pharma sheet # 3 - Abrar sa3adeh

Hey everybody.. In the last lecture we started talking about hypothalamic hormones and we discussed some of them.. Today WE will continue what we’ve started by talking about GnRH .. but excuse me .. I would like to mention some abbreviations & pieces of information that they would be useful in this sheet and in other places … so the following paper includes extra information to refer it or not its up to you ,, Let’s start :




GnRH (Gonadotropin releasing hormone ; Gonadorelin) :
The last hormone related to hypothalamus .. it’s a very nice hormone in many aspects ..
First of all it’s a decahormone (means 10 A.A) .. which indicates the small size of it .
Released in a pulsatile manner (in pulses) each pulse is followed by LH,FSH pulse each 30 min .
So normally in our bodies it’s release in a pulsatile pattern … where it interacts with specific receptors on the ant.pituitary gland .. stimulating the LH ,FSh synthesis and release ..(Alpha and Beta subunits that were discussed in the introduction) ..
Again its unique by :
1- it’s a small peptide.
2- it’s one hormone that stimulates two different hormones from ant.pituitary gland.

LH .. in females stimulates estrogen and progesterone production.
FSH .. MAINLY is responsible for follicle development.
So LH is responsible for ovulations .. and as you know Ovulation occurs when a mature egg is released from the ovary, pushed down the fallopian tube, and is available to be fertilized.’
So we need for ovulation and follicle development LH,FSH NOT estrogen and progesterone.
In Males GnRH also stimulates LH,FSH ..
In the testicle LH stimulates the testosterone production which is the major androgen in the male’s body ..FSH stimulates spermatogenesis.
We have negative feed back from those steroids (estrogen, progesterone and testosterone) on the GnRH in hypothalamus as well as on pituitary .

The structure of GnRH :

Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.

The Dr said that “it’s a very very nice Hormone.. I really LiiiiKe it ,, as I love it so much Be careful..”



Now the structure activity relation..
It’s v.imp in pharmacological view the first 3 a.a are essential for the agnostic activity of this hormone .. Therefore any chemical modification or change in these 3 a.a results in..
Changing the physiological characteristic of this hormone to be ANTAGONIST.
So ..we can get huge amount of antagonists for GnRH by playing with those 3 a.a.
While the rest a.a in the structure 4-10 are imp for binding characteristic of the hormone to its receptors, any change in those a.a especially Glysin residues at position 6 & 10 results in many number of agonists that are similar to GnRH in function .. not just agonist they are SUPER agonist , means stronger effect more than the GnRH itself .

This is another property of GnRH that any change in the chemical composition results in many number of agonists and antagonists which is an imp property in pharmacology.
Again.... we said that the pattern of release of GnRH is In pulses.. released from hypothalamus go the ant.pituitary through capillaries (portal system), acts with specific receptors ..resulting in the synthesis and release of LH and FSH simply this is how GnRH works.

The mechanism is through Ca2+ as a second messenger .. so it mediates the effect of GnRH when it’s released in PULSES ( please keep it always in ur mind PULSES and after awhile you will now why  )
NOW .. if we give GnRH in large doses or if we give SUPER agonists ..then we are decreasing the synthesis and release of LH,FSH, SO the pattern of release or administration of GnRH is very IMP and even we can classify chemical uses for this hormone into two different categories .
So ..giving the hormone in small doses in a pulsatile manner (as it’s normally in our bodies ) to increase the synthesis and release of LH,FSH .
And giving the hormone in large doses or SUPER agonist or even by giving it in a continuous administration if we want to decrease the synthesis and release of LH,FSH .

**SO.. by controlling the pattern of administration we can DOWN REGULATE the LH,FSH.
NOT by inhibiting Ca2+ second messenger , NOT by regulating the synthesis pathway the Glycosilation ..etc..

