Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacology and therapeutics > Opioida > Flashcards

Opioida Flashcards

1
Q

What is meant by an opioid

A

An alkaloid derived from the poppy, Papaver somniferum

Opiate- nautral product – alkaloids that come from poppy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Give some examples of opiates

A

Morphine
Codeine
Thebaine
Papaverine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is meant by an opioid

A

Opiod- anything with opiate like activity- synthetic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the importance of the tertiary nitrogen in the opiate structure-activity relatiobship

A 
Tertiary nitrogen
= analgesia
Permits receptor
anchoring
Extend side chain to
3+ carbons and you
generate antagonist

The tertiary form of the nitrogen appears to be crucial to the analgesia of morphine; making the nitrogen quaternary greatly decrease the analgesia, since it cannot pass into the central nervous system. Changes to the methyl group on the nitrogen will decrease analgesia as well, creating antagonists

Tertiary nitrogen- important for affinity
Extend this chain- determines whether its agonist or antagonist

Afiinity and efficaycy- need teriary niterogen and short side chain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Describe the importance of the hydroxyl groups at position 3 and 6 in morphine

A

Hydroxyl groups- sites for modification

Heroin- is di-acetyl morphine- hydroxyl groups replaced by acetyl groups

Hydroxyl group
at position 3:
Required for 
Binding
i.e. codeine is 
a prodrug
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is important for the activity of morphine

A

Aromatic ring- all 3 parts of molecule interacting with receptor- vand der waals forces

Morphine best at bidnign to receptor- all 3 compnents, hydroxyl group, aromatic ring and 3 nitrogen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How is the structure of codeine different to morphine

A

Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the hydroxyl group at position. 6 in morphine

A 
Hydroxyl group
at position 6:
Oxidise the OH 
group and 
lipophilicity
Increases 
10-fold

Heroin most lipid soluble
Di-acetyle instead of two hydroxyl groups

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe methadone and fentanyl

A

Methadone conforms to the ‘Morphine Rule’ – tertiary nitrogen, quarternary carbon, phenyl group.
Fentanyl – moving away from the morphine rule has generated even more potent opioids i.e. fentanyl has a tertiary carbon NOT a quarternary carbon.

Morphine rulep- gap between aromatic ring and teriary nitrogen, also quaternary cartbon

Need to look like morphine to have an effect
Rule has broken down

 2 other similar drugs to morphine include – methadone and fentanyl.
o Methadone – tertiary nitrogen.
o Fentanyl – 2x tertiary nitrogen’s?

They are extremely lipid soluble

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the key pharmacokinetic properties of opiates

A

Opioids are weak bases and thus are likely to be ionised in the acidic stomach and poorly absorbed from this site.
In the small intestine, they will be unionised and more readily absorbed. However, first pass metabolism will decrease the bioavailability.
Blood pH = 7.4. Therefore most opioids will be largely ionised in the blood. Usually <20% unionised. This is the component that can access tissues.

S.I- 5-7

Opioids are weak bases – mostly pKa > 8

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why is the comparison of potency of the opiates complex

A

Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How is the lipid solubility of the opiates determined

A

Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe the lipid solubility of the different opiates

A 
morphine - 1
heroin- 2.3
codeine- 1.2
methadone - 116
fentanyl - 816

Lipid Solubility: Methadone/Fentanyl&raquo_space; Heroin > Morphine
General rule of thumb – More lipid soluble, more potent - except for codeine

potency:
morphine 1:1
heroin 2:1
codeine 1:10
methadone 4:1
fentanyl: 100:1
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe the active and inactive metabolites of the opioids

A

Morphine:
Inactive metabolite - normorphine
Active metabolites - Morphine 3-G glucuronide
Morphine 6-G glucuronide (10%)

Heroin:
Inactive metabolites- normprphine
Active metabolites- Morphine

Codeine:
Inactive metabolite- nor codeine
Active metabolite- codeine

Methadone
inactive - EDDP
Active- none

Fentanyl
inactive - norfentanyl
active- none

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the metabolism of morohine, methadone and fentanyl

A

Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists
In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. For example, in a 2001 clinical trial, 50 patients with cancer who did not respond to morphine or were unable to tolerate it were switched to methadone, which undergoes complex metabolism involving up to 6 CYP enzymes.
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

Active metabolites- cxaude euophori but not respiratory depression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Compare the rate of metabolism of fentanyl and methadone

A

Fentanyl is metabolised rapidly (it can be broken down by cholinesterases in the blood)
Methadone is metabolised slowly so remains in the blood for longer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is a use of methadone based on its metabolism

