Lecture 15 - Analgesics Flashcards
What are the relevant mediators of Nociceptors?
Bradykinin 5HT Prostaglandin H+ ions
What are the different stimuli the Nociceptor nerve ending is responsive to?
Heat Cold
Pressure Tissue injury
What are nociceptor nerve endings referred to as?
Polymodal receptors (respond to more than one type of input)
What does tissue injury induce?
Local inflammatory response
What substances can be released to potentiate inflammatory response and have effect on blood vessels and mast cells?
Substance P and CGPR
Where are signals conducted?
Up the spinal cord and enter CNS via a simple pathway
What does NMDA receptor target?
General anaesthetics Target for modulation of nociceptive inputs in CNS
What blocks NMDA receptors?
Ketamine
What properties does ketamine have ?
Anaesthetic and analgesic properties
Where does glutamate act at?
Several receptors e.g. NMDA receptors
Where does ketamine block the NMDA receptor ?
Spinal cord
What are the different levels of the brain?
Cortex Midbrain Medulla
Where can you induce analgesia in subject?
Periaqueductal Grey
What regions can be found further up the cerebral cortex?
Locus coeruleus Amygdala Hippocampus
What region can modulate sensitivity to brain?
Hippocampus via hypothalamus
What Brain region is involved with regulation of autonomic functions, cardiovascular and respiratory systems?
Rostroventral medulla (RVM)
What happens when one senses a painful stimuli?
Has significant effect on cardiovascular system (alter heart rate and BP)
What transmitters are important for the descending inhibition?
5HT and enkephalins
What is the main site of noradrenergic cell bodies?
Locus coeruleus
What mechanisms are involved in the processing of pain?
Peripheral and central mechanism
What is most important in nociceptive processing ?
TRPV1
What happens when various stimuli activates TRPV1?
Subsequent depolarisation and excitation
What is the active component found in chilli?
Capsaicin
What happens when we stimulate NACH receptor enough?
Desensitisation
What does bradykinin Upon inflammatory response act and do?
Act via its own GPCR and increase levels of protein kinase C and phosphorylate the receptor
What does bradykinin do?
Modulate the responsiveness of TRP receptor in a positive way
What else modulates TRP?
Tyrosine kinase receptor
What does prostaglandin do?
Sensitize nociceptive nerve endings by enhancing pain-producing effect of other agents
What activates TRPV1?
Capsaicin Temperature and acidity
What is the role of nociception?
Cause subsequent peptide release
What does ATP act on to modulate nociceptive Information?
Purinergic receptors
What are the 3 isoforms that the cyclooxygenase exhibit?
Cox-1, Cox-2 and Cox-3
What are prostaglandin?
General inflammatory mediator
What can NSAID be?
Non-selective: Aspirin, ibuprofen, Diclofenac Selective: croxibs (Rofecoxib)(COx-2),paracetamol
What does ibuprofen and diclofenac produce?
Cardiovascular side effects
Where does paracetamol have an effect upon?
COX-3 and effects on prostaglandin seen in CNS only
What increases the descending modulation?
Endogenous opioids
What nerve fibres are involved in descending inhibition?
A delta fibres - small diameter/ myelinated C fibres - unmyelinated
What evidence has been provided in ascending and descending modulation Upon nature of pain?
Alteration and population of Na+ and K+ - affect speed of transmission and whether there is increase in sensitivity to nociceptive input
What is pain associated with?
Activity of small diameter afferent fibres which have sensory ending in the peripheral tissues
What does afferent fibers innervate?
Cells in the dorsal horn which give rise to projection pathways to the thalamus
What does thalamus in term of function allow?
Sorting of Information
What is lamina II (substantial gelatinosa) rich in?
Opioid receptors
What does the descending inhibitory pathway reduce ?
Transmission of pain
Apart from being rich in opioid receptors what does periaqueductal gray matter do?
Central to pain processing and if stimulated electrically can reproduce analgesia
What is enkephalins responsible for?
Modulation of pain transmission Subjected feelings of highs and lows
What are are examples of Enkephalins?
Pentapeptides Leu-enkephalins and Met-enkephalins Endogenous ligands and micro and delta receptors
Where are enkephalins distributed and produced?
Widely distributed in CNS and synthesised in cell body Processed during axonal transport
What are some examples of Endorphins and Dynorphins?
