Lecture 25: Analgesic drugs: OPIOIDS Flashcards
What type of receptors are Opioid receptors and what is their mechanism of action
They are GPCRs. Presynaptic neuron 1. Activate Gi proteins 2. Inhibit adenylate cyclase enzyme 3. Reduce Ca2+ channels permeability 4. Block transmitter release
Post synaptic neurons
- binding at the mu receptor leads to outflux of K+ from the post synaptic neuron
- Leads to hyperpolarisation
- Needs increased stimulation to depolarise and conduct signal
Therefore leads to reduced conduction of nociceptive and inflammatory pain signals
What are the 6 possible routes of administration of opiates
Oral, parenteral: injection, transmucosal, transdermal, nasal or sublingual
What is Opium and what is it made of
Opium is dried latex from opium poppies containing
- Narcotic alkaloids: eg. morphine, codeine
- Non-narcotic alkaloids (eg. papaverine, thebaine, noscapine)
What is the difference between an Opiate and Opioids
Opiates are
natural narcotic analgesic derived from opium poppy
Opioids are synthetic narcotics which mimic the poppy plant.
What are 3 commonly used opioids that are very strong, strong and weak.
Which are synthetic, semi synthetic and natural
- Very strong: Fentanyl; augments anaesthetic agents. synthetic used for operating table. It is 50-100x more potent that morphine.
Strong: Morphine: natural; for severe post operative pain.
Semisynthetic is heroin- diamorphine
Weak: Codeine: natural , tramadol: synthetic,
Where are opioid mu, kappa, delta opioid receptors and how many subtypes do they have
Mu and Kappa both have 3 subtypes.
Both are in the Spinal cord and periaqueductal grey of brainstem.
Mu is also in cortex and thalamus
Kappa is also in limbic system, hypothalamus,
Delta has 2 subtypes. It is in cerebral cortex, olfactory bulb, nuc. accumbens, amygdala, and pontine nucleus
How are opioid receptors produced in the periphery
- Certain inflam mediators are released from damaged tissues in the periphery
- Stimulates Dorsal root ganglia cell body to produce opioid receptors.
- Transported toward the central terminal in the dorsal horn and Distribute along the primary afferent fibre (peripheral nociceptor terminals)
- They are stimulated by endogenous (monocyte + macrophage delivered) & exogenous opioids within hours of local tissue damage.
What are the adverse effects of Opioids
generally given for sedation and analgesia,
and what conditions should you be aware of before you give them
AE:
- Respiratory depression
- Somnolence and dizziness
- Release of histamine causing itching, hypotension
- Ileus and Constipation
- Nausea + vomiting, - Vagally mediated bradycardia
Precautions:
- Patients with sleep apnea , COPD, and elderly patients
-Euphoric effect can lead to physical, psychological dependence, drug tolerance and addiction
What are the effects of mu1, mu2 and kappa opioid receptor stimulation and the adverse effects
All have analgesia for nociceptive and inflammatory pain- not neuropathic (pain due to nerve damage)
Kappa also has dysphoria
Mu2 have have side effects + euphoria and substance dependence
What does antagonist, agonist - antagonist and partial agonist opioids mean
Antago: no effect - good for overdose
Agonist-antagonist: they have both functions depending on the receptor type
Partial agonist has activity at one or more but not all receptor types.
What are the 4 Endogenous opioid peptides and their opioid receptors they activate
- Endorphins: mu
- Endomorphins: mu
- Enkephalins: delta
- Dynorphins: kappa
How should you choose which opioid to use in real life?
- To choose the most effective and comfortable route. Severe - IV
- Give opioids continuously for severe to moderate pain. Don’t leave patient to suffer
- Consider patient inter-variability
- Use of adjuvants (eg. NSAIDS) for enhancing opioids analgesia and reduce side effects bc don’t need high dose of opioids.
What are the 2 ways to help opioid addiction
- Firstly change the addicted opioid to ones that have less side/euphoric effects: eg. Methadone or Bup-re-norphine.
Then slowly over time the dose is reduced. - Rapid opiate detoxification:
Give high doses of naltrexone antagonist to the patient under anaesthetic for 5-6hrs where they are unable to feel the withdrawal symptoms.
