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Pharmacology > Opioids > Flashcards

Opioids Flashcards

1
Q

What is an opiate?

A

An alkaloid derived from the poppy, Papaver somniferum.

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2
Q

What is an important structural component of morphine and its relation to opiate activity?

A

Tertiary nitrogen- allows analgesic effects, permits receptor anchoring.

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3
Q

What is heroin in relation to morphine?

A

Diacetylmorphine- hydroxyl groups of morphine replaced with acetyl groups. Opiate.

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4
Q

What is codeine in relation to morphine?

A

Methylmorphine- methyl group at position 3. Prodrug. Opiate.

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5
Q

How is an opiate antagonist generated from morphine?

A

Extend the tertiary nitrogen side chain to 3+ carbons.

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6
Q

How are heroin and codeine activated?

A

Need hydroxyl groups- have to be converted to morphine.

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7
Q

How does the lipid solubility of an opiate relate to its potency?

A

More lipid soluble = more potent.

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8
Q

What are the usual routes of administration of opioids, and how do these affect bioavailability?

A

Therapeutic- usually oral:

  • well absorbed in alkaline small intestines
  • opioids are weak bases- mostly pKa > 8
  • heavily metabolised in liver
  • pH of blood = 7.4, largely ionised in blood
  • 20% bioavailability

Drug of abuse- usually i.v., 100% bioavailability.

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9
Q

List opioid drugs from highest to lowest lipid solubility.

A 
Fentanyl
Methadone
Codeine
Heroin
Morphine
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10
Q

How potent is heroin compared to morphine?

A

Heroin is twice as potent.

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11
Q

How potent is codeine compared to morphine?

A

Morphine is ten times more potent than codeine.

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12
Q

How potent is methadone compared to morphine?

A

Methadone is 4 times more potent than morphine.

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13
Q

How potent is fentanyl compared to morphine?

A

Fentanyl is 100 times more potent than morphine.

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14
Q

What is the duration of action of morphine?

A

3-6 hours

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15
Q

What is the duration of action of heroin?

A

2-4 hours

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16
Q

What is the duration of action of codeine?

A

3-4 hours

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17
Q

What is the duration of action of methadone?

A

24-32 hours

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18
Q

What is the duration of action of fentanyl?

A

2-4 hours

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19
Q

What are the active metabolites of morphine?

A

Morphine-3-glucuronide

Morphine-6-glucuronide

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20
Q

What is the rate of clearance of morphine?

A

20ml/kg/min

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21
Q

Give an inactive metabolite of morphine.

A

Normorphine.

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22
Q

What is the rate of clearance of methadone?

A

0.5ml/kg/min

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23
Q

What is the rate of clearance of fentanyl?

A

15ml/kg/min

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24
Q

What is the most potent active metabolite of morphine?

A

Morphine-6-glucuronide.

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25
Q

Where is heroin converted to morphine?

A

In the brain.

26
Q

Where is codeine metabolised to morphine?

A

Outside the brain, so less potent.

27
Q

What is the difference between rate of metabolism of fentanyl and methadone?

A

Fentanyl is more effectively metabolised by CY3A4 and cleared more effectively- fast effect, quickly lost.

Methadone- 6 or 7 different enzymes metabolise it- slow metabolism, cleared slowly, accumulates in fat because lipid soluble- frequently used as heroin replacement.

28
Q

How is codeine metabolised?

A

5-10% codeine → morphine CYP2D6 O-dealkylation- activates (slow); CYP3A4- deactivates.

29
Q

How do opioids work?

A

Act via specific opioid receptors.

30
Q

List endogenous opioid peptides.

A

Endorphins
Enkephalins
Dynorphins/neoendorphins

31
Q

What opiate receptors do the respective endogenous opioid peptides act on?

A

Endorphins act on Mu (µ) or delta (∂)
Enkephalins act on delta (∂)
Dynorphins act on kappa (k)

32
Q

What are the three main types of opiate receptors?

A

mu, delta and kappa.

33
Q

Where are mu opiate receptors found?

A

Cerebellum
Caudate nucleus
Nucleus accumbens
PAG

34
Q

What are mu opiate receptors responsible for?

A

Pain

Sensorimotor

35
Q

Where are delta opiate receptors found?

A

Nucleus accumbens
Cerebral cortex
Hippocampus
Putamen

36
Q

What are delta opiate receptors responsible for?

A

Motor/cognitive function

37
Q

Where are kappa opiate receptors found?

A

Hypothalamus
Putamen
Caudate

38
Q

What are kappa opiate receptors responsible for?

A

Neuroendocrine effects

39
Q

What is the cellular mechanism of action of an opiate receptor?

A

Depressant- depress (slow) cellular activity.

Hyperpolarisation of cells (increased potassium efflux).

Decreased calcium inward current- affects exocytosis and release of neurotransmitters.

Decreased adenylate cyclase activity.

40
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
GI effects- constipation

41
Q

What are the two main ways in which opioids have an analgesic effect?

A

Decrease pain perception.

Increase pain tolerance.

42
Q

Where might opioids act?

A

Activate PAG, NRM and NRPG- suppress pain
Suppress thalamus, cortex, hypothalamus, locus coeruleus, dorsal horn and periphery- transmission of pain to the brain
Opioids act on dorsal horn to prevent information relay from periphery to spinothalamic tract, directly depressant
Activates PAG and NRPG via disinhibition- switch off GABA, suppressing normal inhibitory signal

43
Q

How do opioids produce euphoria?

