Opiods Flashcards
What is an opiate
An alkaloid derived from the poppy, Papaver somniferum
What is an opoiod
Anything that has opiate activity, be it natural or synthetic
Give examples of opiates
Morphine and codeine
thebaine and papaverine
Structure of opiate (morphine in this case…. the others are modifications mostly)
Tertiary nitrogen… important for analgesic activity (binds mostly strongly to receptor)
OH groups (at C3 and C6)
Quaternary carbon
What determines whether an opiate is an agonist or antagonist
Whether the tertiary nitrogen has a long or short side chain….
if just 1 or 2 carbons on the side chain, still an agonist
if lots, then antagonist
If you make it quarternary it will not get into the CNS
The tertiary nitrogen impacts the efficacy of the natural opioid for the receptor. What is important for affinity?
- Tertiary nitrogen)- important for both efficacy and affinity. Because tertiary nitrogen allows the molecule to bind the receptor (gives it its affinity and permits receptor anchoring)
- The hydroxyl groups at the C3 and C6 positions (especially C3…which is required for binding)
What is the difference between heroin and morphine
Heroin is di-acetyl morphine (has 2 acetyl groups instead of 2 OH groups at C3 and C6)
This makes it MORE LIPID SOLUBLE (but as there are no OH, it doesn’t have any activity in this form… heroin is prodrug)
What is the difference between codeine and morphine
methyl-morphine
Also more lipid soluble than morphine. but not as much as heroin which has OH groups removed for acetyl (but again not much effect because the C3 is required for opiate receptor binding)….. codeine also a prodrug
Give 2 examples of synthetic opioids and their structures
So morphine, and codeine are natural opioids (i.e. opiates). Heroin is a synthetic opioid but with a traditional morphine structure
Fentanyl and methadone are both synthetic opioids.
They don’t look like morphine (they are ‘open chain opioids’), but still have the tertiary nitrogen/aromatic ring which is important for opioid activity.
Fentanyl has tertiary carbon not quaternary though
What is necessary for an opioid to work on the receptor
Methadone and fentanyl
- Tertiary nitrogen
- Central quaternary carbon
- Aromatic ring
- Spacer (gap between carbon and nitrogen)
How are opiates given
Oral or IV
What is the pKa of opiate
They are weak bases
So pKa>8 (this makes no sense as pKa is for acid but go with it)
(if pH and pKa are the same, then good absorption..)
Outline the absorption of opiates
In stomach, where pH is 2 then the drug is ionised and poorly absorbed (pKa above pH so poor absorption)
in intestine, less ionised so better absorbed (as pH more similar to the pKa)
Note there is HIGH FIRST PASS METABOLISM which affects bioavailability (IV provides 100% BA)
What proportion of opioid is ionined 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
How is morphine metabolised
Morphine 3-G glucuronide
Morphine 6-G glucuronide (also a mu-opioid receptor agonist like morphine)
M6G is ACTIVE METABOLITE (but only 10% of the metabolites of morphine are the active forms)
Outline the lipid solubility of
morphine heroin codeine methadone fentanyl
Methadone/Fentanyl»_space; Heroin > codeine>Morphine
What can be said to determine potency of opioid? What is the exception
General rule of thumb – More lipid soluble, more potent.
EXCEPTION: codeine more lipid soluble than morphine but less effective
What are the metabolites of heroin and codeine
The active metabolites of heroin and codeine are MORPHINE
The heroin and codeine are lipid soluble, but not active at opioid receptor as they do not have the critical C3 OH group until converted into morphine
Why is codeine less potent than morphine and heroin
Less potent than morphine because morphine gets into CNS and binds effectively to opioid receptor
Codeine and heroin have to be broken down to morphine (their metabolites) to become active. They are otherwise inactive at opioid receptor (or 300x less active)
The reason codeine is less effective than morhine, but heroin is more effective:
Heroin is more lipophilic than morphine. Passes through the BBB and into the CNS. Then, when in the CNS, can be converted into morphine, and have morphine effects.
