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Boards: Pharmacology > Opioids > Flashcards

Opioids Flashcards

1
Q

Opiate

A

drug derived from opium, mixture of compounds from poppy, Papaver somniferum

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2
Q

Opioid

A

drug not derived from opium but interactions with opioid R
o Prototypical analgesics, antitussives, antidiarrheal drug class

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3
Q

Opioid R system/opiod R effects identified in:

A

ascarids, scallops, fish, reptiles, birds, mammals

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4
Q

Variants of MOR

A

o Alternative splicing may produce differences in structure, function of R despite R produced from same gene
o Single nucleotide polymorphism identified in dogs may also increase diversity in R structure, function –> altered drug effects
 SNP identified with high prevalence in dogs experienced dysphoria with opioid admin
 Different sensitivities to opioids may be due in part to individual differences in types of MOR subtypes

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5
Q

Nociception/ orphanin FQ receptor

A

 Often called N/OFQ [NOP] receptor
 Significant homology to other ORs
 Naloxone hydrochloride does not have significant antagonistic action at R
* N/OFQ[NOP] R investigated, but details of interactions of endogenous ligand with R not well described
 Antagonists of N/OFQ [NOP] produce analgesia
* May be target for future development of analgesics, analgesic adjuncts

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6
Q

MOR endogenous ligand

A

Beta-Endorphin

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7
Q

DOR endogenous ligand

A

Dynorphin A

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8
Q

KOR Endogenous Ligands

A

leucine, methionine-enkephalin

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9
Q

Full Agonist

A

dose-dependent increase in effect until maximal stimulation of R achieved

Y axis of dose response curve

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10
Q

Partial Agonist

A

dose-dependent increase in effect, plateaus at maximum effect less than maximum effect of full agonist
 Can act as antagonist by partially reversing effects of full agonist
 May be preferred over full antagonist if some analgesia needed

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11
Q

Antagonist

A

binds to R with high affinity, produces no effect, inhibits binding of agonists (both endogenous, exogenous) DT greater R affinity of antagonist
 Also displaces previously bound agonists
 Most opioid R antagonists considered competitive
* Lack of intrinsic activity, ability of agonists to overcome effect to produce maximal effect
* Shifts dose-response curve right

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12
Q

Potency

A

How much drug required for 50% Emax? (x axis on dose response curve)

 Response = analgesia measured as change in latency of withdrawal or increased threshold to noxious stimulus
 Fentanyl > morphine: dose of fentanyl (0.01mg/kg) needed to produce equivalent analgesia response to morphine (1mg/kg) is lower

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13
Q

Location of OR in Higher Centers

A

o Brain, brainstem: neurons, microglia, astrocytes
 Periaqueductal grey
 Locus coeruleus
 Rostral ventral medulla
 CRTZ/vomiting center

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14
Q

Location of OR in SC

A

o SC: lamina II of DH (substania gelatinosa); Adelta, C fibers synapse with projection neurons
 Neurons, microglia
 Conflicting evidence about astrocytes

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15
Q

Other Sites of ORs

A

o GIT
o Synovium
o UT
o Leukocytes
 Immune cells can actually synthesize opioid peptides
o Uterus
o Periphery: neuronal, non-neuronal cells  immune cells, periphery sensory neurons (A and C fibers)
o Others

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16
Q

Opioid R MOA

A

GPCR via Gi/o

Inhibition of AC
Decreased formation of cAMP
Inhibition of Ca2+ channels in presynaptic neurons resulting in decreased release of excitatory neurotransmitters (glutamate and substance P)

Enhanced outflow of K from postsynaptic neurons - increased activation thresholds, hyper polarization of nociceptive neurons/nociceptors

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17
Q

Functions Mediated by MOR

A

-Analgesia (+KOR, DOR)
-Antidiuresis
-Decreased biliary secretions, GI motility (+KOR), GI secretions (+KOR)
-Decreased urine voiding reflex
-Emesis/antiemesis (drug specific)
-Euphoria
-Immunomodulation (+DOR)
-Increased appetite (+KOR, DOR)
-Decreased uterine contraction
-Miosis/mydriasis (species specific) (+KOR)
-Resp Depresson
-Sedation (+KOR)

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18
Q

Functions Mediated by KOR

A

–Analgesia (+MOR, DOR)
–Decreased GI motility, GI secretions (+MOR)
–Diuresis via inhibition of ADH release
–Increased appetite (+DOR, MOR)
–Miosis, mydriasis (species specific) (+MOR)
–Sedation (+MOR)

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19
Q

Functions Mediated by DOR

A

–Analgesia (+MOR, KOR)
–Immunomodulation (+MOR)
–Increased appetite (MOR, KOR)

