12 – Opioids I Flashcards
Opium
- Unrefined extract from poppy
- Contains ~20 naturally occurring pharmacologically active compounds
Opiates
- Group of purified natural agents
- Morphine
- Codeine
Opioid
- Any natural, synthetic, endogenous substance with morphine-like properties
Endogenous opioids peptides
- Small molecules that are naturally produced in CNS and various glands throughout the body (pituitary and adrenal)
4 distinct families of endogenous opioid peptides
- Beta-endorphin (mu)
- Enkephalins (delta)
- Dynorphins (kappa)
- Nociception (NOP)
Anatomical distribution of opioid receptors
- Supraspinal
- Spinal
- Periphery
Supraspinal distribution of opioid receptors
- Brain stem (periaqueductal grey area)
- Hypothalamus
- Amygdala
- Corpus striatum
Spinal distribution of opioid receptors
- Dorsal horn: substantia gelatinosa
Periphery distribution of opioid receptors
- ID on the process of sensory neurons
- **Upregulated during inflammatory-pain states
Opioid receptors ‘type’:
- GPCRs
- Mediate inhibition of neurotransmission and endocrine secretion
Opioid receptors pathway: 3 actions
- Inhibit adenyl cyclase activity
- Inhibition of pre-synaptic voltage gated Ca-channels
- Increased K+ efflux ->neuronal hyperpolarization of post-synaptic SC projection neurons
Inhibition of pre-synaptic voltage-gated Ca-channels
- Decreased Ca INFLUX
- Reduce NT release
- Inhibition of synaptic transmission of nociceptive input
Increased K+ efflux
- neuronal hyperpolarization of post-synaptic SC projection neurons
- inhibition of ascending nociceptive pathways
3 well defined types of opioid receptors
- Mu
- Delta
- Kappa
- (recent years: nociception receptor)
Mu receptor agonist effects
- *profound analgesia (spinal and supraspinal)
- Respiratory depression
- Bradycardia
- Sedation (dose-dependent)
- Euphoria/dysphoria
- Miosis
- Hypothermia
- Antitussive
- Decreased GI motility
- Urinary retention
- Emesis
- Anti-emetic at vomiting center
- Minimal CV effects
Kappa receptor agonist effects
- *spinal analgesia (mild to moderate pain)
- Mild sedation
- Miosis
- Minal respiratory depression and vagally mediated bradycardia
- Dysphoria
- Diuresis
Opioid effects: clinical significance
- Analgesia
- Sedation (part of premedication)
- Anesthetic sparing
- Reversible
Opioid effects: clinical significance side effects
- Bradycardia
- Respiratory depression
- Emesis (nausea)
- Abuse potential
- Dysphoria
Opioids in different species
- Receptor distribution differs among species and within species
Mu receptor agonist: example in different species
- CNS depression: dogs, monkeys, humans
- Excitement and/or spontaneous locomotor activity: PAIN FREE mice, cats, horses, goats, sheep, pigs, cows
Morphine Mania in cats (historical)
- Elicited by doses 100-fold higher than those used clinically
- *do get mydriasis (dilated pupils)
Birds: opioids in different species
- Raptors:
o Mu-opioids agonists provide analgesia
o Kappa oppioda agonists appear ineffective - Psittacines (buggies)
o Kappa opioid agonists more effective than mu-opioids
Reptiles: opioids in different species
- Mu-opioid agonists provide effective analgesia in most reptiles
Individual variability (pharmacogenetics)
- Don’t assume every patient will respond the same way
- *treatment should be tailored to the individual
2 properties(terms) of drug-receptor interaction
- Affinity
- Intrinsic activity or efficacy
Affinity
- How well a drug binds to receptor
Intrinsic activity or efficacy
- Magnitude of effect the drug has once bound
Full agonist
- High affinity and high intrinsic activity
- Able to generate maximal response from receptor
- Stimulate both mu and kappa
- Ex. morphine
Partial agonist
- Submaximal effect compared with full agonist
- Low intrinsic activity
- *Less analgesia
- Ceiling effect
- Higher affinity
Example of partial agonist
- Buprenorphine
o Higher affinity but less intrinsic activity than morphine
o Ex. if want to give morphine=buprenorphine will block the receptor for 6-8hours (‘ceiling effect’)
Antagonist
- No intrinsic activity, but HIGH affinity
- Rapidly reverse all opioid-induced clinical effects (including ANALGESIA)
o Use for EMERGENCY SITUATIONS (overdose or profound respiratory depression) - Non-emergent situations=ALWAYS titrate to effect
Inappropriate use of antagonist
- May cause the development of intense acute pain and activation of SNS
Competitive antagonist
- Can DISPLACE opioid agonists from Mu and Kappa receptors
Opioid antagonist examples
- Naloxone
- Naltrexone
Naloxone
- Pure mu, kappa, delta antagonist
- Can reverse all opioid agonist effects