However codeine cannot be metbaolised in the CNS. It must be metabolised by the liver. Only 10% max is metabolised to morphine, whilst the rest is inactivated (see next card)
Give more detail on codeine metabolism
and metabolism of opioids generally
5-10% goes via slow route to produce morphine… CYP2D6… o-dealkylation
The rest goes through fast route CYP3A4, which deactivates the codeine so it doesn’t even become morphine
GENERAL: The majority of opioids are metabolised in the liver by either CYP3A4 and CYP2D6
Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.
What makes a drug really addictive
Rapid clearance
Why is methadone used in addiction recovery
It has really slow clearance, so it will last for ages rather than keep needing to take heroid
fentanyl has similar clearance to morphne (only slightly less) so not used in addiction recovery
What produces the negative effects like respiratory depression with opioids and who is most likely to get them
Morphine (not M6G)… (individuals who don’t metabolise morphine very well are more likely to have negative side effects)
Because 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
Differentiate the metabolism of fentanyl and methadone and their active metabolites
Fentanyl fast metabolism
Methadone slow metabolism
No active metabolites (they are really active themselves at the opioid receptor)
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
How do opioids work
They act via specific ‘opioid’ receptors
What are the endogenous opioid peptides
Endorphins
Enkephalins
Dynorphins/neoendorphins
Which receptors do each of the endogenous opioid peptides act on
Endorphins: Mu or delta
Enkephalins: delta
DynorphIns: kappa
What function are endorphins doing
Which brain regions are affected
Pain/sensorimotor
Mu: Cerebellum NAcc Caudate nucleus PAG
What function are enkaphalins doing
Which brain regions are affected
Motor/Cognitive function
delta:
NAcc
Cortex
Hippocampus
Putamen
What function are dynoprhins doing
Which brain regions are affected
Neuroendocrine (e.g. appetite):
kappa:
Hypothalamus
Putamen
Caudate
What is the cellular mechanism of opiate receptor action
DEPRESSANT
Hyperpolarisation (increase K+ efflux)
Reduced Ca2+ inward current so reduced NT release
Reduced AC activity
via mu, delta and kappa receptors
What are the therapeutic effects of opiods
Analgesia
Euphoria
Depression of cough centre (anti-tussive)
What are the side effects of opioids
Depression of respiration (medulla)
Stimulation of chemoreceptor trigger zone (nausea/vomiting)
Pupillary Constriction (IMPORTANT, MOST OTHER DRUGS CAUSE MYDRIASIS SO THIS IS GOOD DIAGNOSTICALLY)
G.I. Effects
What are the analgesic effects of opioids
Decrease pain perception (depressant of the nociceptive fibres)
Increase pain tolerance (NRPG, NRM and PAG)
Impact central pain perception
Outline pain pathway
- Peripheral nerve
- To the dorsal horn (note that transmission fro peripheral nerves to spinal cord neurons is usually glutamate mediated, but also mu and kappa receptors, which can allow for inhibition)
- Spinothalamic tract
- At the thalamas (mu receptors)
Thalamus sends signal:
a. immediately activates PAG (peri-aqueductal gray region) (mu, kappa)
b. cortex (mu and delta) …. cortex can then modulate the PAG
3. PAG activates effector arm of pain tolerance (NRM… nucleus raphe magnus) (mu)
NRM sends descending fibres down the spinal cord and interferes with pain transmission at the level of the dorsal horn
What is PAG
Peri aqueductal gray matter
Pain integrating centre
Determines the degree of pain tolerance sent down the spinal cord
What else can impact on the NRM, in addition to PAG
nucleus reticularis paragigantocellularis (NRPG)
Negative feedback works independent of thalamus/cortex/PAG and immedaitely initiates the NRM to reduce pain
(from spinothalamic tractm fibres go to thalamus or NRPG –> NRM)
What is the role of hypothalamus in pain transmissin
The hypothalamus constantly gives information to the rest of the brain about current state of health
In a poorer state of health, you are likely to be more sensitive to pain
We want sick people to be in pain so that they don’t expend their energy doing activities
What is the locus coerclus and what are the effects on pain
Part of the SNS. Independent of analgesia system
Works independently…. directly inhibits the dorsal horn to suppress pain when stress pathway activated
What is the substantial gelatnosa
You can directly inhibit the spinothalamic tract from the NRM
Also substantia gelatinosa is like mini brain in spinal cord can decide on the level of inhibition of pain in the spinal cord acting on the dorsal horn
Where might opioids act
- On the peripheral nerve (prevent info relay from periphery to the spinothalamic tract (DEPRESSANT)
- INHIBITION in spinal cord:
- dorsal horn
- lots in the substantia gelatinosa - DISINHIBITION (i.e. reducing ihibition by switching off GABA) to increase PAG
- DISINHIBITION to increase NRPG
ENHANCING PAIN TOLERANCE IN ALL THESE REGIONS
Note how the descending pathways from the PAG are the same as those refered to in neuro, noradrenaline INHIBITS pain transmission in the dorsal horn, whereas serotonin facilitates pain transmission. With opioids, you are increasing descending inhibition from the PAG, but you can also use SNRIs, which will prevent the reuptake of NA in the descending pathway and further increase pain tolerance.