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20
Q

Absorption of Opioids

A

Lipophilic Compounds - typically well absorbed SC, IM; rapid absorption

Unless SR formulas used, prolonged effect vs IV not typically expected from IM or SC admin

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21
Q

Oral Absorption

A

 PO: usually substantial first-pass metabolism so low PO bioavailability, may be ineffective when admin PO at standard doses
 Exception: drugs that can produce active metabolites, eg codeine in humans

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22
Q

First Pass Metabolism

A

 Drugs absorbed from GIT, usually following PO admin
 Drugs pass through mucosa –> intestinal metabolizing enzymes (both Phase I metabolic reactions, Phase II conjugation reactions) biotransformation drug before enters intestinal capillary system
 If enters intestinal capillaries intact, enters portal vein/liver  site of metabolism
 Any drug that makes it through the liver intact can enter systemic circulation, be distributed to elicit effect
* Despite large fraction of opioid absorbed, relatively small amt enters systemic circulation in active form where interactions with R elicit effect

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23
Q

Benefit of Transdermal Administration

A

–Bypasses first-pass metabolism
–Stratum corneum presents substantial barrier to drug absorption for some drugs
–Ex: Zobrium for cats, fentanyl patches/transdermal solution dogs

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24
Q

Transmucosal Opioids

A

bypasses first-pass metabolism
 Mucosa: thinner, more vascular than stratum corneum –> less of a barrier
 Buprenorphine = lipophilic, only effective if not swallowed
* Viable route of admin in cats but still somewhat variable due to conditions (eg pH) that can alter chemical properties
 Absorption of TM buprenorphine in dogs small: may not be practical route of delivery DT volume, cost limitations

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25
Q

Distribution of Opioids

A
  • Lipophilic compounds –> diffuse throughout body, easily cross blood-brain barrier
    -Large Vd
    -Primary effect site = CNS for analgesia, antitussive effects, sedation
    -Drug must penetrate CNS (ie cross BBB) for effects
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26
Q

Role of P-glycoprotein efflux pump

A

-Active transporter
-Efflux absorbed drug from CNS back to vasculature, causes limitation of central effects

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27
Q

Loperamide

A

Absorbed, rapidly in the brain, but pumped back out as a result of P-glycoprotein efflux pumps, most effects non central now (Anti-diarrheal)

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28
Q

MDR1

A
  • Deficient in functional P-glycoprotein efflux pump
  • Significant central effects following loperamide administration including heavy sedation –> reversible by naloxone
  • In people, rodents: morph, methad, fenta, bup, oxycod have substrate for P-glycoprotein
  • When using known MDR1 substrates in heterozygote/homozygote MDR1 gene mutation carriers, increased duration/intensity of effect may be recognized
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29
Q

Regional Blood Flow of Tissues, Organs and Opioid Uptake

A
  • Tissues receive greatest blood flow per tissue mass, equilibrium, btw plasma concentrations and tissue concentrations occurs most rapidly
    o Assuming drug = lipophilic, rapidly crosses tissue barriers
     IV bolus admin results in highest plasma concentrations at end of bolus dose –> plasma concentrations decrease over time DT drug metabolism, excretion, movement of drug from plasma into tissues (redistribution into SkM, adipose tissue)
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30
Q

Why is redistribution important?

A

Loss of effect DT drug movement out of CNS more rapidly than that predicted by elimination half life

May play greater role than metabolism in termination of CNS effect for some anesthetic vs analgesia drugs

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31
Q

Lipophilicity: morphine vs fentanyl

A

–Morphine: less lipid soluble vs fentanyl
–Slow distribution into, out of CNS –> beneficial for epidural admin where have longer duration at spinal OR

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32
Q

Metabolism

A

extensive metabolism in mammalian species
o Phase I +/- Phase II metabolism depending on specific drugs, species
 Most species metabolize morphine by Phase II glucuronide conjugation to morphine-3-glucoronide
* Hepatic 60%, renal 40%
* Approx 10% metabolized to morphine-6-glucoronide, which is more potent than morphine

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33
Q

Opioid Metabolism in Cats

A

relatively deficient in glucuronide action, eliminate via sulfate conjugation

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34
Q

Remifentanil metabolism

A

hydrolyzed by plasma esterases, independent of hepatic metabolism

Virtually no context sensitive half life

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35
Q

Morphine Metabolism

A

-Most species: hepatic metabolism - phase II glucuronide conjugation to morphine-3-glucoronide (M3G)
-Hepatic 60%, renal 40%
-10% metabolized to M6G - more potent than morphine

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36
Q

Cats and Morphine Metabolism

A

relatively deficient in glucuronide action, eliminate via sulfate conjugation

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37
Q

Opioid Metabolites

A

generally less potent or complete loss of activity vs parent drug
 Morphine glucuronide listed as active metabolite but must be given intracerebroventricular to elicit effect
 Not lipophilic so cannot penetrate CNS on own

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38
Q

Chloramphenicol..?

