Pharm Exam 7

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Pharm Exam 7
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  1. Age Related Changes to voiding system
    • 1. Decrease in bladder capacity
    • 2. Increase in involuntary bladder contractions
    • 3. Increase in post void residual
    • 4. Decrease in estrogen
    • 5. Prostatic hypertrophy
    • 6. Increase in fluid excretion at night, decrease in ability of kidney to concentrate, increase in free water loss
  2. Bladder: Normal values
    • 1. PVR < 50-100 ml (PVR > 200 ml = abnml)
    • 2. Variable volume/low pressure --> until urge to voice
    • 3. 300-600 ml = capacity
    • 4. Urge to void at 150 cc
    • 5. Urine velocity 20-25 ml/sec, <12-15 ml/sec is abnml, empty bladder within 20 seconds
  3. Drugs that extend or exacerbate urge incontinence
    • 1. Urinary Retention: Anticholinergics, antidepressants, antipsychotics, beta-adrenergic agonists, CCBs, Opiods
    • 2. Polyuria, frequency, urgency: EtOH, caffeine, diuretics
    • 3. Urethral Relaxations: Alpha-adrenergic blockers
    • 4. Muscle relaxation: Sedatives, hypnotics
  4. Medical Problems that cause urge incontinence
    • 1. Uncontrolled DM
    • 2. Bladder infxns
    • 3. Urinary retention
    • 4. Fecal impaction
    • 5. Restricted mobility (unable to get to bathroom
  5. Classification of Chronic UI in Men
    • 1. Overactive bladder
    • 2. Overflow incontinence
    • 3. Mixed incontinence
    • 4. Functional incontinence (secondary to dementia, parkinsons, CVA, etc)
  6. Overactive bladder (OAB)
    Cause: Detrusor muscle contraction --> involuntary or spontaneous --> patient attempts to suppress--> most cases without identifiable cause

    Sx: Frequency (> 8 times/day, urgency, and nocturia), normal PVR (usually) 

    Tx: Anticholinergics (block M2/M3 receptors in the bladder, decrease detrusor muscle contraction), others (botox, beta-3 adrenergic agonists)
  7. Oxybutinin (Ditropan and generic)
    MOA: Anticholinergic. Most lipophilic. 

    Use: Prototype ACH drug for UI. 

    Dose Form: short and long-acting oral tables, transdermal patch (available as OTC as Oxytrol for Women, applied every 4 days, must get Rx for men), and topical gel

    Adverse effects: ACH (dry mouth, etc) with short acting dose. Most adverse effects of ACH drugs for UI. Transdermal has lowest incidence of adverse ACH effects of three dosage forms. Least expensive agent (generic). 

    Cost: Oxytrol for men is $350 for 8 patches
  8. Tolterodine (Detrol and generic)
    MOA: Anticholinergic. More selective antagonists of M3 receptors in bladder than oxybutinin. Less lipophilic and somewhat less incidence of ACh affects than oxybutinin

    Metabolism: CYP 3A4 to active metabolite

    Dose: short and long acting oral tablets. Same efficacy. Less likely ACH effects with long acting forms
  9. Trospium (Sanctura and generic)
    MOA: Anticholinergic. Quaternary ammonium cpd. Does not cross BBB. Theoretically less CNS effects in elderly

    Metabolism: not by CYP 3A4

    Dose: Must be given 2x/day. Now available as generic ($70)
  10. Fesoterodine
    MOA: Anticholinergic. Prodrug which is metabolized to active product. Same active metabolite as tolterodine (Detrol).

    Metabolism: CYP 2D6 and 3A4. 

    Cost: $190/month
  11. Solfenacin (Vesicare)
    MOA: Anticholinergic

    Metabolism: 3A4. T1/2=60 hrs

    Dose: 1/day

    Adverse effects: Similar to other anticholinergic agents
  12. Darifenacin (Enablex)
    MOA: specific for M3 receptor

    Metabolism: CYP 3A4 and 2D6. T1/2=16 hrs
  13. Onabotulinumtoxin A (Botox)
    MOA: Botulinum Toxin. Blocks ACH release at NMJ of detrusor muscle. 

    Dose: IM injection into detrusor muscle during cytoscopy

    Adverse effects: Urinary retention, patients may need to self catheterize
  14. Mirabegron (Myrbetriq)
    MOA: Beta-3-adrenergic agonist for overactive bladder. Causes detrusor relaxation. No anticholinergic activity. (Only placebo controlled trials) 

    Adverse effects: Can increase BP

    Drug interactions: CYP 2D6 inhibitor

    Cost: $250/month
  15. Overflow incontinence
    Involuntary loss of urine related to overdistension of the bladder. 

    Sx: Frequent dribbling, urge/stress incontinence

    Cause: underactive/atonic detrusor or Outlet obstruction (BPH, prostate CA). Exacerbated by anticholinergic drugs. *PVR increased*

    Tx: Treat BPH and/or use intermittent or indwelling catheter
  16. BPH
    Prostate gland (composed of epithelial tissue) grows larger with age (under androgen control, 5-alpha-reductase at puberty causes rapid growth) --> pressure on urethra restricts urine flow --> compensatory hypertrophy of detrusor muscle (stromal tissue --> sm. mm. with alpha adrenergic receptors)

    Up to age 40, growth of prostate is balanced by cell death --> after 40? imbalance --> prostate may triple in size

    Sx: frequency, hesitancy, overflow incontinence 

    Chronic obstruction of ureters --> may result in kidney damage

    Tx: Non-selective alpha-1-adrenergic agonists, Selective alpha-1-adrenergic agonists, 5-alpha-reductase inhibitors, phosphodiesterase-5 inhibitors, herbal products
  17. Alpha-1-Adrenergic agonists for BPH
    MOA: Relax sm. mm. of bladder neck and prostate. Improve urine flow and reduce BPH Sx. 



    • Adverse effects: Avoid co-administration with PDE 5 inhibitors (Viagra and Levitra) --> 
    • severe hypotension
  18. Non-selective alpha-1-adrenergic agonists
    • 1. Terazosin and doxazosin
    •   MOA: primarily developed for HTN (now 3rd line for HTN)
    •   Adverse effects: require titration to limit orthostatic hypotension and reflex tachy. Dizziness, HA, drowsiness

    • 2. Alfuzosin (UroXatral) 
    •     MOA: new agent only for BPH
    •    Dose: Sustained release, more tolerable than above
    •    Metabolism: CYP 3A4 (avoid strong inhibitors)
    •    Adverse effects: may increase QT interval
  19. Selective-Alpha-1 Adrenergic Agonists
    • 1. Tamsulosin (flomax and generic) 
    •     MOA: Selective for receptors in prostate, very little effect on systemic vasculature. Less need of titration to prevent orthostatic hypotension
    •      Dose: 0.4 mg 1/day after meal. May increase 0.8 mg/day after 2 weeks

    • 2. Silodosin (Rapaflo)
    •      MOA: recently approved for BPH, similar in efficacy to tamsulosin
    •      Contraindications: CrCl < 30 ml/min, or patient is taking strong CYP 3A4 inhibitors

    Caution with these drugs: floppy iris syndrome after surgery
  20. 5-alpha-reductase inhibitors
    MOA: long term control of BPH. Reduce prostate volume, reduce circulating dihydrotestosterone, decrease severity of urinary Sx. Decrease PSA by 50% w/i 6 mos. 

    Adverse: pregnancy category X (should not be handled by women, can be absorbed through skin). Other adverse effects usually mild. May decrease libido, impotence, ED

    Drugs: Finasteride, Dutasteride, Dutasteride/tamulosin combo
  21. 5-alpha-reductase inhibitors
    • 1. Finasteride (Proscar and generic) 
    •    Dose: 5 mg/day with clinical response w/i 3-6
    •             mos. 
    •    *Also marketed as propecia for the Tx of alopecia in men* 

    • 2. Dutasteride (Avodart)
    •      Dose: 0.5 mg/day

    • 3. New approval: Dutasteride and tamulosin (Jalyn)
    •     Combination therapy with alpha-adrenergic antagonists is now considered safe and more effective than either class alone for BPH
  22. Herbal Products
    • 1. Saw Palmetto
    •    MOA: Active ingredient is beta-sitosterol which has antiandrogenic effect. Most effective products contain berry extracts w/ lipophilic solvents. 
    •    *Limited evidence suggests it may be as effects as finasteride* 
    •    Natural Medicins Comprehensive Database: rates as likely effective
    • Dose: 1-2 gm of whole berry or 320 mg/day of extract containing 80-90% fatty acids (not recommended as tea) 
    • JAMA study: no difference from placebo for BPH Sx.
  23. Prostatitis
    Pathogens usually similar to those causing UTI (ID by urine culture). Chronic prostatitis common cause of recurrent UTI in men

    Tx: Therapy for 4 weeks for acute and 6-12 weeks for chronicTMP-SMX usu. drug of choice unless contraindicated by allergy or drug interxns. Choose fluoroquinolones for gram-negative bacteria non sensitive to TMP-SMX
  24. Erectile Dysfunction
    Medications that cause ED: see slide 52
  25. PDE 5 inhibitors
    MOA: Tx of ED. PDE5 metabolized c-GMP, reducing cell concentrations of the enzyme --> causes a decrease in intracellular Ca2+ in arterial sm. mm. cells in the penis--> relax of arterial sm. mm. cells --> inflow of blood to intercavernosal trabeculae--> erection

    Originally studied in men who had ED secondary to organic or psychogenic causes for more than 5 yrs. Sexual stimulation required for response. Agents primarily differ in pharmacokinetic profile

    Other uses: Pulmonary arterial hypertension. Relaxes pulmonary vascular sm. muscle producing vasodilation of pulmonary blood vessels. Indicated of PAH to increase exercise ability. Different brand name but same drug interxns and contraindications. Use 20 mg of Sildenafil or 40 mg of Tadalafil

    Vision and Auditory adverse effects

    Vision disturbances in 3% --> blurred vision, blue-green tinged vision, blue halo effect secondary to PDE6 inhibition in retina --> more common with higher doses. Less likely with Tadalafil (Cialis)

    NAION- Nonarteritic ischemic optic neuropathy --> sudden onset of blindness secondary to reduce blood supply to optic nerve. No known way to prevent or treat. 14 cases with viagra, also occurs with other PDE5 inhibitors. Patients > 40 yo undergo opthalmologic screening for small cup/optic disc ratio before PDE5 inhibitors

    Sudden hearing loss
  26. Sildenafil (Viagra)
    MOA: PDE 5 inhibitor. 1st developed. 

    Kinetics: metabolized by CYP 3A4. T1/2=4 hrs, peak effect delayed by 60 mins with high fat meal

    Dose: 24,50, 100 mg tablets. Start with 50 mg 1 hr before sex. Do not take more than once/day. Increased dose = increased efficacy

    Adverse Rxns: HA, facial flushing, nasal congestion, dyspepsia. Sever effects: priapism, hearing loss, vision disturbances, vision loss. Increase with dose. 

