Module 2.1.1 (Analgesics and Opioids) Flashcards
What are the two types of nerve pathways/type of pain in the ascending pathway?
A delta (fast)
- Pain localization
- Withdrawal reflexes
- Intense, sharp, stinging pain
C (slow)
- Autonomic reflexes
- Pain memory
- Pain discomfort
- Dull, burning, aching pain
Gate control. The activity of dorsal horn relay neurons is modulated by several inhibitory inputs includes?
Local inhibitory neurons which release opioid peptides
Descending inhibitory noradrenergic fibres
Descending inhibitory serotonergic fibres
How do neurons in the substantia gelatinosa (SG) of the dorsal horn act to inhibit the transmission pathway?
- SG is activated by descending inhibitory neurons
- or by non-nociceptive afferent input
- SG is inhibited by nociceptive C/A delta-fibre input
> Persistent C/A delta-fibre activity facilitates excitation of the transmission cells
Opioid receptors rich regions
PAG - periaqueductal grey matter NRPG - nucleus reticularis paragigantocellularis NRM - nucleus raphe magnus SG – substantia gelatinosa
What are the inhibitory neurons?
- From NRM, 5-hydroxytryptamine (5-HT)- and enkephalincontaining neurons run to SG of the dorsal horn – inhibits transmission
- From locus coeruleus (LC) noradrenergic neurons run to the dorsal horn, which also inhibit transmission
The afferent nociceptive pathways are subject to?
The afferent nociceptive pathways are subject to inhibitory control
Descending inhibitory pathways involve?
Involve NA, 5HT; local inhibitory pathway involves enkephalin
How do NSAIDs work to stop pain impulses?
- Block peripheral generation of the nociceptive impulses
- inhibit production of PGs
- reduce sensitivity of sensory nociceptive nerve ending to substance P
How do opioids work to stop pain impulses?
- Act on spinal cord & limbic system
- Stimulate descending inhibitory pathways
- Inhibit transmission at dorsal horn
- Minimal peripheral actions
> atypical drugs agonist-antagonist
What are the main opioid receptor type?
Mu (μ), Kappa (κ) , Delta (δ)
What are the effects of mu (μ) opioid receptors?
Analgesia (supraspinal μ1, spinal μ2)
Respiratory depression(μ2)
Euphoria, Sedation
Miosis
Physical dependence
Urinary retention
Nausea, vomiting, Constipation
What are the effects of Delta (δ) opioid receptors?
Analgesia (spinal)
Respiratory depression
Nausea, vomiting
What are the effects of Kappa (K) opioid receptors?
Analgesia (spinal)
Sedation
Miosis
Dysphoria
Where do full opioid agonists ect e.g. morphine
Act principally at μ-receptors
morphine, pethidine, codeine and dextropropoxyphene
Also have weak agonist activity at δ- and κ-receptors
Tramadol and Methadone act primarily at μ-receptors
Where do mixed partial opioid agonist-antagonist act?
Buprenorphine, potent partial agonist at the μ-receptor
Has antagonist activity at κ-receptors
What are examples of opioid antagonists?
naloxone, naltrexone
- without analgesic actions
- used in the treatment of opioid overdose
What type of receptors are the opioid receptors?
All three opioid receptors are G-protein coupled receptors
What does activation of opioid receptors lead to? What is the net effect?
- inhibition of adenylyl cyclase
- decrease in the concentration of cyclic adenosine monophosphate (cAMP)
- increase in K+ conductance (opening)
- decrease in Ca2+ conductance (closing)
- Activated Gαi subunit of the G protein directly inhibits the adenylyl cyclase enzyme
Net effect
- presynaptic inhibition of neurotransmitter release
- postsynaptic inhibition of membrane depolarization
What is the action of opioids in the spinal cord?
- Morphine and other opioid agonists activate μ (mu) δ (delta) or κ (kappa) opioid receptors
- Receptors coupled to adenylyl cyclase (AC) via G proteins (Gi)
- Inhibition of cAMP formation –> opening of potassium channels closing of calcium channels
- Potassium efflux –> membrane hyperpolarization
- Closing of calcium channels –> inhibits release of neurotransmitters, such as substance P and glutamate
For MOA of opioid analgesics
A) What happens in presynaptic inhibition
B) What happens in postsynaptic inhibition
A)
- Closing of calcium channels
- inhibits release of neurotransmitters, such as substance P and Glutamate
B)
- opening of potassium channels
- membrane hyperpolarization
- Inhibit transmission to brain
What are THREE steps for the MOA of opioid after local inhibitory at doral horn?
- Opiate-sensitive pathways in PAG stimulation of Mu opiate block the release of GABA which normally projects to the medulla including LC ( locus coeruleus) and NRM ( nucleus raphe magnus) This leads to activation
- Descending inhibitory noradrenergic fibres
- Descending inhibitory serotonergic fibres
“SHUTTING OF GATE” Opioid peptides release cause analgesia
What are the pharmacological effects of opioid agonists on:
A) CNS effects
B) Cardiovascular effects
C) GI and biliary effects
D) Genitourinary effects
E) Neuroendocrine effects
F) Immune system effects
G) Dermal effects
A)
- Analgesia
- Sedation
- Miosis diagnostic of an opioid overdose
- Nausea, vomiting
- Dysphoria or euphoria
- Inhibition of cough reflex
- Physical dependence
- Respiratory depression - common cause of death in opioid overdose
- Reduction in sensitivity of the respiratory centre to stimulation by carbon dioxide
B)
- Decreased myocardial oxygen demand
- Vasodilation and hypotension via vasomotor centre (histamine release)
C)
- Constipation (decreased GI motility)
- Increased biliary sphincter tone and pressure
- Nausea and vomiting (via CTZ)
D)
- Increased bladder sphincter tone
- Urinary retention
- Prolongation of labor (pethidine less effect on smooth muscle)
E)
- Inhibition of release of luteinizing hormone
- Stimulation of release of antidiuretic hormone and prolactin
F)
- Suppression of function of natural killer cells (endothelial cells, Tlymphocytes and macrophages) via Kappa receptors
G)
- Flushing
- Pruritus
- Urticaria (hives) or other rash
What are the adverse effects of opioids?
Respiratory depression
- major adverse effect of morphine and other opioids
- usually cause of death in severe overdoses
- reversed by IV opioid antagonist, naloxone
Sedation and drowsiness
Hallucinations, confusion
Constipation
Nausea and vomiting
- Stimulation of the chemoreceptor trigger zone in the medulla
Rashes, pruritis, flushing
- Opioids cause mast cells release of histamine
- Flushing reaction - redness and a feeling of warmth over the upper torso
Allergic reactions
- A patient who is allergic to a particular opioid can use an opioid from a different chemical class
- if allergic to codeine will probably not be allergic to propoxyphene or fentanyl
What is the first and second step to treating constipation in opioid therapy?
first step: laxatives
second step: change mode of administration
What are strong opioid agonists?
Morphine Pethidine Methadone Oxycodone Hydromorphone Fentanyl