A

significantly decrease metabolism of methadone in dogs

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39
Q

Elimination of Opioids

A

o Typically metabolized prior to elimination in mammals
o +/- excretion of parent drug in urine, feces
o Opioid metabolites usually more water soluble, often eliminated in urine –> can be eliminated in feces by biliary secretion as well

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40
Q

Tolerance

A

loss of in vivo potency over time, shift of dose-response curve right
 Higher doses of opioids may be needed IOT achieve similar effect
 Not as well recognized in vet med vs human med
 Know that tolerance, withdrawal observed in animals

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41
Q

Drug Dependence in Dogs

A

dogs administered MOR agonists for >7d could display signs of opioid withdrawal if given drug can reverse MO effects eg partial MOR agonist, MOR antagonist/KOR agonist, MOR antagonist

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42
Q

Effect of Pain on Opioid Response

A

o Presence of pain may blunt some of undesired effects
 Ex: vomiting, dysphoria less common in painful dogs following morphine admin
 Ex: sedation/euphoria observed in painful cats following morphine, dysphoria rarely observed

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43
Q

General MOA

A

decrease release of excitatory NT, hypopolarize nociceptors –> decreased transmission within SC

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44
Q

Supraspinal Analgesia

A

–Mediated by PAG
–Binding of opioid agonists to R within PAG results in inhibition of GABA interneurons leading to activation of medullary pathways that selectively inhibit dorsal horn nociceptive neurons

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45
Q

Spinal Analgesia

A

mediated by inhibition of presynaptic NT release, postsynaptic hyperpolarization of neuronal membranes –> decreased excitability

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46
Q

Bulbospinal Pathways

A

Results in release of NE, serotonin in DH of SC

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47
Q

Peripheral Analgesia (eg IA admin)

A

localized peripheral opioid R
o Reversible by naloxone
o Peripheral opioid R activated, upregulated by trauma/inflammation
o Can be targeted by local admin of opioids to produce analgesic effect
o IA opioids reduce nerve terminal excitability of primary afferents with enhanced spontaneous activity

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48
Q

Analgesic Effects of Systemic Opioids

A

more effective at decreasing pain transmitted by C-fibers than A-delta fibers

o Reason why analgesic doses of opioids alone may not produce effective analgesia for surgical stimulation
 Higher IV doses, epidural administration (saturate spinal opioid R at site of administration) result in effects on both C fiber and A-delta fiber nociceptors

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49
Q

Epidural Opioids

A

will not prevent transmission of all tactile and nociceptive input (this can be done with local)  blunted, not blocked

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50
Q

Sedation, Excitation Assoc with Opioids

A

–Cat, horse: more likely to experience excitation than other species
–Breed can also influence response eg Huskies, vocalizing
–Rapid IV administration produces high concentrations initially, even at clinically appropriate doses –> can produce transient excitement in any species

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51
Q

Cats vs Dogs

A

Smaller volume of distribution of opioids

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52
Q

Opioid Induced Neuroexcitation in horses

A

o 0.6-0.66mg/kg IV (2.5x recommended dose) = excitement
o Increased locomotor activity = another manifestation of opioid-induced neuroexcitation in horses
 Pacing, weaving patterns in horses admin opioids
 Agonists-antagonists also produce increased locomotor activity, often accompanied by ataxia

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53
Q

Possible MOA of Increased Locomotor Activity

A

increased dopamine activity
* Drugs that decrease dopamine release show some efficacy at reducing step counts
* Admin of specific DA1, DA2 R antag not successful in reducing activity

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54
Q

Opioid Induced Resp Depression

A

increased PaCO2, primarily mediated by MOR
 Impt to distinguish btw drop in resp rate (bpm) vs true respiratory depression (decreased alveolar minute ventilation)
 RR can be depressed but not result in depression if VT increases to maintain alveolar minute ventilation

Less of risk vs humans

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55
Q

Wooden Chest Syndrome

A

 Increased chest wall rigidity reported in human pediatric and adult patients admin large doses of mu agonists
 Not common in veterinary medicine, anecdotally reported in dogs

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56
Q

MOA Wooden Chest Syndrome

A

 Experimentally, supratherapeutic doses of fentanyl (20-60mcg/kg IV) decrease inspiratory and increase/prolong expiratory neuron activity (tonic discharges) –> increased excitatory drive to IC neurons and abdominal motor neurons that control chest wall compliance
* Increase in IC, abdominal m tension –>increase in chest wall rigidity, decreased chest wall compliance
* Similar effects produced on pharyngeal constrictor, motor neurons –> tonic vocal fold closure, pharyngeal obstruction of airflow –> increases airflow resistance, resting abdominal wall tension

