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notes to flashcards year 2 - LCRS1 > opioids > Flashcards

opioids Flashcards

1
Q

what is an opiate?

A
  • alkaloid derived from poppy

- e.g. morphine, codeine

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2
Q

describe the structure of morphine

A
  • tertiary nitrogen: permits receptor anchoring, essential for analgesic effect
  • has methyl group on nitrogen but extending side chain can produce anatagonist
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3
Q

where are the hydroxyl groups in morphine? what are they needed for?

A
  • at position 3 and 6
  • position 3: required for binding
  • position 6: when in oxidised form, lipophilicty of drug inc. 10 fold
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4
Q

why is codeine not active compared to morphine?

A
  • codeine must undergo some metabolism to become activated

- to reveal hydroxyl group

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5
Q

what are the different routes of admin of opioids?

A
  • oral

- IV

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6
Q

are opioids acids or bases?

A
  • weak bases (pKa >8)

- more readily ionized in stomach and blood so poorly absorbed

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7
Q

rank the opioids in terms of lipid solubility?

A

most lipid soluble:

  • methadone/fentanyl
  • heroin
  • morphine
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8
Q

what is the link between lipid solubility and potency?

A

more lipid soluble, more potent

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9
Q

describe the metabolism of morphone

A
  • morphine –> morphine-6-glucuronide (M6G)
  • mui receptor agonist = potent analgesic activity
  • morphine has greater affinity for mui 2 receptors than M6G, related to adverse side effects
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10
Q

describe the metabolism of fentanyl

A
  • fast metabolism

- CYP3A4 enzymes

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11
Q

describe the metabolism of methadone

A
  • slow metabolism

- 6CYP enzymes

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12
Q

what are the best tolerated opioids?

A

one that undergoes CYP-mediated metabolsim

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13
Q

describe the metabolism of codeine

A
  • codeine –> morphine
  • only 5-10% of codeine is metabolized to produce morphine as they are activating and inactivating enzymes in liver
  • activation via CYP-2D6
  • deactivation via CYP-3A4
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14
Q

what are the examples of opioid peptides?

A
  • endorphins
  • enkephalins
  • dynorphins/neoendorphins
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15
Q

what opioid receptors do endorphins act on? causing what effect?

A
  • mu/delta receptors

- pain/mood/CVS

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16
Q

what opiod receptors do enkephalins act on? causing what effect?

A
  • delta

- pain/mood/CVS

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17
Q

what opioid receptors do dynorphins act on? causing what effect?

A
  • kappa

- appetite

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18
Q

what are the opiate receptors cellular MoA?

A

depressant actions

  • hyperpolarisation (inc. K efflux)
  • reduce Ca influx (for NT exocytosis)
  • reduce adenylate cyclase acticity (general cell activity)
19
Q

what are the opioid effects?

A
  • analgesia
  • euphoria
  • anti-tussive (anti-cough)
  • resp depression
  • stimulation of CTZ (nausea/vomiting)
  • pupillary constriction and GI effects
20
Q

what are the analgesic effects mediated by?

A
  • dec. pain perception

- inc. pain tolerance

21
Q

what is the mechanism of analgesia?

A
  • sensory info from periphery into thalamic via spinothalamic tract
  • thalamus and extra-cortical and cortical inputs activate PAG (co-ordinates pain)
  • PAG activated NRM
  • NRM sends inhibitory signals to dorsal horn
  • NRM inc. pain tolerance
22
Q

what is the NPRG?

A
  • negative feedback centre of brain
  • independent of thalamus
  • automatically suppresses pain before brain has had a chance to process it
23
Q

how does the hypothalamus input to pain pathway?

A
  • constantly signals PAG independent of pain sensation
24
Q

what is the LC? how does it input into the pain pathway?

