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Year 2 - LCRS - Pharmacology > Opioids (10.02.2020) > Flashcards

Opioids (10.02.2020) Flashcards

1
Q

What is an opiate?

A

An alkaloid derived from the poppy, Papaver somniferum

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2
Q

Opiates vs. opiods

A
  • Opiates are the natural products (alkaloids) of the poppy plant
  • Opiod = anything with opiate like activity (e.g. Heroin), this includes synthetic products.
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3
Q

Name some examples of opiates

A

= natural products from the poppy plant (Papaver somniferum)

  • morphine
  • codeine
  • thebaine
  • papaverine
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4
Q

What plant are opiated derived from?

A

Papaver somniferum

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5
Q

What are some important structural parts of the morphine molecule?

A
  • tertiary nitrogen
  • hydroxyl group at position 3
  • hydroxyl group at position 6
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6
Q

Tertiary nitrogen in the morphine molecule

A
  • important for anchoring to the receptor -> affinity depends on this tertiary nitrogen
  • if you extend the chain on the tertiary nitrogen position (3+ carbons) the agonist becomes an antagonist)
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7
Q

What is the structural difference between heroin and morphine?

A
  • In heroin the two hydroxyl groups are replaced with acetyl groups.
  • Heroin = diacetylmorphine / 3,6-diacetylmorphine
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8
Q

Structural difference between morphine and codeine?

A
  • Codeine is methylmorphine

- the hydroxyl group at position 3 is replaced with a methyl (CH3) group.

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9
Q

OH-group at position 3 in morphine

A
  • OH group with aromatic ring is required for binding to the receptor
  • because of this, morphine binds to the receptor much better than heroin or codeine
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10
Q

OH-group at position 6 in morphine

A
  • if the OH-group is oxidised / removed and replaced with e.g. an acetyl-group, the lipophilicity increases 10-fold
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11
Q

Morphine or heroine - what are their differences in biding?

A
  • Morphine has an OH-group at the 3 position which is needed for good binding to the receptor (hydroxyl group at position 3 with aromatic ring)
  • Heroin is much more lipid soluble because of the acetyl group so it can access the receptors much easier.
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12
Q

What structural elements are necessary for the action of opioids?

A
  • tertiary nitrogen
  • aromatic ring
  • OH group at position 3

(earlier the morphine rule was that you need 3*N, aromatic ring, gap between them, quaternary carbon center) fentanyl is very potent and does not have the latter characteristic only the first 3 mentioned at the top)

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13
Q

RoA of opioids

A
  • ingestion (oral)

- injection (i.v.)

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14
Q

What is the pKa of morphine? How is it absorbed in different places?

A
  • pKa = 8
  • stomach = ionised (pH 2-3)
  • small intestine = better absorption but still ionised (early pH 5-6 then later around 7)
  • in the blood it is the least ionised (pH = 7.4) but still it is less than 20% is unionised -> this fraction can effectively leave the blood and enter tissues.
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15
Q

Potency of different opiates

A

codeine < morphine < heroin < methadone < fentanyl

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16
Q

Lipid solubility of different opiates

A
  • Lipid Solubility: Methadone/Fentanyl&raquo_space; Heroin > Morphine
  • General rule of thumb – More lipid soluble, more potent.
  • morphine < codeine < heroin < methadone < fentanyl
  • codeine is more lipid soluble than morphine but less potent due to metabolism.
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17
Q

Which is the longest lasting opiod?

A

Methadone (24 - 32 h)

clearance rate is much lower than the other opioids (0.5 ml/kg/min compared to 10-30 lm/kg/min)

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18
Q

Metabolism of different opioids

A

Morphine:

  • metabolised to morphine-3G-glucuronide and morphine-6G-glucuronide
  • metabolised normorphine (inactive)
  • the metabolites cause euphoria but don’t cause respiratory depression.

Methadone and fentanyl don’t have active metabolites. Methadone has slow clearance.

