Adrenal Cortex & Response to Stress

Adrenal Cortex & Response to Stress

1. Steroid Hormones

   • CORTISOL (Glucocorticoid)
     • Regulation
       • HPA Axis: CRH and ACTH
         • NB. ADH (aka AVP) from Posterior Pituitary also stimulates ACTH
         • Stressors (starvation, dehydration, injury, infection, emotional) >
       • Circadian rhythms - high in morning but stress can override circ rhythms
         • Hypothalamus associated with SUPRACHIASMIC NUCLEUS (SCN)
     • Actions (no single target tissue - widespread effect)
       • Provide FUEL
         • ^Glycogenolysis & gluconeogenesis in liver. ^Breakdown of fats & proteins. ^Plasma [glucose, fatty acids, aa's]
           • Hypoglycaemia triggers... vInsulin, ^Glucagon, ^Adrenaline, ^GH, ^Cortisol
       • Protect KEY SYSTEMS (CVS)
         • ^Contractility
         • ^Peripheral resistance by: ^effects of adrenaline & NA, ^adrenergic receptors (mainly alpha-1), ^angiotensin receptors
           • Hypotension in Addison's. Hypertension in Cushing's.
         • (Can also activate Aldosterone receptors)
       • Depress INFLAMMATION & IMMUNE response
         • Inhibit prostaglandin (Eicosanoid hormone) synthesis. Immunosuppressive
           • Inhibit secretion of CYTOKINES, HISTAMINE release, IMMUNE CELL proliferation, ANTIBODY synthesis
         • Clinical use: Give cortisol - INHIBITS Interleukin-1 (IL-1), an inflammatory cytokine that stimulates ACTH release
           • eg. HYDROCORTISONE for psoriasis, eczema. PREDNISONE for organ transplant treatment (prevent rejection) or anaphylactic shcock
     • Disorders
       • ADDISON'S (Too little cortisol)
         • Primary deficit (adrenal cortex fails to secrete cortisol)
           • ^CRH & ^ACTH
           • Cause: Autoimmune destruction of adrenal cortical cells
           • Ttment: HYDROCORTISOL (a glucocorticoid) + FLUDROCORTISONE (a mineralocorticoid) as also aldosterone deficient - resolves hypovolemia and hyperkalemia.
         • Secondary deficit (pituitary fails to secrete ACTH)
           • ^CRH but low ACTH
           • Causes: - Chronic glucocorticoid treatment (exogenous glucocorticoids eg. hydrocortisone inhibit ACTH secretion) - Infection (eg. TB, HIV) - Drugs that inhibit cytochrome P450 enzyme
             • Ttment: HYDROCORTISOL (a glucocorticoid. High dose via IV so also stimulates MR).
               • EXOGENOUS CORTICOSTEROID
                 • ATTENTION! Exogenous steroids reduce ACTH secretion via -ve feedback.THEY SHOULD NOT be stopped suddenly as pt will secrete no ACTH > Atrophy of cortex > adrenocortical insufficiency
                   • Solution - Tapering off exogenous steroids allows ACTH to rise slowly. Stimulates growth of cortex > can release endogenous cortisol again.
                     • If cannot give orally, give via IV
                 • Reduce inflammation (in asthma, IBD, injury)
                 • Suppress immune system (rheumatoid arthritis, multiple sclerosis)
         • HYPOtension HYPOglycemia HYPOnatremia HYPOvolumia HYPERpigmentation* (*only in primary. High [ACTH] stimulates MSH receptor in melanocytes ^melanin - mouth/palm creases)
           • Usually detected via Addisonian Crisis (nausea, vomiting, collapse, depression, weakness)
       • CUSHING'S (Too much cortisol)
         • Muscle wasting on limbs. HYPERglycaemia. HYPERtension. Central obesity/Abdominal striae (cortisol ^GNG which stimulates insulin > fatty acids stored in adipose). Skin infections/boils.
           • (Excessive cortisol will stimulate MR so acts like aldosterone - ^blood volume, ^BP and hypernatraemia)
         • Cushing's SYNDROME (ACTH low)
           • Causes: Adrenal neoplasm/hyperplasia. Chronic glucocorticoid treatment
             • Ttment for Syndrome: slowly reduce glucocorticoid ttment
         • Cushing's DISEASE (ACTH high)
           • Causes: Pituitary tumour (benign) > Makes excessive ACTH
             • Treament for DISEASE: Remove/destroy pituitary tumour (surgery/radiotherapy/medicines)
   • ALDOSTERONE (Mineralocorticoid)
     • Kidney Function & Control
     • Actions
       • stimulates ENaC (Na+ channels) / Na-K-ATPase in distal tubule/collecting ducts
         • Na+ REABSORBED from filtrate (in excess > hypernatremia)
         • K+ SECRETED into filtrate (in excess > hypokalemia)
         • H2O RETENTION (vUrine, ^blood volume)
     • Cause
       • Low Na+/BP stimulates renin release in kidney > Renin cleaves angiotensinogen to Ang I > converted to Ang II...... Ang II STIMULATES Aldosterone release from adrenals
   • Cortisol RESPONDS TO STRESS = starvation, dehydration, injury, infection, emotional. (See also catecholamines)
   • Aldosterone REGULATES Na+, K+ & fluid volume
   • Steroid Hormone integration
     • Cortisol & Aldosterone lipid soluble - cross membranes. Can stimulate eachother's receptors due to similar structures ie. excess exogenous cortisol can stimulate MR
     • Most cells have GR. Kidney & Gut have MR.
     • Termination of action
       • Cortisol ~60mins half-life Aldosterone ~15mins half-life
       • Inactivated in LIVER. Excreted via KIDNEY > inactivated forms into urine

