amp levels are low Low T4 amp T3 don t provide negative feedback amp TSH levels 90 UP Because TSH is a trophic hormone thyroid gland grows Resulting in a goiter Normal thyroid If iodine l If iodine Low inadequate T3 adequate T3 and T4 and Low negative feedback T4 Excess TSH Growth goiter Hypertrophy produces goiter Negative feedback Fig 1125 1155 Diseases of the Thyroid Hyperthyroidism Goiters are also produced by Grave39s disease Autoimmune disease where antibodies act like TSH amp stimulate thyroid gland to grow amp oversecrete hyperthyroidism Characterized by exopthalmos weight loss heat intolerance irritability high BMR 1157 Diseases of the Thyroid Hypothyroidism People with inadequate T4 amp T3 levels are hypothyroid Have low BMR weight gain lethargy cold intolerance amp myxedema puffy face hands feet During fetal development hypothyroidism can cause cretenism severe mental retardation 1156 CayyrighmThnMcGImHln cmam InmPalmlsalan unqmmrnmpmmcunn urdlmlay Table 1 LB Comparison of Hypothyroidism and Hyperthyroidism Feature Hypothymld Hypar vymld Growm and dm cpmm mam gmwvh Auc emmd gm Am vkyan sup mmnmed 5129p harmed mm decreased sweep Tempmwre meme mmm 2 mm nmlmnm m m Skin mama s Cmmry skin Norm skin Periviradon AMEN Excesw ve N5 Shaw Raw Rb exes srow Rapid Psycnulugm 15pm Depress on ma my Nervvu emulnmquot Sm Phil T lmk Damned Increased 11758 Calcitonin Secreted by the Parafollicular C cells in Thyroid Gland It works in concert with parathyroid hormone and Vitamin D3 to regulate the calcium level of the blood Lowers blood calcium level by inhibiting the dissolution of calcium phosphate crystals of bone by inhibiting the activity of osteoclasts Lowers blood calcium level by inhibiting the reabsorption of calcium and phosphate in the nephrons Physiological significance of calcitonin in adults is not understood Parathyroid Glands Yellowbrown ovoid bodies 4 connected to the posterior surface of the thyroid gland 00530gm Secrete parathyroid hormone parathormone PTH Primary function of parathormone appears to be the proper maintenance of the calcium phosphorous ratio in the blood and tissues Parathormone influences calcium metabolism in three ways Increases calcium absorption from the intestinal tract Increases calcium mobilization from bone Increases calcium reabsorption from the kidneys Parathyroid Glands Are 4 glands Flg 1128 embedded In lateral lobes of thyroid gland Secrete Parathyroid hormone PTH Pharynx Thyroid gland Parathyroid Most important glands hormone for control of blood Ca2 levels Esophagus Trachea 11 59 Parathyroid Hormone oopyn39gm o The alpaca lnr ruprom uon or display Ca2 39 i Release stimulated by decreased blood Ca2 Parathyroid Acts on bones kidney Jimmie amp intestines to increase blood Ca2 levels Heabsorion Dissolution oli of Ca CaPO4 crystals Negative Increased feeglggck blood Ca2 Decreasi ci urinary Fig 1129 excretion of Ca2 1160 The Thymus Gland Two elongated flask shaped lobes which occupy a region above the heart and between the lungs Divided into lobules of medullary and cortical tissue Prominent at birth grows until puberty then regresses to fat and connective tissue Abnormalities associated with Myasthenia gravis and several other diseases Thymus Cupy ght em McerwHil Companies Inc Permission required for reproduction or display ls located around trachea below thyroid Produces T cells of immune system amp hormones that stimulate them Pe cardlum Heart W 11 68 The Thymus Gland Seeds lymph nodes with activated t lymphocytes late in fetal life Secretes several immune system hormones Thymopoietin l and Thymopoietin lI promote the transformation of lymphocytes into T cells Thymosin may promote the maturation of T lymphocytes Acquired Immune Deficiency Syndrome Caused by the virus Human Immunode ciency Virus Has increased the overall adult mortality rate in the US in men by 07 and in women by 007 Much more deadly in Africa People at high risk for acquiring AIDS include Homosexual and bisexual men IV drug users People who received a blood transfusion prior to 1985 Women who have had sexual relations with men at high risk Haiti and Central Africa Children infected in utero by women with the virus Acquired Immune Deficiency Syndrome Laboratory tests for the severity of the AIDS syndrome include counting the number of Helper to Suppressor T cells by counting antigens on their surface Helper T cells T4 antigen Suppressor and Cytotoxic T cells T8 antigen Normal person T4IT8 antigen ratio gt 1 Person with AIDS T4IT8 antigen ratio 05 or lower Causes reduced immunological function and increased susceptibility to opportunistic infections such as Pneumocystis carinii pneumonia Kaposi s sarcoma rare form of cancer Treatment cocktail of expensive drugs which maintain immune function The Adrenal Glands Two pyramid shaped structures lying close to the upper pole of each kidney Composed of two functionally distinct regions Medulla central region cells derived from cells that embryologically split off from the neural crest Cortex surrounding zone of tissue 89 times larger than the medulla derived from cells that also gave rise to the gonads steroid hormones Medulla secretes two hormones gt numerous physiological