pharma sheet # 1 - Alaa Istamboli

Endocrine pharmacology
--------------------------------------------------------------------------(Slide 1)
There is no sharp difference between endocrine pharmacology and endocrine physiology, the only different that we r going to deal with as drugs (as chemical substances given from outside). physiologeist talking about normal function of the hormone (physiological action of hormone) while pharmacologest talking about drug synthetic natural ,pharmacological action, clinical uses and sides effect .. and thats the difference between the physiology and pharmacology with respect to endocrine system.
*They say that the most imp. System in your body is the CNS (bcoz its contains most of the center that control so many biological process in your body)
* hypothalamus a number of nuclei present in the brain, therefore endocrine system comes second or as imp.as the CNS, in another word; whatever external internal stimuli affect the CNS will be reflected on the endocrine system since the hypothalamus is part of the CNS.

Hormone (by definition) : chemical substances that are synthesize in highly specialized type of cells collectively known as endocrine gland,so hormone synthesized in place and act in somewhere else. Again…chemical substances that are synthesized in endocrine cell (endocrine gland)and they are released from such gland to blood stream(immediately) and then travels to somewhere else.
<>>
Since the endocrine gland are ductless glands, We need a rapid effect to such hormone ,hormone synthesized in place and they act somewhere else,unlike Neurotransmitter\ acetylcholine\ or hormonal like substances (like prostaglandin)… they are synthesized in a place and they act in the same place and even it metabolite there and this is the difference between it and hormone.(its not that much difference)

( Slide 2 )Endocrine gland that we will talk about:
1. hypothalamus: its anumber of nuclei present in the CNs.
2. pituitary gland: with ant and post part at the base of skull.
3. thyroid gland: in the neck .
4. four parathyroid gland: post. to thyroid gland.
5. adrenal gland, pancrease, ovary and testis.
(Slide 3)
Hormonal Regulation up or down: Whenever we use a term regulation it doesn't mean always stimulatory effect (Remember that).
An example: prolactin its Mainly under inhibition by the hypothalamus.
So prolactin is regulated by dopamine (we will deal with dopamine as ahormone rather than as a Neurotransmitter ( its catacholamine) it’s a precursor to know epinephrine, but here dopamine is ahormone in the hypothalamus (synthesize in hypothalamus, release from hypothalamus and regulate prolactine synthesis release).
Other example: Most of the hormones are mainly under the stimulation of the hypothalamus with the exception of Dopamine.
So hormonal Regulation:
1. is essential for Growth and development ( not only Growth hormone is involved in Growth but thyroid hormone more than essential for growth, without these hormone dwarfism happen).
2. Imp. For Reproduction, fertility, sexual Function ( without hormone No pregnancy),
3. Response to environmental situation (responding to stress):
• Cortisol is a major in counteracting effect of stress in addition to epinephrine and Norepinephrine.
• Sympathetic system is the first system triggening in responding to stress.
• Not just catecholamine respond to stress, many many death have been reported following adrenal insufficiency due to cortisol deficiency ,therefore cortisol is essential for responding to the rxn of stress.
4. Maintenance of normal homeostasis:
We mean ـ maintaining normal composition of the ECF
Example : Normalizing blood glucose level, Normalizing ca++ blood flow level and normalizing diff.electrolytes…So hormone play an essential roles in regulating diff substances in body like glucose ,CHO, prs ,fat..etc.
These 4 major function of the endocrine summarize the important of that system.


