pharma sheet # 4 -

Pharmacology sheet # 4
Date of lecture: 20/2/2011
Done by Haneen Bahzad

Continue of Ant. Pituitary hormones

Gonadotropins: LH & FSH

• Are glycoproteins
• Each of them consists of alpha and beta subunits
• Alpha subunits are encoded by a single gene
• Beta subunits are encoded by different genes
• The biological activity of these hormones mainly contribute to beta subunits
• All the synthetic steps of these hormones are under regulation by the hypothalamic hormone (GnRH) but the first process to be affected by GnRH is the release process.
• GnRH stimulate LH, FSH
• In female,LH,FSH responsible for estrogen & progesteron production, follicle development & ovulation.
• LH is mainly responsible for ovulation
• While follicle development is the function of FSH
• In male, testosterone is essential for spermatogenesis
• In the male testosterone production is mainly under the control of LH
• While spermatogenesis mainly under the control of FSH
• Fertility in males depends on sperms, in females depends on ova
• No GnRH, there is a problem in fertility whether in males or in females
• No LH, FSH also infertility problem
• No estrogen, progesterone also infertility problem
• the whole system has to be intact for fertility whether in male or in female
• any deficiency in these hormones could result in infertility either in male or in the female
• if the problem is sexual function in male we place usually testosterone
• even if the problem is sexual function in female due to estrogen deficiency for example , we place estrogen or a lady in postmenopausal period , developing certain manifestation known as postmenopausal syndrome we replace it with estrogen
• but remember if the problem is in fertility and it is in FSH,LH we have to place FSH,LH
• if LH,FSH deficiency is secondary to GnRH deficiency we can replace by GnRH but in this case GnRH has to be given normally in a pulsatile manner ( in pulses ) , each GnRH pulse is followed by LH,FSH by half an hour [this is the normal]
• we divided the clinical uses of GnRH into 2 parts: most conditions where it is required to be given in pulses , and those conditions that required to be given in large doses
• Mechanism of action is mediated through second massenger cAMP
• LH has a function in male it help in decent of testes
(Testes develop inside the abdomin (in the fetus life) after delivery it decent into the scrotum by LH )
• The major source of LH &FSH is from the urine of postmenopausal woman (human menopausal gonadotropins) " menotropin "
which give LH &FSH in the ratio of 1:1 .
• However LH is metabolized very quickly so we considered that human menopausal gonadotropin "menotropin" is responsible mainly for the production of FSH , but remember menotropin contains both LH,FSH
• So there is other hormone we use it for induction of ovulation and IVF procedure to be more successful, this hormone is human chorionic gonadotropin hormone


Human chorionic gonadotropin hormone ( hCG )

• "Gonadotropin" since it acts in gonads ( testes In male and ovaries in female )
• Is produced mainly by placenta during pregnancy
• It is the hormone along with progesterone that maintain pregnancy
• Its pharmacological action is exactly similar to LH( hCG a little bit more potent and resist the metabolism by liver as compared to LH)
• Obtained from urine of pregnant ladies.

*clinical uses to gonadotropins:
1-infertility in male & female due to LH&FSH deficiency .
2-I.V.F (ovarian hyperstimulation syndrome is the major limitation of this procedure)
3-cryptochidism(hCG ; I.M)
Note: cryptochidism is a condition of undecending testicules, Human choronic gonadotropin can help in decending it.


* side effects of gonadotropin:
1-allergy
2-ovarian hyperstimulation syndrome,which is very dangerous, some time it is fatal in ladies.
3-multiple births, it is advantage especially in I.V.F procedure.
4-production of specific antibodies.
5-precocions puberty and gynecomastia.


*** If the problem is sexual function:
 Give estrogen(♀’s); or testosterone(♂’s)

*** If the problem is infertility: give
 GnRH in pulses
 LH, FSH, hCG both in males and females.
 Estrogen (♀’s); testosterone (♂’s)
 Bromocriptine:
- we use bromocritine in the case of infertility due to excess production of prolactin
Note: if prolactin increase, LH&FSH will decrease in both (♀’s); (♂’s)
- Is dopamine agonist
- Inhibitor of prolactin synthysis and release
- Highly effective in the management of hyperprolactenemea.


In the excess of estrogen , this will lead to strong negative feedback on GnRH at the level of hypothalamus hence lower the level of LH , FSH in both male and female.
At the level of female: estrogen produced by the ovaries which will lead to strong negative feed back, this will lower the level of LH & FSH
At the level of male: testosterone is usually converted to estrogen especially at the level the hypothalamus by aromataze enzyme
(aromatization rxn) which will lead to negative feed back……………. ……

Note:
o Androgen is converted to estrogen in ovaries and testicles
o The first step in the synthesis of steroids is cholesterol

The solution of strong negative feed back of estrogen is by given
(Estrogen antagonist):
 They are widely used in the management of certain cases of infertility which is due to strong negative feed back both in (♂’s) ; (♀’s)

MOA of estrogen antagonists as anti-infertility agents :
X GnRH X -
- ↓ E2
LH; FSH
- ↓ -
E2 ; Progesterone (♀)
Testosterone (♂)


