Lecture 27 - Novel Analgesics I Flashcards
Difference between modulators and blockers
Modulators don’t block channel, but instead modulate amount of ion that can travel through
Proportion of Australians that suffer from chronic pain at one point in their lives
~20%
How might chronic pain lead to secondary conditions?
1)
2)
1) Deconditioning, postural changes
2) Changes to psyche, sleep, appetite, behaviour, thoughts
Definition of chronic, persistent pain
Present for over three months
Three broad groups of chronic pain
1) Defined nocicieptive basis (EG: arthritis)
2) Well-defined neurologic basis (EG: post-herpetic neuralgia, phantom limb pain)
3) Idiopathic (EG: chronic musculoskeletal pain, some types of headaches)
Neuropathic pain 1) 2) 3) 4)
1) Generated, perpetuated by nervous system
2) Might be initiated by trivial injury to CNS or PNS
3) Pain persists independently of initial injury.
4) Response to conventional analgesics is poor (under 50%)
What does post-herpetic neuralgia occur after?
Shingles
Characteristics of neuropathic pain
1)
2)
3)
1) Spontaneous pain (shooting, burning, electric shock, pins and needles)
2) Hypersensitivity/hyperalgaesia
3) Allodynia
Value of animal models in pain research 1) 2) 3) 4) 5)
1) Human studies can’t directly test anatomical, biochemical, physiological pain responses
2) Animal models offer good neurochemical, biochemical pain models.
3) Can standardise genetic, environmental backgrounds
4) Can denervate, experiment on animals
5) A molecule or pain-related phenomenon has never been found in humans that didn’t have a rodent analogue
Example of a successful forward translation of a drug from animal models to humans
Ziconotide
From snail conopeptide
Binds N-type ca2+ channels
Chung neuropathy model
1)
2)
3)
1) Surgical tight ligation of spinal nerves L5 and L6 on left side. Right side is not operated on,
2) L5/L6 lead to sciatic nerve.
3) Neuralgia, allodynia appear within days
Von Frey test
Use Von Frey filaments to test allodynic response.
Poke feet with filaments calibrated to bend at a specific grams of force.
What does von Frey test test?
Assessment of tactile allodynia of plantar skin.
Composition of voltage-gated Ca2+ channels 1) 2) 3) 4)
Four subunits:
1) Alpha1 - 4 homologous domains, each 6-pass transmembrane. Forms pore.
2) Beta - Intracellular
3) Gamma - Transmembrane segments
4) Delta - Transmembrane segment attached to alpha2 via disulphide bond.
Number of genes encoding alpha1 subunits of voltage-gated Ca2+ channels
Ten
Type of voltage-gated Ca2+ channel that ziconotide affects
N-type
Which part of voltage-gated Ca2+ channel do gabapentin and pregabalin affect?
Alpha2/delta subunit
Where are L-type voltage-gated Ca2+ channels found?
Mostly in cardiac, smooth muscle
Where are N-type voltage-gated Ca2+ channel found?
In pre-synaptic neurons
Function of alpha2/delta subunit
1)
2)
1) Accessory subunit of voltage-gated Ca2+ channel
2) When present, increases amount of time until channel inactivation, leading to greater Ca2+ influx
What is upregulated in dorsal root ganglia and central terminals in neuropathic pain?
Alpha2/delta subunits of voltage-gated Ca2+ channels
Gabapentinoids
1)
2)
3)
1) Anti-epilepsy drugs
2) Also effective in management of neuropathic pain
3) Designed to mimic GABA, but don’t interact with GABA-A or -B receptors, aren’t metabolised to GABA and don’t block GABA reuptake or metabolism.
Pregabalin 1) 2) 3) 4) 5) 6)
1) A gabapentinoid
2) An amino acid
3) Readily crosses blood-brain barrier
4) A voltage-gated Ca2+ channel modulator
5) Binds alpha2/delta subunit with high affinity in CNS.
6) Not metabolised in the liver
Pregabalin mechanism of action 1) 2) 3) 4)
1) Binds alpha2/delta subunit on voltage-gated Ca2+ channels.
2) This reduces Ca2+ influx to presynaptic neurons.
3) This decreases amount of excitatory neurotransmitters released.
4) Analgesia from reducing ectopic discharges of hyperexcited neurons.
Pregabalin bioavailability
90%
Why is pregabalins metabolism good?
Not metabolised in the liver.
Used in cancer patients, who are often on other medications. It isn’t metabolised in the liver, so doesn’t exacerbate liver damage
Most common side-effects of pregabalin 1) 2) 3) 4)
1) Somnolence
2) Dizziness
3) Ataxia
4) Weight gain
How well-tolerated are pregabalin and gabapentin?
Very well-tolerated
Useful combination therapy for analgesia
Morphine+gabapentin
What do conantotoxins target?
NMDA receptors
What do omega-conotoxins target?
Voltage-gated Ca2+ channels
What do mu-conotoxins target?
Voltage-gated Na+ channels
What do kappa-conotoxins target?
Voltage-gated K+ channels
What is ziconotide derived from?
Omega-conotoxins
What are upregulated in dorsal horn after peripheral inflammation or nerve damage?
N-type Ca2+ channels
What does ziconotide target?
N-type Ca2+ channels
Ziconotide mechanism of action
1)
2)
1) Adelta/C fibre neurotransmitter release primarily controlled by N-type Ca2+ channel action
2) Ziconotide binds N-type channels, disrupts Ca2+ influx to presynaptic neurons in dorsal horn
How is ziconotide administered?
Intrathecal injection (to spinal cord)
Why does ziconotide have to be administered intrathecally?
Major cardiovascular side effects if delivered intravenously.
Bradycardia (slow heart rate), drop in blood pressure, orthostatic hypertension
Addiction potential of ziconotide
Extremely low
Ziconotide efficacy compared to morphine
At least ten times as potent as morphine
Ziconotide side effects
1)
2)
1) CNS side effects when delivered intrathecally (dizziness, abnormal gait, ataxia, confusion, memory impairment, somnolence)
2) Cardiovascular side effects if administered intravenously (bradycardia, hypotension)
