pharma sheet # 9 -Lana Obeidat

بسم الله الرحمن الرحيم

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pharma 9.doc

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We started talking last time about glucocorticoids ( cortisol as an example )
If you remember the structure of cortisol which is made form cholesterol (4 rings and side chains )
So we have a huge variety of manipulating the structure of cortisol in order to have a good glucocorticoid with good effects , what we aim for when making a drug is having minimum side effects ( the major and serious side effect is suppressing the axes ) , also a major limitation in the development of a good glucocorticoid is the aldosterone like activity .
We will try to reach a dosage form of glucocorticoids to give a sufficient anti-inflammatory , anti allergic , immune suppressive effect without producing aldosterone like effect ( like by putting a double bond in one ring, methyl group on c no. 9 and so on)
Glucocorticoids is available in all dosage forms

Metabolism :
In the liver more than 95% is modified by reduction and conjugation and a little( 5%) by hydroxylation reaction


Table :


There’s no need to memorize the numbers learn it in general
Prednisone is 4 times more potent as an anti inflammatory action compared to cortisol but it still has some aldosterone like activity
• You should know which ones are short , intermediate , long acting
• Long acting doesn’t have an aldosterone like activity ( = zero ) , but actually there’s nothing absolute zero
When we compare them to cortisol the half life of dexamethasone is longer , dexamethasone is widely used as a glucocorticoid and it’s anti inflammatory action is 50 times more potent, it’s aldosterone like activity is almost zero

Plasma half life and nuclear half life: ( certain steroid have short half lives but they act for a long period because they have longer half life in the nucleus , their binding with the nucleus is strong)
Dexamethasone has little affinity to the carrier protein it so it binds to the cell very quickly and can last for at least 15 or 16 hours due to it’s nuclear affinity
Bronchial asthma is divided into two types :
a) steroidal dependent
b) none steroidal dependent
there are some cases that we can control the bronchial asthma only with glucocorticoids , and the patient will have to take glucocorticoids for life .
the important idea is that when you decide to stop the glucocorticoids therapy you should stop it gradually to maintain the function of the axis
Clinical uses:
1) Adrenal insufficiency ( by hormonal replacement therapy , since there’s no cortisol we need HRT)
2) Adison’s disease
3) Inflammatory conditions ( it has anti inflammatory effect ) used in rheumatoid arthritis , SLE “Systemic lupus erythematosus” , arteritis, dermatomycosis, vertebral edema , ulcerative colitis, rheumatic carditis , active chronic hepatitis, procitits , acute gout )

4) Allergic reactions (hay fever, eczema, dermatitis , or even due to bites)
if someone was bitten by a bug or a snake and he has an allergic reaction then he’s given two injections : 1) anti histamine intra muscular 2) hydrocortisone IV and that is life saving

5) Immunosuppressant ( in organ transplantation , hemolytic anemia, leukemias, tumors and due to this effect it has a role along with anti cancer drugs in the management of different cancers ,You’ll find a lot of the anti cancer drugs that contain cortisol in them and that is hormonal therapy of cancer )
The advantage of glucocorticoids in comparison with cancer drugs that they do not suppress
bone marrow

6) Hypercalcimia ( irrespective to the cause of hypercalcimia , glucocorticoids are known to decrease the calcium reabsorption from lipids )
7) Hyper parathyroidisim
8) Many ear , eye and skin diseases whether they are allergic or inflammatory
In sever allergy glucocorticoids are given , but in the normal ( mild to moderate) allergy anti histamine is given.

Side effects :
1) Suppression of hypothalamic – pituitary – adrenal axis ( which is the major and most dangerous side effect )
2) Cushing syndrome ( the most common cause of Cushing syndrome is drug induced by glucocorticoids )
3) Salt and water retention ( it’s a universal side effect to all steroids – estrogen , progesterone , androgens , cortisol ) this is the aldosterone like activity and this cause hypertension
4) Peptic ulcer disease ( we said that this is due to the inhibition of prostaglandins synthesis and this causes GI ulcerations as well
5) Osteoporosis ( due to the increase of catabolism of proteins ) Osteoporosis is a major side effect while using the glucocorticoids as therapy , that’s why it’s suggested not to use glucocorticoids for a long time
If a patient has rheumatoid arthritis , we give him NSAIDs in the beginning of therapy , we only use glucocorticoids as the last resort of treatment because of the suppression of the axis
6) Diabetes mellitus : increase level of glucose in blood
7) Increase the incidence of viral and fungal infection due to immune suppression
Contra Indications : with patients who have peptic ulcers , viral or fungal infections , allergy
8) Decrease wound healing and causes skin atrophy and myopathy mainly due to the decrease in the anabolism of proteins
9) Suppression of growth of children
10) Cataract

