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AC- CNS lectures > 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

Descending inhibitory serotonergic fibres

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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

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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9
Q

What are the main opioid receptor type?

A

Mu (μ), Kappa (κ) , Delta (δ)

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10
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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11
Q

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

A

Analgesia (spinal)

Respiratory depression

Nausea, vomiting

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12
Q

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

A

Analgesia (spinal)

Sedation

Miosis

Dysphoria

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13
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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14
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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15
Q

What are examples of opioid antagonists?

A

naloxone, naltrexone

  • without analgesic actions
  • used in the treatment of opioid overdose
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16
Q

What type of receptors are the opioid receptors?

A

All three opioid receptors are G-protein coupled receptors

17
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
  • postsynaptic inhibition of membrane depolarization
18
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
19
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
20
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

21
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
22
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
23
Q

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

A

first step: laxatives

second step: change mode of administration

24
Q

What are strong opioid agonists?

A

Morphine Pethidine Methadone Oxycodone Hydromorphone Fentanyl

25
Q

What are weak opioid agonists?

A

Codeine Dextropropoxyphene

26
Q

What are other opioid agonists?

A

Tramadol Tapentadol

27
Q

What are partial opioid agonist?

A

Buprenorphine

28
Q

What are 2 opioid antagonist?

A

Naloxone Naltrexone

29
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
30
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

31
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.
32
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

33
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

34
Q

What is neuropathic pain?

A

Injury to the nerve in the pain pathway in nervous system

35
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

36
Q

How to classify neuropathic pain

A

Classified as either peripheral or central neuropathic pain

37
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
38
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

39
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

AC- CNS lectures (28 decks)

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