Drugs Acting on The Endocrine Sy

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Drugs Acting on The Endocrine Sy Powered By Docstoc
					Drugs Acting on The
Endocrine System

D’Andrea F. Skipwith, Pharm.D.
     Samford University
McWhorter School of Pharmacy
Discuss the mechanism of action, side effects
and drug interactions for drugs effecting the
endocrine system
Describe how occupation can be affected by
disruptions in the endocrine system
Discuss safe administration of medication
and medication of illness and medication
Describe how medication effects and side
effects can affect functional performance
The Endocrine system
Maintenance of internal homeostasis through
the secretion of hormones
Endocrine glands make and release these
endogenous substances to regulate
   Reproduction
   Growth and development
   Energy metabolism
   Fluid and electrolyte balance
   Response to stress and injury
Can be classified as drugs
Exogenous sources can include animals and
synthetic or semi-synthetic compounds
Often used for replacement therapy; also
used for therapeutic and diagnostic purposes
   Replacement therapy during deficiency
   To accentuate endogenous counter agents
   Treatment of endocrine hyperactivity
   Regulate normal function
Therapeutically useful hormones and
related drugs include
 Pituitary hormones
 Thyroid hormones and thyroid inhibitors

 Antidiabetic agents

 Gonadal hormones

 Adrenocorticosteroids
   Pituitary Hormones
Pituitary is subdivided into anterior,
intermediate,and posterior lobes
Hormones divided based on site of
    Pituitary Hormones
Anterior pituitary
   Protein molecules are used therapeutically
        ACTH (adrenocorticotropic hormone)/ Corticotropin
              synthesis of adrenal steroid
             Used to diagnose and differentiate primary and secondary
              adrenal insufficiency
        TSH (thyroid-stimulating hormone/ Thyrotropin
              synthesis of thyroid hormones
        TRH (thyrotropin-releasing hormone)
        GH (growth hormone)
              growth and development of tissue
             Stimulates protein, carbohydrate, and lipid metabolism
             Somatrem, somatropin
     Pituitary Hormones
Anterior pituitary (continued)
   Gonadotropins not available for therapeutic use
        FSH (follicle-stimulating hormone)
            Female:  follicular development and synthesis of estrogen

            Male: enhancement of spermatogenesis

        LH (luteinizing hormone)
            hCG (human chorionic hormone)

            Female:  ovulation;  synthesis of estrogen and
            Male: spermatogenesis

        Menotropins (hMG/human menopausal gonadotropin)
            High in FSH and LH-like activity; obtained from urine of
             postmenopausal women
            Produce ovarian follicular growth and induce ovulation

            Used to induce ovulation and pregnancy; induction of
             spermatogenesis in men
        PR/LTH (prolactin/luteotropic hormone)
            Initiation of lactation
     Pituitary Hormones
Intermediate pituitary
   MSH (melanocyte-stimulating hormone)
      No significant amounts produced in humans

      No physiologic or pharmacologic significance

Posterior pituitary
   ADH (antidiuretic hormone)
      Effects exerted on kidney; promotes reabsorption of
      Used to treat neurogenic diabetes insipidus

      Vasopressin and desmopressin (DDVAP)

   Oxytocin
      Stimulation of uterine contractions and lactation

      Used to promote delivery by initiation and improving
       uterine contraction; control of postpartum bleeding or
   Minimal differences in structure but different biological
    Pituitary Hormones
Adverse effects
   Corticotropin
        ADRS are rare; hypersensitivity
   Growth hormone
        Development of antibodies to GH-typically do not
         interfere with treatment
   Menotropins
        Hypersensitivity, arterial thromboembolism, febrile
         reactions, ovarian enlargement hyperstimulation
         syndrome, hemoperitoneum
        Gynecomastia in men
     Thyroid Hormones
Two hormones are thyroxine
(T4,levothyroxine) and triodithyronine (T3,
Liotrix is a mixture of T4 and T3 (4:1)
Iodine (Lugol’s solution)
Antithyroid agents
   Propylthiouracil (PTU), Methimazole, Sodium
    Iodide I 131
T4 is less potent than T 3 but has longer
duration of action (6-7 days vs. 1-2 days)
     Thyroid Hormones
Functions include
   Metabolism of proteins, fat, and carbohydrates
   Maintenance and regulation of body heat
   Growth and development of normal bone
   Positive inotropic and chronotropic effects on
   CNS development
     Thyroid Hormones
MOA – not well understood
   Control of DNA transcription and protein synthesis
   Principle effect is increase of metabolic rate of
    body tissues
        Increases in oxygen consumption, respiratory rate, body
         temp, cardiac output, heart rate, blood volume, enzyme
         system activity, fat, protein, and carbohydrate
         metabolism, growth and maturation
   Administration increases basal metabolic rate
    Thyroid Hormones
Indications include
 Hypothyroidism
 Myxedema coma

