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Neuro Pharmacology > Neurophysiology of Pain Pathways and Non-opioid analgesics > Flashcards

Neurophysiology of Pain Pathways and Non-opioid analgesics Flashcards

1
Q

What is Pain?

A

Unpleasant sensory and emotional experience associated w/ actual or potential tissue damage.

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2
Q

What are the two basic types of pain?

A
  1. Nociceptive

2. Neuropathic

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3
Q

What is Nociceptive pain and what kinds are there?

A

Transduction of noxious stimuli, irrespective of cognitive awareness.

  1. Somatic (cutaneous or deep tissue)
  2. Visceral (internal organs)
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4
Q

What is Neuropathic pain?

A
  1. Caused by a primary lesion or dysfunction in the nervous system.
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5
Q

What kinds of nerve fibers mediate itch and pain?

A

BOTH by thin, unmyelinated nerve fibers from the skin but mediated by different mechanisms.

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6
Q

What is an itch?

A
  1. Unpleasant sensation that elicits the desire or reflex to scratch.
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7
Q

What is an itch induced by:

A
  1. Pruritogens
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8
Q

What are examples of pruritogens?

A
  1. Histamine
  2. Environmental chemicals
  3. Drugs
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9
Q

What was an itch considered as long ago?

A
  1. a sub-modality of pain.
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10
Q

What is MrgprA3?

A
  1. Member of the family of Mas-related G protein-coupled receptors.
  2. Shown to mediated itch.
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11
Q

What are Acute pain examples?

A
  1. HA & Migraine

2. From minor injuries, labor, dysmenorrhea, kidney stones.

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12
Q

What is Fibromyalgia?

A

CNS pain state, that might be accompanied by peripheral pain states.

  • Osteoarthritis
  • RA
  • Lupus
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13
Q

Stimuli that initiate chronic pain also provoke what?

A
  1. Inflammatory and immune responses.
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14
Q

What are examples of neuroimmune pain mediatiors?

A
  1. TNF-alpha

2. IL-1beta

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15
Q

What to neuroimmune pain mediators act on?

A
  1. Peripheral nociceptive nerve terminals
    - promote abnormal discharge and hyperexcitability.
  2. Peripheral nerves
    - Produce neuropathic hyperalgesia.
    - Allodynia
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16
Q

What is neuropathic hyperalgesia?

A
  1. Exaggerated response to a painful stimulus.
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17
Q

What is allodynia?

A
  1. Pain from a stimulus that does not normally cause pain.

- light touch or temp variation.

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18
Q

What kinds of cells also release neuroimmune mediators?

A
  1. Cancer cells.
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19
Q

What is central synaptic sensitization?

A

Spinal cord neurons become more responsive to nociceptive input due to persistent firing, changes in descending controls.

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20
Q

What does central synaptic sensitization do?

A
  1. Enhances efficacy of nociceptive transmission through the spinal cord dorsal horn and perception of spontaneous and breakthrough pain.
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21
Q

Where is the site of nociception (noxious stimulus)?

A

1.

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22
Q

What is the anterolateral spinothalamic pathway?

A

Neurons snapse IN the dorsal horn then cross and ascend to the brain.

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23
Q

What are 3 important aspects of pain inhibition?

A
  1. Site of drug action.
  2. Timing
  3. Nature of pain.
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24
Q

What is more effective pre-emptive analgesia or after sensitization develops?

A

Pre-emptive (b/c of timing aspect)

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25
Q

What is the difference between nociceptor drug action and CNS drug action?

A
  1. Nociceptor NSAIDs & APAP.

2. CNS Opioids.

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26
Q

What are the target sites to treat pain?

A
  1. Site of pain initiation.
  2. Transmission Pathway.
  3. Spinal Cord
  4. Spinothalamic Tract Fibers
  5. Spinal Cord & Brain.
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27
Q

What is used at the site of pain initiation?

A
  1. Methylene Blue

2. ASA, NSAIDs.

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28
Q

What is used at the transmission pathways of pain?

A
  1. Local Anesthetics.
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29
Q

What is used at the spinal cord target site?

A
  1. Topical counterirritants.

2. Transcutaenous electrical nerve stimulation.

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30
Q

What is done at the target of spinothalamic tract fibers?