A

It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe the metabolism of codeine

A

 Metabolism 2: Codeine  morphine – only 5-10% of codeine is metabolised to produce morphine as there are activating (slow) and inactivating enzymes found in the liver:
o Activation (slow) via CYP-2D6 (O-dealkylation) – can have a polymorphism so don’t respond to codeine.
o Deactivation via CYP-3A4.
 Most opioids are metabolised by CYP-2D6 and CYP-3A4 in the liver.
Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Essentially, how do opioids work

A

They act via specific ‘opioid’ receptors

Endogenous opioid peptides:

Endorphins
Enkephalins
Dynorphins/neoendorphins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What do endorphins act on

A

Mu or delta receptors

Cerebellum
Caudaute
Nucleus accumbent
PAG
All mu-mediated

Pain/Sensorimotor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What do the enkephalins act on

A

Delta

Nucleus accumbens
Cerebral cortex
Hippocampus
Putamen

Motor/cognitive function

22
Q

What do the dymorphins act on

A

Kappa

Hypothalamus
putamen
caudate

Neuroendocrine

23
Q

Describe the cellular actions of opioids at the opiate receptors

A

Hyperpolarisation (increased K+ efflux)
Reduce Ca2+ influx (affects neurotransmitter exocytosis)
Reduce adenylate cyclase activity (general reduction in cellular activity)

24
Q

What are the clinical effects of opioids

A

Analgesia

Euphoria

Depression of cough centre (anti-tussive)

25
Q

What are the side effects of opioids

A

Depression of respiration (medulla)

Stimulation of chemoreceptor trigger zone (nausea/vomiting)

Pupillary Constriction

G.I. Effects

26
Q

Summarise how opioid modify pain transmission

A

ANALGESIA
Decrease pain perception
Increase pain tolerance

Central pain perception?

27
Q

Which type of nerve responds to painful stimuli

A

Noiciceptors

Responds to stimulus rleases by damaged tissue

28
Q

Describe the passage of the painful stimulus from the periphery to the thalamus

A

The painful stimulus is detected by a sensory neurone
This then synapses with a spinothalamic neurone in the dorsal horn, which then passes the information to the thalamus

mu receptors in thalamus and dorsal horn
kappa receptors also in dorsal horn

29
Q

What happens as the painful stimulus reaches the thalamus

A

The thalamus immediately activates the PAG (central pain coordinating region of the brain)
The thalamus also sends the pain information to the cortex, which processes the pain and modulates the firing of PAG
The way in which the cortex affects PAG firing is based on previous experiences, memories etc.

for example, if twisted ankle in sports- cortex will know that the outcome is not bad- so will increase activity of PAG to increase painful tolerance

pain tolerance is important in preventing the brain from becoming overwhelmed by painful stimuli

30
Q

What does the PAG activate

A

The PAG activates the nucleus raphe magnus

It sends descending inhibitory neurones down to the dorsal horn
The NRM is responsible for reducing painful sensation (pain tolerance)

PAG has mu and kappa receptors

NRM has delta receptors

31
Q

What does the NRPG do

A

NRPG – nucleus reticularis paragigantocellularis
It is independent of the thalamus
As soon as you sense pain, the NRPG is activated, which then activates NRM
You’re trying to suppress pain even before the brain has had a chance to think about it

32
Q

Describe the role of the hypothalamus in this system

A

The hypothalamus constantly feeds into the PAG about the general health of the organism
Hypothalamus- samples current state of health
Poor health- paoinful stimuli exacerabated

33
Q

Describe the role of the locus coreuleus in this system

A

The locus coeruleus is the sympathetic outflow that has a negative effect on pain perception
A stress response will activate LC
Reason: at a time of stress, you wouldn’t want a painful stimulus to affect your fight or flight response

34
Q

What structure in the spinal cord acts like a mini-brain

A

Substantia gellatinosa
Some of the descending input from the NRM will be processed by the substantia gellatinosa, which then decides the level of inhibition necessary

35
Q

Where might opioids act to modulate pain transmission

A

Dorsal horn and noicieptors – increase inhibition
PAG – enhance PAG firing - inhibiting GABA interneurones
NRPG – activates this - inhibits GABA interneurones
 Opioids are very good at switching OFF GABA.
o GABA has an inhibitory effect on many of the pain tolerance centres so blocking GABA activates the pain tolerance centres.

