Pharm Exam 8

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Pharm Exam 8
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  1. ADA Criteria for Diagnosis of DM (2014)
    • 1. Classic Sx of DM and glucose >200
    •                  or
    • 2. Fasting plasma glucose > 126
    •                  or
    • 3. 2 hour plasma glucose > 200 during a 75 gm oral glucos tolerance test
    •                  or
    • 4. HbA1C > 6.5%
  2. Monitoring DM
    • 1. Fasting plasma glucose (normal= 70-100) 
    • 2. Post-prandial plasma glucose  (normal<140 2 hrs post meal)
    • 3. HbA1C --> percentage of HbA that has been irreversibly glycosylated. (normal = 4-6% for DM goal is , 7%). Best indicator of overall blood sugar control
  3. Diabetes Medication Classes
    • I. Traditional 
    •    A. Drugs that sensitize body to insulin and/or 
    •        control hepatic glucose production (biguanides, thiazolidinediones) 
    •    B. Drugs that stimulate the pancreas to make more insulin (sulfonylureas, Meglitinides) 
    •    C. Drugs that slow the absorption of starches (alpha-glucosidase inhibitors) 

    • II. New
    •     A. Incretin mimetics
    •        1. depeptidyl peptidase IV inhibitors- enhance incretin levels by inhibiting enzyme responsible for inactivation
    •        2. Glucagon-like peptides- stimulate insulin secretion in the presence of glucose and block glucagon release
    •    B. Synthetic amylin analogs - slow gastric emptying and decrease post-prandial glucagon
    •    C. Sodium glucose cotransport-2 inhibitors- decrease renal glucose reabsorption to increase urinary glucose excretion
    •    D. Bromocriptine - ergot derive dopamin agonist that mildly lowers glucose via unknown mechanism
  4. Metformin
    MOA: Biguanide. Decreases hepatic glucose production. Considered an insulin sensitizer

    Dose: start with 500 mg 1/day w/breakfast and titrate up to max 1000 mg bid or 850 mg tid w/meals. Available a cheap generic

    Uses: weight loss (DOC for obese patients). Little to no hypoglycemia. Also used in PCOS for insulin resistance and hyperinsulinemia and to improve menstrual cycle


    Adverse: Nausea, diarrhea, abdominal discomfort (50%). Contraindicated in renal insufficiency. Lactic acidosis --> occurs with tissue hypoperfusion and hypoxemia and can be fatal. Metformin is contraindicated in patients w/renal dysfunction or metabolic acidosis.

    Pregnancy: Category C
  5. Sulfonylureas
    MOA: increase secretion of insulin, bind to beta cells. All have equivalent effect, differ in duration of action and clearance. Reduce HbA1C by 1.5-2%. 2/3 of patients respond, 20% need 2nd agent

    • Drugs: 
    • 1. Older agents (not used): Chlorpropamide, tolazamide, tolbutamide
    • 2. Glipizide - 12-18 hr duration
    • 3. Glipizide extended release - 24 hr duration
    • 4. Glyburide -12-24 hr duration. Has active metabolites that accumulate in renal failure
    • 5. Glimeperide - 24 hr duration

    *for doses: see slide 25* 

    Adverse: Hypoglycemia (dose dependent, increased risk with longer T1/2, older patient, and reduced renal fcn), weight gain. Contraindicated if Hx of sulfa allergy (probably not actually a problem).
  6. Meglitinides
    MOA: similar in action and side effects to sulfonylureas w/o sulfa compound. 

    Use: High post-prandial glucose --> only taken with meal

    • Drugs: Repaglinide (prandin) and Neteglinide (Starlix), no generic. 

    Caution: renal failure and w/ CYP 3A4 inhibitors
  7. Thiazolidinedeones (Glitazones)
    MOA: selective agonist for peroxisome proliferator activated receptor which regulates transcription of insulin responsive genes. Promote skeletal muscle glucose uptake and reduce insulin resistance. Decrease A1C by 1-1.5%. Effects may take several months

    • Drugs: Pioglitazone (Actos) and Rosiglitazone (Avandia) 
    • Adverse effects: Weight gain, edema (resistant to diuretics), mild anemia, exacerbation of heart failure, elevated LDL, osteoporosis and fracture risk in women, hypoglycemia (w/insulin). Avandia increases risk of MI (?). Actin increases risk of bladder CA (?) Contraindicated in Class III or IV heart failure
  8. Glucosidase inhibitors
    MOA: inhibit intestinal breakdown of carbohydrates and delay absorption of monosaccharides. Useful for high post-prandial glucose

    Drugs: Acarbose and miglitol

    Metabolism: Acarbose--> low absorption, dose dependent hepatoxicity. Miglitol --> almost totally absorbed and renally excreted

    Dose: 25 mg TID with each main meal then increase to max dose of 100 mg TID if > 60 kg

    Adverse effects: associated with undigested carbs --> cramping, abdominal pain, flatulence, and diarrhea


  9. Incretin Mimetics: DPP-4 inhibitors
    MOA: enhance incretin system in body. Inactivate enzyme (DPP-4) that inactives GLP-1 and GIP and prolong action. Potentiate insulin synthesis and release, decrease glucagon production. DPP-4 peptide same as CD26 w/many diverse immunological functions. Decrease HbA1C by 0.4-0.7%. 

    Drugs: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin. For comparisons, see slide 37
  10. Sitagliptin (Januvia)
    MOA: DPP-IV prototype.

    Indications: Type 2 DM as monotherapy or combo w/ metformin, sulfonylurea, glitazone, or insulin

    Dose: 100 mg 1/day w/ or w/o food

    Metabolism: renally eliminated, reduce dose with CrCl < 50

    Adverse: hypersensitivity to drug, URI, rare pancreatitis

    Pregnancy: Category B
  11. Sodium Glucose Cotransporter-2 inhibitors (SLGT2 inhibitors)
    MOA: inhibits SLGT2  in proximal tubule of kidney to increase urinary excretion of glucose and decrease blood glucose. Decreases HbA1C by 0.7-1%. Can be added to other oral DM therapy or insulin

    • Drugs: Canagliflozin (Invokana) approved in 2013
    • Dose: 100-300 mg 1/day orally

    Adverse: increase in genital mycotic infections (15% in women) and UTI (5%), increased diuretic effect.
  12. Bromocriptine (Cycloset)
    MOA: ergot derived dopamine receptor agonist used of parkinson's disease for years but now out of favor due to adverse effect profile. Lower HbA1C by 0.3% alone and 0.5% w/sulfonylureas

    Drug: Cycloset newly approved for type 2 DM 

    Metabolism: extensively metabolized by CYP3A4. 

    Interactions: CYP3A4 inducers and dopamine antagonists

    Dose: taken alone or in combination w/ sulfonylureas
  13. Exenatide (Byetta)
    MOA: Similar to GLP-1. Stimulates insulin secretion in the presence of glucose, blocks glucagone release, slow gastric emptying and increases satiety. Synthetic form of protein found in the saliva of the Gila monster

    Indicated for Type-2 diabetics unable to achieve control with metformin and/or sulfonylurea

    • Dose: Supplied as auto-injectable pen of 5 mcg or 10 mcg doses. Given in thigh, upper arm, or abdomen. Start with 5 mcg may increase to 10 mcg at 1 month
    • Adverse: N/V/D, hypoglycemia (w/sulfonylurea). New FDA warning about cases or hemorrhagic or necrotizing pancreatitis, some resulting in death.
  14. Exenatide Extended-Release
    Dose: releases exenatide from microspheres over period of 10 weeks. 2 peaks in serum levels, one at 2 weeks and one at 6-7 weeks. 2 mg powder for injectable supension. Injected SC 1/week

    HbA1C: reduction higher in ER form vs IR form in randomized trial.

    Adverse: same as non-extended release form
  15. Liraglutide (Victoza)
    MOA: GLP-1 agonist simlar to exenatide (Byetta). Used alone or with other oral antidiabetic agents. Statistically more effective than exenatide in reducing A1C over 26 weeks

    Dose: once daily S/C without regard to meals

    Adverse: boxed warning about risk of thyroid cancer. Cases of pancreatitis reported. High cost/month ($280-$380)
  16. Injectable Amylin Analog: Pramlintide (Symlin)
    MOA: Synthetic amylin analog- amylin normally secreted by pancreatic beta-cells along with insulin. Decreases plasma glucose by slowing gastric emptying, decreasing post meal glucagon, and increasing satiety. Approved in 2005 for Type 1 DM. Indicated for type 1 and type 2 DM already on insulin

    Dose: 60 mcg Sc injection before meals

    Adverse: N/V, HA, severe hypoglycemia w/insulin. Must reduce insulin dose by 50%
  17. ACCORD Trial (2008)
    To determine the effect of lowering of glucose to near-normal levels on CV risk patients w/ type 2 DM

    Increase in mortality with therapy and no reduction in major CV events. 
  18. Insulin Therapy
    Goals: maximise glycemic control, minimize hypoglycemic risk, provide insulin to mimic physiologic needs

    Secretion: Basal (50% of body's daily insulin prduction) or Bolus (stimulates glucose disposal and storage after meals and accounts for body's remaining daily insulin production) 

    • Types: 
    • 1. Rapid-Acting - Insulin aspart and Lispro
    • 2. Short-Acting - regular insulin
    • 3. Intermediate acting - NPH and (Lente- off market) 
    • 4. Long-acting - Glargine, detemir, and (Ultralente- off market) 
    • 5. Pre-mixed: insulin 70/30, 50/50, Humalog 75/25

    • Methods of Delivery
    • 1. Syringes and vials- smaller, thinner needles, autoinjectors available for anticipation/accuracy
    • 2. Insulin pens - some w/ special devices for pts w/ arthritis
    • 3. Insulin pumps - variety of pumps, some w/ tubing, some w/o tubing
  19. Rapid acting Analogue insulins
    • Lispro: Humalog (Lilly)
    • Aspart: Novolog (Novonordisk)

    Amino acid substitutions in insulin proteins. New insulins with more reliable absorption, faster onset, short duration, peak at 1 hr. 