    Drug interactons: Contraindicated w/ nitrates such as NTG, isosorbide (NTG action potentiated). Caution with alpha-adrenergic blocking agents (hypotension). Caution with CYP 3A4 inhibitor agents that may increase drug levels and incidence of adverse effects. 

    Cost: $14/label
  27. Vardenafil (Levitra)
    MOA: PDE5 inhibitor. Very little difference from sildenafil. 

    Kinetics: Slightly longer T1/2 than sildenafil

    Dose: 2.5, 5, 10, 20 mg tablets. Usually starts with 10 mg, taken 1 hr before sex
  28. Tadalafil (Cialis)
    MOA: PDE5 inhibitor

    Kinetics: metabolized by CYP 3A4. T 1/2 = 18 hrs. Time to peak levels=2 hrs. Duration of effect: up to 36 hrs. 

    Dose: 5, 10, and 20 mg tablets. Usually 10 mg 1-2 hrs before sex

    Adverse effects: flushing, HA, congestion, dyspepsia. Unique: back pain or muscle aches due to PDE11 inhibition in skeletal muscles. Vision disturbances rare. 

    Other uses: just approved by FDA for signs and Sx of BPH in men w/ or w/o ED. May be drop in BP if added to alpha1blocker therapy. Medical letter: participants in double blind trials may have known whether they were taking the active drug or the placebo
  29. Male Hypogonadism
    • 1. Primary hypogonadism --> late onset or "andropause". Slow loss of testosterone is a natural part of the agin process in males. 
    •    Sx: loss of libido, impotence, loss of muscle mass and strength, fatigue, depression, inability to concentrate

    2. Secondary hypogonadism --> caused by obesity, metabolic syndrome, DM, and some medications

    Tx: Testosterone replacement therapy. Only Tx in men w/ clinical Sx and unequivocally low T levels (<200 ng/dL) 
  30. Testosterone Replacement Therapy
    • Products (C-III). 
    •    1. Oral (rarely used --> hepatic effects) 
    •    2. Depot injections (every 2-4 wks) 
    •    3. Transdermal patch
    •    4. Transdermal gel (androgel, fortesta, 
    •        testim) to arm, shoulder, abdomen
    •    5. Trandsermal gel (axiron) to underarm
    •    6. Subcu pellets
    •    7. Buccal tablet

    Evidence: most studies non-randomized, poor quality, short duration. Recommendations made based on expert opinion. Only 1 randomized placebo controlled trial (2010) that was halted early due to increased CVD in testosterone group. Large trial by National Institute of agin to be completed in 2014

    Adverse effects: increase in prostate and breast CA, increase in prostate growth, polycythemia, infertility, hepatic toxicity, cardiovascular toxicity, thrombophlebitis, lower HDL
  31. Pain
    • 1. Nociceptive Pain: concious experience of noxious stumulus
    •       a. transduction - tissue damage releases 
    •           PGE2, bradykinin, substance P, 
    •           histamine (sensitizing)
    •       b. Transmission- impulse --> brainstem
    •           --> cortex via NTs such as substance P
    •           and glutamate
    •       c. Perception of pain
    •       d. Modulation --> pain impulses changed 
    •           or inhibited by endogenous opioids, 
    •           serotonin, norepinephrine, GABA
    • 2. Inflammatory pain: prevents movement until healing is over. Mediated by PGE2 (sensitizing) 
    • 3. Neuropathic pain: caused by damage to the nervous system --> disturbance of function. May be central or periphseral. Ex. Diabetic neuropathy, phantom limb...
    • 4. Functional pain: pain with no pathology. Abnormal response of nervous system. Ex. Fibromyalgia
  32. Classes of Analgesics
    • 1. Non-opioid: acetaminophen, salicylates, NSAIDs (non-selective/selective COX 2 inhibitors
    • 2. Opioid: Agonists, partial agonists, antagonists

    3. Adjuvant agents: antidepressants, anticonvulsants, Local anesthetics
  33. Acetaminophen (Tylenol, paracetamol)
    MOA: exact mechanism of analgesia still unknown. Weak COX 1 and 2 inhibitor in pheriphery and COX 3 in brain (stops PGE synthesis) 

    Use: Analgesis, Antipyretic, no anti-inflammatory activity. Used by 23% of US adults in any given week

    Metabolism: Major pathway --> conjugation to metabolites excreted in urine. Minor pathway --> P450 oxidation producing toxic intermediate which is detoxified by conjugation with glutathione

    Dose: Capsules, tablets, suppositories, solution 80-500 mg (extra strength), 650 mg (Tylenol Arthritis Strength). Pediatric liquid (160 mg/5 ml). Combined with opioids such as oxycodone (Percocet), hydrocodone (Vicoden), and codeine (Tylenol #3). Adults: not to exceed 4 gm/day (give every 4-8 hrs). Do not exceed 3 gm/day in elderly, in kids 10-15 mg/kg every 4-6 hrs. 

    Adverse effects: generally safe at therapeutic doses, no effect on bleeding time or GI tract, potential for renal tubular necrosis with chronic dosing. 

  34. Acetaminophen Hepatotoxicity
    Hepatoxocity:Acute or chronic overdose (>4gm/day), Therapeutic  dosing w/risck factors such as ethanol abuse, pre-existing liver disease, and other hepatotoxic drugs. Conjugation pathways saturated --> glutahione stores in liver deplete --> toxic metabolite binds to hepatocytes --> necrosis. 

    Antidote is N-acetylcysteine--> restores glutathione. Best if given w/i 8 hrs of injestion (140 mg/kg loading dose orally than 70 mg/kg every 4 hrs x 17 doses or IV Acetadote given over 21 hrs)
  35. Ofirmev
    IV Acetaminophen approved in 2011 for adult pts after abd surgery. 

    Max serum conc. 70% higher than same dose of oral tylenol. More effective than placebo. Reduced use of morphine (still necessary). 


    Dose: 1000 mg every 6 hrs or 650 mg every 4 hrs to max of 4000 mg/day. Available in 100 ml vial (10 mg/ml). Infused over 15 mins
  36. NSAIDs
    MOA: inhibit COX-1 and/or COX-2 to prevent PGE synthesis. Includes salicylates

    Use: pain relief (HA), fever, inflammatory conditions (arthritis), primary dysmenorrhea

    • Doses:
    • A. Low doses comparable to 650 mg of acetaminophen (extra strength) for pain. Ibuprofen 200 mg, Naproxen 250 mg
    • B. Moderate doses comparable to acetaminophen/hydrocodone combinations for pain. Ibuprofen 400 mg, Naproxen 500 mg
    • C. High doses for anti-inflammatory effect. Ibuprofen 1800-2400 mg/day. Naproxen 1000 mg/day
    • OTC only for ibuprofen 200 mg and naproxen 250 mg strengths
  37. Parenteral NSAIDs for pain
    • 1. Ketorolac (Toradol). Given IV or IM. Indicated for pain relief. High dose comparable to morphine. Cannot use > 5 days --> high incidence of GI ulceration and bleeding. Not indicated for osteoarthritis or rheumatoid arthritis. 
    • 2. Ibuprofen (Caldolar)- FDA approved in 2010. IV infusion that is not limited to 5 days like ketorlac
  38. Opioids
    Opium --> 20 different alkaloids, 10% morphine. Word Opioid: morphine like drugs, natural or synthetic, agonist or antagonist.

    AKA narcotics (nonpharmacologic term that can encompass many sedating drugs)

    Opioid receptors. 

    • Endogenous peptides modulate pain perception --> enkephalins and endorphins 
    • --> act on mu, kappa, and delta receptors. Functions vary depending on type and location (CNS, GI, bladder). Agonists and antagonists for all receptors exist. Agonists may have full or partial activity

    Adverse effects: Respiratory depression (most toxic, dose dependent). Sedation. Constipation, N/V, itching, urinary retention

    *see charts for opioid dosage equivalents on Slide 52*

    Therapeutic Window: maintain opioid level which lies inside TI. Above upper parameter "hungover" and under lower parameter "breakthrough pain"
  39. Conversion algorithm for Switching opioids
    Add up total daily opioid dose --> use equinalgesic dosing chart --> reduce dose by 50% to offset incomplete cross-tolerance --> divide  daily dose based on drug and dosage form --> if long-acting dose Rx IR dose for breakthrough pain. 

    Ex: Transdermal Fentanyl Conversion. 1:2:3 ratio of mgs daily IV morphine, to the hourly mcg of fentanyl, to the mgs daily oral morphine. 

    Ex switching from oral opioid to methadone: see MEDD chart on slide 56
  40. Alternative Opioid delivery techniques
    PCA pump --> usu. morphine, preprogrammed basal IV dose, self bolus dose, and lockout period

    Epidural--> usu. fentanyl + anasthetic) 

    Patient controlled epidural analgesia --> for labor
  41. Opioid Agonists
    • All have similar pharmacodynamic activities. 
    •    - stimulate mu (endorphin) receptor for              analgesia
    •    - Also cause respiratory depression,                euphoria, constipation, and dependence
    •    - Apparent differences in potency                    explained by correcting physiochemical
    •      and pharmacokinetic differences

    All opioids can be made equianalgesic by correcting for dose and route of administration. Conversion factors are just guidlines (not actual rules ;). Individual variation in first pass metabolism and cross tolerance. 

    Strong agonists for moderate to severe pain. Ex. Morphine, Oxycodone, Oxymorphone, hydromorphone, Meperidine, Fentanyl, Methadone

    Moderate to weak opioid agonists used for mild to moderate pain, higher doses for severe pain will cause excess adverse effects. Ex. Codeine, hydrocodone, tramadol, propozyphene.
  42. Morphine.
    Standard that all opioids are compared to. Greatest variety of dosage forms. 

    Metabolism: First pass to H20 active metabolites that are renally excreted

    • Dose: Parenteral/oral dose ratio. 1/3 for chronic pain, 1/6 for acute pain. Reduce dose by 25% in elderly or during renal failure (accumulation of metabolites) Injection 1-50 mg/ml. 
    •       - Immediate release (q4 hrs). Tablets, 
    •         capsules, solutions, rectal suppositories
    •       - Extended release (MS Contin q 12 hrs)
    •         30-200 mg.
  43. Oxycodone
    Oral Dosage form (C-II).

    Metabolism: CYP 3A4. Avoid strong inhibitors. 

    Dose: 20-30 mg = 30 mg oral morphine. Immediate release: 5 mg, Extended release (Oxycontin): 10-80 mg. Combined with acetaminophen (percocet): 5 mg + 325 mg

    Side effects: none, dose limiting. 

    Adverse: reduce does if CrCl < 60 ml/min. High cost. Oxycontin abuse.
  44. Hydromorphone
    Shorter acting and more potent than morphine. 

