Biochem- Steroid Hormones
What controls the outer zone?
Angiotensin II
What is Spironolactone?
- A competitive antagonist of aldosterone - Action occurs int he distal portion of tubule - only effective if sufficient sodium reaches the distal tubule and if excess aldosterone is present - has demonstrated tumorigenic actioin in rodents; not humns - causes occasional hormonal problems; ex: gynecomastia in males - has gradual onset; activity peaks in 2-3 days - 80% is metabolized to canrenone (active drug that acts at the receptor) - Aldactone is the pro-drug - has thioester at 17th position, SCOCL3 is lost and db is formed
Fludrocortisone
- A potent steroid with both glucocorticoid and mineralcorticoid activity - Used mainly for its mineralocorticoid activity in Addison's disease - dose 0.1 mg 2-7 times weekly - Fluorene at 9 alpha position - Has dual action
Drospirenone
- A progesterone which has anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin aldosterone angiotensin system, and is not androgenic. Similar to aldactone that leads to less water retention. - Component of 3 products: Yasmin, Yaz, and Angeliz usually in combination with ethinyl estradiol. Has all different types of biological properties
What is the breakdown of the amino acids for ACTH?
- AA 1-24 require full activity - AA 25-33; species differences and immunologic specificity - AA 34-39 sequence common to all species (biological half life is approx 10 mins)
Adrenocrtical insufficiency for acute adrenocortical insuffiency?
- Adrenal crisis (Waterhouse-Friderichsen syndrome) - weakness, dehydration - abdominal pain, high fever - vomiting and diarrhea - low BP and eosinophilia - increased skin pigmentation - low sodium, high potassium serum levels - usually due to infection of renal gland - causes extreme dehydration
What are the adrenocortical hormones?
- Adrenal means ontop of the kidneys - Glands are made up of two types of cells: center it the medulla, which secretes catacholemines, epi and norepinephrine,
What are typical glucocorticooid inhalers?
- Advair (beta aganoist, powder inhaler, very popular, as well as pulmicort, used to treat asthma) - Pulmicort - Azmacort
Indications for systemic glucocorticoids for respiratory diseases?
- Asthma is a big one - Symptomatic sarcoidosis - berylliosis - disseminated pulmonary tuberulosis - pulmonary emphysema - aspiration pneumonitis - aspiration penumonitis - diffuse intersitial pulmonary fibrosis
Indications for systemic glucocorticoids for rheumatic disorders?
- BIG ONE - rheumatoid arthritis - ankylosing spondylitis - acute subacute arthritis - acute nonspecific tenosynovitis - patients tend do to better with steroids, especially in short term
Mineralocorticoid receptor antagonists
- Compounds or drugs which interfere with the action of aldosterone - Currently 2 such drugs are available in the U.S.: spirolactone (Aldactone) and eplerenone (Inspra) - other drugs: canrenone, potassium carenoate (not available in the U.S.) - mainly in distal tubule in collecting duct of kidney
Adrenocortical overactivity
- Cushing's syndrome or adrenal hyperfunction - Cushing's disease or pituitary bashophilism
Fluticasone Propionate (Cutivate) and Hydrocortisone Probutate (Pandel)
- Cutivate is very hydrophobic
Mineralcorticoid antagonist
- Differentiated by spiro chemistry at 17th carbon, which has two rings that share on carbon - Lactone shares 17 carbon with D ring of steroid
What are the 3 major functional types of hormones
- Endocrine (excreted into blood stream)- steroid hormones - Paracrine (work very close to where they are being synthesized)- prostaglandins - Autocrine (act at a cellular level where they are being produced)- interleukin-2
What families are enzymes part of?
- Enzymes are part of the cytrochrome family, which originate from cells that have a reddish appearance, sometimes known as cyp - Heme is a prostethic group that gives it red color
Diflorasone (Psorcon) and Prednicarbate (Dermatop)
- Equally effective for variety of inflammatory positions
What is the first step in steroid hormone biosynthesis?
- First step is degradation of side chain via desmolase (p450) and formation of pregnenolone (c21)
What makes prendisolone water soluble?
