Tuesday, November 10, 2009Scribe: Strud Tutwiler

Endocrinology: 3:00-4:00pm

Dr. PillionAdrenocorticosteroid DrugsPage1 of 6

Adrenocorticosteroids by Dennis Pillion, PhD Dept of Pharmacology & Toxicology [S1]
Pick up today on Adrenocorticosteroid theme. All three of lectures have overlap and shared pathways and slides. I hope that by seeing material repeatedly, you remember it better. This helps you to appreciate normal physiology, pharmacology, and pathology better.
This lecture is based upon how pharmacology, specifically adrenocorticosteroids, is used to treat patients.
Hypothalamic-Pituitary-Adrenal Axis[S2]
Corticotropin Releasing Factor (from hypothalamus)Corticotropin (or Adrenocorticotropic Hormone, ACTH from pituitary gland) Adrenocorticoids (cortisol, estrogen, testosterone, et al)
Appreciate the fact that the adrenal cortex releases multiple hormones. Usually think of one hormone (i.e. testes releasing testosterone and thyroid gland releasing thyroid hormone). The adrenal glands secrete a lot of stuff that is chemically related including cortisol, aldosterone, progesterone, testosterone, etc.
Cells in the adrenal cortex all start with precursor, cholesterol, and modify it in different ways.
Regulation of the Secretion of Cortisol by the Adrenal Cortex [S3]
Pathway seen already
(CRH) Hypothalamus  Pituitary Gland with ACTH production Adrenal Gland stimulated Cortisol, Aldosterone, & Dehydroepiandrosterone produced
Stress can overcome this process, but normally it is a feedback loop.
Talking about what goes wrong or where we intervene in this loop.
The Adrenal gland secretes many hormones [S4]
Cortisol is the primary glucocorticoid (number one job is to raises glucose levels in response to ACTH)
it increases blood glucose levels
it is secreted in response to ACTH
testosterone is a glucocorticoid in the sense that it comes from the adrenal cortex and it raises glucose levels
Aldosterone is the primary mineralocorticoid (controls levels of minerals in blood stream specifically Na & K)
it increases water and Na+ retention by the kidney
it is secreted in response to angiotensin
Dehydroepiandrosterone (DHEA) is the primary androgen
it can be converted to estrogen
TEST QUESTION: A tumor overproducing cortisol can affect mineralocorticoid receptor. The mineralocorticoid receptor primarily binds Aldosterone (the ligand). The primary ligand for the glucocorticoid receptor is Aldosterone.
An adrenal tumor produces Cushing’s syndrome because it is over producing cortisol. The effect is that cortisol binds glucocorticoid receptor and causes excess levels of glucose. However, it will also bind mineralocorticoid receptor and stimulate retention of sodium and water.
Cushing disease (high levels of cortisol) will show high levels of glucose, as well as sodium and water (Pillsbury doughboy appearance). Appreciate that there are two pathways with two receptors, but the things that bind are related.
A large excess of one ligand will affect both receptors. Cortisol at high levels can give mineralocorticoid effects.
Someone with arthritis, give them cortisol to diminish effects (lower white cells & inflammation). It will make a patient’s knees feel better, but it makes their sodium and water go up (hypernatremia and hypertension). This is bad in patients with CHF.
Pharmacologists try to develop analogs to cortisol that only binds glucocorticoid receptor and not to mineralocorticoid receptor.
If you modify cortisol, it cannot fit into the same binding site as aldosterone. Cortisol (with large group added) will not bind mineralocorticoid receptor, but will still bind to the glucocorticoid receptor. The opposite holds true.
A mineralocorticoid can be fabricated to bind only to its receptor and not the glucocorticoid receptor. This is good because it will not cause the glucose level to increase and does not cause the inflammatory reaction to be turned off. You might not want a glucocorticoid response when giving a patient a mineralocorticoid.
These two compounds overlap, but chemically derived will do one or the other. Derived drugs are different from the natural chemicals in that they are selective.
Be very familiar with this slide.
Major Pathways in Adrenocortical Hormone Biosynthesis [S5]
This is the pathway seen early with cholesterol going to Pregnenolone.
Important: 21-hydroxylase is the normal enzyme not present in a deficiency. If 21-hydroxylase is not present in adequate amounts, you do not make deoxy-corticosterone, deoxycortisol, corticosterone, cortisol, and aldosterone.This means you have a lot of progesterone, 17-hydroxy-progesterone, and androstene-dione.