    Used a mealtime. Dosed w/i 15 mins prior to eating

    Advantages: twice as fast a regular human insulin w/ rapid onset and short duration and multiple delivery systems

    Limitations: must eat immediately following dose. No meal=hypoglycemia. Multiple injections. No basal insulin coverage. Cost $90 for 10 ml vial (100 units/ml)
  20. Short acting (regular) insulins
    • Humulin R - Lilly
    • Novolin R - NovoNordisk

    Usually reaches bloodstream w/i 30 minutes w/ slightly longer duration than rapid-acting insulins. Available w/o Rx

    Advantages: long history of use, usually only twice daily dosing. Onset and duration can provide postprandial control. Most common insulin given IV. Cost: $40 for 10 ml vial (100 units/ml) 

    • Limitations: 30-60 minute onset. No longer best available for mealtime dosing. Chance of hypoglycemia after meals because duration is 2-5 hrs. Must be dosed 30 minutes prior to eating.
  21. Intermediate-Actin Insulins
    • Humilin N (NPH) - Eli Lilly
    • Novolin N (NPH) - Novo Nordisk
    • Humulin L (Lente) - Lilly - discontinued
    • Novoloin L (Lente) - Novo Nordisk - discontinued 

    Use: mimic basal insulin

    Dose: often combo with rapid and short acting insulins 

    *NPH contains protamine and some zinc* 

    Advantages: long duration of action (up to 20 hours), can be mixed with regular insulin to decrease injections, available w/o Rx

    Limitations: protamin and zinc implicated in rare immunologic rxns at injection site, longer action increases risk of hypoglycemia, cannot be given IV
  22. 2/3-1/3 rule
    Starting basic insulin with regular and NPH insulin

    • Two injections/day
    •    -2/3 total insulin dose in AM
    •    -1/3 total insulin dose before dinner
    •    - 2/3 of dose is NPH insuline
    •    - 1/3 of dose is short acting regular insulin

    • Three injections/day
    •   -Same as 2 injections/day but give NPH at bedtime rather than before dinner if having nocturnal hypoglycemia and early morning hyperglycemia
  23. Pre-mixed insulins
    Contain both rapid/short and intermediate acting combos

    • -70% NPH/30% regular
    •    Humulin 70/30 and Novolin 70/30
    • -70% NPH/30% Aspart
    •    Novolog 70/30
    • -75% NPL/ 25% Lispro
    •     Humalog 75/25

    Advantages: eliminate difficulty of mixing, combines fast action of rapid or regular insulin with extended duration of intermediate acting insulin, comes in pre-filled, portable delivery systems, only twice daily dosing

    Limitations: Not recommended for IV use, not available w/o Rx
  24. Insulin Glargine (Lantus)
    MOA: long acting, peakless insulin that provides 24 hr basal coverage

    Dose: clear solution with pH of 4.0 that micro-precipitates on injection to form a depot that releases insulin over 24 hrs

    Advantages: lower risk of nocturnal hypoglycemia, lower risk of wt gain compared to NPH, can be Rx with oral agents

    Limitations: cannot be mixed with other insulins, cannot be given IV, does not provide bolus release (often used with otehr rapid and short acting insulins), must be used w/i 1 month of opening, very expensive
  25. Insulin Detemir (Levemir)
    • MOA: newly approved basal insulin, free fatty acid attached to insulin molecule binds albumin in plasma and interstitial fluid producing a slow and consistent rate of release. Duration of action increases with dose
    • Dose: once or twice daily (twice for lower doses) 

    Levemire and lantus are not interchangeable 
  26. Insulin Therapy
    Augmentation: use basal insulin. Replacement: use both basal and mealtime insulin (mandatory in type 1 diabetes) 

    • 500 rule for pre-meal insulin requirement
    •   -for patients already on insulin, estimates number of grams of carbs covered by 1 unit of rapid acting insulin
    •    - 500/total daily insulin dose = grams of carbs covered by 1 unit. 

    • 1700 rule for reducing blood glucose
    •     - for patients already on insulin
    •     - 1700/total daily insulin dosing = expected blood glucose drops (mg/dL)  for every unit of rapid-acting insulin administered

    For more info see slides 88-end
  27. Thyroid Hormone Release
    TRH (from hypothal) -> TSH (ant pit) -> Thyroid hormones (T4, T3, typically bound to thryoglobulin in thyroid, released 5:1 ratio, undergoes proteolysis from T4->T3 in plasma, though typically bound to Thyroid-binding globulin)
  28. Circulating Thyroid Hormones
    T4 secreted solely from thryoid gland

    T3 - <20% secreted from thryoid, vast majority derived from peripheral conversion of T4->T3

    T3 is 4-5x more potent

    Proteins transport hormones in blood - TBG, TBPA, and albumin - 99.96% T4 if bound, 99.5% T3 bound

    Only free hormone exerts bio effects
  29. Prevalence of Thyroid Dysfunction
    Mild (subclinical) hypothyroid - 5-17%

    Hypo - 2%

    Mild (subclinical) hyperthy - 0.1-6%

    Hyper - 0.2%
  30. Hyperthyroid - Signs/Symptoms/Etiology
    (Elderly may be atypical)

    • Absent goiter
    • Anorexia with wasting
    • Palpitations
    • A-fib (and other arrhythmias)
    • CHF

    1/10 as likely as being hypothyroid

    • Increased RAIU (radioactive iodine uptake)
    • Graves dz
    • TSH-secreting tumors
    • Pit resistance to T4
    • Trophoblastic dz
    • Toxic adenoma
    • Multinodular goiter

    • Decreased RAIU
    • Thyroiditis
    • Ectopic thyroid tissue
    • Medication induced -
    • exog thyroid hormone
    • amiodarone
    • iodinated radiocontrast dye
    • iodine in diet
  31. Lab Reading of Thyroid Dz
    • Normal
    • Free T4 - 0.8 - 1.5 ng/dL
    • TSH - 0.2-5.5 mlU/L

    • Subclinical hyperthyroidism - FT4 - normal, TSH low
    • Hyperthyroidism - FT4 way up, TSH way down

    Subclinical Hypothyroid - FT4 normal, TSH high

    Hypothyroid - FT4 way low, TSH way high
  32. Hyperthyroidism Goals of Tx
    Eliminated excess thyroid hormone -> Euthyroid

    Alleviate symptoms, eliminate long-term consequences
  33. Beta Blockers for Hyperthyroid
    • Adjunctive Tx
    • Usually non-selective such as propanolol

    MOA - block B-adrenergic receptors and partially block conversion of T4 to T3 to ameliorate thyrotoxic symptoms

    Dose - may require TWICE the usual dose to control symptoms and heart rate

    Contraindicated with CHF, bradycardia

    Caution with ashtma, COPD
  34. Methimazole
    Thioamide antithyroid agent (Tx for hyperthyroid)

    MOA: blocks organification of iodides and inhibits coupling of MIT and DIT

    Decreased thyroid hormone production

    Drug of choice in most (if non-preg)

    T1/2 - 6-9 hrs

    • Dose - 15-30mg/day initially, taper monthly to maintenance dose of 5-10mg/day
    • Taper beta-blocker with symptoms after 4-6 wks

    Preg Category D
  35. Propylthiouracil (PTU)
    Thioamide antithyroid agent (for Hyperthyroid tx)

    MOA: blocks organification of iodides and inhibits coupling of MIT and DIT

    Also inhibits peripheral conversion

    Drug of choice for thyroid storm

    T1/2 - 2.5 hrs

    • Dose: Initially 100mg 3x/day
    • Taper monthly to maintenance dose of 100-200mg/day

    Preg Category D - BUT IS PREFERRED OVER METHIMAZOLE DURING FIRST PREG TRIMESTER
  36. Thioamides - Adverse Effects
    Tx for hyperthyroidism

    Minor Adv Eff - rash, arthralgias, fever, benign transparent leukopenia - may try other agent but cross sensitivity is ~50%

    • Major Adv Eff -
    • Agranulocytosis (w/in first 3 mos) along with fever, malaise, sore throat
    • aplastic anemia
    • arthralgias, lupus-like syndrome (post-6 mos)
    • hepatotoxicity (within first 3 mos)
    • IF THERE IS MAJOR ADV EFF, DO NOT TRY OTHER AGENT
  37. Thioamides - Monitoring
    Tx for hyperthyroidism

    Baseline Ft4 and TSH, CBC with differential

    Symptoms and hormone levels normalize in 4-8 weeks

    Monitor FT4 4-6 wks after initiation and after dose changes

    FT4 normalizes after 4-8 wks but TSH may remain suppressed for several months after euthyroid

    Reassess TFTs every 3-6 months once euthyroid

    Typically treat for 12-24 mos

    Remission rate 40-50%
  38. Iodides
    Lugol's solution or Saturated Potassium Iodide Solution (SSKI)

    MOA: Acutely blocks thyroid hormone release, inhibits thyroid hormone synthesis, decreases gland vascularity

    SSKI dose: 1-3 drops TID in juice/water (120-400 mg)

    Used pre-op before thyroid surg or after RAI tx

    Symptoms improve in 2-7 days

    Adv eff: hypersensitivy reactions, iodism, gynecomastia
  39. Potassium Iodide for Nuclear Exposure
    Risk of developing thyroid cancer after exposure to radioactive iodine is greatest in neonates, infants, small children (risk smallest in adults >40 y/o)

    Potassium iodide competitively inhibits uptake of RAI

    Available OTC in tablets/liquid
  40. Radioactive Iodine - 131
    Now most common tx for hyperthyroid in US

    MOA: incorporated into thyroid hormones and thyroglobulin, leading to follicular necrosis

