Pharmacology of Opioids Flashcards
What are opioids?
Any substance (natural or synthetic) that mediate an analgesic effect through opioid receptors that can be blocked by naloxone
Natural (Endogenous) –>
Morphine, codeine (Papaver somniferum)
Semi-synthetic (Derivatives of morphine)
Diamorphine, dihydrocodeine, buprenorphine, naloxone
Examples of synthetic opioids:
Synthetic
- Phenylpiperidine series
Pethidine, fentanyl, alfentanyl, remifentanyl
- Diphenylpropylamine series
Methodone, dextropropoxyphene - Benzomorphan series
Pentazocine - Thebaine derivatives
Buprenorphine
Clinical effects of Opioids:
- Setting nociceptive threshold
- Controlling nociceptive processing
- Role in cognition
- Modulation of autonomic function
- Modulation of endocrine function
- Modulation of endocrine function
Endogenous Opioids:
Enkephalins
- Met-enkephalin
- Leu-enkaphalin
Endorphins
- a-neoendorphin
- b-neoendorphin
- g-neoendorphin
Dynorphins
- Dynorphin A
- Dynorphin B
Endomorphins
- Endomorphin 1
- Endomorphin 2
All are derived from precursor proteins by proteolytic cleavage of proopiomelanocortin (POMC)
What are opioid receptors?
Defined by structural similarity and sensitivity to naloxone
IUPHAR nomenclature:
MOP: m1; m2; m3
DOP: d1; d2.
KOP: k1a; k1b; k2a; k2b; k3
(NOP – nociceptin : non-opioid member of opioid family)
Dop = delta (delta 1 and 2)
Kop = kappa
NOP = a lot of drug development is aimed towards this in
Ligand and receptor relationship:
MOP
B-endorphins
Endomorphin 1
Endomorphin 2
KOP
Dynorphin A
Dynorphin B
DOP
Met-enkephalin
Leu-enkephalin
NOP
nociceptin
Opioid receptor mechanism:
G protein coupled receptors (Gi/Go)
- Presynaptic
Postsynaptic
Depends on where they’re located
Inhibits adenylate cyclase
Decreases cAMP
Decreases neurotransmitter release
Activation of voltage-gated inward rectifying K+ channels
Hyperpolarises cells
Decreases responsiveness to depolarising stimuli
Reduces neurotransmitter release
Inhibition of voltage-gated (N-type) Ca2+ channels
Reduces neurotransmitter release
Opioid receptor location:
- Vagal Centres
- Chemoreceptors of Area Postrema
- Oculomotor Centre
- Antinociceptive system
(Brain & Spinal Cord) - Smooth muscle
- stomach
- bowel
- bladder
- Pain sensation
- Mood alertness
- Respiratory Centre
Definitions: Pain
- Is a natural defensive awareness and response to a noxious stimulus
- It is the higher centre processing of signals which allows the body to minimise exposure to and damage from the noxious stimuli
- Psychological factors will influence the extent to which an individual will feel suffering and distress with pain
Definitions: Nociception
The sensory processing associated with firing of small diameter nociceptive afferents
Activated by different stimuli
- Chemical
- Mechanical – crushing trauma
- Thermal - cold or hot
- -> C-fibres – unmyelinated; dull, diffuse burning pain
- -> Ad fibres – myelinated; sharp localised pain
Stimulation of nociceptors:
Cancer cells, inflammatory cells, tissue injury, osteolysis --> Noxious factors: - Bradykinins - Prostaglandins - Nerve growth factor - Serotonin - ATP - H+ --> Nociceptors = inflammation - Sensory neuron to dorsal root ganglion to spinal cords to brain = PAIN
Ascending Pain Pathway:
Nociceptor is stimulated
- Action potential travels along axon to cell body in dorsal ganglion (first order afferent)
- Action potential potentiated along to dorsal horn
- Signal transferred to next nerve: crosses over to other side of spinal cord (second order afferent) I
- Action potential travels to thalamus
- Signal transferred to next nerve (third order afferent) which terminates in somatosensory cortex – this maps out to different parts in the body to find exact location.
Descending Pathway:
- Somatosensory cortex connects with brain regions which co-ordinate the response
- The amygdala, anterior cingulate cortex, insular cortex and hypothalamus send projections to the periaqueductal grey (integrates response)
- PAG sends signal to rostroventral medulla
- RVM sends signal to dorsal horn, where nerve interacts with the ascending pathway
What are pathways:
- Not just connection of nerves.
