Download PharmacoTheraputics

Endocrine Patophysiology: Pharmacology of the Endocrine System
PHARMACOLOGY OF THYROID DISORDERS:

Drug Induced Thyroid Dysfunction:
Amiodarone:
o Intrinsic Effects:

Reduces enzymatic conversion of T4 to T3

Block T3 binding at nuclear receptor (leads to hypothyroidism)

Direct toxic effects on thyroid follicular cells (leads to destructive thyroiditis with transient hyperthyroidism)
o Iodine Containing Agent:

Iodine Load in Normal Patient (No Thyroid Dysfunction):
 High levels of iodine increase iodine transport into gland and cause temporary inhibition of TH
synthesis (Wolff-Chakoff block)
 Once iodine load normalizes, block is lifted

Iodine Load in Patient with Underlying Thyroid Disease:
 Patients unable to escape WC block, resulting in HYPOTHYROIDISM, OR
 Areas of thyroid may lack autoregulation, and increased iodine results in HYPERTHYROIDISM (↑TH)
Immunedysregulation:
o IL-2
o IFN-alpha
Agents Inhibiting Thyroid Hormone Synthesis and/or Release:
o Iodine
o Lithium
Other Agents Inducing Hypothyroidism:
o Nitroprusside
o Perchlorate
o Aminogltethimide

Treatment of Hypothyroidism:
Goal of Therapy: restore TH concentrations in tissues, resolve clinical symptoms and prevent progression to myxedema coma
MOA of Thyroid Hormones:
o T4/T3 enters the nucleus
o T3 binds its receptor:

Dissociates co-repressor proteins (CoR) that silence gene expression from the thyroid receptor

Coactivators (CoA) recruited to the T3-bound receptor

Gene expression altered
-
Available Preparations:
o Natural:

Dessicated Thyroid (T3+T4):
 Animal derived (hog/cow/sheep)
 Antigenic potential
 Unstable bioavailability and potency
o Synthetic:

Levothyroxine (T4): DRUG OF CHOICE*
 Features:
o Long half life (7 days)
o Stable and potent
o Free of antigenicity
o Inexpensive
 Monitoring:
o For Clinical Improvement: should be seen in first few weeks of therapy
o TSH Levels: steady state achieved after 6-8 weeks

Monitor levels 6-8 weeks after initiation of therapy or dose adjustment
o Once Patient Euthyroid: monitor every 6-12 months

~20% of patients recover thyroid function (discontinue levothyroxine)

Increased age requires decreased dose (decreased T4 clearance)

Monitor for supraphysiologic thyroid levels, as they can cause:
 Osteoporosis
 Cardiac toxicity, tachycardia, atrial arrhythmias
 Decreased exercise performance
 Increased risk of cardiac mortality
 Inability to Achieve Euthyroid State:
o Compliance: be sure to check adherence
o Dose Adjustment: may be required in some conditions

Pregnancy, malabsorption syndromes
o
-
-

Drug Interactions: assess for the presence of possible DDIs

Resin binders (cholestyramine, colestipol)

Aluminum containing preparations (AlOH3, sucralfate)

Enzyme inducers (phenytoin, phenobarbital, rifampin, carbamazepine)

Increased thyroid binding globulin (estrogen, raloxifene)
 Patient Counseling:
o Take at the same time of the day every day
o Take on an empty stomach (ie. in the morning before eating)
o Do not take any of the following at the same time:

Iron products (ie. multivitamins, iron sulfate)

Calcium products (ie. dairy products, multivitamins, calcium carbonate

Liothyronine (T3):
 Short half life (1.5 days)
 Cardiac adverse effects
 High cost

Liotrix (T4 + T3):
 Expensive
 Lack of clinical rationale for use
Bioequivalence of Thyroxine Products:
o Basics: FDA approved generics may differ from brands by up to 33%
o Issue: narrow therapeutic index drug; slight dose alterations can lead to sub/supratherapeutic effects
o Recommendations:

Maintain patients on the same levothyroxine product if possible

If it needs to be changed, check TSH in 6-8 weeks
Special Considerations in Hypothyroidism:
o Subclinical Hypothyroidism:

Presentation: increased TSH and normal free T4 (asymptomatic)

Prevalence: 4.3% (progresses to overt hypothyroidism at a rate of 2-5% annually)

Therapy Considerations:
 No studies have shown that treatment decreases morbidity or mortality
 May result in development of subclinical HYPERthyroidism
 May result in symptomatic/laboratory improvements

Treatment:
 Serum TSH 5.4-10mIU/L: therapy not recommended unless patient is symptomatic
o Monitor TFTs every 6-12 months in these patients
 Serum TSH >10mIU/L: levothyroxine therapy is reasonable
o Myxedema Coma: end-stage of long-standing UNCORRECTED hypothyroidism