After waking up they are kept on oral naltrexone for a long time to reduce risk of relapse.
What are 4 medications to manage opioid withdrawal symptoms
- To reduce autonomic symptoms of withdrawal (sweating, piloerection, increase HR, BP, RR, mydriasis, lacrimation) use Clonidine
- To reduce nausea and vomiting use promethazine
- To reduce muscle cramps use diazepam
- To reduce diarrhoea use antidiarrheal
What are the notable effects, side effects, half life, VD and route of administration relating to bioavailability of Morphine
Effects: Miosis (pinpoint pupil), euphoria, cough suppression
Side effect : aggravate biliary stones- sphincter of Oddi constriction.
Half life of 3 hours due to low lipid solubility- slower onset and longer duration.
Only 1/3 bound to plasma protein so large volume of distribution.
75% first pass metabolism for oral delivery so generally given through IV - can
Patient controlled analgesia.
IM possible
Epidural/intrathecally given to mix with lower dose of local anaesthetic.
Where is morphine metabolised, what are the metabolites and where is excretion
Metabolised in the liver via glucuronidation: 70% to M3G - no analgesia. others to M6G- half as potent as morphine.
Excretion mainly in the urine
What are the notable effects, side effects , drug interactions and metabolism of Pethidine
Effects: (blocks parasymp)
Less marked miosis. dry mouth, tachycardia. less biliary spasm.
Basic side effects.
Metabolised through conjugation of two metabolites, pethidinic acid and Norpethidine for urine excretion.
However Norpethidine has a long half life and can accumulate in renal failure causing hallucinations and seizures. Therefore given only short term to avoid accumulation.
DI: Accumulation can also happen with MAOI (antidepressants)
What is the route of administration and metabolism of Fentanyl
similar side effects and main effect
Has high lipid solubility: fast onset of action:
Delivered IV, IM, nasal, sublingual spray and sublingual tablet
For slower onset release and inability to rapidly change dose: Transdermal patches for chronic pain
Transmucosal losenges
Metabolised to nor-fentanyl (inactive) in the liver and excreted in urine over days.
What is Iontophoreseis
A method of Transdermal Patient Controlled Administration of ionizable drugs in which the electrically charged components are propelled through skin by external electric field, allowing it to enter skin quicker than normal TDP.
What are the available routes of administration, notable effects, and uses of Methdone
- It has good bioavailability (70%) from all routes: rapid onset of analgesia effect:
Oral, rectal, subcutaneous, IV and sublingual.
Effects: no significant cognitive impairment, euphoria, safe in renal and liver failure
Uses: Because it has some NMDA antagonism can treat neuropathic pain, chronic pain. Also used for opioid withdrawal/detox
What is the effects, bioavailability, and side effects (cautions) for Tramadol
Bioavailability: >70%.
It is only a weak mu opioid agonist. Mainly Inhibits NA and 5HT reuptake.
Side effects:
- N&V, dizziness, sedation, little respiratory depression
- Can lead to Serotonin syndrome (ataxia, sweating, fever, myoclonus etc) if administered with SSRI.
- Decreases the threshold for epileptic seizures
What are the notable effects, side effects and metabolism
of Codeine
Effects: can suppress cough, anti diarrhoeal.
Side effect: commonly drowsiness/constipation otherwise normal side effects of opioids. Physical dependence
Metabolised by cytP450 into morphine.
Be careful of ultra rapid metabolisers leading to toxic opioid effects and slow metabolisers which may not recieve adequate analgesia
What are two opioid antagonists and what is the difference between them two
Naloxone is given IV. works against mu, delta and kappa receptors.
Naltrexone has a longer acting duration for detoxification
What are Co analgesics, give 6 examples
Medications given with opioids to improve/enhance its analgesic effects despite not being analgesics on their own. Can help patients that are not responsive to opioids on their own.
eg.
- TCA (prolong NA and 5HT)
- Anticonvulsants (for neurogenic pain, facilitating GABA preventing glutamate)
- Anxiolytics
- Corticosteroids
- Ketamine (NDMA ant)
- Clonidine (alpha2 agonist)