36
Q

How do opioids cause euphoria

A

Opioids bind to mu receptors on GABA neurones and switch them off
This removes the inhibitory effect of GABA neurones on the dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens  increase in dopamine release at the nucleus accumbens

37
Q

Outline the cough reflex

A

Stimulation of mechanical or chemoreceptors
(throat, respiratory passages, or stretch receptors in the lungs)

Affterent impulses to cough centre (medulla)

Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lungs

Increased contraction of diaphragmatic, abdominal and intercostal muscles – noisy expiration (cough)

38
Q
  1. What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus?
A

Acetylcholine
Neurokinin
By c-fibres

39
Q

Describe the peripheral anti-jussive effects of opioids

A

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

opioids inhibit both eNANC nerve activity and cholinergic contraction of smooth muscles.

40
Q

Describe the central anti-jussive effects of opioids

A

 Central:
o 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 of this receptor increases serotonin so less cough.
o Medulla direct depression

Reduced 5HT1A receptor function in the dorsal raphe nucleus leads to an increase in 5HT levels which may depress discharges from inspiratory motorneurones.
NTS is a strong candidate for the cough centre. Opioids may directly inhibit cough responses from this site.

41
Q

Describe how opioids can lead to respiratory depression

A

The most opioid sensitive aspect of respiration is rhythm generation.
The pre-Bötzinger complex is a small area in the ventrolateral medulla that can generate a ‘respiratory’ rhythm. The pre-Bötzinger complex is active during inspiration and is inhibited by opioids.
Central chemoreceptors provide tonic drive to the respiratory motor output by sensing changes in pH and are inhibited by opioids.

HIGH DOSE
Urge to breath is impaired

mu 2 receptors on central chemoreceptors

42
Q

How do opioids cause nausea/vomiting

A

Opioids switch off GABA, which is normally suppressing the chemoreceptor trigger zone
This leads to activation of the chemoreceptor trigger zone, which then stimulates vomiting via the medullary vomiting centre
Low doses of opioids can do this

43
Q

Why do opioids cause pinpoint pupils

A

The preganglionic parasympathetic nerve to the eye is the oculomotor nerve (CN III)
This begins in the Edinger-Westphal nucleus
There are lots of GABA neurones with mu opioid receptors within the Edinger-Westphal nucleus
The removal of the inhibitory GABA input stimulates firing of the oculomotor nerve – MIOSIS

44
Q

Why are pinpoint pupils clinically diagnostic

A

 Most overdoses exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction but opiates cause “pin-prick” eyes.
So indicates opioid overdose

45
Q

Summarise the function of the enteric nervous system

A

Sensory neurone 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 neurones release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle

46
Q

Describe how opioids can lead to G.I disturbances

A

 Many opioid receptors (kappa and Mu) are found in the myenteric plexus.
o Motor neurones release Ach or substance P to contract SM.
o Motor neurones release VIP (vasoactive intestinal peptide) or NO to relax SM.
 Opioids cause:
o Decrease in gastric emptying. Decreased GI motility.
o Increase in water reabsorption. CONSTIPATION.

47
Q

Summarise how opioids cause urticaria

A

 Not all opioids cause histamine release – it is the hydroxyl group found on some opioids that cause mast cell degranulation (non-IgE-mediated).
o 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).
Not an allergic response

Strucutre of opiod drives this- not receptor driven

48
Q

Why do opioids cause urticaria

A

Opioids bind to mast cells in the skin and promote histamine release (skin mast cells appear to be particularly sensitive)
The hydroxyl group at position 6 appears to be vital to this

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.

Itching (pruritis)
Hives (urticarial)
Hypotension

49
Q

Describe the mechanism of tolerance to opioids

A

 Opioids upregulate levels of arrestin in the tissues.
 Arrestin promotes receptor internalisation.
 The over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant.

Tissue tolerance

50
Q

What is withdrawal from opioids associated with

A

 Withdrawal associated with:
o Psychological craving.
o Physical withdrawal (resembling the flu):
 Opioids normally depress cell activity by reducing AC activity and so the body responds by upregulating AC activity. When you remove the opioid drug, the body is overstimulating AC and so general cell activity is greatly increased for a few weeks after  withdrawal.

may get increased muscle cramps
Stopping opioids will result in increased adenylate cyclase activity in tissues  shakes, headaches, sickness etc.

51
Q

Describe the features of opioid overdose and how it is treated

A

Coma

Respiratory depression

Pin-point pupils

Hypotension

Treatment: Naloxone (opioid antagonist) i.v

52
Q

Explain the treatment for opioid overdose

A

 Treatment – I.V. Naloxone (opioid antagonist).
o Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors.
o Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors.

Pharmacology and therapeutics (30 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions