Endocrine pharmacology (3)
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1 بسم رلا هللا Endocrine pharmacology (3) Natural hormone characterized by short of action : a lot of them ineffective orally ( for example ), but when we give it from outside it enters the body exactly in the same way as naturally secreted hormone in your body. ** Endocrine system : - uses chemical signals for cell to cell communication - Coordinates the function of cells - Response to an endocrine signal occurs usually within minutes to hours ( the action of the hormone is immediate : very quick ) Glands where the hormone is synthesis known as ductless gland so their product are secreted immediately into the blood stream following this secretion usually it is carried to somewhere else by definition its mean : hormone synthesis in a place and acts in another place this is the major difference between the hormone and the neurotransmitter neurotransmitter usually they are senthysis in a place and they release there and they act there and even metabolize there. ** Hormones : Cell to cell communication molecule They are made in glands or cells. And Transported by blood to distant ( or site ehich is faraway from the site they are senthysed ) or to local target tissue receptors and then activates physiological response. - once the hormone reches the target cell it will interact with specific receptor if the receptor are not there : no response (specific )
2 ** Hormonal regulation : regulation up and down ( could be activating or inhibitory ) increase the response or decrease it a lot of people think that its stimulatory in nature but it could be inhibitory e.g prolactin release is inhibited by dopamine. ( hypothalamic hormone usually they stimulate other hormone from anterior pituitary gland ) ** hormonal regulation is essential 1- for growth and development : * Growth hormone deficiency results in dowarfism * thyroid hormone deficiency results in hypothyroidism 2- very important in reproduction, fertility, sexual function In addition, they play important role in pregnancy and menstrual cycle. 3- response to environmental situations (particlarly stress) especially hormones like cortisol : (( In stress states, the sympathetic system has the major role, and it affects the cortisol secretions from adrenals, so if the cortisol level in the body has been disturbed for any reason this will lead to adrenal insufficiency then immediate death )) clinical significance : patient on steroid therapy ( cortisol therapy ), if you stopped it suddenly and the paitent faces minor stress can lead to severe consequences including death. 4- maintenance of normal homeostasis : Regulation of glucose level by insulin and glucagons, and electrolytes concentrations in the ECF (Na and K ions.) - (maintenance Normal composition of extra cellular fluid ) Parathyroid hormone is essential for calcium metabolism. Aldosteron is essential for sodium.
3 ** Chemical Nature of Hormones : 1-amino acid derivatives: such as thyroid ( T3, T4 ) and dopamine which are tyrosine derivatives. ( dopamine major hormone that regulates prolactin synthesis and release from anterior pituitary ) Another class of hormone : small peptide, polypeptides, large protein or even complex glycoprotiens ( polypeptides binding sugar ) : alpha, beta subunits ( LH, TSH, FSH ) : first we have to know that genes of alpha and beta are Different. by synthesis of mrna we will get the alpha protein and beta protein then by glycosylation "adding sugars" and combine the 2 subunits we get the whole hormone. making alpha and beta glycoprotein and combine them together and stored in storage vesicles ready to be released into the blood. 2- steroids : are synthesized from cholesterol which is a 4 ring- structure (A,B.C, D )with side chain. cortisol, aldosterone, estrogen, progesterone, testosterone, androgen belong to this family. ( they are all have steroidal nucleus ). 3- amine hormones : Derived from the amino acid tyrosine. Include thyroid hormone and catecholeamines ( dopamine synthesized in the CNS ) Stored in specific vesicles before being released in the blood stream. dopamine usually interacts with surface membrane receptors ( presents on plasma membrane). - whereas T3 T4 interact with nuclear receptor. - There is a defferince between dopamine and thyroid hormone with the location of their receptors.
