L16-L17 Corticosteroids-3 PDF

Corticosteroids 1 Learning objectives  Explain how the hypothalamus and the pituitary regulate the biosynthesis of cortisol.  Describe the difference in regulation of synthesis of glucocorticoids and mineralocorticoids.  Identify the structural difference betwe...

Corticosteroids 1 Learning objectives  Explain how the hypothalamus and the pituitary regulate the biosynthesis of cortisol.  Describe the difference in regulation of synthesis of glucocorticoids and mineralocorticoids.  Identify the structural difference between glucocorticoids and mineralocorticoids.  Describe the two different mechanisms of actions of glucocorticoids.  List the physiological effects of glucocorticoids.  Identify the cause for Addison’s disease and Cushing’s disease from the levels of cortisol, ACTH, and CRH.  Identify the structural features responsible for drug properties in synthetic glucocorticoids.  Compare the potency levels of synthetic glucocorticoids.  Explain the structural and chemical characteristics of systemic, inhaled, and topical glucocorticoids.  Describe the desired properties of inhaled glucocorticoids. 2 PHRM 825 Learning objectives  Identify the structural modifications that are responsible for increased lipophilicity and increased metabolism in inhaled glucocorticoids.  Identify topical glucocorticoids based on the drug structures.  List the adverse effects of glucocorticoids.  Describe the strategy to minimize the adverse effects of glucocorticoids. 3 PHRM 825 Outline  Adrenal glands  Regulation of the synthesis of glucocorticoids and mineralocorticoids  Mechanism of glucocorticoid action  Physiological effects  Disorders in glucocorticoid production  Synthetic glucocorticoids  Adverse effects 4 PHRM 825  Adrenal glands ↳attach to - Kaney top on of releases : releases : A Kidney Glucocorticoids - Mineralocorticoids - Epinephrine ladrenalin) - Norepinephrine weak Androgens CNS Control ANS - different than epi , NE Image from http://uvahealth.com/ Copyright © Nucleus Medical Media, Inc. 5 PHRM 825 Adrenocorticoids  Glucocorticoids  Stress hormones  Increase circulating glucose concentrations.  Potent anti-inflammatory effects in  Mineralocorticoids produced body ?  Na+ retention Cortisol (hydrocortisone)  Increase blood volume. helps to cope my stress Gas drug When stressed ↑  Increase blood pressure. Aldosterone 6 PHRM 825 Contrasting modes of action of stress hormones  Epinephrine  Binds to β-adrenergic receptor (GPCR).  Initiates signal transduction cascade.  Induces immediate response.  Breaks down glycogen and release glucose.  Cortisol (hydrocortisone) Epinephrine  Binds to glucocorticoid receptor (nuclear hormone receptor). transcriptionfactor  Regulates gene transcription, and thus translation and protein production. regulate gene expression  Induces long term, persistent biological response. need to deal ul stress  Induces gluconeogenic enzymes. liver produces more glucose  Inhibit pro-inflammatory processes. Immediate response wi Cortisol (hydrocortison) epi persistent response ↳ suppress Immune response 7 reduce pain PHRM 825 suppress inflammation get sick Regulation of glucocorticoid synthesis Hypothalamic-pituitary-adrenal (HPA) axis Stress Pain Noise Emotional reactions CRH Corticotropin releasing hormone ACTH (corticotropin) Feedback Adrenocorticotropic hormone loop Physiological responses 8 PHRM 825  Regulation of mineralocorticoid synthesis  When the pituitary gland is surgically removed in animals, aldosterone synthesis is not affected significantly.  The anterior pituitary does not control the synthesis of mineralocorticoids  Renin-angiotensin-aldosterone system ↑ Nat Inactive form Liver Angiotensinogen protease Renin Kidney Antagonists - Angiotensin I ↳ Angiotensin converting enzyme (ACE) ACE Inhibitors b aldosterone Angiotensin II (peptide renin B-blocker-suppress are binds to receptor in Adrenal glands Aldosterone not controlled by pitritary 9 PHRM 825 Mechanism of action Glucocorticoids Heat shock proteins Proteins hsp GR hsp Translation mRNA Cytoplasm bind to Transcription GR GR Nucleus 10 gene PHRM 825  Hormone response elements  DNA-binding domains of activated dimers bind to specific DNA sequences called Glucocorticoid Responsive Elements (GRE), upstream of steroid responsive genes.  