pharma sheet # 10 - Sura Ala3mar

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pharma sheet # 10 - Sura Ala3mar

Post by Shadi Jarrar on 15/3/2011, 4:02 pm

بسم الله الرحمن الرحيم

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Pharma 10.doc
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By the Name of God
Lecture 10/Pharmacology 13/3/2011
Last One For Dc. Asem

Anti-Estrogens … Progesterone … Contraception

Last lectures we start talking about Steroids, and we begin with Androgens, anti androgens and we end up with estrogen. Today we will continue talking about Anti-estrogens, progesterone, anti-progesterone and Finally Contraception.

Anti-Estrogens

We discus that under infertility, there is a strong negative feedback by estrogen on GnRH, LH and FSH. We also said that Androgens act as anti-estrogens But the most widely used Anti-estrogens are Competitive antagonists at estrogen receptors.
The Anti-estrogens are classified into 3 major groups :

1. Competitive antagonists at estrogen receptors
This Group is antagonist at estrogen receptor at the level of the hypothalamus. It’s include clomiphene citrate which is primarily used for management of infertility (strong negative feedback) in male and female.

Also include Tamoxifen which is more effective in management of certain types of Breast Cancer but also may be used for management of infertility.
It has agonist/antagonist mixed action , that it acts as Estrogen antagonist in breast but It may also act as Estrogen agonist on bone and endometriam, So the long term use of Tamoxifen lead to endometrial cancer.
So both Tamoxifen and clomiphene citrate can be used for management of infertility, and they are given orally.

Note that estrogen, anti-estrogen, androgen, anti-androgen, Progesterone and anti- Progesterone are used in management of breast cancer but which is used depend on the type of the breast cancer.


2. Selective Estrogen Receptor Modulators (SERM)
They are non-hormonal agents that bind to estrogen receptors to act as agonist in certain sites and antagonists in other sites. They act as antagonist in breast and endometriam but agonist in bone as in the last group, that’s why nowadays they consider Tamoxifen and clomiphene citrate belonging to this group, BUT For EXAM we consider them in separate group.


3. Aromatase Inhibitor.
As we know that Aromatase enzyme converted Androgens(Testosterone and Androstenedione) into Estrogen, so this group inhibit this enzyme in order not to produce estrogen.
The Drugs of this Group are either Non-selective or selective drugs.

- Nonselective Drugs
This group act not only to inhibit aromatase enzyme, but also act on other enzymes in the estrogen synthesis pathway. This include Aminoglutithemide which acts to inhibit aromatase enzyme and act as Desmolase Debranching (DE) enzyme inhibitor ; so it inhibits DE enzyme in the 1st step in synthesis of different steroids. So it’s MAIN function is to block the production of steroids derived from cholesterol.

- Selective Drugs
Which act only to inhibit aromatase enzyme and include Anastrazol which is mainly used in management of Breast Cancer.



Progesterone

Progesterone synthesize in ovaries and placenta during pregnancy. It’s synthesize from cholesterol by Debranching Enzyme (DE) to form Pregnenolone which is converted by Dehydrogenase (Deh) enzyme to Progesterone as figure shown.

DE Deh
Cholesterol Pregnenolone Progesterone

Now regarding Physiological and pharmacological Effect of Progesterone…
- important for function of ovaries and uterus and responsible for changes in ovaries and uterus in the 2nd half of menstrual cycle.

- Most important effect of it, is development of breast at the time of puberty and during pregnancy.

- maintain pregnancy so endometrial Growth and Has weak aldosteron-like activity.

- There is some effect on cervical and vaginal secretions ; by increasing mucus content of vagina, decrease sodium secretions and increase viscosity of cervix.

- Thermogenic Effect just prior to LH surge (in method which we use or follow under what is known behavioral contraception).

 The Absorption and Metabolism are important in progesterone because Natural
Progesterone are ineffective orally But there are many synthetic preparations that are widely used orally in the management of conditions requiring progesterone. Also we can give progesterone by Intramuscular (I.M) injections and even we have sub dermal implant dosage that act at least for 5 years as a method of contraception.


 Regarding Progesterone preparations they are many but the most important is
Dydrogesterone which is a widely orally effective progestin and it’s not Teratogenic as other progestins and estrogen which are Teratogenic when given from outside the body not the natural ones.
It’s used immediately following In Vitro Fertilization (IVF) to maintain it ;in which egg cells are fertilized by sperm outside the body and IVF is a major treatment of infertility and it’s expensive.
Natural estrogen and progesterone should be given parentrally.

 About Clinical Uses of Progesterone , they are many …
- It’s a major component of oral contraceptive pills (OCP) which act by producing
Negative Feedback on pituitary so No LH,FSH.

- In Endometrial , breast and prostate cancers.. prostate cancer are androgen dependent and u must know that progesterone are anti-androgens so we use it here.

- In Endometriosis which is a condition that related to development of endometrial tissue in other places other than uterus especially in abdominal cavity, leading to menstrual disorders and maybe infertility.

 The Side effects of progesterone are not severe compared to estrogen. It may cause
Depression, weight gain and absolutely salt-water retention (which is a universal side effect of all steroids). You must know that withdrawal of progesterone lead to menses.



Anti-Progestins

They are Known as Mifepristone. There are many Clinical uses of there Group of Drugs which are…
- Abortifacient because since we use Progesterone to maintain pregnancy so anti-progesterone used for abortion. But it’s not that highly effective so we must combine it with PG (prostaglandins).

