Pharmacology Flashcards
Name the opioid receptor(s) each opioid acts at.
- Methadone
- morphine
- fentanyl
- sufentanil
- nalbuphine
- buprenorphine
- mu +++
- mu +++, kappa +
- mu +++
- mu +++, delta +, kappa +
- kappa ++
- partial mu +
Morphine pharmacology:
- 40% bioavailability
- 30% protein bound
- major pathway of metabolism of glucuronidation
- metabolized to morphine-6-glucuronide and morpine-3-glucuronide
- converted to hydromorphine
Name 4 opioids in the class of phenylpiperidines?
- Fentanyl
- Remifentanil
- Sufentanil
- Meperidine
Methadone pharmacology
- synthetic
- mu receptor preferential binding
- noncompetitive antagonist at NMDAR
- bioavaliability 50% (41-99%) oral or rectal
- reaches peak plasma levels at 4hrs
- onset to analgesia 30-60min orally
- 90% protein bound
- half life alpha 2-3 hours, beta 15-60 hours
Hydromorphone pharmacology
- semisynthetic
- 5X potency to morphine
- SC route is 80% bioavailable
Oxycodone pharmacology
- semisynthetic
- mu and kappa agonist
- peak plasma levels at 2 hours
- oral bioavailability 60-87%
- half-life 3-5.7 hours
- metabolized by 2D6 and 3A4
- metabolized to oxymorphone and noroxycodone
sufentanil pharmacology
- 10X more potent than fentanyl
- 1000X more potent than morphine
- peak effect is 5min when given IV
- rapid onset of respiratory depression
- highly liophilic
fentanyl pharmacology
- synthetic phenylpiperidine
- 100X more potent than morphine
- IV duration of action is 30-60min
- patch - steady state at 12-24 hours after application; after patch removal 50% decline in plasma levels in 17 hours
codeine pharmacology
- 10% converted to morphine
- codeine itself has very low affinity for mu receptors
- half-life 2-4 hours
- metabolism is primarily by CYP2D6
- 10% of caucasians cannot convert codeine to morphine
- 1-2% are ultrarapid metabolizers
- contraindicated in children undergoing tonsillectomy and adenoidectomy and children and adolescents for pain and cough management
tramadol pharmacology
- synthetic codeine analog
- SNRI + weak mu agonist
- analgesia within one hour and peak effect in 2-3 hours
- can lower seizure threshold
- metabolism is primarily by CYP2D6
- 1-2% are ultrarapid metabolizers
- 10% of caucasians cannot convert codeine to morphine
Acetaminophen sites of action?
- spinal cord
- cerebral cortex
Through what two pathways does acetaminophen exert its analgesic action?
- weak central inhibition through prostaglandin synthetase
- inhibition of nitric oxide pathway (mediated by NMDA, Sub P)
What are side effects of acetaminophen?
- liver toxicity
- cholestatic jaundice
- acute pancreatitis
- thromocytopenia
- agranulocytosis
MOA of NSAIDs?
- inhibition PG production from AA by inhibiting COX-1/COX-2
- direct action on spinal nociceptive processing
- Goal is to COX-2 and not COX-1
Side effects of NSAIDs?
- GIB
- GI ulceration
- disturbance of platelet function
- sodium and water retention
- nephrotoxicity
- hypersensitivity reactions
Name common drugs that interact with NSAIDs
- antacids
- warfarin/anticoagulants
- RA drugs (azothiaprine, gold compounds, methotrexate)
- corticosteroids
- diuretics
- lithium
- oral hypogylcemics
- phenytoin
- probenacid
MOA of calcium channel blockers?
- bind to pre-synaptic alpha2 delta subunit of L(N)-type VGCC
- reduces release of Sub P, glutamate and NE
Sites of action of gabapentinoids?
Central:
- spinal dorsal horn
- brainstem/forebrain (descending pathways)
Side effects of gabapentinoids?
- fatigue
- sedation
- tremor
- ataxia
- peripheral edema
- hallucinations
- suicidal ideation
- gastroretentive gabapentin (OD dosing) has lower incidence of side effects than regular gabapentin
Name common drugs that interact with gabapentinoids?
- hydrocodone
- morphine
- naproxen
- antacids
What is ziconatide?
- inhibits presynaptic N-type calcium channel; thereby inhibits excitatory NT release (Glutamate and Sub P)
- given intrathecally
Indications for ziconatide?
- Chronic cancer pain
- HIV neuropathy
- neuropathic pain
MOA of cannabinoids?
- THC is agonist at CB1-R which inhibits DA neurons mainly by pre-synaptic inhibition.
- CB2-R in CNS but CB1 more in brain.
- CBD stimulates the vanilloid receptor type 1 (VR1)
- Both are G-protein coupled receptors
What are the indications for cannabinoids?
- 3rd line for neuropathic pain
- 2nd line for MS related pain
- Chemotherapy induced nausea/vomiting
- HIV-related neuropathy
- HIV-related weight loss
- MS or SCI related spasticity (not first line)
- possible epilepsy
MOA of NMDAR antagonists?
- NMDA-R is a type of ionotropic glutamate receptor (other AMPA, KA).
- Blocks excitatory neurotransmitters
- Helps to decrease OIH through dampen central sensitization by decreasing NMDA-R hyperexcitability.
What are examples of drugs that are NMDAR antagonists?
- methadone
- ketamine
- memantine
What are the side effects of methadone?
sedation, QTc prolongation, constipation, drug-drug interactions and all other general opioid side effects
What are the side effects of ketamine?
