Pharmacology Flashcards
What is an unpleasant sensory and emotional experience, associated with actual tissue damage or described in terms of such damage?
Pain
What are the three classifications of pain?
- Nociceptive pain - adaptive
- Inflammatory pain - adaptive
- Pathological pain - maladaptive
What does nociceptive pain begin with?
activation of nociceptors
What are specific peripheraly primary sensory afferent neurones normally activated preferentially by intense stimuli that are noxious?
Nociceptors
What does depolarisation due to noxious stimulus elicit?
Action potentials that propagate to the CNS
Nociceptors are first order neurones that relay information to second order neurones in the CNS by what?
Chemical synaptic transmission
What type of pain serves as an early warning system to detect and minimise contact with damaging stimuli?
Nociceptive pain
What threshold is nociceptive pain?
High - provoked only by intense stimuli that activate nociceptors
What does nociceptive pain initiate?
A withdrawal reflex
What pain is activated by the immune system in injury or infection?
Inflammatory pain
What does inflammatory pain response cause?
Pain hypersensitivity (heightened sensitivity to noxious stimuli) and allodynia (innocuous stimuli now elicit pain)
What threshold is inflammatory pain?
Low
What type of pain assists in healing of damaged body part i.e. discourages contact and movement?
Inflammatory pain
What type of pain has no protective function?
Pathological pain
What does pathological pain result from?
Abnormal nervous system function - may be neuropathic, or dysfunctional
What threshold of pain is pathological pain?
Low
What is dysfunctional pain?
No neural lesion, inflammation but positive symptoms
What does congenital insensitivity to pain due to?
Loss of function mutations (missense, in frame, deletions) in the gene SCN9A that encodes a particular voltage-activated Na+ channel that is highly expressed in nociceptive neurones
What are nociceptors comprised of?
Agamma and Cfibres
What type of nociceptors are mechanical/thermal nociceptors that are thinely myelinated - respond to noxious mechanial and thermal stimuli and mediate first pain?
Alpha-fibres
What type of nociceptors are unmyelinated (have a faster conduction velocity) - collectively respond to all noxious stimuli (polymodal) and mediate second, or slow pain?
C-fibres
Name a membrer of the transient receptor potential family which is activated by noxious heat?
TRPV1
In chemical stimuli for activation of terminal polymodal nociceptors: what are the chemical channels and what are they activated by?
- H+ activates acid sensing ion channels
- ATP activates P2X nad P2Y receptors
- Bradykinin activates B2 receptors
In pain, what opens ion channels (cation selective) in nerve terminals to elicit a depolarising receptor potential?
Stimulus (mechanical, thermal or chemical)
In pain the amplitude of generator potential is graded and proportional to what?
Stimulus intensity
What, which is a subset of c-fibres, have afferent and efferent functions?
Peptidergic polymodal nociceptors
How does peptigergic polymodal nociceptors function afferently?
Transmit nociceptive information to the CNS via release of glutamate and peptides (substance P, neurokinin A) within the dorsal horn
How does peptigergic polymodal nicoceptors function efferently?
Release proinflammatory mediators [e.g. calcitonin gene-related peptide (CGRP), substance P] from peripheral terminals - contributes to neurogenic inflammation
What does noxious stimulation in the long term increasing spinal excitability contribute to?
Hyperalgesia and allodynia
What is the first stage in the outline of neurogenic inflammation?
Peptides (SP and CGRP) released from free nerve ending of peptidergic nociceptor due to tissue damage, or inflammatory mediators
In neurogenic inflammation - after peptides SP and CGRP have been released, what does SP cause (three things)?
- Vasodilation and extravasation of plasma proteins (promotes formation of bradykinin and prostaglandins)
- Release of histamine from mast cells
- Sensitises surrounding nociceptors
In neurogenic inflammation - after peptides SP and CGRP have been released, what does CGRP cause?
Induces vasodilation
What is the final stage in neurogenic inflammation?
