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CNS lectures (Bal) > Module 2.1.1 (Analgesics and Opioids) > Flashcards

Module 2.1.1 (Analgesics and Opioids) Flashcards

1
Q

What are the two types of nerve pathways/type of pain in the ascending pathway?

A

A delta (fast)

  • Pain localization
  • Withdrawal reflexes
  • Intense, sharp, stinging pain

C (slow)

  • Autonomic reflexes
  • Pain memory
  • Pain discomfort
  • Dull, burning, aching pain
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2
Q

Gate control. The activity of dorsal horn relay neurons is modulated by several inhibitory inputs includes?

A

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

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3
Q

How do neurons in the substantia gelatinosa (SG) of the dorsal horn act to inhibit the transmission pathway?

A
  1. SG is activated by descending inhibitory neurons
  2. or by non-nociceptive afferent input
  3. SG is inhibited by nociceptive C/A delta-fibre input

> Persistent C/A delta-fibre activity facilitates excitation of the transmission cells

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4
Q

Opioid receptors rich regions

PAG - periaqueductal grey matter NRPG - nucleus reticularis paragigantocellularis NRM - nucleus raphe magnus SG – substantia gelatinosa

What are the inhibitory neurons?

A
  1. From NRM, 5-hydroxytryptamine (5-HT)- and enkephalincontaining neurons run to SG of the dorsal horn – inhibits transmission
  2. From locus coeruleus (LC) noradrenergic neurons run to the dorsal horn, which also inhibit transmission
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5
Q

The afferent nociceptive pathways are subject to?

A

The afferent nociceptive pathways are subject to inhibitory control

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6
Q

Descending inhibitory pathways involve?

A

Involve NA, 5HT; local inhibitory pathway involves enkephalin

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7
Q

How do NSAIDs work to stop pain impulses?

A
  • Block peripheral generation of the nociceptive impulses
  • inhibit production of PGs
  • reduce sensitivity of sensory nociceptive nerve ending to substance P
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8
Q

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.

A

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)

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9
Q

How do opioids work to stop pain impulses?

A
  • Act on spinal cord & limbic system
  • Stimulate descending inhibitory pathways
  • Inhibit transmission at dorsal horn
  • Minimal peripheral actions

> atypical drugs agonist-antagonist

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10
Q

What are the main opioid receptor type?

A

Mu (μ), Kappa (κ) , Delta (δ)

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11
Q

What are the effects of mu (μ) opioid receptors?

A

Analgesia (supraspinal μ1, spinal μ2)

Respiratory depression(μ2)

Euphoria, Sedation

Miosis

Physical dependence

Urinary retention

Nausea, vomiting, Constipation

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12
Q

What are the effects of Delta (δ) opioid receptors?

A

Analgesia (spinal)

Respiratory depression

Nausea, vomiting

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13
Q

What are the effects of Kappa (K) opioid receptors?

A

Analgesia (spinal)

Sedation

Miosis

Dysphoria

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14
Q

Where do full opioid agonists ect e.g. morphine

A

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

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15
Q

Where do mixed partial opioid agonist-antagonist act?

A

Buprenorphine, potent partial agonist at the μ-receptor

Has antagonist activity at κ-receptors

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16
Q

What are examples of opioid antagonists?

A

naloxone, naltrexone

  • without analgesic actions
  • used in the treatment of opioid overdose
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17
Q

What type of receptors are the opioid receptors?

A

All three opioid receptors are G-protein coupled receptors

18
Q

What does activation of opioid receptors lead to? What is the net effect?

A
  • 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

19
Q

What is the action of opioids in the spinal cord?

A
  1. Morphine and other opioid agonists activate μ (mu) δ (delta) or κ (kappa) opioid receptors
  2. Receptors coupled to adenylyl cyclase (AC) via G proteins (Gi)
  3. Inhibition of cAMP formation –> opening of potassium channels closing of calcium channels
  4. Potassium efflux –> membrane hyperpolarization
  5. Closing of calcium channels –> inhibits release of neurotransmitters, such as substance P and glutamate
20
Q

For MOA of opioid analgesics

A) What happens in presynaptic inhibition

B) What happens in postsynaptic inhibition

A

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
21
Q

What are THREE steps for the MOA of opioid after local inhibitory at doral horn?

A
  1. 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
  2. Descending inhibitory noradrenergic fibres
  3. Descending inhibitory serotonergic fibres

“SHUTTING OF GATE” Opioid peptides release cause analgesia

22
Q

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

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
23
Q

What are the adverse effects of opioids?

A

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
24
Q

What is the first and second step to treating constipation in opioid therapy?

A

first step: laxatives

second step: change mode of administration

25
Q

What are strong opioid agonists?

A

Morphine Pethidine Methadone Oxycodone Hydromorphone Fentanyl

26
Q

What are weak opioid agonists?

A

Codeine Dextropropoxyphene

27
Q

What are other opioid agonists?

A

Tramadol Tapentadol

28
Q

What are partial opioid agonist?

A

Buprenorphine

29
Q

What are 2 opioid antagonist?

A

Naloxone Naltrexone

30
Q

Explain why addiction/tolerance/withdrawal to opioids occur?

A

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.

31
Q

Pharmacology of Codeine

A

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
32
Q

Pharmacology of Dextropropoxyphene

A

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

33
Q

Pharmacology of tramadol? What is a contraindication?

A

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.
34
Q

What is the clinical use of tramadol?

A

Useful in situations where one wants to avoid or reduce opioid adverse effects

  • respiratory depression
  • constipation
  • abuse
  • sedation/confusion

> moderate pain

> neuropathic pain

35
Q

Pharmacology of Tapentadol? CI?

A

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

36
Q

What is neuropathic pain?

A

Injury to the nerve in the pain pathway in nervous system

37
Q

define the following terms in neuropathic pain

A) hyperalgesia

B) allodynia

A

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

38
Q

How to classify neuropathic pain

A

Classified as either peripheral or central neuropathic pain

39
Q

What are the treatemnt options for neuropathic pain?

A

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
40
Q

How do TCA and venlafaxine work?

A

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

41
Q

What is the MOA of the antiepileptics used in neuropahtic pain

A) Carbamazepine

B) Gabapentin and pregabalin

A

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

42
Q

Which opioid receptors cause respiratory depression?

A
  • mu 2
  • delta

CNS lectures (Bal) (29 decks)

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