Strategy of glucocorticoids:
1) Use a short acting steroid , we always like to use short acting drugs in general
2) Use minimal possible doses that give proper concentration at site of action without producing side effects
3) Give 2/3rd of the dose in the morning and a 1/3rd in the evening ( mimic the way that cortisol is secreted by the body ) , this is switched if the patient is one of those people who work at night and sleeps in day light ( 2/3rd in night and 1/3rd in the morning is given )

Alternate day therapy ( giving it one day then withholding it the next day then giving it again the day after that ) which is associated with less suppression to growth of children and to the hypothalamic-pituitary-adrenal axis suppression with fewer side effects )

Androgens and anti-androgens


FSH is responsible for spermatogenesis and LH for testosterone , we mentioned in some early lecture about the infertility cases caused by testosterone deficiency
Synthesis : same as cholesterol


Here you should know the inhibitors of the pathway that can be useful to treat any cases that have excess production of whatever steroid
You should memorise the names of the enzymes in this pathway (dehydrogenase enzyme, dehydroxylase and hydroxylase )

With respect to testosterone it is produced by the testicles , then secreted into the blood stream, it’ll then bind to a specific globulin, then it will be transferred to target cells and in those target cells it’ll be converted by a reductase enzyme ( 5α reductase ) to give 5α dihydrotestosterone which is 10 times more potent when compared to testosterone
There are some certain conditions that we use this pathway when we don’t need androgenic effect

Testosterone physiological & pharmacological effects:
1) Virilizing effect ( musculinising effect )
2) 1° & 2° sexual characteristics
1° : development of testicles, vas deferens , epididymis
2° : hair distribution
3) increase spermatogenesis
4) increase erythropoiesis ( increase RBC production ) and they play a role in the management of certain anemia’s particularly anemia’s associated with renal faluire
5) Anabolic or growth promoting effect (bone and skeletal muscle) , this will start around the age of 10 years ( increase in height and mass of the young male’s body) , if it started earlier than that it’s called precocious puberty , if he’s more than 15 years and it didn’t start it’s called delayed puberty ) , in females there is something similar to that considering the menstrual cycle and the breast development but it’s due to estrogen.

Testosterone metabolism: it’s metabolized in the liver producing two metabolites
1) Androsterone
2) Etiocholanolone

Clinical uses:
Anabolic effect : anabolic steroids they build up proteins , unlike cortisol that breaks down proteins
This fact was used by athletes that used androgens to increase their muscle mass to increase their speed , it’s prohibited to take any anabolic steroid now , it’s true that if testosterone was stopped 3 months before the race it won’t be present in the blood at time of the race but their metabolites could be detected after 2 years of stopping the drug .
Also when taking testosterone it’ll cause the axis to be inhibited and when they stopped taking the exogenous hormone a percentage of 10% suffered from irreversible inhibition to the axis and that caused infertility , like wise in females contraceptives these will cause complete atrophy of the ovaries and thus , infertility ,and after that IVF is their only resort .
1) Testosterone deficiency : it’s used to cure Hypogonadism; impotency ( decreased sexual function of the male , though there are some better drugs for this now with less side effects such as sildenafil (Viagra) ) , decreased libido, aging, infertility ( sildenafil has no effect on infertility , testosterone should be taken to solve that )
testosterone should never be taken with nitrates because it’ll cause severe drop in blood pressure and cardiac arrhythmia and then causes immediate death due to cardiac arrest
2) Anemia ( increase erythropoises ) ; leukemia; lymphoma ( since in these types of cancer they take drugs that will suppress the bone marrow and thus low RBC’s and WBC’s so testosterone will increase RBC level )
3) Endometriosis : a condition characterized by the development of endometrial tissues in places other than the uterus , it’s actually common in females , it’s associated with pelvic pain and menstrual disorders and causes problems with fertility , most common site for it to be seen in is the peritoneal cavity, it is LH, FSH dependent ( estrogen progesterone dependent) and as we know that androgens are anti-estrogens ( and estrogens are anti-androgens) so Danazol ( an androgen ) is particularly used for this case.
4) Antiestrogenic effect : used for certain types of breast cancers
( androgens, anti-androgens, estrogens, anti-estrogens and progestin’s and anti- progestins are used to treat breast cancer )
5) Anabolic effect
- Osteoporosis : androgens here can be used to treat females as well!

