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 project from locus cerelus (LC)
Descending inhibitory serotonergic fibres from nucelus raphe magnus (NRM)
> both inhibits onwards passage of pain via spinothalamic tract
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
The gate control theory partially describes the mechanism of how opoid drugs work. Explain the “gate control theory” and how it relates to the mechanism of action of opioid drugs.
The activity of dorsal horn relay neurons is modulated by several inhibitory inputs including:
- Local inhibitory neurons which release opioid peptides
- Descending inhibitory noradrenergic fibres
- Descending inhibitory serotonergic fibres
> Local inhibitory pathway: At the spinal cord level, stimulation of opioid receptors inhibits release of substance P from dorsal horn neurons, and opioids act to “close the gate” in the dorsal horn, thus inhibiting afferent transmission.
> Descending inhibitory noradrenergic fibres project from locus cerelus (LC)
> Descending inhibitory serotonergic fibres projects from nucleus raphe magnu (NRM) –
both inhibits onwards passage of pain via spinothalamic tract (inhibit ascending pathway)
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 (stop the release of substance P)
- postsynaptic inhibition of membrane depolarization (stop impulse to thalamus)
inhibit ascending pathway of pain
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
What are weak opioid agonists?
Codeine Dextropropoxyphene
What are other opioid agonists?
Tramadol Tapentadol
What are partial opioid agonist?
Buprenorphine
What are 2 opioid antagonist?
Naloxone Naltrexone
Explain why addiction/tolerance/withdrawal to opioids occur?
Addiction
- Normally GABA reduces amount dopamine release
- When opioids attach to mu receptors, the release of GABA becomes suppressed, increases dopamine activity and pleasure felt
- Prolonged used of opioids leads to desensitization of receptor signalling and downregulation of receptors –> decreased in sensitivity to effect of opioids –> when opioid use is reduce or stopped = lack of receptor selectivity = withdrawal symptoms.
Tolerance
- Tolerance to opioid effects may be due to both a gradual loss of inhibitory functions and therefore an increase in excitatory pain signalling
Withdrawal
- Withdrawal effects may be due to rebound increase in formation of cAMP:
> This activation occurs through the delta opioid receptors in response to chronic administration of opioids.
Pharmacology of Codeine
Analgesic effect depends exclusively on demethylation to morphine
Demethylated to morphine (5-15%) by the CYP2D6
> 10% Caucasians, 1-2% Asians lack CYP2D6
- Effect and side effects similar to low-dose morphine, however little euphoric effect
- Codeine is about one twelfth potency of morphine
- Incidence of nausea and constipation limits its use
- Given orally for mild to moderate pain
Pharmacology of Dextropropoxyphene
Derivative of methadone
Not potent - Analgesic efficacy ~half codeine
Dextropropoxyphene may cause respiratory depression, neurotoxicity and acute heart failure
Its metabolite nordextropropoxyphene can cause dizziness, confusion and cardiac dysrhythmias
Avoid use in renal impairment!!
Dextropropoxyphene and its metabolite nordextropropoxyphene accumulate when CrCl <10 mL/minute
Caution when used in elderly
Half life in elderly patients up to 50 hrs – can cause CNS side effects, confusion and dizziness
Pharmacology of tramadol? What is a contraindication?
A metabolite of antidepressant trazodone
Acts as an opioid agonist
Morphine-like pharmacological actions
Binds to mu-receptors
Enhancement of 5HT and adrenaline pathways
Weak inhibition of reuptake of NA and 5HT
Undergoes CYP2D6-mediated Odemethylation to O-desmethyltramadol
> 6x more potent than tramodol in analgesia
Lower risk of constipation than morphine
Contraindication
- serotonin toxicity if tmt with an irreversible non-selective MOAIs.
What is the clinical use of tramadol?
Useful in situations where one wants to avoid or reduce opioid adverse effects
- respiratory depression
- constipation
- abuse
- sedation/confusion
> moderate pain
> neuropathic pain
Pharmacology of Tapentadol? CI?
Similar MOA to tramadol
Acts as an opioid agonist
Binds to mu-receptors
Enhancement of 5HT and adrenaline pathways
Weak inhibition of reuptake of NA and 5HT
Metabolism: conjugation with glucuronic acid
CI
similar to tramadol tmt with an irreversible non-selective MOAIs. Not to be used with drugs which enhances monoamines activity
What is neuropathic pain?
Injury to the nerve in the pain pathway in nervous system
define the following terms in neuropathic pain
A) hyperalgesia
B) allodynia
A) increased excitability and sensitivity to pain–> heightened responses to a normally painful stimulus (eg arthritic pain)
B) painful responses to a stimulus that is not normally painful
How to classify neuropathic pain
Classified as either peripheral or central neuropathic pain
What are the treatemnt options for neuropathic pain?
Drugs which enhance the descending noradrenergic and serotoninergic inhibitory pathways
- TCAs antidepressants (amitriptyline, nortriptyline, desipramine) and venlafaxine
Antiepileptics
- Gabapentin, pregabalin, carbamazepine
Drugs acting locally to provide pain relief
- Local anaesthetics - lignocaine
How do TCA and venlafaxine work?
TCA and venlafaxine are non selective NA and 5HT reuptake inhibitors
- Enhance descending inhibitory noradrenergic fibres
- Enhance descending inhibitory serotonergic fibres
> Analgesic effects independent of their antidepressant effects
> SSRIs are not as beneficial as analgesic
What is the MOA of the antiepileptics used in neuropahtic pain
A) Carbamazepine
B) Gabapentin and pregabalin
A)
Blockade of use-dependent sodium channels
Useful in neuropathic pain such as trigeminal neuralgia and in bipolar disorders
B)
Bind to voltage gated calcium channels (specifically the α2δ1 and α2δ2 subunits) –> reduce neurotransmitter release
The α2δ subunits of voltage gated calcium channels are upregulated in damaged sensory neurons
Which opioid receptors cause respiratory depression?
- mu 2
- delta