    Dose: Poor oral potency. 1.5 mg iv = 7.5 mg PO. Available as rectal suppository (3mg). Useful if morphine tolerant. Dilaudid-HP: 10 mg/ml injection. Can be given continuous SC.
  45. Oxymorphone (Opana).
    Oral dose approved by FDA in 2006. A minor metabolite of oxycodone. 10% bioavailability. 

    Dose: 10 mg = 30 mg oral morphine.  Available as IR tablets (5 and 10 mg) or ER tables (5,10,20,40 mg). 

    Adverse (he calls these dangers): heavily marketed and very expensive, crushed and gien IV may be equivalen of 100 mg morphine IV (OVERDOSE). Food increases peak plasma concentration by 50% and alcohol by 200%.
  46. Meperidine (Demerol)
    Synthetic opioid with low oral bioavailability (not useful as oral agent). 


    Short T1/2. 

    Morphine: 10 mg iv= Demerol 75 mg iv= Demerol 300 mg PO. 

    Adverse effects: toxic metabolite (normeperidine) renally excreted. T1/2 16-30 hrs. Accumulation with oral dose, renal dysfunction, can cause neurotoxicity/seizures. Drug interaction with MAO inhibitors.
  47. Hydrocodone
    MOA: similar to codeine, but only available orally. 30-45 mg= 30 mg oral morphine

    Dose forms: Combinations with acetaminophen (CIII) vicodin and lortab. Cough preparations have 2.5-5 mg (CIII)

    Adverse effects: higher abuse potential than morphine due to metabolism by CYP 2D6 and CYP3A4.
  48. Tapentadol
    MOA: similar to tramadol. FDA approved in 2009. Weak agonist/reuptake inhibitor (mu-receptor, NE reuptake). Possibly effective for neuropathic pain

    DEA: schedule II. Very little experience so far
  49. Tramadol
    MOA: weak agonist/NT reuptake inhibitor. Unique analgesic activity --> binds weakly to mu-receptor + inhibits 5HT and NE reuptake

    Metabolism: CYP2D6

    Adverse effects: nausea, dizziness, CNS excitation rather than sedation. Increased risk of seizure at high doses/patients with head injury/taking drugs that lower seizure threshold

    Dose forms: 50-100 mg

    Drug interactions: CYP2D6 inhibitors. Seritonergic syndrome

    Adverse effects: potential for dependence (no DEA controls). Less effective than Vicoden for acute pain when combined with acetaminophen
  50. Propoxyphene (Darvon)
    MOA: structurally related to methadone. Mild analgesic (65 mg = 650 mg Tylenol)

    • Metabolism: Accumulation of metabolite with chronic dosing. T1/2=12 hrs. Norpropoxyphene=24-36 hrs
    • (cardiotoxic).

    • Dose forms: propoxyphene HCL 65 mg, Darvocet N 100 (100 mg PN + 650 mg Tylenol)
    • Removed from market in 2010 (still in Brenner textbook).
  51. Codeine
    MOA: methyl derivative of morphine

    Metabolism: CYP2D6 (polymorphisms and drug interactions)

    Use: usually combined with non-opioid

    Adverse effects: dosing limited due to adverse effects. Nausea, vomiting, and constipation. Antitussive action.
  52. Methadone
    MOA: synthetic opioid

    Kinetics: long T1/2, but analgesic duration only 4 hours. Accumulates w/ repetitive dosing leading to delayed side effects and potential overdose. CYP3A4. 

    Adverse effects: QT interval prolongation at higher doses. Only prescribed by pain experts. Good oral potency.
  53. Butorphanol
    MOA: Partial Agonist-Antagonist. Similar to pentazocine (Talwin). For migraine and post-operative pain

    Dose: transnasal delivery  w/ onset and duration similar to IM. 15 doses/spray pump
  54. Fentanyl
    50-100x more potent than morphine

    Dose forms: Short acting injectable (anasthesia), Transdermal patch (chronic pain, 16 hrs for initial effects, effects last 2-3 days, multiple strengths). Oral transmucosal lozenge (breakthrough cancer pain). Oral effervescent buccal tablet (breakthrough cancer pain) 

    Metabolism: CYP 3A4. Avoid strong inhibitors
  55. Naloxone (Narcan)
    MOA: pure opioid antagonist displacing opioid from receptor site. Immediate reversal of opioid effect. Can also precipitate severe withdrawal Sx if opioid dependent. 

    Metabolism: T1/2=1hr. 

    Dosing: 1 ml + 9 ml NS over SLOW IV push. May need to repeat for longer acting opioids
  56. Naltrexone (Vivitrol)
    MOA: long-acting pure opioid antagonist

    Dose: Extended release injectable suspension. Approved for Tx of EtOH dependence given over 12 wk course to lower cravings. 380 mg IM once monthly. Must be opioid free for 7-10 days

    *new approval for prevention of relapse to opioid dependence following opioid detoxification
  57. Consequences of long term opioid therapy
    Tolerance and cross tolerance, physical dependence and W/D, addiction, pseudoaddiction

    Dependence and W/D Sx: Rhinorrhea, lacrimation, hyperthermia, myalgia, emesis, diarrhea, GI camping, Anxiety, agitation, hostility, sleeplessness
  58. Adjuvant Analgesic Agents
    MOA: indicated for conditions other than pain, but have analgesic properteis from some painful conditions

    •         -Antiepilipetic
    •         - Anti-depressants
    •         - injectable gluco
    •         - topical gluco
    •         - Topical anisthetics
  59. Controlled substances
    Schedules based on potential for abuse and dependence

    • Schedule I (heroin, LSD) 
    • Schedule II (morphine, codeine, oxycodone, amphetamines) --> DEA number and written Rx req'd except in emergency. ED can only Rx 7-days
    • Schedule III (acetaminophen with codeine or hydrocodone --> refills allowed, up to 5 or 6 moths for schedule III-IV
    • Schedule IV (benzos, phenobarbital, chloral hydrate, propoxyphene) 
    • Schedule V (arcotic cought/anti-diarrheal)
    • Schedule VI: all other Rx drugs
  60. Opiates as Oral Antitussives
    MOA: act centrally on respiratory center in the brain to increase the cough threshold

    Meds: Codeine (gold standard, lower dose than for analgesia, combined with guaifenesin, Robitussin AC). Hydrocodone (chlorpheniramine). Dextromethorphan (weak opiate properties, most common OTC cough suppressant. ADE: CNS, respiratory depression, N/V, constipation, robo-tripping, psychosis, mania)
  61. Headache Classification
    • Primary -
    • Migraine
    • Tension-type
    • Cluster

    • Secondary -
    • Infection
    • Stroke
    • Tumor

    Prevalence - 24 millions in US affected by migraine alone
  62. Migraine - Diagnosis and Presentation
    • At least two of the following features
    • Unilateral location
    • Throbbing character
    • Worsening pain with routing activity
    • Moderate to severe intensity

    • At least one of the following features
    • Nausea/vomiting
    • Photophobia and phonophobia

    • Attacks set off by triggers:
    • Smell, chemicals, flickering lights, hormonal changes, menstruation, stress, alcohol, chocolate, caffeine, MSG, etc

    • Visual or sensory aura precedes attacks in 15% of patients:
    • Areas of repressed or no vision within visual field
    • Seeing zigzag lines
  63. Migraine  - Pathophys
    Stimulation of the brainstem by triggers leads to release of various peptides, such as substance P, from the trigeminal neurovascular system

    Peptides cause inflammation and vasodilation of meningeal blood vessels

    This in turn causes stimulation of nociceptive fibers of the trigeminal nerve, resulting in pain sensation
  64. Acute Pain Management - Mild to moderate migraine attacks
    • Acetaminophen
    • NSAIDs
    • Prescribing combincations combining acetaminophen or aspirin with caffeine & butalbital

    • Isometheptene combinations:
    • acetaminophen, isometheptane, and dichloralphenphenazone (C-IV) = Midrin
    • May be removed by FDA soon
  65. Acute Pain Management - Moderate to severe migraine
    • Migraine specific drugs
    • Serotonin receptor (5-HT 1b/1d) agonists
    • (drugs of choice)

    • Ergot alkaloids
    • Dihydroergotamine
    • Ergotamine

    Opiods or opiod combinations

    If nausea - use non-oral dosage form
  66. Therapeutic Strategies for Migraine Headache
    • Abortive Therapy
    • Analgesic Therapy
    • Anti-emetic Therapy
    • Prophylactic Therapy
  67. Abortive Therapy for Migraines - Triptans
    • Almotriptan
    • Eletriptan
    • Frovatriptan
    • Naratriptan
    • Rizatriptan
    • Sumatriptan
    • Zolmitriptan

    Mechanism of action - Serotonin 5HT1b/1d agonists

    Serotonin is a potent cerebral vasoconstrictor

    Also decreases neuronal excitability and release of inflammatory neuropeptides

    Work at dura and brain stem level of brain

    All generally similar in efficacy

    Differ in dosage form available, onset/duration of action and in metabolism and potential drug interactions
  68. Sumatriptan
    Prototype triptan - first one marketed, still most prescribed

    SC, nasal, or oral dosages

    • Adverse:
    • Tingling, flushing, dizziness, drowsiness, fatigue
    • Burning sensation at injection site
    • Coronary vasoconstriction -> angina, MI
    • Contraindicated in patients with CAD or uncontrolled hypertension

    • Drug Interactions:
    • Other triptans or ergot alkaloids within 24 hrs
    • MAOIs within 2 weeks
    • SSRIs and other serotonergic drugs -> serotonin syndrome
  69. Sumatriptan vs Other Triptans
    Rizatriptan - MLT is a wafer that disintegrates without wafer (does NOT have faster onset than tabler)

    Zolmitriptan also available as nasal spray

    • Naratriptan and frovatriptan have longer half-life (6-24 hrs vs 2-3 for sumatriptan)
    • Onset and duration of action longer than other triptans

    Pregnancy category C for all triptans
  70. Ergot Alkaloids
    Abortive Therapy for Migraines

    • Derived from fungus that grows on rye and other grasses
    • St. Anthony's Fire - secondary to eating contaminated grasses

    Mechanism - nonspecific serotonin, dopamine, and adrenergic receptor agonists

    Dihydroergotamine mesylate - preferred

    Ergotamine tartrate

    • Adverse Effects:
    • Nausea and vomiting common and often require pretreatment with antiemetic

    Potential vascular ischemia/occlusion and gangrene (ergotism) necessitate dosage limits

    Contraindicated in CAD

    • Drug Interactions:
    • Contraindicated with any strong inhibitor of CYP 3A4 enzyme system
    • Macrolide antibiotics, azole antifungals, diltiazem, verapamil, protease inhibitors

    Pregnancy category X - causes uterine contractions
  71. Analgesics for Migraines
    May be suficcient for mild to moderate migraine attacks

    Addition of metoclopraminde during acute attack can increase gastric motility and enhance absorption

    • Acetaminophen combinations
    • Fiorcet - acetaminophen, bulabital, caffeine
    • Butalbital not shown to be effective for migraine and associated with tolerance and dependence

    • OTC NSAIDs
    • Ibuprofen FDA approved for migraine attacks
    • Motrin migraine - ibuprofen 200mg

    Opiods

    • Butorphanol nasal spray
    • Opiod mixed agonist/antagonist
  72. Excedrine Migraine vs Sumatriptan
    Excedrin Migraine more effective than sumatriptan or placebo
  73. Medication Overuse Headache
    • Formerly known as "rebound headache"
    • Secondary to use of triptans, ergot alkaloids, opiods, or combincation analgesics for more than 10 days per month or use of acetaminophen or NSAIDs for more than 15 days per months

    More likely with use of butalbital or opiods

    Common pattern is escalating doses of drugs that initially worked at lower dose

    Typically presents as tension-type headache with neck pain

    • Headache symptoms will abate when drug is discontinued or tapered
    • Triptans/NSAIDS usually can be stopped
    • Opiods, butalbital, and caffeine must be tapered

    During taper, use alternative agent

    • Prevention:
    • Limit use of triptant and ergot alkaloids to no more than 10 days per month
    • Avoid use of opiods, butalbital, and caffeine
  74. Antiemetic Therapy for Migraines
    Prochloperazine 10 mg slow IV push

    Metoclopramine - increases gastic motility by blocking Dopamine D2 receptors

    • Increases oral drug absorption
    • Antiemetic with ergot alkaloids
    • 10mg Oral or IV
    • Adverse Effect: EPS
  75. Oral Contraceptives and Migraine
    Current recommendations are to avoid estrogen containing contraceptives in women with migraines, especially if an aura is present.