Binding alters rate of transcription.  Glucocorticoids up-regulate enzymes for gluconeogenesis and anti-inflammatory - proteins.  PEP carboxykinase – catalyzes the rate-limiting step in gluconeogenesis.  lipocortin 1 – suppresses phospholipase A2, which has a critical role in eicosanoid synthesis. activate genes arochidonaid acid 5’- GGTACANNNTGTTCT- 3’ 3’- CCATGTNNNACAAGA -5’ Glucocorticoid response element 11 PHRM 825 anti-inflam Mechanism of immunosuppression by glucocorticoids & pro-inflam transcription factor.  Activated glucocorticoid receptor (GR) binds to NFB and prevents binding of - NFB to its response element. - Genes b -  Transcription of cytokine genes are repressed. Inflam Glucocorticoids bind to specific NFB receptors GR Cytoplasm NFB Nucleus GR GR 12 PHRM 825 Physiologic effects maintain blood  Liver levels ↑ glucose  Increase gluconeogenesis and glycogen storage.  Muscle  Promote protein degradation. An energy source source Increase blood  Decrease protein synthesis. At used as energy glucose levels  Decrease sensitivity to insulin.Istimulate muscle fat cell) , don't bring in glucose as much  Adipose tissues  Promote lipolysis.  Decrease sensitivity to insulin.  Immune system  Block the synthesis of cytokines ( immunosuppression)  Inhibit the production of eicosanoids ( anti-inflammation)feel less pain  Necessary for the full effects of catecholamines (permissive effects)  In the absence of glucocorticoids, the responses of vascular and bronchial smooth muscle to catecholamines is diminished. 13 PHRM 825 Adrenal insufficiency -not working properly  * Hypoadrenalism  Decreased secretion of steroid hormones by the adrenal cortex.  Causes  Destruction of the cortex by tuberculorsis or atrophy (primary; Addison’s adrenal glands - no disease) Scant make cortise or aldosterone- activity  Decreased secretion of adrenocorticotropin (ACTH) due to diseases of anterior pituitary (secondary; no hypoaldosteronism) Cortisa not released  Symptoms aldosterone - fine via renal pathways  Extreme weakness Casthenia)  Anorexia, anemia, nausea, and vomiting  Low blood pressure (in primary only)  Hyperpigmentation of the skin (in primary only) #20 189S  Mental depression  Cessation of long-term systemic glucocorticoid therapy can lead to Addisonian ↳ external drug - > no cortis symptoms. suppress pituitam- breed atrophy- > > related to thyroid hormone to taper If taken off 14 If not glucocorticold drops badly PHRM 825 levels Types of adrenal insufficiency check blood levels Primary Secondary Tertiary Adrenal defect Pituitary defect Hypothalamic defect nomrack CRH ACTH no stimulation Cortisol Aldosterone Not affected Not affected 15 PHRM 825 Cushing’s disease  Hyperadrenalism  Causes  Tumors in the adrenal cortex (adrenal Cushing’s disease)  Increased production of ACTH due to pituitary carcinoma (pituitary Cushing’s disease) cancer  Ectopic production of ACTH due to non-pituitary carcinoma (ectopic Cushing’s disease) Act Why ? lak hap Cancer live ? lung cells/cancer can release  Symptoms  Weight gain, thin arms and legs, moon face  Increased protein catabolism (easy bruising, delayed wound healing, muscle wasting) and increased glucose levels loose muscle tissues suppress protein synthesis ,  Osteoporosis  Opportunistic infections -Cartisa suppresses immune system way too much -  Long-term therapeutic use of systemic glucocorticoids can lead to Cushing’s symptoms. 