pharma sheet # 2 - Abdulhameed Nawwaf

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pharma sheet # 2 - Abdulhameed Nawwaf

Post by Shadi Jarrar on 11/2/2011, 5:04 am

بسم الله الرحمن الرحيم


pharma lecture no. 2_2.docx


• In last lecture , we talked about “ the axis pattern “ for example the adrenal gland is under the control of anterior pituitary and the ant. Pituitary is under the control of hypothalamus also the thyroid gland and the gonads are under the control of ant. Pituitary and the hypothalamus. So when we study any of the endocrine hormones we use this axis for example :
• With the respect to the adrenal gland , CRH will stimulate the release of ACTH which stimulates the synthesis and the release of cortisole
• We have synthetic machinery for steroids , proteins and amino acid derivatives …
• So these negative feedback “axis” mechanisms of the hormones are essential for :
1- Diagnosis of deferent endocrine disorders affecting endocrine glands
2- Put a strategy in management and development or getting certain drugs relating to the endocrine disorders[/cutting feedback for example]
• Before discussing the disorders affecting endocrine glands , we will discuss the source of hormones “ where we get hormones from? “ :
• 1- natural sources : either human source or animal source
• A- human source : whatever the hormones that we get from the human for ex. : in the past there used to get growth hormone GH from the human and we know that GH is a large protein synthesizes from ant. Pituitary . so how we get GH from the human ?
• Immediate after the death through very easy extracted surgery of pituitary gland by a probe inserted nasally and then you get the ant. Pituitary . and no consent is needed from the parents or the family unlike the cornea because you could hit the conjunctival vessel and leading to bleed . therefore for immediate extraction of the cornea following death from the cadaver , the consent is need for the previous cause unlike GH from extracted pituitary . by the way . GH constitutes the largest amount among hormones present in pituitary gland.
• Why do not we extracted the hormones from the blood ?
• Because they are present in very little amount (picogram amount pg )
• So , in order to get more amount of hormones , you have to get them where from they are stored and synthesized like GH in ant. Pituitary
• This GH hormone from the human source associated with severe side effect .
• Deficiency in GH especially during childhood may result in dwarfism and the treatment of this deficiency maybe through giving GH hormone from outside and it is highly effective therapy
• Now, with advanced technology like recombinant DNA technology , it is very easy to synthesize hormones even complex protein (glycoprotein) and this is synthetic source
• There are other hormones other than GH that we can get from human source like :
• LH , FSH and HGH (human gonadotropic hormone )
• From where we get LH and FSH hormones ?
• From urine source
• The female usually lose ovarian function at certain age (50 -55) year so, the production of progesterone and estrogen will stopped by the ovary . such ladies are known as menopausal women. so the negative feedback mechanism for LH and FSH will stopped
• LH and FSH are complex glycoprotein with alpha and beta subunits and in the case of stopped ovarian function , they present in large amount and in blood and they are excreted by the kidney through highly active secretory mechanism so they appeare in the urine . so we ask the ladies to urination in page and from the urine , we extract LH and FSH . ALSO there is synthetic source for LH and FSH but the main source is the urine
• Now , HGH is produced by placenta during pregnancy stage in large quantities and excreted in the urine and we extract it from the urine of pregnant ladies and its pharmacological action is similar exactly to LH
• B- animal source : insulin
• There are so many animal sources(that we consume them ) for hormones like cows , pigs and sheep ….etc
• So pharmacological companies use these cheep sources for production of hormones like the pancreas , thyroid glands ( from them we get T3 and T4 that are tyrosine derivatives even from rats, they are the similar as human T3 and T4 in structure but the insulin , there is slight changes but this changes are not like the huge changes in GH and prolactine that we can not take them from the animals ) that we do not eat them
• Now , cow insulin or beef insulin defers from human insulin in three amino acids only but pork insulin defers from human insulin only in just one amino acid so we extract the insulin from the pancreas of either cows or pigs
• So, in the term of allergy , the cow insulin produce more allergy than pig insulin(porcine insulin) which is more allergy than human insulin because of more different amino acids
• In term of potency ,( which is not important in pharmacology , but here is important , because in pharmacology , we concern on efficacy (the max) but the potency is just adjusting the dose to get good efficacy) human insulin more potent than porcine insulin which is more potent than beef insulin