4 4- Protein and Polypeptide Hormones : proteins are usually synthesized from larger precursors this is important clinically: in the beginning, how proteins are synthesized? many from larger precursors in ER ( endoplasmic reteiulum ) pre-prohormone concept is thus introduced this is cleaved in Golgi apparatus in Golgi apparatus broken down into hormone and other substances then stored in specific vesicles before being released. storage vs release : we have synthetic machinery, after synthesis hormones are stored in specific vesicles before being released. we are talking about two pools : storage pools and releasable pool the first pool be affected by whatever stimulus or an inhibitor or by another hormone. ( hormone which regulate another hormone is known as traffic hormone ) The first process to be affected by specific stimulus / inhibitor is the releasable pool and its quick. The action of the hormone is quick therefore you need quick response to the hormone. even following the action of hormones, the hormone action is terminated very quickly: therefore you need quick response regulators we have highly regulated mechanisms of these processes therefore the first to be affected is the releasable pool synthesis always takes time, especially with proteins (DNA / RNA synthesis) but don't underestimate the synthetic machinery suppose that you have a condition of excess production of a specific Hormone the condition will affecting endocrine cell o disease could lead to excess production of specific hormone are adenomas. o How do treat condition charictirized with excess production? o Starting with inhibiting synthesis or releasing or by using blocker/antagonists fo specific receptor. In states of deficiency you can use a specific agonist or promote synthesis Deficiencies begin with storage depletion. Drugs therefore act on hormones that already synthesized :the stored hormone. Anti thyroid drugs don't have a lot of onset of action they start acting after the depletion of the synthesized hormone. This is important clinically.
5 So If you want a quick response either you use something which inhibit synthesis or block receptor by specific antagonist. ** Many hormone are originated from large precursors. can you use this precursor in management of certain states of deficiencies? Is there clinical application? Yes, They can enter blood stream and can be cleaved into the active hormones Pro-insulin, precursor is responsive whereas the insulin creates no response Protein and Polypeptide Hormone Receptors ( membrane receptors ) : there are many different types of interactions of proteins with there specific receptors but the binding of the receptor eventually leads to the physiological response. o certain hormones interact with the receptors and they are coupled with G proteins o G protein transfers signal o they either open ion channels or stimulate production of second messengers o this second messenger usually mediate the action of the hormone o could you pinpoint a hormone that is stimulated by a second messenger? o other types of interaction: activation of tyrosine kinases (like insulin) which transduct the signal to produce biological response o how could you prove whether or not a specific hormone is mediated through a second messenger? o If we take ( CRH-ACTH- Cortisol) Axis CRH, hypothalamic hormone interacts with ACTH on the surface of the anterior pituitary therefore increasing synthesis of cortisol CRH: interacts with specific receptors coupled by adenlyl cyclase... camp mediates its effect [CRH's] you can examine the anterior pituitary treat some cells with the hormone with CRH and treat the others with different second messengers including camp, GAMP, etc. take a sample form the media ( pool )to measure the response: you measure ACTH... the final reponse: you find camp produces same exact amount of ACTH as compared to CRH you can draw conclusions of the response.
6 ** Steroid hormones : debate: some people say they act on receptors present on the membrane others say they interact with speific cell membrane receptors(this is very quick rapid action). the original theory say: ( steroids enters cell and interacts with specific cytoplasmic receptors ) o after that activates H-R (hormone receptor ) complex phosphorylated and activated and then translocated to nucleus and binds to specific nucleur receptors. o more recently, steroid directly enters target cell and interact with specific receptors in nucleus. o we want to make ourselves clear for the sake of the exam: in general, steroids o with specific receptors that are mainly located in the cytoplasm. ** amino acid derivatives: dopamine. proteins all on specific receptors on cell surface steroids on cytoplasm o nuclear binding of steroids is well-documented finding that they interact with receptors on the nucleus where they change the transcription or translation of specific proteins resulting in stimulating or inhibiting which mediates inhibits of the steroids the magic protein of the steroids if you are talking about cortisol receptors, its actions speak for the location of its receptors. estrogen for example there receptors found in ovary, breasts, negative feedback (pituitary and hypothalamus) ** its all about action ** CRH for exampleit/s receptor found in pituitary. ** Steroid administration : o Has two half-lifes o There is plasma half-life and nuclear half-life o Plasma half-life is shorter than nuclear half life action is mediated through production /inhibiting of specific protein and thus acts as a mediator for the steroid therefore you can play with the structure of the steroid to act for a long time in plasma.