A
  1. Kill the fiber (ethanol)

2. Anterolateral cordotomy.

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31
Q

What are spinal segments also called?

A
  1. Dermatomes.
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32
Q

What are the 5 dermatomes?

A
  1. Cervical (C1-C8)
  2. Thoracic (T1-T12)
  3. Lumbar (L1-L5)
  4. Sacral (S1-S5)
  5. Sacrococcygeal.
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33
Q

What are the chemical mediators of pain?

A
  1. Bradykinin in sensory neurons.
  2. 5-HT from platelets.
  3. Histamine from mast cells
  4. Neuropeptides
  5. ATP, K+
  6. Chemokines
  7. Ion Channels.
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34
Q

What are the sex differences in pain and analgesic response?

A
  1. Women demonstrate lower thresholds
  2. Suffer more from fibromyalgia, joint shit, migraine, IBS.
  3. Women respond better to opioid kappa agonists.
  4. Red-headed women have lower threshold to cold and heat pain.
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35
Q

What are 3 methods to evaluate analgesia in animals?

A
  1. Tail flick assay
  2. Hot plate assay
  3. Injection of irritant.
    - Phenylquinone or acetic acid.
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36
Q

What is the difference between nonopioid and opioid analgesics?

A
  1. Structurally heterogenous.
  2. No Tolerance
  3. No Physical Dependence.
  4. Less maximal efficacy.
  5. Good for Mild-moderate pain.
  6. Inflammation and fever
  7. Different MOA
  8. Different AE.
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37
Q

What are examples of Salicylates.

A
  1. Aspirin (Acetyl Salicylic Acid)
  2. Methyl Salicylate (oil of wintergreen)
  3. Triethanolamine Salicylate (Bengay)
  4. Bismuth Subsalicylate (Pepto-Bismol)
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38
Q

What is the Plasma Protein Binding of ASA?

A

50%

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39
Q

What is the Plasma Protein Binding of Salicylate?

A

95% (low therapeutic) to 80% (high therapeutic levels)

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40
Q

What is the PK of ASA?

A
  1. 40% metabolized by liver esterases in first pass.
  2. Metabolized by esterases in blood and RBCs
  3. Half Life = 15 min.
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41
Q

What is the PK of Salicylate?

A
  1. Half Life = 2-3 Hr at low concentrations.

2. Up to 30 Hr at high concentrations.

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42
Q

What is the Excretion profile of Salicylates?

A
  1. Less that pH of 5 = 0%
  2. Normally = 10%
  3. Increased pH up to 30% (ion trapping)
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43
Q

What is the MOA of Salicylates?

A
  1. Inhibition of prostanoid synthesis.

- Inhibits Prostaglandin H synthase & Prostaglandin G/H Synthase (Cyclooxygenase COX)

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44
Q

What do Prostanoids do?

A
  1. Mediate:
    - Thrombosis and Homostasis
    - Glomerular filtration & water balance.
    - Ovulation, Implantation & development.
    - Initiation of labor or abortion.
    - Inflammation & modulation of immune response.
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45
Q

What are other possible MOAs of salicylates?

A
  1. Increased endocannabinoids.
  2. Inhibition of spinal nociceptive processing by 5-HT, NE & ACh.
  3. Reduction of NO production.
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46
Q

What are 3 main metabolites of Arachidonic Acid?

A
  1. Thromboxane (TxA2)
  2. PGE2
  3. Prostacycline (PGl2)
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47
Q

Which COX enzyme is constitutive?

A
  1. COX-1
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48
Q

Which COX enzyme is Induced?

A
  1. COX-2
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49
Q

What is the metabolism pathway of Arachidonic Acid?

A
  1. Arachidonic Acid
  2. Prostaglandin G2
  3. Prostaglandin H2
  4. (Tissue Specific Isomerases and Synthases produce products)
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50
Q

What are the 2 classes of arachidonic acid metabolites?

A
  1. Eicosanoids (20 C’s)
    - Prostaglandins, Thromboxanes, Leucotrienes.
  2. Prostanoids
    - Prostaglandins, Thromboxanes.
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51
Q

What are the actions of Arachidonic Acid Metabolites for Pain & Inflammation?