Primary and secondary hyperalgesia and allodynia ensue
In relation to neurotransmission between the primary afferent and second order neurone in the dorsal horn: what are the four steps occuring at terminal of primary afferent?
- Action potential
- Opening of voltage gated calcium channels
- Calcium influx
- Glutamate release
In relation to neurotransmission between the primary afferent and second order neurone in the dorsal horn: what are the four steps occuring at the projection neurone in dorsal horn?
- Activation of glutamate receptors
- Membrane depolarisation
- Opening of voltage gated sodium channels
- Action potential
In relation to neurotransmission between the primary afferent and second order neurone in the dorsal horn: what is the primary transmitter?
Glutamate
In relation to neurotransmission between the primary afferent and second order neurone in the dorsal horn: how does glutamate produce a fast e.p.s.p and neural excitation?
By activating primarily postsynaptic AMPA receptors with NMDA receptor participation
In relation to neurotransmission between the primary afferent and second order neurone in the dorsal horn: what substances also participate in high frequency stimulation to cause a slow and prolonged e.p.s.p that facilitates activation of NMDA receptors by relieving voltage-dependent block by magnesium?
Peptides - substance P and CGRP
Where are primary afferent cell bodies located?
In the dorsal root ganglia
Where do axon terminates centrally?
In the dorsal horn of the spinal cord in various laminae of Rexed
Where do nociceptive C and Agamma fibres mostly terminate?
Superficially in laminae I and II (and also V for Agamma-fibres)
What do nociceptive specific cells synapse only with?
C and Agamma fibres
Cells that receive input from only Abeta-fibres are what?
Proprioceptive
What do wide dynamic range (WDR) neurones receive input from?
All three types of fibre and thus respond to a wide range of stimuli
Second order neurones ascent the spinal cord in the anterolateral system comprising mainly of what?
Spinothalamic tract (STT) Spinoreticular tract (SRT)
In the STT: Projection neurones originating from lamina I (fast fibre Aδ pain) terminate where?
In the posterior nucleus of the thalamus
In the STT: Projection neurones originating from lamina V (WDR neurones) terminate where?
In posterior and ventroposterior nucleus of the thalamus
In the SRT: what is largely transmitted?
Slow C-fibre pain
In the SRT: extensive connections with what are made in the brainstem?
With reticular nuclei in the brainstem [e.g. periaqueductal grey (PAG) and parabrachial nucleus (PBN)]
What anterolateral spinal cord system is involved in autonomic responses to pain, arousal, emotional responses and fear of pain?
SRT
What does the motor neurone axon divide into near the muscle?
Unmyelinated branches
Action potentials arising in the muscle cell body are conducted via the axon to boutons causing the realse of what?>
Transmitter acetylcholine
Where does presynaptic terminal (bouton) synapse at?
The endplate region of skeletal muscle fibre
What are four key features of skeletal neuromuscular junction?
- Terminal bouton (and surrounding schwann cell
- Synaptic vesicles
- The synaptic cleft
- Endplate region
In the skeletal neuromuscular jiunction - what cluster at the active zones?
Synaptic vesicles containing ACh awaiting release
In the skeletal neuromuscular junction - where are ACh receptors located?
At regions of the junctional folds that face the active zones
During the pre-synaptic process of the skeletal neuromuscular junction - how is choline transported into the terminal?
By choli ne transporter (symport with Na+)
During the pre-synaptic process of the skeletal neuromuscular junction - what happens after choline enters the cytosol?
ACh is synthesised from choline and acetyl coenzyme A (supplied by mitochondria) by the enzyme choline acetyltransferase (CAT)
During the pre-synaptic process of the skeletal neuromuscular junction - what happens when ACh has been made?
It is concentrated in vesicles by the vesicular ACh transporter
During the pre-synaptic process of the skeletal neuromuscular junction - what happens once ACh has been concentrated in vesicles?
Arrival of action potential at terminal causing depolarisation and the opening of voltage-gated calcium channels allowing ca entry to terminal
During the pre-synaptic process of the skeletal neuromuscular junction - what happens when calcium has entered terminal?