Infants born with low levels of this enzyme have problems. The level of cortisol and aldosterone in your blood is low (an Addisonian appearance) with 21-hydroxylase deficiency, but testosterone and estradiol is high.
This can cause young women to develop a mustache. If people are completely deficient in these enzymes, they probably die at birth or before birth. With a modest amount of this enzyme, she will survive. At puberty, her other hormones kick in and now she has an excess showing visual signs.
It can develop early and depends on how much depression of these particular enzymes takes place.
If you lack cortisol, the pituitary gland will keep dumping out lots of ACTH. The adrenal gland will hypertrophy. It will be dumping out lots of these androgens and estrogens.
Doctors can treat this patient with glucocorticoid to feedback and inhibit production of ACTH. Cortisol treatmentwill show reduction of ACTH and reduction in synthesis of estrogens and androgens to the normal level.
Even though they still have the enzyme defect, the inappropriate feedback is turned off because the product is replaced. There are better drugs though than just cortisol.
Hypercortisolemia & its Impact on Normal Feedback Mechanisms [S6]
Normalscenario–Pituitary gland produces normal amount of ACTH. ACTH stimulates the adrenal gland to produce a normal amount of cortisol, which feeds feedbacks and inhibits. Daily or circadian rhythm regulates this with changes in aging.
ACTH-dependent Cushing’s syndrome–Pituitary tumor (rare) will over produce ACTH. Adrenal gland produces lots of more cortisol. The cortisol should shutdown the production of ACTH, but it does not respond to the feedback (due to the pituitary making ACTH). Pt will present with Cushing’s syndrome. Treat pharmacologically by blocking production of cortisol or by surgery, which is much better treatment than pharmacology.
Ectopic ACTH syndrome –Many gut tumors(unknown reason) secrete hormones (ACTH) from intestinal tissues. Overproducing ACTH stimulates the gland to make lots of cortisol. This turns off production of ACTH from pituitary, but not from the tumor. The patient still presents with Cushing’s syndrome (excess cortisol). Treatment is surgically to remove the tumor, unless the doctor cannot for some other reason.
Adrenal adenoma– A tumor is in the adrenal gland itself overproducing cortisol. The ACTH level will be very low though. Cortisol will turn off ACTH production, but this does not stop the adrenal tissue from producing cortisol. Treatment is probably surgically if possible. Doctors cannot treat Cushing’s disease very well pharmacologically. Arthritis, scleroderma, and asthma are treated pharmacologically with steroids, but these diseases are not treated well.
Exogenous steroids administration–“exogenous steroids” are given to a patient for an ocular defect, arthritis, or asthma to prevent inflammation. This turns off ACTH production and secretion of cortisol from the adrenal gland.
Unfortunately, after 14 days (2 weeks) of taking prednisone (steroid therapy), the adrenal gland is semi-permanently turned off. While on steroid treatment over 2 weeks, the adrenal glands are not making cortisol.
Problem: Cortisol is needed in response for a crisis. If a pts foot is cut off and bleeding or dentist comes at patient for extraction, high levels of cortisol are need for survival. If a patient has adrenal deficiency, they may go into a crisis (Adrenal Cortical Insufficiency) and die. In dealing with patients on steroids, recognize that they are not able to ramp up their own production when you cut into their skin, which is the normal response. An exogenous steroid will turn off the gland to produce cortisol.
Golden Rule: If you give someone steroids for less than a week and weanthe pt off, adrenal gland will recover.
Steroids for >2 weeks will cause long-term deregulation of hypothalamic-pituitary-adrenal axis.
Do not give steroid therapy for more than two weeks unless the patient is planned on being on steroids for life-long therapy or real important medical reason.
Fluctuations in plasma ACTH & Glucocorticoids throughout the day [S7]
Seen before; the diurnal rhythm of cortisol and ACTH follow the same flow. If replacement therapy is warranted, patients need to replicate / mimic this graph. There is a disconnect between replacement therapy, therapy for adrenocortical insufficiency crisis, and therapy for inflammation. They are not always treated the same way.
Effects of Glucocorticoids [S8]
First, mention normal effects, then the pharmacological effects of steroid doses.
