Mineralocorticoids and Glucocorticoids – Adrenal Pharmacology

00:01 Let's move on to the zona glomerulosa and mineralocorticoid function.

00:07 Now remember that when we are talking about mineralocorticoids or even corticosteroids, we are talking about using a steroid receptor.

00:15 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.

00:24 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.

00:37 Now, if the steroid binds to the receptor inside the cell, it has to send a message into the nucleus.

00:45 It does so through something called an MRE or mineralocorticoid response element.

00:51 This MRE is part of the DNA molecule.

00:55 The MRE exerts its effects through DNA and you have production of certain enzymes.

01:02 Now the aldosterone agonists are part of the renin angiotensin system, and they have a very strong salt retaining activity just like androgynous mineralocorticoids.

01:12 So, aldosterone agonists are also considered mineralocorticoids as well as diuretics.

01:19 A good example of a mineralocorticoid is Florinef or fludrocortisone.

01:25 Structurally it's very similar to cortisol.

01:28 It has moderate glucocorticoid activity and very strong mineralocorticoid activity.

01:34 It is involved and can be treating cerebral salt wasting syndrome.

01:39 It can be used in Addison's disease.

01:42 It can be used in this disease called POTS or paroxysmal orthostatic tachycardia syndrome.

01:48 And it's also sometimes used in geriatric orthostatic hypotensive syncope.

01:53 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.

02:06 Spironolactone is a diuretic.

02:10 We discussed it already in the hypertension section of pharmacology, but we also use it as its mineralocorticoid function to treat hirsutism.

02:20 It has anti-androgen and mineralocorticoid effect activity.

02:24 Let's move on to the zona fasciculata.

02:27 This is where glucocorticoid production is occuring.

02:31 Now, glucocorticoids also enter the cell as a free molecule.

02:35 It doesn't need to be converted because it's already lipophilic.

02:39 It binds to the intracellular receptor or other proteins, and then enters into the nucleus as a complex.

02:46 Now, instead of an MRE, it binds to a GRE or the glucocorticoid response element which is still also a portion of the DNA.

02:56 The GRE regulates gene expression and transcription for its various functions.

03:03 Now, when we use synthetic glucocorticoids in patients, we have side effects.

03:07 That metabolic effect can be gluconeogenesis, lipolysis and reduced subdermal fat.

03:14 Morphologic changes can have lipid deposits in certain spots such as the face, the neck, and the shoulder.

03:21 So I want to go over that just again so it's clear.

03:24 Reduced subdermal fat refers to, say the back of the skin, so people will have parchment-like skin when they are given synthetic glucocorticoids for a long time.

03:34 People who are given synthetic glucocorticoids will have more fat in the face, shoulder and neck.

03:39 So, I say that they have a 'moon face', they have a round kind of full face, but they have thin parchment-like skin.

03:49 There are some catabolic effects as well.

03:51 Protein catabolism, and tissue wasting, and osteoporotic effects are all part and parcel of glucocorticoid excess activity.

04:00 So in other words, patients who are placed on synthetic glucocorticoids can have protein wasting and reduction of muscle mass.

04:09 And osteoporosis is a major concern.

04:12 And premature bone fracture is a major concern on people who are taking synthetic glucocorticoids for a long time.

04:19 Side effects can also be immunosuppressive as well.

04:23 Cell mediated immunity can be affected by long term glucocorticoid use.

04:28 For example, lymphocyte-dependent 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.

04:42 Renal function can be compromised.

04:44 Remember cortisol is normally required for water excretion.

04:48 Anti-inflammatory effects,or actually, I wouldn't call it necessarily a side effect, it's actually the effect we are looking for.

04:55 There is often a dramatic suppression of multiple markers.

04:59 That's often why we use synthetic glucocorticoids in high doses in the first place.

05:04 There is some neuropsychiatric issues.

05:07 Excess cortisol causes giddiness and euphoria, and synthetic cortisol derivatives can cause that same kind of behaviour change.

05:18 The prototypical synthetic glucocorticoid is prednisone.

05:23 It has a long half life, it has quite good membrane penetration, and it's often used in acute inflammation in most disease states.

05:32 It's often a steroid replacement therapy as well for people who have adrenal suppresion.

05:38 Dexamethasone is another synthetic glucocorticoid.

05:43 It has an even longer half life than the original prednisone.

05:47 It has even better membrane penetration.

05:50 It is often used in cancer chemotherapy as part of an adjunctive treatment regimen.

05:57 Triamcinolone, beclomethasone, budesonide are other glucocorticoids.

06:02 Beclomethasone is readily penetrating the respiratory mucosa so we often use it in pulmonary inhalers.

06:11 Let's take a look at glucocorticoid synthesis inhibitors.

06:15 Now this is a drug, or a set of drugs that we use to actually reduce excess endogenous cortisol production.

06:23 Now, interestingly enough, ketoconazole, you might recognize this as antifungal medication.

06:28 We do use it in adrenal adenoma, breast cancer and prostate cancer.

06:32 And it is also used in hirsutism for the treatment of excess cortisol levels.

06:38 Metyrapone is another medication that we use in glucocoritcoid pharmacology.

06:43 It inhibits synthesis of cortisol.

06:46 We actually use it more for diagnositic testing rather than actual therapy.

06:52 Other agent blocks conversion of cholesterol to the precursors of cortisol and other endogenous steroids.

06:59 It is used in steroid producing cancers to prevent excess steroid in the body.

07:06 The zona reticularis function and adrenal androgens has been covered in another lecture, so I won't go into too much detail here.