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MVST1B NHB > Pharmacology of pain > Flashcards

Pharmacology of pain Flashcards

1
Q

D: pain

A

An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage*.

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2
Q

d: nociception

A

The neural process of encoding noxious stimuli.

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3
Q

Nociceptors are either……

A

Nociceptors are either

thinly myelinated Aδ-fibres

or unmyelinated C-fibres

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4
Q

Nociceptor cell bodies are located in ……..

do their axons have specialised endings?

A

Nociceptor cell bodies are located in the dorsal root ganglia (DRG; trigeminal ganglia, TG, for the head) and their axon terminals do not have specialised endings, rather so-called free-endings.

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5
Q

describe Congenital insensitivity to pain

A
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6
Q

can nociceptors be polymodal?

A

yes - they can repsond to heat, cold, chemicals and mechanical stimuli

some are silent and recruited during inflammation.

can be multimodal or unimodal

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7
Q

t or F

Many ion channels are activated by distinct stimuli at the peripheral terminals giving rise to a receptor potential

A

T

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8
Q

Examples of noxious stimuli and the ion channels activated:

heat

protons

AATP

mechanical stimuli

A
  • Heat–TRPV1, TRPM3, anoctamin-1, TRPA1
  • Cold–TRPM8,TRPA1(yes,senseshot/cold!)
  • Protons–ASICs,TRPV1,TASKs
  • ATP–P2X3
  • Mechanical stimuli–Piezo1/2,TACAN
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9
Q

describe nociceptor sensitisation

A

Following injury, stimuli that previously caused no pain now do (allodynia) and stimuli that previously caused some pain cause even more (hyperalgesia).

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10
Q

what is Allodynia

A

Allodynia is something most of us are familiar with – think of taking a shower when sunburned – hot water that would usually cause no pain now does!

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11
Q
A
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12
Q

can many internally released factors act as potent stimulators of nociceptors?

A

yes - allows detection of tissue damage

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13
Q

give some examples of how substances released from damagaed cells can cause pain

A
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14
Q

what are sensitising agents?

A

A second class of sensitising agents do not directly excite the nociceptive nerve terminals, but instead enhance responses to excitatory agents. This class includes prostaglandins and nerve growth factor (NGF).

Some agents both excite and sensitize nociceptors, examples include bradykinin, ATP and H+.

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15
Q

When stimulated, nociceptive nerve terminals also do what?

many things***

A

When stimulated, nociceptive nerve terminals also release factors such as calcitonin gene-related peptide (CGRP) and substance P (SP), peptides that cause vasodilatation and an increase in the permeability of blood vessels; these effects are both direct and indirect through SP inducing mast-cell degranulation.

The inflammation caused by the release of CGRP and SP from nerve terminals causes a redness (“flare”) surrounding the site of injury and is referred to as neurogenic inflammation.

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16
Q

Arachidonic acid can be metabolised to prostanoids by….

A

Arachidonic acid can be metabolised to prostanoids by cyclooxygenases (COX),

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17
Q

what are the isoforms of COX

A

COX-1 and COX-2.

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18
Q

which 2 reactions does COX catalyse

A

COX catalyses two reactions: AA is first cyclised and oxygenated forming the endoperoxide PGG2;

the hydroperoxyl in PGG2 is then reduced to form PGH2.

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19
Q

what does PGE synthase do?

A

PGE synthase produces PGE2 from PGH2, which acts upon nociceptors to cause excitatory stimuli to have greater effect, i.e. the nociceptor has been sensitised: compare the response to bradykinin (Brad.) in the figure above before and after of PGE2.

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20
Q
A
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21
Q

how does PGE cause sensitisation

A
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22
Q

describe neuropathic pain

A

Peripheral nerve damage can result in pain that often outlasts the initial nerve injury, sometimes indefinitely:

    • Phantom limb pain – sensation of pain in an amputated limb, long after its removal
    • Infectious disease (e.g. leprosy, HIV and hepatitis)
    • Diabetic neuropathy
    • Trigeminal neuralgia
    • Postherpetic neuralgia
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23
Q

describe how NSAIDS lower pain

A

Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX enzymes and therefore the production of prostaglandins (PGs).