- increased BP
- tachycardia
- N/V
- blurred vision
- nystagmus, dissociation
- altered MS
- hepatotoxicity
- ketamine induced cystitis.
MOA of sodium channel blockers?
- inhibits development and propagation of ectopic discharges
- block normally conducting non-nociceptive nerves
What drugs are included in the category of sodium channel blockers?
- antiepileptics
- anticonvulsants
- local anesthetics
- TCAs
- antiarrhythmics
what are the max doses of:
Lidocaine
Bupivicaine
Ropivicaine
Lidocaine 4.5 (7 with epi)
Bupivicaine 2.5 (3 with epi)
Ropivicaine 2-3
Side effects of sodium channel blockers?
- delayed urinary retention
- paresthesia
- paresis/gait impairment
- orthostatic hypotension
- dyspnea
- lidocaine
- dizziness, blurred vision, seizure, bradycardia.. cardiac arrest
What p450 enzyme metabolizes oxycodone?
- 2D6
* 10% of Caucasian population are poor metabolizers and do not get good analgesic effects from oxycodone
Opioid receptors are what type of receptors?
- g-protein coupled receptors
Opioid receptors act where (cellularly)?
- presynaptic (decrease calcium influx and subsequent NT release
- post-synaptically through opening of K channels and subsequent hyperpolarization
Opioid receptors act where (anatomically)?
- PAG - activate descending projections that involve NE and 5-HT and modulate excitability of dorsal raphe and locus coeruleus which project limbic/forebrain (emotional strcutures)
- selectively depress the discharge of dorsal horn neurons
What are two different strategies for opioid rotation as per Canadian guidelines?
Method 1: Decrease the total daily dose of the current opioid by 25–50% and convert to new opioid equivalent dose
Method 2. Decrease the total daily dose of the current oral opioid 10-30% while starting the new oral opioid at the lowest total daily dose for the formulation
OR
decrease the total daily dose of the current opioid 10-25% per week while titrating up the total daily dose of the new opioid weekly by 10-20% with a goal of switching over 3-4 weeks
What three main treatment approaches available to clinicians managing patients with opioid-induced sleep disordered breathing?
- Reduce opioid dose without specific treatment for sleep apnea
- Don’t change the opioid dose but provide specific sleep apnea treatment (CPAP, MRD, etc.)
- Reduce opioid dose and provide specific treatment for apnea.
What are long-term consequences of opioid therapy?
- OIH
- Sleep apnea
- hypogonadism
What are three strategies for opioid tapering as per Canadian guidelines?
- Gradually reduce dose by 5–10% of morphine equivalent dose every 2–4 weeks with frequent follow-up.
- Switching from immediate release to controlled
release opioids on a fixed dosing schedule may assist some patients in adhering to the withdrawal plan. - Switch opioid to methadone or buprenorphine/naloxone preparations and then gradually taper
* Reduce the opioid dose rapidly over a few days/weeks or immediately but must be carried out in a medically supervised withdrawal centre.
How do you taper fentanyl patch?
- Consider reducing fentanyl by 12–25 μg/h patches every 2–4 weeks
- Consider adding immediate release oral opioid for pain relief (e.g. morphine IR 5 mg q 4–6 h prn)
- Once fentanyl is at the lowest available dose (e.g. 12 μg/h every 72 hours), stop the fentanyl transdermal patch and only use the immediate release oral opioid for pain relief
When does opioid tolerance become clearly evident?
- 3 months
* a reasonable opioid trial is 3-6 months
What are common acute side of opioids?
- sedation
- constipation (most common)
- urinary retention
- nausea
- pruritis
What are four opioids that would theoretically be useful for treating neuropathic pain?
- methadone
- tramadol
- tapentadol
What opioids are in the the class named phenanthrenes?
All the morphines - heroin, hydromorphone, naloxone, oxycodone, morphine, buprenorphine
Which opioids do not show up on UDS?
synthetics (fentanyl, methadone) and semisynthetics (oxycodone, hydromorphone, hydrocodone)
What are the pharmacological properties of antidepressants?
- monoamine transmission
- cholinergic transmission
- glutamatergic
- opioid receptor
- sigma receptors
- neurokinin receptors
- corticotrophin releasing factor receptors
Pharmacological mechanisms of antidepressants in nociception?
- descending inhibition
- monoamine modulation
- glutamatergic neurotransmission (NMDA suppression)
- opioid interactions (stimulate endogenous opioid release, decreased opioid utilization, synergistic effects)
Miscellaneous: - through adenosine
- ion channels (Na channels, Ca and K channels)
- TCAs can decrease inflammatory responses
Antidepressants with the best evidence for pain control?
- TCAs
- Venlafaxine
- Duloxetine
- Milnacipran
Side effects of TCAs?
- sedation
- orthostatic hypotension
- urinary retention
- dry mouth
- falls
- confusion
tapentadol pharmacology?
- opioid agonist and NE reuptake inhibitor
- works at both ascending and descending pathways
- metabolized primarily by glucuronidation
- 3.3mg of tapentadol = 1mg morphine
- lower incidence of nausea and constipation
- can result in serotonin syndrome through indirect effects
tapentadol indications?
- moderate to severe acute pain
- acute low back pain and radicular pain
- OA
- post-op pain
- ER formulation approved for severe DPN
- moderate to severe cancer pain
How to do a rotation to Tapentadol?
- D/C all other long-acting opioids, and initiate tapentadol ER at 50% of oral morphine equivalents