How do opioids cause euphoria
DISINHIBITION:
GABA neurons suppress the dopaminergic neurons from the VTA to NAcc
Opioids act on opioid receptors on the GABA to reduce inhibition on the dopaminergic
What is the normal cough pathway
Stimulation of mechno/chemo receptors in airway
Afferent to cough centre in medulla (acetlycholinergic or neurokinin mediated c fibres)
Efferent impulses via PNS and motor nerves to diaphragm or intercostal muscles
Increased contraction of diaphragm and abdominal musdcles
How does opioid act as an anti-tussive
Ach and neurokinin via C fibres to the brain … OPIOID BLOCKS so reduces firing rate of C fibres
Sertanonin is anti-cough. 5-HT1a are negative feedback receptors and reduce seratonin in the cough centre. Opioids block these so that they increases seratonin which reduces coughing
How can opioids cause respiratory depression
- Central chemoreceptors drive the urge to breathe though pH sensing (and thus PACO2) and relaying this to the medullary control centre
Opioids inhibit this.
Forms the tonic drive to breathe
- Prebotzinger complex in the ventrolateral medulla provides tonic constant stimulus for breathing (esp. inspiration)
Opiods inhibit this
In overdose
How do opioids work to induce nausea
At therapeutic dose….
DISINHIBITION…
GABA keeps the chemoreceptor trigger zone under inhibition
Opioids switch the inhibition off.
CTZ signals to medullary vomiting centre
(mu receptor)
What can transfer signals to the medullary vomiting centre
Vestibular system
CNS
GI tract and heart
Chemoreceptor trigger zone (=area postrema)
How do opoiods cause miosis
Activates the parasympathetic nervous system.
On the Edinger-Westphal nucleus, overexpression of opiod receptors, switching of GABA inhibition and this activates PNS CNIII
(mu receptor)
important in diagnosis (most drugs’ OD will cause pupillary dilation)
note….. he said something different on the lecture, but opioids do not enhance so must be DISINHIBITION
What is the action of opites in the gut
Constipation
Mu and kappa receptors on the myenteric plexus,
just mu receptors on the submucosal plexus.
Opioid receptors everywhere in the ENS and they reduce cholinergic transmission and thus reduce gut function
REDUCE ACH!
Why does opioid slook like an allergic reaction
Urticaria… but not an allergic response
Opioids (particularly those which have OH at position 6), they activate mast cells to release histamine…. especially codeine and morphine (not heroin)
PKA NOT through mu receptors
Why is tolerance to opioids developed
Not pharmacokinetics… TISSUE TOLERANCE
You get upregulation of arrestin
This promotes internalisation of receptors (so increase in this physiological process)
Less receptors on the tissue surface
Which withdrawal is associated with opioids
Psychological craving
Physical withdrawal (resembling flu)
Cocaine causes same physical withdrawal as herion T/f
F… only has the psychological craving
What is the basis of physical symptoms following opioid withdrawal
Due to cells trying to compensate for the opioid whilst you were taking the opioid (cell tries to increase cAMP to compete with the suppression from opioid)
Then when you remove the opioid you’re just left with a cell trying to upregulate cAMP levels with no suppression. Overactivation of cells…. leads to diarrhoea, muscle shaking
What occurs in opioids overdose
Coma
Respiratory depression
Pin-point pupils
Hypotension
What is the treatment of opioid overdose
Treatment: Naloxone (opioid antagonist) i.v.
Naloxone has longer carbon chainon the tertiary nitrogen, so acts as an antagonist