    Dose - 5-15 mCi, slow onset

    Remission: 60% in 6 mos, another 40% in 1 year with additional doses

    Often requires concomitant antithyroid/adjunct agents

    Contraindicated in children, preg/lactation

    Major adv: hypothyroid

    Has largely replaced surg (now last resort)
  41. Thyroid Storm
    Life threatening medical emergency

    Severe thyrotoxicosis, high fever, tachycardia, tachypnea, dehydration, delirium, N/V/D

    Precipitated by infection, trauma, surg, RAI, withdrawal of antithyroid meds

    Average duration ~72 hrs with tx

    With aggressive tx, mortality is about 20%

    • Tx includes:
    • PTU, iodides, propanolol, corticosteroids, supportive measures
  42. Hypothyroid: Signs, Symptoms, Etiology
    Elderly may present atypical

    • Failure to thrive
    • Hoarseness/deafness
    • Confusion/ataxia
    • Depression

    • Neonate - mental retardation
    • child - growth retardation

    • Primary:
    • Hashimoto's
    • S/p thyroid ablation
    • Iodine deficiency
    • Drug-induced:
    • Lithium, amiodarone, interferon alfa
    • Iodides, thioamides

    • Secondary:
    • Pituitary insufficiency
    • Hypothalamic dysfunction
  43. Hypothyroidism Goals of Tx
    Restore normal thyroid hormone levels -> Euthyroid

    Alleviate symptoms, reverse biochemical abnormalities

    Prevent neurological defecits in infants/children
  44. Levothyroxin
    Tx of hypothyroid

    Synthetic T4 - drug of choice

    Undergoes deiodination to bioactive T3

    Advantages: no antigenicity, uniform potency, low cost

    T1/2 - ~7 days, single daily dosing

    Steady state in 4-6 wks after start/dosing change

    Average starting dose: 1.6 mcg/kg/day

    Initiate lower doses (25 mcg) and titrate slowly (every 4-6 wks) in elderly and those with cardiac dz

    Average maintenance adult daily dose - 100-125 mcg/day

    Preg women may require doses up to 45% higher

    • Drug/Food Interactions
    • Increase in thy hormone clearance by inducers
    • Rifampin
    • Carbamazepine
    • Phenytoin

    • Impaired absorption of thy hormone
    • Drugs: Calcium, iron, antacids
    • Foods: Soy, fiber, coffee

    • Inhibition of conversion from T4 to T3
    • Amiodarone
  45. Liothyronine
    Tx of hypothyroid

    Synthetic T3

    Not recommended for replacement therapy - highly fluctuating plasma levels

    T1/2 - 1.5 days

    Disadvantages - cost, increased cardiac adverse effects, monitoring
  46. Liotrix
    Tx of hypothyroid

    Synthetic T4:T3 in 4:1 ratio

    Predictable potency, expensive, therapeutic rationale - majority of studies show no benefit over levothyroxine
  47. Thyroid USP
    Tx of hypothyroid


    Dessicated thyroid derived from porcine thyroid glands

    Variable ratio of T4 and T3

    1 grain = 60mg dessicated thyroid

    60mg = about 100mcg T4

    Inexpensive, unpredicatble hormonal stability, antigenic

    Rarely used except in older, stable patients who won't switch to newer product
  48. Monitoring for Hypothyroid
    Baseline TSH, FT4

    • TSH should be evaluated 6-8 wks after initiating therapy or after dose increase
    • FT4 can be checked to assess adherence or malabsorption

    Once euthyroid - TSH/FT4 can be eval every 6-12 mos

    Dose requirements increase in preg: monitor TSH every trimester

    Dose req may decrease w age
  49. Subclinical Hypothyroidism
    Elevated TSH level but normal FT4

    May or may not have symptoms of hypothyroid

    • Consider levothyroxine if:
    • Initial TSH > 10mlU/L
    • Elevated thyroid peroxidase antibody titers
    • TSH levels between 5 and 10 mlU/L and symptoms suggestive of hypothyroidism
    • Patients who are pregnant
  50. Myxedema Coma
    End stage of uncontrolled, long-standing hypothyroidism

    Advanced hypothyroid symptoms, hypothermia, delirium, coma

    Mortality 60-70%

    Need aggressive TX with IV thyroxine, glucocorticoids, and supportive measures

    • Levothyroxine 400-500mcg IV x 1
    • 300mcg if cardiac dz
    • Then 50-100 mcg/day IV