• 2- Biosynthetic source : as we said before, porcine insulin defers only from human insulin in one amino acid but cow insulin defers in three amino acids , so , we prefer to use the porcine insulin so what we do is , they extract the insulin from the pigs and they exchange the amino acid that defers from that of human by human amino acid but is still produce allergy and its more potent than porcine insulin . so this is called biosynthetic source
• Remember , allergy is the universal side affect of all drugs even human source makes allergy and also even the treatment of the allergy which is anti histamine drugs they produce allergy in some people
• 3- synthetic source : through knowing the chemical structures of most hormones so it is very easy to synthesize them . as I said before through recombinant DNA technology , we can synthesize complex hormones like human insulin , human LH and FSH ….etc
• Also , knowing the chemical structures of most hormones , allow us to manufacture deferent synthetic analogues ( different agonists and different antagonists )
• The purposes to have a lot of analogues , ex. Having 600 different steroid related to cortisol available in market , is to produce different pharmacokinetics properties (different duration of action , half life …etc)
• LH ,FSH , TSH and HGH are glycoproteins each of them consists of alpha and beta subunits :
• The alpha subunits are similar(polypeptides chains and the suger are the same) and are encoded by single gene
• Beta subunits are different in structures and are encoded by different genes
• Both (beta and alpha) are glycosylated (they have sugars) but the polypeptide chains in beta subunits are different
• Even they say that the biological activity of these hormones mainly contribute to beta subunits , this is not 100% correct because neither alpha nor beta subunit alone is biological active, but the combination of them is the active form with few exceptions for ex. The synthetic beta subunit of FSH through recombinant DNA technology is biological action alone but not as the whole hormone (but in general the combination of beta and alpha subunits is the biological active form
• The biological action of the beta subunit is easy to prove by simple experiment :
• If you separate the beta and the alpha subunits of different hormones by acid treatment or by urea and if you combine the alpha of LH with beta of TSH , the action will be related to TSH or alpha of LH with beta of HGH the action will relate to HGH …etc
• Synthetic machinery inside the cell :
• For example : inside the endocrine cell , which produces LH, FSH TSH but HGH is produced inside the placenta , by the way all these hormones produced by different cells (highly regulated and specific system ) :
• First step : Alpha subunit : produced by alpha DNA which transcribed into alpha m RNA which translated to alpha protein and the same for the beta subunit
• Second step : is the glycosylation (addition of sugar ) to such subunits
• Following that is the combination of alpha and beta subunits forming the complete hormone which stored in storage organ
• Then , whenever we need the hormone , it will release into blood stream through ductless gland in the presence of proper stimuli then it will produce the proper biological action
• The most important site for storage of hormones is the site of the production
• So , here we are talking about two poles : storage pole and releasing pole
• The first pole to be affected by the regulator (stimulator or inhibitor ) is the releasing pole because synthesis is always taking time
• Irrespective , the steps of production of hormones (like ex. Transcription of alpha DNA into alpha m RNA ) are the possible sites for regulation
• In the disorders that affecting endocrine glands , they produce their affect either through deficiency state of hormones or excess production state. which is more common ??
• The deficiency state and the treatment of the deficiency state by hormonal replacement therapy (HRT ) or enhancement of production.
• The treatment of excessive production are specific antagonists , inhibitor of release and inhibitor of synthesis
• Example : in deficiency state , I will give the hormone which is deficient or enhancing the synthesis by whatever drugs or mean that will increase the release of such hormone
• Excess production state , I will give specific antagonist of the receptor of the hormone or by giving inhibitor to any steps of synthesis for example , drug that will prevent the transcription of the DNA of such hormone
• So , all of these sites of production are possible sites of regulation by Hypothalamic hormones or other drugs.
• Back to the negative feedback mechanism , for example GnRH will stimulate the release of LH and FSH ,in other world, GnRH will stimulate all the synthetic steps of LH and FSH (the Doctor proved the GnRH will stimulate the transcription of alpha DNA to alpha m RNA of the LH hormone ) and also GnRH is small peptide (only ten amino acids )