Heroine and Codeine are prodrugs that are metabolised to morphine as the active metabolite.

  • The majority of opioids are metabolised in the liver by either CYP3A4 and CYP2D6.
  • In the case of codeine, CYP2D6 metabolism is slow but converts codeine to morphine i.e. codeine is a prodrug. CYP3A4 metabolises and deactivates codeine.
  • As a result only 10% of the codeine is metabolised to produce morphine – this is what is responsible for codeine analgesic property.
  • Some individuals have a 2D6 polymorphism, so won’t respond well to codeine.
  • Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.
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19
Q

Name some endogenous opioid peptides

A

Endorphins (mu, delta)
Enkephalins (delta)
Dynorphins/neoendorphins (kappa)

20
Q

How do opioids act?

A

They act via specific ‘opioid’ receptors

21
Q

Cellular MoA of opioids

A

Depressant –>

  • Hyperpolarisation (increased K+ efflux so that the cell is harder to depolarise -> activity decreases)
  • decreased Ca2+ influx (important in terms of NT release, decresases cellular activity)
  • ⬇️ Adenylate cyclase activity -> less cAMP
22
Q

What are the effects of opioids?

A
  • Analgesia
  • Euphoria
  • Depression of cough centre (anti-tussive)
  • Depression of respiration (medulla)
  • Stimulation of chemoreceptor trigger zone (nausea/vomiting)
  • Pupillary Constriction
  • G.I. Effects
23
Q

What are the 3 subtypes of opiate receptors?

A
  • Mu (Endodrphins)
  • Delta (Enkephalins, Endorphins)
  • Kappa (Dynorphins)

=> we know a lot less about delta and Kappa.
Analgesia and Euphoria are mainly Mu mediated.

24
Q

Pain Pathway and pain tolerance

A
  • Painful stimulus from nociceptors in the periphery
  • dorsal horn
  • spinothalamic tract to..
  • Thalamus where the pain is relayed to..
  • Cortex

Pain tolerance:

  • PAG is responsible for pain tolerance
  • once a painful stimulus reaches the thalamus, there is always a minimal level of PAG activation to suppress pain
  • the cortex can suppress or enhance pain tolerance via PAG depending on e.g. memory.
  • PAG and NRPG signal to
  • NRM signals to the periphery (predominantly to the spinal cord)
  • hypothalamus and LC also have influence on pain tolerance
25
Q

PAG

A

= periaqueductal gray

  • primary control center for descending pain modulation
  • has enkephalin producing cells that suppress pain
  • gray matter located around the cerebral aqueduct within the tegmentum of the midbrain.
26
Q

NRM

A

= nucleus raphe magnus

  • signals to the periphery (predominantly to the spinal cord)
  • interferes with the signal from peripheral nerve to upper nerve in the spinothalamic tract
  • endogenous analgesia
27
Q

NRPG

A

= nucleus reticularis paragigantocellularis

  • feedback mechanism of the brain that turns the NRPG on to automatically activate pain tolerance, doesn’t have to go to the brain.
28
Q

Hypothalamus and pain

A
  • hypothalamus signals to PAG if you are healthy or not
  • if you are healthy and you can cope with the pain well
  • if you are in poor health, painful stimuli are exaggerated and this stops you from overdoing it if you are already poorly
29
Q

LC

A

= locus coeruleus

  • sympathetic arm of the brain
  • not part of the brain pathway
  • if SNS is on, it will try and suppress painful stimuli
  • e.g. when you hurt yourself during exercise you feel the pain a lot more once you stop exercise and SNS activation goes down.
30
Q

Substantia gelatinosa

A
  • one point where first order neurons of the spinothalamic tract synapse.
  • receives a lot of peripheral information -> signal is modified based on info received
  • responds to minute to minute homeostatic balance -> determines what level of pain tolerance you receive
31
Q

Where do opioids act in the pain pathway?