Mortality: 60-70%

Treatment:
 IV bolus of thyroxine (with maintenance doses until stabilized)
 IV hydrocortisone (until adrenal suppression ruled out)
 Supportive therapy (ventilation, restore euglycemia, BP, temperature)

Monitoring:
 Vital signs (should normalize within 24 hours)
 Consciousness
 TSH levels
Treatment of Hyperthyroidism:
Goal of Therapy: decrease excess thyroid hormone, minimize symptoms and decrease risk of thyroid storm
Anti-Thyroid Medications:
o Thionamides:

Agents:
 Propylthiouracil (PTU)
o Shorter half life
o 60-80% protein bound
o Hepatic metabolism
 Methimazole (MMI)
o Longer half life
o Not protein bound
o Hepatic metabolism

Treatment of Choice for:
 Children and adolescents
 Grave’s disease (in uncomplicated young adults)
 Pregnancy
 Adjunctive therapy in severe cases or pre-operatively



-
MOA:
 Inhibits thyroid peroxidase
 Inhibits coupling of iodotyrosines
 Inhibits peripheral conversion of T4 to T3 (PTU only)
Duration of Treatment: 1-2 years
 Results in permanent remission in some cases (40-50%)
 Frequent relapses are common and may require a different treatment
Adverse Effects:
 Maculopapular Rash:
o Variable onset
o Resolves spontaneously
o May treat symptomatically with antihistamines or prednisone (for severe cases)
o May use alternate thionamide
 GI Intolerance:
o Nausea
 Arthrlagis and Lupus Like Syndrome:
o Seen after 6 MONTHS of treatment (later in treatment)
 Hepatotoxicity:
o Seen within 3 MONTHS of starting treatment
o Present with RUQ pain, anorexia, jaundice, hepatic necrosis and hepatitis
o CANNOT switch to a different thionamide (cross-reactivity)
 Agranulocytosis:
o Granulocytes <250/mm3
o Seen within 3 MONTHS of starting treatment (sudden onset)
o Unexplained fever, malaise, sore throat, stomatitis and unusual bleeding or bruising

STOP THERAPY!
o CANNOT switch to a differen thionamide (cross-reactivity)
 Benign Transient Leukopenia:
o WBC <4,000
o Continue therapy and monitor WBC count
Radioactive Iodine:
o Treatment of Choice for:

Toxic autonomous nodules

Multinodular goiters

Thionamide failure or adverse effects

Elderly patients

Patients with cardiac disease

Poor surgical candidates or patients who failed on surgery
o Contraindications:

Pregnancy/breast feeding

Children
o Preparations:

Sodium Iodide 131 Oral Solution: colorless and tasteless
 Easy administration, low cost, painless
 Effective (60% of patients euthryoid in 6 months; 2nd treatment at 6 months if results not achieved)
o MOA:

Disrupts TH synthesis

Cellular necrosis and follicular breakdown

Edema and fibrosis of tissue
o Adverse Effects:

Hypothyroidism

Transient increase in thyroid hormone levels (RAI causes initial release of stored TH)

Thyroid tenderness

Dysphagia
o Monitoring:

TFTs every 3 months for the first year after RAI and then annually after that

Monitor for presence of hypothyroid symptoms
o Patient Counseling:

Pregnancy is CONTRAINDICATED within 6-12 months post therapy
o Pretreatment:

Beta Blockers: ALL patients (symptomatic relief, do not interfere with RAI)

Thionamides: used in select patients (withdraw 4-6 days before RAI)
 Patients with severe or long standing hyperthyroidism
 Elderly patients
 Patients with cardiac disease
o
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Post-RAI Treatment:

May need to reinstate thionamide (4 days post RAI)

May use beta blockers

May use iodides
Surgery:
o Treatment of Choice for:

Malignancy

Large thyroid gland (>80g)

Severe opthalmopathy

Lack of remission on thionamide treatment or contraindication to thionamide use

Pressure/obstructive/cosmetic symptoms
o Outcomes:

Morbidity: 2.7%

Persistent Hyperthyroid: up to 17.9%
o Adverse Effects:

Hypothyroidism

Hypoparathyroidism

Vocal cord abnormalities
o Pretreatment:

Thionamides: use until patient is euthyroid (6-8 weeks)

Iodide Therapy: 10-14 days before surgery (decreases size and vascularity of thyroid gland)

Propanolol: several weeks pre-operatively
o Post-Surgery Treatment:

Propanolol for 7-10 days post-operatively, OR

Propanolol + iodide for 10-14 days postoperatively
Adjunct Therapy:
o Potassium Iodide:

Use:
 Preparation for surgery
 Severe thyrotoxicity with cardiac decompensation
 Psot-radiactive iodine treatment
 Patients exposed to radiological nuclear events (KI administered to bind the thyroid gland and prevent
radioactive iodine from binding)

MOA:
 Acutely blocks thyroid hormone release
 Inhibits thyroid hormone synthesis
 Decreases size and vascularity of the gland

Preparations:
 Saturated solution (SSKI)
 Lugol’s solution

Adverse Effects:
 Hypersensitivity
 Swelling of salivary gland
 Iodism (metallic tasted, burning throat, sore teeth/gums)
 Gynecomastia
o Adrenergic Antagonists:

Use: symptomatic treatment*
 Thyroiditis
 In combination with antithyroid medication
 In combination with RAI
 In preparation for surgery
 Thyroid storm

Agents Use:
 Beta Blockers: PROPANOLOL is the DOC
o Controls symptoms (palpitations, tremor, anxiety, heat intolerance)
o Inhibits peripheral conversion of T4 to T3 (small effect)
 Other Agents: used if BBs contraindicated
o CCBs: verapamil, diltiazem
o Centrally Acting Sympathomimetics: clonidine
Special Considerations in Hyperthyroidism:
o Subclinical Hyperthyroidism:

Presentation: decreased TSH and normal free T4 (asymptomatic)

Cause: most often caused by levothyroxine therapy
o Thyroid Storm:

Basics: severe thyrotoxicosis (medical emergency- mortality rate 100% without intervention)



Presentation:
 Fever, tachycardia, tachypnea, N/V/D, dehydration, delirium, coma
Precipitating Factors:
 Infection
 Trauma
 Surgery
 RAI treatment
 Antithyroid drug withdrawal
Treatment: decreases mortality to <7%
 Support vital functions (sedation, oxygenation, fluid/electrolytes, antipyretics, Abx, steroids)
 Block synthesis and release of THs (PTU, iodides)
 Inhibit metabolic effects (propanolol)
 Eliminate/correct precipitating factors
 Remove circulating hormones (dialysis, plasmapheresis)
FEMALE GONADAL PHARMACOLOGY:

Estrogens:
Structure: 18-carbon backbone and contain a phenolic A ring (required for high affinity binding to estrogen receptor)
Naturally Occurring Estrogens:
o 17-B Estradiol (E2): most potent, most abundant
o Estrone (E1): 10x less biologically active than estradiol
o Estriol (E3): synthesized by the placenta (present in high concentrations during pregnancy)
Synthesis of Estrogens: steroid hormone with cholesterol backbone
o Premenopausal Women: ovarian aromatase converts androstenedione to estrogen (in follicular cells)
o Postmenopausal Women: adrenal DHEA converted to estrogen by aromatase in adipocytes
o Men: aromatase converts androstenedione to estrogens in adipose tissue; testes produce a small amount
o Pregnancy: placenta produces a large amount of estriol
Pharmacology of Estradiol:
o Tissue Distribtution: lipophilic and distributes rapidly to tissues
o Bioavailability: readily absorbed in via the GI tract, skin and mucus membranes
o Rapid Hepatic Metabolism: short half life when taken orally due to first pass effect

Hepatic metabolites renally eliminated or may undergo enterohepatic recirculation

Micronized estradiol allows for better bioavailability
Estrogen Derivatives (Synthetic):
o Agents:

Ethinyl estrogen

Mestranol (demethylated in the liver to ethinyl estrogen)
o Pharmacokinetics:

Bypass First Pass Effect: C17 modification inhibits first pass effect

Circulation: not bound to SHBG (free in circulation)

Release: slowly released from adipose tissue
Adverse Effects of Estrogen:
o Postmenopausal bleeding (minimize dose, co-administer progestin)
o Nausea
o Breast tenderness
o Hyperpigmentation
o Migraine headaches
o Cholestasis
o Hypertension
Estrogen Risks:
o Endometrial cancer
o Breast cancer
o CV outcomes (possible increased risk for primary CHD events, stroke/TIA, DVT)
Estrogen Benefits:
o Decrease risk of hip or other fracture
o Decrease risk of colorectal cancer
Estrogen Contraindications:
o Estrogen dependent neoplasm
o Undiagnosed genital bleeding (must first determine cause)
o Hepatic disease (risk for cholestasis)
o History of thromboembolic disorder (increased risk fo clots)
o Pregnancy (category X)

Progestins:
Synthesis of Progesterone:
o Synthesized/secreted from corpus luteum during luteal phase of menstrual cycle (in response to LH surge)
o



If pregnancy/implantation occurs:

Initially, trophoblast secretes hCG to sustain corpus luteum and progesterone levels