    Improvement of symptoms within 24 hrs

    Switch to oral levothyroxine once patient stable
  51. Describe the lipid transport HDL does
    reverse cholesterol pathway
  52. Drugs Indicated for Treating Lipid Disorders
    • For decreasing cholesterol
    •      HMG-CoA reductase inhibitors (statins) [#1]
    •      Cholesterol absorption inhibitors
    •      Bile acid sequestrants
    • For decreasing trigycerides
    •      Fibric acid derivatives
    •      Omega-3 fatty acids
    • For decreasing both cholesterol and trigycerides
    •      Nicotinic acid
    • (for picture see slide 14 of lipids dis lect)
  53. HMG-CoA Reductase Inhibitors (Statins)
    • Inhibit 3-hydroxy-3-methylglutaryl (HMG) coenzyme A conversion to mevalonate
    •      rate limiting step preventing intracellular cholesterol biosynthesis
    • Cause up-regulation of LDL receptors and increased removal of LDL cholesterol from plasma
    • Primary effect  is a decrease in LDL-C.
    • Some decrease in triglycerides (10-20%) and increase in HDL-C (5-15%) also
    • Also pleiotropic effects:
    •      Inhibition of vascular smooth muscle proliferation
    •      Inhibition of platelet-thrombus formation
    •      May be reason for immediate beneficial effects after acute coronary syndrome
    • Differ in:
    •      Chemical structure
    •      Pharmacokinetics
    •      Cholesterol-lowering potency
  54. HMG-CoA Reductase Inhibitors: list of drugs
    • Lovastatin
    • Pravastatin
    • Simvastatin (Zocor, generic)
    • Fluvastatin (Lescol, generic)
    • Atorvastatin (Lipitor, generic)
    • Rosuvastatin (Crestor) - Astra Zeneca
    • Pitavastatin (Livalo) – Kowa and Lilly
  55. Results of Various Statin Drug Trials
    _____slides 19-23____
  56. Comparison of Statin Doses and Avg % LDL-C Reduction
    see slide 22 in Lipid Dis Lecture
  57. HMG-CoA Reductase Inhibitors: Pharmacokinetcs
    • Absorption: need to give lovastatin with food. For others there is no or slight decrease in absorption with food
    • Half-life: usually short (0.5 - 3 hrs) except for atorvastatin (12 hrs) and rosuvastatin (18 hrs)
    • Time of administration: at night except for atorvastatin and rosuvastatin
    •      HMG-CoA activity highest from 12mn to 3:00 AM
    • Hepatic metabolism: via CYP3A4 enzymes for atorvastatin, lovastatin, and simvastatin
  58. HMG-CoA Reductase Inhibitors: Adverse Effects
    • Frequent but minor: abdominal cramps, heartburn, diarrhea
    • Less frequent
    •      Elevated liver enzymes (1-2%)
    •            –Clinical hepatitis rarely seen
    •      Fatigue (5-10%)
    •            –Possibly related to decrease in protein prenylation and ubiquinone production, essential for mitochondrial energy production
    •      Decrease in cognition
    • Pregnancy risk category: X
    •      Statins contraindicated in pregnancy and for children
    • Myopathy (see other card)
  59. Safety Label Changes Added to Statins by FDA in 2012 + New warning on Dosing of Simvastatin (2011)
    • Label Changes
    • Liver function tests no longer need to be routinely monitored. However should be obtained before start of therapy
    • People over 50 years old may experience notable memory loss or impairment
    • Statins may increase the incidence of diabetes or worsen glycemic control
    • -------------------------------------------
    • Dosing Warning
    • FDA recommends that healthcare
    • professionals should:
    • Maintain patients on simvastatin 80 mg only if they have been taking this dose for 12 or more months without evidence of muscle toxicity.
    • Not start new patients on simvastatin 80 mg.
    • Place patients who do not meet their LDL cholesterol (LDL-C) goal on simvastatin 40 mg on alternative LDL-C lowering treatment(s) that provides greater LDL-C lowering
    • Follow the recommendations in the simvastatin-containing medicines labels regarding drugs that may increase the risk for muscle injury when used with simvastatin
  60. HMG-CoA Reductase Inhibitors: Adverse Effect - MYOPATHY
    • Exact mechanism unknown but related to diffusion of statins into muscle cells
    • Recent evidence suggests decrease in isoprenylated proteins increases rate of apoptosis (cell death) of skeletal muscle cells
    • More common with lipophilic statins: lovastatin, simvastatin, rosuvastatin
    •      Seems to be dose related
    •      Increased risk with CYP450 inhibitors
    • Least likely with fluvastatin and pravastatin – does not accumulate
    • ---------------------------------------------
    • Earliest stage: muscle aches and weakness (10%)
    •      May or may not be associated with increased creatinine kinase (CK) levels
    • Middle stage: myositis – inflammation and acute pain
    • Late stage: rhabdomyolysis, myoglobinuria, and acute renal failure
    • Myalgia may be related to low vitamin D levels
    • Vitamin D supplementaion may reverse myalgia
    •      For patients with Vitamin D levels < 32 ng/mL, myalgia resolved in 90% despite statin continuation
    • --------------------------------------------
    • outpatients with elevated cholesterol on high
    • dose statin for > 3 months
    • (there are differences in incidence of mm ADE btw statins)
    • Muscle-related symptoms:
    •      Fluvastatin XL 40 mg – 5.1%
    •      Pravastatin 40 mg – 10.9%
    •      Atorvastatin 40 to 80 mg – 14.9%
    •      Simvastatin 40 to 80 mg – 18.2%
  61. Risk Factors for Statin Toxicity
    • Endogenous Risks:
    • Age > 65
    • Low BMI and frailty
    • Multisystem disease
    • Thyroid disorders
    • High triglycerides
    • Metabolic muscle diseases
    • Family history of muscle symptoms
    • Personal history of elevated CK
    • ---------------------------------------------
    • Exogenous Risks
    • Heavy exercise
    • Alcohol consumption
    • Drugs affecting CYP 450 system
    • Consuming grapefruit juice
  62. HMG-CoA Reductase Inhibitors: Drug Interactions
    • CYP3A4 enzyme inhibitors
    •       Increase serum levels of lovastatin, atorvastatin, and simvastatin
    •       Macrolide antibiotics, except azithromycin
    •       Azole antifungals
    •       Diltiazem, verapamil
    •       Grapefruit juice (intestinal wall)
    • Fibric acid derivatives
    •      Usually associated with just gemfibrozil
    •      Increase serum levels of all statins and risk of myopathy
  63. Cholesterol Absorption Inhibitors - Ezetimibe (Zetia)
    • Must be absorbed and metabolized to active glucuronide metabolite
    • Hepatic metabolite localizes in intestinal brush border cells and inhibits absorption of both dietary and biliary cholesterol
    • Used alone or in addition to a statin
    • Reduces LDL-C by 15-18% when used alone
    • Some reports of increased myopathy when used in combination with statins
    • ENHANCE trial 2008: No difference in carotid artery intima thickness between simvastatin or simvastatin/ezetimibe (Vytorin) after 2 years treatment
  64. Bile Acid Sequestrants (BAS)
    • Older BAS agents:
    •       Cholestyramine (Questran) - granules
    •       Colestipol (Colestid) – granules and tablet
    • More recent: Colesevalam (Welchol) – hydrophilic polymer
    • Anion exchange in bowel removes bile acids from circulation. Stimulates liver to convert cholesterol to bile acid and up-regulates LDL receptors.
    • Reduces LDL by 10-25% depending on dose. However, can raise TG by 5-10%.
    • Works best if combined with a statin
    • GI effects: constipation, pain, bloating, nausea
    •      Limit use
    • ------------------------------------------
    • >Cholestyramine and colestipol
    •      Start 1-2 packets/scoops/ day. Mix with juice or water, give with meals.
    •      Usually can only tolerate 2-4 packets/day. Tolerance develops to GI effects. Fiber supplement may relieve constipation and bloating.
    •      Can bind polar drugs (statins, warfarin, digoxin, diuretics). Give 2 hrs before or 6 hrs after resin. Can deplete fat soluble vitamins
    • -------------------------------------------------
    • > Colesevalam (Welchol)
    •      Fewer GI symptoms than older BAS
    •      Does not interfere with absorption of statins or other drugs
    •      Strength: 625 mg tablets
    •      Dose: 3.75 gm (6 tablets) daily
  65. Fibric Acid Derivatives
    • Gemfibrozil (Lopid) – 600mg twice daily
    • Fenofibrate (Tricor) – 145 mg once daily
    • ---------------------------------------------------
    • For elevated triglycerides and VLDL in absence of elevated LDL – can reduce risk of pancreatitis
    • Reduce hepatic synthesis of VLDL and  increase lipoprotein lipase activity which breaks down VLDL .
    • Decrease triglycerides by 20-50% and increase HDL by 10-155
    • Latest evidence (2011): little or no improvement in cardiovascular outcomes
    • Suggest only using if TG > 500 mg/dL
    • ------------------------------------------------
    • ADE
    • Gemfibrozil: nausea, dyspepsia
    • Fenofibrate: rash (3%)
    • Caution: may cause cholelithiasis due to increased secretion of cholesterol in bile acids
    • Gemfibrozil contraindicated with statins --> associated with myopathy
    • Fenofibrate may be used with statins
    • -------------------------------------------------
    • > Fenofibric Acid (Trilipix)
    • Approved by FDA in 2008
    • Active metabolite of fenofibrate
    • Has FDA-approved indication that it is safe to use with statins
    • However, fenofibrate has been combined with statins for years
  66. Omega-3 Fatty Acids for Lipid Disorders
    • Includes eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
    • Lovaza: 1 gm capsules containing 465 mg EPA and 375 mg DHA
    •      Approved by FDA in 2005 for prescription only
    •       Dose for high triglycerides: 4 gm/day
    • Also available as dietary supplement or in fatty fish (salmon, herring, sardines, rainbow trout)
    •      Sam’s Club: 1200 mg capsules contain 410 mg EPA and 274 mg DHA
    • Can reduce triglyceride levels by 20-50%
    •      Have no effect on LDL-C or HDL-C
    •      1 gm/day lowers TG levels by 5-10 %
    •      May need to give 2-4 gm/day of OTC or Rx product
    • Also associated with decreased cardiovascular mortality by 32% - platelet inhibition, anti-inflammatory effect, etc
    • Adverse effects: fishy aftertaste and GI disturbances are dose-dependent
  67. Nicotinic Acid (Niacin) for Lipid Disorders
    • Immediate-release (IR) and long-acting (LA) forms available as nutritional supplements
    •       bypass FDA restrictions on labeling
    • Niaspan - Extended-release (ER) form available by prescription
    • MOA: Inhibits mobilization of FFA from adipose tissue. This decreases synthesis and secretion of VLDL in liver
    • Lowers LDL-C (15-25%) and triglycerides      (20-50%) while raising HDL-C (15-35%).
    • Most potent drug for raising HDL-C.
    • ----------------------------------------------
    • >Pharmacokinetics:
    • IR quickly metabolized to conjugated form that causes prostaglandin mediated vasodilation (T ½ = 1 hr)
    • LA in various delayed-release forms slowly absorbed over >12 hrs resulting in metabolism to compounds that can be hepatotoxic
    • ER (Niaspan) intermediate in absorption and seems to be best tolerated
    •      Generic version now available
    • ----------------------------------------------
    • Adverse effects:
    • Flushing, itching, rash, headache, GI distress  due to prostaglandin release
    •      Primarily with OTC IR
    •      Pre-medicate with ASA or ibuprofen
    • Hepatotoxicity – primarily with OTC LA
    •      Associated with > 1500 mg/day of LA or ER
    • Hyperglycemia – may necessitate medication change in diabetics
    • Hyperuricemia
    • ------------------------------------------------
    • > Dosing
    •      IR – start with 100 mg TID with meals and slowly titrate up over several weeks to months up to max of 3 gm/day or LDL goal
    •      ER – start at 500 mg at bedtime and titrate up to max of 1.5-2.0 gm/day
    • Drug interactions
    •      can combine with statins but increased risk of myopathy with higher doses of both
    • Monitor: liver function tests, blood glucose, uric acid
  68. Combination Products for Tx'ing Lipid Disorders
    • Advicor = Niaspan + lovastatin
    • Vytorin = Zetia + simvastatin
    • Simcor = Niaspan + simvastatin
  69. Lipid-lowering therapy indicated (flow chart)
  70. ATP III Guidelines for Lipid Lowering Therapy for Prevention of CV Disease
    • = Previous guidelines that were published in 2001
    • decisions = made based on:
    •      lipoprotein profile
    •      +/- coronary heart dz
    •      risk category
    • use to estimate 10 yr risk for men
    • -----------------------------------------------
    • Statins for Prevention of Cardiovascular Disease – Guidelines Until Fall, 2013
    • For almost all patients withexisting cardiovascular disease (secondary prevention)
    • For most patients with diabetes
    • Optional for high risk patients without known cardiovascular disease (primary prevention)
    •      No difference in 5 year mortality vs placebo (Ray KK et al)
    • No evidence of benefit in women and very elderly
    • Controversial for patients with normal cholesterol and elevated high-sensitivity C-reactive protein (rosuvastatin and JUPITER trial) - statistical, but not clinical significance (+ conflicts of interst)
  71. New AHA/ACC Cardiovascular Event Prevention Guidelines (2013)
    • Replace ATP III guidelines
    • 1 (of 4) = Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
    • Lots of controversy
    • see end of Lipid Dis lecture for "10 points to Remember"
  72. Osteoporosis Impact/Incidence
    • 24% of patients over 50 years old who develop hip fractures die within one year
    • (there is more on slide 2, but this was all that was in yellow)
    • hip fx is associated w/ high morbidity & mortality
  73. Osteoporosis: Basic Pathophys/quick overview
    • Increased Resorption (osteoclastic activity):
    • inc age
    • hormonal deficiencies
    • medications
    • disease states
    • Decreased formation (osteoblastic activity):
    • Sufficient calcium   
    • Sufficient vitamin D
    • Wt bearing exercise
    • affects trabecular bone first-bones with largest % trabecular bone = vertebral (>/= 75%) & areas of the femur (50%)
  74. Primary Osteoporosis
    • Postmenopausal
    •      Cause:dec estrogen levels result in ­inc osteoclastic activity without ­ in osteoblastic activity
    •      Bone loss: 2-3% per year of total bone mass
    •      Affects trabecular bone = vertebral fx
    • Age-related
    •      Cause: normal age-related changes and reductions in osteoblastic activity
    •      Bone loss: 3rd decade of life starts slow decline in bone mass at rate of 0.5-1% per year
    •      Affects cortical and trabecular bone= vertebral and hip fx
  75. Secondary Osteoporosis
    • Medication-related
    •      antidepressants
    •      anticonvulsants
    •      antipsychotics (1st gen)
    •      aromatase inhibitors
    •      excess thyroid hormone
    •      glucocorticoids
    •      heparin >6 months
    •      medroxyprogesterone depot
    •      PPIs
    •      thiazolidinediones (glitazones)
    • Disease-related
    •      anorexia
    •      Cushing’s syndrome
    •      hyperparathyroidism
    •      hypogonadism
    •      malabsorption syndromes
    •      rheumatoid arthritis
  76. Dx of Osteoporosis
    • Gold standard -  bone mineral density (BMD)
    • BMD should be performed on
    •      All women > 65 YO
    •      Postmenopausal women <65 with >/= 1 additional risk factor
    •      Postmenopausal women presenting with fractures
    •      Women considering therapy for osteoporosis if BMD testing would facilitate decision
    •      Women who have been on postmenopausal hormone for prolonged periods
    • ---------------------------------------------
    • DEXA Scan = method to measure BMD
    • DEXA Report gives T-scores and Z-scores for different locations & total T-/Z-scores
    • T-score
    •       Based on number of standard deviations (SD) a patient’s BMD deviates from the BMD of a reference population of mean peak value in young adults.
    •      Same gender and ethnicity but compared to 30 yo
    • Z-score
    •      Based on the number of SD a patient’s BMD deviates from the BMD of a reference population of normal subjects of the same age and sex.
    •      Same gender, ethnicity and age.
    • ------------------------------------------
    • BMD criteria for dx (by the WHO):
    • Normal: 0--> (-1)
    • Osteopenia: (-1) --> (-2.5)
    • Osteoporosis: < (-2.5)
    • [dx only req's low BMD at one sight]
  77. Osteoporosis: Who Should be Treated?
    • If there is a fragility fracture of the spine or hip
    • If T-score </= -2.5
    • If T-score is -1.0 to -2.5 (osteopenia) and...
    •      10-year hip fracture probability >/= 3% or
    •      10-year all major osteoporosis-related fracture probability of > 20%
    • -------------------------------------------
    • FRAX = the WHO fracture risk assessment tool
    • Assesses10-year risk of hip fracture and all major osteoporotic fractures (spine, forearm, hip, or shoulder)
    • Based on risk factors plus or minus femoral neck BMD
    •      risk factors incld: sex, wt, previous fx, smoking, steroids, etc
    • Fracture probability calculated from 12 world-wide cohorts (59,000 people) and validated in 11 independent cohorts (> 1 million person-years)
  78. Osteoporosis: Nonpharmacologic Therapy
    • Eliminate cigarette smoking and excess alcohol
    • Weight-bearing exercise
    • Maintain adequate  intake of calcium and vitamin D
    • Fall prevention strategies
    • The best treatment is prevention!
    • [my notes: VERY important]
  79. Calcium recommended daily intake
    • *based on mg of elemental calcium
    • Adults:
    • 19-50 years               => 1,000
    • 50+ years                  => 1,200
    • 50+ years not on HRT => 1,500
    • ------------------------------------
    • to calc dietary Ca2+ (based on info on nutrition label):
    •      1. drop the %
    •      2. Add a "0"
    •      3. Equals the # of mg of elemental Ca per serving
  80. Calcium Supplements
    • Calcium Carbonate  40% Ca2+ (=>1250mg = 500mg Ca2+)
    • Calcium Citrate  21% Ca2+ 
    • Calcium Gluconate    9% Ca2+