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57
Q

Placental/Fetal Effects

A

–Readily cross placenta
–Can depress fetus

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58
Q

Antitussive Effects

A

–Direct effect at cough center in medulla oblongata by actions at both MOR, KOR
–Independent of resp effects
–VAA paper: dose of fentanyl just as efficacious as suppressing cough for ETT as IV lidocaine

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59
Q

CV Effects

A

–Bradycardia in dogs: centrally mediated enhanced PSNS activity in neurons innervating heart
–CO usually maintained by increases stroke volume, typically results in beneficial or protective effect on heart DT less work and oxygen consumption

–Awake horses, cats: no change or HR increases IRT to opioids
–Under GA: decreased in cats, no change in horses

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60
Q

Histamine Release with Morphine

A

 Circulating histamine levels can increase 800-fold following 3mg/kg morphine IV
 Mast cell degranulation, histamine release with associated hemodynamic and anaphylactic responses (hypotension, tachycardia, bronchospasm) dependent on opioid administered, dose, ROA
* Rapid IV injection being most provocative method for triggering histamine release

Clinically relevant doses of morphine (<0.5mg/kg IV) in healthy dogs usually produce no detrimental effect on MAP IV SLOWLY

Caution or avoid in dogs with MCT

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61
Q

Emetic Effects

A

o Produce emetic or antiemetic effects depending on opioid, dose, ROA
o Emetic effects
 Stimulation of dopamine R in CRTZ
 Mediated by DOR effects –> MOR, KOR appear to be anti-emetic

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62
Q

Maropitant and vomiting

A

o Maropitant (NK1 R antagonist) admin 1h prior to opioid admin can reduce incidence of emesis, retching, CS of nausea in dogs by preventing binding of substance P to NK1 R in emetic center of brain

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63
Q

ACP and vomiting

A

Prior admin ACP significantly reduces likelihood of opioid-induced emesis in dogs

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64
Q

More Lipid Soluble Opioids and Vomiting

A

Fentanyl, butorphanol, methadone: tend to produce more prominent antiemetic effect DT faster penetration into CNS and inhibition of emetic center

IV: inhibitory effects first
IM: stimulatory effects first, then inhibitory

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65
Q

Low vs High Doses Morphine and Vomiting

A

o Low doses of morphine tend to produce emetic effect through stimulation of dopamine R in CRTZ
 Higher doses: antiemetic effect (subsequent antiemetic effect = stronger)

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66
Q

Pupil Constriction MOA

A

increased outflow in parasympathetic neurons leaving Edinger-Westphal nucleus

Parasympathetic neurons innervate sphincter pupillae (constrictor) m, leading to ctx of iris

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67
Q

Species that Experience Pupil Constriction

A

o Dogs, rabbits, rats

68
Q

Species that experience pupil dilation

A

Cats, horses, ruminants

69
Q

MOA Pupil Dilation

A

 Mechanism incompletely understood
 Peripheral component: sympathetically mediated response generated by release of catecholamines from adrenal glands acting on pupil
 Central component: possibly at Edinger-Westphal nucleus

70
Q

Normal Control of GI Motility

A

myenteric plexus, dependent upon NT released from enteric neurons
o Major NTs: ACh, serotonin (5-HT), vasoactive intestinal peptide, nitric oxide (NO)
 ACh activates cholinergic excitatory motor neurons
 NO, VIP control non-cholinergic inhibitory motor neurons
 Balance btw ACh and NO plus VIP release coordinates contractile, propulsive gut motility

71
Q

Role of Opioids with GI Motility

A

inhibit release of motility-modifying NTs –> impair coordination of motility, inhibition of colonic motility (morphine), jejunal motility (butorphanol)
o Peripheral effect DT MOR, central DT MOR, KOR
o Primary effects on GIT, thought to be mediated by release of ACh, substance P
 Decreased propulsive ctx
 Increased non-propulsive ctx (enhancing fluid absorption)
 Decreased GI fluid secretions

Net effect = constipating or antidiarrheal effect depending on condition of GIT

72
Q

Effect of Opioids on Stomach Antrum, Duodenum Tone

A

Increases tone - can be more difficult to pass endoscope

73
Q

MOR Effect on Bile Duct

A

dose dependent
 Increased bile duct tone, increased bile duct sphincter tone observed with low doses and decreased tone at high doses
 Sphincter of Oddi spasm, increased GB pressure documented SE of MOR agonists

74
Q

Morphine GI Effects in Horses

A

 Correlation of reduced GIT motility, lower fecal production, increased incidence of colic leads to conservative use of opioids in horses
* Other studies failed to identify increased risk for colic following opioid admin –> differences in opioid admin duration, concurrent medications play contributing role
 GI inhibitory effects more profound when opioids combined with a2s

