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Year 2 LCRS - Pharmacology > Opioids > Flashcards

Opioids Flashcards

1
Q

What is an opiate?

A

anything that comes from the opium poppy. An opiate is an alkaloid derived from the poppy, Papaver somniferum

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2
Q

What are common natural opiates?

A
  • morphine
  • codeine
  • thebaine
  • papaverine
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3
Q

What role does the tertiary nitrogen on morphine play?

A

The tertiary nitrogen seems to be incredibly important for the analgesic effect of morphine. If you extend the nitrogen side chain, you go from agonist -> antagonist

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4
Q

How are heroine and codeine activated?

A

hydroxyl groups associated with morphine are needed for activity. As a result, heroine and codeine have to be converted to morphine to exert an effect

*For heroine, this conversion can happen in the brain. This is not the case for codeine (codeine à morphine conversion must take place outside the brain)

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5
Q

Describe the structures of some synthetic opioids

A

Methadone looks very similar to morphine (tertiary nitrogen, along with phenolic groups).

Fentanyl is less like morphine, but it still possesses the tertiary nitrogen (incredibly important for receptor binding).

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6
Q

How are opioids administered?

A

For therapeutic uses, this is often oral – for abusive uses, this is often intravenous (heroine is injected)

  • Intravenous injection provides 100% bioavailability
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7
Q

How are opioids absorbed and metabolised?

A

Opioids are weak bases – pKa >8 – so they won’t be very unionised in the stomach (-> poor absorption)

once they enter the small intestines, they are well absorbed (alkaline environment)

Opioids are heavily metabolised in the liver (first pass) – this impacts their bioavailability

Because the pH of the blood is around 7.4, opioids are largely ionised in the blood (80%)

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8
Q

How does lipid solubility relate to potency?

A

the more lipid soluble, the more potent (exception: codeine - more lipid soluble than morphine but less potent)

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9
Q

How does metabolism of morphine affect the likelihood of experiencing negative side effects?

A

Morphine seems more likely to cause the negative side effects (e.g. respiratory depression)

The active metabolites (morphine 3-glucuronide and morphine 6-glucuronide) are less likely to do this

  • individuals who don’t metabolise morphine very well are more likely to have negative side effects
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10
Q

Compare the rate of metabolism of fentanyl to morphine. What is the significance of this?

A

fentanyl - fast - metabolised by cytochrome 3A4 quickly, and is cleared equally fast

morphine - slow - metabolised by several enzymes and drug isn’t cleared well from the body

  • both very lipid soluble but morphine cleared slowly -> accumulation in fatty tissue - often used as heroine replacement
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11
Q

Describe the metabolism of codeine

A

metabolised by two cytochrome P450 enzymes:

  • One enzyme activates codeine (CYP2D6) to morphine – 5-10% of the codeine is converted via this route
  • The other enzyme (CYP3A4) deactivates codeine – all conversion takes place in the liver
  • people may have good metabolism of codeine -> more powerful effect (more morphine)
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12
Q

What are the man types of opiate receptors?

A
  1. Endorphins act on Mu (μ) receptors OR delta (δ) receptors
    - Located in the cerebellum, caudate nucleus, nucleus accumbens and PAG
    - Important in pain and sensation
  2. Enkephalins act on delta (δ) receptors
    - Located in the nucleus accumbens, cerebral cortex, hippocampus and putamen
    - Important in motor and cognitive function
  3. Dynorphins act on kappa (κ) receptors
    - Located in the hypothalamus, putamen and caudate
    - Important neuroendocrine role (via the hypothalamus)
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13
Q

What are endogenous agonists of opiates?

A
  • endorphins
  • enkephalins
  • dynorphins/ neoendorphins
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14
Q

What is the cellular MoA of opioid receptors?

A

Opioids are depressant – they tend to slow cellular activity

They can hyperpolarise cells -> (increase K+ efflux)

They can reduce the Ca2+ inward current – this massively impacts exocytosis and NT release

  • Within the cell, they can decrease adenylate cyclase activity
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15
Q

What are the effects of opioids?

A

positive:

  • Analgesia
  • Euphoria
  • Depression of cough centre (anti-tussive)

negative:

  • Depression of respiration (medulla)
  • Stimulation of chemoreceptor trigger zone (nausea/vomiting)
  • Pupillary Constriction
  • G.I. Effects
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16
Q

What is the mechanism of analgesia caused by opioids?

