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Corticosteroids

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					Endocrine 2: Glands,
Hormones and Steroids
Dr Gareth Noble (and Dr Sue Jordan)
Amino Acid Derivatives
   Small molecules structurally related to amino
    acids
   Synthesized from the amino acids tyrosine
    and tryptophan
Tyrosine Derivatives
   Thyroid hormones
   Compounds:
       epinephrine (E)
       norepinephrine (NE)
       dopamine, also called catecholamines
Tryptophan Derivative
   Melatonin:
       produced by pineal gland
Peptide Hormones
   Chains of amino acids
   Synthesized as prohormones:
       inactive molecules converted to active hormones
        before or after secretion
2 Groups of Peptide Hormones
   Group 1:
       glycoproteins:
         more than 200 amino acids long, with carbohydrate side
          chains:
              thyroid-stimulating hormone (TSH)
              luteinizing hormone (LH)
              follicle-stimulating hormone (FSH)
2 Groups of Peptide Hormones
   Group 2:
       all hormones secreted by:
           hypothalamus
           heart
           thymus
           digestive tract
           pancreas
           posterior lobe of pituitary gland
           anterior lobe of pituitary gland
2 Classes of Lipid Derivatives
   Eicosanoids:
       derived from arachidonic acid
   Steroid hormones:
       derived from cholesterol
Eicosanoids
   Are small molecules with five-carbon ring at
    one end
   Are important paracrine factors
   Coordinate cellular activities
   Affect enzymatic processes in extracellular
    fluids
Leukotrienes
   Are eicosanoids released by activated white
    blood cells, or leukocytes
   Important in coordinating tissue responses to
    injury or disease
Prostaglandins
   A second group of eicosanoids produced in
    most tissues of body
   Are involved in coordinating local cellular
    activities
   Sometimes converted to thromboxanes and
    prostacyclins
Steroid Hormones
   Are lipids structurally similar to cholesterol
   Released by:
       reproductive organs (androgens by testes,
        estrogens, and progestins by ovaries)
       adrenal glands (corticosteroids)
       kidneys (calcitriol)
Steroid Hormones
   Remain in circulation longer than peptide
    hormones
   Are absorbed gradually by liver
   Are converted to soluble form
   Are excreted in bile or urine
Hormones
   Circulate freely or bound to transport proteins
Free Hormones
   Remain functional for less than 1 hour:
       diffuse out of bloodstream:
           bind to receptors on target cells
       are absorbed:
           broken down by cells of liver or kidney
       are broken down by enzymes:
           in plasma or interstitial fluids
Thyroid and Steroid Hormones
   Remain in circulation much longer
   Enter bloodstream:
       more than 99% become attached to special
        transport proteins
The Drugs
Hypothalamus and Pituitary Glands
   Anti-oestrogens (Clomiphene Citrate):
        The anti-oestrogens clomifene (clomiphene) and tamoxifen are used in the treatment of female
         infertility
        MoA: induce gonadotrophin release by occupying oestrogen receptors in the hypothalamus, thereby
         interfering with feedback mechanisms
              risk of multiple pregnancy (rarely more than twins).
        Cautions: polycystic ovary syndrome (cysts may enlarge during treatment), ovarian
         hyperstimulation syndrome, uterine fibroids, ectopic pregnancy, incidence of multiple births
         increased (consider ultrasound monitoring), visual symptoms (discontinue and initiate
         ophthalmological examination); breast-feeding
        Contra-indications: hepatic disease, ovarian cysts, hormone dependent tumours or abnormal
         uterine bleeding of undetermined cause, pregnancy
        Adverse effects: visual disturbances (withdraw), ovarian hyperstimulation (withdraw), hot flushes,
         abdominal discomfort, occasionally nausea, vomiting, depression, insomnia, breast tenderness,
         headache, intermenstrual spotting, menorrhagia, endometriosis, convulsions, weight gain, rashes,
         dizziness, hair loss
        Dose: 50 mg daily for 5 days, starting within about 5 days of onset of menstruation (preferably on
         2nd day) or at any time (normally preceded by a progestogen-induced withdrawal bleed) if cycles
         have ceased; second course of 100 mg daily for 5 days may be given in absence of ovulation; most
         patients who are going to respond will do so to first course;
              3 courses should constitute adequate therapeutic trial;
              long-term cyclical therapy not recommended
   Hypothalamic hormones:
       Gonadorelin when injected intravenously in normal
        subjects leads to a rapid rise in plasma concentrations of
        both luteinising hormone (LH) and follicle-stimulating