- Functionalization at C21 to produce a water soluble steroid - If want to admin drug IV or solution, gotta make this insoluble compound soluble - Can achieve water solubility by forming phosphate esters
Mitotane and Aminoglutethimide
- Glucocorticoid antagonists - Mitotane (Lysodren) and aminoglutethimide (Cytadren) both interfere with biosynthesis of glucocorticoids. - Aminoglutethimide is also an aromatase inhibitor involved in estrogen biosynthesis - Mitotane was used as a by product of DDT (insectiside), very powerful inhibitor of biosynthesis of glucocorticoids
What are the steroid hormone classes?
- Glucocorticoids- (from adrenal cortex) - Mineralocorticoids- (from adrenal cortex) - Androgens- (produced gonadotropins) - Estrogens - Progestins - Vitamin D
How are steroid hormones effective?
- Have to enter the nucleus to be effective, where they interact with hormone responsive allomer, which then transfers to a messenger rna
Examples of glucocorticoids
- Hydrocortisone- the most active natural glucocorticoid - Prendisolone- delta 1 derivative with greater potency (made synthetically), has a db between carbon 1 and 2 - These have to have hydroxyl group at positions 11,17,21
What are hormone?
Hormones are chemical messengers that transport signals from one cell to another
Mineralocorticoid pathway
cholesterol -> pregnenolone -> progesterone-> deoxycorticosterone -> corticosterone -> aldosterone
What are the actions of ACTH on adrenal cortex?
- Increase in adrenal weight (due to increase in proteins and enzymes) - Decrease in adrenal lipids (b/c lipids are primarily cholesterol and its being used to make steroids) - decrease in adrenal cholesterol - decrease in adrenal ascorbic acid - increase in protein synthesis (enzymes which hydroxylate steroids) - increase in oxidative phosphorylation - increase in rate of glycolysis
What are the major functions of adrenal steroids for glucocorticoids?
- Increases gluconeogensis - increases glycogenesis - increases protein catabolism - decreases antibody response (more vulnerable to infections) - anti-inflammatory response - anti-neoplastic response (used in chemotherapy, anticancer drugs, have antilymphatic activity, they suppress formation of WBC in leukemia
What pathways can pregnenolone follow?
- It can be converted to progesterone which can be converted into gluco and mineralocorticoids, c21 (in adrenal cortex) - It can also be converted through several steps into testosterone (c19) which in turn can be aromatized into estradiol (c18)
What are the physiologic effects on anti-inflammatory effects?
- Negative effect on lymphocytes, monocytes, and macrophages - inhibit the release of IL-1, IL-2, and IL-6 and TNF-alpha - reduced migration of inflammatory cells to site of injury - decreased lymphocyte production - impairment of delayed-type hypersensitivity
What are the indications for systemic mineralocorticoids?
- Replacement therapy for primary and secondary insufficiency in Addison's disease (most occuring) - treatment of salt-losing adrenogenital syndrome
What is ACTH produced by?
- Single polypeptide chain produced by basophilic cells of adenohypophysis (pitutiary gland) - controlled by CRH (corticotropin releasing hormone) from hypothalamus
Indications for systemic glucocorticoids for collagen diseases?
- Systemic lupus erythematosus - acute rheumatic carditis - systemic dermatomyositis
Dexamethasone and Triamcinolone
- These are synthetic glucocorticoid with more potent glucocorticoid activity - Dexamethasone is more potent than methylprednisolone - Triamcinolone, same as prendisolone, but has an additional hydroxyl group at C16. The hydroxyl group at c16 and c-17 are cis and very close together, can react two adjacent carbons with a ketone and form acetonides, which have a greater tendency to penetrate tissues than triamcinoline base
How are glucocorticoids synthesized from cholesterol?
- To prenenolone->progesterone->17-alpha-hydroxyprogesterone->11-deoxycortisol->cortisol
Other uses for Mitotane and Aminoglutethimide
- Used for tumors of adrenal cortex if it can't be operated on, but very toxic - Aminoglutethimide is related to treat epilepsy, inhibits biosynthesis of glucocortocoids
What are the three layers that make up the adrenal cortex?
