pharma sheet # 8 - Tamara mousa

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pharma sheet # 8 - Tamara mousa

Post by Shadi Jarrar on 11/3/2011, 5:27 pm

بسم الله الرحمن الرحيم

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4shared.com/file/lBoUBxmV/pharma_8.html
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Q : we know that PTH increases reabsorption of calcium in the kidney , so why do we have in hypoparathyroidism an increase in calcium level in urine ??
A: due to compensatory defense mechanisms , due to excess calcium in blood ,so some of it will be excreted in urine , it’s true there is a great absorption but the amount that’s moved from bone to the blood and the absorbed one will increase its level in the blood and some will be excreted in the urine , as compared to normal calcium level in urine will be high, which is a good thing ,despite this fact the amount which is excreted by the kidney is not that good enough to lower high blood calcium level so some will be excreted in the urine , so calcium isn’t totally reabsorbed in the kidney, the capacity of PTH in hyperparathyroidism is not that much in respect to its effect on the kidney { as we said the primary target organ is BONE , the second messenger involved is ( cAMP )
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- Aldose reductase (AR) inhibitors
Tolrestat; Alconil (inhibits the enzyme which converts glucose to fructose and fructose to sorbitol)
AR AR
Glucose Fructose Sorbitol
Sorbitol is a substance that is deposited in neurons, in the retina, in the kidney , and is believed to be the responsible for the late complications of diabetes (retinopathy, neuropathy and nephropathy)
In an attempt to prevent its formation we should inhibit AR enzyme ( but keep in mind we can’t totally prevent the late complications of diabetes, we only aim by controlling blood sugar level to delay the onset of those late complications )
Still under clinical trials: we are still working on creating drugs that inhibit rather than delay such complications
Side effects:
- Allergy (skin rashes, fever, chills)
- Myalgia and lymphadenopathy


- Somatostatin
It’s effect on blood glucose level is dose dependent
In low doses → ↓ glucagon release from the pancreas
Under evaluation because even these low doses are associated with severe platelet abnormalities, and abdominal pain ..
** Pancreatic transplantation >>it’s successful but very expensive and immunosuppressants are used
** Gene therapy: treats diabetes, by the implantation of the gene that encodes for insulin and this can be performed percutaneously, this is especially good for ones with very low amounts of insulin, (hard to do this treatment for those with very high insulin levels )
** Role of Glucagon in diabetics?!!!
We have to be familiar with drugs that affect blood glucose level ,because diabetics could get sick from any reason and we need to place them on certain drugs , so if we know that a certain drug elevates blood glucose level and the patient is on insulin therapy , we have to increase insulin dose and vice versa , if you give a diabetic patient any drug that decreases blood glucose level and you maintained the same dose of insulin this will be very dangerous .
** Drugs ↓ blood glucose levels:
β-blockers, salicylates, indomethacin, naproxin, alcohol, sulfonamides, clofibrate, anabolic steroids, lithium, Ca++ ampicillin, bromocriptine

β-blockers :
can both decrease and increase blood glucose level , BUT in general they decrease it.. how ?? >> they oppose the action of neurotransmitters that elevate blood glucose level(such as norepinephrine) and some reports say that they decrease the insulin release from the pancreas .
another important thing about β-blockers :
you can’t put a diabetic patient with hypertension on β-blockers , because they can MASK hypoglycemic manifestation
(over activity of the sympathetic system >> tachycardia, tremors, nervousness, sweating) and the best drugs to control such manifestations are β-blockers, so if you give this patient β-blockers and he’s already taking insulin, those manifestations will not be apparent, his blood sugar level can go to less than 40 mg/dl without him noticing that, so instead of β-blockers we use ACE inhibitors (angiotensin converting enzyme inhibitors)
** Drugs ↑ blood glucose levels:
β-blockers, thiazides and loop diuretics
Glucocorticoids
Oral contraceptive drugs
Ca++-channel blockers
Phenytoin, morphine, heparin
Nicotine
H2-receptor blockers

Goals of DM treatment!!=Control
 Ensure good Pt.-clinic relationship
 Control symptoms
 Prevent acute metabolic crisis of KA & hypoglycemia
 Maintain normal growth & BW
 Encourage self-reliance & self-care
 Eliminate risk factors
Smoking, ↑ BP, ↑ lipids…
 Prevent psychological complications
- Accept restrictions on life
- Diet control
- Monitoring blood glucose & insulin adjustment
- Know manifestations of hypoglycemia & how avoiding them
 Early treatment of complications
Photocoagulation, foot care advices...