 It is also used in IVF procedure
 Clomiphene citrate or Tamoxifen (estrogen antagonists)



Post. Pituitary hormones

 There is 2 hormones secreted (not synthesized) by post. pituitary : Antidiuritic hormone (ADH) & Oxytocin
 nonapeptides (9 a.a)
 They are synthesize in the hypothalamus & stored in post. Pituitary and released from it & there existence in CNS give you a hint that they have a role in neurotransmitters .
 role of oxytocin in man is unkown but he have it in his body
Note: All female's hormones are in males and visa versa






A. ADH "vasopressin"

Physiological and pharmacological actions:
1. Vasoconstriction (V1 receptors)
Note: the action mediated by three receptors (mainly by two receptors)
V= vasopressin
2. ↑ reabsorption of H2O from collecting ducts (V2 receptors), it is the major effect of ADH
3. ↑ synthesis of certain clotting factors (V2 receptors)
4. ↑ ACTH release (V3 receptors)
5. Oxytocin-like activity
Note: ADH has some Oxytocin activity and Oxytocin has some ADH activity due to similarity in structure as we mention before the similarity in structure of GH & prolactin hormone.

The importance of knowing factors are of two terms:
• Factors/Drugs ↑ ADH release (Factors/Drugs utilized in ADH deficiency )
Factors/Drugs ↓ ADH release (Factors/Drugs used in case of ADH excess production)
• Side effects


Factors/Drugs ↑ ADH release (Factors/Drugs utilized in ADH deficiency ):
- Hypovolemia, hyperosmolarity, Pain, Stress, nausea, fever, hypoxia
- Angiotensin II
- Certain prostaglandins
- Nicotine, cholinergic agonists, β-adrenergics
- Tricyclic antidepressants
- Insulin, morphine, vincristine…


Factors/Drugs ↓ ADH release (Factors/Drugs used in case of ADH excess production):
- Hypervolemia
- Hypoosmlarity
- Alcohol (due to the inhibition of ADH not a diuretic effect)
- Atrial natriuretic peptide
- Phenytoin
- Cortisol
- Anticholinergics, α-adrenergics, GABA...

*Disorders affecting ADH release:
Excess production → Dilutional hyponatremia (excess water will be reabsorbed)
Causes:
- Head trauma, encephalitis
- Meningitis, oat cell carcinoma
Treatment:
- Hypertonic saline solution (is the best)
- Fludrocortisone ( which has a mineralocorticoid activity, which has "aldosterone" like activity) → ↑ Na+ blood level
- ? ADH antagonists


Deficiency of ADH( more common) →Diabetes insipidus (DI) (common)→ sever polyurea ( more than 10 L /day of urea )

note: This patient differs from patient with diabetes mellitus (Diabetes mellitus 2-3 L/day of urea "max. 4L / day" )

- Deficiency of ADH is easy to diagnose & easy to treat .

Causes:
- Idiopathic DI ( unknown etiology )
- Congenital
- Hypothalamic surgery, head trauma, malignancies
- Familial DI, deficiency of vasopressinase
Treatment:
ADH preparations (HRT= hormonal replacement therapy)

*ADH preparations
1) Natural human (Pitressin):
 Given I.M, S.C {injection},
 Has short half-life (15 min) so they not used widely nowadays.

2) Lypressin: ( synthetic, porcine source) { very very important }
 Given intranasally, I.V, I.M,
 Has short duration of action (4hrs) {has a longer duration as compared to the natural ADH}

3) Desmopressin: (synthetic ADH-like drug)
 Given intranasally(most used) one puff/ day { convenient rout of administration, even allergy in the nose has not been reported following the use of desmopressin preparation}, S.C .
 Most widely used preparation, has long DOA (12 hrs).
 Has a great selectivity for V2 receptors (vasoconstriction is not that much).
 It is given for such patient for life so it is a control rather than treatment. Most of the cases are from idiopathic type of DI


4) Felypressin (synthetic ADH-like drug)
 Has strong vasoconstrictor activity .
 Wildly used in dentistry.
 Local anesthetic may be combined with vasoconstrictor or alone
{ prefer to use local anesthetic alone (using one drug better than using two drugs)}
 The major action of felypressin is to extend the action of local anesthesia.
 The major point regarding the use of felypressin is to extend the action of local anesthetic or to limit bleeding or to limit systemic absorption of local anesthetic.
 Better than epinephrine ( felypressin associated with less side effects)


• Clinical uses to ADH:
1- Diabetes insipidus (DI)
2- Nocturual enuresis ( التبول الليلي اللاإرادي) = ( البوالة التفهة)
In the past they use imipramine (tricyclic antidepressant) to treat it.
Imipramine act by increases the synthesis, release of ADH .
Nowaday the treatment is done by diven desmopressin intranasally to the child until it relieved { 50 puffs/ day are enough to treat this condition} .
3- Hemophilia:
Due to increase production of certain clotting factors .
4- Bleeding esophageal varices .
It is a very sever condition