    Citrate absorption not dependent on gastric pH

    • **Make sure people are getting enough ELEMENTAL calcium**
    • --------------------------------------------
    • Considerations for administration
    •      Maximal absorption » 500-600 mg elemental calcium per dose
    •      Citrate preferred for patients taking PPIs or H2 antagonists – does not require acid for absorption
    •      Adverse effects (constipation, intestinal gas)
    •      Vitamin D supplementation required for patients who have insufficient sun exposure or poor dietary intake
    •      Drug interactions – decreased absorption of levothyroxine, tetracyclines, and fluoroquinolones
  81. Vitamin D
    • Function
    •      Now considered an essential hormone rather than a vitamin
    •      Required for calcium absorption and bone mineralization
    •      Required for normal neuromuscular activity
    • Properties
    •       90% is formed in the skin as vitamin D3 (cholecalciferol) upon exposure to sunlight
    •       Needs to be metabolized by both the liver and kidneys to the active form, calcitriol, which has activity that lasts 3-5 days
    •      25 (OH) Vitamin D formed by liver is best indicator of Vitamin D stores
    • *know how to differentiate different forms of vitD (D3/cholecalciferol, D2/ergocalciferol, calcidiol, calcitriol)
    • Classic Deficiency Syndromes
    •      Rickets in children
    •      Osteomalacia in adults
    •      Muscle weakness and pain, postural sway
    • Vit D metabolism chart in lecture
    • ---------------------------------------------
    • Toxicity
    •      Symptoms of hypercalcemia
    •           –weakness, anorexia, N&V, polydipsia, polyuria
    • Calcification of soft tissue, including heart
    •      Can occur if intake greater than 10,000 IU/day
    • Supplementation recommended inpatients with inadequate sun exposure or dietary intake
    •      Sun Exposure: 10-15 min/day and 2-3 times/week of sun on the hands, arms, and face is enough
    •      Persons with dark skin may need more exposure time
    •      Sunscreen blocks D3 production
    • ----------------------------------------------
    • Recommended supplemental dose:
    •      800–2000 IU D3/day
    • Current therapeutic use
    •      Chronic renal failure
    •           –unable to produce active calcitriol
    •      Hypoparathyroidism
  82. VitD Associated with...
    • Osteoporosis and fracture
    • Muscle weakness and falls
    • Cancer
    •      Prostate, breast, colon, brain
    • Coronary Heart Disease
    • Myocardial Infarction
    • Heart Failure
    • Hypertension
    • Multiple sclerosis
    • Rheumatoid arthritis
    • Crohn’s Disease
    • Upper respiratory tract viral infections
    • TB
    • Allergies
  83. VitD Dosing
    • Preferred 25(OH) Vitamin D range: 30-50 ng/ml
    • Intoxication: > 160 ng/ml
    • Vitamin D2 = ergocalciferol
    •      In all prescription products (ie 50,000 IU)
    • Vitamin D3 = cholecalciferol
    •      Converted from previtamin D3 by exposure to sunlight
    •      In many OTC compounds
    •      More potent than Vitamin D2
    • 1,000 IU of Vitamin D3 (cholecalciferol) = 3,000 IU of Vitamin D2
    • Every additional 40 IU Vitamin D3/day increases 25(OH) Vitamin D by 0.4 ng/ml
    •      ie. To increase level by 20 ng/ml, give 2,000 IU D3/day
  84. Drugs for Prevention and Treatment of Osteoporosis
    • Antiresorptive Drugs – block osteoclastic bone resorption
    •      Estrogen
    •      Raloxifene
    •      Calcitonin
    •      Bisphosphonates** "by far the most important drugs in this class"**
    •      Denosumab
    • Anabolic Drugs – promote osteoblastic bone formation
    •      Teriparatide
  85. Estrogen Therapy for osteoporosis
    • [anti-resportive tx]
    • Indication:  FDA approved for the prevention of osteoporosis
    • MOA: Decreases osteoclast activity
    • Effects on bone
    •      bone density (1-5%) and inc risk of fracture (vertebral, nonvertebral including hip)
    •      duration of use = inc ­ fracture protection
    •      Once discontinued, bone loss accelerates
    • ----------------------------------------------
    • Advantages:
    • Relief of menopausal symptoms
    • Positive effects on HDL, LDL
    • Prevention of colon cancer?
    • Relatively inexpensive
    • ------------------------------------------
    • Disadvantages
    • WHI (EPT=estrogen-progestin therapy) - increased risk for breast cancer, stroke, VTE, CHD events
    • WHI (E-alone) - ­ CVAs, vv thromboembolism
    • inc risk endometrial cancer (mainly if + uterus without progestin)
    • Side effects:  breast tenderness, GI, mood changes (depression)
    • ------------------------------------------
    • PROs:
    • efficacy: inc BMD, dec fx (EPT), dec LDL, inc HDL, dec vasomotor sx
    • price: $30/mo
    • simplicity: QD
    • CONs:
    • safety: risk VTE, endometiral CA w/o progestin, EPT-breast CA, CHD events, CVA
    • tolerability: nausea, bloating, breast tenderness
  86. Raloxifene (Evista)
    • [anti-resportive tx]
    • Selective estrogen receptor modulator (SERM)
    •       Estrogen agonist/antagonist
    • Indication: prevention and treatment of osteoporosis
    • MOA: estrogenic effects on bone, antiestrogenic effects on breast and endometrium
    • Effects on bone
    •       inc bone density (2-3%) and dec risk of vertebral fracture (30-60%)
    •       Does not prevent nonvertebral fractures
    •       Dose - Raloxifene 60 mg QD
    •       MORE Trial: dec breast CA
    • --------------------------------------------
    • PROs:
    • safety: no inc risk breast & uterine CA
    • efficacy: inc BMD, dec vertebral fx, dec LDL
    • simplicity: QD, avoids need for progestin
    • CONs:
    • safety: (+) risk vv thromboembolism
    • tolerability: hot flashes, breast tenderness, spotting
    • efficacy: no benefit for nonvert fx (+ mb other)
    • price: $$ (200/mo)
    • --------------------------------------------
    • The MORE Trial
    • Study population:
    •      Postmenopausal women with clinically defined osteoporosis
    • Intervention: Raloxifene vs placebo (36 months)
    •      All patients received calcium 500
    • mg/day and Vitamin D
    • Outcome: Incidence of vertebral fracture
    • Results: 50% reduction in incidence of vertebral fractures in women without previous history of fracture who took Evista
    • (to see chart of results/%s see lecture slides)
  87. calcitonin
    • [antiresporptive drug]
    • (don't see much)
    • Approved agents: Miacalcin Nasal Spray, Miacalcin  injection
    • Dose:
    •      Nasal:  200 IU intranasally in alternate nostrils daily
    •      SC, IM:  100 IU QD
    • Effect on bone:  directly inhibits osteoclastic bone resorption
    •      incBMD, dec vertebral fractures only
    • Adverse effects:  nasal - rhinitis, mucosal ulceration (rare)                       
    • Comments:  May provide analgesic effect on bone pain associated with vertebral fractures although generally less effective for osteoporosis
    • Cost: nasal spray $125/mo, IM/SC $500/mo
  88. oral bisphosphonates
    • [anti-resorptive drugs]
    • *most used group for osteoporosis
    • Drugs:
    • Alendronate (Fosamax and generic)
    •      Daily or weekly dosing
    •      Also available as 70 mg/75 ml liquid
    • Risedronate (Actonel)
    •      Weekly or monthly dosing
    • Risedronate delayed-release (Atelvia)
    •      Weekly dosing
    • Ibandronate (Boniva and generic)
    •      Monthly dosing
    •      IV form every 3 months
    • ----------------------------------------------
    • Mechanism of action:
    •       Bind to hydroxyapatite at sites of active bone resorption, inhibiting osteoclast function.  Incorporated into bone.
    •        BOTH inc osteoblastic and dec osteoclastic activity
    • Pharmacokinetics:
    •       Poorly absorbed, not metabolized (LOW BIOAVAILABILITY; F=0.76%, 0.53mg @ best)
    •       50% excreted by kidney, 50% bound to bone
    • Indications:
    •       All approved for prevention or treatment of post-menopausal osteoporosis
    •       Alendronate & risedronate approved for steroid-induced osteoporosis and Paget’s Disease
    •       Alendronate approved to increase bone mass in men
    • -------------------------------------------
    • Effects on bone
    •      inc BMD by 1-6%, dec vertebral and nonvertebral fractures
    • Contraindications
    •      Abnormalities of the esophagus that delay esophageal emptying, hypocalcemia, CrCl<30-35ml/min, and patients unable to remain upright for at least 30 (or 60) min.
    • Adverse reactions: 
    •       Upper GI:  nausea, abdominal pain, dyspepsia, heartburn, esophageal erosion, ulceration
    •       osteonecrosis of jaw after invasive jaw surgery
    •      New: Severe bone, joint, or muscle pain after short or long term use
    • Length of therapy
    •      At least 5 years – some suggest discontinuation after 5 years
  89. Oral Bisphosphonates: Patient Counseling Tips
    • First thing in the morning on an empty stomach
    • With a full glass of water (6-8 oz.)
    • Nothing to eat or drink (including other meds) for at least 30 minutes
    • Do not lie down for at least 30 min.