 Cretinism

 Simple goiter

 Endemic goiter

 Thyrotropin-dependent carcinoma
     Thyroid Hormones
Use contraindicated in acute MI
Can exacerbate diabetes mellitus, diabetes
insipidus, and adrenal insufficiency
Adverse reactions
   Overdose: palpitations, tachycardia, arrhythmias,
    angina, cardiac arrest, tremors, headache,
    diarrhea, vomiting, nervousness, insomnia, weight
    loss, menstrual irregularities,sweating, heat
    intolerance, fever
    Thyroid Hormones
Drug Interactions
 Cholestyramine
 Colestipol
 Estrogens
 Anticoagulants
 Beta blockers
 Digoxin
 Theophylline
   Thyroid Hormones
Should not change from one brand to
another without consulting physician
or pharmacists
Do not discontinue
Taking levothyroxine on empty stomach
will increase absorption
    Thyroid Hormones
 Lugol’s solution
 Adequate iodine intake required for normal
  thyroid function; large doses can inhibit T4
  and T3 synthesis
 Indications
       Adjunct therapy with anti thyroid drugs in
        hyperthyroid patients
     Thyroid Hormones
Iodine (continued)
   Adverse effects
      Skin rash, swelling of salivary glands
      Iodism – metallic taste, burning mouth and
       throat, sore teeth and gums, head cold
       symptoms, upset stomach and diarrhea
      Allergic reaction – fever and joint pains,
       swelling of parts of face and body, severe SOB
     Thyroid Hormones
Iodine (continued)
   Drug interactions
        Lithium
Pancreas secretes two hormones - insulin and
Needed for regulation of blood glucose; release is in
turn stimulated by glucose concentrations in blood
Glucagon is secreted by -cells
  Stimulates release of glucose from storage sites
   in liver
Insulin is secreted by -cells
  Removes glucose from blood and facilitates it
   storage in liver and muscle; normalizes glucose
   Indications:
        Antidote for hypoglycemia
   Adverse reactions
        Hypotension, urticaria, nausea, vomiting, respiratory
   Drug interactions
        Anticoagulants- may increase possibility of bleeding
   Typically advised for DM patients to carry
    preparation in case of needed administration for
    insulin shock
   Indications for insulin preparations
        Treatment of diabetes mellitus not controlled by diet
        Duration of actions varies based on preparations (i.e.
         Regular, Semilente, NPH, Ultralente)
   Adverse effects
        Hypoglycemia: sweating, tachycardia, hunger;
         convulsions in presence of insulin shock
        Hypersensitivity
        Local irritation at injections site
   Drug interactions
      Decrease hypoglycemic effect
      Increase hypoglycemic effect
   Gonadal Hormones
Steroids that influence sexual and
reproductive functions
Release is controlled by hormones from
hypothalamus and anterior pituitary
Estrogen – produced in ovaries
      Natural, Semi-synthetic, Nonsteroidal synthetic, Estrogen
Progestin – produced in ovaries
      Natural, Synthetic
Androgens and anabolic steroids – produced
in testes
     Gonadal Hormones
   Primary estrogenic hormone is estradiol (Estrace)
   Antagonists or antiestrogens (e.g. Clomiphene
    and tamoxifen) are structurally related to estradiol
    but have different binding sites and functions
   Some estrogen responsive tissues include the
    vagina, uterus, mammary glands, anterior
    pituitary, and hypothalamus
     Gonadal Hormones
   Indications
        Oral contraception
        Menopausal symptoms (vasomotor disorder, urogenital
         atrophy, psychological disorder)
        Acne
        Osteoporosis
        Prostate cancer
   Antiestrogens used to treat estrogen dependent
    breast cancer (tamoxifen) or in induction of
    ovulation (clomiphene)
   SERMS (selective estrogen receptor modulators)
    for treatment and prevention of osteoporosis, e.g.
    raloxifene (Evista)
     Gonadal Hormones
Adverse effects
   GI effects (GI distress, nausea, vomiting, anorexia,
   CV effects (hypertension, increased risk of
    thromboembolic diseases, stroke, MI)
   Fluid and electrolyte disturbances ( increased fluid
    retention, increased TG)
   CA risks ?????
   Migraines, nausea vomiting, breakthrough
    Gonadal Hormones
   Drug interactions
      Oral anticoagulants
      Tricyclic antidepressants