SE: ileus, constipation, obstruction

75
Q

Effect of methylnaltrexone administered to horses

A

partially prevented adverse GI effects while preserving central analgesic effects

76
Q

Urinary Effects via spinal, epidural route

A

May cause urinary retention to varying degree DT spinal OR-mediated decrease in detrusor m contraction, increased tone of urinary sphincters, inhibition of micturition

Morphine: longer duration of urine retention DT longer residence time in the epidural or SAS allowing for continued spinal inhibition of micturition

Incidence of urine retention following epidural admin of opioids in dogs: 0-44% for epidural, 5-8% intrathecal; cats 9% in epidural bup+morp

Reversible with naloxone

77
Q

Urine Production

A

KOR agonists enhance urine production: diuretic response DT decreased release AVP

Exact MOA of MOR decrease in urine production unknown

78
Q

Thermoregulation

A

directly interact with neurons in preoptic anterior hypothalamus to alter thermoregulatory set point, compensatory responses

Resets - pants bc think hotter than are

Generally temps in dogs decrease - hypothermia assoc with prolonged recovery

79
Q

Hyperthermia

A

 Cats: up to 41.6C/107F  hydro, morph, buprenorphine, torb for up to 5h after extubation
 Ax with sx may increase magnitude of hyperthermic response
 Ideally monitor body temp in cats for at least 5h following end of ax

80
Q

Other Species that Become Hyperthermic with Opioids

A

cats, horses, swine, goats, cattle

81
Q

Hyperthermia in zoo, wildlife species

A

–Potent Opioids
– Partially DT effect on preoptic anterior hypothalamus to change thermoregulatory set point as in domestic species
 Predominantly DT stress response generated by capture
 Much higher doses of opioids used –> possible dose-dependent effect

82
Q

Immunomodulatory Effects: Morphine

A

natural killer cell activity, IFM cytokines, mitogen-induced lymphocyte proliferation through supraspinal mechanisms

83
Q

Immunomodulatory Effects of fent, Remi, tramadol:

A

protective effects on natural killer cell function, can increase function at some doses

84
Q

Pain and Immune System Function

A

o Pain produces immunosuppressant effects, withholding opioids worsens immune system function in painful p
o Opioids assoc w both immunostimulatory, immunosuppressive effects
–Cats: admin of morphine delayed effects of experimentally induced FIB
–Humans: immunosuppressive effects observed, unclear whether applies to vet med

85
Q

MAC Sparing Effect - dogs

A

 Full MOR agonists  dose-dependent MAC reduction in dogs, ceiling effect observed
o Ax-sparing effects generally accomplished with single IV doses of longer acting opioids or CRIs of short-acting opioids
 Non-IV routes (epidural) also produce ax-sparing effects

86
Q

MAC Sparing Effects - Cats

A

Minimal with opioids
comparatively less inhalant ax-sparing effects compared to dog
 One study: no ax-sparing effect in cats admin remifent infusions up to 75x analgesic effective dose concentration (EC50)

87
Q

Horses and MAC Sparing Effects of Opioids

A

Morphine INCREASES MAC at higher doses

88
Q

MAC Sparing Effects - other LA (goats, cows, sheep, pigs)

A

more MAC-sparing effects than horses, cats; less than dogs

89
Q

MAC Sparing Effects in Rodents

A

dose-dependent inhalant-sparing effects in rodents
 Partial agonists: equal sparing to full agonists

90
Q

Birds

A

Forebrain opioid R distribution in avian species likely differs most from mammals

Full MOR, mixed ag-antag: similar MAC reduction in multiple avian species - effect of KOR???

Inhalant-sparing effects of tramadol appear to be result of action at opioid R vs effects on serotonin, NE reuptake inhibition or alpha-adrenergic R

91
Q

Morphine

A

MOR agonist with KOR effects at higher doses

Mild to severe pain, increasing doses producing increasing analgesic effects

Widely used DT safety, efficacy, tolerability, cost-effectiveness
o Less lipophilic
 Octanal/water partition coefficient of 1.2
 Ideal opioid analgesic for epidural injection - provides sustained analgesia for 24hrs

92
Q

Morphine Administration

A

-Slow onset (5-15’), max effect at 30-45’ with HL 1hr
-PO, rectal poorly absorbed
-Near complete absorption via IM, SC ROA
-Also IA

93
Q

Metabolism of Morphine in Dogs

A

Primarily metabolized to morphine-3-glucuronide in dogs not active metabolite
* Very low concentrations of active metabolite morphine-6-glucuronide formed
* No accumulation after 7d of infusion