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24
Q

how do most NSAIDS act - mechanism of action?

A

Most NSAIDs act by entering a hydrophobic channel on the enzyme and forming hydrogen bonds with an arginine residue at position 120, which prevents the entrance of fatty acids, like arachidonic acid, into the catalytic domain.

Aspirin is an exception; it enters the active site and acetylates a serine at position 530, which irreversibly inactivates COX, an action that explains certain long-lasting actions of aspirin.

25
Q

which COX isoform is constitutive

A

cox 1

26
Q

which cox isoform is upregulated in inflammation?

A

cox 2

27
Q

how come aspirin has long acting effects on COX enzymes?

A

Aspirin acetylates serine 530 in active site – irreversible inactivation

28
Q

how come some drugs are COX 2 specific?

A

The bulky side group of COX-2 enables some drugs with large, sulphur-containing side groups to selectively act upon COX-2, but not COX-1.

29
Q

. Inhibition of COX-2 is thought to result in……….

whereas inhibition of COX-1 is responsible for …….

A

. Inhibition of COX-2 is thought to result in the anti-inflammatory/analgesic effect, whereas inhibition of COX-1 is responsible for most unwanted side effects

30
Q

where are NSAIDS most effective?

A

NSAIDs are most effective in inflammatory conditions when COX-2 is upregulated, e.g. arthritis, muscular pain, toothache, bursitis and dysmenorrhoea (period pain).

A less well-characterised route of analgesia may be centrally where PGs are thought to facilitate nociceptor neurotransmission.

31
Q

give some details on Aspirin

A

weakly COX-1 selective,

irreversible acetylation,

used mainly for cardiovascular protective effects of inhibiting platelet derived thromboxane;

used in migraine

32
Q

describe teh characteristics of Ibuprofen/phenylbutazone

A

Ibuprofen/phenylbutazone

– weakly COX-1 selective,

symptomatic relief in rheumatoid arthritis, gout and soft tissue disorders

33
Q

describe the characteristics of paracetamol

A

Paracetamol –

analgesic/antipyretic,

poor anti-inflammatory,

but good antipyretic (not really an NSAID)

34
Q

describe the characteristics of Etoricoxib/robenacoxib –

A

Etoricoxib/robenacoxib –

COX-2 selective,

osteoarthritis and rheumatoid arthritis

35
Q

side effects of NSAIDS?

A

largely due to COX 1 activity

gastrointestinal bleeding (PGs inhibit gastric acid secretion and increase the release of protective mucin, patients often take a drug to counteract the effects on acid secretion),

renal insufficiency (PGE2/PGI2 involved in maintenance of renal blood flow),

stroke/myocardial infarction (COX-2 is constitutively expressed in endothelial/vascular smooth muscle cells, inhibition results in decreased PGI2 production, PGI2 is vasodilatory and decreases platelet aggregation)

and bronchospasm (COX inhibition implicated, mechanism unclear).

36
Q

what is an opioid

A

An opioid is a substance producing morphine-like effects that are reversed by antagonists such as naloxone, an opiate is a substance found in the opium poppy Papaver somniferum.

37
Q

opioids are antagonists by

A

naloxone

38
Q

4 opioid receptors?

A

4 receptors - μ, κ, δ or ORL1 (and subtypes),

all Gi/Go-protein coupled receptors

39
Q

how do opioid receptors decrease pain

A

All receptors are Gi/Go-protein coupled receptors and the βγ subunit interacts with inwardly rectifying potassium channels, GIRKs, to promote opening (neuronal hyperpolarisation = action potential firing less likely) and to inhibit the opening of CaVs (mainly N-type; decreased Ca2+ entry = decreased neurotransmitter release).

Adenylate cyclase activity is also decreased.

40
Q

nhibition of adenylate cyclase activity counteracts the sensitising effect of ….

A

nhibition of adenylate cyclase activity counteracts the sensitising effect of PGs

41
Q

Opioids can also reduce the affective component of pain due to their ability to evoke ________, which is also _-mediated.