We should always advice the diabetic patient to stay in direct contact with the clinic frequently






The adrenal gland
We have two adrenals...each one consists of an inner medulla “responsible for epinephrine, norepinephrine” and an outer cortex that’s made of three zones:
1- an outer zone that secretes aldosterone the major mineralocorticoid in our body
2- the middle layer secretes glucocorticoids “ cortisol, the major naturally secreted glucocorticoid”
3- and the inner layer secretes in both males and females the sex hormones (this is the source of testosterone in females and estrogen and progesterone in males)













If we have a defect in it ( an adenoma for instance) in females there’ll be an increase in testosterone levels and what follows it of consequences like more prominent male characteristics “coarse voice and moustaches”
Whereas in males this adenoma leads to an increase in progesterone/estrogen levels and therefore appearance of more prominent feminine characteristics like thinning in the voice and less growth of body hair and moustaches..
Estrogens are antagonists to androgens and androgens are antagonists to estrogens
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Mineralocorticoids: naturally secreted aldosterone
Aldosterone :
1-increases the reabsorption of sodium and the excretion of potassium
2-It’s mainly under the control of the renin-angiotensin-aldosterone system
3-The synthesis of aldosterone is from cholesterol, all steroids are synthesized from cholesterol, the initial step is always cholesterol , we start the first step by a debranching enzyme (dezmolaze) that gives Pregnenolone “1st steroid” and then the dehydrogenase enzyme produces progesterone ( that we find in the placenta and in the ovaries)
(Dezmolaze and dehydrogenase are both needed in the initial step of the synthesis of all steroids) but where are they distributed? Well it depends on the steroid:
**cortisol :in the adrenal and a little bit in the liver ,
** aldosterone : in the adrenal ,
** testosterone in the testis or the inner layer of the cortex ,
** estrogen/progesterone: in the ovaries and in the placenta
And we get aldosterone from progesterone by different hydroxylases enzymes in the adrenal gland
So cholesterol is an essential substance, has its own mechanism to be synthesized, even if we stopped the exogenous source of cholesterol like food, it can still be synthesized from acetate in our body (de novo synthesis) because it’s of extreme importance in the maintenance of membrane integrity and hormonal synthesis, and without it no sex hormones are produced.
Renin is an enzyme produced by the kidney, converts angiotensinogen into angiotensin 1 that’s converted into angiotensin 2 by (ACE > angiotensin converting enzyme) And angiotensin 2 is a potent vasoconstrictor and indirectly stimulates synthesis and release of aldosterone from the adrenal So we have 2 components, if the patient is hypertensive, it’s either aldosterone is high or angiotensin 2 is high
Whenever you have a condition of vasodilation this system is turned on to counteract this vasodilation so it’s a compensatory method to produce aldosterone that causes vasoconstriction and increases the reabsorption of sodium and water .
The net result of aldosterone effect is hypernatremia and hypokalemia

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If the patient has a problem in aldosterone axis, has excess aldosterone (primary, secondary….) or any hypertensive patient, they all can benefit from drugs that could affect this axis , like renin release inhibitors ,angiotensinogen antagonists , angiotensin 1 antagonists.
But actually the most widely used drugs are the ACE inhibitors (Captopril, Enalapril, Benzopril, fosinopril, Lisinopril…
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Angiotensin 2 receptor blockers ARB’s (the sartans)
Are widely used nowadays, they inhibit angiotensin 2 formed by this axis and the angiotensin 2 produced by another pathway :
Candesartan, Losartan, Irbesartan, telmesartan…
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ACE inhibitors inhibit angiotensin 2 that’s formed through this axis only .

