Let's move on to the zona glomerulosa
and mineralocorticoid function.
Now remember that when we are talking about
mineralocorticoids or even corticosteroids,
we are talking about using a steroid receptor.
If you remember from your pharmacology lectures way back
at the beginning, when we were looking at receptors,
there are five major types of receptors.
Steroid receptors are intracellular receptors and so the drug,
because it's lipophilic can cross the membrane easily
and that's how the medications or the hormones work.
Now, if the steroid binds to the receptor inside the cell,
it has to send a message into the nucleus.
It does so through something called an MRE
or mineralocorticoid response element.
This MRE is part of the DNA molecule. The MRE exerts its effects
through DNA and you have production of certain enzymes.
Now the aldosterone agonists are part of the renin angiotensin
system, and they have a very strong salt retaining activity
just like androgynous mineralocorticoids.
So, aldosterone agonists are also considered
mineralocorticoids as well as diuretics.
A good example of a mineralocorticoid
is Florinef or fludrocortisone.
Structurally it's very similar to cortisol. It has moderate
glucocorticoid activity and very strong mineralocorticoid activity.
It is involved and can be treating cerebral salt wasting
syndrome, it can be used in Addison's disease,
it can be used in this disease called POTS
or paroxysmal orthostatic tachycardia syndrome.
And it's also sometimes used in
geriatric orthostatic hypotensive syncope.
So, what we're doing here is we're retaining salt
so that the blood pressures are a little bit higher
and it prevents the drop in blood pressure that
geriatric patients have when they stand up.
Spironolactone is a diuretic, we discussed it already
in the hypertension section of pharmacology,
but we also use it as its mineralocorticoid function
to treat hirsutism.
So, it has mild androgen and mild mineralocorticoid activity.
Let's move on to the zona fasciculata.
This is where glucocorticoid production is occuring.
Now, glucocorticoids also enter the cell as a free molecule.
It doesn't need to be converted cause it's already lipophilic.
It binds to the intracellular receptor or other proteins,
and then enters into the nucleus as a complex.
Now, instead of an MRE, it binds to a GRE or the glucocorticoid
response element which is still also a portion of the DNA.
The GRE regulates gene expression and transcription
for its various functions.
Now, when we use synthetic glucocorticoids in patients,
we have side effects.
That metabolic effect can be gluconeogenesis,
lipolysis and reduced subdermal fat.
Morphologic changes can have lipid deposits in certain spots
such as the face, the neck, and the shoulder.
So I want to go over that just again so it's clear.
Reduced subdermal fat refers to say the back in the skin,
so people will have parchment like skin when
they are given synthetic glucocorticoids for a long time.
People who are given synthetic glucocorticoids
will have more fat in the face, shoulder and neck.
So, I say that they have a moon face, they have a round
kind of full face, but they have thin parchment like skin.
There are some catabolic effects as well. Protein catabolism,
and tissue wasting, and osteoporotic effects are all
part and parcel of glucocorticoid excess activity.
So in other words, patients who are placed on
synthetic glucocorticoids can have protein wasting
and reduction of muscle mass. And osteoporosis is a major
concern, and premature bone fracture is a major concern
on people who are taking
synthetic glucocorticoids for a long time.
Side effects can also be immunosuppressive as well. Cell
mediated immunity can be affected by long term glucocorticoid use.
For example, lymphocyte dependant infections can become
more rampant and so you have to be very careful
of patients developing severe viral infections
or increased susceptability to viral infections.
Renal function can be compromised. Remember cortisol
is normally required for water excretion.
Anti-inflammatory effects, I wouldn't call it necessarily
a side effect, it's actually the effect we are looking for.
There is often a dramatic suppression of multiple markers.
That's often why we use synthetic glucocorticoids in
high doses in the first place.
There is some neuropsychiatric issues.
Excess cortisol causes giddiness and euphoria.
And synthetic cortisol derivatives
can cause that same kind of behaviour change.
The prototypical synthetic glucocorticoid is prednisone.
It has a long half life. It has quite good membrane pentration.
And it's often used in acute inflammation
in most disease states.
It's often a steroid replacement therapy as well
for people who have adrenal suppresion.
Dexamethasone is another synthetic glucocorticoid.
It has an even longer half life than the original prednisone.
It has even better membrane presentation. It is often used in
cancer chemotherapy as part of an adjunct to treatment regimen.
Triamcinolone, beclomethasone, budesonide
are other glucocorticoids.
Beclomethasone is readily penetrating the respiratory mucosa
so we often use it in pulmonary inhalers.
Let's take a look at glucocorticoid synthesis inhibitors.
Now this is a drug, or a set of drugs that we use
to actually reduce excess endogenous cortisol production.
Now, interestingly enough ketoconazole,
you might recognize this as antifungal medication.
We do use it in adrenal adenoma,
breast cancer and prostate cancer.
And it is also used in hirsutism
for the treatment of excess cortisol levels.
Metyrapone is another medication that we use
in glucocoritcoid pharmacology.
It inhibits synthesis of cortisol. We actually use it more
for diagnositic testing rather than actual therapy.
Other agent blocks conversion of cholesterol to the
precursors of cortisol and others endogenous steroids.
It is used in steroid producing cancers
to prevent excess steroid in the body.
Zona reticularis function and adreanal androgens
has been covered in another lecture,
so I won't go into too much detail here.