- Duration of action: 30-60 mins
- Watch for re-narcotization
Naltrexone
- Clinical effects last ~2x longer than nalozone
- Not readily available (may used in wildlife immobilization)
Agonist-antagonist
- Agonist effects at one receptor (kappa) but antagonist effect on another receptor (mu)
Example of an agonist-antagonist
- Butorphanol
o Kappa receptor agonist
o Mu receptor antagonist
o Ceiling effect
o Maintains analgesia (kappa)
Efficacy
- Maximum effect that a drug can produce regardless of dose
Potency
- Amount of drug that is needed to produce a given effect
- Ex. less concentration/dose required=more potent
- *determined by affinity of drug for receptor and number of receptors available
Potency is compared to morphine on an ‘equal-analgesic basis’
- Morphine was the first = 1
- Meperidine = 1/5
- Fentanyl 10,000
Mild and short example (efficacy vs. duration)
- Meperidine
Profound and long example (efficacy vs. duration)
- Morphine
- Hydromorphone
- Methadone
Buprenorphine efficacy and duration
- Moderate effect
- Long duration
Fentanyl, sufentanil efficacy and duration
- Profound effect
- Short duration
Opioid pharmacology
- Highly lipid soluble
- Hepatic transformation
- Oral opioids in animals: poor bioavailability (high first pass effect in liver)
- Differences in metabolisms among species
- Some metabolites are active (analgesic and other effects)
- Elimination: biliary and renal excretion
IV, IM: opioids systemic administration
- Onset rapid (except buprenorphine)
- Histamine release after IV administration (morphine, meperidine)
Continuous rate infusions (CRI)
- Medication continuously administered IV to maintain consistent plasma levels and analgesia
- Short acting mu-agonist well suited (fentanyl, remifentanil, sufentanil)
- Morphine, hydromorphone
- *reduction of unwanted side effects (after intermittent bolus administration)
SC: opioid systemic administration
- Unreliable absorption
- Great individual variability in pain relief
- Ex. high-concentrated formulation of buprenorphine
High-concentration formulation of buprenorphine
- SC
- Up to 24h postoperative analgesia
- May be administered up to 3 consecutive days
Buccal (oral transmucosal, OTM)
- Non-invasive and pain-free
- Minimal physical restraint required
- Bypass first-pass GI clearance=allows higher bioavailability
- Ex. buprenorphine
Buprenorphine buccal administration
- Cats: acceptable bioavailability and analgesia
- Dogs: high dose required ->cost prohibitive, risk of swallowing
- In clinic setting: IV, IM provide better analgesia
- Suitable for late postoperative analgesia
Transdermal administration: fentanyl patch
- Human safety consideration
- Evolved to reduce potential to abuse
- Species differences how skin effects drug movements
Fentanyl patch evolved to reduce potential abuse
- Reservoir: filled with liquid
- Drug-in adhesive matrix: active drug mixed with polymer
Fentanyl patch bioavailability and delayed onset: dogs
- 63%
- 12-24hours (duration 3 days)
Fentanyl patch bioavailability and delayed onset: cats
- 35.9%
- 8-12 hours (duration up to 5 days)
Need to continue pain assessment and monitoring with transdermal administration
- Great individual variability in drug absorption
- Changes in body T, skin preparation, patch placement affect rate of absorption, plasma fentanyl levels and analgesic efficacy substantially
- Care with heating pads (increased circulation increases uptake): CAREFUL OF OVERDOSE
Transdermal fentanyl solution (recuvyra) (in the states)
- Postoperative pain control
- Liquid solution applied to skin dorsally between shoulder blades (stratum corneum)
- No need necessary
- Requires RISK training
- Applied 2-4hrs prior surgery
- Last up to 4 days in dogs
- No PEAK effect
- Adverse effects are long lasting
Epidural/spinal administration
- Often used in epidural or subarachnoid space to manage ACUTE or CHRONIC PAIN
- All are lipid soluble but solubility differs between opioids
- *depends on how lipophilic they are
Lower lipid solubility drugs and epidural/spinal administration
- Less systemic absorption
- Slower onset time (passage across dura matter)
- Longer duration and further cranial migration
o Morphine: 12-24 hours
o Hydromorphine: 8 hours
Fentanyl epidural/spinal administration
- Short duration
- Segmental analgesia
- Doesn’t travel very far
- Ex humans and epidural catheter for post pain management
Intraarticular administration
- Significant increase in mu-opioid receptors in articular and peri-articular tissues occurs after joint inflammation
- *of morphine after arthroscopy surgery (knee, elbow) as part of MULTIMODAL ANALGESIA pain