After 8 weeks, placenta secretes estrogen and progesterone (no longer requires corpus luteum)
Synthetic Progestin:
o Northeindrone
o Medroxyprotesterone
Progestin Pharmacology:
o Development of secretory endometrium during secretory phase of menstrual cycle
o Secretion just prior to ovulation leads to 1 degree rise in body temperature
o Maintenance of pregnancy (suppresses menstruation and uterine contractility)
o Proliferation of mammary gland acini during pregnancy
Pharmacokinetics:
o Rapidly absorbed orally
o Large first pass effect (similar to estrogen)
o Synthetic derivatives and micronized progesterone allow for better oral bioavailability
Therapeutic Uses of Estrogen and Progesterone:
Hormone replacement therapy
Primary hypogonadism (stimulate secondary sex characteristics)
Dysmenorrhea
Endometriosis
Endometrial cancer
Prostate cancer
Contraception
PCOS
Hormone Replacement Therapy:
Basics:
o Estrogen used alone if NO uterus present (ie. hysterectomy)
o Estrogen + progesterone if uterus present (due to increased risk for endometrial hyperplasia)
Use:
o Relieve moderate to severe menopausal symptoms (hot flashes, sweating, atrophic vaginitis, sexual dysfunction)
o Reduce bone resorption/osteoporosis prevention (only used for osteoporosis if also treating menopausal symtpoms)

Does NOT restore bone loss (only preventative)

May be considered in patients with high risk of osteoporosis (smokers, thin, Caucasian, sedentary, family Hx)
Drug Interactions:
o Drugs Interfering with HRT: decreased efficacy of HRT

Rifampin

Anticonvulsants

Some antibiotics
o HRT Interferes with Efficacy of Other Drugs: decreased efficacy of other drugs

Warfarine

Benzodiazepines

Thyroid agents

Metformin
Polycystic Ovary Syndrome:
Basics: treatment revolves around symptoms and patient goals
o Reduce androgenic symptoms
o Weight loss (for obese patients)
o Reduction of insulin levels
o Address fertility goals
Goal of Therapy: early diagnosis and treatment may reverse some of the risks associated with PCOS
Lifestyle Modification:
o Weight Loss

Regular aerobic exercise

Controlled eating patterns (carbohydrate, fat and calorie reduction)

Pharmacologic agents (ie. Orlistat)
o Avoid Tobacco
Therapy for Androgen Excess:
o Hair Removal (Hirsutism):

Mechanical hair removal

Eflornithine cream (inhibits ornithine decarboxylase to RETARD hair growth)
o Oral Contraceptives: estrogen and progestin combination therapy

Estrogen:
 Decreases LH decreased androgen production
 Increases SHBG less free androgens

Progestin: need to use derivatives with the LEAST androgenic effects (norgestimate, desogestrel, drospirenone)

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Benefits of OCP Use:
 Improve hirsutism and acne
 Protection against unopposed estrogen in the endometrium
 Induces withdrawal bleed

Concerns Regarding OCP Use:
 Insulin resistance
 Glucose intolerance
 Vascular reactivity and coagulability
o Spironolactone:

MOA: inhibits androgen biosynthesis AND competitive inhibitor of the androgen receptor (large doses)

Use: synergistic effects with oral contraceptives
 Use if hirsutism or acne uncontrolled despite OCP therapy

Adverse Effects:
 Vaginal bleeding
 Hyperkalemia (K sparing diuretic)
o Other Agents:

Flutamide: androgen receptor antagonist (limited use in PCOS)

Glucocorticoids: HPA axis suppression to decrease ACTH and androgen production (limited use due to SEs)

Finasteride: inhibition of type 2 5α-reductase enzyme (limited use in PCOS)
Endometrial Protection:
o Why is it required?

Patients with PCOS suffer from CHRONIC ANOVULATION
 Increases risk for endometrial hyperplasia
 Increases risk of dysfunctional uterine bleeding
 Possible increase risk for endometrial cancer
o Combined OCPs:

Progestin antagonizes endometrial proliferation (estrogen effect)

Requires a documented NEGATIVE pregnancy test before starting on OCP

If patient does not have menstrual period for >6 weeks:
 Give medroxyprogesterone daily for 10 days to induce withdrawal bleeding
 Minimizes breakthrough bleeding when starting OCP
o Medroxyprogesterone Acetate:

Used when OCPs are contraindicated or patient does not want to go on them

Given every day for 7-10 days every 1-2 months
 Induces withdrawal bleed, offering endometrial protection

Does NOT reduce acne or hirsutism

Does NOT provide contraception
o Metformin:

Restores menstrual cyclicity

Protective effects on endometrium not well established
Therapy for Induction of Ovulation:
o Weight Loss: decreases serum testosterone, allowing for reduction of ovulation and pregnancy
o Metformin: alone or in combo with clomiphene
o Clomiphene: increases FSH and LH; 80% of PCOS women ovulate in response
o Thiazolidinediones: rosiglitazone +/- clomiphene
o Gonadotropin therapy
Therapy for Insulin Resistance:
o Weight Loss: reduces insulin levels
o Metformin: MAINSTAY OF THERAPY*

MOA: improves hepatic insulin sensitivity
 Decrease hepatic glucose output
 Decrease circulating insulin
 Decreased androgen production in the theca cells

Additional Benefits:
 Weight loss
 Decreased BP and LDL
 Improved ovulation
 Decreased rates of spontaneous miscarriage
 Decreased gestational diabetes
o Thiazolidinediones:

Agents: rosiglitazone, pioglitazone

MOA: improves insulin sensitivity in adipose tissue, skeletal muscle and liver
 Improved glucose uptake
 Decreased circulating insulin
 Decreased androgen production in theca cells
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
AACE PCOS Recommendations:
o Early recognition of the syndrome
o Lifestyle modification
o Measurement of glucose +/- insulin (consider OGTT)
o Detect and treat lipid abnormalities
o Monitor and treat BP if necessary
o Measure atherogenic markers
o Initial treatment with metformin (especially if overweight/obese)
o Nonandrogenic OCPs for androgenic symptoms
o TZDs for impaired glucose tolerance (IGT) or T2DM
Fertility Pharmacology:
Goals:
o Ovulation induction (to induce an anovulatory female to ovulate 1 follicle)
o Superovulation (to induce multiple ova to mature and ovulate in a normally ovulating female, ↑ the chance of pregnancy)
Clomiphene Citrate:
o MOA: competitive antagonist of the estrogen receptors in the hypothalamus

Hypothalamus detects hypoestrogen state and increase GnRH release

Pituitary stimulated to release 50-60% more FSH (results in follicular development)

Only effective in women with adequate estrogen levels
o Administration:

Administered for 5 days early in the follicular phase (days 3-7 or 5-9)

Administered at this time because it is before the follicle dominance occurs, increasing the change of multiple
follicle recruitment and maturation (increased FSH increased follicles)
o Adverse Effects:

Antiestrogen effects (hot flashes, inhibition of endometrial proliferation)

Risk for multiple gestation

Ovarian cancer (controversial association)
Aromatase Inhibitors:
o MOA: block conversion of androgen to estrogen

Decreases estrogen negative feedback to hypothalamus, increasing GnRH and FSH
o Features:

Similar dosing regimen to clomiphene

No anti-estrogenic effect at the endometrium

More commonly used for estrogen-sensitivty malignancies
Gonadotropins:
o Basics: injectable FSH and LH
o FSH: administered once daily subQ for duration of follicular phase

May inhibit normal LH surge, resulting in need to exogenously produce LH surge

Derived from purified menopausal urine OR recombinant FSH
o Mimic LH Surge with Injectable HCG:

Has a longer half life than exogenous LH

Stimulates ovulation and final maturation of ova (becomes fertilzable)
 Ovulation typically occurs 34-36 hours after hCG administration

Derived from pregnant women’s urine OR recombinant hCG
o Effects: 8-15% chance of conception with each cycle

20%, 5% triplets, risk for quadruplets or more
o Monitoring:

Trans vaginal ultrasound (assess number of mature follicles)
 If too many, stop FSH and do NOT give hCG (cancel cycle)

Serum estradiol
o Complications:

Ovarian Hyperstimulation Syndrome (OHSS):
 Seen in women given ovulation induction or superovulatory drugs
 Excess vasoactive substances released during follicle leutinization (esp. VEGF)
o Increases capillary permeability (ascites, hypovolemia, hemooncentration)
 Occurs 5-10 days after ovulation trigger
DIABETES MELLITUS PHARMACOLOGY:

Sulfonylureas:
MOA: increase insulin secretion from beta cell (binds sulfonylurea receptor on islet cell, blocking the K+-ATP channel)
o Blockage of K+ channel leads to depolarization and influx of Ca++ release of vesicles containing insulin
Use:
o Relative insulinopenia (need to be able to make insulin)
o Lean patients (may cause weight gain)
Onset of Action: full effects seen in 7-10 days (titrate dose after 1-2 weeks)
-

Efficacy:
o Decrease HbA1c by 1-2%
o Decrease blood glucose by 70mg/dl
o Primary (never works) and secondary (diminished efficacy) failure both possible
Adverse Effects:
o Hypoglycemia
o Weight gain
o GI effects
o Hepatotoxicity
o Hematologic effects
o Skin rash (sulfa group- hypersensitivity)
Agents:
o First Generation:

Chlorpropamide

Tolbutamide

Tolazamide
o Second Generation:

Glipizide: 80-85% renally excreted, but excretion is of an INACTIVE metabolite
 Therefore, SAFE to use in renal insufficiency

Glyburide: 50% renally excreted, but excretion is of an ACTIVE metabolite
 Therefore, CANNOT use in renal insufficiency (increased risk for hypoglycemia)
o Third Generation:

Glimepride
Drugs that INCREASE SU Effects: increased risk for hypoglycemia
o Cimetidine
o Alcohol
o Warfarin
o NSAIDs
o Salicylates
Drugs the DECREASE SU Effects:
o Rifampin
o Diuertics
o Beta blockers
o Estrogens
o Corticosteroids
Biguanides (Metformin):
MOA: decreases hepatic gluconeogenesis AND reduces peripheral insulin resistance
Use:
o Obesity + insulin resistance
o Hypoglycemia due to SUs
o PCOS
Onset of Action: see effect within days (titrate dose after 1-2 weeks)
Efficacy:
o Decrease HbA1c by 1-2%
o Decrease blood glucose by 60-80mg/dl
Other Benefits:
o Decrease TG and LDL
o Increase HDL
Adverse Effects:
o GI effects (N/V/D, abdominal bloating)

Reason for dose titration
o Lactic acidosis
Contraindications: due to risk for lactic acidosis
o Renal impairment (SCr >1.5 in males or >1.4 in females)
o Hepatic disease
o CHF (increased production of lactic acid already due to hypoperfusion)
o Alcohol use
o Contrast media
Drug Interactions:
o Drugs that INCREASE metformin effect (inhibit renal tubular secretion)

Furosemide

Cimetidine

Digoxin




Thiazolidinediones (TZDs):
MOA: decrease peripheral insulin resistance (binds to PPARγ to increase GLUT4 expression)
Use:
o Insulin resistance
o PCOS
Onset: effects in 2 weeks with maximum effects in 6-8 weeks (titrate dose after 6-12 weeks)
o Longer onset than the other 2 classes discussed so far
Efficacy:
o Decrease HbA1c by 0.5-1.5%
o Decrease blood glucose by 50mg/dl
Adverse Effects:
o Increase LFTs (contraindicated in patients with hepatic disease)
o Edema
o CHF exacerbation
o Weight gain
o Anemia
o Avoluation
o Myocardial ischemic events (black box warning)
o Fracture
Agents:
o Rosiglitazone
o Pioglutazone: use more often
Meglitinides:
MOA: increase insulin secretion when glucose exceeds threshold level
o Do NOT release insulin in fasting state (glucose-dependent)
o Otherwise, similar mechanism to sulfonylureas (but bind to different receptor)
Agents:
o Repaglinide
o Nateglinide (more raid and short-lived effects)
Use:
o Relative insulinopenia (requires that patient can still make insulin endogenously)
Onset: effects are rapid (titrate dose after 1 week)
Efficacy:
o Decrease HbA1c by 1-1.5%
Adverse Effects:
o Hypoglycemia (less than sulfonylureas since glucose dependent)
o Headache
Patient Counseling: must be taken with meals
Alpha-Glucosidase Inhibitors:
MOA: slows the breakdown of complex CHO in the GI tract (slows absorption)
Agents:
o Acarbose
o Miglitol
Use:
o Postprandial hyperglycemia
o Patients with severe hypoglycemia from small doses of SUs
Onset: start with lose dose and titrate after 4-8 weeks
Efficacy:
o Decrease HbA1c by 0.5-0.8%
o Reduce postprandial glucose
o Minimal effect on fasting plasma glucose
Adverse Effects: limit usefulness
o GI effects
o Flatulence
Patient Counseling:
o Take with meals
o Use glucose tablets for hypoglycemia (cannot digest complex carbohydrates)
Other Agents:
Pramlintide: synthetic amylin analog
o MOA:

Liver: regulates postprandial glucose

Alpha cells: decreases postprandial glucagon secretion

Stomach: slows gastric emptying

CNS: promotes satiety and reduces appetite
o Use: T1DM or T2DM patients currently on insulin therapy (inject immediately before meals)
o

Efficacy:

Decreases HbA1c by 0.5-1%

1-1.5kg weight loss
o Adverse Effects:

Nausea

Hypoglycemia (especially in T1DM); need to reduce mealtime insulin by 50%*
Incretin Mimetics:
o Agents:

Exenatide (BID or weekly injections)

Liraglutide (daily injections)
o MOA mimic GLP-1

Beta Cells: increase glucose dependant insulin secretion
 May also increase beta cell mass and proliferation (use early to slow progression?)

