Analgesic drugs
NSAIDs
Paracetemol -> analgesic, antipyretic, antithrombotic, but lacks anti-inflammatory effects (brain COX-headaches)
Ulceration, GI bleeds (less so but cardiac for COX-2), renal toxicity
COX converts arachadonic acid to prostanoids -> prostaglandins + thromboxanes
Opiate action
Some opioids can act as agonists or partial agonists at one receptor and antagonists at another
Some have tissue selective agonism/antagonism
Receptors form homomeric and heteromeric complexes - even with non-opiod receptors
Morphine
euphoria, sedation, sleep
Free hydroxl on benzene ring (sub. hydroxyls)
Acute + chronic pain (slow-release tabs), less useful for neuopathic
3-4h half life, metabolized in liver
μ partial agonist (less afinity for others)
GI upset + lowered activity, antitussive, hormonal (red. LH, incr. prolactin + ADH)
Morphine-related antagonists
Morphine-analogue agonists
More potent antitussent, mild pain
Prodrug -> codeine-6-glucuronide + 10% morphine (7% caucasians dont have)
Codeine: weak μ agonist
Diarrhoea, IBS, narcolepsy
Diamorphine/heroin: Inactive, metabolised to μ agonist 6-monoacetylmorhpine then morphine (3x morphine)
Subcutaneous pallitative care
Naloxone: affinity for all 3 (μ > κ ≥ δ)
Blocks endogenous opiods (hyperalgesia in inflam. cond.) + morphine-like, reverse OD
2-4h half life, withdrawal symp. in addicts
Naltrexone: similar MoA, 10h half life
Addiction treatment, S/E's GI cramping + diahrroea
Nalorphine: μ antagonist, δ, κ agonist (reverse OD) Discontinued due to psychomimetic effects (+anx.)
(Syn.) Methadone series
Propoxyphene: discontinued dt OD's + arrhythmias
Tramadol: codeine analogue, short half life -> post-op
S/E's: nausea, sleepy, dizzy, sweaty
Meptamizol: High efficacy partial μ, shorter onset + duration., lacks euphoria
Oral, no tolerance, extensively metabolized
Methadone: 20-24h, μ agonist
Thebaine series
Benzamorphin series
Pentazocine: weak μ, strong κ (supraspinal agonism -> dysphoria + psychotic eff.), combined with naloxone
Buprenorphine: partial μ agonist, μ, κ antagonist, highly lipophillic 25-50x morphine, combined with naloxone
(Syn.) Pethidine series
Pethidine: fully syn. opiod, structurally diff to morphine, metabolic toxicity convulsions. Fentanyl 100x, Sufentanyl 500-100x
Neuropathic pain
Anaesthetics: Ketamine: NDMA antagonist reduce central sensitization, inhibits NO production
Local anaesthetic Lidocaine blocks VGNaC, increases depolariation threshold -> reduced spontaneous discharge from damaged neurons (fibromyalgia)
Gabapentin (designed as mimetic) binds to alpa2-delta subunit to modulate VGCCs, 30% metab + rest excreted - OD
Anticonvulsants Carbamazepine, lamotrigine, phenytoin stabilize inactive Na channels
Antidepressants block NA and 5-HT uptake, enhances inhibition
TRPV1
Phophorylation by PKC + PLC (PIP2) sensitize -> hyperalgesia, allodynia
Capsaicin
4 subunits, 6-membrane spanning domains
Competitve antagonists capsazepine
Non-competitive antagonists block aqueous pore (more active against over-activated), S/E hyperthermia
TRP fam respond to physical, protons, natural (capsaicin) + endovanillods, change in membrane potential, IC sig. cascades