- Zona glomerulosa (outer zone)- produces aldosterone, which is most potent in outer zone - Zona fasciculata (middle zone)- produces cortisol (glucocorticoids)- ex is hydrocortisone - Zone reticularis (inner zone)- produces corticosterone and androgens, (when there is a tumor in the inner zone, women tend to developp male characteristics
Eplerenone (Inspra)
- a selective aldosterone receptor antagonist (acts on the mineralocorticoid receptor) - chemical similarity to aldosterone - used in the management of hypertension - Has typical spiral ring structure at the 17th carbon
What are the most common agents for mineralocorticoids?
- aldosterone (main one and used to retain water) - desoxycorticosterone - Fludrocortisone (Fluorinef)- most commonly used, when lose a lot of water and sodium, want to replace them, use fludrocortisone, not aldosterone, just aldosterone with an extra fluorine at 9th carbon, good to treat addison's disease
What are indications for systemic glucocorticoids for ophthalmic diseases?
- allergic conjunctivitis - keratitis - allergic corneal marginal ulcers - herpes zoster ophthalmicus - iritis and iridocyclitis - optic neuritis - retrobulbar neuritis
Primary hyperaldosteronism
- also known as Conn's syndrome - due to benign tumor that secretes large amounts of aldosterone - suppression of the RAS (remin-angiotensin system) - increase in BP and hypokalemia
About aldosterone and corticosterone
- both have mineralocorticoid activity, however are not used therapeutically - Aldosterone is the most powerful agent, is a natural product but the drug used is fludrocortisone
Steroid hormone biosynthesis
- common precursor is cholesterol (cholesterol is the precursor for all steroid hormones) - cholesterol is a c27 steroid, and most steroid hormones have a lower number of carbons
What is the anti-inflammatory effect of glucocorticoids?
- effect on protein synthesis * inhibit protein-translation of inducible COX-II (which also inhibits PG and thromboxanes) * promote synthesis of lipocortins (annexin 1) which inhibit phospholipase A2 (this inhibits production of arachidonic acid and hence prostaglandins and leukotrienes) - physiologic effects
What is the ACTH test?
- gives ACTH and measures cortisol (helps to distinguish between primary and secondary adrenal insufficiency - should see a dramatic increase in both mineral and primarily glucocrticoids, can distinguish between primary and secondary using ACTH
Indications for systemic glucocorticoids for hematological disorders?
- idiopathic and secondary thrombocytopenia in adults - acquired (autoimmune) hemolytic anemia
What are the major functions of adrenal steroids for mineralocorticoids?
- increase sodium and water retention - promote potassium loss
What are the permissive effects for glucocorticoids required for certain actions?
- inhibit fibroblasts (connective tissue loss) - negative calcium balance (osteoporosis) - negative nitrogen balance (catabolism- muscle mass gives a neg nitrogen balance) - CNS: euphoria, behavioral changes, psychosis - GI: increase stomach acid and pepsin production - cardiovascular effects (increase BP, heart rate) - uptake of fat by fat cells - gluconeogensis - insulin release and glycogen deposition
Indications for systemic glucocorticoids for neoplastic diseases?
- leukemias and lymphomas in adults - acute leukemia of childhood - glucocorticoids decrease life span of WBC, used in lymphomas and leukemias, not used by themselves
What is spirolactone (aldactone)?
- mineralocorticoid antagonist - is a steroid - If asks a question, which is a steroid....answer is this
What is ketoconazole (nizoral)?
- non-specific inhibitor of adrenal and gonadal steroid biosynthesis - mainly used as an anti-fungal
Indications for systemic glucocorticoids for dermatological diseases?
- pemphigus - bullous dermatitis herpetiformis - severe erythema multiforme (Stevens-Johnson) - exfoliative dermatitis - Mycosis fungoides - Severe psoriasis - Treats many types of conditions from bug bites to very severe like Stevens-Johnson syndrome
Toxicity of adrenocorticoids
- pituitary- adrenal suppresion (adrenal insufficiency) - fluid and electrolyte disturbances - hyperglycemia and glucosuria - increased suspectibility to infections - peptic ulceration - myopathy (weakness of muscles of arms and legs) - osteoporosis and vertbral compression fractures - posterior subcapsular cataracts
What are the indications for systemic glucocorticoids for endocrine disorders?