A

Binds to opioid receptor and depresses firing rate of GABA interneurons that suppress reward pathway
Disinhibition
Dopaminergic neuron increases firing rate
More dopamine = more reward and euphoria

44
Q

How is the hypothalamus involved in pain modulation?

A

Constantly gives information to rest of brain about current state of health
Poor state of health = more sensitive to pain
Relays information to PAG

45
Q

Describe the normal mechanism of modulation of pain transmission.

A

Pain is sensed peripherally, recognised by sensory neurons and relayed to spinal cord.

Spinal cord- spinothalamic neurons relay information up into brain.

Thalamus- receives information and decides where to send it

Information sent to cortex and directly activates descending pain tolerance pathway.

Periaqueductal grey region (PAG)- receives information and determines output.

Information relayed to nucleus raphe magnus- effector.

Descending neurons suppress pain through periphery and spinal cord.

46
Q

What is the role of the locus coeruleus in pain modulation?

A

Sympathetic nervous system effector, largely independent of whole system.

If stress pathway is activated, locus coeruleus is active, automatic signal to dampen pain, sympathetic nervous system suppresses pain information getting from periphery to brain.

47
Q

What is the role of the substantial gelatinosa in pain modulation?

A

‘Mini brain’- processing within spinal cord and modification of signal determines how much inhibition there is.

48
Q

What is the role of the dorsal horn in pain modulation?

A

Signals suppress information moving from periphery to brain.

Some of that information comes straight down, inhibits flow of information from sensory nerve to spinothalamic nerve.

49
Q

What is the role of the nucleus reticularis para-giganta-cellularis (NRPG) in pain modulation?

A

Auto-feedback element of the brain- switch on pain tolerance without higher centre functioning, not as powerful, but important mechanism.

50
Q

What is the role of the thalamus in pain modulation?

A

Gatekeeper, receives information and decides where to send it, not processed, sends information to cortex (higher centres).

51
Q

What is the role of the periaqueductal grey region (PAG) in pain modulation?

A

Integrating centre for pain tolerance pathway, receives information and determines output.

52
Q

How are opioids used as antitussives?

A

Stimulation of mechano- or chemoreceptors (throat, respiratory passages or stretch receptors in lungs).

ACh/neurokinin (NK) C-fibres relay to vagus- opioids decrease firing rate of these.

Afferent impulses to cough centre (medulla)- opioids have direct depressant effect on cough centre.

5HT1A receptors- negative feedback receptors for serotonin, serotonin is anti-cough- opioids inhibit these receptors and increase serotonin, thus suppressing cough.

Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung
Increased contraction of diaphragmatic, abdominal and intercostal (ribs) muscles → noisy expiration (cough).

53
Q

How does an opioid overdose lead to respiratory depression?

A

Central chemoreceptors sense carbon dioxide in blood and relay information to respiratory control centre- tonic drive, constantly tell the brain the level of respiration needed.

Within control centre, prebotzinger complex deals with rhythm generation- determines respiratory rate.

Opioids inhibit central chemoreceptors and medullary control centre (prebotzinger complex), reducing rhythm generation and respiratory rate.

54
Q

What is the most powerful side effect of opioids?

A

Respiratory depression.

55
Q

How can opioids cause nausea/vomiting?

A

Opioids act on chemoreceptor trigger zone directly- disinhibition of GABA via mu receptors.

Chemoreceptor trigger zone sends signal to medullary vomiting centre.

56
Q

How can opioids cause miosis?

A

Opioid receptors are expressed in the Edinger-Westphal nucleus where they switch on the parasympathetic nerve and trigger miosis.

Disinhibition- switching off GABA.

Pupil constriction.

Classic sign of heroin overdose.

57
Q

How can opioids cause gastrointestinal disturbance?

A

Sensory neuron connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food.

Information relayed to submucosal and myenteric plexus via interneurons.

Motor neurons release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle.

Opioid receptors everywhere within enteric nervous system.

Prevent sensory information being relayed in.

Affect motor function- secretions and gut contractions.

Suppress enteric nervous system.

Much less gut contraction, fewer secretions, etc.

Constipation.

58
Q

How can opioids cause urticaria, and what is it?

A

Skin
Histamine release
Not allergic response
PKA mediated
Direct interaction of opioids with mast cells
Not through mu receptors
Need hydroxyl group- codeine, morphine- not so much heroin or fentanyl

59
Q

How does tolerance develop against opioids?

A

Not pharmacokinetic.

Tissue tolerance.

Receptor internalisation.

Arrestin is an important protein that drives receptor internalisation.

If opioids are constantly available and suppressing cells, cell responds by withdrawing opioid receptors from cell- desensitise cell to opioids.

Arrestin concentration increases, tissue internalises opioid receptor more effectively, tolerant to opioids.

60
Q

What symptoms is opioid dependence and withdrawal associated with?

A

Withdrawal associated with:

  • psychological craving
  • physical withdrawal
  • resembling flu

Adenylate cyclase increases- overactive: muscle cramps, nausea, diarrhoea.

61
Q

What are the signs/symptoms of opioid overdose?

A

Coma
Respiratory depression- major problem
Pinpoint pupils
Hypotension

62
Q

How is an opioid overdose treated?

A

Naloxone (opioid antagonist) i.v.

Pharmacology (21 decks)

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