    Evidence for increased risk of stroke in this group goes back to the 1970’s when high doses of ethinyl estradiol (50 mcg) were used in COCs

    Recent evidence suggests that COCs with low dose ethinyl estradiol (< 20 mcg) are safe if women are < 35 years old, do not smoke, or do not have high blood pressure

    Menstrually associated migraines (MAM) are related to a low level or sudden drop in estradiol. COCs are effective in stopping the migraines, especially the extended cycle formulations
  76. Migraine Prophylaxis Therapy
    First line drugs - FDA approval for prophylaxis:

    • Beta blockers:
    • propranolol, metoprolol, and
    • timolol

    Limited evidence for other beta blockers

    • Tricyclic antidepressants: amitriptyline, nortriptyline
    • Valproic acid derivatives (Depakote and Depakene)

    • ADE:
    • nausea, drowsiness, tremor, weight gain, alopecia
    • Topiramate (Topamax)

    ADE: paresthesias, fatigue, nausea, anorexia

    Adverse effect profiles limit long-term usefulness of anticonvulsants

    Botox pericranial injections approved for patients with chronic migraine (> 15 headache days/mo for > 3 mo)

    • Second line drugs – not FDA approved
    • Amitriptyline
    • Venlafaxine
    • Triptans for menstrually associated migraine (MAM)
    • ACE inhibitors
    • ARBs
    • Clonidine
    • Cyproheptadine (an antihistamine)

    Methysergide (ergot alkaloid) removed from market secondary to toxicity - still in textbook
  77. Migraines - Children and Adolescents
    • Very limited information
    • Acute tx based on evidence
    • Ibuprofen
    • acetaminophen
    • sumatriptan nasal ONLY

    • Prophylactic TX
    • Propanolol - identified Cochrane review as only drug showing improvement compared to placebo
    • Insufficient evidency to recommend any other tx
  78. Migraines During Pregnancy
    Acute treatment

    • Triptans are Category C, but there does not appear to be an increased risk of birth defects
    • Acetaminophen and opioids are commonly used
    • Avoid NSAIDS in 3rd trimester
    • Avoid opioids late in 3rd trimester
    • Ergot alkaloids are Category X

    • Preventive therapy
    • Not recommended
    • Anticonvulsants, such as valproate and topiramate, are strongly associated with birth defects
  79. Herbal Supplements for Migraines
    • Feverfew leaves
    • Butterbur root
    • Riboflavin
    • Coenzyme Q10
  80. Tension-Type Headache
    Most common type of primary headache

    Presentation: bilateral pain of non-throbbing quality not aggravated by physical activity

    • Treatment:
    • Relaxation therapy, physical therapy, stretching
    • Acute: OTC analgesics
    • Preventative: TCAs or SSRIs have been used
  81. Cluster Headache
    Attacks occur daily for a period of weeks or months separated by intervals of months or years - often precipitated by alcohol or volatile substances

    • Presentation
    • Severe unilately pain, usually around eye, with tearing - patients tend to pace and apply pressure to eye

    • Treatment
    • Acute: Oxygen therapy works best - also triptans and ergot alkaloids
    • Preventative: verapamil, lithium, anticonvulsants
  82. Older Antiepileptic Drugs (for funzies)
    • Available prior to 1990
    • More experience, known efficacy, less expensive (generic), but many patients either fail therapy or cannot tolerate adverse effects
    •       (aka: cheap but more adverse effects)