2. Adrenal Gland

   • Cortex = STEROIDS
     • Zone Glomerulosa G - ALDOSTERONE
     • Zone Fasiculata F - CORTISOL (& androgens)
     • Zone Reticularis R - ANDROGENS (& cortisol)
     • Medulla = CATECHOLAMINES
       • Chromaffin cells - Adrenaline & Noradrenaline
     • 'Corticosteroids'
       • Based on cholesterol. SAIDS not NSAIDs! Synthesised on demand (not stored). Expression of key enzymes regulated. Similar structures.

3. STRESS RESPONSE TO TRAUMA/SURGERY

   • SIGNALS
     • Afferent neuronal impulses from site of injury
       • Neuronal and cytokine signals stimulate BRAIN (cortex, limbic system - emotions, reticular formation - sleep, hypothalamus - homeostasis)
         • STIMULATES: arousal, aggression, defence, vigilance
         • INHIBITED: sexual activity, feeding
     • Release of cytokines by macrophages and monocytes in damaged tissues
   • ACUTE RESPONSE
     • Macrophages produce INTERLEUKIN 6 > FEVER
     • ^Blood counts of granulocytes - NEUTROPHILS & PLATELETS
       • ^Neutrophils (indicate neutrophilia) ^Platelets (indicate reactive thrombosis) causes ^TOTAL WHITE CELL COUNT
     • Liver produces CRPs (protein > phagocytosis of bacteria)
     • CATECHOLAMINES
       • Adrenaline (from Adrenal medulla - acts on adrenoreceptors)
         • ALPHA adrenoreceptors
           • -Relaxation of smooth muscle in G.I. tract. -Pupil DILATES (mydriasis). -Constriction of arterioles in SKIN and SPLANCHNIC circ
             • -Hepatic GNG and GLYCOGENOLYSIS
               • Macrophages > PRO-inflammatory cytokines
         • BETA adrenoreceptors
           • - Relaxation of smooth muscle in wall of G.I. tract -^HR & contractility -BRONCHODILATION -Relaxation of bladder DETRUSOR muscle -Dilatation of arterioles in SKELETAL muscle
             • -Hepatic GNG and GLYCOGENOLYSIS -LIPOLYSIS in adipose tissue -RENIN secretion by kidney
     • CORTISOL ^activity of HPA axis (CRH-ACTH-Cortisol) & ^adrenoreceptors
     • SALT & WATER RETENTION
       • SYMP stimulation of kidney > RAAS system > Na+ retention
       • Release of ADH from post pituitary > H2O retention
         • ATTENTION! In post-op pt's = dangerous to give hypotonic fluids eg. 5% dextrose as they have an elevated ADH > brain swelling
   • CYTOKINE BALANCE (pro- and anti- inflammatory cytokines released by macrophages)
     • Pro- are localised and have SHORT half-life
       • BUT if gets out of local control > SYSTEMIC RESPONSE > SEPSIS
         • ^Temp, ^HR, Tachypnoea, CO2 <4.3kPa, ^/v white cell count >12,000/μL / <4,000/μL or >10% immature [band] forms
           • TAKE ACTION: Within 3 hours...
             • 1 Measure blood [LACTATE] - anaerobic metabolism if tissues not oxygenated
               • 2 BLOOD CULTURES *prior to giving antibiotics (24hr result delay)
                 • 3 Broad spectrum ANTIBIOTICS
                   • 4 Give 30 ml/kg CRYSTALLOID (eg. 0.9% saline) for hypotension or lactate >4mmol/L - Boosts tissue perfusion (^CO due to Starling's Law)
             • Treating Sepsis
               • BUT are "normal" physiological values always the appropriate target? Maybe not... Sometimes insulin administration ^death in ICU. Permissive hypotension can limit bleeding in pt's with haemorrhage. High temp destroys bacteria.
                 • Solution: stress responses have NEW EQUILIBRIUM on body - MONITOR THIS to understand what is happening
               • Ventilators, Aortic pump ^BP, ^BP drugs, IV fluids, IV food,
     • Can we use macrophage pro/anti inflammation RECEPTORS as DRUG targets - affect macrophage/cytokine response? eg. vagal stimulator with ACh-Nicotinic receptor
   • eg. major trauma, severe burns, surgery, bacterial sepsis (popura),
   • LEADS TO:
     • HYPERGLYCAEMIA as glucose made via:
       • INSULIN deficiency
         • NB. if HYPERKALAEMIC - Give INSULIN - ^K+ uptake into cells by stimulating Na-K-ATPase
           • Insulin ^K+ --- Aldosterone vK+
       • PROTEIN CATABOLISM (stim by cytokines & cortisol) > Glucogenic aa's form Pyruvate for GNG. Muscle wasting.
       • LIPOLYSIS (stim by cortisol, catecholamines & low insulin). Weight loss.
       • IMPAIRS WOUND HEALING, ^INFECTION SUSCEPTIBILITY

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