      P450 inducers – barbiturates, rifampin

      Corticosteroids

      Hydantoins
    Gonadal Hormones
   Natural – progesterone
   Synthetic- medroxyprogesterone and megestrol
   Indications
        Oral contraception ( alone or in combo with estrogens)
        Menstrual disorder (dysfunctional uterine bleeding,
        Endometriosis
   Adverse effects
        Gynecological ( irregular menses, bleeding, amenorrhea)
        Weight gain and edema
        Exacerbation of breast carcinoma ???
        Insomnia, rash, breast changes, edema
    Gonadal Hormones
Androgens and anabolic steroids
   Primary natural androgen is testosterone
        Used for androgenic and anabolic effects
        Anabolic steroids only differ slightly in structure from
              e.g. oxandrolone
   Indications
        Androgen-replacement therapy
        Breast cancer and endometriosis
        Female :hypopituitarism, in combo with estrogen therapy;
         metastatic cancer
        Anabolic therapy (in those with negative nitrogen
        Anemia
Androgens and anabolic steroids
   Drug interactions
      Anticoagulants
      Insulin, sulfonylureas

      Corticosteroids, ACTH

      Cyclosporine
     Gonadal Hormones
Androgens and anabolic steroids
   Adverse effects
        Fluid retention
        Increase in LDL and decrease in HDL cholesterol
        Psychological changes
        Liver disorders
        Development of masculine features in females
        Decreased fertility in males
        Amenorrhea in females
Synthesized by adrenal cortex
Two major types are glucocorticoids
and mineralcorticoids
Epinephrine and Norepinephrine are
produced in adrenal medulla but will not
be covered at this time
Pathways of adrenal steroid
 P.449, figure 29-1
 3 primary pathways which can lead to
  production of major steroid hormones
 Predominant pathways are those
  synthesizing glucocorticoids and
Inhibitors – suppression of excess
adrenosteroid production (Cushing’s
 ACTH- stimulation of adrenal cortex to
produce and secrete its natural steroids
Mechanism of Action
   Mimic activity of natural glucocorticoids and have
    metabolic, anti-inflammatory, and
    immunosuppressive activity
 Primary endogenous glucocorticoid is
  Cortisol (hydrocortisone)
 Release is controlled by circadian rhythm
  and also stimulated by stress
 Possess anti-inflammatory, protein-
  catabolic, and immunosuppressant effects
 Regulate glucose metabolism