- The signals are communicated between nerves using neurotransmitters
- “Pain” transmitters – cause us to perceive and feel paimn
- -> Glutamate; substance P; CGRP (Calcitonin gene-related peptide); nitric oxide. All tend to be released as part of the ascending pathway.
“Analgesic” transmitters – descending pathway – dampen down
- Endogenous opioids; 5HT; noradrenaline; endocannibinoids
- glycine; GABA
Role of the opioid receptors in pain:
- MOP involved in motor and sensory processing
- MOP also involved in integration and perception of pain
- Located presynaptically on primary afferent neurones in the dorsal horn
- Inhibit glutamate release and therefore transmission of nociceptive stimuli
- MOP also in high concentrations in PAG
- Prevent GABA neurones inhibiting descending control pathway.
- -> GABA tonically inhibits 5HT and NA nerves that project from RVM to dorsal horn
- -> Removing this tonic control allows 5HT and NA nerves to fire and release these transmitters onto ascending pathway
- -> 5HT and NA inhibitory receptors then prevent the transmission of signal along the ascending pathway
- DOP receptors are located presynaptically on primary afferent neurones in the dorsal horn and secondary afferent neurones in the brain
- Inhibit neurotransmitter release and therefore transmission of nociceptive stimuli
- KOP receptors are highly expressed in the brainstem
Opioid analgesics full agonists:
- MOP receptors (weak KOP receptors)
- Morphine, diamorphine, fentanyl, pethidine, dihydrocodeine, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, oxycodone, oxymorphone
Mixed agonist-antagonist:
Pentazocine weak agonist KOP (k receptor); weak antagonist MOP (m receptor)
Mixed partial agonist-antagonist
Buprenorphine partial agonist MOP (m receptor); weak antagonist KOP (k receptor)
Opioids with additional properties:
Meptazinol
- MOP (m) receptor agonist and muscarinic agonist
Tramadol
- MOP (m) receptor agonist and blocks neuronal serotonin and noradrenaline uptake
Methodone
- MOP (m) receptor agonist; blocks neuronal serotonin and noradrenaline uptake; antagonist at NMDA receptors. Not traditionally used as an analgesic.
Analgesic Effects:
- Most effective against chronic visceral pain – some kind of peripheral stimuli . Opoids not good for neuropathic pain
- No anti-inflammatory effect. Don’t reduce inflammation
- Tolerance and dependence can occur
- Partial agonists or mixed agonist-antagonist at MOP (m) receptors can precipitate withdrawal. Got to be careful when you’re swapping.
- Short acting opioids fentanyl and remifentanil are used as analgesics during anaesthesia
Traditional classification of opioids:
Strong
- Morphine, pethidine, fentanyl, alfentanil, remifentanil
Intermediate
- Buprenorphine, pentazocine,
Weak
- Codeine
Pharmacokinetics of opioids:
Opioids are weak bases (pKa 6.5-8.7).
- In the acidic environment of stomach, opioids are highly ionised and therefore poorly absorbed.
- Conversely, in the alkaline small intestine, they are predominantly unionised and are readily absorbed.
- They undergo extensive first-pass metabolism in the intestinal wall and liver, resulting in low oral bioavailability.
- High lipid solubility facilitates opioid transport into the biophase or site of action and therefore a more rapid onset of action.
- Most opioids are extensively distributed in the body and their volumes of distribution exceed total body water.
- Small intravenous dose of short acting opioid (like alfentanil, sufentanil or fentanyl) produce short duration of action because plasma (and brain) concentration remain above the threshold for therapeutic action for only a brief period as the drug rapidly redistributes from the CNS to other tissues.
- Larger doses produce longer durations of action because plasma concentrations remain above the threshold at the completion of drug redistribution and depend upon the slower elimination process to be reduced below the threshold level.
Metabolism of opioids:
- Metabolism occurs in the liver
Main mechanism is conjugation with glucuronide
- Neonates lack glucuronide
- Pethidine not conjugated with glucuronide
- Therefore, preferred in labour
Entero-hepatic recirculation can occur
- Glucuronides metabolised by gut flora back to parent opioid
Active metabolites?
- Morphine-6-glucuronide > morphine
- Diamorphine –> 6-methylmorphine morphine
- Codeine –> codeine-6-glucuronide
Tolerance and Withdrawal and opioids:
Tolerance is the decrease in effect seen despite maintaining a given concentration of a drug.
–> The mechanism is not fully understood but could involve down regulation of opioid receptors or decreased production of endogenous opioids.
Dependence exists when the sudden withdrawal of an opioid, after repeated use over a prolonged period, results in various physical and psychological signs.