It causes vesicles docked at active zones to fuse with presynaptic membrane - ACh diffuses into synaptic cleft to activate post-synaptic nicotinic ACh receptors in endplate region.
In relation to the post-synaptic process of skeletal neuromuscular junction - how are nicotinic ACh receptors assembled?
As a pentamer of glycoprotein subunits [(a1)2B1Gd], that surround a central, cation selective pore
In relation to the post-synaptic process of skeletal neuromuscular junction - how does the pore inside the pentamer glycoprotein open and close?
closed in absence of ACh but open when two molecules of ACh bind to exterior of receptor
In relation to the post-synaptic process of skeletal neuromuscular junction - what is the open channel permeable to?
Equally permeable to Na and K
In relation to the post-synaptic process of skeletal neuromuscular junction - what enters and exits when the gate is open?
Na enters and K exits
In relation to the post-synaptic process of skeletal neuromuscular junction - how is end plate potential generated?
Driving force for Na is greater than K at resting membrane potential
What does each neuromuscular junction vesicle contain?
A quantum of neurotransmitter
During the post-synaptic process of skeletal neuromuscular junction - what does an e.p.p that exceeds threshold trigger?
An all or none propagated action potential that initiates contraction
During the post-synaptic process of skeletal neuromuscular junction - what does the e.p.p trigger the opening of?
Voltage-activated Na channels causing a muscle action potential
On a muscle fibre - what allows the e.p.p to propagate from the end plate over the length of the fibre?
The adjacent voltage gated sodium channels
How does rapid termination of neuromuscular transmission occur?
Hydrolysis of ACh by acetylcholinesterase (AChE), an enzyme associated with the end plate membrane
Once AChE has hydrolysed ACh to choline and acetate, what happens to the two products?
Choline taken up by choline transporter
Acetate diffuses from the synaptic cleft
What is another name for neuromyotonia?
Isaac’s syndrome
What condition has symptoms of multiple disorders of skeletal muscle function including cramps, stiffness, slow relaxation *(myotonia) and muscle twitches?
Neuromyotonia
What is the drug treatment for neuromyotonia?
Anti-convulsants - carbamazepine, phnytoin which block voltage-gated sodium channels
What condition is characterised by muscle weakness in the limbs , bery rare and assocaited with small cell carcinoma of the lung?
Lambert-Eaton Myasthenic Syndrome
What condition has an autoimmune origin: antibodies against voltage-activated calcium channels in the motor neurone terminal resulting in reduced ca entry in response to depolarisation and hence reduced vesicular relase of ACh?
LEMS
What is the drug treatment for Lambert-Eaton Myasthenic Syndrome?
Anticholinesterases (pyridostigmine) and potassium channel blockers (3,4-diaminopyridine) which increases concentration of ACh in synaptic cleft
What disease is characterised by progressively increasing muscle weakness during periods of activity. Often weakness of the eye and eyelid muscles is a presenting feature?
Myasthenia Gravis
What condition has an autoimmune origin: antibodies against nicotinic ACh recepotrs in the endplate result in reduction in the number of functional channels and hence the amplitude of the e.p.p
Myasthenia gravis
What is the drug treatment for Myasthenia Gravus?
Anticholinesterases (edrophonium for diagnosis, pyridostigmine for long term treatment) and a variety of immunosuppressants (azathioprine)
What condition has an extremely potent exotoxin (related to tetanus and diptheria toxins) that act as motor neuron terminals to irreversibly inhibit ACh release?
Botulinum toxin
What toxin enters presynaptic nerve terminal to enzymatically modify proteins involved in the docking of vesicles containing ACh?
Botulinum toxin
What interfere with the postsynaptic action of ACh by acting as competitive antagonists of the nicotinic ACh receptor (vecuronium, atracurium)?
Curare-like compounds
What do curare-like compounds do?
Reduce the amplitude of the endplate potential to below the threshold for muscle fibre action potential generation
