13. Analgesics Flashcards
List medical analgesics
- non steroidal anti-inflammatories
- pioid analgesics
- general anaesthetics
- local anaesthetics
- anxiolytics
List non-medical analgesics
- alcohol
- nicotine/caffeine
- cocaine
- LSD
Why do dentists need to understand analgesics?
- prescribed for post operative dental pain
Noxious stimuli are sensed by …
Process?
- peripheral receptors/nociceptors
- nociceptive fibres travel to CNS (dorsal horn) and excite transmission fibres running to the thalamus
- nociception is process whereby noxious peripheral stimuli transmitted to CNS
Are pain and nociception the same thing?
- no
- pain is subjective and amount of pain a stimuli produces depends on more than stimulus itself
- pain has sensory and emotional components
Chemical mediators for nociception/pain
- in most cases, stimulation of nociceptive endings in periphery is chemical in origin
- mechanical and thermal stimuli can cause acute pain but chronic pain results due to chemical mediators
Polynodal nociceptors are what?
receive afferent fibres in high proportions in periphery to send to brain
high receptor threshold
3 types of afferent fibres in nociception
- C fibres
- A delta
- A beta fibres
Where are C fibres?
outer dorsal horn
Properties of C fibres
- non-myelinated
- low conduction velocity
- nociceptor/thermoreceptor/machanoreceptor
Properties of A-delta fibres
- myelinated
- rapid conduction velocity
- nociceptor/mechanoreceptor
What kind of receptor is A-beta fibres
mechanoreceptors
Explain the neural pathway of nociception from primary afferent neurons to superficial lamina of dorsal horn of spinal cord
- signal goes from pain trigger to PAN, to dorsal horn to brainstem (pons/medulla) to midbrain
- goes to thalamus to the cingulate and somatosensory cortexes and the limbic system
- ## negative feeback system from limbic system to PAG, down RVM to dorsal horn
Chemical mediators (stimulate pain endings in skin) include …
- 5-HT
- kinins like bradykinin
- metabolites of intermediary metabolism e.g lactic acid
- capsaicin (responsible for burning taste of chilli peppers)
… is a chemical mediator that enhances the pain producing effects of other agents but they do not …
- eicosanoids
- stimulate nociceptive endings
4 properties of NSAIDS
- analgesic - relieve pain
- anti-inflammatory - reduce inflammation
- antipyretic - decrease elevated body temp
- antiplatelet - reduce platelet aggregation
Mechanism of action of NSAIDs
- inhibit prostaglandin (eicosanoid) production by irreversibly inhibiting cyclooxygenase (COX) function
- therapeutic effects related to inhibition of COX 2 (induced in activated inflammatory cells)
- unwanted side effects related to inhibition of COX1 - enzyme expressed in most tissues
Prostaglandin synthetic pathway
- phospholipids in cell membrane
- get phospholipase A2 and related enzymes
- arachidonic acid (goes to lipoxygenase then leukotrines) or cyclo-oxygenase (COX)
- various intermediates (PGG2, PGH2) like thrombocanes, prostaglandins and prostacyclin
Where do NSAIDs work in prostaglandin synthetic pathway?
- NSAIDs act on cyclo-oxygenase inhibiting COX or its reduction
How does aspirin fill the 4 NSAIDs properties?
- analgesic as has decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators like 5-HT, kinins etc
- anti-inflammatory same as above
- antipyretic - centre in hypothalamus regulates body temp, in fever temp is raised due to synthesis of PGE2 due to pyrogens
- aspirin decreases this PGE2 synthesis
- antiplatelet - from blood clotting
When would aspirin be the first choice of drug?
- in mild analgesia
- cheap and effective
ADME of aspirin
- orally taken
- rapidly hydrolysed by esterases to salicylate
- half life of 4-15 hrs - dose dependent
Unwanted effects of aspirin
- low doses gives GI irritation, hypersensitivity
- salicylism in high doses - tinnitus, vertigo, decreased hearing
- Reye’s syndrome, rare childhood disorder
- interacts with warfarin
How does Reye’s manifest?
- massive brain and liver swelling in children coming out of heightened immune state
How does ibuprofen fill the NSAID categories?
- decreased prostanoid synthesis leads to less sensitisation of nociceptors to effects of mediators e.g 5-HR, kinins makes it analgesic and anti-inflammatory
- antipyretic as centre in hypothalamus regulates body temp. In fever, temp raised due to synthesis of PGE2 due to pyrogens and ibuprofen decreases this
- no antiplatelet vibes
When is ibufropen first choice NSAID?
- for inflammatory joint disease
- effective and better tolerated than most
ADME of ibuprofen
- oral, topical, rectal
- rapid absorption in 1-2 hours
Unwanted effects of ibuprofen
- uncommon and mild
- local sensitivity reactions
- less gastric irritation than aspirin
- suitable for kids
How is paracetamol still an NSAID when it’s not anti-inflam or antiplatelet?
- analgesic and antipyretic in exact same ways as aspirin and ibuprofenW
When would paracetamol be the first choice NSAID?
- safe and effective mild analgesic at therapeutic dose
- less analgesic activity in inflammatory conditions
ADME for paracetamol
- oral, rectal, IV
- peak plasma conc within 30-60 mins
- half life 2-4 hrs
- mainly conjugated to glucuronic acid/sulphates
Unwanted effects of paracetamol
- uncommon
- hepatotoxicity in overdose or chronic usage
- allergic skin reactions
Morphine analogues OPIOIDS
- diamorphine (heroin)
- codeine
Synthetic derivatives OPIOIDS
- pethidine
- dextropropoxyphene
Opioid neurotransmitters
- enkephalins
- endorphins
- dynorphins
Opioid receptors
- mu, delta and kappa
- mu responsible for most analgesic effects
- opioid analgesics act as agonists at mu
- all opioid receptors linked through G-proteins to inhibition of denylate cyclase
Therapeutic effects of opioid analgesics
- analgesia
- euphoria and sedation
ADME of opioid analgesics
- oral, rectal, IV, IM
- erratic absorption from gut
- extensive first pass metabolism
Indications of opioid analgesics
- moderate to severe pain with strong opioids e.g morphine, pethidine
- mild to moderate pain/cough suppressive/antidiarrhoel - weak opioids e.g codeine
Adverse CNS effects of opioid analgesics
- drowsiness and sedation
- respiratory depression
- tolerance and dependence
- cough suppression
- nausea-vomiting
Adverse PNS effects of opioid analgesics
- constipation
- histamine release
- pinhole pupils
Give 2 strong opioids
- morphine
- pethidine
Give 2 weak opioids
- dextropropoxyphene
- dihydrocodeine
Explain morphine
- most valuable for severe pain relief
- terminal care
Explain pethidine
- more lipid soluble than morphine
- rapid onset/short duration
- less constipation than morphine
- prescribed by dentists
Explain dextropropoxyphene
- very mild analgesic
- used in combo with aspirin and paracetamol
Expplain dihydrocodeine
- pharmacologically similar to codeine
- nausea and constipation limit dose and duration of use
Tolerance with opioids
- detected in 12-24 hrs
- sensitivity will return on withdrawel
- extends to all pharmacological actions
Dependence on opioids
- following abrupt withdrawal after chronic treatment
- abstinence syndrome after acute treatment