A

Opioids can also reduce the affective component of pain due to their ability to evoke euphoria, which is also μ-mediated.

42
Q

Opioids are generally used for …..

A

Opioids are generally used for both acute (e.g. post-operative) and chronic (e.g. cancer) pain, not always considered sensible in treating neuropathic pain because the dose often needed to provide analgesia is coupled with excessive side effects.

43
Q

how does peripheral opioid analgesia work?

A

inhibition of adenylate cyclase acts against sensitising effect of PGs

44
Q

how does spinal opioid analgesia work?

A

Spinal – presynaptically to reduce nociceptor neurotransmitter release

– postsynaptically to decrease spinal cord dorsal horn neurone excitability

45
Q

how does supraspinal analgesia wokr?

A

Supraspinal – numerous brain regions, including periaqueductal grey region

46
Q

T or F or opioids

Less efficacious in neuropathic pain – dose needed for analgesia often produces excessive side effects

A

T

47
Q

describe morphine

A

Morphine – widely used for treating acute/chronic pain

48
Q

describe dimorphine

A

Diamorphine (heroin) – higher blood-brain-barrier permeability = more rapid onset than morphine, a prodrug

49
Q

describe codeine

A

Codeine – less potent than morphine, also fewer side effects, used for mild pain, often combined with an NSAID

50
Q

descibe buprenorphine

A

Buprenorphine –

partial agonist, i.e. moderate analgesia/less respiratory depression than full agonist; used post-surgery in rodents/cats/dogs, and as a patch for chronic pain in humans

51
Q

describe naloxone

A

Naloxone – broad spectrum opioid receptor antagonist, rapid reversal of opioid-induced respiratory depression

52
Q

describe NSAID/opioid combination therapy –

A

NSAID/opioid combination therapy –

different mechanisms of action = additive analgesia, less of each drug required = less side effects, e.g. co-codamol = paracetamol + codeine

53
Q

descxribe teh side effecst of opioids

A
  • Respiratory depression – μ-mediated, respiratory centre and central chemoreceptors
  • Nausea/vomiting – δ/μ-mediated
  • Constipation – μ, κ and δ-mediated
  • Chronic use complicated by tolerance and physical dependence
54
Q

can antidepressatns relieve pain?

A

Serotonin selective reuptake inhibitors (SSRIs, e.g. fluoxetine) are largely inefficacious

Serotonin-noradrenaline reuptake inhibitors (SNRIs, e.g. duloxetine) and tricyclic antidepressants (TCAs, e.g. amitriptyline, also block serotonin and noradrenaline reuptake) both relieve several forms of neuropathic pain

Emphasises role of the descending, inhibitory pain control pathway from the locus coeruleus, which is is noradrenergic

55
Q

describe Gabapentin/pregabalin

A

developed as a GABA analogue for treatment of epilepsy, has no activity at GABA receptors

is efficacious against neuropathic pain in some patients, no effect on acute pain.

Decreases cell surface expression of the CaV α2δ1 subunit

The CaV α2δ1 subunit increases CaV current density and is often upregulated in neuropathic pain

Gabapentin therefore causes decreased CaV currents in spinal cord = less neurotransmitter release = less pain

Pregabalin developed as more potent analogue with better pharmacokinetic properties

56
Q

how do NaV inhibitors block pain

A

Lidocaine is a local anaesthetic, works by blocking NaV subunits

Can be applied topically as patch

Inhibits spontaneous peripheral neurone discharges often observed in neuropathic pain – useful in trigeminal neuralgia patients to provide pain relief when eating a meal

Carbamazepine also blocks NaVs, used as an anti-epileptic, but also an option for neuropathic pain, especially trigeminal neuralgia

57
Q

describe Ziconotide

A

Synthetic analogue of N-type CaV blocker ω-conotoxin MVIIA from Conus magus

Intrathecal administration to prevent widespread, deleterious side effects

Expensive/invasive/dangerous method, i.e. reserved for patients refractory to other treatments

58
Q

fat

A

mamba

MVST1B NHB (25 decks)

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