50% hepatic metabolism, 50% extrahepatic vs near complete hepatic metabolism of other opioids –> acceptable in p with hepatic dysfunction, dose adjustments needed

94
Q

Morphine - Patient Populations

A

-Avoid with head trauma: increased ICP with vomiting
-MCT - histamine release
-Can be admin to neonates as young as 2d old with minimal resp depression (more sensitive than adults

95
Q

Cats and Morphine

A

 Effective analgesic, well-tolerated
 CNS excitation at high doses: 5-20mg/kg
 Clinically useful doses: 0.1-0.25mg/kg, though 2-3mg/kg well-tolerated
 Unwanted behaviors similar to those in dogs
* Also: purring, kneading, rubbing, euphoria, mydriasis, marked affection

96
Q

Cats, Metabolism of Morphine

A

 Metabolism: rapid sulfate conjugation
 Terminal half-life ~1hr (similar to dogs)
 Volume of distribution smaller for cats, why clinically recommended doses lower for cats than dogs

97
Q

Morphine in Horses

A

 IA morphine: analgesia, anti-inflammatory effects in experimentally induced LPS synovitis models for up to 24hrs – 0.05mg/kg

Well tolerated

Higher doses: excitation, other effects

98
Q

Oxymorphone

A

o Synthetic opioid, full MOR agonist
o 10-15x more potent than morphine
o Effects similar to morphine, less nausea/vomiting when admin at equianalgesic doses, does not commonly produce histamine release when admin IV
o Duration of effect ~morphine

99
Q

Absorption, Metabolism, Excretion of Oxymorphone

A

o Routes: IM, CRI, SQ, IV
o PO bioavailability poor

Metabolism: conjugate formation
 Dogs: small amount excreted as other metabolites, intact drug

Similar effects to morphine in horses

Expensive, not currently available

100
Q

Hydromorphone

A

–Full MOR agonist: effects very similar to morphine at equianalgesic doses
o 8x potent than morphine, duration similar to morphine
o Minimal histamine release IV in dogs
o May be more likely to cause postoperative hyperthermia in cats vs other opioids
 Hyperthermia also noted following morph, bup, butor
o Cats: SQ = slow absorption, long lag time
 IM, IV > SQ

o Routes: IV, IM, SC, CRI
 Not effective orally DT poor bioavailability

101
Q

Fentanyl

A

o Full MOR agonist
o 100x more potent than morphine
o Short DOA IV, IM, SC
–30min to2hr depending on ROA
o Less nausea, vomiting –> predominantly antiemetic effect
 If admin results in ileus, nausea/vomiting may occur
o PK IV, SC reported: can admin as IV bolus, IV infusion, SC, IM
 Poor bioavail PO: not effective
o Mild pain on SC admin, if mixed with 8.4% sodium bicarbonate (1mL Nabicarb:20mL fentanyl) eliminates pain on inject
o Use by routes other than IV usually limited by lrg volume of inj needed for all but smallest p

102
Q

Fentanyl and context sensitive half life

A

Dramatically increases after 2-3 hours

103
Q

Transdermal Fentanyl Solution

A

–Approved for Use in Dogs Only
–Effective if applied 4h prior to sx with DOE of at least 4d after admin in postop orthopedic p
–Significant variability in absorption, DOE –> monitor for analgesia, SE
–Effects reversed by naloxone, single admin can improve p responsiveness
–Dose: 2.7mg/kg once

104
Q

Risk Minimization/Action Plan (RiskMAP) for TFS

A

developed for TFS
* Educational training for vets, staff, clients required prior to use
* Safety precautions for admin: gloves, protective glasses, lab coat to minimize exposure
* Restrain dogs for 2min after application, warm patch with gloved hands over p, site should not be disturbed for 5min
* Advise clients: no contact with site for 72h, isolate from children for 72h
* Absorption not the same in cats, product not approved for use in cats
* Dose in dogs: 2.7mg/kg once

105
Q

Transdermal Fentanyl Patch

A

 Used in: horses, sheep, dogs, cats
 Dogs: up to 24h may be required until effective drug concentrations reached –> longer than 4h lag time for TFS
 DOE: 24-72h after patch application, approx 48h efficacy
 Lag time to reach effective plasma concentrations shorter in cats, approx 12hr
* DOE 100h (~4d) after application
 Horses: effects with 6hr, 48hr duration
 Variability in absorption, effect of TFP substantial: some animals may have pain poorly controlled with patch, adverse effects

106
Q

Dosing of TFP

A

1-5mcg/kg/hr

107
Q

Placement Locations for TFP

A

Dogs: Thorax, inguinal area, metatarsal/carpal areas, base of tail, dorsal or lateral cervical area (no leashes)

Cats: Lateral thorax, inguinal area, metatarsal/carpal areas, base of tail, Avoid cervical area because patch tends to fall off