    *  Unless dietary intake is sufficient, patients should receive supplemental calcium and Vitamin D
  90. Bioavailability of Alendronate (as ex of bisphosphonates)
    • F = 0.76% (0.53 mg) at best
    • ---------------------------------------
    • water before --> dec F
    • Reduce absorption by 30%, esp 1/2 hr before take
    • NPO 2hrs --> F = 0.69% = 0.49 mg
    • NPO 1/2 hr --> F = 0.48% = 0.34 mg
    • ---------------------------------------------
    • coffee/OJ before/with
    • reduce absorption by 60%
    • F = 0.29% = 0.21 mg
    • -----------------------------------------------
    • with food
    • reduce absorption by 90%
    • F = 0.09% = 0.06 mg
  91. Alendronate (Fosamax) Dosing
    • = go to oral bisphosphonate
    • Prevention
    •      35 mg once-weekly
    • Treatment (postmenopausal women)
    •       70 mg once-weekly
    • Treatment (men)
    •       70 mg once weekly
    • Treatment (glucocorticoid-induced)
    •       5 mg daily except in postmenopausal women not on ERT, dose is 10 mg daily
    • Cost:
    •      Fosamax: $100/month
    •      Generic: $9/month
  92. Risedronate (Actonel®) Dosing
    • = oral bisphosphonate
    • Prevention (postmenopausal)
    •      35 mg once-weekly or 150 mg monthly
    • Treatment (postmenopausal)
    •       35 mg once-weekly or 150 mg monthly
    • Treatment (glucocorticoid-induced)
    •       5 mg daily
    • Cost: $190/month
  93. Risedronate Delayed-Release (Atelvia)
    • = oral bisphosphonate
    • Recently approved by FDA
    • 35 mg delayed-release tablet
    • Take once weekly after breakfast with at least 4 oz of water
    • Do not have to take 30 to 60 minutes before meals or liquids
    • Cannot lie down or take other medications for at least 30 minutes after taking
    • Should avoid H2 antagonists or PPIs
  94. Ibandronate (Boniva)
    • = oral bisphosphonate
    • FDA indications: PMOP
    • Dosage: 150mg monthly by mouth
    • Administration: empty stomach, 60 min before breakfast, no meds/food/liquid/reclining
    • Well tolerated
    • Offers a 3 week dosing window if forgotten
    • Cost: $100/month for generic
  95. Intravenous Bisphosphonates
    • Ibandronate (Boniva) 1mg/ml
    •      3mg IV every 3 mo infused over 15-30 sec
    •      Cost: $500 every 3 months
    • ----------------------------------------------
    • Zoledronic acid (Reclast)
    •       For postmenopausal osteoporosis prevention
    •              –5 mg in 100 ml infused IV over 30 min once every 2 years
    •       For postmenopausal osteoporosis treatment
    •             –5 mg in 100 ml infused IV over 30 min once a year
    •      Caution: acute phase reactions from IV infusion
    •      Cost: $1200/year
  96. Osteonecrosis of the Jaw w/Bisphosphonates
    • see with invasive surgery of the law
    • --------------------------------------------
    • Amer Dental Association guidelines for prevention:
    • Low incidence in non-cancer patients (0.1%)
    • Associated with both oral and IV antiresorptive agents
    •       Previously only linked to IV bisphosphonates
    • Associated with invasive bone procedures such as dental extractions
    • Increased risk with:
    •      Age > 65
    •      Periodontitis
    •      Bisphosphonate use > 2 years
    •      Smoking
    •      Diabetes
    • Routine dental care does not need to be modified if patients taking antiresorptive agents
  97. Duration of Biphosphonate Therapy
    • Bisphosphonates effective in decreasing fractures over first 3 to 4 years of therapy
    • However, little efficacy date for use > 5 years
    • Bisphosphonates can have persistent effect in bone 3 to 5 years after discontinuation
    • Many reports of atypical fractures of femoral diaphysis or in subtrochanteric region after prolonged use
    • Latest recommendations for continuing after 3 to 5 years (NEJM, May 31, 2012):
    • If T < -2.5  at femoral neck: continue treatment
    •      If T > -2.0 at femoral neck: stop therapy
  98. PROs & CONs of bisphosphonates
    • PROs:
    • safety: no inc risk breast & uterine CA or vv thromboembolism
    • tolerability: avoids hormone side effects
    • efficacy: inc BMD, dec vertebral & nonvertebral fx*
    • simplicity: QD, Qweek, Qmo,Q3mo, or Qyr dosing
    • -------------------------------------------
    • CONs:
    • risk of GI complications, osteonecrosis of the jaw
    • tolerability: GI side effects
    • efficacy: no effect on lipid panel
    • cost: $10-200/mo
    • simplicity: complex dosing instructions
  99. Denosumab (Prolia)
    • Newest Agent for Osteoporsis
    • Human IgG2 monoclonal antibody
    • Inhibits RANK ligand, a member of tumor necrosis factor family
    • Inhibition of RANK receptor on osteoclasts prevents osteoclast formation and function, thus decreasing bone resorption
    • Indicated for treatment of postmenopausal women with osteoporosis with high risk for fracture
    • Increases BMD and decreases incidence of new vertebral, hip, and other nonvertebral fractures in postmenopausal women
    • Effects are reversible after discontinuation
    • Dose: 60 mg SC every 6 months
    • Contraindication: uncorrected hypocalcemia
    • Precautions: hypocalcemia must be corrected before therapy
    • Adverse effects:
    •       Serious infections, including endocarditis
    •       Dermatitis, eczema, and rashes
    •       Osteonecrosis of the jaw
    • Cost: $800 per dose ($1600/yr)
  100. Teriparatide (Forteo)
    • Recombinant human parathyroid hormone (PTH 1, 34)
    • (only use in very serious cases)
    • ---------------------------------------
    • Mech:
    • Chronically high PTH levels activate osteoclasts
    •       break down bone to release calcium
    • Intermittently administered PTH stimulates osteoblasts
    •       build bone
    • -----------------------------------------------------
    • Given subcutaneously daily for up to 2 years
    • Effects on bone
    •      Women:  study demonstrated ­inc BMD, dec vertebral & nonvertebral fractures in postmenopausal women with prior vertebral fractures over 19 weeks of treatment
    •       Men:  ­ inc BMD lumbar spine & femoral neck in men with idiopathic or hypogonadal osteoporosis over 11 months
    • Dose:  20 mcg SC daily
    • Side effects:  Nausea, orthostatic hypotension, asymptomatic hypercalcemia (all generally mild and transient), leg cramps
    • Black Box Warning: Risk of osteosarcoma (based on animal data)
    • Contraindications:  Paget’s disease, open epiphyses, h/o irradiation involving skeleton
    • Forteo Delivery Device: 2.4 ml pen containing 28 day supply
    • Cost: $1500/month
    • -----------------------------------------------
    • Forteo is the most potent medication available to increase BMD
    • -----------------------------------------------
    • Indications
    •      Treatment postmenopausal osteoporosis
    •      Men with idiopathic or hypogonadal osteoporosis at high risk for fracture or who have failed or are intolerant to previous osteoporosis therapy
    • When are some people using Forteo?
    •       Patients with very low bone density ( T-score <-3)
    •      Patients already with fractures and high risk for another
    • Patients with fractures while already on other therapy
    •      Patients who cannot tolerate oral bisphosphonates
  101. osteoporosis meds and what type of fx they reduce
    see last slide of lect
  102. Salicylates
    • Aspirin - ASA
    • Nonacetylated salicylates - trilisate, disalcid, dolobid
  103. Aspirin
    • First NSAID
    • Weak acid, rapidly absorbed - can lead to damage of gastric mucosal barrier