- These include; restlessness, irritability, increased salivation, lacrimation and sweating, muscle cramps, vomiting and diarrhoea.
Clinical Effects of Individual Opioid Receptors:
MOP:
- Analgesia
- Depression
- Euphoria
- Physical dependence
- Respiratory depression
- Sedation
DOP
- Analgesia
- Inhibition of dopamine release
- Modulation of MOP receptors
KOP
- Analgesia
- Diuresis
- Dysphoria
NOP
- Analgesia
- Sedation
Euphoria and Dysphoria in opioids:
Euphoria, elevated feeling of well-being
–> MOP receptors
Contributes to analgesic effect
–> Alters perception of pain
Dysphoria, feeling of restlessness and agitation
–> KOP receptor
Nausea and Vomiting in opioids:
- Opioids stimulate chemoreceptor trigger zone
- Usually short lived -
- Worse in ambulatory patients
- For equi-analgesia codeine > morphine for vomiting
- Blocked by dopamine antagonists
- Similarity in structure for morphine and apomorphine….
Convulsions in opioids:
High doses excite hippocampal pyramidal neurones
- Inhibition of GABA release
- Blocked by opioid antagonists
Pethidine is metabolised to norpethidine
- -> Norpethidine is proconvulsant
- -> Blocked by anti-convulsant not opioid antagonist
Respiratory effects in opioids:
- Action at medullary respiratory centre
- ->MOP receptors (m2)
- ->m1-receptor selective less depression (meptazinol)
- Decreases response to increased pCO2
- Decreases respiratory rate
- Decreases FEV1
- Usually equal analgesia and respiratory depression
Gastrointestinal effects in opioids:
- Increased tone in propulsive muscle
- Decreased contractions in propulsive muscle
- Contracts GIT sphincters. Increase pain in biliary colic (sphincter of Oddi)
- Leads to decreased water movement into lumen
Likely to result in constipation - Act on MOP, DOP and KOP receptors on myenteric plexus. Reduced ACh release from nerves
Can agonists be used to treat diarrhoea:
Kaolin and morphine
- Has abuse potential
- Morphine in very small dose
Loperamide
- Not absorbed, reduced abuse risk
Diphenoxylate
- Contains atropine in ratio 1:100
Gastrointestinal effects in opioids:
- Increased tone in propulsive muscle
- Decreased contractions in propulsive muscle
- Contracts GIT sphincters. Increase pain in biliary colic (sphincter of Oddi)
- Leads to decreased water movement into lumen
Likely to result in constipation - Act on MOP, DOP and KOP receptors on myenteric plexus. Reduced ACh release from nerves
Can agonists be used to treat diarrhoea:
Kaolin and morphine
- Has abuse potential
- Morphine in very small dose
Loperamide
- Not absorbed, reduced abuse risk
Diphenoxylate
- Contains atropine in ratio 1:100
Treatment of Opioid-Induced Constipation:
Methylnaltrexone
- Opioid antagonist
- Poor penetration of CNS
- Does not affect central analgesic action
Suppression of Cough reflex (Anti-tussive Action):
Suppress activity of the cough centre in medulla
- > MOP and DOP receptors
- > Increase threshold for stimulation
-Anti-tussive action due to large substituent at position 3 of morphine molecule
- Codeine, pholcodine
(Dextromethorphan)
Ocular effects:
- Mediated via MOP opioid receptors and KOP opioid receptors on the Edinger-Westphal nucleus of occulomotor nerve (3rd cranial nerve)
- Increases parasympathetic outflow to iris sphincter
miosis - Increases parasympathetic outflow to ciliary body
accommodation for near vision - Pinpoint pupils (+ coma, slow respiration) are signs of overdose
Suppression of Cough reflex (Anti-tussive Action):
Suppress activity of the cough centre in medulla
- > MOP and DOP receptors
- > Increase threshold for stimulation
-Anti-tussive action due to large substituent at position 3 of morphine molecule
- Codeine, pholcodine
(Dextromethorphan)
Histamine release and itching:
- Basic nature of morphine greater than histamine
- Displaces histamine from histamine-heparin complex in mast cells
- Causes urticaria, itching, bronchospasm, hypotension
- More pronounced on face, nose, torso
Other effects of opioids:
Sedation
- Interfere with sleep cycle
Relief of pain allows sleep?
Cardiovascular effects (high doses) - Bradycardia and hypotension
Immunity
- Immune response decreased with long term use
- Greater risk of infection
What is an opioids antagonist:
Naloxone
Competitive antagonist at all three receptors
(Inverse agonist)
Used to treat respiratory depression
- In neonates
- In overdose