16 PHRM 825  know exam Types of Cushing’s disease which site ? ↓ -- Adrenal Pituitary Ectopic Icancer CRH ACTH Cortisol Ectopic ACTH 17 PHRM 825 Therapeutic uses of corticosteroids  Primary adrenal insufficiency (Addison’s disease) > - give corticosteriods  Allergic reactions  Insect stings  Angioedema > face - swells  Inflammation and autoimmune diseases  Bursitis, synovitis, tendonitis inflammation of joints tendons ,  Rheumatoid arthritis  Systemic lupus erythematosus (SLE or lupus) autoimmune -  Inflammatory bowel disease IBS  Chronic hepatitis  Asthma - chronic inflammation  Miscellaneous uses  Immunosuppressive  Anti-cancer 18 PHRM 825 Cortisol versus cortisone  Oxidation of 11 hydroxyl to ketone inactivates glucocorticoids.  Catalyzed by 11β-hydroxysteroid dehydrogenase in the liver.  The reaction is reversible.  Cortisone is as effective as cortisol, when used systemically.  Cortisone should not be used to patients with impaired liver functions. Cannot be activated Il-ketone group Ithydroxy OH O O OH O Cortisol (hydrocortisone) - Cortisone - pro-drug Active Inactive ⑪ doesn't work on Skin 19 for sin cream needs to be metabolizedIn PHRM 825 liver Systemic corticosteroids  Short-acting (t1/2 in tissues = 8 – 12 hrs)  Hydrocortisone ⑳  Cortisone  Intermediate-acting (t1/2 in tissues = 12 – 36 hrs)-USS SE. e  Prednisone  Prednisolone  Methylprednisolone  Triamcinolone  Long-acting (t1/2 in tissues = 36 – 54 hrs)  Dexamethasone > most potent = severe SE for long term use  Betamethasone 20 PHRM 825  Properties of corticosteroids t1/2 plasma t1/2 tissue GC MC (min) (hr) activity activity Cortisol 90 8-12 1 1 Cortisone 30 8-12 0.8 0.8 Prednisone 60 12-36 4 0.3 m Jor Prednisolone 200 12-36 4 0.3 ic Methylprednisolone 180 12-36 5 0.25 Triamcinolone 300 12-36 5 0 gee sa Dexamethasone Betamethasone 100-300 100-300 36-54 36-54 25 25 0 0 J morePotent a Fludrocortisone 200 8-12 10 125 Esynthetic 21 PHRM 825 , used as MC (strong activity Synthetic glucocorticoids Fludrocortisone  9α-F  Greater glucocorticoid activity  Strong mineralocorticoid activity  Intense Na+ retention leading to edema  Used in mineralocorticoid replacement therapy ↳ used in addison's disease Hydrocortisone 22 PHRM 825  Synthetic glucocorticoids Prednisone/prednisolone  Extra double bond between C1 and C2 (Δ1).  Altered ring structure  More potent glucocorticoid activity  Stronger binding to the glucocorticoid receptor  Reduced mineralocorticoid activity Hydrocortisone  Interconvertible by 11β-hydroxysteroid dehydrogenase arrall band alters ring structure in-active W * binds better Prednisone Prednisolone ACTIVI X5 better than Cortisa 23 PHRM 825 pro-drug-systemic activated in liver  Synthetic glucocorticoids Methylprednisolone Triamcinolone - He modify form  6α-methyl group  9α-F and 16α-OH  Potency similar to that for  Glucocorticoid activity similar to prednisolone prednisone ↓ Reduced mineralocorticoid activity  Reduced mineralocorticoid activity be of methyl group  Increased hydrophilicity & most commonly used  Low oral bioavailability poor absorption in gut 24 PHRM 825 Synthetic glucocorticoids Dexamethasone Betamethasone  16α-methyl group  Enantiomer of dexamethasone at 16  Increased lipophilicity  Has similar properties as  A Increased receptor binding dexamethasone.  Significantly stronger effect -  A Increased stability in human plasma  b Reduced mineralocorticoid activity binds to receptor better enationer -S more hydrophobic good oral bioavail Betamethasone 25 PHRM 825 21-esters -  The hydroxyl group at 21 can be modified to an ester to control the property of glucocorticoids.  Prodrugs activated through hydrolysis by esterases IM  Acetate (R = -COCH3) and butyrate (R = -COC3H7) hydrophobic  Increased lipophilicity stay in location Slowly release 21-hudroxy- > ester  Prolonged action upon IM or intra-articular injection &  Succinate (R = -COCH CH COO–) 2 carboxylic groups prodrug Charge (very scubel) OR 2 2 more neg.  Soluble HO O  Slow hydrolysis (peak in 30 – 45 min)- > active drug released OH ↑ [drug]  Phosphate (R = -PO2–) removed quickly  ↑ Increased solubility dramatically O  Rapid hydrolysis by phosphatases (~10 min)  IV or IM injection for emergency conditions - not seluble soluble -> nigh [C] u/phosphate 26 PHRM 825 SAR Structure-activity relationship summary 11β-OH required for full 21-OH, F, or Cl required for GR/MR activity; more GR/MR activity; ester prodrug important for GR must be hydrolyzed to OH for maximum activity. 