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Pharmacology and Therapeutics > 18. Opioids > Flashcards

18. Opioids Flashcards

1
Q

What is an opiate?

A

Alkaloid derived from the poppy - Papaver somniferum

Opioid = natural and synthetic

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2
Q

What are the 4 most common natural opiates?

A
  • Morphine
  • Codeine
  • Thebaine
  • Papaverine
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3
Q

What part of opiates’ structure makes it an analgesic?

A
  • Tertiary nitrogen
  • Permits receptor anchoring
  • The side chain attached to the nitrogen determines the efficacy
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4
Q

What happens if you extend the tertiary nitrogen side chain of morphine (so it has 3+ carbons)?

A

Agonist => antagonist

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5
Q

How is the solubility of heroin and codeine different to morphine?

A

They are more lipid soluble (theoretically can pass the BBB easily)

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6
Q

Why are the hydroxyl groups at position 3 and 6 significant in morphine?

A
  • Position 3 - required for binding

* Position 6 - oxidising this increases the lipophilicity by 10-fold

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7
Q

Where is codeine and heroin converted into morphine?

A
  • Codeine - must happen outside the brain

* Heroin - can happen in the brain

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8
Q

What is heroin and codeine also known as?

A
  • Heroin - diacetylmorphine
  • Codeine - methylmorphine

(they are prodrugs of morphine)

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9
Q

Give 2 examples of synthetic opioids and their relationship with morphine

A
  • Methadone and fentanyl
  • Both have tertiary nitrogen and phenolic groups
  • Fentanyl is less like morphine
  • They are both more lipid soluble - more gets into the brain
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10
Q

How are opioids usually administered therapeutically?

A

Orally

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11
Q

What is bioavailability of IV administered opioids?

A

100%

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12
Q

Describe the absorption and metabolism of opioids administered orally?

A
  • Weak bases - pKa > 8, not very unionised in the stomach
  • Small intestine has alkaline environment - more unionised and well absorbed
  • Heavily metabolised in liver - first pass (impacts bioavailability)
  • Blood is pH7.4 - opioids largely ionised (20% remain unionised)
  • You want pH=pKa, so at this point absorption is quite good
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13
Q

Compare the lipid solubility of methadone, heroin, codeine, fentanyl and morphine (in order starting with least soluble)

A
  • Morphine
  • Codeine
  • Heroin
  • Methadone
  • Fentanyl
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14
Q

How does lipid solubility affect potency?

A

• More lipid soluble = more potent
• Exception: codeine
- codeine is a bit more soluble than morphine, but less potent

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15
Q

What is the most potent active metabolite of morphine and how do the side effects of the metabolites compare to morphine?

A
  • Morphine-6-glucoronide (10% of active metabolite)
  • Morphine seems more likely to cause negative side effects e.g. respiratory depression
  • Therefore individuals who don’t metabolise morphine well are more likely to have negative side effects
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16
Q

How does the potency of heroin and codeine compare to morphine on its own?

A

200 times less potent than morphine at the receptor

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17
Q

Why is heroin more potent than codeine?

A
  • More lipid soluble
  • Converted in the brain so has more of an effect there
  • Codeine is converted outside the brain - less potent
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18
Q

How does the speed of fentanyl metabolism compare to methadone?

A
  • Fentanyl - fast metabolism (metabolised and cleared equally fast - effect is quickly lost - addictive)
  • Methadone - slow metabolism (means it can accumulate in fatty tissues and prolong effect)
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19
Q

Describe the metabolism of codeine in the liver?

A
  • CYP2D6 converts codeine to morphine (5-10% as it’s slow)

* CYP3A4 deactivates codeine => norcodeine (quicker)

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20
Q

What effect does the poor metabolism of codeine?

A

Causes codeine to have little effect

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21
Q

How can heroin be metabolised outside the liver?

A

Esterase enzymes in the blood converts heroin => morphine

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22
Q

What are the 3 main types of opioid receptors, where are they located and what are they functionally important for?

A

Mu (μ) receptors
• cerebellum, caudate nucleus, nucleus accumbens, PAG
• pain and sensation

Delta (δ) receptors
• nucleus accumbens, cerebral cortex, hippocampus, putamen
• motor and cognitive function

Kappa (κ) receptors
• hypothalamus, putamen, caudate
• neuroendocrine role

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23
Q

On which opioid receptors do the different endogenous agonists act?

A
  • Endorphins - μ (or δ)
  • Enkephalins - δ
  • Dynorphins - κ
24
Q

What effect do opioids have on cells?

A
  • Depressant - slow cellular activity
  • Hyperpolarisation - increase K+ efflux
  • Reduce Ca2+ inward current - impacts exocytosis and NT release, impairs nerves
  • Decrease adenylate cyclase activity - decreases cellular activity
25
Q

What positive effects do opioids have?

A
  • Analgesia
  • Euphoria
  • Depression of cough centres (anti-tussive)
26
Q

What negative effects do opioids have?

A
  • Depression of respiration (medulla) - easy to OD
  • Stimulation of chemoreceptor trigger zone (nausea)
  • Pupillary constriction
  • GI effects
27
Q

How do opioids act as an analgesic?

A
  • Decrease pain perception - information relayed to brain

* Increase pain tolerance - brain suppresses signals

28
Q

Which region in the brain is the integrating centre for the pain tolerance pathway?

A

PAG (periaqueductal gray region)

29
Q

Where is information for pain tolerance and perception relayed to?

A

NRM (nucleus raphe magnus)

30
Q

What does the NPRG (nucleus reticularis paragigantocellularis) do?

A
  • Auto-feedback element of the brain

* Switches on pain tolerance without any higher centre functioning

31
Q

What does the thalamus do in the pain pathway?