Or use aldosterone competitive antagonists that are highly effective in the management of hyperaldosteronism, or many cases of salt-water retention such as :
Spironolactone, Eplerenone
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β1 receptors are involved in increasing renin release,
β1-blockers : they lower blood pressure by blocking β1 adrenergic receptors and by decreasing renin release
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All these drugs are highly effective in lowering aldosterone level being really effective in the management of primary , secondary hyperaldosteronism and in the management of hypertension
These drugs mediate their effects through steroid receptors that are located “mainly” in the cytosol >> cytoplasmic receptors

so we have to know the Factors/drugs that ↑ renin-angiotensin-aldosterone axis like :
- Volume depletion (hemorrhage, low Na+ intake, dehydration, overuse of diuretics…)
- Upright posture
- K+
- ACTH
- Vasodilators
- Adrenoreceptor antagonists

 Aldosterone effects:
Receptor-mediated
Acts on distal convoluted tubules in the kidney
- ↑ reabsorption of Na+ → hypertension
- ↑ excretion of K+ & H+ → hypokalemia & metabolic alkalosis
- ↑ EC volume
- ↑ BP
((Aldosterone antagonists just oppose those effects))
Its major effect is leading to salt-water retention and excretion of potassium
 Disorders affecting aldosterone release:
* Hypoaldosteronism...rare
* Hyperaldosteronism


1º 2º
↑ Volume ↓ Volume*
↑Na+ ↓Renin ↑Na+ ↑Renin
↑Ald.* ↑Ald.
* Initial defect

disorders that could affect aldosterone synthesis can be primary : like adenoma in the outer layer of the cortex leading to “ the initial event which is excess aldosterone” so the cells that actually secrete aldosterone are defective .
Secondary hyperaldosteronism: the initial event triggering aldosterone release is hypovolemia (the defect is in the blood volume or any cause of hypovolemia like hemorrhage) this leads to an increase in renin levels therefore increasing aldosterone levels to overcome the loss of sodium by the body






Glucocorticoids (Cortisol)
 Feedback control
CRH
+ -
ACTH
+ -
Cortisol
CRH: from the hypothalamus (corticotropin releasing hormone)
it acts to increase ACTH levels
Acth : from the anterior pituitary , which regulates the synthesis and the release of cortisol from the adrenal
Cortisol negatively feedbacks on the CRH and ACTH therefore regulating the system
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Circadian rhythm (diurnal variation)
We mentioned it when we discussed ACTH that’s released in a circadian manner , being higher during the day , and lower during the night , in individuals who work during the day and sleep during the night , this could be shifted or reversed in individuals who work during the night ..We used to say that “when measuring cortisol level using radioimmunoassay specific for cortisol .
They used to say that I have Cushing in the morning and then it disappears and this is normal because that’s how cortisol is released.

Cortisol :
is needed in stressful conditions
Patients on cortisol therapy are compromised patients, the major and most dangerous side effect of cortisol and cortisol derivatives is suppression of this axis, by exogenously administered glucocorticoids
The major common use of cortisol is for the management of deficiency states “Hormonal replacement therapy” and usually the hormone is given in low doses “physiological doses” >> such treatments are not of any significance in the suppression of this axis , but remember that cortisol is widely used in other diseases not related to this axis or this system by being used as ( a STRONG ANTI-INFLAMATORY AGENT , an IMMUNOSUPRESSIVE and an anti-allergic agent ), so giving such pharmacological doses to A NORMAL person” with respect to this axis” will cause no problems UNTIL you stop the treatment , here the problems arise , when treatment is stopped suddenly and without making sure you have some endogenously secreted cortisol , the patient could die even when facing minor stress , caused by severe adrenal insufficiency and therefore death
- There is a test done for measuring cortisol level but it doesn’t tell me which is endogenous and which is exogenous it’s just done to assess the function of this axis, but if you inhibit the endogenous synthesis of cortisol ( by Metyrapone (Metopirone)) for example , if you give this drug to the patient while he is taking an exogenous glucocorticoid , this drug will inhibit endogenous synthesis of cortisol , then we measure ACTH and CRH if there’s slight increase [ slight because they’re both under inhibition of the exogenous source and the endogenous too ] the axis is working ( only then you can stop the glucocorticoid therapy safely) even while the patient is on exogenous glucocorticoid , don’t ever stop glucocorticoid therapy suddenly it should be a gradual withdrawal
Glucocorticoids are used in bronchial asthma, allergic reactions, especially when given chronically you are suppressing this axis , in order to limit or decrease the severity of this suppression we try as much as possible to mimic the exact physiological release of cortisol in our body by giving 2/3 of the dose in the morning and 1/3 of the dose in the evening , and the reverse to those who work during the night ,>> this has been associated with less suppression to the axis ..