A

PERCEPTION

  • periphery
  • dorsal horn -> to interfere with transmission from periphery to spinothalamic neurones

PAIN TOLERANCE

  • PAG (via disinhibition (block GABA neurones which suppress PAG) , this is the pain tolerance pathway)
  • NRPG (via disinhibition (block GABA neurones which suppress NRPG), this is the pain tolerance pathway)
32
Q

What is the integrating center for pain tolerance?

A

Periaqueductal grey (influenced by cortex e.g. memory o previous injury)

  • some levels of response is determined by it and switches of pain tolerance
  • mediated by NRM that projects down to the spinal cord directly but also though the substantial gelatinosa (more effective) to suppress pain signals going up to the brian.
33
Q

How do opioids cause euphoria?

A

act as a depressant of GABAergic neurones (via Mu receptor) synapsing onto cell bodies in VTA that synapse in the nAcc -> more dopamine is release

-> disinhibition causes increased activation of pleasure centers.

34
Q

How do opioids act as antitussives?

A
  • interfere with the ability of the cough sensation to get to the brain (via Ach/NK C-fibres relay to Vagus)
  • also stop the efferent pathway from the medulla (5HT1a receptors)
  • opioids inhibits the 2 pathways
35
Q

How is cough mediated?

A
  1. Mechano/chemoreceptors send afferent impulses to the cough center in the medulla (ACh/Neurokinin C-fibres to Vagus nerve)
  2. efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung (5HT1a Receptors)
  3. increased contraction of these muscles -> noisy expiration (cough)
36
Q

Respiratory depression due to opioids

A
  • at high doses
  • most severe problem with opioids
  • opioids interfere with the central chemoreceptors that respond to CO2 in the blood
  • impairs with and reduces the urge to breathe
37
Q

Nausea and vomiting due to opioids

A
  • disinhibition of chmemoreceptor trigger zone (the part that samples the blood for noxious content)
  • this signals to the medullary vomiting center and makes you feel nauseous.
38
Q

What can activate the vomiting center?

A
  • things in GIT and heart
  • thoughts
  • vestibular system
  • opioids (disinhibition; interfere with signalling from chemoR trigger zone)
39
Q

Miosis due to opioids

A
  • constricted pupils - heroin/opioid overdose.
  • usually if you are unconscious your pupils dilate a little
  • opioids act on mu receptors in the Edinger Westphal nucleus
  • disinhibition
40
Q

GI disturbane due to opioids

A
  • constipation due to long term opioids (slowed down gut motility)
  • mu and kappa receptors
41
Q

Urticaria due to opioids

A
  • chemically driven: Not all opioids cause histamine release – in fact it is the combination of the N-methyl group and the 6-hydroxyl group that is common to all opioids that induce non IgE mediated histamine release.
  • massive histamine release
  • mechanism not fully understood
  • particularly with codeine
42
Q

Opioid tolerance

A
  • you can become very tolerant
  • you have to up the dose to get the same response in chronic use
  • opioids increase the amounts arrestin-> down regulation of R on cells -> less responsive to opioids
  • receptors come back if you stop using opioids
43
Q

Arrestin

A
  • protein within cells that mediates receptor internalisation
44
Q

Opioid dependance

A

Withdrawal associated with

  • Psychological craving
  • Physical withdrawal (resembling flu)

All drugs of abuse cause a psychological dependence but in opioids you have a physical reaction!
Cells up regulate cell activity (i.e. increase adenylate cyclase) to compensate for opioid induced suppression -> BUT if you stop taking the opioids you have cells that are far more active (increased adenylate cyclase) -> overactive muscles, cramps

45
Q

What are the symptoms of opioid overdose?

A

Coma
Respiratory depression
Pin-point pupils
Hypotension

46
Q

How do you treat opioid overdose?

A

Naloxone (opioid antagonist) i.v.

extended side chain on tertiary Nitrogen

Year 2 - LCRS - Pharmacology (34 decks)

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