    Acetylsalicylic acid -> salicylic acid, the active form of aspirin

    Highly protein bound

    Conjugated + renal elim 1st order - pathway can become saturated w high doses, leading to zero order kinetic, long half life (15 hrs) and toxic serum levels

    Nonselective inhibitor of COX 1 and 2 (anti-inflamm, analgesic, antipyretic)

    Irreversible inhibition of platelet function - single dose lasts 8-10 days, Non-acetylated salicylates and nonselective NSAIDs have reversible effect

    • Adverse:
    • Gastritis, gastric bleeding
    • Increase in bleeding time (nonacetylated salicylates do not have an irreversible effect on platelets)
    • Airway hypersensitivity (10% of asthmatics w history) - cross reactivity with other NSAIDs

    • Toxicity-
    • Salicylism (salicylate poisoning) - tinnitis, N&V, hyperventilation, hypokalemia, metabolic acidosis, dizziness, agitation, hallucinations

    Bleeding

    Reye's Syndrome - hepatic encophalopathy and liver failure in young children, assoc w aspirin use to tx febrile viral inf, do not give aspirin to children for fevers due to chicken pox or upper resp viral inf

    • Clinical Uses
    • Primarily for prophylaxis of stroke or MI (81mg) - higher doses only increase risk of GI bleeding

    Rarely used for arthritis or pain (adv eff higher than OTC NSAIDs, risk of accum, salicylate poisoning, Reye's in children)
  104. NSAID's
    • Major classes -
    • Tradition nonselective NSAIDs
    • Selective COX-2 inhibitors

    • Mech of Action
    • Inhibition of COX1 and COX2 enzyme to prevent PG synthesis

    • COX-1 continuously expressed and widely distributed to most organ systems including GI tract
    • Needed for production of thromboxanes for clotting
    • COX-2 primarily induced at sites of inflammation and neoplasm
    • Continuously expressed in kidney, intestine, uterus, brain

    • Adverse:
    • GI effects - dose-related
    • Dyspepsia, ulceration, bleeding, perforation (clinically important)
    • Risk increases with:
    • Cox-1 selective agents
    • dose/duration of tx
    • alcohol use
    • steroid use

    • Renal Adv Eff -
    • Sodium, water retention - can exacerbate HF and HTN
    • Acute tubular necrosis -
    • Decrease renal blodd flow, PGs necessary for autonomic control of blood flow to glomerulus
    • Risk increases wth dehydration, hypovolemia, use of ACE-I and ARBs

    • Reversible Platelet inhibition
    • CNS: dizziness, drowsiness, confusion
    • Thrombosis assoc w COX-2 selective agents - Rofecoxib and valdecoxib removed from market due to increased risk of MI
    • Caution with celecoxib in patients with heart disease

    • Drug Interactions -
    • Aspirin -
    • Ibuprofen - may inhibit antiplatelet effect
    • Celecoxib - potential GI protective effect is lost

    Other antiplatelet drugs such as clopidogrel (plavix) increase risk of bleeding

    Diuretics - antagonize diuresis and sodium loss

    ACE-I - antagonize renal effects

    ARBs - antagonize renal effects

    Methotrexate - may increase serum concentration and toxicity

    Clinical Uses - pain relief, including headache, fever, inflammatory conditions, primary dysmenorrhea
  105. GI Toxicity with NSAIDs
    • Low-moderate risk:
    • Ibuprofen
    • Naproxen
    • Ketaprofen
    • Diclofenac
    • Nabumetone
    • Meloxicam
    • Celecoxib
    • Salsalate

    • High risk
    • Indomethican
    • Piroxicam
    • Flurbiprofen
    • Fenoprofen
    • Oxaproxin
  106. Methods to Reduce GI Toxicity Secondary to NSAIDs
    • Add H2 antagonists or PPI
    • 80% with NSAID-induced ulcers are healed with PPI vs 60% with H2 blocker

    • Substitute celecoxib
    • But should pay attn in patients w heart dz

    • Add misoprostol, PG analog that protects gastric mucosa
    • Arthrotec = diclofenac + misoprostol
    • Poor tolerance due to diarrhea and cramping
    • Contraindicated in preg (cat x)
    • Used sequentially with mifepristone for abortions
  107. NSAIDs for Pain vs Inflammation
    • Low doses comparable to 650mg acetaminophen for pain
    • Ibuprofen - 200mg
    • Naproxen - 250mg

    • Moderate doses comparable to aceta/hydrocodone combos for pain
    • Ibupro - 400mg
    • Naproxen - 500mg

    • High doses for anti-inflamm
    • Ibupr-1800-2400mg/day
    • Naproxen - 1000mg/day

    OTC only for ibuprofen 200mg and 250mg strengths
  108. Parenteral NSAIDs for Pain
    • Ketorolax (Toradol)
    • Given IM or IV
    • Indicated for pain relief
    • Higher dose - comparable to morphine
    • Cannot use >5 days : high incidence of GI ulceration and bleeding
    • Not indicated for osteoarthritis or RA

    • Ibuprofen (Caldolar)
    • IV infusion not limited to 5 days
  109. OA - Treatment Options
    NSAIDs

    Acetaminophen - relieves mild pain, but inferior to NSAIDs for mod-severe pain

    Topical NSAIDs - may be as effective as oral NSAIDs and avoid systemic toxicity

    • Ibuprofen 10% or ketoprofen 5% compounded by pharmacist
    • Diclofenax 1% topical gel

    Topical capsaicin cream (OTC) - relieve pain by inhibiting substance P - 50% experience local burning sensation diminishing over time
  110. Rheumatoid Arthritis Tx
    • Non-drug
    • Joint protection
    • Energy conservation
    • Passive exercise
    • Heat

    • Short-term
    • NSAIDs (no disease modifying activity)
    • Corticosteroids - local injection, low-dose systemic therapy

    DMARDs
  111. Non-Biologic DMARDs
    • Disease Modifying AntiRheumatic Drugs (DMARDs)
    • Slow onset of effect (3-6 mos) - Slow or reverse disease progression
    • Require regular eval for adverse effects
  112. Hydroxychloroquine
    Hydroxychloroquine
    Least toxic of all DMARDs
    Hemolytic anemia if G6PD deficient
    Potential retinal damage in elderly
    • DMARD for mild RA
    • Least toxic of all DMARDs
    • Hemolytic anemia if G6PD deficient
    • Potential retinal damage in elderly
  113. Suldasalazine
    • DMARD for mild RA
    • Nausea rash
    • Hemolytic anemia if G6PD Defic
    • Rare - leukopenia, hepatitis
  114. Methotrexate
    Non-bio DMARD for mild-moderate RA

    • DMARD of choice
    • Antifolate mech of action
    • Usually see response in 4-6 weeks
    • Low oral doses once weekly (10-25mg)
    • Start at 10, increase up to 25 as tolerated
    • Renally excreted - avoid if CrCl <30ml/min
    • Folic acid supplement necessary

    • Adv Effects
    • GI - nausea, anorexia, stomatitis

    • Hepatic - elevated liver enxymes in 15% (discontinue if 2x upper limit)
    • Should avoid alcohol

    Bone Marrow Suppression - must give folate supplement, can reverse with leucovorin rescue (THF)

    Hypersentivity pneunomonitis in 1-2%

    Teratogenic: Preg Cat X

    Abortifacient and decreases fertility in both sexes

    Avoid other antifolate drugs such as trimethoprim
  115. Leflunomide (Arava)
    NON-BIO DMARD

    Inhibits pyrmidine synthesis (affects DNA)

    Used in place of, or in combination with, methotrexate

    Adverse effects: diarrhea, alopecia, elevated liver enzymes

    Preg Cat X

    Less expensive than biologic DMARDS
  116. Older Non-biologic DMARDs
    Not used because of toxicities

    Gold - many adverse effects, req weekly urinalysis and blood count

    • Azathioprine
    • Metab to 6-mercaptopurine
    • Immunosuppressive - inhibits DNA syn
  117. Biologic DMARDs
    • Five categories so far for tx of RA
    • Tumor Necrosis Factor Inhibitors
    • CD-20 monoclonal antibodies
    • T-cell activation inhibitors
    • IL-6 antagonists
    • JAK inhibitors

    • Advantages:
    • Selective target TNF and other cytokines in synovium of RA patients
    • Act much quicker than non-biologics
    • Greater than 20% improvement in up to 75% of patients when added to DMARD
    • Usually given with MTX for synergistic effect
    • Preg Cat B/C

    • Disadvantages:
    • Parenteral route for all but one
    • Injection/infusion rxns
    • Risk for serious disseminated inf including TB
    • Expensive

    • Precautions:
    • TB screening
    • Vaccinations for influenze, pneumococcal dz, hep B, herpes zoster
    • Avoid live virus vaccines
    • Do not give if active infection
  118. Etanercept
    Bio- DMARD for RA

    • TNF inhibitor -
    • Soluble TNF receptor
    • Given SC once/twice weekly
  119. Infliximab
    Bio- DMARD for RA

    • Chimeric human/mouse anti-TNF monoclonal antibody
    • Given IV at 0,2, and 6 weeks and then every 8 weeks
    • MTX enhances efficacy
  120. Adalimumab
    Bio- DMARD for RA

    Human anti-TNF monoclonal antibody

    Given SC once weekly as monotherapy or SC every other week w MTX
  121. Certolizumab pegol
    Bio- DMARD for RA

    Humanized pegylated anti-TNF monoclonal antibody with supposedly longer T1/2

    Given SC every other week
  122. Golimumab
    Bio- DMARD for RA

    Human anti-TNF monoclonal antibody

    Given SC monthly
  123. Rituximab -"Need to Remember"  - Tom Lynch
    Bio- DMARD for RA

    CD-20 monoclonal antibody

    Targets B-cell specific surface antigen

    Given as 2 IV infusion 2 weeks apart

    Anaphylaxis and late development of progressive multifocal leukoencephalopathy have been reported (highly fatal)
  124. Abatacept
    Bio- DMARD for RA

    T-Cell activation inhibitor

    Used if unresponsive to anti-TNF agents

    Given IV at 0,2,4 weeks and then monthly
  125. Tocilizumab
    Bio- DMARD for RA

    IL-6 receptor antagonist

    IV infusion every 4 weeks

    Only if inadequate response to TNF-inhibitors
  126. Tofacitinib
    Bio- DMARD for RA

    • First oral biologic DMARD for RA
    • JAK inhibitor

    Lynch says it's useless

    • Indicated if inadequate response or intolerant to MTX
    • Given orally twice daily

    Adv effects: severe infection, TB, diarrhea, GI perforation
  127. Current Approach for Drug TX of RA
    • Initial Tx:
    • Start MTX at low dose once weekly and slowly increase to max of 25mg
    • Add NSAID as bridge therapy to reduce therapy and swelling until DMARD takes effect
    • Possibly add second nonbiologic DMARD

    • If inadequate response:
    • Add TNF inhibitor to MTX

    If inadequate response to 1st TNF-Inhibitor, substitute another

    If still inadequate response, try a non-TNF bio-DMARD
  128. Gout - Acute Tx
    • Relieve pain - short term
    • Nonselective NSAIDs - drugs of choice
    • Naprosyn 750mgx1, then 250mg TID

    • Indomethican - traditional NSAID but less safe
    • Corticosteroids - prednisone 20mgx1, then 10 day taper
    • Colchicine

    • Rule out other causes
    • Drugs: Thiazides, cytotoxic chemo, cyclosporine, pyrazinamide, salicylates, levodopa

    Diet: anchovies, sweetbreads, kidney, liver, and meat extracts
  129. Colchicine
    Relatively specific for acute gout

    • Inhibits tubulin polymerization and cell mitosis
    • Does not alter metab or excretion of uric acid

    Old dosing: .6mg every 2 hrs until pain relieved or nausea, diarrhea appear

    Old prophylactic dosing - .6mg one to three times daily

    • Precautions:
    • Can cause bone marrow aplasia and death in high doses, especially if given IV

    Avoid in renal and liver dz, elderly patients

    Used to be generic, taken off market, now much more expensive since is branded
  130. Hypouricemic Tx of Gout
    After freq attacks, uric acid stones, or nephropathy from stones

    Hypouricemic tx not useful for acute attacks

    • Uricosuric drugs -
    • Increase excretion of uric acid
    • For underexcretors of uric acid
    • Probenecid
    • Sulfinpyrazone

    • Xanthine Oxidase inhibitors
    • Decrease serum uric acid by decreasing uric acid syn
    • Allopurinol
    • Febuxostat
  131. Probenecid
    Usually used if intolerant to allopurinol

    Competes with uric acid for renal tubule reabsorption - secretion of other weak acids also inhibited (penicillin)

    Start with low dose and slowly increase

    Need high fluid intake to prevent renal stones

    Do not use if CrCl < 30mL/min or have renal stones
  132. Allopurinol
    Xanthine-oxidase inhibitor

    Most common drug used for long term control of gout

    Allopurinol has 2 hr half life but its active oxypurinol metabolite has 24 hr half life

    Renal elim - need to reduce dose in renal dz

    Start w 150mg QDx 2 wks then increase

    Average gose needed is 300mg QD

    Max daily dose is 800mg in divided doses

    • Hypersensitivity Rxns: switch to Probenecid
    • Stop drug if patient begins to have mild skin eruptions
    • Can develop into life threatening Stevens-Johnson syndrome and organ failure

    • Drug Interactions:
    • Ampicillin or amoxicillin - high incidence of rash
    • Azathioprine - increases concentration of 6-mercaptopurine resulting in bone marrow depression
  133. Febuxostat
    • Approved in 2009
    • First new gout drug in 40 years

    More selective xanthine oxidase inhibitor - different structure than allopurinol - theoretically fewer hypersensitivity reactions

    Lowered uric acid levels sif more than allopurinol w 40-80mg QD, but used low dose allopurinol

    Cost is 50x higher than allopurinol
  134. Basic Principle of Immunopharmacology
    Kill the pathogen w/o harming the host
  135. Immune Cells
    Pluripotent hematopoetic cells give rise to

    • 1) Lmyphoid cells (adaptive) --> B and T cells
    • 2) Trilineage (innate)--> neutrophils etc
  136. Reasons to use immunosuppressants
    • 1) Transplant Rejection- due to MHC mismatch between unrelated donors and recipients (alloimmunity)
    •   Three phases: Acute, hyperacute, chronic
    •      *drugs work on acute rejection, there is 
    •        no Tx for chronic rejection
    •    GVHD - Sx: rash, diarrhea, pneumonitis, 
    •                     veno-occlusive disease of the 
    •                     liver
    •               Tx: remove recipient T-cells, may
    •                     not be beneficial for pts with
    •                     hematological cancers, takes 
    •                     away T-cell recognition of
    •                     malignant cells
    • 2) Autoimmunity: host immune system attacks host (RA, SLE, Type 1 DM)
  137. Corticosteroids
    MOA: stop production of inflammatory cytokines and inhibit phospholipase A2 enzyme which decreases inflammatory mediators

    Dose: normally high doses of prednisone

    Adverse: Cushing's, osteoporosis, obesity, mood disturbances, weakness, decreased wound healing, impaired glucose tolerance, and DM (due to increased gluconeogenesis)
  138. Antimetabolites
    Structural analogues of natural metabolites to inhibit normal pathways
  139. Azathioprine
    MOA: prodrug of 6-mercaptopurine, first antimetabolite made. Slow release of 6-MP from AZA favors immunosuppresion

    Use: Solid organ transplants

    *he didn't have much to say in the lecture beyond this*
  140. Methotrexate
    MOA: folate analogue, inhibits dihydrofolate reductase, increases adenosine levels (maybe?) and induces T-cell apoptosis

    Dose: high for malignancy, low dose for auto-immunity

    ADR: Folic acid depletion, anemia, must supplement leucovorin to increase folate
  141. Mycophenolic acid
    MOA: inhibits inosine monophosphate dehydrogenase (rate limiting step in production of guanosine)--> depletes guanosine for DNA synthesis, and increases adensoine for anti-inflammatory effect.

    Uses: Works better than AZA for solid organ transplant, aslo works well for autoimmune diseases

    Dose: note decreased oral bioavailability
  142. Leflunamide
    MOA: inhibits pyramidine synthesis by inhibiting dihydro-orotate reductase, decreases UMP

    *again, not much to say about this one*
  143. Alkylating agents
    Drug: Cyclophosphamide

    MOA: alkylates DNA, decreases B-celss, increases T-cell response, prodrug is converted to aldophosphamide

    ADR: production of acrolein leads to hemhorrhagic cystitis (Tx: mesna)
  144. Calcineurin inhibitors
    Normally cyclophilin binds calcineurin, leading to NFAT activation and IL2 production

    • 1. Cylcosporine
    •    MOA: forms a complex with cyclophilin which binds calcinuerin, inhibiting pathway
    • 2. Tacrolimus 
    •    MOA: binds FKPB which binds calcineurin, inhibiting pathway

    Uses: organ transplatation, RA, psoriasis

    Dose: combined with glucocorticoids and Azathioprine

    ADRs: nephrotoxic, tremor, hisrutism, hyperlipidemia, HTN, gingival hyperplasia, hyperglycemia

    Drug interactions: CYP inhibitors and inducers (3A4). Be careful with glucocorticoids as well (hyperglycemia)
  145. Sirolimus
    MOA: inhibits IL2 production by binding FKPB12 which binds mTOR, stops cells cycle at G1-S phase

    Uses: solid organ transplantation

    Dose: combined with caclineurin inhibitors and glucocorticoids

    Adverse: dyslipidemia, anemia, leukopenia, thrombocytopenia
  146. TNF alpha inhibitors
    Drugs: Etanercept, infliximab (partly humanized mouse monoclonal ab) and Adalimumab (human ab)

    Uses: RA, crohn's, and UC

    • Adverse: increased risk of infections and reactivation of latent infections. Must test patients for TB before use
  147. IL-1 and IL-6 inhibitors
    Drugs: Anakinra (IL-1 receptor antagonist) and Tocilizumab (IL-6 receptor antagonis) 

    Use: RA
  148. OKT3
    MOA: mouse monoclonal ab against human CD3, repid internalization of TCR and decrease in T-cell pool

    Dose: Used with steroids

    Use: acute transplant rejection

    Adverse: cytokine release syndrome (fever, myalgias, nausea, and diarrhea after administration)
  149. Rituximab
    MOA: part-humanized mouse monoclonal anti-CD20 ab

    Use: RA not responding to TNF-alpha inhibitors
  150. Levamisole
    MOA: increases immune system effects by increasing proliferation of T-cells, B-cells, monocytes, and macrophages

    Use: adjuvant with 5 fluorouracil after surgical resections in patients with colon cancer
  151. Thalidomide
    Use: erythema nodosum leprosum, multiple myeloma

    ADR: SEVERE birth defects
  152. Rho(D) immune globulin
    MOA: IgG with abs against RhD ag on surface of RBCs

    Use: prevention of hemolytic disease of the newborn in Rh (+) fetuses with Rh (-) moms. Administered unless it is known that the baby is also Rh(-)

    Doses: 2 doses before and after birth
  153. Bacillus Calmette-Geurin
    MOA: attenuated live culture of M. Bovis bacterium, actual MOA unclear

    Use: immune enhancer, management of bladder carcinoma in citue

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