Horses: Neck, antebrachium

Pigs, Rabbits: Lateral thorax

Sheep, goats :Abdomen, cervical area

108
Q

Application of Transdermal Fentanyl Patch

A
  • Direct contact with heating pads will significantly increase fent absorption, risk toxicity
  • WEAR GLOVES
  • Clip area, no scrub – alcohol, sx scrubs may “de fat” skin, alter drug absorption
  • Hold patch in place on skin for 2-3’ – heat of hand allows adhesive to bind to skin, failure to perform will cause patch to fall off
  • Cover with light bandage, clear adhesive, label with dose/date
109
Q

Side Effects of Fent Patch

A

bradycardia, resp depression, urinary retention, constipation

110
Q

Methadone

A

–Full MOR - similar effects, potency (1.5x) morphine
–NMDA antag effects, more effective analgesic for chronic and refractory pain than morph
*Decreases development of tolerance
*Two optical isomers: D/L forms  both bind to, antag NMDA R

111
Q

PK of Methadone

A

Similar to morphine: IV bolus, SC, IM
 Repeated IM or SC admin may result in tissue damage, irritation

Low bioavail in most vet species (not case in humans): not effective when admin PO

112
Q

Metabolism of Methadone

A

o Metabolized by metabolic pathways inhibited by chloramphenicol (possibly other hepatic enzyme inhibitors) in dogs (potentially other species)
 Markedly prolonged effects can occur in animals tx concurrently with both drugs
o Exhibits synergistic effects when admin with some other MOR agonists eg morphine

113
Q

Levomethadone

A

Dose would be half racemic methadone

114
Q

DOA Methadone

A

dogs, cats 3-4hr; horses 4-8hr

OTM in horses, cats: well-tolerated

115
Q

Meperidine

A

–MOR, less potent than morphine (0.16x)
–Risk of serotonin syndrome: meperidine, normeperidine (metabolite) = serotonergic effects
 Do not admin with other serotonin drugs, MOA inhibitors
 Normeperidine: minor metabolite in dogs

116
Q

Meperidine ROA

A

o Used alone for IV regional anesthesia
o Routes: IV (bolus 2-3’, slower than other opioids), SC, IM
 PO bioavailability poor
o Short duration of action: 2-4hrs in dogs, cats

117
Q

Horses and Meperidine

A

hyperesthesia, m fasciculations, sweating adverse CV effects

118
Q

Hydrocodone

A

o Poor PO bioavailability in dogs, variably metabolized to hydromorphone which may produce opioid effects
o Long used as effective antitussive in dogs
o 0.2-0.5mg/kg PO Q8-12hrs anticipated to produce plasma drug concentrations consistent with analgesia
 Analgesic efficacy studies not reported
 No studies in cats
o Most formulations combination products with NSAIDS, acetaminophen/paracetamol or hamtropine
 No Tylenol in cats!!!

119
Q

Codeine

A

-MOR agonist
-Routes: IV, CRI, SC, IM
-Dogs: 4% PO bioavailability, negligible amount of morphine as a metabolite in dogs and cats
* Efficacy of codeine PO in dogs low at best
 Lrg amts codeine-6-glucuronide formed in dogs –> some opioid effect?
 Norcodeine (active metabolite) produced in cats

120
Q

Oxycodone

A

MOR
o Oral dosage forms, not commonly used in vet med DT low PO bioavailability in dogs, rapidly eliminated
o No data/evidence for use in cats

121
Q

Remifentanil

A

o Remi: fent derivative, metabolized by extrahepatic metabolism by nonspecific plasma and tissue esterases
 Very short elimination half-life, approx 6min
 Animals with impaired hepatic function still should have consistent and predictable elimination of the drug
 Must have CRI DT short HL –> clinical analgesic effects subside quickly after d/c, need additional opioids with more sustained DOA for pain control
 As efficacious as fentanyl, similar doss used for producing MAC reduction in dogs, cats –> ceiling effect in both species

122
Q

Sufentanil, alfentanil

A

Potency: alfent < fent < sufentan

123
Q

Buprenorphine

A

o MOR partial agonist, approximately 25x more potent than morph
o ROA: IV bolus, IV infusion, SC, IM, OTM (CATS ONLY), transdermal (CATS ONLY)
 SC, OTM less effective than IM or IV in perioperative setting
o Effects: similar to morphine, lower maximal efficacy
 Possibly more effective than morphine for chronic pain

Poor PO bioavailability

124
Q

Safety Profile of Buprenorphine

A

o Safety profile very large
 Even supratherapeutic doses produce minor adverse effects on CV, resp systems
 Produces less nausea, vomiting than morph
 May produce fewer adverse effects in cats vs morph