(Slide 4) Basic principle of the endocrine system:
Under normal condition (Basal condition or rest) we don’t need hormones in tremendous amount, they are released in v. little amount ( in minute quantity range from 10^-13 to 10^-9 molar concentration) So they are present in the blood in very very little amount to the extent that we need ahighly sensitive method to measure the conc. of such hormone in blood.
Radio immune assay: is used to measure conc. of diff hormone in your body we tag the hormone with radioactive material.
( Radioactivity : is a tool by which we can detect V.little amount of substances on body) so we need a highly sensitive technique to measure conc. whether increased or decreased( the problem with the little decrease, sometimes we are doubt if this individual has really deficiency of a particular hormone , and in this condition we resorb to some other tests to make sure whether or not the individual is under low levels or such v. little amount hormone in the blood.
We can give some stimulation to such hormone,( if no stimulation defiantly the hormone is in a low conc in blood).. so under normal condition hormone present in minute amount in blood but whenever we need any particular hormone in your blood, It is stimulated synthesis, and release of that particular hormone increase tremendously.
Ex: ( LSH at the mid of cycle build up of estrogen progesterone during pregnancy).
Normaly v. little amount is produced.
ex: ( under stress, we need cortisol (but if u r exposed to even minor stress cortisol secretion increase tremendously)in other situation hormonal releasing increase up to one thousand time
ex: prolactin at the time of lactation (after delivary)… the LH level is V.imp for ovulation and fertility in the female .
ex: if u have a heavy CHO meal .. what happen to secretion ?
under normal situation (if u r normal ) no proplem with insulin secretion (,the level of glucose dosent go more than 180 mg/dl. Bcoz insulin is ahighly efficient hormone in reducing blood sugar level)
but if you r abnormal here … theres aproplem .
so… whenever we need this hormone , synthesis and releasing will increase in blood stream .
<< what stimuli could lead to increase synthesis and release of particular hormone ? >>>
• nerve impulse
• change in composition of ECF ( glucose,. insuline , hypoglycemia glucagon, hyperglycemia insuline secetion , hypocalcemia PTH … we will discus all these later on )
• another hormone ( trophic hormone )
hormone could lead to stimulation or inhibition, regulation of another hormone .
any hormone which regulate synthesis , release of another hormon is known as ( trophic hormone )
following this stimulus The hormone is release into blood stream then travels and bound to aspecific protein, and since we r going to deal with hormone as drug(given from outside).and this bounding to aspecific protein present a resource to that particular hormone and since this bounding to specific albumin or globulin in blood present a resource( مخزون للهرمون ) not only that ,but mean by which the hormone travels from one place to another .
not only that .. also binding to specific prs represet amajor site of drug-drug interaction and this is V. IMP for pharmacologist.
Release into blood stream ----- Bound to specific prs -------- Reaches target cell (Where that particular hormore interact with specific receptor).
Receptor studies allowed us as pharmacologist to synthesize manufactured diff. agonist and antagonist, we utilize the understanding the Nature of the binding of aspecific substance ( not only hormone) with specific receptor allowed us as pharmacologist to synthesize manufactured diff agonist and antagonist and this binding starts for triggers an initial change in target cell leading a No. of rxn changing.
<>>
A: Change in cell permeability
Example: insuline with glucose .. how insulin decrease blood glucose level?
-- the Major Mechanism is by inhancing (exist) of glucose from blood to inside the cell, this is the Major Mechanism by which insulin decrease blood sugar level. (We have some other Mechanism but this is the Major one).

the following changing that happen when the hormone binds to its receptors:
A) Changing in cell permeability.
B) Stimulation or inhibition of prs synthesis and this is related to hormone of prs nature.
Change of rate transcription translation or even glycosidation steps (Some hormone are glycoprotein).
C) Stimulation or inhibition of 2nd messenger (Mediator) release
(Here the hormone when bind to its receptor doesn't have effect but some other thing),
*so the hormone in this case is a 1st Messenger
* and if regulate production of another substance,,, this substance known as 2nd Messenger.
*2nd Massenger that could mediate the effect of that particular hormone like :
( CAMP / CGMP / DAG/ ITP (IP3) / Ca++ )
*Ca++ is essential for hormonal release, not only that, but also it act as a 2nd messenger to certain hormones mediating the effect of such hormone.
Ex : * ant. pituitary under the influence of hypothalamus
*TSH under the in influnce of hypothalamus
* TRH stimulation for TSH then TSH go to thyroid.
<<>>> HOW ???? .
We take a pituitary cells and put it in dish and treat such cells with diff. second messenger and one or two dishes with TRH, then take a sample of the media … if 4 example the response following treatment of such cell with CAMP Is the same as those cell treat with TRH then we can prove that CAMP mediate the effect of TRH.
<<<>>>.
You take diff. cells from pituitary gland and treats with diff. 2nd messenger and one cell treat with TRH.If the final response of the cell that treat with TRH was the same response of cell was treat Of DAG ( 4example) then we say that TRH effect are mediated through DAG
<<<< So its not that difficult to prove 2nd Massenger that mediate the effect of particular hormone.>>>

Slide 5
Classification of hormone according to there chemical Nature (Structure)
*** a.a derivative
- t3 ,t4, Dopamine ( they are tyrosine derivative )
- small peptide , larg protein or glucoprotien ( Hypothalamic hormone , GH, PRL , insulin) .
Most of hormone are of prs nature , and this is also bring us to the fact that such prs are synthesized through DNA ..
<<**** steroid ( like: cortisone , androgen , progesterone ,estrogen and aldosterone)
all these are steroids …. with the famous steroid nuclueus ( for ring nucleus ) :
cortisol , aldosterone , sex hormone .!!!!!!