A
  1. PGE2 produced by COX
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52
Q

What are the actions of Arachidonic Acid Metabolites in Blood Vessels?

A
  1. Vasodilators
    - Prostaglandins & Prostacyclin (good guys)
  2. Vasoconstrictor
    - Thromboxane (bad guy)
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53
Q

What are the actions of Arachidonic Acid Metabolites in Blood?

A
  1. Platelet Aggregation
    - Thromboxane (platelets)
  2. Platelete Disaggregation
    - Prostacyclin (endothelial cells lining blood vessels)
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54
Q

What are the actions of Arachidonic Acid Metabolites in the GI Tract?

A
  1. Inhibit gastric acid secretion
  2. Increase secretion of mucous + HCO3
    - PGE2 & Prostacyclin for both.
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55
Q

What are the actions of Arachidonic Acid Metabolites in the Kidney?

A
  1. Maintain renal blood flow, Increase Na+ water retention.

- PGE2 & Prostacyclin.

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56
Q

What are properties of COX-1?

A
  1. Produces arachidonic acid metabolites that:
    - Mediate protective features of Prostaglandins and Prostacyclin.
    - Predominant enzyme producing Thromboxane.
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57
Q

What are properties of COX-2?

A
  1. Produces arachidonic acid metabolites:
    - Mediate pathological inflammatory processes.
    - Predominant enzyme producing prostacyclin
    - PGE2 most abundant product of BOTH COX1 & COX2.
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58
Q

What are the COX2 selective NSAIDs

A
  1. Celecoxib
  2. Valdecoxib
  3. Rofecoxib
  4. Etoricoxib
  5. Lumiacoxib
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59
Q

What is the set point of temperature maintained by?

A
  1. Hypothalamic Nuclei
    - Anterior (Heat)
    - Posterior (Cold)
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60
Q

What is the Mechanism of temperature control in the hypothalamus?

A
  1. PGE2 Increase cAMP production
  2. Increase Temperature by Increasing Heat Generation
  3. Decrease Heat Loss.
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61
Q

How do NSAIDs and APAP work as anti-pyretic?

A
  1. Block Hypothalamic response to cytokines released from monocytes and macrophages by decreasing PGE2 Production.
  2. Increase Heat loss by vasodilation and sweating.
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62
Q

What happens in RA?

A
  1. Increased pro-inflammatory cytokines increases PGE2.

2. NSAIDs first line therapy.

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63
Q

What is first line treatment for Osteoarthritis?

A
  1. Oral acetaminophen, but less effective by intraarticular injection.
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64
Q

What are the GI effects of COX inhibition?

A
  1. Gastric Intolerance, Dyspepsia (most common)

2. Ulcer

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65
Q

Why is Gastric intolerance, dyspepsia caused by COX inhibition?

A
  1. Due to chemoreceptor trigger zone stimulation.
  2. Direct Chemical Irritant
  3. COX-1 Inhibition.
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66
Q

Why can Ulcers be produced by COX inhibition?

A
  1. Breakdown of gastric mucosal layer by COX1 inhibition.
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67
Q

What are the Roles of PGE2 and PGI2 in the GI Tract?

A
  1. Decrease gastric acid secretion.
  2. Increase Mucus secretion.
  3. Increase HCO3 secretion.
  4. Increase mucosal blood flow (PGI2)
68
Q

What is involved in ASA and GI bleeding?

A
  1. Produces occult blood loss.
  2. Acute GI hemorrhage
  3. Risk of GI bleeding dose related.
69
Q

Which drugs increase the risk of GI bleeding?

A
  1. Clopidogrel
  2. Warfarin
  3. NSAIDs
70
Q

What are the risk factors for NSAID induced GI complications?

A
  1. Hx of PUD
  2. Hx of GI bleeding
  3. Anticoagulants
  4. Long-term NSAID use.
  5. Excessive Dose
  6. Age 65 over
  7. Smoking/Alcoholism
  8. Hx of side effects
  9. Hx of CVD.
71
Q

What are approaches to reduce GI side effects due to COX inhibition?

A
  1. Buffered ASA
  2. Enteric coated tablets.
  3. Adjunct Therapy.
72
Q

Why does buffered ASA reduce GI side effects?