        hormone (FSH).
           endometriosis and infertility and in breast and prostate cancer
       Protirelin is a hypothalamic releasing hormone which
        stimulates the release of thyrotrophin from the pituitary.
           mild hyperthyroidism or hypothyroidism.
       Rare Adverse Effects: nausea, headache, abdominal
        pain, increased menstrual bleeding; rarely,
        hypersensitivity reaction on repeated administration of
        large doses; irritation at injection site
   Anterior pituitary hormones:
       Corticotrophins: Tetracosactide (tetracosactrin), an analogue of
        corticotropin (ACTH), is used to test adrenocortical function
       Gonadotrophins: Follicle-stimulating hormone (FSH) and
        luteinising hormone (LH) together (as in human menopausal
        gonadotrophin), follicle-stimulating hormone alone (as in follitropin),
        or chorionic gonadotrophin, are used in the treatment of infertility in
        women with proven hypopituitarism or who have not responded to
        clomifene, or in superovulation treatment for assisted conception
        (such as in vitro fertilisation).
       Growth hormone: use for proven growth-hormone
        deficiency;Turner’s syndrome; Prader-Willi syndrome; chronic renal
        insufficiency before puberty.
       Thyrotrophin: used for the detection of thyroid remnants and thyroid
        cancer in post-thyroidectomy patients.
Posterior Pituitary Hormones
   Diabetes insipidus:
       an uncommon condition that occurs when the
        kidneys are unable to conserve water as they
        perform their function of filtering blood
       Main Rx agents:
           VASOPRESSIN
           DESMOPRESSIN
   Vasopressin (antidiuretic hormone, ADH):
       Cautions: heart failure, hypertension, asthma, epilepsy, migraine or other
        conditions which might be aggravated by water retention; renal impairment;
        pregnancy
       Contra-indications: vascular disease (especially disease of coronary
        arteries) unless extreme caution, chronic nephritis (until reasonable blood
        nitrogen concentrations attained)
       Adverse effects: fluid retention, pallor, tremor, sweating, vertigo, headache,
        nausea, vomiting, belching, abdominal cramps, desire to defaecate,
        hypersensitivity reactions (including anaphylaxis), constriction of coronary
        arteries (may cause anginal attacks and myocardial ischaemia), peripheral
        ischaemia and rarely gangrene
       Tailored Dose:
            By subcutaneous or intramuscular injection, diabetes insipidus, 5–20 units every
             four hours
            By intravenous infusion, initial control of variceal bleeding, 20 units over 15
             minutes
Thyroid Gland
   Thyroid hormones:
       used in hypothyroidism (myxoedema), and
        thyroid carcinoma.
           NB: Neonatal hypothyroidism requires prompt
            treatment for normal development.
       Levothyroxine sodium (thyroxine sodium) is the
        treatment of choice for maintenance therapy.
           Liothyronine sodium has a similar action to
            levothyroxine but is more rapidly metabolised and has
            a more rapid effect
   Levothyroxine sodium:
       Cautions: predisposition to adrenal insufficiency, elderly,
        cardiovascular disorders, long-standing hypothyroidism, diabetes
        insipidus, diabetes mellitus; pregnancy and breast-feeding;
       Adverse Effects (usually at excessive dosage): anginal pain,
        arrhythmias, palpitation, skeletal muscle cramps, tachycardia,
        diarrhoea, vomiting, tremors, restlessness, excitability, insomnia,
        headache, flushing, sweating, fever, heat intolerance, excessive loss
        of weight and muscular weakness
       Dose (adult): initially 50–100 micrograms (50 micrograms for those
        over 50 years) daily, preferably before breakfast, adjusted in steps of
        50 micrograms every 3–4 weeks until metabolism normalised (usually
        100–200 micrograms daily)
   Antithyroid drugs:
       used for hyperthyroidism either to prepare patients for
        thyroidectomy or for long-term management.
       Most common agent is Carbimazole
           Caution: liver disorders, pregnancy, breast-feeding
           Adverse effects: nausea, mild gastro-intestinal disturbances,
            headache, rashes and pruritus, arthralgia; rarely myopathy,
            alopecia, bone marrow suppression (including pancytopenia and
            agranulocytosis, see CSM warning above), jaundice
           Dose: 5mg tablets
Corticosteroids
   Corticosteroid medications are synthetic versions of the hormones
    secreted by the adrenal cortex. These hormones are essential for
    maintenance of several systems, particularly the cardiovascular
    system. They also play a major role in the body's response to
    stress.