• Major clinical uses of hormones :
1- Hormonal replacement therapy in the case of deficiency state (which is the major one “question of exam” . example: no insulin you will replace it with insulin replacement therapy and the same for GH and so on ..
• and in best case , hormone usually used in very little amount because hormone is needed in very small amount. So this is called “physiological doses” and usually given in units like insulin unit
2- hormones not always used for endocrine disorders , it is also used as anti inflammatory agents like cortisole which is potent anti inflammatory agent but in such cases the hormones are given in “supra-physiological doses “ in large doses so there will be side effect but in case of hormonal replacement therapy : the side effects are minimal
3- also hormones used as diagnostic tool .

• note: sometimes, we used drugs that are not hormones in their nature , but they are used to control endocrine disorders example : anti-thyroid drugs that are not hormones in their nature . there are synthetic drugs used in management of hyperthyroidism also as oral hypoglycemia drugs like insulin that maybe effective orally

4- some drugs are used to treat diseases not related to endocrine system but they could affect the function of endocrine system . the best example : is anti-cancer drugs that they usually affect highly dividing cells like the ovary so they could result in [/in]fertility in male and female
5- contraceptive drugs ??? doctor said that never used drugs in contraceptive …. Later we will discuss the contraceptive issue

• back to the “axis “ . example : remember that deficiency is more common state so in the case of cortisol deficiency , the treatment immediately is cortisol replacement therapy because the manifestations of cortisol deficiency like Addison disease is due to cortisol deficiency not due to CRH deficiency or ACTH deficiency but the reason for this deficiency could be : hypothalamic , ant. Pituitary or adrenal causes .
• tests that I can use to know causes :
1- CRH test : if the cortisol increases after given of CRH , so we can conclude that the defect mainly in hypothalamic
2- If the cortisol does not increase following CRH , we go to ACTH test : if the cortisol increases following given of CRH , the defect mainly in ant. Pituitary . if it is not increases , the defect definitely in adrenal gland
• The question is that , it is important to do these costly testes ?
• The answer is yes because it is essential to know where the defect is for example in case of cortisol deficiency , I will give cortisole but if the defect in for example in ACTCH, that it is function is to enhance the release and the synthesis of cortisole only, the amount that is going to release in response to ACTH is the releasable amount so the system will be control beter than of giving cortisole from the beginning . so they prefer to go a little bit higher in management of deficiency disorders provided that the end organ is normal for example , if the defect is in the ACTH , I will prefer to give CRH because CRH will lead to release the physiological amount of ACTH and the ACTH will lead to release the normal amount of cortisol . and even if I give large doses of CRH , it won’t not be associated with sever side affect and also hypothalamic hormones are small peptides in nature . but if I am going to use cortisole start from the beginning, I must adjust the doses and monitoring the patient for side effect … now we finished the introduction

Hypothalamic hormones

• The hypothalamus that synthesizes the ADH (anti diuretic hormone )or vasopressin and the oxytosin is posterior hypothalamus and they (ADH and oxytosin ) reach pos.lobe of pituitary through neuro secretory axons . so the connection is neuronal between hypothalamus and pos. pituitary
• Hypothalamus synthesizes and secretes different hormones that regulate the action of ant. Pituitary hormones which are ACTH , ESH , LH and FSH which are mainly under stimulatory control and GH , prolactin and melano stimulating hormone MSH which are under stimulatory and inhibitory control of the hypothalamus
• The hypothalamic hormones or factor(in past they are called factors because of unknown chemical structure but now they known as hormones because of known chemical structure )reach the ant. Pituitary through portal system (networks of capillaries ) . so the connection is vascular between hypothalamus and ant. Pituitary.
• General characteristics of hypothalamic hormones :
For thyroids hormones : under the control of TRH
For LH and FSH : under the control of GnRH
For GH : under stimulatory and inhibitory control
For prolactin : stimulatory and inhibitory (dopamine )
• So , they are peptides and small peptides with the exception of dopamine which is amino acid
• They have low molecular weight so they are small hormones
• They are needed in very low concentration (pico gram amount (pg))
• They (native hormones)have short half life (t1/2): that does not exceed five minutes so the native hormones of hypothalamus are not used , we used synthetic analogues
• They act on the receptors on the plasma membrane coupled with adenylase cyclase (so they act through c AMP )

Thyroid releasing hormone : (TRH)
• The job of TRH is to stimulate TSH
• It is small peptide (tripeptide) and it is orally affective (resistant to acid breakdown )
• Mainly used as : diagnostic tool (TRH test ) and also treat certain cases of hypothyroidism provided that ant. Pituitary is ok and thyroid gland is ok
• Note by the doctor : the doses that the doctor said , you should remember only (the doses of TRH are not mentioned by the doctor
• Certain cases of hypothyroidism are successfully treated by TRH same as therapy with T3 and T4 and even better

• Same as TRH mainly used as diagnostic tool also it can be used in certain cases of adrenal insufficiency

Growth hormone (GH) : under stimulatory and inhibitory controle
• They release GH under stimulatory control known as GHRH and it is not really will identified (given intravenous (IV))
• GHRH Used in diagnostic manner and in certain cases of dwarfism
• SO the principles are all hypothalamic hormones used in diagnostic (asses the function of ant. Pituitary) and in cases of deficiency

• Growth hormone inhibitory hormone (GHIH): SOMATOSTATINE :

• It has different pharmacological actions as compared to other hypothalamic hormones and it is very famous hormone

• The major action of it is to inhibit GH synthesis and release but it is also inhibitor to release and synthesis of number of other hormones like ACTH , TSH , insulin , glucagon ,gastric and serotonin : it good inhibitor to serotonin release and synthesis and serotonin is consider as neurotransmitter and it interacts with at least 5-7 different receptors peripheral and central and it is produced by certain cells in GI tract and 95% of serotonin produced by GI tract . if there is certain tumor affecting certain cells , the serotonin produced in tremendous amount and result in sever diarrhea

• So I can use somatostatine in the management of the cases that result from production of previous hormones

• Also , they found that somatostatine has different affect on blood glucose level and this affect is dose dependant :
Low dose : leads to hypoglycemia due to inhibition of glucagon release
High dose : leads to hyperglycemia due to inhibition of insulin release
• Also we have synthetic analogue to somatostatine : octreotide , landiotide :
• Octreotide :is good subcutaneous agent and it is short acting but longer than native somatostatine (that have(the somatostatine ) half life from 3-5 minutes)but the octreotide : has one an half houre half life
• Landiotide : have longer half life than somatostatin because it is synthetic and given intramuscularly IM in 14 days in cases of :
Acromegaly and carcenoid hormone : that associated with excess production of serotonin ….Synthetic analogues of somatostatin associated with severe side affect ….
Done by : Abdullhameed Mahmoud
Lecture NO. : 2 DATE OF LECTURE : 8/2/2011

Shadi Jarrar
مشرف عام

عدد المساهمات : 997
النشاط : 12
تاريخ التسجيل : 2009-08-28
العمر : 26
الموقع : Amman-Jordan

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