A

Reduces disintegration time.

NOT neutralize stomach contents.

73
Q

What are adjunct therapies involved in reducing GI side effects due to COX inhibition?

A
  1. H2 receptor antagonists
  2. Anti-secretory agents
  3. Prostaglandin E1 analog
  4. H. pylori eradication.
  5. Acid Neutralizers/Acid barrier compounds.
74
Q

What is an example of H2 receptor antagonists?

A
  1. Cimetidine
75
Q

What is an example anti-secretory agents?

76
Q

What is an example of a Prostaglandin E1 analog?

A

1.Misoprostol

77
Q

What is another important effect of COX inhibition regarding blood cells?

A
  1. Inhibition of Platelet aggregation
    - Induced by various agonists.
    - Causes release of arachidonic acid.
    - Inhibition of COX-1, NO Thromboxane A2, no aggregation.
78
Q

What is the difference in inhibition of platelet aggregation between ASA and other NSAIDs?

A
  1. ASA irreversibly inhibits platelet COX-1

2. NSAIDs reversible inhibition

79
Q

When are salicylates & other NSAIDs used for inhibition of platelet aggregation?

A
  1. Decrease risk of vascular death, MI, and Stroke.
80
Q

What is an effect of COX inhibition regarding Cancer Risk?

A
  1. Reduction of most cancers.

2. Daily use of ASA reduced risk by 16%

81
Q

What are the theories why COX inhibition leads to a lower risk of cancer?

A
  1. Less Inflammation, Less cell turnover, Less mutations.

2. COX inhibition decreases cell proliferation, more apoptosis, Less blood vessels forming.

82
Q

What has Dr. Tai’s lab shown about NSAIDs?

A
  1. Up-regulate 15-hydroxyprostaglandin dehydrogenase

- Key prostaglandin catabolic enzyme and tumor suppressor.

83
Q

Which prostaglandin produces Dysmenorrhea?

A
  1. PGF2alpha.
84
Q

What are the effects of Salicylates regarding metabolism?

A
  1. Decreased conversion of ADP to ATP
    - Uncouples oxidative phosphorylation.
    - Protons able to cross
    - Interference causes increased O2 & heat.
85
Q

What are the effects of Salicylates regarding the kidneys?

A
  1. Decreased renal blood flow due to COX inhibition.

2. Competes for acid transporter (URAT1) in renal proximal tubule

86
Q

What kind of acid is ASA?

A

Organic Acid

87
Q

What is the URAT1?

A

Urate Anion Transporter.

-Reabsorbs uric acid, organic acids (drugs & metabolites)

88
Q

What happens with the URAT1 in the presence of Low Salicylate? High Salicylate?

A
  1. Decrease Urate Excretion by exchanging for urate.

2. Increases Urate excretion.

89
Q

What are the effects of Salicylates regarding dermatology?

A
  1. Erythema (redness)

- Dilate capillary smooth muscles

90
Q

What is ASA intolerance?

A
  1. Proven hypersensitivity to ASA
  2. OR Hx of severe indigestion caused by low dose.
  3. Prevalence 6-20%
91
Q

What is ASA hypersensitivity?

A
  1. ASA exacerbated respiratory disease
  2. Cutaneous Reactions.
  3. Systemic Reactions.
92
Q

What are examples of ASA exacerbated respiratory diseases?

A
  1. Asthma

2. Rhinitis/nasal polyps.

93
Q

What are examples of cutaneous reactions of ASA?

A
  1. Urticaria

2. Angioedema.

94
Q

What is the possible reason for universal cross reactivity with NSAIDs

A

Altered eicosanoid metabolism.

95
Q

What is medication overuse headache?

A
  1. Secondary Chronic Daily HA associated w/ overused drug in HA prone patient.
  2. Present for 15 days/month
96
Q

What is considered overuse of NSAIDs?

A
  1. Use of simple analgesic 15 or more days/month for 3 months.
  2. Use of ergotamine, combination analgesics, triptants, opiodis, or the combination of short-term meds 10 days/mo
97
Q

What pregnancy category are salicylates in?