   ACTIONS
       Corticosteroids suppress inflammation, allergy and the immune
        system. They prevent and relieve the symptoms of many conditions,
        including asthma and rheumatoid arthritis.
Indications for corticosteroids include:
   Symptom control: asthma, allergic rhinitis, rheumatoid arthritis and
    related connective tissue disorders, temporal arteritis, inflammatory bowel
    disease, inflammatory skin conditions, emesis following chemotherapy,
    chronic pain, anaphylactic shock

   Prevention: transplant rejection, respiratory distress in the newborn,
    cerebral oedema

   Treatment: certain tumours, hypercalcaemia, some blood disorders,
    nephrotic syndrome

   Replacement therapy in Addison’s disease (under-activity of the adrenal
    cortex).
Doses and Administration
   (For asthma see British Thoracic Society Guidelines in BNF.)
   Regular medication reviews are needed to ensure doses are kept to the
   minimum necessary to manage the underlying condition.

   Inhaled beclomethasone, budesonide daily doses >800 mcg (adult)
    >400mcg (child) are associated with systemic (general) side effects. Side
    effects are seen at half these doses for fluticasone. Some ‘high dose’
    regimens include daily doses up to 2 mg and 1mg (fluticasone). Advice to
    patients should include:
   Keep to the same spacer device.
   Mouth rinsing may reduce candidiasis and systemic absorption.
   Pre-treatment with bronchodilator may reduce cough.
Doses and Administration
   Oral prednisolone. Side effects appear if daily dose >7.5 mg. Maintenance
    doses usually 2.5-15mg/ day. Severe disease may necessitate much higher
    doses.

   Administer as a single dose after breakfast, but before 9.00 am., with milk
    or food plus a full glass of water.

   Topical applications should avoid the face, and be free of occlusive
    dressings (including disposable nappies).

   Rectal administration may give erratic absorption and cause local pain and
    bleeding.

   If giving intramuscular injections, use each site only once and document.
Managing the Common Adverse
Effects of Corticosteroids
   Short courses at high dosage for emergencies
    appear to cause fewer adverse effects than
    prolonged courses using lower doses.

   Many adverse effects, for example, those
    related to nutrition, only arise with long-term
    therapy.
Actions of corticosteroids are grouped:
   Glucocorticoid effects, including metabolic
    changes and anti-inflammatory actions.

   Mineralocorticoid effects, mainly retention of
    salt and water, together with loss of potassium
    and hydrogen ions.
       Classification of Corticosteroids
       ORAL CORTICOSTEROIDS
     Glucocorticoid Effect                Mineralocorticoid   Duration of
    (dose equivalent)                      effect              effect (in hours)

     SHORT ACTING
     Cortisone           25mg             ++++                8-12 hours
     Hydrocortisone      20mg             ++++                8-12 hours

     INTERMEDIATE-ACTING
     Prednisolone       5mg               ++                  18-36 hours
     Triamcinolone      4mg               -                   18-36 hours
     Methylprednisolone 4mg               -                   18-36 hours
     Fludrocortisone    -                 ++++                24-36 hours

     LONG-ACTING
     Dexamethasone       750 micrograms          -            36-54 hours
     Betamethasone       750 micrograms          -            36-54 hours
    INHALED CORTICOSTEROIDS
   (dose equivalent                             Time in circulation*
for adverse effects)
 Beclometasone      1000 micrograms             -     19.5 hours
 Budesonide         1000 micrograms             -     6.9 hours
 Fluticasone        500 micrograms              -     43.2 hours
  propionate

*calculated as 3 times the terminal half life.

(Karch 2000, BNF 2002, Cave et al. 1999, Lipworth 1999)
Corticosteroids may affect:
   inflammatory and immune responses
   metabolic pathways:
       the starvation response + redistribution
           skin
           gastrointestinal tract
           bones
           muscles
   cardiovascular system
   central nervous system
   eyes
   reproductive system
   adrenal glands
  POTENTIAL PROBLEM                 SUGGESTED PREVENTION



Increased risk of infections   Teach good hand washing
                                techniques
                                Monitor body temperature at 5-6 p.m.
                                daily
                               Avoid exposure to infectious disease
                                Contact doctor on exposure to
                                chickenpox or measles.
                                Caution with immunisations: avoid live
                                vaccines (also for 6 months after
                               discontinuation).
 POTENTIAL PROBLEM          SUGGESTED PREVENTION


                       Encourage a well balanced, low calorie
Nutrition              diet. Ask dietician to provide diet plan

Increase in appetite   Monitor intake by asking patient to
                       record intake for 24-hour periods.

