Lec 16 Pain & Inflammation

Question 1

Aspirin-Like Analgesics

mechanism

Answer 1

-selectively inhibit cyclooxygenase, blocking synthesis of prostaglandins and thromboxanes from arachadonic acid

Question 2

COX1 vs COX2

Answer 2

COX1: constitutively expressed
COX2: induced by pro-inflammatory stimuli

Question 3

Aspirin-Like Analgesics

side-effects, 4

Answer 3

• increased bleeding time
• gastic ulcers
• reyes syndrome (encephalopathy)
• hepatotoxicity (acetominaphen)

Question 4

Increased Bleeding Time w/ Asprin

Answer 4

• aspirin irreversibly inhibits COX1/2
• in order for metabolites, especially thromboxanes to rebuild stores, have to resynthesize proteins, which takes time
• without thromboxanes, loose ability to properly and effectively clot

Question 5

Opioid Analgesics

vs. aspirin-like

Answer 5

-much higher analgesic efficacy and more potent

Question 6

Opioid Analgesics 
(mechanism at sensory afferent fibers Ad, C)

Answer 6

• opioid binding to MOR on presynaptic blocks opening of VGCaC, prohibiting NT release
• binding to MOR on postsynaptic enhances K+ channel opening, hyper-polarizing the membrane and preventing transmission of any signal that may arrive
• overall attenuates afferent evoked excitation of the neuron

Question 7

Opioid Analgesics 
(mechanism at brain nuclei)

Answer 7

• binds to MOR, increasing descending inhibitory neuron signaling on pain transmission
• NTs: 5HT, NE

Question 8

Opioid Receptor Signaling & Desensitization

Answer 8

• activation of receptor (GPCR) causes arrestin to bind which signals internalization of the receptor and loss of response to the agonist
• easy to build up tolerance

Question 9

Narcan (Naloxone)

Answer 9

• addition of alkyl chain to agonist, forming an antagonist with high affinity for the MOR, blocking binding of the agonist
• antagonist has no efficacy, but has short duration of action

Question 10

Opioid Analgesic Side Effects

Answer 10

• psychological/physical dependence (addictive)

- pinpoint pupils, sedation, constipation, respiratory depression (life threatening)

Question 11

Local Anesthetics

Answer 11

• selective inhibition of nerve conduction by binding to a site within Na+ channel protein in nerve membrane, inhibiting the Na+ flux necessary for AP propagation
• injected directly into the site, often with an alpha-agonist for vasoconstriction. also safety to prevent build up in circulation (can have cardiac and CNS effects)
• along nodes of ranvier (myelinated) or evenly spaced (non-myelinated)

Question 12

General Anesthetics

Answer 12

• nonselective loss of neuronal activity in the brain leading to analgesia and loss of consciousness
• inhaled vapors of gas, low therapeutic index
• potentiate inhibitory GABA synapses (Cl- channel open), inhibit excitatory ACh synapses (block ion pore)

inc oil:water =dec Panesthetic = inc potency = dec MAC (median alveolar conc, 50%)

Question 13

Inflammatory Response Characteristics (4)

Answer 13

1. increased blood flow
2. exudation of vascular fluid and proteins into tissue (increased vascular permeability)
3. chemoattraction of leukocytes and migration of blood into tissue
4. proliferative phase w/ tissue degeneration and fibrosis

Question 14

Mediators of Acute Inflammation (3)

Answer 14

1. Histamine
   - vasodilation, vascular permeability
   - from mast cells with tissue injury or antigen activation
2. Bradykinin
   - vasodilation, vascular permeability, pain
   - released with tissue injury
3. Prostaglandins & Leukotriens
   - vasodilation, vascular permeability, chemotaxis, pain

Question 15

Mediators of Chronic Inflammation (2)

Answer 15

[lead to fever, sleep, b- and t-cell activation, COX2 and lipoxygenase induction, fibroblast proliferation

1. IL-1, IL-2
   - from macrophages, t-cells
   - inflammation from b- and t-cell activation
2. TNF-a
   - from macrophages
   - inflammations via NF-kB singaling

Question 16

Antihistamines

histamine receptors and antagonists

Answer 16

1. H1 Receptor
   - itching, vasodilation, vascular permeability
   - histamine released by proinflammatory stimuli
   - antagonist: antihistamines, antagonize vascular permeability and vasodilation at nerve endings (1st gen: sedating, 2nd gen: nonsedating)
2. H2 Receptor
   - mediates gastric acid secretion
   - antagonist: anti-ulcer drugs

Question 17

NSAID

Answer 17

[non-steroidal anti-inflammatory drugs]

• inhibit COX2, and thus PGs
  ex. aspirin, ibuprofen, celecoxib (NOT acetaminophen)

Question 18

Glucocorticoids & NF-kB

anti-inflammatory and immunosuppressant effects

Answer 18

1. antagonism of NF-kB
   - increased translocation of gene for I-kB (inhibitor of NF-kB)
   - nuclear binding by ligand-bound GC receptor
2. block release of arachidonic acid and its metabolites
   - increased transcription of gene for lipocortin, which inhibits phospholipase two, thus
   - decreasing COX2 transcription

Question 19

Cytotoxic Drugs

ex and mech

Answer 19

ex. methotrexate

- inhibit cell replication, block t- and b-cell replication

Question 20

T-cell Specific Inhibitors

ex and mech

Answer 20

ex. cyclosporine
bind cytosolic proteins that blood transcription required for t-cell activation, thus:
-block antigen-triggered t-cell activation
-inhibit cellular immunity
-prevent transplant rejection

Question 21

TNF-a antagonists

Answer 21

monoclonal antibodies and receptor analogues that bind to the cytokine TNF-a
(cytokine antagonists, NOT receptor)