    • Carbamazepine (Tegretol)
    • Phenytoin (Dilantin) and fosphenytoin (Cerebyx)
    • Valproate: valproic acid (Depakene) or divalproex sodium (Depakote)
    • Ethosuximide (Zarontin)
    • Phenobarbital
    • Primidone (Mysoline)
  83. Newer Antiepileptic Drugs (for funzies)
    • Since 1990
    • Gabapentin (Neurontin)
    • Pregabalin (Lyrica)
    • Topiramate (Topamax)
    • Zonisamide (Zonegran)
    • Oxcarbazepine (Trileptal)
    • Lamotrigine (Lamictal)
    • Levetiracetam (Keppra)
    • Tiagabine (Gabitril)
    • Felbamate (Felbatol)
    • Clonazepam (Klonipin)
    • -------------------------------
    • Since 2009
    • Lacosamide (Vimpat)
    • Vigabatrin (Sabril)
    • Ezogabine (Potiga)
    • Clobazam (Onfi)
  84. Mechanism of Action of AEDs (in general)
    • AEDs may have one or more of the following mechanisms of action:
    • 1.Prolong inactivation of sodium channels to delay neuronal cell depolarization
    • 2.Block T-type calcium channels
    • 3.Facilitate GABA neurotransmission by binding to GABA receptor subtype
    • 4.Increase GABA release
    • 5.Inhibit GABA degradation
    • (#3-5 are methods of inc GABA)
  85. Principles of Antiepileptic Drug Selection
    • Primary choice is based on seizure classification
    • Drugs of choice are equally effective in preventing seizures
    • Monotherapy preferred to polytherapy
    •      Majority of patients can be controlled on one drug
    •      Lower costs
    •      Less lab monitoring
    •      Lower incidence of adverse effects and drug interactions
    •      Better compliance
    • Adjunctive therapy should only be tried after 2-3 primary drugs have failed
    • Select least sedating agents, if possible
    •      Most sedating are:
    •          –Phenobarbital
    •          –Primidone
    •          –Benzodiazepines
    • Select agent least likely to cause drug interactions for patient
    • Initiating
    •      Start with low dose and slowly escalate for effect
    •      Adverse effects most often seen at start of therapy with AEDs
  86. Principles of Antiepileptic Drug Usage
    • Plasma drug monitoring
    •      Documents concentration associated with good seizure control
    •      Helps evaluate noncompliance
    •      Essential when combining enzyme inducers and inhibitors
    •      Usually obtain in morning before 1st dose, after steady state reached
    • Withdrawal
    •      Consider discontinuing AED if seizure free for over 2 years
    •      Must gradually reduce dose over 1 to 3 month interval
  87. Primary Antiepileptic Drugs
    • Carbamazepine
    • Oxcarbazepine
    • Phenytoin
    • Valproate
    • Topiramate
    • Levetiracetam
    • Lamotrigine
    • Gabapentin
    • Ethosuximide
    • -----------------------
    • Rarely used: (but mb still on boards)
    • Phenobarbital
    • Primidone
  88. Adjunct (Add-on) Antiepileptic Drugs
    • Pregabalin
    • Zonisamide
    • Lacosamide
    • Ezogabine
    • Clobazam
    • Vigabatrin
    • Tiagabine (rarely used)
    • Felbamate (rarely used)
  89. Carbamazepine (Tegretol)
    • Use in Epilepsy: partial and secondarily generalized T-C seizures
    • MOA: blocks sodium channels
    • Kinetics:
    •      Metabolized by CYP 1A2 and 3A4
    •      Undergoes autoinduction resulting in decrease in T ½ from 30 hrs to 12 hrs over 1st month. (AKA: induces its own metabolism)
    •      Must slowly increase dose to keep therapeutic.
    • Dosage forms: IR and ER tablets and suspension
    • Adverse effects:
    •       Dose-related: nausea, sedation, diplopia, dizziness, weight gain
    •      Severe/idiosyncratic: rash (5%), leukopenia (10%), SLE, aplastic anemia, SIADH and hyponatremia
    • Risk of Stevens-Johnson syndrome is 10-fold in Asian population – must be genetically screened for HLA-B*1502 allele
    • Effect on CYP 450: induces 2C9, 2C19, 3A4 (lots drug interactions)
    • Drug Interactions: multiple
    • Monitoring: CBC at baseline and every 2 weeks for 1st 2 months, then q 3 months
    • Pregnancy Category: D
    • Aggravates: absence and myoclonic seizures
    • Other Uses: trigeminal neuralgia, neuropathic pain, bipolar disorder
    • Generic available
  90. Strong inducers of CYP450 enzymes
    see AED lecture slide 19
  91. Oxcarbazepine (Trileptal)
    • Use in Epilepsy: partial seizures
    • MOA: analog of carbamazepine with similar effects
    •      But causes less CYP 450 enzyme induction (but not none)
    • Kinetics:
    •      Metabolized by liver to active 10-monohydroxy metabolite (MHD) which is renally eliminated with T ½ = 8 hrs.
    •       Does not undergo autoinduction
    •       CYP 450 substrate: none
    • Dosage forms: tablet and suspension
    • Adverse effects:
    •      Dose-related: headache, somnolence, dizziness, nausea
    •       Severe/idiosyncratic: hyponatremia (3%), rash (cross sensitivity with carbamazepine in 20-30% of patients)
    • Effect on CYP 450: induces 3A4 (weaker than carbamazepine)
    • Drug Interactions:  phenytoin, oral contraceptives
    • Monitoring: serum sodium
    • Pregnancy Category: C (should be D?)
    • Aggravates: myoclonic and absence seizures
    • Other Uses: bipolar disorder
    • Generic available
  92. Phenytoin (Dilantin) and  Fosphenytoin (Cerebyx)
    • Use in Epilepsy: partial and secondarily generalized seizures
    • MOA: blocks neuronal sodium and calcium channels
    • Kinetics:
    •      Highly bound to albumin.
    •      Exhibits zero-order kinetics at upper end of dose range due to saturation of metabolizing enzymes. T ½ can vary from 1 day to 5 days depending on saturation.
    •      Loading dose necessary at start of therapy
    •      CYP 450 substrate: 2C9 and 2C19
    •      *phenytoin serum levels based on drug dose are VERY unpredictable--if change doses, make small changes
    • Dosage forms:
    •      Free phenytoin acid in chewable tablets and suspension
    •      Sodium phenytoin in capsules
    •          –Contains 92% phenytoin acid
    •          –Dilantin Kapseals only product approved for once daily dosing
    • Dosage forms:
    •       Fosphenytoin (Cerebyx) – water soluble injection that is prodrug of phenytoin and can be given IM or IV (better abs than phenytoin)
    •             –Has replaced phenytoin sodium injection
    • Plasma drug levels: must adjust value (Cp) for low albumin levels
    •       Cp adj = Cp / [(0.2 x alb) + 0.1]
    •       Narrow therapeutic range of 10-20 mcg/ml
    • Adverse effects:
    •      Dose-related: nystagmus, diplopia, dizziness, drowsiness
    •      Severe/idiosyncratic: dyskinesias, gingival hyperplasia, facial coarsening, vitamin deficiencies, severe rash
    • Effect on CYP 450: induces 2C9, 2C19, 3A4
    • Drug Interactions: inducers/inhibitors of CYP 2C9 and 2C19
    • Monitoring: plasma drug levels at regular intervals
    • Pregnancy Category: D
    • Aggravates: absence seizures
    • Other Uses: trigeminal neuralgia
    • Generic available
  93. Valproate (Depakene and Depakote)
    • Use in Epilepsy: all types of seizures
    • MOA: blocks sodium and calcium channels, increases GABA transmission
    • Kinetics: metabolized by liver with T ½ = 12 hrs
    •      CYP 450 substrate: 2C9, 2C19 (my notes: ex of drugs metabolized by these CYPs: warfarin & phenytoin, respectively)
    • Dosage forms:
    •      Valproic acid (Depakene and generic)
    •      Divalproex sodium (Depakote and Depakote ER).
    •       Depakote ER dose 20% higher than Depakote
    •       Both Depakene and Depakote dissociate to valproate in GI tract
    • Adverse effects:
    •       Dose-related: nausea, vomiting, tremor, drowsiness, sedation (must slowly titrate dose)
    •      Severe/idiosyncratic: alopecia (10%), weight gain (50%), hepatotoxicty, thrombocytopenia
    •      (lots)
    • Effect on CYP 450: inhibits 2C9, 2C1
    • Drug Interactions: lamotrigine, phenytoin, carbamazepine
    • Monitoring: liver function tests and platelet count every month for 1st two months, then every 3-6 months
    • Pregnancy Category: D
    •       *new warning: lower IQ in kids of mothers who took valproate during pregnancy
    • Other Uses: bipolar disorder, migraine prophylaxis, trigeminal neuralgia
    • Generic available
  94. Pregnancy warning for Valproate (Depakene and Depakote)
    • new warning: lower IQ in kids of mothers who took valproate during pregnancy
    •       lower compared to other AEDs
  95. Topiramate (Topamax)
    • Use in Epilepsy: partial and generalized T-C seizures
    • MOA: blocks sodium channels and activates GABA receptors
    • Kinetics:
    •       Renally eliminated with T ½ = 24 hrs
    •       CYP 450 substrate: none
    • Dosage forms: tablet and sprinkle capsule
    • Adverse effects:
    •      Dose-related: drowsiness, ataxia, dizziness, paresthesias, poor concentration, weight loss
    •      Titrate dose slowly to minimize
    •      Severe/idiosyncratic: decreased sweating, hyperthermia, kidney stones, metabolic acidosis
    • (my notes: ADEs not nice)
    • Effect on CYP 450: inhibits 2C19, induces 3A4
    • Drug Interactions: phenytoin, oral contraceptives
    • Monitoring: serum bicarbonate levels periodically (carbonic anhydrase inhibitor)
    • Pregnancy Category: D (was C before 2011)
    • Other Uses: migraine prophylaxis, neuropathic pain
    • Generic available
    • Qsymia (topiramate + phentermine) approved for weight loss by FDA in 2012
    •      *"very dangerous combo"
    •      FDA warnings incld: contraind in pregnancy, suicidal thoughts/actions
  96. Levetiracetam (Keppra)
    • Use in Epilepsy: FDA approved as adjunct for partial seizures, generalized seizures, and myoclonic seizures. However, often used off-label as primary agent
    •      beign used a lot as primary AED, even though it's off-label
    • Exact  mechanism of action unknown
    • Kinetics:
    •      50% excreted renally unchanged with T ½ = 8 hrs => less drug interactions
    • *     CYP 450 substrate: none
    • Adverse effects:
    •      Dose-related: somnolence, dizziness, fatigue
    •      Low incidence of cognitive effects
    •      Severe/idiosyncratic: hallucinations, psychosis
    • Drug Interactions: none
    • Pregnancy category: C (one of the few)
    • Generic available
  97. Lamotrigine (Lamictal)
    • Use in Epilepsy: primary for partial and generalized seizures
    • MOA: blocks sodium channels
    • Kinetics:
    •       Metabolized by UGT enzyme in liver to inactive products with T ½ of 25 hrs
    • Dosage forms: oral and chew tablets
    • Adverse effects:
    •      Dose-related: dizziness, headache, diplopia, ataxia, somnolence
    •      Severe/idiosyncratic:
    • *          –Severe rash (10%) -> Stevens-Johnson syndrome (= BIG #)
    •            –New warning - aseptic meningitis
    • Effect on CYP 450: none
    • Drug Interactions: 
    •      AED enzyme inducers
    •      Valproate inhibits lamotrigine metabolism
    •      Lamotigine induces valproate metabolism
    • Monitoring: skin rash severity (increases with dose)
    • Pregnancy Category: C (Should be D?)
    •      ie infant cleft lip/palate
    • Other Uses: trigeminal neuralgia, bipolar disorder
    • Generic available
    • ----------------------------
    • (my notes: not used as much as others)
  98. Gabapentin (Neurontin)
    • Use in Epilepsy: adjunct for partial seizures but also used as primary agent
    • MOA: GABA analogue which increases GABA concentrations
    • Kinetics:
    •       Renally eliminated with T ½ = 5-7 hrs, dose must be reduced in renal failure
    •       CYP 450 substrate: none
    • Dosage forms: capsules, tablets, and solution
    • Adverse effects:
    •       Dose-related: somnolence, fatigue, dizziness, confusion, blurred vision
    •       Severe/idiosyncratic: weight gain
    • Effect on CYP 450: none
    • Drug Interactions: none
    • Monitoring: serum creatinine
    • Pregnancy Category: C
    • Aggravates: myoclonic seizures
    • Other Uses: postherpetic neuralgia, neuropathic pain (80% of Rx’s), RLS
    • Generic available
    • Gabapentin encarbil (Horizant) recently approved for RLS (prodrug of gabapentin)
    • *lots of illegal marketing -> lawsuits
    • ------------------------------
    • (my notes: not used as much for epilepsy as for pain, see % above)
  99. Ethosuximide (Zarontin)
    • Use in Epilepsy: absence seizures (=> usu for kids)
    • MOA: unknown
    • Kinetics:
    •      Metabolized by the liver with T ½ = 30-60 hrs
    •      CYP 450 substrate: 3A4
    • Dosage forms: capsule and syrup
    • Adverse effects:
    •      Dose-related: sedation, nausea, headache
    •      Severe/idiosyncratic: irritability, psychosis, leukopenia
    • Effect on CYP 450: none
    • Drug Interactions: CYP 3A4 inhibitors
    • Monitoring: CBC every 6-12 months
    • Pregnancy Category: C
    • Other Uses: none
    • Generic available
  100. Pregabalin (Lyrica)
    • Use in Epilepsy: adjunct for partial seizures
    • MOA: structurally similar to gabapentin
    • Kinetics:
    •      Renally eliminated with T ½ = 6 hrs,dose must be reduced in renal failure
    •      CYP 450 substrate: none
    • Dosage forms: capsules
    • Adverse effects:
    •       Dose-related: somnolence, dizziness, ataxia, peripheral edema, weight gain
    • Effect on CYP 450: none
    • Drug Interactions: none
    • Monitoring: serum creatinine
    • Pregnancy Category: C
    • Other Uses: FDA-approved for diabetic neuropathic pain, post herpetic neuralgia, and fibromyalgia
    • Cost: $270/mo for lowest effective dose
  101. Zonisamide (Zonegran)
    • Use in Epilepsy: FDA-approved for adjunct for partial seizures. But broad spectrum of activity and often used as monotherapy in children
    • MOA: Blocks T-type calcium channels and prolongs inactivation state of sodium channels
    • Kinetics:
    •       60% renally excreted
    •       40% metabolized by CYP 3A4 in liver with T ½ = 60 hrs
    • Adverse effects: similar to topiramate
    •       Dose-related: somnolence, fatigue, anorexia, weight loss, paresthesias
    •      Severe/idiosyncratic: Stevens-Johnson syndrome, kidney stones
    • Generic available
  102. Benzodiazepines for epilepsy
    • Diazepam (Valium)
    •       Diastat AcuDial – rectal gel formulation in pre-filled syringe for treatment of increased seizure activity while on other AEDs
    • Clonazepam (Klonopin)
    •       Used for treatment resistant absence and myoclonic seizures
    •      Tolerance eventually develops
    •      Highly sedating at effective doses
    • Clorazepate (Tranxene)
    •       Used as adjunct for partial seizures
    •       Metabolized to DMDZ, the long-acting active metabolite of diazepam
    • Pregnancy category: D
    • -------------------------------------
    • (my notes: relatively more sedating than other AEDs and worry about tolerance - even though effect of inc GABA = similar)
  103. Rarely Used Primary Agents for Epilepsy
    • both = barbituates
    • -----------------------------------------
    • Phenobarbital
    •      Use in Epilepsy: partial and generalized seizures
    •      MOA: barbiturate that facilitates GABA transmission
    •      Kinetics: very long T ½ = 100 hrs (need loading dose to start)
    • –CYP 450 substrate: 2C9
    •      Adverse effects:
    •           –Dose-related: highly sedating, nystagmus, dizziness, ataxia
    •           –Severe/idiosyncratic: hyperactivity in children, cognitive impairment, rash
    •      Drug interactions: many , induces  CYP1A2, 2C9, 2C19, 3A4
    • (my notes: mb use @ CHKD as 3rd line for status)
    • ----------------------------------------
    • Primidone
    •      Partially metabolized to phenobarbital
    •      Same adverse effect and drug interaction profile
  104. Rarely Used Adjunctive Agents for Epilepsy Tx
    • (rarely used d/t bad ADE)
    • --------------------------
    • Tiagabine (Gabitril)
    • Use in Epilepsy: adjunct for partial seizures (rarely used)
    • Kinetics: metabolized by liver with T ½ = 8 hrs
    •      CYP 450 substrate: 3A4
    • Adverse effects:
    •      Dose-related: dizziness, fatigue, nausea, nervousness, inattention
    •      Severe/idiosyncratic: non-convulsive status epilepticus with high doses
    • --------------------------------
    • Felbamate (Felbatol)
    • Use in Epilepsy: adjunct therapy for drug-resistant seizures only
    • Kinetics:
    •      50% metabolized by liver, the rest excreted renally with a T ½ = 24 hrs
    • Adverse effects:
    •      Dose-related: headache, nausea, somnolence, anorexia, fatigue, dizziness
    •      Severe/idiosyncratic: high risk of aplastic anemia and/or acute hepatic failure
    • (last ditch effort)
  105. Risk of Depression and Suicide With AEDs
    • Low risk
    •      Conventional AEDs
    •      Lamotrigine, gabapentin, pregabalin, oxcarbazepine
    • High risk
    •      Levetiracetam (used dt less drug interactions)
    •      Tiagabine
    •      Topiramate (used a lot for wt loss & diabetic neuropathy)
    • -------------------------------------
    • however, warning about risk of suicidal thoughts/behavior = req'd to put on all AED
  106. Antiepileptic Drugs of Choice (DOC) - general information
    • Guidelines from the American Academy of Neurology and the American Epilepsy Society
    •      Includes drug recommendations based on evidence, but not necessarily FDA-approved indications
  107. Antiepileptic Drugs of Choice (DOC) for
    Partial Seizures
    • Drugs of Choice
    • Carbamazepine
    • Oxacarbazepine
    • Levetiracetam
    • Lamotrigine*
    • -------------------------------
    • Alternative Agents
    • Gabapentin
    • Pregabalin
    • Phenytoin
    • Tiagabine
    • Topiramate
    • Valproate
    • Zonisamide
    • Lacosamide
    • Ezogabine
    • --------------------
    • NOTE:  * not FDA-approved
  108. Antiepileptic Drugs of Choice (DOC) for Generalized Tonic-Clonic Seizures
    • Drugs of Choice
    • Levetiracetam
    • Valproate
    • Lamotrigine*
    • ------------------------------------
    • Alternative Agents
    • Oxcarbazepine
    • Phenytoin
    • Topiramate
    • Zonisamide
    • -----------------------------------
    • NOTE:  * not FDA-approved
  109. Antiepileptic Drugs of Choice (DOC) for Generalized Absence Seizures
    • Drugs of Choice
    • Ethosuximide
    • Valproate
    • ----------------------------
    • Alternative Agents
    • Clonazepam
    • Lamotrigine*
    • Levetiracetam
    • Zonisamide
    • ----------------------------
    • NOTE:  * not FDA-approved
  110. Antiepileptic Drugs of Choice (DOC) for Myoclonic, Atonic, and Atypical Absence Seizures
    • Drugs of Choice
    • Valproate
    • Lamotrigine
    • Levetiracetam
    • --------------------------------
    • Alternative Agents
    • Clonazepam
    • Topiramate
    • Felbamate
    • Zonisamide
  111. AEDs and Pregnancy
    • Teratogenicity
    •      6% incidence of fetal abnormalities in women with epilepsy taking AEDs
    •       30% of abnormalities are cleft lip or cleft palate
    •       Most serious are neural tube defects such as spina biifida
    •       Higher incidence with polytherapy
    •       Greatest risk with valproate, carbamazepine, and phenobarbital
    • Ideally should stop AED 6 months before pregnancy to see if seizures recur
    • Not recommended to stop AED during pregnancy
    • Plasma drug level monitoring important since AED levels usually decrease during pregnancy
    • ------------------------------------
    • Oral contraceptive failure
    •       Common interaction with enzyme inducing AEDs
    •       Secondary to increased estrogen metabolism (bc induce CYP 3A4)
    • -------------------------------
    • Folic acid prophylaxis (1 mg/day)
    •      For all women of child bearing age to decrease potential neural tube defects
    •      AEDs such as carbamazepine, phenytoin, and phenobarbital decrease folic acid absorption
    • --------------------------
    • Vitamin K supplementation (10 mg/day)
    •      In last month of pregnancy to prevent deficiency and potential hemorrhage at birth
    •      Deficiency caused by induction of enzymes that metabolize Vitamin K-dependent clottingfactors
  112. Miscellaneous supplements for AED use (not associated with pregnancy/teratotenicity)
    • Calcium and Vitamin D
    •       Supplementation recommended for all women to prevent AED-induced osteoporosis
    •       Osteoporosis possibly related to increased Vitamin D metabolism by enzyme inducing AEDs
  113. Status Epilepticus + Tx
    • Recurrent episodes of generalized tonic-clonic seizures without regaining consciousness
    • Life-threatening
    • Drugs of choice: diazepam or lorazepam given as slow IV injection every 10 to 15 minutes until seizures controlled
    • Follow-up with IV administration of fosphenytoin
    • Levetiracetam (Keppra) considered 3rd line agent
    • Phenobarbital still used in children if benzodiazepines or fosphenytoin have failed
  114. Drugs That May Provoke or Exacerbate Seizures
    • Class 1b Antiarrhythmics
    • Antimicrobials
    •       Beta-lactams
    •       Fluoroquinolones
    •       Isoniazid
    • Antivirals
    •       Acyclovir
    •       Ganciclovir
    • Drugs of abuse
    •      Amphetamine
    •      Cocaine
    •      Methylphenidate
    •      (sympathomimetics)
    • Psychotropic Agents
    •      Antidepressants
    •      Antipsychotics
    •      Lithium
    • Sedative-hypnotics
    •      Ethanol
    •      Barbituates (short-acting)
    • Miscellaneous
    •      Lindane
    •      Cyclosporine
    •      Metoclopramide
    •      *Meperidine (metabolite) [analgesic lect]
    •      Tramadol
    •      Theophylline
  115. Pregnancy Category for AEDs
    • Most are Pregnancy Category D, except:
    •      Levetiracetam (Keppra)
  116. AEDs for Neuropathic Pain
    • Neuropathic pain: pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system   (~ 1% of population)
    • Pain described as burning or shock-like
    • Most common: diabetic neuropathic pain and post herpetic neuralgia
    • Gabapentin most commonly used of AEDs
    •      NNT to obtain 50% pain relief = 5-6 (published trials) [=> not as great as people think]
    •      ex of published paper (summary): specific people excluded (low Cr clearance, no response to gabapentin), only pain REDUCTION with HIGHEST dose, not statistically different from placebo in final week (wk 8), ~40% dizziness as ADE
    • High placebo response in trials for all AEDs
    • TCAs --> NNT = 2.1 (best results of anti-depressants for neuropathic pain)
    • -----------------------------------------
    • [see slides 68-71 for more detail/graphs]
  117. Synthesis of Progestins, Androgens, and Estrogens
    • Progestins, androgens, and estrogens are
    • steroid hormones derived from cholesterol.

