Analgesia & Opioids Flashcards
Define opioid.
Any substance that mediates an analgesic effect through opioid receptors that can be blocked by naloxone
Give examples of natural opioids.
Morphine
Codeine
What are the four classes of synthetic opioids?
Phenylpiperidine
Diphenylpropylamine
Benzomorphan
Thebaine
Give examples of phenylpiperidine opioids.
Pethidine
Fentanyl
Alfentanyl
Give examples of diphenylpropylamine opioids.
Methadone
Dextropropoxyphene
Give examples of benzomorphan opioids.
Pentazocaine
Give examples of semi-synthetic opioids.
Diamorphine
Dihydrocodeine
Buprenorphine
Give an example of thebaine opioids.
Buprenorphine
What are the general undesired effects of opioids?
Modulation of GI, endocrine and autonomic function
Role in cognition
What are endogenous opioids derived from?
Precursor proteins via proteolytic cleavage of pro-opiomelanocortin
What are the two enkephalins?
Met
Leu
What are the two dynorphins?
A
B
What are the three endorphins?
A-neo
B-neo
Bh-neo
What are the two endomorphins?
1
2
What are the four subtypes of opioid receptor?
Meu (MOP)
Delta (DOP)
Kappa (KOP)
Nociceptin (NOP)
What are the IUPHAR standard nomenclatures for opioid receptors?
MOP 1-3
DOP 1,2
KOP 1a, 1b, 2a, 2b, 3
Describe the effects of MOP receptors.
Analgesia Depressions Euphoria Physical dependence Respiratory depression Sedation
Describe the effects of DOP receptors.
Analgesia
Inhibition of dopamine release
Modulation of MOP
Describe the effects of KOP receptors.
Analgesia
Diuresis
Dysphoria
Describe the mechanism of opioid receptors.
G-Protein Coupled receptors present on both pre and postsynaptic membrane
Inhibition of adenylate cyclase which reduces cAMP and neurotransmitter release by dissociated α substrate
Dampens down activity of pain nerves
Dissociated β and 𝜸 substrates alter ion movement
Activation of voltage-gated inward rectifying potassium channels
- Hyperpolarisation of cells
- Decreased responsiveness to depolarising stimuli
- Reduced neurotransmitter release
Inhibition of voltage gated (N type) calcium channels
Reduces neurotransmitter release
What are nociceptive fibres?
Free nerve endings present throughout the periphery
Respond to multiple types of stimuli
Describe the structure of C nociceptive fibres? What response are they responsible for?
Unmyelinated
Dull, diffuse, burning pain
Describe the structure of Aẟ nociceptive fibres? What response are they responsible for?
Myelinated
Sharp, localised pain
Describe the stimulation of nociceptors.
Release of neurotransmitters causing inflammation and exacerbation
Prostaglandins able to sensitise nociceptor to allow perception of pain
Describe the ascending pain pathway.
Nociceptor is stimulated
Action potential travels along axon to cell body in dorsal ganglion
First order afferent- peripheral to dorsal ganglion
Action potential potentiated along to dorsal horn
Signal transferred up to next nerve- second order afferent
Action potential travels to the thalamus
Signal transferred to next nerve which terminates in somatosensory cortex- third order afferent
Describe the descending pain pathway.
Somatosensory cortex connects with brain regions which co-ordinate response
The amygdala, anterior cingulate cortex, insular cortex and hypothalamus send projections to the periaqueductal grey
PAG sends signals to rostroventral medulla
RVM sends signals to dorsal horn, where nerve interacts with ascending pathway
Descending pathway may synapse onto the nociceptor AND/OR cell body in the spinal cord to dampen activity
How do opioids act on the pain pathway?
At the spinal cord, opioids are able to interact and dampen down the ascending transmission to reduce pain stimulation
Acts as negative feedback
List the neurotransmitters involved in the ascending pain pathway.
Glutamate
Substance P
CGRP (calcitonin gene-related peptide)
Nitric oxide
List the neurotransmitters involved in the descending pain pathway.
Endogenous opioids 5-HT Noradrenaline Endo-cannabinoids Glycine GABA
Describe the role of MOP receptors in pain.
Involved in motor and sensory processing, integration and perception of pain
Located pre-synaptically on primary afferent neurones in the dorsal horn
Inhibit glutamate release and therefore transmission of nociceptive stimuli
Describe the role of DOP receptors in pain.
Located pre-synaptically on primary afferent neurones in the dorsal horn and secondary afferent neurones in the brain
Inhibit neurotransmitter release and therefore transmission of nociceptive stimuli
Give examples of opioid analgesics that are full agonists.
Morphine, diamorphine, fentanyl, pethidine, dyhydrocodeine, codeine, hydrocodone, levorphanol, methadone, oxycodone
Give examples of opioid analgesics that are mixed agonist-antagonists.
Pentazocine weak agonist at KOP and weak antagonist at MOP
Give examples of opioid analgesics that are mixed partial agonist-antagonists.
Buprenorphine partial agonist at MOP, weak antagonist at KOP
Describe the additional properties of the opioid meptazinol.
MOP receptor agonist and muscarinic agonist
Describe the additional properties of the opioid tramadol.
MOP receptor agonist
Blocks neuronal serotonin and noradrenaline uptake
Describe the additional properties of the opioid methadone.
MOP receptor agonist
Blocks neuronal serotonin and noradrenaline uptake
Antagonist at NMDA receptors
What are opioids most effect against?
Chronic visceral pain
Peripheral noxious stimuli consistently activating
Give examples of strong opioids.
Morphine Pethidine Fentanyl Alfentanil Remifentanil
Give examples of intermediate opioids.
