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What is pain made up from?
Stimulus and emotional perception
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What are the two types of the occurrence of pain and how are they managed?
- Acute - treat the cause may be possible rather than symptom
- Chronic - preferable to treat in anticipation
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What are the four types of sensory fibres and what do they sense?
A aplha - proprioception, low threshold of activation
A beta - low intensity touch, vibration, pressure, low threshold for activation
A zeta - sharp pain, high threshold for activation
C fibres - transmit throbbing pain, slower conduction, non myelinated
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Nociciptive fibres can be activated without specific receptor - direct activation. Some receptors detect stimuli, give examples:
- Heat > 42, acid pH, capsaicin, very hot, mustard (TRPV1)
- Cold, methanol (TRPV8)
- Mechanical stimuli (TRPA)
- ATP from damaged cells (P2X and P2Y ATP receptors)
- low extra cellular pH (lactic acid) (ASIC)
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Name NSAIDS? What is a COX-2 inhibitor?
- Aspirin
- Ibuprofen
- Naproxen
- Meloxicam
- Etodolac
- Indometacin
- Diclofenac
- Celecoxib - COX-2 inhibitor
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What are the functions of COX-1 and COX-2?
- COX-1: 'housekeeping'
- constitutive expression
- gastric protection, vascular homeostasis, platelet aggregation, kidney function.
- COX-2: 'inducible'
- constitutive expression in the brain, kidney (see coxib ADR) bone
- Induced during inflammation (expression inhibited by glucocorticoids)
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What are the functions of prostaglandins?
- They bind GPCR to act as local signalling molecules
- Pain
- PGE2 increases sensitivity of nociceptive fibres
- Temperature
- Pyrogne - increase PGE2 synth (leukcyte) raises temp set point (hypothalamus)
- Inflammation
- Role within inflammatory process
- Respiration
- GI protection (COX-1)
- PGI2 (prostacyclin) inhibits gastric acid secretion
- PGE2, PGF2 stimulate protective mucous secretion
- Platelet aggregation
- Prevents activation
- Kidney
- PGE2 and PGI2 maintain renal perfusion - synthesised in response to reduced perfusion
- Vasoconstriction
- Inhibit prostacyclin induced vasodilation
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How does aspirin work?
Irreversible acetylation of COX1 and 2
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What is the two chemical derivative of NSAIDs?
Propionic acid and Acetic acid
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What drugs are propionic acid derivatives, how do they work? What are the indications? Cautions? Contraindications? Drug interactions?
- Inbuprofen, naproxen, ketoprofen.
- Reversible COX1 and 2 inhibitors
Anti-pyretic, anti-inflammatory, analgesic: arthritis, back pain.
Renal insufficiency, hypertension, avoid pregnancy.
Active peptic ulcers, sever heart failure
Avoid concomitant use with anticoagulation
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What drugs are acetic acid derivatives, how do they work? What are the indications? ADR? Cautions? Contraindications? Drug interactions?
Indometacin, sulindac
Reversibly inhibit COX1 and 2
Anti-pyretic, anti-inflamatory, analgesic: arthritis, gout
GI effects and CNS disturbances common
Avoid unless other NSAIDs ineffective
Sever heart failure, peptic ulceration
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What is the benefit of oxicams? An example? Indication? Dosing?
Relatively COX-2 selective (10 fold) less GI irritation
Piroxicam
Arthritis, gout
Once daily due to long t1/2
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What is diclofenac an inhibitor of? What is it's indication?
COX-2 inhibitor
Long term tx of arthritis
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Coxibs. Name two drugs. Selectivity COX1 or 2? Recommended use and why? Onset of action time for analgesia and anti-inflamation? Contraindications?
Celecoxib, etoricoxib.
Selective COX-2, Lower risk of GI bleeding, no antiplatelet effect.
Low dose, for short duration if possible, risk of MI/stroke associated with long term tx. For patients who need NSAID but risk of GI toxicity.
Full analgesia 1 week, full antiinflammatory up to 3 weeks.
Ulcerative colitis, Crohn's disease - worsen bowel inflammation. Ischaemic heart disease, heart failure, vascular disease
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Paracetamol. Uses (indications), mechanism, ADR, cautions, interactions?
Analgesic (regular use more effective than as required) antipyretic, (poor anti-inflammatory)
Probably inhibits PG synthesis in CNS by COX-3
Few at therapeutic dose
Hepatic impairment. Most common drug used in overdose.
Warfarin? may increase INR (unclear and contradictory evidence)
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Where are opioid receptors found and what functions are they involved with?
Brain stem: respiration, cough, nausea, bp, pupil diameter
Spinal cord & thalamus: pain
Limbic system: emotional behaviour
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Give examples of full agonists, pro-drugs and mixed agonist/antagonist & partial agonist. Indications?
Morphine, fentanyl, sufentanil
codiene (10% metabolised to morphine)
Buprenorphine, pentazocine
- Morphine = pain
- codeine = mild pain, coughing, diarrhoea
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What is naloxone and what is it used for?
Opioid receptor antagonist
Used to reverse coma and respiratory depression after opioid overdose.
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