- primary and secondary adrenocortical insufficiency (main diff btwn two is the adrenal cortex is not synthesizing enough) - congenital adrenal hyperplasia - nonsuppurative thyroiditis - hypercalcemia associated with cancer - shock unresponsive to conventional therapy
Synthetic steroids
- produced mainly from animal and plant steroids - Diosgenin is a steroidal saponin, which is extracted from the root of wild yam, known by its botanical name as Dioscorea - natural glucocorticoids is the hydrocortisone - most drugs today are used from synthetic steroids - an example is prednisolone, derived from this compound
Indications for systemic glucocorticoids for allergic states?
- seasonal or perennial allergic rhinitis - bronchial asthma - contact dermatitis - atopic dermatitis - serum sickness - drug hypersensitivity reactions
What are the four major chemical classes of hormones?
- steroid hormones- i.e. progesterone - peptide hormones- i.e. insulin - amino acid derivatives- epinephrine - prostaglandins and related compounds
Cloderm and QVAR
- steroids generally have multiplicity of pharmacologic effect
What does angiotensin II
- stimulates adrenal cortex to release aldosterone
Information on Spirloactone
- useful in patients with gout or diabetes, since it has no hyperuricemia or impairment of glucose tolerance - do not administer potassium supplement- hyperkalemia - effective in the management of primary and secondary aldosteronism - dosage: 10 mg/day initially for edema; for essential hypertension: 100-400 mg - frequently combined with HCTZ (Aldactazide)
Chronic adrenocortical insufficiency for Addison's disease
- weakness and anorexia - nausea, vomiting and diarrhea - hypotension - sparce axillary hair - increased skin pigmentation of creases, niplles and pressure areas (due to ACTH production) - eosinophilia and lymphocytosis - get massive discharge from pituatry of ACTH
Desonide and Synalar (fluocinolone acetonide)
- will ask what makes this particular glucocorticoid better or more potent than cortisol? Synlar has two fluorides - Two cis hydroxyl groups
What enzymes require hydroxylating enzymes?
- 21-beta hydroxylase (CYP 21A2) - 17-alpha hydroxylase (CYP17A1)- has 2 fxns, hydroxylation at C17 and cleavage of the 17,20 bond (lyase action) - 11-beta hydroxylase (CYP11B1)
What are the products for enteric inflammations?
- Colocort - Entocort
What are the general characteristics of hormones
- Hormones are required in very small quantities (example 1 molecule of epinephrine- 1*10^11 molecule of glucose - Degraded very rapidly, so very difficult to study - Concentrations vary from 10^-6 to 10^-12M - from 1 ton of bull testis- 270 mg of testosterone - modern analytical techniques and chemical synthesis are very important
What are examples of hydrocortisone products?
- Locoid lipocream - Proctocort - Hydrea 2% - Hydrocortisone cream - Westcort
What controls the middle zone?
- Middle zone is under control of ACTH (adrenocorticotropic hormone), which means it stimulates it
Methylprednisolone
- a little more potent than cortisone
Glucocorticoid antagonists
- amphenone B block hydroxylation at 11,17, and 21 position. - Metyrapone is more selective in blocking beta 11-hydroxylation at low doses. Used more commonly in testing adrenal function. - Metyrapone is not a steroid, inhibits 11 beta hydroxylation
Cushing's disease or pituitary basophilism
- buffalo obesity (moon face and buffalo hump) - easy bruisaility (ecchymoses) - purple striae - impotence or amenorrhea - osteoporosis - hypertension, glucosuria - low serum potassium - low eosinophils and lymphopenia
What is the metyrapone test?
- confimatory test for secondary adrenal insufficiency - metyrapone inhibits 11-beta hydroxylation and thus cortisol synthesis - should result in high ACTH levels (if not, we know the problem is secondary)
What are ACTH products?
- corticotropin Injection (Acthar) - Respository corticotropin injection (H.P. Acthar Gel) - Cosyntropin (Cortrosyn)
What are ACTH products used for?
- mainly for diagnostic purposes (short half-life) - limited therapeutic value in conditions responsive to corticosteroids
What are other indications for systemic glucocorticoids?
- ulcerative colitis (via rectal enemas) - thrichnosis - dental inflammatory reactions - tuberculous meningitis