** GnRH has a stimulatory effect .. it stimulates transcription and storage .

But the FIRST process to be affected by GnRH when it’s given in pulses is the RELEASE (releasable amount of the hormone), Cause when we inhibit the release it’s a very quick process, and we as human beings we always like to heal and recover quickly by giving drugs that control the releasing step , also down regulation or desensatization of the receptors is very imp in the issue of inhibiting GnRHLH,FSH .[/so we downregulate LH & FSH by two mechanisms.. by giving large amounts of GnRH or by inhibiting it]


GnRH synthetic preperations:
We have many synthetic analogs to GnRH could be given subcutaneously ,intramuscular and intravenously ,But it’s ineffective if it’s given ORALLY .

There are certain preparations designed for using GnRH as contraceptive agent :
 Intranasal
 Suppositories
 Sub dermal
 Implants and vaginal pessaries forms

subcutaneous pattern is Mainly used.

GnRH clinical uses:
Mainly we classify the clinical uses of GnRH into two parts:
1. the situations when we need GnRH to be given in small doses (pulsatile manner) and we use it :
A- in the HRT(hormonal replacement therapy) in deficiency of GnRH like in Kallmans Syndrome((Kallmann syndrome is a hypgonadisim (decreased functioning of the glands that produce sex hormones) caused by a deficiency of (GnRH), which is created by the hypothalamus. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia)) No GnRH means No LH,FSH NO estrogen OR progesterone in female and no testosterone in males .
So GnRH is responsible about the infertility in both sexes..GnRH deficiency is treated by small doses of GnRH in a PULSATILE administration in order to get it’s effect .



B-Diagnostic tool ..to assist the LH,FSH secreting services.
 As we said GnRH is used in treatment of infertility by induction of ovulation (by LH)
 treatment of hypogonadism
 delayed puberty
 amenorrhea : when the female has never had a menstrual cycle.
 cryptorchidism :condition in males where the testicles don’t move down into the scrotum.

Testicles are developed in the abdomen in fetal life and then descend shortly before birth.. if they don’t you can help such a process by giving LH.
LH and Human chorionic gonadotropin which acts as a neutralizing hormone help the descending of testicles during childhood.

2-(of GnRH uses)..situations when we need to give GnRH continuously ..
A-Cancer of prostate :
This type of cancer is androgen dependent in it’s :
 growth
 metastasis
 even the pain that it causes
SO GnRH is the treatment to be used in this case and it’s superior to other treatments.
This cancer if discovered early then there is NO problem ..we remove the prostate surgically .. but usually we discover it very late .. we open then we find the prostate sticking to the bladder and to the intestine.

In the past they used Estrogen (which is an anti-androgen) but NOW they use GnRH in large doses as the first line of therapy and the best treatment. 

B-Endometriosis : a condition associated with the development of endometrial tissue in other places than the uterus especially Ovaries and abdomen, results in menstrual abnormalities and abdominal pains.

C- IVF (In vitro fertilization) :
Normally the female produces one ovum and sometimes 2 ova ..
But here in this situations we have infertility so she is not able to produce any ..
This infertility maybe because of many reasons… maybe their hormones are normal (male and female),But for a reason or another the lady doesn’t get pregnant.
IVF,, is a very expensive procedure ,,so we have to do everything we can to increase the incidence of pregnancy… and to increase the success rate we have to take more than one ovum.. HOW??
By over stimulating the Ovary ,, How??
By LH,FSH NOT GnRH .
LH is responsible for ovulation to form the ovum.

So we supress the whole process (the whole axis)

GnRH
↓
LH; FSH
↓
E2 ; Progesterone, follicle development
& ovulation (♀’s)
Testosterone; spermatogenesis (♂’s)

And then we give LH ,FSH from outside with other hormones and other drugs to enhance the production of more than one ovum .
The major drugs used to suppress the axis is (GnRH) by giving it in large doses or by giving SUPER agonists .. After suppressing we give the lady LH,FSH -which we get them from urine- and other drugs like :anti-estrogen ((the dr said we will understand them better later on)).

Then we will end up with at least with 6-7 ova,, we take them and then inject the sperms into these ova .. when the zygotes are ready we implant them inside the lady’s uterus.

