Opiates/Opioids Flashcards by Alexandra Chan

Give examples of opiates

Morphine
Codeine
Thebaine
Papaverine

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Describe the nitrogen structure of morphine

Tertiary nitrogen
Permits receptor anchoring for the analgesic effect
Affinity is dependent on the tertiary nitrogen

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Describe the hydroxyl structure of morphine

2 Altered hydroxyl groups
Hydroxyl group at position 3 = binding site
Hydroxyl group at position 6 = oxidise this OH and lipophilicity increases 10 fold

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What do changes to the methyl group on nitrogen in morphine cause

Extending the side chain to 3+ carbons -> antagonists

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Describe the lipid solubility of codeine

More lipid soluble than morphine, but less potent due to metabolism

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Why may codeine and heroin be considered prodrugs

they do not possess the position 3 hydroxyl group, therefore are unable to bind receptors as well as morphine

Their active metabolites are morphine

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Which structural elements are necessary for activity of opioids

Aromatic Ring
Tertiary nitrogen
(Quaternary carbon centre)

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What are the two major routes of administration of opioids

IV or oral

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Describe the absorption pharmacokinetics of opioids

Opioids are weak bases (mostly pKa > 8)
Likely to be ionised in the acidic stomach and poorly absorbed
Unionised in the SI - more readily absorbed
First pass metabolism decreases the bioavailability

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Describe the ionisation of opioids in the blood

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.

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Describe the lipid solubility of opioids and its general rule

Methadone/Fentanyl&raquo_space; Heroin > Morphine

More lipid soluble, more potent

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Describe the metabolism of morphine

Morphine have the active metabolites Morphine 3-G glucuronide and Morphine 6-G glucuronide

Morphine-6- glucuronide (10% - active metabolite)
These metabolites are active in their ability to cause euphoria but are not active in causing respiratory depression

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What is the major difference between fentanyl and methadone

Fentanyl - fast metabolism
Methadone - slow metabolism

As methadone is lipid soluble, it accumulates in adipose tissue. As a result it is not cleared very quickly and slowly diffuses from adipose tissue, therefore resulting in a long half life.

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Why is codeine less potent than other opioids despite its high lipid solubility

Codeine must be converted to morphine to have an effect. There are two cytochrome enzymes that metabolised codeines.
CYP2D6 – activates slowly
CYP3A4 - deactivates rapidly

As a result, 90% of the codeine is metabolised quickly to more codeine which is inactive, and 10% is converted into active morphine.

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How do opioids work

Action via specific opioid receptors
Endorphins
Enkephalin
Dynorphins

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Which receptors do endorphins bind to and what is the result of this

Mu or Delta

Pain/sensorimotor

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Which receptors do enkephalins bind to and what is the result of this

Delta

Motor/cognitive function

Which receptors do dynorphins bind to and what is the result of this

Kappa

Neuroendocrine

Describe the cellular mechanism of action of opiate receptors

Depressant
Hyperpolarisation (promote K+ efflux)
Decrease in Ca2+ inward current
Decrease in adenylate cyclase activity

What are the therapeutic effects of opioids

Analgesia
Euphoria
Depression of cough centre (anti-tussive)

What are some side effects of opioids

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

What are the 2 main mechanisms of analgesia

Decrease in pain perception

Increase in pain tolerance

Describe the pain perception pathway

Nociceptors recognise peripheral pain
Relays information into the spinal cord through the dorsal horn
Spinothalamic tract from the dorsal horn to thalamus
Thalamus distributes the signal to other areas of the brain
For example, the signal is sent to the cortex

Describe the pain tolerance pathway

The cortex can suppress pain tolerance due to memory. It can also increase the activation of pain tolerance pathways due to memory
Any painful stimuli that reaches the thalamus activates the PAG
Activation of NRM
NRM signals back to the periphery, predominantly down the spinal cord
Suppression/interference of the pain signal through the dorsal horn/spinothalamic pathway.
NRPG is automatically activated in pain

How does the hypothalamus affect pain tolerance

samples the current state of health, communicating with the PAG. If you're healthy, the hypothalamus will increase pain tolerance. If in poor health, the painful stimuli are exacerbated.

How does the LC affect pain tolerance

sympathetic arm of the brain. It is not connected to the pain pathway. When activated, it will suppress painful stimuli

What is the role of the substantial gelatinosa in pain tolerance

inhibits the passage of painful stimuli from periphery up the spinothalamic tracts. It receives other peripheral information and modifies the inhibitory signal based on this.

Where are the sites of opioid action

Dorsal Horn and periphery PAG NRPG

Explain the analgesic effect of opioids

Opioids suppress GABA which would normally suppress PAG and NRPG. When GABA is suppressed, PAG and NRM firing rate increases

Explain the euphoric effect of opioids

1. Opiates bind to mu receptors on GABAminergic neurones 2. Reduced GABA release 3. VTA 4. Increased dopamine release at the nucleus Accumbens

Describe the cough reflex

1. Stimulation of mechano/chemoreceptors 2. Afferent impulses to cough centre in medulla 3. Efferent impulses via parasympathetic and motor nerves to the diaphragm, intercostal muscles and lung 4. Increased contraction of diaphragmatic, abdominal and intercostal muscles 5. Noisy expiration / cough

Explain the anti-tussive effect of opioids

Targets ACh/NK C-fibres relay to the vagus and 5HT1A receptors Interfere with ability of cough sensation getting to the brain and stops the medulla signalling back down the efferent pathway to cause contraction

Explain how opioids cause respiratory depression

At high dose, opioids interfere with the central chemoreceptors that respond to CO2 conc in the blood. The urge to breath is impaired and respiratory depression become prominent.

Explain how opioids cause nausea and vomiting

Opioids suppress GABA release which leads to activation of the chemoreceptor trigger zone, which signals to the medullary vomiting centre

Explain the appearance of the eyes in opioid overdose

Diagnostic of an opioid overdose - constricted pupils | Switching off of GABA to directly stimulate the parasympathetic nerve

Explain the effects of opioids on the GIT

There are many opioid receptors in the enteric nervous system. There is slowing down of gut motility and this results in constipation

Explain how opioids cause urticaria

Histamine release from mast cells under the skin which is chemically driven by opioids.

Describe the drug tolerance to opioids

Taking opioids long-term, the dose has to be escalated to give the same response. Opioids increases the amount of arrestin (mediates receptor internalisation), leading to tissue tolerance

Which symptoms are associated with withdrawal of opioids

Psychological craving Physical withdrawal (resembling flu)

Which symptoms are associated with opioids overdose

Coma Respiratory depression Pin-point pupils Hypotension

What is the treatment for opioid overdose

Naloxone (opioid antagonist) i.v.