Cortisol synthesis (from cholesterol)

Note : the steroid ring is made of 4 rings , attached to them is the side chain

The first step of cortisol synthesis is done by side chain cleaving enzyme “cleaves the side chain in cholesterol “therefore many chemical modifications can be done to end up with a huge number of different cortisol derivatives and different potencies and absorption and dosage forms and kinetics,, such modifications lead to specific agonists of cortisol derivatives that vary in their side effects, and in the severity of the side effects in suppression of the axis , and in the duration of action >
DE Deh.
Cholesterol pregnenolone Progesterone
(17) Hyd’s
Cortisol (11) Deoxy- (21) Hydroxy-
corticosterone progesterone

DE= debranching enzyme; side chain cleavage enzyme; desmolase
Deh.= 3β-hydroxysteroid dehydrogenase enzyme
Hyd’s= Hydroxylases

(The initial step is from cholesterol)
 Steroid synthesis inhibitors:
- o,p’-DDD (Mitotane)
Causes selective atrophy (direct toxic effect) of Zona Fasciculata and Zona Reticularis(inner two zones) , it spares the aldosterone zone
Useful in Rx of adrenal Ca when radiotherapy or surgery are not feasible and in certain cases of breast cancer
Inhibits synthesis of cortisol ,estrogen ,progesterone and could be used in certain cases for the management of breast cancer (orally) (especially estrogen dependent/progesterone dependent cancer) because it prevents synthesis/release of estrogen/progesterone ..



- Aminoglutethimide
Selective desmolase (debranching enzyme) inhibitor, same uses as mitotane>> treatment of adrenal cancer along with radiotherapy or chemotherapy
- Trilostane
Competitive inhibitor of 3β-hydroxysteroid dehydrogenase enzyme (the second step which converts pregnenolone to progesterone ) so it can be used in cortisol/aldosterone axis and estrogen/progesterone etc..
- Ketokonazole
An antifungal agent
Mechanisim of action:
An inhibitor of different hydroxylases in the synthetic machinery of different steroids; inhibits steroidogenesis in the adrenals and the testes >> decreasing the sexual function
Effective in Cushing’s syndrome and CA of prostate

- Amphenone B:
An inhibitor of different hydroxylases but very toxic not approved yet in humans
Causes severe CNS depression, GIT upset and many skin disorders

- Metyrapone (Metopirone)
11β-hydroxylase inhibitor
1- Effective as a diagnostic tool (metyrapone test) >> for the assessment of the function of the adrenal …when cortisol level decreases the level of ACTH and CRH increases >> this means the axis is normal
2- Used in the management of Cushing’s syndrome because It’s not that much toxic , it inhibits the last step in cortisol synthesis
3- Orally or parenterally effective drug

 Release and transport of glucocorticoids
- Glucocorticoids receptors

Cortisol is synthesized in the middle layer of the adrenal cortex and is released into the blood stream ,binds to a specific protein ,reaches the target cell , interacts with cytoplasmic receptors , these receptors or complexes are activated and translocated to the nucleus, binds to specific genes, changing(increasing or inhibiting) transcription and translation of specific protein (they call it the magic protein) it mediates the effect of such steroids (estrogen,progesterone,testosterone,cortisol,aldosterone.)