    The major progestins include progesterone and 17α-hydroxyprogesterone.

    The androgens include dehydroepiandrosterone (DHEA), androstenedione, and testosterone.

    Estrogens include estrone and estradiol. Estrogens are aromatized forms of their conjugate androgens: androstenedione is aromatized to estrone, and testosterone is aromatized to estradiol.

    Estradiol and estrone are both metabolized to estriol, a weak estrogen
  118. Hypothalamic-Pituitary-Reproduction Axis
    The hypothalamus secretes gonadotropin releasing hormone (GnRH) into the hypothalamic–pituitary portal system in a pulsatile pattern.

    GnRH stimulates gonadotroph cells in the anterior pituitary gland to synthesize and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones, referred to as gonadotropins, promote ovarian and testicular synthesis of estrogen and testosterone, respectively.

    Estrogen and testosterone inhibit release of GnRH, LH, and FSH. Depending on the time in the menstrual cycle, the concentration of estrogen in the plasma, and the rate at which estrogen concentration increases in the plasma, estrogen can also stimulate pituitary gonadotropin release (e.g., at ovulation).

    Both the ovaries and testes secrete inhibin, which selectively inhibits FSH secretion, and activin, which selectively promotes FSH secretion.
  119. Pertinent Target Cells for FSH/LH
    • Male: Leydig/Sertoli Cells
    • Female: Thecal/Granulosa Cells

    Sertoli Cells and granulose cells synthesize inhibin A, inhibin B, and activin

    Inhibins inhibit and activin stimulates the anterioir pituitary release of FSH (not LH)
  120. Mechanisms of Reproductive Tract Disorders for Which Pharmacologic Agents Are Currently Used
    • Disruption of H-P-R Axis:
    • PCOS, prolactinoma

    • Inappropriate growth of hormone-dependent tissue:
    • Breast cancer, prostatic cancer, endometriosis

    • Decreased estrogen or androgen secretion
    • Hypogonadism, menopause
  121. Polycystic Ovarian Syndrome (PCOS)
    • Characterized by:
    • Anovulation/oligo-ovulation
    • Increase levels of plasma androgen

    • LH hypothesis for PCOS:
    • increased freq and amplitude of LH pulses
    • stimulated thecal cells -> increased androgens
    • prevent normal follice growth and secretion of large amounts of estrogen
    • absence of estrogen "trigger" prevents LH surge and ovulation

    • Insulin hypothesis:
    • many women with PCOS are obese and insulin resistant and secrete increased insulin
    • Increased insulin binding decreases the production of sex hormone-binding globulin -> higher concentration of free testosterone and greater androgenic effects on peripheral tissues

    • Ovarian hypothesis:
    • Dysregulation of sex steroid synthesis at the level of the thecal cell
  122. Prolactinoma
    Clonal, benign tumors of lactotrophs in the anterior pituitary gland

    • Increased prolactin levels suppress estrogen synthesis by:
    • antagonizing the hypothalamic release of GnRH
    • decreasing gonadotroph sensitivity to GnRH
  123. Hormone Dependent Tissues
    • May breast cancers express the estrogen receptor-
    • Growth of such cancers is stimulated by estrogen

    Prostate growth is androgen-dependent and requires the conversion of testosterone to DHT by 5-alpha reductase -> BPH + Prostate Cancer
  124. Endometriosis
    Growth of endometrial tissue outside of the uterus

    Because the tissue responds to estrogen, endometriosis grows and regresses with the menstrual cycle -> leads to severe pain, abnormal bleeding
  125. Hypogonadism and Menopause
    • Hypogonadism results if sex hormone production is impaired before adolescence:
    • Patients with hypogonadism do not undergo sexual maturation

    • Menopause - normal physiologic repsonse to exhaustion of ovarian follicles
    • This leads to a decrease in estrogen and inhibins and an increase in LH and FSH

    Many woman experience hot flashes, vaginal dryness, and decreased libido
  126. Pharmacological Modulation of Gonadal Hormone Action
    Pharmacologic modulation of gonadal hormone action can be divided into inhibitors of hormone synthesis and hormone receptor antagonists.

    Continuous administration of GnRH suppresses LH and FSH release from the anterior pituitary gland, thus preventing gonadal hormone synthesis.