 Enhance capability to deal with stress
   MOA
     Alteration of protein synthesis by affecting DNA
      transcription and thus changing RNA synthesis
      and translation leading to changes in cellular
     Have rapid and delayed effect on cell function
Glucocorticoid effects on glucose,
protein, and fat
 P. 453, figure 29-4
 Cortisol increases blood glucose and liver
  glycogen by acting on fat and muscle cells
 Cortisol can also act directly on liver to
  promote glucose production thus
  increasing levels on the blood
Anti-inflammatory effects of
 Inhibit function of cells and substances
  needed to respond to inflammation
 Prevent localized damage at sites of
 Cause vasoconstriction and suppress
  histamine and kinin release
Immunosuppressant effects of
   Hinder hypersensitivity reactions
        Delayed or cell-mediated allergic reactions
Other effects of Glucocorticoids
   Renal function
   CNS function
   Blood
   Cardiac and skeletal muscle function
Glucocorticoids (continued)
   Natural – e.g. cortisone and hydrocortisone
   Semi-synthetic and synthetic – e.g. prednisolone,
    fludrocortisone, triamcinolone, dexamethasone,
   Preparations available: systemic, topical,
    inhalation, ophthalmic, otic, nasal
   Discontinuation/withdrawal of therapy should be
    gradual after long-term use
   Replacement therapy (acute and chronic adrenal
   Severe disabling arthritis
   Severe allergic reactions
   Chronic ulcerative colitis
   Rheumatic diseases
   Renal diseases including (nephrotic syndrome)
   Collagen vascular diseases
   Cerebral edema
   Skin disorders and inflammatory ocular disorders
    (topical uses)
Glucocorticoids (continued)
 Use contraindicated in presence of
  systemic fungal infection, administration of
  live virus vaccines (e.g., smallpox) in
  patients receiving immunosuppressive
 May mask signs of infection

 Stress may require higher doses
Glucocorticoids (continued)
   Adverse Effects
        CV – thromboembolism or fat embolism, cardiac
         arrhythmias or ECG changes due to lowered potassium,
         syncope, HTN
        CNS – convulsions, headache, vertigo, increased
         intracranial pressure with papilledema, steroid psychosis,
         aggravation of existing psychiatric conditions
        Derm – impaired wound healing, thin fragile skin,
         erythema, SC fat atrophy, acne, hirsutism
        Endocrine – amenorrhea, menstrual irregularities and
         post-menopausal bleeding, Cushingoid state,
Glucocorticoids (continued)
   Adverse Effects
      Electrolyte – sodium and fluid retention,
       hypokalemia, hypocalcemia
      GI – pancreatitis, weight gain and increased
       appetite, nausea, vomiting, peptic ulceration,
       ulcerative esophagitis
      Musculoskeletal – muscle weakness, steroid
         myopathy, loss of muscle mass, osteoporosis, vertebral
         compression fractures
        Aggravation/masking infections; glaucoma, cataracts,
         malaise, fatigue, insomnia
Cushingoid state/Cushing Syndrome
 Exhibit symptoms of Cushing syndrome
 Reduction in doses

 Toleration of symptoms is worth benefits of
  treatment in some patients
Tissue breakdown
 Wasting effects on bone, ligaments,
  tendons, and skin
 Weakening of supporting tissues by
  inhibiting collagen formation
 Impeding of muscle protein synthesis

 Risk of osteoporosis
Other effects
 Infection

 Suppression of growth

 Glaucoma and Cataract formation


 Glucose metabolism
Glucocorticoids (continued)
   Drug Interactions
      Barbiturates
      Cholestyramine + Hydrocortisone

      Contraceptives

      Ephedrine + Dexamethasone

      Estrogens

      Hydantoins

      Ketoconazole
Glucocorticoids (continued)
   Drug Interactions
      Macrolide antibiotics + Methylprednisolone
      Rifampin

      Anticholinesterases

      Oral Anticoagulants

      Cyclosporine

      Digoxin

      Isoniazid
Glucocorticoids (continued)
   Drug interactions
      Muscle relaxants
      Potassium lowering agents

      Salicylates

      Somatrem

      Theophyllines
   Control of electrolyte and fluid levels
   Possess sodium-retaining and potassium
    excreting effects
   Primary hormone produced is aldosterone
        Increase reabsorption of sodium from renal tubules while
         inhibiting potassium reabsorption and increasing
         excretion of potassium
   e.g. fludrocortisone (Florinef)
        Potent mineralcorticoid and high glucocorticoid activity
         (15 times more potent than hydrocortisone)
        Only used for mineralcorticoid activity
Mineralcortocoids (continued)
   Indications
      Replacement therapy for adrenocortical
       insufficiency in Addison’s disease
      Management of severe orthostatic hypotension