                       Weigh patient weekly

                       Measure waist circumference
                       regularly
  POTENTIAL PROBLEM         SUGGESTED PREVENTION



Nutrition               Encourage scrupulous dental
                        hygiene
Risk of dental caries
                         & low-sugar diet.

                         Arrange 6 monthly dental
                        inspections

                        Consider using a mouthwash
  POTENTIAL PROBLEM        SUGGESTED PREVENTION



Nutrition              Foods rich in salt should be avoided,
                       except with replacement regimens.
Risk of hypertension   Condiments and processed foods are
                       high in sodium. Avoid salt-containing
                       medicines e.g. some antacids. Avoid
                       liquorice.

                       Monitor blood pressure regularly.
  POTENTIAL PROBLEM        SUGGESTED PREVENTION



Nutrition              Encourage patient to eat foods high in
                       calcium. Low fat dairy products are
Risk of osteoporosis   suggested.

                       Suggest vitamin D supplementation,
                       together with monitoring for vitamin D
                       intoxication.
  POTENTIAL PROBLEM              SUGGESTED PREVENTION


Nutrition
                             Venous blood samples to monitor
Loss of potassium, causing   electrolytes
muscle weakness,
depression, constipation,    Encourage foods that are high in
cardiac complications.       potassium e.g. raisins, bananas,
                             meat.
  POTENTIAL PROBLEM            SUGGESTED PREVENTION


Nutrition                  Limit salt intake.
Salt and water retention
                           Fluid balance records and daily
                           weighing are important during
                           initiation of therapy
  POTENTIAL PROBLEM              SUGGESTED PREVENTION

Cardiovascular disease
                            Monitor blood glucose concentrations
Hyperglycaemia / diabetes   regularly and if thrush appears on the
                            skin
Increased cholesterol and
 triglycerides              Monitor lipid profile

Congestive heart failure    Observe for breathlessness. Monitor
                            fluid retention. Minimise salt intake.
? increased risks of
thrombosis                  Monitor full blood count
  POTENTIAL PROBLEM              SUGGESTED PREVENTION


Skin
(particularly topical       Provide advice on managing acne
preparations)
                            Consult podiatrist regarding foot-care.
Increase in body hair and
 acne                       Anticipate poor healing and contact
                            wound care specialists promptly.
Poor wound healing
                            Take swabs if healing delayed.
  POTENTIAL PROBLEM          SUGGESTED PREVENTION

Skin
(particularly topical   Increased vigilance of pressure areas.
preparations)            Evaluate pressure damage risk score
                         regularly
Thinning of the skin
                        Avoid friction and shearing forces on
                         the skin, for example, teach patients in
                         the correct use of moving and handling
                         aids (glide sheets) when moving along
                         the bed/chair.
  POTENTIAL PROBLEM           SUGGESTED PREVENTION



Skin                    Allow extra time for procedures
(particularly topical    involving tissue handling, such as
preparations)            transfer to hoist, care of infusion sites.

Thinning of the skin    Ensure good communication within
                        the multidisciplinary team: for example,
                        orthopaedic surgeons, and plaster
                        technicians, or nurses applying plaster
                        casts, need to be aware that the patient
                        is prescribed corticosteroids, and adjust
                        treatment, if possible.
  POTENTIAL PROBLEM              SUGGESTED PREVENTION


Gastrointestinal Tract      Take oral corticosteroids with food or
                             milk
Irritation of stomach and
 oesophagus                 Observe and test stools for blood loss
  POTENTIAL PROBLEM          SUGGESTED PREVENTION



Bones                    Encourage moderate exercise
Osteoporosis
 (see nutrition above)   Bone densiometry assessments

                         Consider HRT
Growth
                         Plot height and weight on centile
                         charts at regular intervals.
 POTENTIAL PROBLEM        SUGGESTED PREVENTION



Muscles              Routine exercise may help to prevent or
                     decrease muscle weakness.
Muscle weakness
                     Assess activities such as rising from a
Cramps               chair

                     Monitor respiratory function

                     Check electrolytes if cramps occur
  POTENTIAL PROBLEM              SUGGESTED PREVENTION


Mental health
                             Monitor behaviour.
Emotional changes such as
moodiness, depression,
euphoria or hallucinations   Consider the possibility of steroid
                             psychosis and refer as necessary.