Metabolic
Increased glycogenolysis & gluconeogenesis
Increased protein catabolism and decreased protein synthesis
Decreased osteoblast formation and activity
Decreased Ca absorption from the GI tract
Decreased TSH secretion
Net effect: With long-term glucocorticoid therapy, expect changes to occur that are consist with these.
Antiinflammatory: local and systemic effects
Decreased production of prostaglandins, cytokines, and interleukins
Decreased proliferation and migration of lymphocytes and macrophages
All of this is meant to increase glucose levels in the bloodstream. This is why they are called “glucocorticoids.”
Think the original site of action of glucocorticoids is very close in the prostaglandin biosynthetic pathway. Remember the lecture on NSAIDS with cyclooxygenase converting arachidonic acid to the first member of the prostaglandin pathway. Aspirin inhibits this.
The step before that was the release of arachidonicacid from the lipids. Arachidonic acid is usually in membrane phospholipids, there is a phosphorylated group with two side chains of fatty acids. The middle side chain is arachidonic acid. This is taken off, converted to prostaglandins, and is involved in cytokine production.
Cortisol and the other glucocorticoids prevent arachidonic acids from being taken off the membrane. You do not make leukotrienes, prostaglandins, or any of the inflammatory cytokines. Shutdown all mechanisms used in inflammatory response, so it is a great anti-inflammatory drug.
Adrenocortical Drugs: [S9]
Natural and Synthetic Steroids
Steroid Hormones [S10]
Hydrocortisone – natural compound; another name for cortisol; chemically related to cholesterol; no charges, so can easily pass through the cell membrane, but is very poorly water-soluble. It binds proteins in the blood stream, so it is not filtered in the kidneys. Has a longer half-life (hrs) due to being protein-bound; Binds glucocorticoid receptor very well and mineralocorticoid receptor fairly
Fludrocortisone – only principle mineralocorticoid (TEST QUESTION): If a patient has inflammation and want to give an anti-inflammatory drug, is Fludrocortisone a good or bad choice? Bad choice. If pt with adrenocortical insufficiency and you want to give replacement therapy, is Fludrocortisone a good or bad choice? This is good for the mineralocorticoid need, but it would not be given alone. Give in combination with glucocorticoid.
Aldosterone, hemiacetal derivative – opposite of hydrocortisone; binds mineralocorticoid receptor very well, but not good to glucocorticoid receptor
All of the rest of the drugs, except fludrocortisone, are glucocorticoids.
Triamcinolone, Dexamethasone, Prednisolone, Cortisone, & Betamethasone are glucocorticoids analogs.
Artificial ones: Triamcinolone, Dexamethasone, Prednisolone, & Betamethasone are more anti-inflammatory than the natural compounds. Bind exclusively to glucocorticoid receptors. Give these two a patient with CHF because they do not cause salt / water retention.
They are very effective orally (pass through gut membrane). Can modify drugs to give shot directly into joint (knuckle, knee, tennis elbow, or pitching arm for inflammation)
Do not want to give shots every week, because repeated shots into a joint will cause damage due to the needle. To make drugs have extended half-life and stay there longer, modify by (TEST QUESTION – answered later).
Example: you cut into a patient and they experience an adrenocortical insufficiency. The patient lacks enough glucocorticoid. Their blood pressure, blood sugar, and blood volume will be low. Give the patient glucocorticoids. You cannot give a patient his own Prednisone pill because he is passed out. Can give him Epinephrine to temporary keep him from dying, but this will not solve his problem. If giving the patient an IV, add glucose and cortisol-sodium phosphate (charged water-soluble form of cortisol) to the fluids. Cortisol-sodium phosphate, cortisol hemisuccinate, cortisol glutamate are salts, and the charge affects water solubility (soluble in water) and onset/duration of action. These are used for emergencies. The difference between these drugs and cortisol is charge, and thus ability to put it into the blood stream.
Do not want to give a pitcher with joint pain, cortisol-sodium phosphate because it would leave site of action very quickly due to water solubility. Make it more lipid-soluble by adding hydrophobic (lipophillic) groups to it.
By adding uncharged hydrophobic groups include acetate or hexacetonide, the steroid derivatives are not water-soluble at all. If treating someone with a joint inflammation, give him or her oral Prednisone (pill) or injection of cortisol derivative that is water-insoluble to stay put.