 Pharmacological effects/side effects(of glucocorticoids) :
- On proteins
↑ Catabolism ↓ anabolism >>> they breakdown proteins which is very dangerous leading to :
→ Osteoporosis; steroid myopathy; delayed wound healing; delayed peptic ulcer healing ”ulceration in the GI tract” , skin atrophy …)
- On CHO(carbohydrates):
↑ blood sugar level ( ↑ gluconeogenesis; ↓ peripheral utilization of glucose)

- On lipids
↑ lipolysis and results in redistribution of fat >> when you see someone with Cushing {excess cortisol due to adenoma or exogenously administered BUT the major cause of Cushing is drug induced like for instance after eye (ophthalmic) application or application of the steroid on the skin } so we see deposition of fat in the abdomen that’s easily diagnosed as it looks like striae and buffalo hump in the neck , and the moon-like face ( red in color , mnawwir)

- On electrolytes
Aldosterone-like effect (salt-water retention) +(excretion of potassium)

The major limitation for the development of a good glucocorticoid effect is aldosterone-like activity meaning that I’ve played so much with the structure that I got in the end some derivatives with good effects that have a little if any aldosterone-like activity , and on the other hand I got derivatives using chemical modification that have more potent anti-inflammatory effect as compared to cortisol and a very strong aldosterone like activity (used in one case which is Hypoaldosteronism [ when someone doesn’t have aldosterone we don’t give him aldosterone , when someone has sever loss of sodium (dehydration) I could use something that increases sodium and water reabsorption , by giving one of these synthetic analogues that has strong aldosterone like activity ]
Also glucocorticoids:
↓ Ca++ absorption from intestine : for the management of hyperparathyroidism
↑ Ca++ excretion by kidney
↑ uric acid excretion : which is good for patients with gout

Anti-inflammatory effect : by the inhibition of phospholipase A2 in the arachidonic pathway , by the inhibition of prostaglandins and leukotrienes the major mediators of inflammation that are formed from phospholipids by phospholipase A2
Major mechanism:
Phospholipids
Pospholipase A2
Arachidonic acid

Lipoxygenase cyclooxygenase

Leukotreines PG’s
(SRS-A)

We have two types of anti-inflammatory agents:
1- steroidal work on phospholipase A2
2- non-steroidal agents (aspirin, ibuprofen , diclofenac) that inhibit cyclooxygenase
We have some possible mechanisms for the anti-inflamatory effects:
- Also inhibit neutrophil and macrophage function
- Inhibition of platelet activation factor (PAF)
- Inhibition of tissue necrosis factor or receptor (TNF; TNR)
Inhibition of nitric oxide reductase

So we talked about the 1st useful effect of glucocorticoids which is the anti-inflammatory, now the second one is their use as IMMUNOSUPRESSANTS
- Immunosuppressant effect
Major mechanisms
↓ initial processing of Ag
↓ Ab formation
↓ effectiveness of T-lymphocytes
↓ lymphocyte induction & proliferation
↓ lymphoid tissue including leukemic lymphocytes (antileukemic effect)
so we benefit from this in the management of different cancers particularly leukemia, lymphoma, and in the cases of organ transplantation
We said their disadvantage is in the suppression of the axis, but they don’t suppress the bone marrow unlike other immunosuppressants
Now the third and last useful effect :
- Antiallergic effect
Supress allergic response : allergy to drugs can be so severe leading to severe bronchoconstriction , suffocation and death from anaphylactic shock
anaphylactic shock is caused by the (slow reacting substance of anaphylaxis SRSA ) , even the bronchoconstriction we see in asthmatic patients is caused by this substance
NSAIDs are dangerous, why? Because they shift the whole thing toward the lypooxygenase pathway as they are inhibitory to the cyclooxygenase one which is contraindicated due to the fear of SRS-A

↓ histamine release
↓leukotriens production
↓ eosinophils

[[[ we use 2 anti-allergic drugs : 1- anti histamine (intramuscularly) 2-hydrocortizone (intravenously) .. producing immediate effect within 15 minutes this could save lives .

- CNS manifestations
Euphoria
Psychosis


Pharma lecture # 9
Date of lecture 6/3/2011
Done by Tamara Madhat Mousa \m/




Last edited by Shadi Jarrar on 12/3/2011, 12:55 am; edited 1 time in total
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Shadi Jarrar
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عدد المساهمات : 997
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تاريخ التسجيل : 2009-08-28
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الموقع : Amman-Jordan

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