The success rate nearly 20-25% just even when we put the 6-7 ova ,, some of them will drop ,, and even if the lady get pregnant abortion may occur .. so we do it again and again ,, till it succeed .
In the past they used to put both ova and sperms in the Petri dish under certain conditions waiting for fertilization then they implant the zygote ,, NOW they do it by injections..

D-precocious puberty :
In delayed puberty we use a pulsatile administration of GnRH but here is the opposite.. in this situation the female has menses at an early age such at 6 or 7 instead of 12-14..,, so we can suppress it by large doses .

E-uterine fibroids and uterine lieomyomas ,, certain tumors and fibrosis in the uterus could be treated by large doses of GnRH.

F-contraceptive agents :
Since it inhibits estrogen , progesterone ,LH,FSHovulation in females
And testosterone and spermatogenesis in males ,,so we use as contraceptive agent cause relatively it’s safe in comparing it with estrogen and progesterone .
Contraceptive works as a –ve feed back on pituitary to decrease the secretion of LH ,FSH,, but the failure rate is high .. and the major effective administrating pattern is subcutaneously ..

GnRH side effects:
We said it’s relatively safe ,, but there is nothing without a price ,,
1- production of GnRH antibodies overcomes by increasing the dose(??) (here once the dr said we increase it and the second time he said we decrease it ,,, so I’m sorry I’m not sure . )
2- headache, abdominal pain ,, but don’t worry tolerance will develop to these side effects.
3- Osteoporosis , which is the main side effect of GnRH.
4- GnRH specific antagonists (ganirelix which can be used in IVF cause as we said we need to suppress the famous axis ,, that is achieved either by:
Increasing the dose and continuous administration OR by giving GnRH antagonists.
Why to suppress.. why not to keep the LSH ,FSH that are already presented in the lady normally ?
A:
The major purpose for that is to avoid overstimulation of the ovaries which is a very severe syndrome,, resulting in severe abdominal pain and in some cases could be fatal .
So they found that suppressing the axis by high dose of GnRH decreasing the incidence of ovarian hyper stimulation syndrome,, that’s why we suppress it .

A Q was asked by Al -3omari but I didn’t hear it clearly ,, but it was about the structure of GnRH ,, dr : when we change the last 7 a.a .. we change affinity of GnRH to it’s receptors and the binding strength  all of them increase if we give super agonist.
Whatever we change in th last 7 a.a the hormone will still be an agonist,, till we play with the first 3 a.a ,, then it will change to antagonists.




Pituitary hormones

Anterior pituitary gland’s hormones are classified chemically into:

Simple peptides:
 ACTH
 MSH
Proteins :
 GH
 PRL
Glycoprotein:
 LH
 FSH
 TSH
You have to care about the abbreviations and to memorize them..

The pituitary gland is divided into two major lobes :
Anterior and Posterior.
Posterior lobe secretes the two hormones which are synthesized mainly in the hypothalamus : (Simple peptides (9 a.a)
 ADH (Vasopressin)

 Oxytoxin

Hypothalamic hormones regulate the ant.pituitary hormones by reaching it through the portal system .
Mainly the ant,pituitary hormones under stimulation of the hypothalamus except for prolactine mainly under inhibition .
We can prove this by stimulating the hypothalamus and measuring the ant.pituitary hormones,, the result will be stimulation of all the pituitary hormones except for prolactine it’s concentration will drop down,, or by removing it and then all the ant.pituitary hormones will decrease except for prolactine will increase…

TSH (thyroid stimulating hormone) :
It stimulates the thyroid gland this will increase ..
 T3 and T4 through increasing the cAMP
 ↑ Iodine uptake
 ↑ iodination and hydrolysis of thyroglobulin

Mainly used as a diagnostic tool .


ACTH: (Adrenocorticotropic hormone)

Derived from larger precursor (Pro-opiocortin)
Again to the axis:
CRH


ACTH



Cotrisol
So ACTH major use is as a diagnostic tool assist the function of adrenal and could be used in some cases of adrenal insufficiency provided that the deficiency in the ant.pituitary gland not in the adrenal.