A
  • Spinothalamic neurones relay pain to the thalamus

* Thalamus directs the information to the cortex

32
Q

How is the hypothalamus involved in pain?

A
  • Gives information to the rest of the brain about current state of health
  • Worse health => higher sensitivity to pain
  • This prevents sick people from expending their energy on activities
33
Q

How is the Locus Coeruleus involved in pain?

A
  • It is a nucleus in the pons
  • Symapathetic NS effector
  • Stress => activates LC => signal to dampen down pain
  • Reason for lack of pain during sports injury
34
Q

What is the sustantia gelatinosa and why is it important in pain?

A
  • When the brain senses pain it tries to suppresses it
  • Certain amount of signal comes down the spinal cord
  • SG is a collection of cells in the gray area (dorsal horns) at all levels of the spine
  • Processing and modification of the signal takes place here
35
Q

Which areas of the pain pathway do we want to activate and suppress for analgesic effects?

A

Activate (these parts suppress pain)
• PAG
• NPRG
• NRM

Suppress (involved in pain transmission)
• Thalamus
• Cortex
• Hypothalamus
• Periphery
• Dorsal horn
36
Q

How do opioids act in the pain pathway?

A
  • Act in the dorsal horn
  • Prevent information relay from the periphery to the spinothalamic tract (substantia gelatinosa)
  • Enhance signals from PAG and NRPG - increase pain tolerance
  • Do this by suppressing normal inhibitory signals to pain tolerance (by switching off GABA)

• Can also interfere with pain perception through sensory neurones

37
Q

How do opioids cause euphoria?

A
  • Enter brain and bind to their receptors
  • Depress firing rate of GABA interneurons
  • Less inhibition of dopaminergic neurones
  • Dopaminergic neurones increase firing rate => increased dopamine secretion => feelings of reward
38
Q

How does irritation in the lungs cause a cough?

A
  • Mechno/chemoreceptor detection
  • C-fibres send the information via the vagus nerve
  • Information reaches medulla
  • Effector arm stimulated - parasympathetic/motor nerves
  • Reaches diaphragm, IC muscles and lung
  • Increased contraction => cough
39
Q

What are the 2 neurotransmitters involved in coughing?

A

ACh and neurokinin (NK)

40
Q

Why are 5-HT1A receptors important in coughing?

A
  • Negative feedback receptors for serotonin
  • Reduce amount of serotonin
  • Serotonin is anti-cough
  • So stimulation increases the likeliness to cough
41
Q

How do opioids act as anti-tussives?

A
  • Decreases firing rate of C-fibres
  • Directly depress the cough centre
  • Inhibit 5-HT1A feedback receptors => more serotonin to inhibit cough
42
Q

What are the 2 important parts of respiratory rhythm generation?

A
  • Central chemoreceptors

* Pre-Botzinger complex

43
Q

What do central chemoreceptors sense in respiratory rhythm generation and where do they relay this information?

A
  • CO2 in blood
  • CSF
  • Information relayed to medullary control centre
  • Provides a constant stimulus to breath
  • Tells the brain the level of respiration needed
44
Q

How do opioids depress respiration?

A

Inhibits the central chemoreceptors and pre-Botzinger complex

45
Q

How is the pre-Botzinger complex involved in breathing?

A
  • Provides constant tonic stimulus for breathing

* Mainly inspiration

46
Q

Where is respiratory depression most commonly seen with reference to opioids?

A
  • Heroin addicts

* Those who wean themselves off then go back to the same dose after losing tolerance

47
Q

How do opioids cause nausea/vomiting?

A
  • GABA keeps the chemoreceptor trigger zone (CTZ) suppressed
  • Opioids switch off this inhibition
  • CTZ signals to the medullary vomiting centre (CTZ is located right behind) - nausea
48
Q

How do opioids cause miosis (constricted pupils)?

A
  • Optic nerve relayed information to the pretectal nucleus
  • Signals transmitted to parasympathetic nerve in the Edinger-Westphal nucleus
  • GABA suppresses the parasympathetic nerves here - opioids switch inhibition off => miosis

(most other drugs cause pupil dilation as they become unconscious, but opioids cause constriction)

49
Q

How does the presence of food in the gut cause contraction/relaxation in the enteric nervous system?

A

• Sensory neurone (connected to the mucosal chemoreceptors and stretch receptors) detect chemical substances or tension
• Information relayed to submucosal and myenteric plexus via interneurons
• Motor neurones release:
- ACh or substance P to contract smooth muscle
- Vasoactive intestinal peptide or nitric oxide to relax smooth muscle

50
Q

How do opioids affect the GIT?

A
  • Prevent sensory information from relayed into the enteric nervous system
  • Also affects motor function => less gut contraction (heavy constipation) and fewer secretions
51
Q

How do opioids cause urticaria?

A
  • Opioids directly interact with mast cells under the skin
  • Causes histamine release
  • Involves PKA but not opioid receptors
  • Caused mainly by morphine and codeine (OH position 6)
  • Not allergic reaction
52
Q

What causes opioid tolerance?

A 
Tissue level (not liver)
• Arrestin - drives receptor internalisation
• Arrestin concentration increases => increase internalisation => tolerance
53
Q

What causes withdrawal symptoms (and dependence) to opioids?

A

• Psychological
• Physical (flu-like)
- cells try to up-regulate activity while taking opioids (increased adenylate cyclase)
- once opioids are removed, adenylate cyclase is overactive
- muscular shakes, diarrhoea

54
Q

What happens to the body if you OD on opiates?

A
  • Respiratory depression
  • Pin-point pupils
  • Hypotension
  • Coma
55
Q

What is the treatment for opiate OD?

A
  • Naloxone (opioid antagonist)

* Has 3 carbons on the tertiary nitrogen side chain

Pharmacology and Therapeutics (33 decks)

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