As a test, I’m going to try writing up my revision notes on here. Bit of a strange place to start, but it’s as good a place as any, I suppose. So here we go, a quick rundown on the drugs used to treat hyperadrenal disorders.
Specifically this will be about hypersecretion of hormones of the adrenal cortex. A quick reminder of the anatomy of the adrenal glands (or suprarenal, if you prefer):
So you have the inner medulla and the outer cortex, the latter consisting of the zona reticularis, zona fasciculata and zona glomerulosa. I remember these names by thinking of the letters GFR (because this also means Glomerular Filtration Rate which, as a side note, is around120ml/min).
Basically, the adrenal cortex pumps out steroids. A quick rundown of what the different sections of the adrenal cortex produce:
1.) Zona glomerulosa - mineralocorticoids (aldosterone etc.)
2.) Zona fasciculata - glucocorticoids (e.g. cortisol)
3.) Zona reticularis - sex steroids (e.g. dehydroepiandrosterone, DHEA)
So, there are three drugs I’ll talk about:
The first two work by inhibiting steroid biosynthesis.
Spironolactone is a mineralocorticoid receptor (MR) antagonist i.e. it binds to the receptor, but does not produce a physiological response, thereby blocking the effect of agonists (things that bind and DO produce a response).
Firstly - Metyrapone
Like we said before, Metyrapone works by inhibiting steroidogenesis - specifically it inhibits a rather important enzyme by the name of 11-beta hydroxylase. I’ll show in a diagram why this is important:
As you can see, 11-beta hydroxylase converts 11-deoxcortisol into cortisol, and 11-beta corticosterone into corticosterone. Therefore, if it is blocked by Metyrapone, neither cortisol nor corticosterone will be synthesised - thereby treating the hypersecretion of cortisol, for example in Cushing’s Syndrome.
Cortisol works on a feedback loop - if it stops being produced, this will send negative feedback back to the hypothalamus and pituitary, which translates to increased production of ACTH (which stimulates cortisol production).
As I mentioned before, Metyrapone can be used to control Cushing’s Syndrome prior to surgery or for long-term amelioration of hypercortisolism if it persists/if surgery isn’t possible.
It does, however, come with some unwanted actions, like many drugs:
1.) Nausea, vomiting, dizzines
2.) Sedation, hypoadrenalism
3.) Hypertension on long term administration (11-deoxycorticosterone accumulates in the z. glomerulosa and has aldosterone-like (mineralocorticoid) effects => salt retention and hypertension.)
4.) Hirsuitism (excessive hairiness)
Okay, so that’s Metryrapone! Now for the second drug…
This is mainly used as an antifungal agent, but at higher concentrations can inhibit steroidogenesis (glucocorticoids, mineralocorticoids and sex steroids). As with Metyrapone, it can also be used to treat Cushing’s
Unwanted actions include nausea, vomiting and abdominal pain. Also unwanted are:
1.) Alopecia (baldness)
2.) Gynaecomastia (enlargement of breasts in males, oligospermia (deficiency of sperm in the semen), impotence and decreased libido
3.) Ventricular tachycardia
4.) Liver damage - possibly fatal. Liver function must be monitored on a weekly basis
This drug is used to treat primary hyperaldosteronism, also known as Conn’s Syndrome.
It must first be converted into its active metabolite, Canrenone. As I mentioned before, Spironolactone works not by inhibiting steroidogenesis, but by working as a competitive antagonist to the mineralocorticoid receptor. This blocks Na+ resorption and K+ secretion in the kidney tubules, so is classed as a potassium sparing diuretic.
Unwanted actions include:
1.) Menstrual irregularities
2.) Gynaecomastia (due to androgen receptor binding)
3.) GI tract irritation
N.B. Spironolactone must not be used in patients with renal/hepatic disease; it is contraindicated.
And that’s about it. Forgive the rather disorganised/potentially unclear nature of this post, but it was my first one like this. I might do more. I’m not really sure - there’s a hell of a lot to get through and writing this out, while a good reminder, does take an extra bit of time. We shall see!