02/12/2009 13:59:00

← Pain:
←
Acute: Short term; persisting only for tissue damage duration
← Chronic: Presnt even when the normal healing mechanisms have been
completed and is long term e.g. RA
←
← 1. Activation of nociceptors in peripheral tissues
← - BK and Histamine stimulate nociceptors
← (BK acts via a G-protein coupled receptor = proinflammatory effects
ex. Vasodilation and oedema
← BK also activates membrane bound phospholipase A2 enxyme activity
–membrane de-esterification, leading to the release of arachidonic acid –
prostaglandins (PGE2 and prostacyclin PGI2) by COX.
←
← Prostaglandins cause hyperalgesia but NOT alagesia
←
← Hyperalagesia = tenderness +/- pain from relatively innocuous stimuli
←
← PGs accentuate the pain producing effect of mechanical/chemical
stimulation or BK/histamine.
←
← 5-HT released from degranulating mast cells at the site of tissue
damage and triggers a powerful painful response. (greater than
BK/histamine)
←
← A variety of metabolic substances released from damaged cells e.g.
ATP, K+ an lactic acid exhibit algesic activity.
←
← 2. Pain perception is the transfer of info from stimulated nociceptors to
SC
← - Myelinated Ad fibres ~15 m/s = Sharp intense pain
← - Unmyelinated C fibres ~1m/s = less well localized; dull, throbbing
ache
←
← 1st order Dhorn neurons enter through dorsal root and synapse with 2nd
order (nociresponsce_ neurons in the superficial laminae I and II.
← Substance P, glutamate and neurokinin A = Neurotransmitters
←
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← Opiods: Any substance whose actions are reversed by Naloxone
←
← 3 major classes of opiod receptor: G protein coupled
← 1. (u) mu = Underlies analgesic effect
← 2. (d) Delta =
← 3. (k) Kappa =
←
← Sigma has also been suggested but a number of other drugs act as
ligands here.
←
← 3 families derived from 3 prohormones:
← 1. B-endorphins from POMC
← 2. enkephalins from proenkephalin
← 3. Dynorphins from pro-dynorphin
←
← - Activation of all 3 receptor subtypes
← - Inhibits adenyly cylase – decreased cAMP
← - Inhibits Ca2+ entry into nerve terminals
← - Open K+ channels
← (Reduce neuronal excitability- hyperpolarized- and Neurotransmitter
release- due to Ca2+ inhibition).
← Inhibit release of glutamate and substance P
← Overall effect = INHIBITORY
←
← Opiods produce disinhibition of transmission in all PAG and NRPG thus
increasing output from these nuclei. *****
←
← Full agonists = Morphine (all 3), Methadone
← Partial agonists = Pentazocine, Buprenorphine
← (this will antagonize the effects of Morphine- for every receptor
occupied by buprenorphine there will be a lower analgesic effect)
← Antagonists = Naloxone, Naltrexone
←
← Used to treat moderate to severe pain
← less effect against neuropahtic pain e.g CN V neuralgia/phantomlimb
← Associated Euphoric effect – helps calm anxiety ass with MI
← Nausea and vomiting – admins with prochlorperazine (anti-emetic)
← Cough suppressant – pholcodeine used in cough remedies,
diamorphine linctus for lung cancer patients
←
← u/d receptor:
← - Spinal and supraspinal analgesia
← - Resp depression (less sensitive to CO2) (in OD)
← -Miosis (in OD)
← - Euphoria and sedation (physical dependence)
←
← K receptor:
← Spinal analgesia
← Slight resp depression
← Dysphoria and sedation
← Phys dependence
←
←
←
←
←
←
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← NSAIDs:
←
← Inhibit the biosynthesis of hyperalagesic and proinflammatory PG’s
←
← Anti-inflam, Anti-pyretic and mild analgesic.
←
← Tissue damage e.g. inflammation and plasma membrane distortion
activate phospholipase A2 enzyme.
← Cleaves free arachiadonic acid from its binding site and it become
accessible to COX (cyclo-oxygenase).
←
← All NSAIDs inhibit COX
←
← COX-1 : Constitutive enzyme found in many cells including platelets.
• Housekeeping role; involved in tissue homeostasis
• Responsible for production of PGs involved in platlet agg and renal
blood flow autoregulation + GASTRIC CYTOPROTECTION
← COX-2: Synthesised in inflammatory cells e.g. neutrophils, mast cells
• Following exposure to bacterial endotox +/-cytokines (TNFa & IL-1)
• Responsible for generating PG’s at site of tissue damage/inflamm
← * Some COX-2 present in CNS and other tissues althought unclear why
←
← Mostly non-selective inhibition of both COX-1 and COX-2
←
← Believed that anti-inflam and analgesia is mainly from inhibition of
COX-2
← Unwanted Side effects mainly due to COX-1.
← COX-2 selective ass with increased CV risk possibly due to lack of
inhibition of TXA2 production.
←
← Side effects:
← 1. gastric bleeding/ulceration:
• 1/5 users
• Inhibition of PGs in gastric mucosa; involved in regulating acid
secretion and producing protective mucus layer.
• Reduced by co-admins of PG analogue e.g. Misoprostol
• Inhibit platelet agg by inhibiting TXA2 (vasoconstricting+pro agg)
← 2. Skin reactions:
• Mild rashes – photosensitivity (withdrawal of Benoxiprofen)
← 3. Renal insufficiency:
• PGs involved in regulating renal blood flow
• Only a problem with pre-existing renal problems.
←
← Asprin – covalently modifies serine residues in both COX-1 and COX-2
thus preventing further biosynthesis of Prostanoids.
←
Newer NSAIDs bind reversibly to COX-1 and COX-2
e.g. ibruprofen, ketorolac, mefenamic acid, acetominophen

Given P/o and analgesia lasts for about 6-8 hours (piroxicam can last longer)
Not effective against severe pain (esp. visceral origin)

Provide relief for mild-moderate pain:

1. Pain asso with inflamm componant e.g. RA, gout, toothache
2. Pain of cancer metastasis, injury (bone fractures) and some headaches
3. Dysmenorrhea – results from increased uterine PG

Ketorolac and acetominophen = good analgesics, weak anti-inflam