Testosterone preparations:
1° use for androgen replacement:
- Testosterone : intramuscularly , subcutaneous
- Testosterone propionate Intra muscular, Sublingual
- Testosterone cypionate Intra muscular; depo Intra muscular
- Methyltestosterone orally, sublingually
- Fluoxymestrone orally
it’s effective parentally ,orally even sublingually

1° use for breast cancer:
Testolactone Orally effective
1° use for anabolism: to treat osteoporosis
- Ethylestrenol orally
- Stanozolol orally
- Oxandrolone orally
- Nandrolone decanoate intramuscularly




Testosterone side effects:
- Virilization (masculinization) appearance of 2◦ sexual characteristics in the female “ female regarding the use of it in breast cancer treatment and endometriosis”
- Hirsutism; acne; menstrual disorders in females
- Precocious puberty & hirsutism in children
- Salt & water retention ( universal side effect )
- Jaundice due to the damage to the liver , gall bladder stones

Antiandrogens
- Estrogens: examples of estrogens that act as antiandrogens : Diethylstilbesterol; mestranol
- Progestins: Cyproterone acetate
- GnRH super-agonists( when GnRH is given continuously it’ll inhibit LH , FSH ) GnRH antagonists( no LH, FSH , no testosterone )
- Flutamide : it’s none estrogen , non progestin compound that will interferes with binding of testosterone at nuclear level
- 5α- reductase inhibitors: Finasteride ( highly effective in benign hyperplasia of the prostate which is a normal to happen in males – we’re not talking about prostate cancer which is androgen dependent in metastasis and growth , anti-androgen is used for it GnRH superagonist is the most commonly used for it superior to any other drug but again all of those anti androgens can be used -
- Ketoconazole : ( anti fungal agent , has inhibitory effect on steroidogenesis involving on testicles and adrenal gland )
- Spironolactone : antagonist to aldosterone found to be effective in ladies with hirsutism
- gossypol : ( phenolic compound obtained from cotton seeds , orally effective , widely used in china as a male contraceptive : this drug unlike estrogen , progestins will not kill the sexual function in males but it is associated with sever side effects .

Antiandrogens clinical uses:
- prostate cancer
- Benign hyperplasia of the prostate (Finasteride)
- Precocious puberty
- Severe acne and hirsutism in females (Spironolactone : it’s important for hirstism, and many ladies with excess hair use it , it has no side effects
- Males anti-fertility agents male contraceptive) (Gossypol)
- Males’ baldness

Antiandrogens side effects:
Decrease libido, causes impotency and decreases spermatogenesis

Estrogens & Antiestrogens
Major hormonal changes in the menstrual cycle

We have two phases in the menstrual cycle :
Phase no.1 : follicular phase
Phase no. 2 : luteal phase
In the beginning of the period there is bleeding ( 4-7 days) , the length of the whole period is around 28 days ( 22 – 35 days ) , if it happens every 20 but it’s regular without Menorrhagia (which is excessive bleeding) it’s considered normal
Follicular phase: 14 days , the major steroid in this phase that is responsible for the changes in the uterus and the ovaries is estrogen
Luteal phase : 14 day , , the major steroid in this phase that is responsible for the changes in the uterus and the ovaries is progesterone