    GnRH receptor antagonists (cetrorelix, ganirelix) are also used for this purpose.

    Finasteride and dutasteride inhibit the enzyme 5α-reductase, thus preventing conversion of testosterone to the more active dihydrotestosterone.

    Aromatase inhibitors (exemestane, formestane, anastrozole, letrozole) inhibit production of estrogens from androgens.

    A number of hormone receptor antagonists and modulators prevent the action of endogenous estrogens (some SERMs), androgens (flutamide, spironolactone), and progesterone (mifepristone).
  127. GnRH Agonists and Antagonists
    Physiologically GnRH is released in a pulsatile fashion

    • The frequency of GnRH pulses control the release of LH and FSH
    • Continuous administration of GnRH suppresses FSH and LH

    • We can suppress H-P-R axis by:
    • continuous administration of GnRH agonist (Leuprolide, goserelin, or naferelin)

    Administering GnRH receptor antagonist (cetrorelix or ganirelix)

    • Uses:
    • Hormone dependent tumors - prostate and breast cancer

    Their use in managing pain in endometriosis is under clinical trial
  128. Aromatase Inhibitors
    Block Testosterone to Estradiol and Androstenedione to Estrone

    Estrogens are synthesized from androgen precursors via the action of aromatase

    So blocking aromatase can effectively inhibit estrogen formation

    Anastrozole and Letrozole are competitive inhibitors of aromatase

    Exemastane and Formestane covalently bind to aromatase inhibiting their activity

    • UsesL
    • ER positive mestastatic breast cancer - to inhibit the growth of estrogen dependent tumors

    Also used in prevention of recurrences in cancers primarily treated with surgery and radiation

    **Recent data suggest that these drugs are more effective than SERM for tx of breast cancer

    • Adverse:
    • Causes profound suppression of estrogens

    Leads to lack of protective actions of estrogen on bone: carry risk for osteoporosis
  129. Selective Estrogen Receptor Modulators (SERM)
    Estrogen - stimulatory effects in breast, endometrium, bone

    Tamoxifen - antagonish in breast tissue, used in tx of receptor-positive breast cancer

    Raloxifene - agonist in bone, antagonist in breast, endometrium, so used for prevention/tx of osteoporosis

    "Mixed" agonists/antagonists - inhibit estrogenic actions in some tissues while promoting estrogenic effects in others

    ER-alpha found in endometrium, breast cancer, ovarian cells, and hypothalamus

    ER-beta found in kideny, brain, bone, heart

    ERs are regarded to be cytoplasmic/nuclear receptors
  130. Tamoxifen
    Only SERM currently approved for tx of breast cancer

    ER antagonist in breast but partial agonist in endometrium and bone

    Leads to inhibition of estrogen dependent growth of breast cancer but also endometrial growth stimulation

    Associated with 4-6 fold increase in incidence of endometrial cancer

    Currently not administer for not longer than 5 years
  131. Raloxifene
    Agnosistic activity in bone but antagonistic activity in both breast and endometrium

    Used in management of post-menopausal osteoporosis and also in prevention of breast cancer
  132. Clomiphene
    SERM used to induce ovulation. The drug acts as an estrogen receptor antagonist in the hypothalamus and anterior pituitary gland and as a partial agonist in the ovaries.

    The antagonist activity of clomiphene in the hypothalamus and anterior pituitary gland results in relief of the negative feedback inhibition imposed by endogenous estrogen and, therefore, in the increased release of GnRH and gonadotropins, respectively.

    The increased levels of FSH stimulate follicle growth, resulting in an estrogen trigger signal, an LH surge, and ovulation.

    The main adverse effect is that clomiphene can cause multiple follicles to grow, resulting in an increased ovarian size.
  133. Androgen receptor antagonist
    Flutamide and Sprionolactone

    These competitively inhibit the biding of endogenous androgens to androgen receptors thus blocking actions of DHT and testosterone

    Uses: metastatic prostate cancer, BPH

    Sprionolactone also has aldosterone blocking effects

    Uses: K-sparing diruetic, hirsutism in female
  134. Progesterone receptor antagonist
    Mifepristone - used to induce abortion at up to 63 days of pregnancy

    Progesterone stabilizes the uterine lining and promotes vessel growth and secretory activities of the decidua

    Inhibition of progesterone activity by mifepristone causes decay and death of decidua - leads of death and detachment of blastocyst from uterine wall

    Given along with misoprostol to stimulate uterine contractions
  135. Estrogen
    • Ethinyl estradiol
    • Mestranol

    • Used in:
    • HRT
    • Acne

    Adverse Rxns:

    • Hypertension
    • Thomoboembolic disorder
    • Gall bladder dz
  136. Contraception
    • Act locally in reproductive tract
    • Spermicides
    • Condoms/diaphragms
    • IUD

    • Oral
    • Combine estrogen/progestin pills
    • Progestin only pill

    • Implants/Injectables
    • Usually progestin only preparations
  137. Oral Contraceptive Pills
    Principle is to use body's neg feedback system to prevent ovulation and implantation of embryo

    • Two basic types of OCPs:
    • Combination estrogen-progestin pills
    • Progestin only pills
  138. Combination Estrogen-Progestin Pills
    Suppress GnRH, LH, and FSH - thus suppressing follicular development and inhibiting ovulation

    • Other mechs include:
    • Altered tubal peristalsis
    • Decreased endometrial receptivity
    • Decreased cervial mucus secretions

    • Adverse Effects:
    • Unopposed estrogen actions promotes endometrial groweh -> increases risk of endometrial cancer

    For a female w/ uterus - estrogens always given along with progestine

    Currently available progestins have varying degrees of androgenic activity

    • Highest: Norgestrel, levonorgestrel
    • Lower: Norethindrone
    • Lowest: Norgestimate, Ethynodiol
    • Anti-Androgenic: Drospirenone

    Classical regimen consists of 21 days drug regimen followed by 7 day placebo - placebo period removes exogenous hormone stimulation causing endometrium to slough and causing withdrawal bleeding

    Clinical trials show increased risk of DVT, PE

    Increased risk of gallbladder disease

    OCPs should not be given to women older than 35 and smoking

    • Drug Interactions:
    • Antibiotics such as penicillin and tetracyclines decrease effect of estrogens

    • Estrogens can inhibit metabolism of:
    • Cyclosporine
    • Antidepressants
    • Glucocorticoids

    • Estrogens increase synthesis of Vit-K dependent clotting factors
    • Antagonize effects of warfarin
  139. Oral Contraceptive Pills: Monophasic, Triphasic
    • Monophasic:
    • Constant dose of estrogen and progestin for all 21 days

    • Triphasic:
    • Constant dose of estrogen with a dose of progestin increasing each week during the 21 day period (advantage is reduced total amount of progestin over a month)

    Recent trend: use least amount of estrogen and progestin
  140. Progestin Only Pills
    Used when estrogen may be contraindicated

    Referred to as mini pills

    Norgestrel and Norethindrone

    Medroxyprogesterone acetate is a "depot" preparation

    Patients on these typically do not menstruate, but may encounter some breakthrough bleeding or spotting

    • Adverse Effects:
    • Progestins with androgenic effects can cause acne, hirsutism, increased libido, and oily skin

    • Drospirenone has anti-androgenic activity
    • Being an aldosterone antagonist, it lowers BP
  141. Emergency contraception
    Prevent pregnancy after failure of barrier or recent unprotected intercourse

    Levonorgestrel (1.5mg) most effective, least ADR (Plan B)

    Most effective within 120 hrs of exposure

    Acts by blocking LH surge thus disrupting normal ovulation and produce endometrial changes not conducive for implantation
  142. Tx of PCOS
    Estrogen-progestin contraceptive (suppress ovarian production of testosterone)

    Anti-androgen, such as sprionolactone  (address masculinizing effects of increased circulating testosterone)

    Metformin (reduced insulin resistance, result in regular ovulatory menses and normalization of testosterone levels)
  143. Tx of Prolactinoma
    Dopamine receptor agonist
  144. Breast/Endometrial Cancer
    • SERM
    • Aromatase inhibitors
  145. Endometriosis
    • OCP
    • GnRH analogs (continuous/long acting)
    • Danazol - androgen analog, acts by suppressing FSH and LH resulting in a relatively hypoestrogenic state
  146. Menopause
    Hormone Replacement Therapy
  147. Five Primary effects of Anesthesia
    • unconsciousness
    • amnesia
    • analgesia
    • inhibition of autonomic reflexes
    • skeletal mm relaxation
    • ---------------
    • NOTE: no one available anesthetic agent can do all 5 of these => must use combo of IV and inhaled drugs (balanced anesthesia techniques)
  148. Classification of anesthetics (general) and drugs in each category
    • Gases
    • N2O
    • Cyclopropane
    • Xenon
    • ----------------
    • Volatile Liquids
    • Ether
    • Halothane
    • Desflurane
    • Isoflurane
    • Sevoflurane
    • Methoxyflurane
    • ----------------------------
    • Inducing Agents
    • Thiopentone sodium
    • Methohexitone sodium
    • Etomidate
    • Propofol
    • -----------------------------
    • Dissociative anesthetic
    • Ketamine
    • ----------------------------------
    • Benzodiazepines
    • Diazepam
    • Midazolam
  149. MOA of anesthetics
    • Theories:
    • inhibit glutamate
    • inhibit GABA transmission
    • (don't know MAO for sure)
  150. Ideal Anesthetic
    • *Rapid onset (induction)
    • *Rapid termination of effect (recovery)
    •      -to achieve this, the conc of anesthetics in CNS must change rapidly
    •      -several factors determine how quickly CNS conc changes (see another slide)
  151. Inhaled anesthetics
    • Gases
    • N2O
    • Cyclopropane
    • Xenon
    • ----------------
    • Volatile Liquids
    • Ether
    • Halothane
    • Desflurane
    • Isoflurane
    • Sevoflurane
    • Methoxyflurane
  152. Factors Affecting CNS Concentration of Inhaled Anesthetics
    • *Partial pressure inspired air
    •       -inc inspired partial pressure of Rx -> accelerate induction
    • Pulmonary ventilation rate
    •      -hyperventillation -> inc speed of induction
    • Alveolar exchange
    • Solubility of anesthetic in blood
    •      -dec blood gas solubility -> faster onset of action (induction)
    • Solubility of anesthetic in tissues
    •      -accumulation is tissues -> prolonged exposure -> slow recovery/elimination
    • *Pulmonary blood flow & cardiac output
    •       -inc CO (which -> inc pulm blood flow) -> inc anesthetic uptake  BUT dec rate of induction (d/t inc distribution of anesthetic to tissues other than CNS)

    (for more details refer to lecture slides)
  153. Blood gas solubility of inhaled anesthetics: action of onset AND elimination/recovery
    • Onset of Action:
    • blood:gas coefficient defines relative affinity of an anesthetic for the blood compared with that of inspired gas

    • EX: anesthetics with low blood solubility have a faster onset of action:
    •      Relatively few molecules are required to raise its partial pressure
    •      Arterial tension rises rapidly
    •      Faster onset!