A
  • Sensory from the periphery into the thalamus via the spinothalamic tract.
  • Thalamus and extra-cortical and cortical inputs activate the PAG (co-ordinates pain).
  • PAG activates the NRM (Nucleus Raphe Magnus).
  • NRM sends inhibitory descending signals to the dorsal horn – NRM increases pain tolerance
17
Q

What does the NPRG do?

A

Nucleus Reticularis Paragigantocellularis

automatically suppresses pain before the brain processes it - independent of thalamus

  • negative-feedback centre of the brain
18
Q

How are the hypothalamus and locus coeruleus involved in the analgesic effects of opioids?

A

Hypothalamus:

  • Constantly signals PAG independent of pain sensation
  • In a poorer state of health, you are likely to be more sensitive to pain

LC (Locus Coeruleus) – major SNS outflow:

  • Activated during a stress response
  • During fight/flight, you do NOT want the pain response interfering with fight/flight
  • Pain worse after an accident than during!
19
Q

How is pain transmission modulated?

A

Spinal cord can modulate pain tolerance

descending inhibition from NRM:

  • Some go directly into decreasing pain transmission in the spinothalamic tract.
  • Some project into the Substantia Gelatinosa (can modulate/determine level of inhibition necessary on the sensory neurones from the NRM)
20
Q

How do opioids cause analgesia?

A

Opioids act in the dorsal horn to prevent information relay from periphery to the spinothalamic tract (DEPRESSANT)

They also suppress the normal inhibitory signal (GABA) in the NRPG and PAG -> more pain toleranc

21
Q

How do opiates cause euphoria?

A

bind to Mu receptors and decrease GABA exocytosis -> reduces inhibition of VTA -> more dopamine released

22
Q

How do opioids cause an anti-tussive effect?

A

Central:
- 5HT1A-receptor antagonist:
> 5HT1A-receptor is a negative feedback receptor for serotonin and firing leads to suppression of serotonin and activation of the cough reflex - inhibition -> increased serotonin -> less cough
- Medulla direct depression

Peripheral:
- ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents

23
Q

How do opioids cause respiratory depression?

A

Depression of the Pre-Botzinger complex in the ventrolateral medulla – this generates respiratory rhythm so less rhythm with depression.

Central chemoreceptors are also inhibited by opioids and so depress the firing rate of the central chemoreceptors

24
Q

How do opioids cause vomiting/ nausea?

A

can be seen at therapeutic dose via direct effect at chemoreceptor trigger zone (Mu receptors)

GABA keeps the CTZ suppressed – opioids switch this inhibition off. The CTZ signals to the medullary vomiting centre, and you feel nauseous

25
Q

How do opiods cause miosis (constriction)?

A
  • most overdoses exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction but opiates cause “pin-prick” eyes

Activation of the Mu receptors causes a dis-inhibitory effect by decreasing GABA secretion and thus stimulates the pupil constriction in the Edinger-Westphal nucleus

26
Q

How do opioids cause GI disturbances?

A

Many opioid receptors (kappa and Mu) are found in the myenteric plexus

  • Motor neurones release Ach or substance P to contract SM
  • Motor neurones release VIP (vasoactive intestinal peptide) or NO to relax SM

Opioids cause:

  • Decrease in gastric emptying
  • Decreased GI motility
  • Increase in water reabsorption
  • CONSTIPATION
27
Q

How do opioids cause uticaria (local inflammation)?

A

Not all opioids cause histamine release – it is the hydroxyl group found on some opioids that cause mast cell degranulation (non-IgE-mediated - not an allergy)

You can switch people to different opioids if they display this response (one without the OH group)
- This reaction is PKA mediated (not receptor-mediated).

28
Q

How do tissues become tolerant to opioids?

A

Opioids upregulate levels of arrestin in the tissues. -> promotes receptor internalisation

The over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant

29
Q

What is withdrawal associated with?

A

Psychological craving

Physical withdrawal (resembling the flu):
- Opioids normally depress cell activity by reducing AC activity and so the body responds by upregulating AC activity -> general cell activity is greatly increased for a few weeks after -> withdrawal
30
Q

What are the features of an opiate overdose?

A
  • coma
  • respiratory depression
  • pin-point pupils
  • hypotension (due to histamine release)
31
Q

How do you treat an opiate overdose?

A

I.V. Naloxone (opioid antagonist)

  • Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors
  • Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors

Year 2 LCRS - Pharmacology (32 decks)

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