Now the sensitivity of uterus to PG is the same in early as well as in late pregnancy BUT sensitivity of uterus to oxytocin is Maximum at time of delivery (so it’s drug of choice to induce labor).but many Doctors usually start with PG.
Anti-progesterone are given in cases of abortive -as we said- when there is no way by which we preserve pregnancy. Now if there is severe bleeding so usually we use certain things such as PG, Anti-progestin and Oxytocin which is ineffective in early pregnancy but could be used in the 2nd trimester as abortifacient.
This lady –who suffer from sever bleeding- will end up by something known as Dilation of the uterus (cleaning of uterus).


- In Induction of labor again with PG.
- In progesterone dependent cancer such as Breast Cancer.
- Cushing’s Syndrome because these anti-progestins compete with cortisol at it’s receptor.


Contraception

Contraception defined as reversible method of inhibition of pregnancy, the major purpose is birth control. Strongly nowadays advice separation between kids. We have so many means of contraception :-

Male Contraception
Drugs contraception used in male result in total inhibition of sexual function of the male and all have percentages of failure.
They are ….
1. Behavioral contraception
same in both male and female as to avoid intercourse at high risk period in female (LH surge) two days before it and two days after it. But it’s associated with high failure rate which is 20%.

2. Mechanical contraception
such as condom with or without spermicidal agents. This also may be associated with failure.

3. Drugs contraception
such as Estrogen, progestins, Danazol, GnRH agonist and antagonist, spermicidal agent which are agent that kill sperms such as Gossypol. These drugs may have percentage of failure.

4. Surgical procedures
As ligation of the vas deference so as you interrupt the pass of sperms, and this is reversible procedure.



Female Contraception
They are …
1. Behavioral
as the one in male

2. Mechanical
female also use mechanical contraception which have different sizes such as…
- condoms with or without spermicidal agent
- Diaphragms
- Intrauterine device (IUD) which is widely used and they are the loops and coils provided with or without progestin. If they inserted coil inside the uterus so it will irritate the uterus lead to inflammation (Mechanical irritation) and thus make the uterus improper for implantation so it interfere with implantation.

The female has to ask the doctor before use it and it’s association with some sort of vaginal bleeding and with pelvic infection and the failure rate is present because some pregnant occur above the IUD, in this case we must remove the IUD.

3. Drugs
They are of 2 types…

- Estrogen alone Drugs
called Morning after pill, it’s used by taken large dose of estrogen for 5 days after intercourse so also called postcoital pill. This will expose the female to the estrogen side effects thus it’s associated with high failure rate.
Its include Ethinylestradiol and mestranol.


- Progesterone alone Drugs
widely used to inhibit menstruation. They are used as minipill. They are of 3 types..
1. Northisteron Tab.
Consist of 20 pill taken at day 5 of menstrual cycle to stop menstruation and used only for 20 days then after that she must stop in order not to change her normal physiology because normally she must menstruate.

2. Intramuscular MedroxyProgesterone.
Including Depo-Provera That could provide contraception for 3 months, meaning each 3 months she should take I.M injection. Failure rate high but less than of that of behavioral Method and even pregnancy could occur during this period (3 months).

3. sub dermal progesterone implant.
Including Levonoregesrel . Last for 5-6 years, it may cause bleeding spotty and pregnancy may occur so have also rate failure.

4. Sequential
Here estrogen followed by progesterone but also associated with failure rate and expose the lady in the 1st half of menstrual cycle to high level of estrogen.

5. Combined Oral Contraception Pill
To put estrogen and progesterone in the same pill and these are the most widely used nowadays and associated with zero failure rate. They put lower estrogen level as possible and high level progesterone as much as possible but in a limit not to reach the side effect and to end up with zero failure rate.


Now…
 The Mechanism of Action (MOA) of these OCD…
- The major MOA is Negative feedback on Anterior Pituitary so the site of action is on pituitary to inhibit the ovulation.
- Others include Increasing the viscosity of cervical mucus
- And change the fallopian tube motility


 The Side Effects of OCP are those related to estrogen Part which are …

-Nausea, vomiting, dizziness, headache, migraine, nervousness, depression
-Salt & water retention → ↑ BP
-Thromboembolic disease due to increased clotting factors by estrogen, embolism, MI
-Vaginal yeast growth
-Post pill amenorrhea and infertility
because when we give estrogen and progesterone from outside so suppression of the natural pathway in the body occur. Now 90% of ladies receiving contraceptives got reversible normal axis after stop it BUT 10% got irreversible stopped axis .the axis need 6 months – 1 year to recover after stop the pills.

 Because of these side effects,, OCP are contraindicated in these cases ..

-History of thrombomebolic disease
-Severe headache
-Severe nausea & vomiting
-Liver dysfunction
-Pregnancy
-Abnormal menstrual cycles
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The End
Sura Al-a3mar


Last edited by Shadi Jarrar on 16/3/2011, 2:30 am; edited 1 time in total
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Shadi Jarrar
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Re: pharma sheet # 10 - Sura Ala3mar

Post by Mohammad Bustani on 15/3/2011, 9:01 pm

hehe .. m3lomat pharma w dr micro w esmha patho :P
tz pharma , dr suhail
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Mohammad Bustani

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Re: pharma sheet # 10 - Sura Ala3mar

Post by Shadi Jarrar on 16/3/2011, 2:30 am

بسيطة بستاني .. ضغط شغل هاد Xp
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Shadi Jarrar
مشرف عام

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

http://jude.my-rpg.com

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