Chemical Structures of Glucocorticoids [S11]
Hydrocortisone
Prednisolone
Betamethasone
Triamcinolone (acetonide) – hexacetonide has six uncharged groups, which is better for an injection (water-insoluble)
Oral prednisone is not as good as a shot directly into the joint. Oral prednisone will affect bones, liver, adipose, kidneys, and muscle tissue. A patient can become osteoporotic while on oral prednisone. An injection will minimize the effects to the rest of the body.
10yr old child with asthma treatment choice is inhaled steroid derivate. Used to treat asthmatic children with Prednisone, and they all developed cataracts and shortened stature with osteoporosis.
The development of the drugs has improved with delivery to reduce the amount of toxicity.
Prednisolone is the active version of Prednisone. Prednisone is cheap, been around for 50yrs, and has to become activated in the liver. Test Question: In an alcoholic with liver disease, Prednisone will be ineffective as an anti-inflammatory because Prednisone  Prednisolone in the liver. Give alcoholics Prednisolone (not expensive either, was developed shortly after Prednisone).
Mineralocorticosteroids and Regulation of Na balance [S12]
***For some reason, [S12] in the PowerPoint is not showing up as it did in class.
Already talked about water regulation in distal convoluted tubule in renal lecture
In pathway, Angiotension II is the hormone from the renin-angiotension system and stimulated activity of the enzyme, CMO 1 and 2, and stimulated production of Aldosterone. Aldosterone binds to a receptor and increases the activity and amount of Na/K exchanging. One side of cell is kidney tubule where urine is located, and the other side of the cell is the basolateral membrane with the blood.
Na/K-ATPase is always on the basolateral membrane, and Na/K channel is on the side with urine.
Spironolactone is a diuretic used for hypertension that competes with aldosterone for its receptor (it blocks the pathway). Alternative way to block pathway is with Amiloride or Triamterene (block the Na/K channel).
Spironolactone is an analog aldosterone, but it is a competitive antagonist.
Treatment of Addison’s Disease: Oral Cortisol [S13]
Glucocorticosteroid Replacement Therapy: give drug in divided doses 2/3 in the morning and 1/3 in the afternoon. Treat with hydrocortisone given orally. Not giving a glucocorticoid and mineralocorticoid separately, but giving one chemical (cortisone)  poor man’s treatment. Cortisone being a natural chemical, will give you some overlap with a mineralocorticoid (mostly a glucocorticoid). Not perfect therapy
Commonly Used Natural and Synthetic Corticosteroids [S14]
Drugs to remember:
Hydrocortisone or cortisol: for comparison look at anti-inflammatory # and salt-retaining #. Cortisol is given a value of one just so everything can be given a relative scale. This does not mean it has an equal amount of salt-retaining and anti-inflammatory. Numbered one so other drugs can be put into ratio compared to it.
Salt-retaining refers to how much the drug makes you retain sodium and water.
Anti-inflammatory drugs: Prednisone, Prednisolone, Methylprednisolone, and Meprednisone are all ~5x more effective as anti-inflammatory drugs.
Triamcinolone, Paramethasone, Betamethasone, and Dexamethasone are extremely potent anti-inflammatory drugs. The salt-retaining activity or mineralocorticoid activity is zero for these drugs. Very good for patients with other diseases
The opposite is true for fludrocortisone with huge salt-retaining effect and a small anti-inflammatory effect. Used at a low dose.
Forms available include oral, injectable, and topical. With sunburn or poison ivy, rub cortisol cream for anti-inflammatory effect to remove itching & redness. Drugs are lipid soluble enough to pass through the skin.
Therapeutic Indications for use of Glucocorticoids in Nonadrenal Disorders [S15]
Do not memorize this whole list, but appreciate that you will see patients with all of these disorders. These patients will be on steroid therapy. Ex. Allergic rxns, neurologic disorders, GI diseases, eye disease, skin disease, renal diseases Lupus, collagen disease, optic neuritis, inflammatory bowel disease, hemolytic anemia, sprue, uveitis, hepatic necrosis, etc.
For all of these diseases, the inflammatory response is the normal response.
Giving a person a steroid to dampen the inflammatory response can be a good and bad thing. Good if inflammatory response is making the patient miserable. Bad since it limits the immune response (defense).
Debate over whether steroids are overprescribed.