Alpha Cells: decrease glucose dependant glucagon secretion

Stomach: slows gastric emptying time

CNS: promotes satiety and reduces appetite
o Use: T2DM, in combination with SU, metformin or TZD

Requires empiric SU dose reduction
o Efficacy:

Decreases HbA1c by 0.5-1%

1.5-3kg weight loss
o Adverse Effects:

Nausea

Hypoglycemia

Pancreatitis
o Contraindications:

Severe kidney disease

Gastroparesis

History of pancreatitis

Thyroid cancer or endocrine tumors
DPP-4 Inhibitors:
o Agents:

Sitagliptin

Saxagliptin
o MOA: inhibits DPP4 enzyme, prolonging GLP-1 action by inhibiting it’s inactivation
o Uses: T2DM (either as monotherapy OR in combination with metformin or TZD)
o Efficacy: decrease HbA1c by 0.7-1%
o Adverse Effects:

URI/nasopharyngitis

Headache

Uritcaria

SJS (rare)
o Important Points:

Dose adjust for renal function

Empiric SU dose reduction
Insulin Therapy:
MOA:
o Replaces defective insulin secretion
o Suppresses hepatic glucose production
o Increases glucose uptake by tissues
Indications:
o T1DM
o T2DM in certain scenarios

Acute stress, infections or surgery

Pregnancy

Renal or hepatic disease

Allergy to or failure of oral agents
Analog Insulins: modifications made to human insulin molecule to alter the pharmacokinetic profile
o Peakless/Long Acting: last 20-24 hours

Glargine

Detemir
o Rapid Acting Insulin: last 4-6 hours

Aspart

Lispro

Glulisine
o

Short Acting: last 6-10 hours

Regular insulin
o Intermediate Acting: lasts 12-20 hours

NPH insulin
Basal/Bolus Therapy Regimen: best therapy because it mimics physiologic insulin release
o Basal insulin administered before bed to provide peakless basal insulin levels throughout the day
o Bolus insulin (rapid acting) injected before each meal to prevent postprandial spike
Factors Affecting Insulin Pharmacokinetics:
o Site of injection
o Depth of injection
o Insulin concentration
o Insulin dose
o Insulin mixing
o Exercise
o Local heat or massage
Adverse Effects:
o Hypoglycemia
o Local skin reactions
o Hypersensitivity
o Lipodystrophy
o Weight gain
o Hyperinsulinemia
Summary of Take Home Points:
T2DM:
o Renal Insufficiency:

Metformin: contraindicated due to increased risk for lactic acidosis

Glyburide: contraindicated due to increase risk for hypoglycemia
o CHF:

Metformin: contraindicated due to increased risk for lactic acidosis

TZDs: contraindicated due to increased edema and exacerbation of CHF
o History of Hypoglycemia: use medications less likely to cause hypoglycemia

Metformin: does not increase insulin release

TZDs: do not increase insulin release
T1DM:
o Insulin therapy is required (basal/bolus regimen the most effective)
MALE GONADAL PHARMACOLOGY:

Uses of Androgens:
Hypogonadism
Male sexual dysfunction
Catabolic states
Athletic performance
Erythropoiesis stimulation

Androgen Formulations:
17α-Hydroxyl Group Esters:
o Esterification makes the more lipophilic (oil preparations)
o Hydrolyzed to testosterone in circulation
o Administered IM every 1-2 weeks
o Adverse Effects:

Cough (unclear mechanism)

Pain at injection site

Fluctuations in serum testosterone and symptoms
17α-Alkylated Testosterone (Methyltestosterone):
o Alkyl group retards hepatic metabolism, allowing for oral use
o Less androgenic than testosterone
o Associated with liver toxicity (not recommended for use)
o Also difficult to monitor therapy (not easily detectable via immunoassay)
Transdermal Delivery:
o Patch: applied to back, abdomen, upper arms or thighs

2.5 or 5mg patches

Some adverse site reactions (rotate site or use hydrocortisone cream)
o Gel: administer 5 gm of gel once daily

Allow gel to dry and cover with clothing

Do not come into contact with women/children

Better skin tolerability than patch
-




Buccal Testosterone (Striant):
o Small tablet that adheres to the gums (becomes moistened and molds to it)
o Testosterone absorbed through the gums into the bloodstream (bypasses liver metabolism)
o Adverse effects include taste changes
Testosterone Pellets:
o 3-6 pellets implanted subcutaneously (lasts up to 6 months)
o Pellets may extrude spontaneously
Monitoring Testosterone Therapy:
Serum Testosterone Levels:
o Goal: 3-6 months after the initiation of therapy, testosterone should be in the middle of the normal range
o Checking Serum Testosterone Levels:

Injectable: check midway between injections

Patch: check 3-12 hours after application

Buccal: check immediately before or after application

Gels: check anytime after the first week of therapy

Pellets: check at the end of the dosing interval (adjust the number of pellets/next dosing interval accordingly)
Hematocrit:
o Check:

Baseline level

Levels at 3-6 months

Levels annually after that
o Importance: discontinue if hematocrit >54% (reintroduce at a lower dose when it normalizes)
Bone Mineral Density: check after 1-2 years OR if osteoporosis or fracture occurs
Prostate Screening:
o Baseline: PSA/DRE (for men >40 years old with PSA >0.6ng/ml)
o Follow Up: at 3-6 months after initiating therapy, and then per cancer screening guidelines after that
Symptom Improvement: in 3-6 months and then annually
o Sign/Symptom Improvement:

Increased libido

Improved erectile dysfunction

Improved fertility

Improved weakness, fatigue

Improved depression, loss of motivation, irritability

Increased body hair

Increased muscle ass

Increased size of prostate/testes

Reduction in gynecomastia

Improvement of osteoporosis

Improvement of anemia
Adverse Drug Reactions: in 3-6 months and then annually
Contraindications to Testosterone Therapy:
Metastatic prostate cancer
Breast cancer
Unevaluated prostate nodule or induration
Elevated PSA >4ng/ml (or 3ng/ml is high risk- AA, first degree relative)
Hct >50%
Severe lower urinary tract symptoms with BPH
Uncontrolled CHF
Adverse Effects of Testosterone Therapy:
Erythrocytosis (esp. if predisposed- COPD, chronic hypoxia)
Acne/oily skin (androgenic stimulation of sebaceous glands)
Detection of subclinical prostate cancer
Reduced sperm production/fertility (feedback inhibition of LH/FSH)
Induction/worsening of obstructive sleep apnea
Virilization in women and children (facial hair, hirsutism)
Initial growth spurt in children without epiphyseal closure, followed by premature closure and stunted growth
Aromatization of androgens to estrogen (gynecomastia)
Anabolic Steroids:
Oxandrolone, Stanozol:
o Only oxandrolone available in the US

HIV/AIDs wasting

Post-burn patients who have lost muscle mass
o Greatest ratio of protein anabolic effects (ie. increase muscle mass) compared to virilizing effects
Androstenedione:
o Weak natural androgen (synthesized by adrenal glands)

o Converted to testosterone in tissues by 17-dehydrogenase
o May aromatize to estrogen
Tetrahyrogestrinone (THG):
o Newer anabolic that is metabolized quickly and more difficult to detect
o ~20% of the potency to DHT
o Toxicity profile is unknown
Danazol:
o Derivative of 17α-ethinyl testosterone
o Weak progestin and androgen activity
o Used in the treatment of endometriosis (suppresses ovarian function- inhibits midcycle LH surge and FSH)
Side Effects of Anabolic Steroids:
o No serious side effects with short term use
o Long term use associated with several side effects

CV risk factors (decreased HDL, increased TG)

Hepatotoxicity (with oral anabolics)

Behavioral effects (increased aggressiveness, irritability)

Infertility
Anti-Androgens:
Uses of Antiandrogens:
o Female virilization
o Alopecia
o Precocious puberty
o Prostate cancer
o BPH
o Paraphilia
GnRH Receptor Agonists:
o Agents:

Leuprolide

Goserelin

Triptorelin (long acting, considered for use in paraphilia)
o MOA: continuous stimulation of GnRH receptor causes downregulation

Because of mechanism, initially results in surge of testosterone
GnRH Receptor Antagonists:
o Centrorelix: IVF protocols, inhibit premature LH surge (allows doctors to retrieve eggs before ovulation)
o Ganirelix: IVF protocols, inhibit premature LH surge
o Degarelix: prostate cancer
o Abarelix: palliative care in prostate cancer (not available in the US)
Non Steroidal Androgen Receptor Antagonists:
o Flutamide: used in prostate cancer

High incidence of hepatotoxicity

Associated with gynecomastia

Requires dosing every 8 hours
o Bicalutamide: used in prostate cancer

Lower incidence of hepatotoxicity

Dosed once daily
5α-Reductase Inhibitors:
o Agents:

Finasteride

Dutasteride
o MOA: block conversion of testosterone to DHT
o Indications:

BPH (both agents)

Androgenic alopecia/male pattern baldness (finasteride only)
o Adverse Effects:

Induces genital abnormalities in male fetus (avoid in pregnancy)

Decreased libido and sexual dysfunction
Other Antiandrogen Agents:
o Ketoconazole:

Antifungal agent that inhibits glucocorticoids and androgen synthesis in the adrenal gland
o Spironolactone:

Competitive androgen receptor angtagonist and K sparing diuretic

Used to treat hirsutism and PCOS