A

Category C (no evidence of teratogenicity)

98
Q

Is low dose ASA effective to prevent subsequent pregnancy loss in women w/ Hx of loss?

99
Q

What are the effects of salicylates on labor and delivery?

A
  1. Increase duration of labor due to inhibition of Prostaglandins (E&F)
  2. Increase complicated deliveries and still births.
  3. Increase bleeding.
100
Q

What are the effects of salicylates on newborns?

A
  1. Increase bleeding.
101
Q

What should you tell a patient who is pregnant about salicylate use?

A

Avoid ASA near-term.

102
Q

What is Preeclampsia?

A
  1. Woman’s BP suddenly gets too high during prego.
  2. Delivery of fetus, often prematurely is treatment.
  3. Responsible for 15% of preterm births.
  4. Low dose daily ASA after 1st trimester lowered risk for people at high risk of this.
103
Q

What are signs of salicylate poisoning?

A
  1. Increased Temp
  2. Tinnitus
  3. Nausea/Vomiting
  4. Lethargy/Exciibility
  5. Hyperventilation leading to respiratory alkalosis.
104
Q

What are signs of severe salicylate poisoning?

A
  1. Metabolic Acidosis.

2. Seizures.

105
Q

What is the toxic level of salicylates for a 30lb child?

A
  1. 12 adult ASA

2. 48 baby ASA.

106
Q

What symptoms of salicylate intoxication show at 50-80mg/dl?

A
  1. Tinnitus (seen as low as 20)
  2. Drowsy
  3. Sweating
  4. No or delayed symptoms.
107
Q

What is stimulated when salicylate levels are above 35 mg/dl?

A
  1. Medullary respiratory center
  2. leads to Hyperventilation
  3. leads to Respiratory alkalosis
  4. Leads to renal excretion of HCO3, Na, and K to compensate for respiratory alkalosis; reduced buffering capacity.
108
Q

What happens at salicylate levels of 50mg/dl?

A
  1. Depresses medullary respiratory center.
  2. Hypoventilation, increases CO2 retention.
  3. Respiratory acidosis, cannot be buffered well due to prior loss of HCO3.
109
Q

What is indicative of salicylate levels of greater than 160 mg/dl?

A

Lethality!

110
Q

What happens when there is a decrease in renal function?

A
  1. Accumulation of acids of metabolic origin.
  2. Disruption of carb metabolism to cause accumulation of organic acids
  3. leads to metabolic acidosis.
  4. Increase of fat catabolism leads to accumulation of acetone and ketone bodies.
  5. may not be adequately buffered.
111
Q

What is the treatment of salicylate intoxication?

A
  1. Lavage or Charcoal for large ingestion.
  2. Enteric coated tablets: whole body irrigation w/ PEG solutions until rectal effluent is clear.
  3. Correct dehydration
  4. Alkaline diuresis to urine pH 7.5-8
  5. Symptomatic Tx.
112
Q

What are the interaction mechanisms of ASA?

A
  1. Competition for plasma protein binding
  2. Competition for renal organic acid excretion at low ASA doses. (Opposite at high doses)
  3. Synergistic effect w/ other GI irritants.
113
Q

What drugs are displaced by salicylate?

A
  1. Sulfonylurea hypoglycemics.
  2. Valproate
  3. Oral anticoagulants.
114
Q

What is Salsalate (Disalcid) metabolized to?

A
  1. Salicylate.
115
Q

What is Diflunisal (Dolobid) metabolized to?

A

NOT salicylate.

116
Q

What are uses and effects of Non-selective NSAIDs?

A
  1. As analgesics
  2. Anti-inflammatory agents
  3. Dysmenorrhea
  4. Antipyretics
  5. Reversible Inhibitors of platelet aggregation.
117
Q

What are structural families of non-selective NSAIDs?

A
  1. Acetic acids
  2. Phenylacetic acids
  3. Propionic acids
  4. Fenamic acids
  5. Oxicams (enolic acids)
118
Q

What are the PK properties of non-selective NSAIDs?

A

A: good orally
D: Small Vd, extensive PPB
M: Variable
E: Low urinary excretion of parent drug.

119
Q

What are some Non-oral NSAIDs?

A
  1. Ketorolac

2. IBU

120
Q

What are the characteristics of Ketorolac?