Bottom line: Steroids almost never cure the disease; it just dampens the inflammation. Relief of pain for chronic arthritis will lead to glaucoma, osteoporosis, and gastic ulcers. Balancing one problem with another
Steroids are toxic, but they are used to balance other toxic situations.
80 yrs old patient with scleroderma (cannot open or close her hand)  give her Prednisone.
Clinical Problems [S16]
Side Effects caused mainly by high concentrations maintained for a long time
Most common Side effects:
Development of cushingoid habitus (truncal obesity, moon facies, buffalo hump), salt retention, and hypertension (i.e. iatrogenic Cushing’s syndrome)
Suppression of immune system (rendering the pt vulnerable to common and opportunistic infections)
Osteoporosis (rendering the pt vulnerable to fractures)
Peptic ulcers (resulting in gastric hemorrhages or intestinal perforation) – MAIN problem: NSAIDS and steroid use cause more deaths than HIV in US mainly from gastric bleeds. Unappreciated
Suppression of growth in children
Behavioral problems
Reproductive problems
Prolonged suppression of the HPA axis after drug discontinuation
Glucocorticosteroid Therapy [S17]
EXAM QUESTION: All of the following are examples of side effects of steroids except one.
Osteoporosis
Glucose intolerance - high levels of blood glucose
Increased risk of atherosclerotic disease
Myopathy
Immune suppression
Cataracts
Avascular necrosis of bone (e.g. hip)
Neuropsychiatric disorders
Many people will display latent diabetes when put on Prednisone for the first time. Blood sugar will increase to 300 and not come down. When they come off Prednisone, the blood sugar should come back down. If the patient stays on Prednisone, they will have to take anti-diabetic medication.
S&S of Cushing’s Syndrome [S18]
Myopathy
Peripheral muscle wasting
Central obesity
Moon facies
Supraclavicular and dorsocervical fat pads – under arms and back
Pigmented abdominal striate – lines across the belly
Acne
Hirsutism – inappropriate hair growth
Plethora
Bruising and capillary fragility
Hypertension – high BP
Glucose intolerance
Hypokalemia – low potassium
Arteriosclerosis
Infections
Neuropsychiatric disorders –people get happy or hyperactive
Osteoporosis
Hypogonadism
Preparations Available [S19-20]
Glucocorticoids for Oral and Parenteral Use(recognize these)
Betamethasone
Cortisone
Know that this is water-soluble: Prednisolone sodium phosphate & Methylprednisolone sodium succinate (Solu-Medrol is brand name, but do not have to know brand name. It is one of the drugs common prescribed at the hospital for IV administration)
Not water-soluble: Prednisolone acetate & Methylprednisolone acetate
Pharmacokinetic Parameters [S21]
Route of Administration: oral, IV, IM, inhaled, topical
Triamcinolone and Betamethasone (mentioned in Respiratory Systems) is used for inhaled therapy in asthmatic pts.
Half-life: short, intermediate, to long
Inhibitors of Glucocorticosteroid Synthesis [S22]
21-hydroxylase is the most common defect. Inhibitors are not used often.
Inhibitor list that you should know: Ketoconazole, Aminoglutethimide, and Mitotane block the first pathway, so none of the chemicals is formed.
Metyrapone, Ketoconazole, and Aminoglutethimideblock at the final product.
These are helpful if a surgical situation arises, that precludes a surgeon from removing a tumor. Can give these drugs to prevent formation of glucocorticoids but there are many problems associated with them (“not clean,” not specific, and have many side effects).
Therapy [S23]
Glucocorticoid Replacement Therapy
administer 2/3 in morning, 1/3 in evening
mimic natural cycle of cortisol secretion
usually increase dose during infection, stress, cold, surgery
include mineralocorticoid therapy if needed (Fludrocortisone)
Anti-inflammatory/immunosuppressive therapy:
Use more glucocorticoid, but lowest effective dose. When starting a patient on long-term treatment, give them an effective dose, and then back off until you see how low you can get. Lower = better because of less side effects in the future
use alternate day dosing if possible or administer 2/3 in morning, 1/3 in evening
increase dose during infection, stress, cold, surgery
wean off medication slowly
do not include mineralocorticoid unless needed

***The following slides are from Dr Pillion’s lecture on “Endocrine Pharmacology” November 6 10-11am.