effects Epinephrine Norepinephrine Ratio 41 Controlled by the sympathetic branch of the autonomic nervous system Adrenal Glands Sit on top of kidneys Each consists of outer cortex amp inner Copyrighl a 39 Adrenal glan Kidney 7 Adrenal Qonnective 39 1 cortex tlssue quot 71 Adrenal caPSU39e medulla 1 1 Z medUIIa g a erulosaI Y 2arise 20m Adrenal dlfferently fasc39cu39ata cortex during Zona 39 development reticularls Adrenal medulla Fig 1118 11 46 Adrenal Medulla Hormonal effects of Epinephrine last 10X longer than Norepinephrine Innervated by preganglionic Sympathetic fibers Activated during quotfight or flightquot response Causes Increased respiratory rate Increased HR amp cardiac output General vasoconstriction which increases venous return Glycogenolysis amp lipolysis 11 49 The Adrenal Glands Adrenal cortex gt corticosteroids Necessary for life Produces steroid hormones At least 28 different hormones divided into three functional groups Androgens cause masculinizing effects Glucocorticoids affect metabolism Mineralocorticoids Aldosterone control electrolyte balance of Na Cl39 and K Controlled by ACTH from the adenohypophysis Ad renal Cortex Zona Zona fasciculala and Fig 3919 glomerulosa 39 zona reticularls Cholesterol Dehydroepianl Pregnenolone r dlktbs ggye Progesterone I Andrpstem Deoxy edlon39e corticosterone 39 Other Cortlcosterone androgens Aldosterone u m Mineralo WV Glucocorticoids corticonds Sex steroids 11748 Stress amp the Adrenal Gland Stress induces a 39 quot v W nonspecific Nonspecmc Stress braiwgg ters response called general adaptation syndrome GAS Causes ACTH amp i cortisol release 5 9 l Often affects TCmtisol 5323 physiology negatively 1 tACTH Fig 1120 1150 Pancreas Behind stomach Exocrine gt digestive enzymes and HCO3 Endocrine gt Islets of Langerhans gtinsulin and glucagon Insulin involved in carbohydrate metabolism Released from 3 cells by elevated blood glucose Tyrosine Kinase second messenger system Stimulates facilitated diffusion of glucose into cells via Glut transporters into the cell membrane Increases the conversion of glucose to glycogen in the liver and muscle Increases the oxidation of glucose by tissues Increases the conversion of carbohydrate to fat and protein Islets of Langerhans Are scattered clusters of endocrine cells in pancreas Contain alpha amp beta cells Pancreatic islet of Langerhans r l Beta l cell Gallbladder forta Celiac N ha Common 39 artery i cel bile duct 4 Flg 1130 Tail of pancreas Duodenum 11 62 Islets of Langerhans Betas secrete insulin in response to high blood glucose Promotes entry of glucose into cells amp conversion of glucose into glycogen amp fat Decreases blood glucose Glucose anpyngmequot H 39 lnc 39 39 umprmmunerdispm 3 cells in pancreavc islets r Insulin i secretion iCellula1 uptake of blood glucose Glu ose Triglyceride Fig 1 1 31 Liver and Adipose skeletal muscle tissue 1164 Islets of Langerhans Alphas cells secrete glucagon in response to low blood glucose Stimulates qlvcoqenolvsis amp lipolvsis Increases blood glucose 1163 Sex amp Reproductive Hormones Gonads testes amp ovaries secrete steroid hormones testosterone estrogen amp progesterone Under the control of LH and FSH Placenta secretes estrogen progesterone hCG and somatomammotropin 1169 Gastrointestinal Tract Hormones Stomach Gastrin Adipose tissue Leptin Intestine Secretin Cholecystokinin CCK Gastric inhibitory peptide Enterocrinin Guanylin Kidney Hormones Juxtaglomerular apparatus gt Renin angiotensin system Erythropoietin Heart Hormones Atrial natiuretic peptide Autocrine and Paracrine Regulation Table 119 p 309 Autocrine regulators are produced amp act within same tissue of an organ All autocrines control gene expression in target cells Paracrine regulators are autocrines that are produced within one tissue amp act on different tissue in same organ Autocrines amp paracrines include Cytokines Iymphokines interleukins Growth factors promote growth amp cell division Neutrophins provides trophic support for normal amp regenerating neurons 11 71 Prostaglandins PGs Are produced in almost every organ Belong to eicosanoid family all derived from arachidonic acid of cell membrane l Phospholipids 0t plasma membrane Fig 1134 Arachidonic acid 600 lipoxvgenase 1 I ijclooxygenase iPGG 39 39quot amma mquot Antiplatelet Smooth Smooth platelet BFDHCHOCODsgfICtIO aggregation muscle uscle vasoconeulctlon relaxation contraction capmary permeab39my Vasodilatian Vasodilation Vasoconstriction Vasnconsb39iction aggregation 1172 Prostaglandins PGs Have wide variety of functions Different PGs may exert antagonistic effects in ssues Some promote smooth muscle contraction amp some relaxation Some promote clotting some inhibit Promotes inflammatory process of immune system Plays role in ovulation Inhibits gastric secretion in digestive system 1173 Prostaglandins PGs Cvclooxv0enase COX 1 amp 2 are involved in PG synthesis Fig 1134 Are targets of a number of inhibitory nonsteroidal anti inflammatory drugs NSAIDs Aspirin indomethacin ibuprofen inhibit both COX 1 amp 2 thereby producing side effects Celebrex amp Vioxx only inhibit COX 2 amp thus have fewer side effects 11 74


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