A
  1. Duration of use limited to 5 days for moderate to moderately severe pain that requires analgesia at opioid level.
    - IM, IV, Intra-nasal
121
Q

What are the characteristics of IV IBU?

A
  1. Mild/moderate adjunct to opioids for pain & fever; for hospital use only.
  2. Acute: 400-800 mg over 30 min q6hr
  3. For Fever: 400mg over 30 min, then 400 mg q4-6hr
    OR 100-200mg q4hr PRN.
122
Q

Which NSAID has the worst increase in CV risk in cardiac patients?

A
  1. Diclofenac.
123
Q

What is the solution to reduce increase of CV risk in cardiac patients?

A
  1. Use more selective COX-1 inhibitor at minimum dose for shortest time.
124
Q

NSAIDs: What is nephrotoxicity due to?

A
  1. Fluid and Electrolyte disturbances caused by decreased prostaglandin synthesis.
    - Na,K,Cl retention
    - Edema
125
Q

NSAIDs: What is acute renal failure?

A
  1. Rapid & Sustained abruption of renal function.
    - Due to no PG synthesis
    - Causes acute ischemic renal insufficiency.
    - Typically dose and duration dependent and reversible.
126
Q

NSAIDs: What is Renal papillary necrosis?

A
  1. Due to impaired blood flow and hypoxia.
127
Q

NSAIDs: What is Nephrotic Syndrome w/ acute interstitial nephritis?

A
  1. Inflammation in spaces b/w kidney tubules.
  2. Drug hypersensitivity (sepsis, glomerular disease)
  3. Occurs days after exposure, REVERSIBLE.
128
Q

NSAIDs: What is Chronic Renal Failure?

A
  1. May be secondary to interstitial nephritis or papillary necrosis.
  2. High (not low) NSAID doses increase the risk.
129
Q

What is the association between renal cancer and NSAID use?

A
  1. Duration of use and dose-dependent increased renal cell cancer compared to non-NSAID users.
    - NOT ASA and APAP.
130
Q

NSAIDs: What is Hepatotoxicity?

A
  1. Quite uncommon
  2. Increased liver enzymes
  3. Unless greater than 8 times normal no concern.
  4. Attributed to metabolites that form covalent adducts w/ hepatocellular proteins (act as immunogens)
    - DICLOFENAC
131
Q

What do Aminotransferases do?

A
  1. Catalyze the transfer of amino group of an amino acid to an alpha keto acid.
132
Q

What does AST do?

A
  1. Glutamic acid + OAA = alpha ketoglutaric acid + aspartic acid.
    - Normal value 0-35 U/L
    - AKA SGOT
    - Indicator of Liver Damage
133
Q

What does ALT do?

A
  1. Glutamate + Pyruvate = alpha ketoglutarate + alanine
    - Normal value = 0-35 U/L
    - AKA SGPT
    - Indicator of Liver Damage
134
Q

What are Contraindications of ASA treatment?

A
  1. Asthma associated w/ ASA.

2. Urticaria & other sensitivity reactions associated w/ ASA.

135
Q

Why should NSAIDs not be used in the 3rd trimester?

A
  1. Possible closure of the ductus arteriosis.
136
Q

What are the drug interaction mechanisms w/ NSAIDs?

A
  1. Competition for PPB

2. Inhibition of platelet aggregation w/ Warfarin (increase anticoagulant effect)

137
Q

Which drugs compete for PPB w/ NSAIDs?

A
  1. Oral Anticoagulants displaced.

2. Phenytoin.

138
Q

What are Highly selective COX-2 Competitive inhibitors also called?

A

COX-1 Sparing NSAIDs.

139
Q

What are highly selective COX-2 competitive inhibitors approved for?

A
  1. Osteoarthritis and RA

2. Some approved for pain.

140
Q

What doe highly selective COX-2 Competitive inhibitors do?

A

Inhibit COX-2 mediation of PGI2 production which is anti-thrombotic so should cause PRO-Thrmobotic effects.

141
Q

Which drugs are highly selective for COX2?

A
  1. Rofecoxib (highest in vitro selectivity)

2. Celecoxib (much less selective)

142
Q

What are the side effects of Selective COX-2 Inhibitors?

