Analgesics Flashcards
What is the WHO analgesic ladder?
- Introduced in 1986 to address cancer pain relied.Revised in 1996
– Move up a step with persistent pain - Move down a step or toxicity reduce dose
- Step 1 : Non-opioid plus optional adjuvant analgesics for mild pain
- Step 2 : Weak opioid plus non-opioid and adjuvent analgesics for mild to moderate pain
- Step 3 : strong opioid plus non-opioid and adjuvent analgesics for moderate to severe pain
Where do analgesics work?
-Activation of descending norandrenergic and/or 5HT systems leads to the activation of spinal inhibitory interneurons (l)
- Spinal inhibitory interneurons (l) release enkepahlins (Enk. endogenous opioids) or GABA as neurotransmitters
- Glutamate (Glu) and substance P (sP) released from primary afferent terminals (A) actiavet glutamate and neurokinin-1 (NK-1) recepoors, respectively on spinal neurons
- Nerve endings respond to stimulation by:
- Acid (H+), temperature, PGE2, 5-HT, nerve growth factor (NGF) etc. released from damaged cells
- Bradykinin (BK) released from blood vessels
- Substance P from nociceptors
- can be synergistic
What are the analgesic effects of NSAIDS?
- Decrease production of prostaglandins - mainly PGE2, which would sensitise nocireptors to inflammatory mediators
- May also have CNS or spinal cord effect
- Likely to be COX2 mediated
- Effective in pain associated with prostaglandin production e.g. arthritis, bursitis, muscular and vascular pain, toothache. dysmenorrhoea, postpartum and cancer metastases in bone
What are the different types of COX?
COX 1:
- physiological roles
- Stomach
- Kidney
- Constitutive
- COX 1 selective
- COX 2:
- Inflammatory roles
- Induced during inflammation
- COx 2 selective = increased risk of myocardial infarction
What is aspirin?
- Acetylsalicylic acid
- Generally replaced by other NSAIDs for inflammation
- Current clinical use as an antiplatelet drug
- Metanolised to salicylate
- Not used in children - Reye’s syndrome
What is paracetamol?
- Actemaniophen in USA
- Analgesic and antupyretic but not anti-inflammatory
- Few gastric or platelet side effects at therapeutic doses
- not really a NSAID
- Action likely in CNS
What happens during paracetamol overdose?
- potentially fatal hepatic necrosis through conversion to a toxic metabolite NAPQI and subsequent depletion of glutathione = oxidate stress and damage
- Treatment of overdose:
- Activated charcoal within 4 hours if dose . 7.5g
- N-acetylcysteine - acts as gluthathione substitute and detoxifies NAPQI
- Liver failure = transplant
What is Ibuprofen?
- Most common choice of NSAID for mild-moderate pain
- Short half-life
- Low solubility in water- preparation for iv is difficult
- Insoluble in the stomach - slow and erratic absorption
- Controlled release formulations using liposomes, polymers or nanoparticles - release in intestine or even colon - plasma concentrations are very low
What are opioids?
- endogenous peptide agonists discovered in 1975 (enkephalins, endorphins etc.)
- semi-synthetic - codeine, oxycodeon, diamorphine
- synthetic : pethidine, fentanyl , methadone,, buprenorphine
What are some uses of opioids?
- Analgesic action via micro pioid receptors.
- Peripheral
- Spinal
- Supraspinal
- Useful for acute pain and “end of life” pain but not neuropathic or
chronic pain - GPCRs — coupled to Gi
- decreased cAMP and increased potassium conductance
- hyperpolarisation
- decreased neurotransmitter release
Other uses :
Sedation
Treatment of diarrhoea
Anti-tussive (Stops coughing)
- Treatment of opioid addiction
What are the different opioid potencies?
0.1 = codeine, tramadol
1= Oxycodeone, morphine
10 = methadone
100 = fetanyl, buprenorphine
What is the onset time of opioids?
- Time to onset varies between different opioids
- Alfentanil—2 min
- Fentanyl —4 min
- Heroin —8 min
- Morphine —20 min
- For a given opioid it also varies with the formulation and route of
administration
What are the unwanted affects of opioids?
- Miosis
- Orthostatic hypotension
- Respiratory depression
- Pain suppression / Pruritis
- Histamine release
- Increased intracranial tension
- Nausea / vomitting - 30% frequency, tolerance = yes. Treatment = metoclopramide, low dose haloperidol
- Euphoria
- Sedation - 20% frequency, tolerance = yes, treatment - usually mid and self-limiting
- Constipation - 99% frequency , tolerance no, treatment : softening and stimulant laxative
- Tolerance
MORPHINESCT
Confusion - 1% frequency , tolerance No , treatment : reduce dose (monitor renal function)
Hallucination - <1% frequency, tolerance no , treatment = reduce dose switch agent, haloperidol
What is the difference between codeine vs morphine?
- Codeine is structurally similar to morphine
- Phase 1 metabolism via CYP3A4 and CYP2d6
- Phase 2 metabolism via glucuronyl transferase
What is tramadol>
Dual action
* Opioid receptor agonist
* Noradrenaline and 5HT reuptake inhibition
Only partially reversed by naloxone (opioid
antagonist)
Metabolised in liver = Active metabolite
* less constipation & respiratory depression
Caution in epilepsy, renal/hepatic impairment, & with drugs that can lower the seizure threshold
- metabolised by CYP2D6, CYP2B6 nad CYP3A4
- CYP2D6 polymorphisms: phenotype can be classifiedd according to the metaboliser status into :
- ultra - rapid
- extensive
- intermediate and poor metabolisers