Buprenorphine
Pentazocaine
Give examples of weak opioids.
Codeine
Describe the pharmacokinetics of opioids.
Opioids are weak bases (pKa 6.5-8.7)
Opioids are highly ionised in the stomach, therefore poorly absorbed
Highly absorbed in the small intestine
Undergo extensive first pass metabolism in the intestinal wall and liver, resulting in low oral bioavailability
High lipid solubility facilitates opioid transport into biophase or site of action, therefore a more rapid onset of action
Most are extensively distributed in the body, volumes of distribution exceed total body water
Small IV doses of short acting opioids produce short duration of action because plasma concentration remains above threshold for therapeutic action for only a brief period as drug rapidly redistributes from CNS to other tissues
Describe the metabolism of opioids.
Mainly occurs in the liver
Main mechanism is conjugation with glucuronide
Entero-hepatic recirculation can occur
Morphine-6-glucuronide has greater analgesic effect than morphine itself
Diamorphine and codeine both have active metabolites
Describe the mechanism by which opioids cause N+V.
Opioids stimulate chemoreceptor trigger zone
Tends to be short lived
Worse in ambulatory patients
In equi-analgesia, codeine is worse than morphine for vomiting
Blocked by dopamine antagonists
Apomorphine is a dopamine receptor agonist with a similar structure to morphine
Describe the mechanism by which opioids cause convulsions.
High doses excite hippocampal pyramidal neurones
Inhibition of GABA release
Blocked by opioid antagonists
Pethidine is metabolised to norpethidine which is a proconvulsant, blocked by anti-convulsant not opioid antagonist
Describe the mechanism by which opioids cause respiratory effects.
Action at medullary respiratory centre by µ2
µ1- receptor selective less depression i.e. meptazinol
Decreased respiratory rate and response to increased pCO2
Decreased FEV1
Describe the mechanism by which opioids cause GI effects.
Increased tone in propulsive muscle
Decreased contractions in propulsive muscle
Contracts GIT sphincters, increased pain in biliary colic
Leads to decreased water movement into lumen, likely to result in constipation
Describe the mechanism by which opioids cause endocrine effects.
Suppression of hypothalamic-pituitary-adrenal axis leading to decline in plasma cortisol
Increased prolactin release
Reduction in LH release leading to testosterone and oestrogen deficiencies
Describe the mechanism by which opioids cause ocular effects.
Mediated via MOP and KOP on the Edinger-Westphal nucleus of the occulomotor nerve (3rd cranial nerve)
Increased parasympathetic outflow to iris sphincter and ciliary body
Accommodation for near vision affected
Pinpoint pupils can be a sign of overdose
Describe the mechanism by which opioids cause 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 and torso
What is naloxone?
Opioid antagonist
Competitive at all three receptors
Used to treat respiratory depression in neonates and opioid overdose
Define pyresis.
Thermostat raised by hypothalamus
Heat production and loss is in balance
Feel cold
Define hyperthermia.
Thermostat not altered
Heat production > heat loss
Feel hot
Describe the mechanism of a fever.
Occurs due to release of cytokines in response to tissue injury or infection
Cause release of prostaglandins and increased synthesis
PGE2 raises thermostat in hypothalamic thermoregulatory centre via binding to E-prostanoid receptors (3 and 4)
Core temperature is sensed as too low, hence feeling cold
Increased heat gain/conservation, despite body temperature not actually matching what the brain thinks
Describe the production of prostaglandins.
Inflammatory stimulus causes phospholipase to mediate conversion of membrane phospholipids to arachidonic acid
COX then converts this to PGs
What is the role of the COX-1 enzyme?
Constitutive
Present in many tissues
Functions to maintain physiological levels of PGs
What is the role of the COX-2 enzyme?
Induced during inflammation
Synthesised in response to inflammatory stimulus
Rapidly produced by macrophages, endothelial cells, synoviocytes, chondrocytes
In CNS (hypothalamus), microvascular endothelial cells are the most important in producing COX-2
What is the role of the COX-3 enzyme?
Constitutive
Splice variant of COX-1
Present in the spinal cord and brain
Describe the action of antipyretics.
Prostaglandin production reduced, thermostat returned to normal
Aspirin and ibuprofen inhibit COX-1 and COX-2
Paracetamol inhibits COX-3 and (weakly) COX-2
Celebrex is a selective COX-2 inhibitor
Action of aspirin is irreversible
Ibuprofen is a reversible, competitive inhibitor
Paracetamol is reversible and non-competitive
Describes the mechanisms of analgesia of paracetamol.
Paracetamol inhibits COX-3 and (weakly) COX-2
AM404 is similar in structure to anandamide, acts as a cannabinoid (CB1) receptor agonist producing analgesic effect at level of spinal cord and brain
Also activates TRPV1 channels causing analgesia through desensitisation of channels after initial activation
Also a free radical scavenger, reactive oxygen free radicals produced by neutrophils and macrophages in response to inflammation
What are the physiological and pathophysiological roles of COX-1?
GI protection
Platelet aggregation
Blood flow regulation
Inflammation, chronic pain, increased blood pressure
What are the physiological and pathophysiological roles of COX-2?
Renal and CNS function Tissue repair and healing Reproduction Uterine contraction Pancreas Blood vessel dilation Inhibition of platelet aggregation Inflammation Fever Blood vessel permeability Chronic pain
Describe the side effects of aspirin and NSAIDs.
Increased HCl in GIT
Bronchoconstriction, promotion of AA to leukotriene production
Change in platelet behaviour, bleeding risk
Hyperventilation, respiratory alkalosis
Increased lactic acid and keto-acid production
