P9: Opiate Analgesics Flashcards
What is an analgesic
What receptor subtypes do selective direct acting sympathomimetics act on
What are the 3 main classes of analgesic
- Opioids
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Local Anaesthetics
Give examples of non-steroidal anti-inflammatory drugs (NSAIDs)
Aspirin
Ibuprofen
Diclofenac
Give examples of local anaesthetics
Lidocaine
Novocaine
Benzocaine
Why is paracetamol not truly an NSAID
Has no appreciable anti-inflammatory activity
What is opium
dried poppy latex, complex mix of analgesic, non-analgesic and inert agents
What are opiates
Drugs derived from opium and semi-synthetic agents from them and from thebaine
What are opioids
All agonists and antagonists with morphine like pharmacology
What are the 5 classes of opioid receptors
μ - 1 and 2 - mu κ - 1, 2 and 3 - kappa δ - 1 and 2 - delta NOP/nociceptin ζ - zeta
What receptors are involved in opioid analgesic actions
μ, κ and δ
What class of receptor are all opioid receptors
7 TMD GPCRs
acting through Gi/o
Give examples of agonist opioid drugs
- Morphine, Codeine and Heroin (opiate agonists)
- Pethidine, Fentanyl and Methadone (synthetic opioid agonists)
- Endorphins, enkephalins (endogenous agonists)
Give an example of antagonist opioid drugs
Naloxone
How can nalorphine and pentazocine act as both opioid agonist and antagonists
Different actions on different receptors - competitive μ antagonists and κ agonists
Dose-dependent effects
Agonists at high temperatures
Name a partial opioid agonists
Buprenorphine - partial μ agonist, much more potent than morphine but lower max effect, blocks morphine actions
What pain fibres is opioid analgesia more effective on
C fibres = continuous dull pain
Describe the mechanism of descending pain control in opioid analgesia
- Periaqueductal gray matter (PAG) sends inhibitory GABAergic projections to the midline raphe nucleus (MRN) and locus coeruleus (LC)
- the MRN and LC send inhibitory 5-HT and NA projections to the substantia gelatinosa in the spinal cord, limiting nociceptive fibre transmission
- opioids act on μ receptors in the PAG and inhibit GABA outflow, relieving inhibition of 5HT and NA and suppressing pain signalling
Describe the mechanism of the spinal actions in opioid analgesia
- Opioids directly stimulate inhibitory interneurons in the spinal cord
- μ receptors on the C fibre are stimulated by the opioid
- suppress excitatory neurotransmitter release directly onto the second order neuron, and inhibitory signalling on to the inhibitory interneuron
- together this suppresses transmission of nociceptive information into the brain
What mechanism is thought to cause the euphoria from opioids
Stimulation of the ventral tegmental area causing the release of dopamine in the nucleus accumbens and frontal cortex
How can opioids result in respiratory depression
- Reduces responsiveness of brainstem centres to plasma partial pressure of CO2
- Depresses activity in the pontine and medullary centres involved in breathing rhythm and depth
Why are high doses of opioid lethal
Respiratory depression leading to hypoxia and cardiovascular collapse
How can morphine and μ/κ agonists cause miosis
They cause miosis (pupillary constriction) by excitatory action at the occulomotor nucleus, activating parasympathetic innervation of the pupil.
Opioids are anti-tussive, what does this mean
Means they suppress cough reflex
NOTE BRUH
Codeine and pholcodine are potent anti-tussives but weaker analgesics
What are the effects of Opioids on the stomach
Decreased gastric motility and delayed emptying time
What are the effects of opioids on the small intestine
- Decreased biliary, pancreatic and intestinal secretion
- Smooth muscle resting tone increased
- Decreased peristalsis
What are the effects of opioids on the large intestine
- Similar to the small intestine
- significant faecal desiccation
- anal spincter tone increased
What are the overall effects of opioids on the GI tract
- Constipation
- Delayed digestion of food in the small intestine
- Retarded absorption of other drugs
Where is the chemoreceptor trigger zone (CTZ)
Floor of the 4th ventricle, in the area postrema of the medulla.
Outside the BBB, monitors blood chemistry via many different receptors.
What inputs does the Vomiting centre get
From the CTZ
Vestibular tract input +
GI tract input ( via the nucleus tractus solitarius)
How do opioids induce emesis and nausea
Direct stimulation of the CTZ in the area postrema of the medulla
What is used to reduce opioid induced emesis
anti emetics e.g. Domperidone (D2 antagonist) or H1 antagonists
How are opioids administered
- IV injection for pain relief
- Oral produces less effect due to first pass but preferred for chronic pain control
How is morphine metabolised
Conjugated with glucuronic acid in the liver to form inactive morphine-3-glucuronide and extra hepaticallly to form highly active morphine-6-glucuronide
How is morphine excreted
Via kidneys primarily as 3-glucuronide form
Why is morphine not given to neonates and what is used instead
Neonates have compromised conjugation mechanisms
Pethidine used instead
Give possible mechanisms for opioid tolerance
Receptor down regulation
Reduced affinity for the the opioid receptor
Increased metabolism
Inhibition of endogenous opioid release
What is physical dependence
Associated with withdrawal syndrome, resembles severe influenza - pupillary dilation, sweating, fever, piloerection, nausea, diarrhoea and insomnia
What is psychological dependence
Craving of drug irresepective of warding off withdrawal symptoms or for its euphoric effects
NOTE
Opioid tolerance is reach quickly so larger doses needed, easily becomes toxic