1,2 double bond; five-fold enhancement in GR/MR ratio 17α-O required for GR activity; can be part of acetonide ring or ester. 16α or β-CH3 or O 9α-F or Cl enhances substituent decreases GR and MR potency. MR activity. 6α-CH3 or F enhances & GR/MR ratio. Check 27 PHRM 825 Mechanism of glucocorticoid action in asthmaprevent reduce chance of asttima attack , -  Glucocorticoids doe not directly relax airway smooth muscle; little effect on acute bronchoconstriction. beta agonist help breathe :  Glucocorticoids will not stop an asthma attack while it is happening.  Effective in inhibiting airway inflammation.  Modulation of cytokine and chemokine production  Inhibition of eicosanoid synthesis  Inhibition of accumulation of immune cells in lung tissue  Decreased vascular permeability  Inhaled glucocorticoids are used prophylactically to control asthma.  Beneficial effects may be seen within 1 week; maximal improvement in lung function may not occur until after several weeks of treatment.  Compliance is a significant concern. 28 PHRM 825 Inhaled glucocorticoids  Desired properties  High potency  Minimal systemic effects micro Micro-  Prolonged action make drug lipophilic - drug form crystals => Its sk bc when Inhaled crystals not so sound stay in airways :prolonged effect  Solutions dissolved Slowly  High lipophilicity  Tighter binding to the receptor  Better tissue penetration  Prolonged action by forming poorly soluble microcrystals  Low oral bioavailability (acht want high-bads)  70-90% of inhaled glucocorticoids is swallowed.  Rapid clearance  Short half-life> - degraded quickly not 1st of SE 29 PHRM 825  Inhaled glucocorticoids * Triamcinolone acetonide Beclomethasone dipropionate  Acetonide is resistant to hydrolysis - -  Converted rapidly to 17-  8x more potent than prednisolone monopropionate by hydrolysis. 14x more potent than dexamethasone systemic-seasonal allergies  like betamethasone nasal spray 17-01-eester /P lipophilicity/hydrophobic) modify : new hydrophobic 2 olt groups too hydrophilic 30 PHRM 825 Inhaled glucocorticoids Flunisolide Budesonide  Rapid absorption from nasal or lung  1:1 mixture of epimers at 16,17- tissue butylacetal  Rapid metabolism by the liver  Faster topical uptake ↳  Extensive first-path metabolism  Low oral bioavailability  Minimal systemic adverse effect - with long-term therapy  Extensive first-path metabolism (cow systemicse) - hydrophobicity 31 PHRM 825  Inhaled glucocorticoids Mometasone furoate safe Fluticasone propionate  Highly potent  Inactivated by hydrolysis of thioester.  More rapid onset of action  Rapid first-path metabolism  Negligible systemic availability  Highly lipophilic and insoluble> micro-crystal - suspended in llquid  Rapid metabolism  Highly potent  Poor absorption from GI oral avail low-  Low oral bioavailability (< 1%) - ↑ ester  Rapid topical uptake 17-0H- ester good lipophilicity Anuarophobicity 215H - 21 4 - more hydrophobla thire-ester 32 PHRM 825  -Skin Topical glucocorticoids  Desired properties of topical glucocorticoids High lipophilicity for fast absorption hydrophobic -  - > penetrate tissue  Minimal systemic effect  Prolonged action helps wh tissue penetration  Halogenated analogues are usually potent topical glucocorticoids. 3 converted OH - > C1 or f (more lipophilic  Once absorbed through the skin, topical glucocorticoids are squck metabolized primarily in the liver and excreted into the urine or in the bile.  