slide 6
classification hormone according to the location of receptors:
1- peptides protein and glycoprs interact with receptor on cell surface, they are large molecule and water soluble so they couldn’t inter the cell.
2- steroid receptor are mainly present in cytoplasm .
so steroid hormone cross plasma membrane of target cell and interact with receptor in cytoplasm (a lot of studies say that they interact with nuclear receptor but … dr. said in exam steroid hormone binds to steroid receptor in the cytoplasm where its mainly present there ) <<< entebho had 7yeje so2al bl2emt7an >>>.
3- in nucleus ---- thyroid hormone are highly soluble that cross the nuclear membrane V.easily and interact with receptor in nucleus.
(The strongest membrane in the body is nuclear membrane and its highly protected bcoz it contain chromosomes, we don’t like to hormone to be highly soluble to the extent that could cross nuclear membrane ( we don’t like that) bcoz it could make many defect like affecting genetic make up during pregnancy) thyroid hormone are highly lipids soluble to the extent that they cross the nuclear membrane v.easily, so they act in receptors that mainly present in nucleus. -------------------------------------------------------------------------------------------------------(slide 7 )How long hormone stay high in blood?
We say that we have a stimulus
*first…. hormone release in v. little amount but if we need that particular hormone, the hormone release in tremendous amount to the blood stream reach target cell then bind to the receptor and producing effect .. after that we don’t need it ( bcoz we don’t like giving drug ).

So How long stayes high in blood? It depend on:
1. Extent of prs binding
prs binding represent aresource , so bounding substances remain longer duration in blood means longer duration of action.
2. Efficiency of degradable enzyme and clearance.
This is Metabolism and excretion, many hormone are excreted unchanged, but also many others they are metabolite then we need help to that particular substances to get out from the body.like toxic material,foreign material..
(Another way which can we getrid of that particular hormone is by metabolism and excretion)
and the major mechanism by which the action of the hormone is terminated with other drug another way which can we get rid of that particular hormone is by :
3.Negative feedback mechanism
Understanding negative feedback mechanism allowed us knows diagnosis to diff. disease affecting endocrine cell and allowed pharmacologist to manufactured drug related to the endocrine system, and put strategies in treating diff disorder affecting endocrine system and also developing certain drug related to hormone and endocrine system <<< its so easy to understand them >>>>
-----------------------------------------------------------------------------------------------------------------slide 8( hypothalamic).*** 1st axis
( CRH ) (Corticotrophin releasing hormone)
Stimulate
( ACTH ) ( Adrenocortico tropic hormone ) from ant.pitutary
Stimulate synthesis and release
( Cortisal )

*Cortisol … after producing the pharmacological physiological action it negatively feed back.
*Negatively feedback on either the ant. pituitary or the hypothalamus,
------------------------------------------------------------

**** 2nd axis

All these will be discussed again and again



----------------------------------------------------------------------------------------------------------------


<<< How negative feedback allowed us to diagnose diff diseases ?????>>>>
Lets say a person have cortical deficiency, this deficiency could be due to what ??
( by understanding the 1st axis)
1*** could be due to CRH deficiency ?
yes if we don’t have CRH no cortisol (despite the adrenal and pituitary being normal)
2*** or CRH its ok.( the hypothalamus normal) but the proplem in the ACTH.
3*** or adrenal deficiency .
Soo .. we have 3 cases for adrenal insufficiency .primary ,secondary ,and tertiary

<<<<< 6ayeb .. how could u make sure where the proplem (defect) exactly happens??
In hypothalamus or in ant.pituitary or in the adrenal ???? >>>>
Astudent answer by measuring the conc.of CRH.
Dr : that’s good .. as the level of CRH high, the negative feedback gone but this could be ant.pituitary or adrenal, we have cortisol deficiency in this case<> we suspect that CRH and ACTH will be high .. u start with measuring development hormone in the blood .
u measure CRH, ACTH but this will not give u 100% to swear that the proplem in the hypothalamus or in the adrenal


step by step:
* cortisol is low maybe CRH high or ACTH high , but u have to do certain other thing
*,u take bld sample then u measure cortisol then u give ACTH.
* if the proplem in ant.pituitary then cortisol will be increased in blood with treatment of ACTH.

* When cortisol is low when give ACTH----- if cortisol level increased tremendously ..
u can prove that the proplem in ant.pituitary (bs lessa fe 3ndk $ak eno el proplem in hypothalamus) the
* so u take bld sample and measure ACTH and then u treat the patient with CRH,
* if ACTH level become increase and cortisol level increase, u can prove that the proplem in the hypothalamus

<<>>
if u have cortisol deficient the manifestation of the disease is the adrenal insufficiency(Adesons disease)
Q : 6ayeb the manifestation r made due to what ??? CRH or ACTH or cortisol ???
A: the manifestation r mainly due to cortisol deficiency bcoz function of CRH give us ACTH, and the function of ACTH give us cortisol … and that’s it .

but the effect we r desired from… is cortisol
soo << leeh e7na bn3`aleb 7alna b kol haye el tests ?? leh ma n36e cortisol o 5ala9??>>

A student ask a Q (ma sme3to bl record )
dr : ana ma 3ndi 3`eer na89 cortisol wl sabab CRH deficiency !!!

( dr: fakro feha mne7 o next time I will repeat it ) !!!!!

1st lec.
6-2-2011
Ala2 istanbuli
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