   MOA – acts on renal distal tubules to
    enhance reabsorption of sodium and
    increase urinary excretion of potassium
    and hydrogen ions

Mineralcortocoids (continued)
   Adverse effects
      CV – edema, HTN, CHF, enlargement of heart,
      Derm – bruising, increased sweating, hives or
       allergic skin rash
      Hypokalemia

      Other side-effects similar to those of
Mineralcortocoids (continued)
   Spironolactone (aldactone)
      Aldosterone receptor antagonist
      Increases sodium and water excretion while
       decreasing excretion of potassium
      Used as diagnostic agent and diuretic

      Can interfere with function of sex hormones

      CNS and GI effects
Adrenal Steroid Inhibitor
   Aminoglutethimide (Cytadren)
   Indication: Suppression of adrenal function in
    patients with Cushing’s Syndrome; post-
    menopausal patients with advanced breast
    carcinoma, metastatic prostate carcinoma
   MOA- blocks the conversion of cholesterol in
    steroid synthesis thus reducing the synthesis of
    glucocorticoids, mineralcorticoids, estrogens, and
Adrenal Steroid Inhibitor (continued)
   Adverse effects
        CNS - drowsiness, headache, dizziness, fever
        CV - hypotension
        Dermatological - rash (reversible), pruritus
        GI - nausea, anorexia, vomiting
        Endocrine - adrenal insufficiency (hypothyroidism),
         masculinization and hirsutism in females, precocious sex
         development in males
        Heme - neutropenia, leukopenia, pancytopenia,
         thrombocytopenia, aganulocytosis
        Myalgia, elevated LFTs
Adrenal Steroid Inhibitor (continued)
   Drug interactions
      Anticoagulants
      Dexamethasone

      Digoxin

      Medroxyprogesterone

      Theophylline
ACTH (adrenocorticotropic hormone)
   Corticotropin and Cosyntropin
   Indications
        Diagnostic testing of adrenocortical function
        Thyroiditis
        Hypercalcemia associated with cancer
        Acute exacerbations of multiple sclerosis
        Tuberculous meningitis
        Same manner as glucocortcoids in many conditions
ACTH (adrenocorticotropic hormone)
 MOA – is secreted from anterior pituitary
  and stimulates release of adrenocortical
  hormones by adrenal cortex
 Cosyntropin is a synthetic derivative which
  exhibits full corticosteroid activity
     Less allergenic
     Only used diagnostically
ACTH (adrenocorticotropic hormone)
 Use contraindicated in scleroderma,
  systemic fungal infections, ocular herpes,
  recent surgery, PUD, CHF, HTN, sensitivity
  to porcine proteins
 Prolonged use in children will inhibit
  skeletal growth
ACTH (adrenocorticotropic hormone)
   Adverse effects
        Infections – pneumonia, abscess and septic infection, GI
         and GU infections
        CV – HTN, CHF, anginitis
        Derm – impaired wound healing, acne, petechiae and
        CNS – convulsions, vertigo, headache, increased
         intracranial pressure with papilledema
        Electrolyte – sodium and fluid retention, loss of
         potassium and calcium
ACTH (adrenocorticotropic hormone)
   Adverse effects
        Endocrine – menstrual irregularities, Cushingoid state,
         decreased carbohydrate tolerance and latent DM,
         hirsutism, suppresses growth in children
        GI – pancreatitis, peptic ulceration, ulcerative esophagitis
        Musculoskeletal – muscle weakness, steroid myopathy,
         loss of muscle mass, osteoporosis, vertebral
         compression fractures
        Cataracts, glaucoma, hypersensitivity (dizziness,
         nausea, vomiting, shock, skin reactions)
ACTH (adrenocorticotropic hormone)
   Drug interactions
        Amphotericin B
        Aspirin, indomethacin
        Insulin
        Diuretics
Effects on Occupation
Blood pressure and   Musculoskeletal
CV effects           Psychological
Balance              changes
Blood glucose        Weight changes
GI effects           Infection
Energy               Vision
Bone growth and      Electrolytes
formation            Compliance