 So ACTH,, ↑ cortisol release.
 Undergoes circadian rhythm
Means dayornal variation “Sry not sure of the spelling ”,, being high in the daytime and low at night .. this is in normal people but in those who work at night and sleep at daytime it will be reversed,,, THE circadian pattern of cortisol is a reflection for the ACTH one’s.
In the past they used the term he has cushion (hh not sure of the word also)at the daytime but at the night he doesn’t ,, then they found that this is the normal physiological pattern of cortisol which counteracts the stress.
Synthetic agonists like:
Acthar and Cosyntropin = (tetracosactrin; Cortrosyn)

Growth Hormone GH : (somatropin)
The third hormone in the pituitary hormones
 Highly species specific ,, WHAT does that mean? that it’s specific for the species itself and not for any other ones ,, for example we can take Insulin from Animals but GH we can’t,, because the structure of human GH is completely different from that of the animal’s .
 MOA : is unclear ,, its effects believed to be mediated through IGFs (Somatomedins) which are formed in the liver , kidneys, muscles and other tissues
 IGFs (Insulin-like growth factor) are secreted from ant.pituitary goes to the liver producing certain factors or hormones (cosuder them as second messenger ) they will mediate the effect of GH.
 The major effect of GH is stimulating the growth of soft tissue and bone.
GHdevelopment .
GH affects the glucose level in the blood by glucogenesis ,, it reduces the utilization of glucose …. ↑ gluconeogenesis & ↓ glucose utilization (diabetogenic effect)
In the future ,,When we talk about the diabetes types 1,2,3and 4 ,, type 4 diabetes which is caused by excess secretion of some hormones that increase the glucose level ,,, GH is one of them ;)
Prolactine-like activity and vise versa .. means also prolactine has a GH-like activity.. due to similarity in the structure.

PRL (prolactine) is Under major inhibition by hypothalamus “Again”
GH is also can be inhibited by It due to the similarity in the structure as we said before.
GH increases Lipolysis.

Factors that increase GH release :
We have to know the factors that increase it or decrease it in order to know the drugs or factors that we have to use in cases of deficiency or over secretion,, cause as WE know  the major disorders affect endocrine system are EITHER deficiencies OR excess production.
Return back ,, Factors that increase the secretion of GH,,
Sleep,, DR : “nam baker w fee2 bakeer shof el97a keef bt9eer”
Due to the latest studies and researches ,,, sleep without any amount of light “even elnwaseh ,, turn it off in order to get normal release of GH”
Backing to Sleep ,, is the major physiological factor affects GH release .
Normally we don’t need GH after the full or closure of the epiphyseal plate ,, so after 20-22 yr we don’t need it .
Hypoglycemia as we mentioned before it’s role in blood-glucose level.
Beta adrenergic agonists , clonidine.(??)
Bromocriptine and levodopa in NORMAL individuals but it inhibits GH synthesis and production in situations where there is excess release of GH .(??)

Factors that reduce the GH secretion:
Bromocriptine & Cabergoline in acromegalics
Somatostatin synthetic analogs like: octreotide S.C or lanreotide I.M
[/so we treat Acromygalies by GH inhibitors..eg : Bromocriptine , levadopa,otereotide,lanreotide]

Disorders affecting GH secreting cells :
Hypersecretion → Gigantism in children and Acromegaly in adults.
Gigantism ,, is a very severe case even if we remove the pituitary gland surgically the outcomes are not good ,,patients usually die ,, here if we remove the pituitary gland we have to make up the other hormones by drugs.
Another treatment is by Somatostatin (GHIH) synthetic analogs .
Also Dopamine agonists (Bromocriptine; Cabergoline) can be used.