A

Generally have PROFILES like traditional NSAIDs.

143
Q

What is the benefit to using selective COX2 inhibitors?

A
  1. Reduced INCIDENCE of GI side effects.
144
Q

What is DVT?

A
  1. A blood clot that forms in a vein deep inside a part of the body. It mainly affects the large veins in the lower leg and thigh.
145
Q

What is Pulmonary embolism?

A
  1. When pulmonary arteries in the lungs become blocked, usually caused by blood clots that travel to the lungs from the legs or rarely other parts of the body.
146
Q

What is the hypothesis that NSAIDs increase venous thromboembolism?

A
  1. COX2 inhibition inhibits prostacyclin synthesis AND stimulates thromboxane release from activated platelets.
  2. Result could be platelet aggregation, induction of clotting cascade, and clot formation.
147
Q

What is important about Celecoxib use?

A
  1. Should not be given to patients who have experienced an allergic reaction to sulfonamides.
    - Contains sulfonamide group.
148
Q

How is Celecoxib metabolized?

A
  1. CYP2C9, inhibits CYP2D6 - basis of potential drug interactions.
149
Q

What are the side effects of Celecoxib?

A
  1. Most common: HA

2. Abdominal pain, diarrhea, dyspepsia.

150
Q

What is the association b/w Celecoxib and GI ulcers?

A
  1. More ulcers seen w/ placebo, fewer with traditional NSAIDs.
151
Q

What other formulations of Diclofenac are available?

A
  1. 1% gel for topical Tx of osteoarthritis.
  2. In a patch
  3. IV bolus injection.
152
Q

What is the dose change recommended for patients taking Celcoxib and cannot tolerate GI effects?

A
  1. Continue less than 100 mg BID or 200 mg daily.
153
Q

What are some alternatives for NSAIDs?

A
  1. APAP for analgesia and Osteoarthritis.
  2. Tramadol
  3. Addition of:
    - Misoprostol
    - PPI
    - High doses of H2 receptor antagonists.
154
Q

What is the proposed MOA of Acetaminophen?

A
  1. Inhibit brain much more than peripheral COX.
  2. appears selective for COX-2
  3. Stimulate descending serotninergic pathways to inhibit afferent pain fibers.
155
Q

What does of APAP is effective for post-op pain?

A
  1. 1000 mg more effective than 650
156
Q

What is the PK profile of APAP?

A

A: Oral (rapid and complete) Rectal (considerable interpatient variability)
D: extensive, PPB: less than 50%
M: 80% in liver, half life 1-3hr.

157
Q

What is the IV formulation of APAP (Ofirmev) used for?

A
  1. Pre- & Post-operative pain management, fever reduction.
158
Q

What is the issue with APAP regarding INR response to warfarin?

A
  1. Can increase INR.

2. Especially when greater than 2g/day for consecutive days.

159
Q

What is the MOA hypothesis of APAP and increased INR?

A
  1. Genetic polymorphism of CYP2C9 warfarin metabolism.
  2. Reduced warfarin metabolism
  3. Shunting to CYP3A4, that APAP can inhibit.
160
Q

What is the minimum toxic single dose in health adults for APAP? Children?

A
  1. 7.5-10g

2. Children greater than 150mg/kg

161
Q

What is the primary problem of APAP intoxication?

A
  1. Hepatotoxicity
  • 6-14 hr: non-specific flue like symptoms, liver enzymes increase.
  • If not fatal recovery w/ damaged liver.
162
Q

What induces CYP2E1?

A
  1. Repeated ethanol consumption and fasting.

2. Hepatotoxicity may occur w/ less than 2-4 g/day APAP.

163
Q

What increases the risk of renal toxicity when taking APAP and by how much?

A
  1. Concurrent light-moderate ethanol (less than 2drink/day)

2. 2 fold.

164
Q

What is the most common source of APAP overdose?

A
  1. Rx combination products containing APAP
165
Q

How do you manage APAP intoxication?

A
  1. N-acetylcysteine
    - effective if given within 8-10hr of OD
  2. Oral: mucomyst
  3. IV: Acetadote.

Neuro Pharmacology (9 decks)

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