Glucocorticoids with low potency are safest for chronic application. -  Hydrocortisone cream (unrenic no Rx)  Glucocorticoids with high potency can have a risk of systemic exposure; should be used only for a short duration of treatment. etopic dermate +is => chronic 33 PHRM 825 Topical glucocorticoids  Acetonide or ester forms have better potency for topical applications due to high lipophilicity. hydrophobic hydrophobic HO O O HO O 17-01 O ester HO O O HO F F O O Triamcinolone acetonide Fluocinonide Betamethasone valerate High potency High potency Medium potency - a most common 34 PHRM 825 halogenated 21-chloro 21-chlorocorticoids  Substitution of a chlorine atom for the 21-hydroxyl group greatly enhances topical anti-inflammatory activity. more Lipophilic-penetrate Tissue 21 OH - 21 C - better Cl Cl O O O 8 O O HO HO C2H5 O F & ester O O 8 F F Clobetasol propionate Halobetasol propionate Halcinonide Very high potency Very high potency High potency very s 21-chloro analogue of betametasone 17-propionate shouldn't be used long term 35 PHRM 825  Topical glucocorticoids  Fluticasone propionate and mometasone furoate have only medium potency.  High lipophilicity and the highest binding affinity, but poor solubility  Poor dissolution into inflamed tissue insoluble micro-crystals Inhaled (stays) - Snasoluble for skin b just removed b doesn't stay on skin Fluticasone propionate Mometasone furoate Medium potency Medium potency 36 PHRM 825 Adverse effects of glucocorticoids H20 retention acts as aldosterone :  Crossover mineralocorticoid activity ↑ Sodium and water retention & Development of hypertension H Correctable with selective synthetic glucocorticoids  Metabolic effects (increased glucose production) anti-inflam loose muscles  Steroid myopathy > -  High doses over a period cause wasting of proximal muscles (e.g. shoulders, - hips, thighs). ↑ protein degradation in muscle  Reduced long bone growth in children (also sex normones  May cause premature closing of epiphyseal junction and stop growth. -  Osteoporosis ↳  Pharmacological doses of - glucocorticoids inhibit osteoblasts.  Can be prevented by bisphosphonate. Tx of Osteoporosis 37 PHRM 825 eX : And Adverse effects of glucocorticoids released a deposited breakdown fat stored -  Cushing's-like effects – redistribution of fat in fact  Moon face  Buffalo hump  Impaired glucose tolerance -  Hyperglycemia from gluconeogenesis  Decreased insulin response  A special problem with diabetes mellitus  May unmask diabetes mellitus. 38 PHRM 825 Adverse effects of glucocorticoids  Suppression of immune system  Increased susceptibility to infections -  Impaired wound healing -  Gastrointestinal  Greater peptic ulcer risk PUP  Central nervous system  Insomnia, irritability -  Depression -  Increased appetite and weight gain↑ hunger weight ,  Cataracts gain Candidiasis of mouth (thrush) in patient taking inhaled glucocorticoid 39 PHRM 825 Adverse effects of glucocorticoids  Adrenal insufficiency upon withdrawal (Addisonian crisis)  Due to negative feedback on hypothalamus and pituitary from prolonged - pharmacological doses of glucocorticoids  Delayed recovery of hypothalamus and pituitary  Depressed ACTH release and adrenal response to ACTH  Directly related to dose and duration of therapy  Symptoms  Inability to withstand stress -  Hypotension -  Weakness - 40 PHRM 825 Incidence of some major side effects Incidence Duration of Minimum Side effects Reversibility (%) therapy daily dose Loss of glucose 7.5 mg 1 – 28 Days – months Yes tolerance prednisone Redistribution 4 – 12 mg 13 < 2 months No of fat triamcinolone 7.5 mg Hypertension 4 – 25 2 weeks Yes prednisone 10 mg Myopathy 10 1 week Yes prednisone 6 mg Psychiatric 1 – 18 Days Yes prednisone 6 mg Cataract 4 2 months No prednisone 41 PHRM 825 Drugs to study  Systemic corticosteroids (Vanceril®, Qvar®)  Hydrocortisone  Flunisolide (Aerobid®)  Cortisone  Budesonide (Pulmicort ®)  Prednisone  Mometasone furoate (Asmanex®)  Prednisolone  Fluticasone propionate (Flovent®)  Methylprednisolone  Topical glucocorticoids  Dexamethasone  Triamcinolone acetonide  Betamethasone  Fluocinonide  Systemic mineralocorticoid  Betamethasone valerate  Fludrocortisone (Florinef®)  Clobestasol propionate  Inhaled glucocorticoids  Halobetasol propionate  Triamcinolone acetonide  Halcinonide (Azmacort®)  Beclomethasone dipropionate 42 PHRM 825