• Side effects to ADH preparations :
1. Allergy .
2. Pallor شحوب الوجه ( due to vasoconstriction )
3. Headache , nausea.
4. Abdominal pain
In female not in male because ADH has Oxytocin like activity which make contraction of uterus .
5. Anginal pain ( coronary artery vasospasm )
6. water intoxication ( massive doses )
Due to excess water reabsorption ( ADH effect)
- Note: in the hand out H2O intoxication (oxytocin-like activity, massive doses)
Here it is wrong eliminate it
It is related to abdominal pain not to H2O intoxication

7. Gangrene ( rare , particularly with desmopressin = has great affinity to V2 receptors ).
Sever vasoconstriction which lead to gangrene .
B. Oxytocin (9 a.a peptide)
It has two major functions

 Milk ejection (milk letdown) through contraction of myoepithelial cells of the breast.

Major stimuli, baby cry & suckling, so Drs Advice the lady to put the baby on her breast immediately after delivery

Remember: prolactin produces milk while oxytocin ejects the milk


 Contraction of the uterus → delivery
The uterus in early pregnancy is completely insensitive to oxytocin
So, if we use it in induced abortion, it will rupture the uterus.

Pregnancy divided into 3 periods; first trimester, 2nd trimester and 3rd trimester. In the pregnancy there is 10-12 Kg excess, the uterus is large and wall is thin (amniotic fluid, baby, placenta, amniotic membrane………).
The uterus is insensitive to oxytocin in early pregnancy but its sensitivity increases with advanced pregnancy reaching maximum at time of delivery.
Q: If bleeding happen during the first three months of pregnancy, what do we call this condition?
A: Abortion (الإجهاض) , the first step in management of abortion is bed rest. If the bed rest is succeeded in limitation of the bleeding and in saving the pregnancy we give progesterone to maintain the pregnancy.
If the bleeding is little bit more excessive, the lady is about to abort and no way to save the pregnancy, what do we use???
We do NOT use oxytocin bcoz the uterus in early pregnancy is completely insensitive to oxytocin, so if we use it in induced abortion, it will rupture the uterus.
We use prostaglandin, it could be a reason for contraction of the uterus, the sensitivity of the uterus to prostaglandin is the same on the first day until the end of pregnancy
So what is used as inducer to abortion is prostaglandin rather than oxytocin
Note: prostaglandin has been discovered after 20 years of discovery of oxytocin



Back to properties of oxytocin:
- Has slight ADH-like activity
- Role in man is unknown


Oxytocin MOA:
- Surface receptors → stimulation of voltage-sensitive Ca++ channels → Depolarization of uterine muscles → contraction of the uterus
- ↑ intracellular Ca++
- ↑ prostaglandin release (Oxytocin increase prostaglandin release especially prostaglandin which are known as contractors to the uterus)


Clinical uses to oxytocin:
A. Induction of labor by (إبرة الطلق الصناعي)
- At the time of delivery or labor, if contraction didn't happen we have to help the lady.
- oxytocin is the drug of choice to induce labor, given in gradually increasing units in an I.V infusion (drip)
- in hospitals, they prefer using vaginal peccary (a tablet of prostaglandin inserted vaginally) also prostaglandin can be given orally. {I'm not sure about this sentence}
B. Postpartum hemorrhage (hemorrhage after delivery):
- Following delivery of baby, is the delivery of placenta (which is
a vascular tissue) associated with bleeding that is called postpartum hemorrhage which is due to the blood vessels in the wall of the uterus.
- any thing contract uterine wall, will press on vessels so stop hemorrhage . In the case of oxytocin there are intervals between contractions (contraction _ relaxation) so we could use it in this case.

There are other drugs like Ergot alkaloids ((I.M.) ( we can give oral) ) which are better than oxytocin because Ergot alkaloids are strong contractor to the uterus and they produced sustained contractions of the uterus and then stop bleeding (immediately after delivery of the baby)
If the bleeding is little bit sever in such ladies we can repeat the injection or oral dose given.
Note: we can not use Ergot alkaloids to induce labor,
if we use Ergot alkaloids, it could associated in death of uterus
EXAMPELS: ergonovine( widly used), methylergonovine, syntometrine=(oxytocin+ ergometrine)

Back to Clinical uses to oxytocin:
C. Breast engorgement
- For example: in the case of death of uterus , the baby died and the milk will engorge inside the breast this may lead to abscess or mastitis
- If there is indication to suppression, the drug of choice is bromocriptine but if the lady is feeding her baby we can help her by intranasal progression to oxytocin or mechanically means which are better before using oxytocin.

D. Abortifacient {induce abortion}, I.V infusion in the 2nd trimester , ineffective in early pregnancy ( in the 1st trimester)

Side effects to oxytocin:
1. Rupture of the uterus ( we do not want to reach to this point) this will lead to removal of the uterus infertility.
It is a Major and most serious side effect.
2. H2O intoxication and hypertension
Due to its ADH-like activity
Specific oxytocin antagonist
Atosiban, effective in the management of premature delivery but beta 2 agonists are better



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