    • EX: anesthetics with high blood solubility have a slow onset of action:
    •      More molecules dissolve before partial pressure changes significantly
    •      Arterial tension of the gas increases less rapidly
    •      Slower onset!
    • -------------------------------------------------
    • Elimination/Recovery:
    • inhaled anesthetics w/ lo blood:gas partition coefficients (low solubility) = eliminated at faster rates
    •      -AKA: faster recovery (ie N2O, desflurane)
    • rate of recovery/elimination also dep on solubility/accumulation in tissues
    •      -more accumulation in tissues ->> slow recovery
    • NOTE: this refers to inhaled anesthetics
  154. Inhaled anesthetics with Fastest and slowest onset of action
    • Nitrous oxide (N2O) = fastest onset of action
    •      -lowest blood:gas solubility
    • Halothane = slowest onset of action
    •      -highest blood gas solubility
    • (graph w/ info also showed desflurane>sevoflurane>isoflurane) [fastest action to slowest]
  155. Minimal Alveolar Concentration (MAC)
    • = minimum concentration of inhaled agent at which no movement is observed to an incision in 50% of subjects
    • = measure of potency of the drug (ONLY)
    •     -MAC and potency are inversely related
    • (*no info about onset of action or safety)
  156. Nitrous Oxide
    • = inhaled anesthetic
    • ------------------------------
    • Positives:
    • Potent analgesic effect
    • “Carrier” and adjuvant to other agents
    • Rapid induction & recovery (why?)
    • No Renal or hepatic damage
    • -----------------------------------------
    • Negatives:
    • Inhibits methionine synthetase
    • Inhibits vit B-12 – causes megaloblastic anemia (with chronic exposure-see next bullet pt)
    • OR personnel at risk of exposure
    • Possible teratogenic effects(?)
  157. Halothane
    • = inhaled anesthetic
    • ------------------------------
    • Positives:
    • Causes bronchodilation
    • Inhibits intestinal & uterine contractions
    • -----------------------------------------
    • Negatives:
    • Poor analgesic
    • Hypotension
    • Sensitizes myocardium to catecholamines (risk of arrhythmias)***
    • Hepatitis (rare)
    • Malignant hyperthermia*** (can -> mm breakdown -> myoglobinemia)
    • Prolongs labor
    • [lots of disadvantages]
  158. Enflurane
    • = inhaled anesthetic
    • ----------------------------
    • ADE: can cause seizures
  159. Desflurane
    • = inhaled anesthetic
    • --------------------------
    • ADE: causes airway irritation and laryngospasm
  160. Sevoflurane
    • = inhaled anesthetic
    • -------------------------
    • ADE: metabolism can cause nephrotoxicity
  161. Isoflurane
    • = inhaled anesthetic
    • ------------------------------
    • ADE:
    • Rapid induction & recovery
    • No seizure
    • No nephro or hepatotoxicity
    • Can cause respiratory depression
  162. IV anesthetic agents
    • Barbituates & Benzodiazepines
    • Thiopental
    • Methohexital
    • Midazolam
    • ----------------------
    • Other:
    • Propofol
    • Etomidate
    • ---------------------
    • Opiods:
    • Fentanyl
    • Alfentanyl
    • Remifentanyl
    • Sufentanyl
  163. Thiopentone
    • = IV anesthetic
    • ----------------------------------
    • Kinetics:
    • Ultra short acting barbiturate
    •       –Rapid induction
    • Undergoes rapid redistribution
    •       –Especially into fat tissues -> hangover effect
    • -----------------------------
    • MOA: inc duration of opening of Cl channels (-> inc GABA) [all barbituates]
    • ----------------------------
    • Effects:
    • Respiratory depression
    •      –decrease the ventilatory responses to hypercapnia and hypoxia
    • Accidental intra-arterial injection causes severe pain, vasoconstriction that can lead to gangrene

    *no antidote (for any barbituates)
  164. Benzodiazepines for anesthetics
    • = IV anesthetics
    • -------------------------------------
    • Rx: Midazolam, lorazepam and Diazepam
    • ----------------------------------------
    • MOA: inc freq of opening Cl channels
    • ----------------------------------------
    • Excessive actions promptly reversed by flumazenil (antidote)
    • Lesser degree of respiratory depression when compared to barbiturates
    • safer, less respiratory depression than barbituates
  165. Propofol
    • = IV anesthetic
    • -----------------------------------
    • Rapid onset (quick induction)
    • Fast awakening
    • Less hangover effect compared to barbiturates
    • Can cause severe bradycardia and hypotension
    • Pain on injection***
    • Myoclonus***
    • Apnea
    • (looks milk-like)
  166. Etomidate
    • = IV anesthetic
    • ------------------------
    • Potent cerebral vasoconstrictor – decreases ICP
    • Changes to systemic blood pressure is very little or absent****
    • Minimal changes to cardiac output and HR***
    •      => use for patient with CV compromise
    • Causes adrenocortical suppression by producing a dose-dependent inhibition of 11β-hydroxylase
    • Inducing agent of choice in patients with compromised myocardial contractility
  167. Ketamine
    • = IV anesthetic
    • ---------------------
    • Derivative of PCP
    • Dissociative anesthetic
    • Acts by blocking NMDA receptors
    • Increases BP, HR and CO***
    • Causes bronchodilation
    • Produces significant analgesia
    • Patient's eyes remain open with a slow nystagmic gaze (cataleptic state).
    • Useful option in pediatric patients
    •       –can be administered by multiple routes (IV, IM, oral, rectal, epidural)
    • Increases IOP
    • Can worsen psychosis and schizophrenia
    • ----------------------------------------
    • CNS Effects:
    • Cerebral vasodilator that increases cerebral blood flow (=> don't use w/ head injury)
    • Unpleasant emergence reactions
    •      –vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity
    • Minimal respiratory depression
  168. Fentanyl
    • = IV anesthetic
    • -------------------------------
    • Opioid
    • Al-, remi- and su- fentanyl are derivatives
    • Rapid onset and smooth recovery
    • Suppression of cough and vomiting**
    • Less drop in BP
    • ADR
    • Respiratory depression
    • Chest wall (and laryngeal) rigidity
    • (also inhibit vasomotor centers -> impaired thermoregulation -> cold
  169. MOA of local anesthetics
    • LA = weak bases (except for Benzocaine: pKa = 3.5)
    • Ionized form is the most active at the receptor site
    • Receptor site for local anesthetics is at the inner vestibule of the sodium channel
    •      –Charged form penetrates biologic membranes poorly.
    •      –Uncharged form is important for cell penetration
    • => may need to alkalinize the serum to have more LA in the nonionized form -> more crosses membranes into cells -> more has an effect (esp in abscesses, other acidic environments)
    • channels in rested state also have lower affinity for LA than activated (open state) or inactivated channels

    [for more detail see lecture slide]
  170. Classification (and drugs in classification) of Local Anesthetics
    • Amides
    • Lidocaine
    • Bupivacaine
    • Mepivacaine
    • Prilocaine
    • Ropivacaine
    • ----------------
    • Esters
    • Procaine
    • Benzocaine
    • Tetracaine
    • Cocaine
    • ------------------
    • Concerns about hypersensitive reactions to and cross sensitivity across Esters: Do not use an ester if history positive for reaction to another ester. Replace ester with an amide.
  171. Amide Local Anesthetics
    • Lidocaine
    • Bupivacaine
    • Mepivacaine
    • Prilocaine
    • Ropivacaine
    • ---------------------
    • Metabolism:
    • hydrolyzed very rapidly in the blood by (plasma) butyrylcholinesterase
    • Excessive concentrations may accumulate in patients with atypical plasma cholinesterase
  172. Ester Local Anesthetics
    • Procaine
    • Benzocaine
    • Tetracaine
    • Cocaine
    • --------------------------
    • Mechanism:
    • in the liver
  173. Nerve Fiber & Effect of LA
    • Least to most sensitive to LA:
    • Type A - least sensitive to LA (least blocked; thickest diameter)
    • Type B
    • Type C - most sensitive to LA (most blocked; thinnest diameter)
    • -------------------------------------
    • myelinated nn blocked before unmyelinated nn
  174. LA and Infected Tissue
    • Local anesthetics are less effective when they are injected into infected tissues
    • Low extracellular pH (of infected tissues) favors the charged form, with less diffusion across the membrane
    • This leads to reduced effect of LA
    • Conversely, adding bicarbonate to a local anesthetic raises the effective concentration of the nonionized form
    •      –Shorten the onset time of a regional block
  175. Effect of Added Vasoconstrictors
    • (ie epinephrine)
    • Localized neuronal uptake is enhanced
    •      –Because of higher sustained local tissue concentrations
    •      –Longer duration block
    •      –Lower total anesthetic requirement
    • -----------------------------------------
    • [exception to use of vasoconstrictor]
    • Reduced risk of systemic toxic effects
    • Avoid use of a epinephrine in an area that lacks adequate collateral flow (eg, digital block)
    •      ie end aa: nose, finger tips, penis tip, earlobe -> (mb) gangrene
  176. epidural block
    injection on LA extradurally
  177. caudal block
    • special type of epidural block
    • needle is inserted into caudal canal via sacral hiatus
  178. perineural block
    injection of LA around peripheral nn
  179. spinal block
    injection of LA into subarachnoid (intrathecal) space (into CSF)
  180. Toxicity of LA
    • Systemic
    • Sedation
    • Light-headedness
    • Visual and auditory disturbances
    • *Circumoral and tongue numbness
    • *Nystagmus
    • *Muscular twitching
    • *Tonic-clonic seizures (give benzo)
    • Bupivacaine: Cardiotoxic
    • -----------------------------------------
    • Local
    • Neural injury
    • Syndrome of transient pain or dysesthesia
    •      –Transient Neurologic Symptoms (TNS)
  181. Articaine
    • = LA
    • Has both amide and ester in structure
    • Used for dentistry as a shorter acting and
    • safer alternative
  182. Benzocaine
    • = ester LA
    • topical anesthetic
    • potential to induce methemoglobinemia
  183. Bupivacaine
    • = amide LA
    • Risk of cardiotoxicity
  184. Chlorprocaine
    • = LA
    • used widely as an epidural agent in obstetric anesthesia
  185. Cocaine as an anesthetic
    • = ester LA
    • use restricted to ENT procedures (why?)
    • does not require use of vasoconstrictor b/c it has sympathomimetic activity
  186. Lidocaine
    • = amide LA
    • Most commonly used. High incidence of TNS
  187. Prilocaine
    • = amide LA
    • propensity to induce methemoglobinemia
  188. EMLA (Eutectic Mixture of Local Anesthetics)
    • 2.5% lidocaine and 2.5% prilocaine.
    • Used in pediatrics to anesthetize the skin prior to venipuncture

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