We also have cyclic changes in respect to gonadotropins ( LH, FSH)
We have an important event which is the LH surge , this surge indicates that the lady is highly fertile and that she’s in time of ovulation
There are two ways of determining this time
1) X – 14 = Y
Ex: length of period : 28 so
28 -14 = 14 , so the day of ovulation is the 14th day , but this is not an accurate method but it just gives a hint about it.
2) The 2nd way is : at the beginning of the 2nd phase, progesterone starts to rise causing a slight elevation in body temperature , some females might notice it, others might not. This is due to the thermogenic effect of progesterone and this happens just before the LH surge ( before ovulation) , this way is used in the behavioral contraceptive method. Intercourse should be avoided two days prior and two days after the rise in temperature, but the problem rises in cases where there is early or late ovulation , so it’s associated with high pregnancy rate . It is a preferred way of contraception because it doesn’t involve taking drugs
Estrogen has a positive feedback mechanism on LH surge
By the end of the cycle progesterone levels drop leading to bleeding ( if there’s a pregnant lady and bleeding occurs ( an abortion case ) we can stop this bleeding by giving progesterone . progesterone is given to female pilgrims to stop their menses ( called mini pill ) , it suppresses the GnRH axis ,Also in IVF after implantation of the zygote the lady is immediately given progesterone (tetragesterone) to maintain pregnancy .)

Natural estrogens:
Estadiol which is more potent than Estrone which is more potent than Estriol .
Natural estrogen is ineffective orally but synthetic ones are orally effective
Synthesis:
From cholesterol , same as testosterone synthesis , but take notice of the role of aromatase enzyme in converting androgens (testosterone & androsteindione) to estrogen



Aromatase inhibitors can be used in cases with excess estrogen production .
( please revise the Clomiphene citrate anti estrogen from a prior lec. And how it works on the infertility of the male , because testosterone changes into estrogen and that will cause the negative feedback on the hypothalamus)

Estrogen is released form the ovaries , bound to a certain type of globulin , reaches a certain cell, interacts with cytosolic receptor and translocates into the nucleus and so on.
Mechanism of action : same as cortisol
Estrogen receptors (ER-α; ER-β)
Modulation of gene transcription (nuclear receptors) ,Stimulation of endometrial nitric oxide
Synthase, nitric oxide vasodilatation and cardiac protection ( it produces cardiac protection )
This is the reason estrogen is used in (estrogen replacement therapy) in post menopausal ladies


Estrogen actions:
- 1◦ & 2◦ sexual characteristics of females ( like hair distribution )
- Proliferation of the endometrium & follicular maturation
- Increase the elasticity of skin
- Increase the synthesis of certain globulins by the liver
( SHBG, corticosteroid binding globulin & thyroid binding globulin)
- The irregular doses used in oral contraceptive pills with high estrogen percentage will cause an increase synthesis of certain clotting factors (fibrinogen, factors VII; IX & X) and decreased activity of antithrombin III ) , so estrogen is dangerous and causes thrombosembolisms
- Decrease cholesterol, increase HDL & decreases LDL blood levels ( and for this reason it protects the heart against myocardial infarction or ischemic heart disease ) note that the doses here are ( used for replacement therapy , NOT high doses )
- Salt & water retention ( universal side effect)
Absorption & metabolism of estrogens:
it goes under conjugation in the liver and estrogen goes under enterohepatic circulation ( given orally, passes through portal system to the liver and back to the intesten for absorption )
a product was synthatized in a conjugated form to by pass the liver conjugation and lower the side effects

Estrogens clinical uses:
- HRT ( hormonal replacement therapy ) for Postmenopausal syndrome & osteoporosis, prevention of heart attacks
- Major components of OCP’s ( oral contraceptive pills)
- Could be used in Prostate, breast, endometrial cancer along with progesterone NOT alone
- Dysmenorrhea ( due to the deficiency of estrogen certain ladies can experience some type of pain in the pelvic or abdomen area NSAID’s especially Ibuprofen is used for that, estrogen can be used if the problem is hormonal)
- Infertility (estrogen deficiency could lead to certain types of infertility)
- Acne, hirsutism (by being an anti androgen)

Estrogen preparations:
- Synthetic steroidal ( Estradiol benzoate; Estradiol valarate ,Ethinylestradiol; Mestranol)
- Non steroidal synthetic estrogens (Diethylstilbesterol )
- Conjugated estrogens (Estrone sulfonate ) conjugated in an attempt to decrease side effects

Side effects :
- Nausea and vomiting
- Headache , migranous headache
- Dizziness and weight gain
- Salt water retention
- Hypertension
- Increased risk of thromboembolisim
- Cancer, increased risk of endometrial cancer if used alone
- Teratogenic effect
Same side effects following oral contraceptive
These side effects are absolute contraindication for using contraceptives.






THE END
Lana Obeidat
8/march/2011