Hyposecretion → Dwarfism
Treatment by ,, GH-replacement therapy(HRT)
In the past they used to use the natural GH but they found that it has many side effects especially Gaycob… disease (sry 7awlt 2sm3o wdwrt kteer bs no way ..)
But now they use the synthetic recombinant human GH ,, they are free of side effects those synthetic recombinant human GH like :
Somatropin (Humatrope)
Somatrem (Protropin)
They are given S.C 1/day or I.M 3 times /week..
Which one is better ??
Here we return to the normal releasing pattern of GH in our body and it’s like the following:
At night

On daily bases

Subcutaneously .

Always in HRT we try as much as possible to SIMULATE or mimic the normal physiological conditions for the hormone in our bodies ,,like : the amount of release or time of release ..To get the BEST outcome .
Giving GH :
On daily bases
Subcutaneously
At night

Is the best treatment of dwarfism.
“the doctor’s story with Growth difficulties ….”
DON’T play with hormonal environment ,, hormones are only used when indicated,,

For how long GH should be given to a child with dwarfasim...????
Till the closure of epiphyseal plate .. means till 20-22 yrs then we stop it …
GH deficiency in adults has no clinical significance ,,
Side effects of GH :
Abs formation → Resistance to Rx ,, overcome by(↑ dose)
↑ intracranial pressure with papillidemia
Acromegaly
Hyperglycemia and glucosuria
The Dr is in hurry so he is just reading this slide

PRL (prolactine ) :

Secreted from Ant. Pit and Placenta in a pulsatile manner.
It’s under inhibition of the hypothalamus ..
Has GH-like activity
Some drugs increase it’s secretions like dopamine antagonists.

PRL major role is in females during puberty for development of the breast and during pregnancy for lactation.
PRL has a significance effect in males which is physiologically not understood ,, but they said that it plays a roll in immune system.
But it’s still there in males,,,
IN hormones there is NO difference between males and females..
Even females have testosterone from adrenal gland but the difference is in the amount of the hormone.
So,, the role of prolactine in males is specific for some clinical situations ,,, where they (doctors , researchers ,, who ever ,,,,)found that it has an inhibitory effect on LH,FSH ,, SO if it increases in small ,,small amounts in the male’s body it will inhibit the spermatogenesis ,,, NO sperms ,, no testosterone.. sometimes ,, in some families they are not able to have a child although everything in the lady is ok ,, and the sex is okay,, here maybe alittle increase in PRL level in the male is the cause,, the treatment is very easy by taking bromocriptine for 2-3 weeks and that’s it and it’s effective orally so it’s soo easy .

“galactorrhea syndrome”(??)

so

In ♀’s:
Breast development (puberty; pregnancy)
Lactation
↓ LH & FSH (galactorrhea amenorrhea syndrome)

Role in ♂’s :
↑ PRL (↓ LH & FSH) → ♂ impotency & infertility


 Factors/drugs that increase PRL:
Pregnancy, sleep, nursing, stress (surgery, exercise)
TRH, Estradiol, DA antagonists (antipsychotics= phenothiazines and haloperidol; metoclopramide..)
Methyldopa(??), reserpine, diazepam, opiates, meclozine, imipramine…


Factors/drugs decrease PRL:
DA agonists (Bromocriptine, pergolide, levodopa)
apomorphine, clonidine , MAO inhibitors (pargyline)
the Dr is just reading in hurry and adding nothing to the slides except:
addicted persons don’t have sex cause their only enjoyment is by taking the morphine ,,, so the addicted male is sexually dead.

Clinical uses to bromocriptine(which is a dopamine agonist):

Hyperprolactinemia in ♂’s and ♀’s irrespective of its causes
Suppression of lactation ,, it’s imp in some cases like when the baby is dead in utero ,, so then we have free milk and if we don’t suppress it and the milk stays in the breast it provides a rich media for inflammation ,mastitis , abscess formation ,, here the factor of choice is bromocriptine .
Acromegaly
Parkinson’s disease
Bromocriptine is given orally.

The END ,,,,
Best wishes for you all..
Corrections are more than welcomed..


Done by : Abrar Sa’adeh .
Date of lec : 13-2-2011.
Dr. Souhail Al-zmaili.
The third pharmacology sheet .

thx Shadi

u r welcome MoHammad