A
  • locus coeruleus
  • major SNS outflow
  • activated during stress response
  • fight/flight don’t want pain response interfering
  • inputs directly into dorsal horn to prevent pain pathway
25
Q

describe the 2 ways the spinal cord can modulate pain tolerance

A
  • descending inhibition from NRM
  • some go directly in to dec. pain transmission in spinothalamic tract
  • some project into substantua gelatinosa
26
Q

what is the substantia gelatinosa?

A
  • mini brain in spinal cord

- can modulate/determine level of inhibition necessary on sensory neurones from NRM

27
Q

which receptors impact the analgesic effect the most?

A

Mu receptors

28
Q

what are the main targets of opioids in pain pathway?

A
  • dorsal horn and periphery = inc. inhibition
  • PAG = enhance firing
  • NRPG = activates
29
Q

how do opioids affect GABA?

A
  • very good at switching off GABA
  • GABA has inhibitory effect on many pain tolerance centres
  • blocking GABA activated pain tolerance centres
30
Q

how do opiods cause euphoria?

A
  • opiates bind to Mu receptor and dec. GABA exocytosis

- reduced inhibition on VTA so more DA release from NA

31
Q

what are the 2 central ways that opioids cause anti-tussive effects?

A
  1. 5HT1A receptor antagonist (5HT1A is -ve feedback receptor for serotonin, suppression of serotonin and activation of cough reflex)
  2. medulla direct depression
32
Q

what is the peripheral way in which opioids are anti-tussive?

A
  • Ach and neurokinin release inhibition so less transmission down sensory nerves to vagus afferents
33
Q

how do opioids cause resp depression?

A
  • depression of pre-botzinger complex (less rhythm)

- central chemoreceptors inhibited by opioids, dec. firing rate of central chemoreceptors

34
Q

how do opioids cause nausea and vomiting?

A
  • activate Mu receptors in CTZ and stimulate vomiting

- Mu receptor stimulated disinhibition by switching off GABA secretion

35
Q

what effect does opioid overdose have on the eyes? how is this different from most overdoses?

A
  • opioid overdose = miosis
  • most overdoses = dilated pupils (mydriasis)
  • dec. brain function reduces level of constriction
36
Q

how do opioids cause miosis?

A
  • activation of Mu receptors causes dis-inhibitory effct by dec. GABA secretion
  • stimulates pupil constriction in EW nucleus
37
Q

how do opioids cause GI disturbances?

A
  • many opioid receptors found in myenteric plexus
  • motor neurones release Ach or substance P to contract SM
  • motor neurones release vasoactive intestinal peptide or NO to relax SM
38
Q

due to this, what do opioids cause?

A
  • dec. in gastric emptying
  • dec. GI motility
  • inc. in water reabsorption
  • so CONSTIPATION
39
Q

how do opioids cause urticaria (local inflammation)?

A
  • hydroxyl group found on some opioids causes mast cell degranulation
40
Q

how do opioids cause tissue tolerance?

A
  • opiods upregulate levels of arrestin in tissues
  • arrestin promotes receptor internalization
  • over internalization of receptors –> tissues become less receptive to opioids
  • tissue becomes tissue tolerant
41
Q

what is withdrawal associated with?

A
  • psychological craving

- physical withdrawal (resembling flu)

42
Q

what causes the physical withdrawal?

A
  • opioids normally depress cell activity by reducing AC acticity
  • body responds by upregulating AC activity
  • when remove opioid drug, body is overstimualting AC
  • general activity is inc. for few weeks after = withdrawal
43
Q

what are the features of an overdose?

A
  • coma
  • resp depression
  • pin point pupils
  • hypotension (due to histamine release)
44
Q

what is the treatment of an overdose?

A
  • I.V. naloxone (opioid antagonist)
  • naloxone also has tertiary nitrogen chain so can bind to opiod receptors
  • naloxone has long side chain of Carbons so has antagonistic properties once bound to opioid receptors

notes to flashcards year 2 - LCRS1 (58 decks)

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