B-endorphin and dynorphin A
What are the 4 classical receptor classification?
Mu, delta, kappa and ORL1 Type
Which opioid receptor have been discounted?
Sigma receptors
Which receptor brings about an analgesic effect?
Mu
What are opioids known to reduce?
Significant respiratory depression
What are Morphine?
Alkaloid extracted from opium Opiate and dried exudate from seed case of poppy
What are the actions of Morphine?
Analgesic, Antidiarrhoeal and Antitussive Sedation, suppression of cough, respiratory depression, decreased peristalsis, decreased gastric acid secretion , euphoria, stimulation of CTZ, miosis, Increased tons of sphincter of Oddi, Increased release of prolactin and ADH, proconvulsant In overdose
What are side effects of Morphine?
If used in analgesic/ drug abuse it can produce sustained constipation Gall bladder conditions
What drug is effective in causing cough suppression ?
Codeine
What happens when mu receptors are stimulated?
Reduction in CAMP generation
Codeine
3-O-methyl Morphine Opiate Metabolised to Morphine. (CYP2D6) Used with NSAIDS
DiaMorphine (heroin)
Effectively a pro drug and a semi-synthetic. Better oral absorption than morphine Terminally ill patients
Where does paracetamol have an effect upon?
COX-3 and effects on prostaglandin seen in CNS only
What increases the descending modulation?
Endogenous opioids
What nerve fibres are involved in descending inhibition?
A delta fibres - small diameter/ myelinated C fibres - unmyelinated
What evidence has been provided in ascending and descending modulation Upon nature of pain?
Alteration and population of Na+ and K+ - affect speed of transmission and whether there is increase in sensitivity to nociceptive input
What is pain associated with?
Activity of small diameter afferent fibres which have sensory ending in the peripheral tissues
What does afferent fibers innervate?
Cells in the dorsal horn which give rise to projection pathways to the thalamus
What does thalamus in term of function allow?
Sorting of Information
What is lamina II (substantial gelatinosa) rich in?
Opioid receptors
What does the descending inhibitory pathway reduce ?
Transmission of pain
Apart from being rich in opioid receptors what does periaqueductal gray matter do?
Central to pain processing and if stimulated electrically can reproduce analgesia
What is enkephalins responsible for?
Modulation of pain transmission Subjected feelings of highs and lows
What are are examples of Enkephalins?
Pentapeptides Leu-enkephalins and Met-enkephalins Endogenous ligands and micro and delta receptors
Where are enkephalins distributed and produced?
Widely distributed in CNS and synthesised in cell body Processed during axonal transport
What are some examples of Endorphins and Dynorphins?
B-endorphin and dynorphin A
What are the 4 classical receptor classification?
Mu, delta, kappa and ORL1 Type
Which opioid receptor have been discounted?
Sigma receptors
Which receptor brings about an analgesic effect?
Mu
What are opioids known to reduce?
Significant respiratory depression
What are Morphine?
Alkaloid extracted from opium Opiate and dried exudate from seed case of poppy
What are the actions of Morphine?
Analgesic, Antidiarrhoeal and Antitussive
Pethidine
Shorter acting than Morphine Used (im) in obstetrics in 1st stage of labour Safer than a drug like Morphine Norpethidine is a metabolite Interaction with MAOIS
Fentanyl
Shorter acting than Morphine due to resdistribution (c.f. Thiopental) Used with general anaesthetics Injectable anaesthetics - shorter generation of action
Methadone
Long acting - used in addicts Used as a substitute for heroine Can be used as analgesic Less like to produce euphoric effects
What is an example of partial agonist?
Buprenorphine
Buprenorphine
Produce strong analgesia Limited respiratory depression Long duration of action Reduces heroin euphoria - it reduces Morphine euphoria
What is an example of antagonist?
Naloxone Naltrexone
Naloxone
Antagonist at all 3 receptor subtypes Diagnose and reverse opiate overdose Short half life give repeatedly Danger or precipitating withdrawal in addicts Experimental tool Little effect on pain Causes hyperalgesia
Naltrexone
Longer duration of action
What is noradrenaline used in?
Treat certain pain conditions
What does neuropathic pain conditions cause?
Significant nerve damage
How do you modulate the effect of central noradrenaline ?
Use of tricyclic antidepressant (amitriptyline)
What are anticonvulsant that inhibit calcium channel opening?
Gabapentin Carbamazepine