7 certain metabolites ( have nuclear binding ) for example have half-lifes that are long as well used to serologically determine presence of original compounds o under basic( normal ) conditions, hormonal release is minimal ( not that much ) we don't need it in large quantities hormones are found in the body in very minimal concentrations range from (10^-13-10^-9 ) molar and in order to measure concentration in blood sample we use high-sensitivity techniques ( called radio immune essay ) ( under normal situation little hormone secreted ) when the body need specific hormones, hormonal secretion increases tremendously ( up to 1000 fold ) androgen during puberty stress for cortisol : cortisol synthesis and secretion are increased to high extent during stress conditions. pregnancy and esterogen other situations: hormone secretion can increase up to 1000 folds what stimulate the release of hormone? nerve impulses change in composition of ECF (heavy carbohydrate-meal insulin is stimulated) ** glucose level in the plasma affect secretion of insulin and glucagon ** another hormone (trophic hormone) may stimulate release of other hormone. trophic hormone : the horone which increase or regulate synthesis / release of another hormone. o The hormone secreted in the blood stream, they reache to their target cells and bind receptors to induce recognizable changes in the cells ( cascade reactions ) either by means of seconed meesengers or directly through H-R complex ( according to the hormone type ) : o These changes may include : o Changes in cell permeability e.g. insulin which increase uptake of glucose by the affected cells along with k+. o Stimulation or inhibithions of protein synthesis. o Stimulation or inhibithion mediator release ( 2 nd messenger ) o
8 protein synthesis: like steroids How long does the hormone stay in blood? It depends on extent of protein binding more extensivelye bound hormone usually they act longer than less binding capacity of other hormones. the deficiency of metabolic pathways if you have a hormone that is metabolized very quickly * peptides : quickly metabolized by peptidases in the blood. synthetic peptides or multification of the chemical structure of peptides allows us to modify the half-life ( the duration of action of the particular hormone ) o ----> major determinant to the duration of action of the particular hormone is the idea of efficiency of degradable enzymes. but the most important : deficiency of negative feedback mechanisms example is GnRH of the genito-urinary system what happens is that under stress, cortisol is needed therefore synthesis is needed in response to CRH, ACTH... cortisol interacts with specific receptors and mediates effect it is no longer needed after couneracting of stress same with TRH aldosterone, etc. major mechanism by whic hormone action is terminated what is known as : (negative feedback ) it represents basis of diagnosis different diseases affecting endocrine system, putting a strategy of treatment and development of certain specific agonists/ antagonists dosage form. Addison's Disease : deficiency of cortisol ( no cortisol in adrenal gland ) due to what? perhaps CRH deficiency therefore you have primary, secondary and tertiary a problem in the adrenal gland "Primary'' a problem in the pituitary gland " secondary '' a problem in hypothalamus '' tertiary '' let's say problem is in adrenal : manifestation of deficiency is due mainly to what? Cortisol deficiency. therefore treatment: cortisol. This is hormone replacement therapy
9 therefore regardless at which level the problem is, the treatment remains the same. the other question: is it important to know where the defect is to know where the defect is, you have to make some tests. If the defect in the pituitary :take a blood sample, Then measure cortisol... treat with ACTH, and measure cortisol again And you also have to test CRH... but these are many tests and costly... you can control the mainfistation simply by administration of cortisol there is a a trend of treating : massive doses of ACTH: ACTH will never ever release except the releasable amount. Manufacturing and developing strategy: ACTH is the problem, therefore you develop a solution for that TRH highly effective in many hypothyroid conditions : 3 amino acids, orally effective. ** Sources of Hormones : animal sources like insulin ( rare use ) or natural human chemical structure of different hormones known, very easy for us to synthesize, even omplex glycoproteins. biosynthetic: in-between they take insulin from pancreas of bigs and replacing amino acid by one that found in human insulin. ( the difference between human and bigs insulin is just one amino acid ). synthetic DONE BY : Israa abu hammoor
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