Steroid abuse/ dependence
                             Refer patients who resist dose
                             reductions.
  POTENTIAL PROBLEM                 SUGGESTED PREVENTION

Eyes
(particularly eye drops or if
 creams applied close to
 eyes)                          Regular eye examinations are
                                important to detect changes before
Increased intraocular           permanent eye damage occurs.
pressure and glaucoma           Arrange appointments on initiation
Cataracts or clouding of        of therapy, after 6 months, then at
    vision                      least yearly.
Infections
  POTENTIAL PROBLEM               SUGGESTED PREVENTION


Reproductive system

Delayed puberty
                             Offer reassurance
Changes in menstrual cycle
                             Advise clients of potential problems
Impotence
  POTENTIAL PROBLEM             SUGGESTED PREVENTION


                           Administer medication before 9.00 am.
Adrenal suppression/
insufficiency:             Monitor pulse, blood pressure,
                           electrolytes and glucose regularly.
Persists 3 months- years   Repeat checks if bruises appear.
after discontinuation
                           After 1 week’s use, advise against
                           sudden discontinuation of therapy.

                           Advise wearing a medical-alert bracelet
                           to inform emergency workers of
                           medication
Control of Glucocorticoid Secretion
(The hypothalamic/pituitary/adrenal (HPA) axis)

       Corticosteroids administered as medications constantly inhibit CRH & ACTH secretion.
          The adrenal cortex eventually shrinks and may fail to synthesise any hormones,
                  even in response to extreme stress, such as surgery or infection.




              In health, when there is not stress, cortisol suppresses secretion of
                      CRH and ACTH by a negative feedback mechanism
  POTENTIAL PROBLEM          SUGGESTED PREVENTION


                        Supervise gradual withdrawal of therapy
Withdrawal of therapy
                        Supervise transition from oral to inhaled
                        administration and conversion to
                        alternate day therapy.

                        Continue to monitor patients for possible
                        adrenal insufficiency for a year after
                        discontinuation.

                        Ensure that patient always carries a
                        'steroid card'
Cautions and contra-indications
   When administering corticosteroids, caution is needed in some
   circumstances:

   Presence of infections. Infections may 'flare up', including HIV/AIDS,
    previous TB, wound infection, Herpes simplex.

   Conditions which will be exacerbated: hypertension, diabetes, heart
    failure, osteoporosis, glaucoma, epilepsy, mood disorders, pressure sores.

   Conditions where potassium loss will prove dangerous: liver failure.

   Situations where muscle weakening could be problematic: Recent
    myocardial infarction, muscle wasting, elderly, bedridden.
Cautions and contra-indications
   Masking of serious symptoms: peptic ulcer,
    inflammatory bowel disease, pneumonia

   Corticosteroids worsen cardiovascular risk factors.
    Their long-term use should be carefully evaluated in
    patients already at high risk of stroke or heart attack.

   Lower doses are needed in patients unable to
    eliminate drugs at the normal rate:
       hypothyroidism, liver failure, renal failure, elderly.
Cautions and contra-indications
   Pregnancy. The risks of intrauterine growth retardation with
    repeated courses of intra-muscular corticosteroids are
    administered to prevent respiratory distress of the new-born
    are currently under investigation. When cortIcosteroids are
    administered for severe maternal disease, the benefits are
    likely to outweigh any risks. Most prednisolone (unlike
    dexamethasone) is inactivated by the placenta.

   Breastfeeding: avoid if >40mg prednisolone /day (or
    equivalent) administered. Doses below those causing
    systemic side effects are considered safe.
Interactions (Not a complete list)
   Corticosteroids interact with many other drugs.

   Some drugs intensify the adverse reactions of corticosteroids:

   Increased risk of gastro-intestinal bleeding: alcohol,
    anticoagulants, aspirin, NSAIDs
   Increased fluid retention and hypertension: beta2 agonists,
    NSAIDs, sodium-containing preparations, oestrogens,
    liquorice, ginseng, some Asian herbal mixtures
   Increased potassium depletion: beta2 agonists, diuretics,
    digoxin, laxatives
Interactions (Not a complete list)
   The effects of some drugs and appliances are antagonised: anti-
   epileptics, anti-diabetics, anti-hypertensives, growth hormone, intra-
   uterine contraceptive devices.

   The dose of corticosteroids is effectively reduced by:

   co-administration with antacids, within 2 hours
   carbamazepine, phenytoin, rifampicin, theophylline

   The dose of corticosteroids is effectively increased by:

   erythromycin, ketoconazole, itraconazole, ciclosporin, some anti-virals

				
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