125
Q

Buprenorphine as an MOR Antagonism

A

antagonize effects of full MOR agonist, but degree of antagonism may not be complete
 Prior administration of bup believed to render subsequent admin of full MOR less effective/ineffective DT much greater affinity for opioid R
 Degree of interference affected by relative doses, timing btw doses, species, type of nociceptive environment
 R interference persists for duration of bup’s effect

126
Q

Duration of Effect of Buprenorphine

A

4-8h, up to 12h depending on dose, route, species, pain intensity, individual response to drug

127
Q

Buprenorphine OTM in Cats

A

 Oral pH in cats (8.0-9.0) closely approximates buprenorphine’s pKa (8.4) –> allows for good absorption of OTM buprenorphine
 Acidifying formulation may limit absorption, clinical efficacy

128
Q

OTM Buprenorphine in Dogs

A

 Reasonable uptake, produces antinociceptive effects
 Large volumes: cost prohibitive

129
Q

OTM Buprenorphine in Horses

A

not effective ROA

130
Q

Transdermal Buprenorphine Patches

A

 Dogs: available in some countries, slow absorption (Tmax range 48-60h), mean plasma levels low for first 36h with total duration of 72h
 Cats: better absorbed than dogs, 12-24h lag to target concentrations  persisted until ~96h even when patch removed at 72h

131
Q

Simbadol

A

 Once daily SC admin for up to 3d to control postop pain in cats
 Safety (up to 5x label dose), efficacy (OVH, castration, onychectomy) studies completed for drug approval processes
 Dosing: 0.24mg/kg SC once daily for up to 3d

132
Q

Simbadol - Hansford et al 2021 (VAA)

A

0.12mg/kg Simbadol (1.8mg/mL) = three compartment model with slow first order input, slow first order elimination
* SQ admin: high volume of distribution, rapid absorption followed by slower, delayed reabsorption
* Further study indicated to determine if obtained buprenorphine plasma concentrates correlate with clinical antinociception
* Bioavail >100% - possible experimental error

133
Q

Zobrium

A

transdermal solution for cats
 Effective for mild to moderate pain in cats, 10-30mcg/kg
 0.4mL for cats 1.3-3kg
 1mL for cats >3-7.5kg
 Contents: solvent, permeation enhancer, buprenorphine

134
Q

Application of Zobrium

A

 Application
* Transdermal onto cervical area, allow to dry for 30’
* Cage sign
* Wear PPE
* Recommended onset time 1-2hr prior to surgery, duration up to 4d

135
Q

Common AEs of Zobrium

A

during first 96hr
* During ax: increased hypoxemia, bradycardia, hypotension
* Postoperatively: increased hyperthermia (days 1-4), sedation (day 1)
* Dysphoria <3hr
* Mydriasis 10-12hr

136
Q

Avoid Zobrium In:

A
  • Debilitated, renal, hepatic, cardiac or respiratory disease
  • Pregnant/lactating, <4mo of age, outside weight ranges
  • Opioid hypersensitivity, intolerance to vehicle
  • Abnormal skin at application site
137
Q

Buprenorphine SR

A

 Compounded, unapproved formulation that is delivered in biodegradable matrix allowing for controlled release over 72h
 SC admin
 Demonstrated to provide analgesic effects up to 72h in post-surgical models (cats, rats) and thermal threshold models (mice, rats)
 No available data for use of compounded drug in dogs
 Dosing, 3mg/mL; cats 0.12mg/kg, dogs 0.12-0.27mg/kg SC
 Unclear if SR compounded formula results in dose-dependent release when surface area changes with volume injected

138
Q

Buprenorphine Extended Release

A

(1mg/mL) marketed as indexed, unapproved drug in USA for use in rats
* Dosing for rats: 1.0-1.5mg/kg SC
* Dosing for mice: 0.5-1.0mg/kg SC
* Provides pain control for 72h

139
Q

Antagonism of Buprenorphine

A

DT high affinity of bup at MOR, complete antagonism with opioid antag may be difficult

140
Q

Butorphanol

A

o MOR antag to partial MOR agonist, KOR agonist approved for use in dog (PO only), cat, horse
o ROA: IV bolus, CRI, SC, IM
o PO bioavail low, not reliably produce effective analgesia in dogs, cats despite ability to produce antitussive and some sedative effects PO

141
Q

Butorphanol Ceiling Effect

A

o Effect plateau (ceiling effect) occurs with torb: increasing doses do not produce increased analgesic effects
 Efficacy of torb = dose dependent, higher doses producing more clinically relevant analgesia but effect less than that with morphine
 Dose-response studies: duration of effect also dose-dependent with higher doses, up to peak effective dose, producing more prolonged effect in dogs, horses
* Not seen in cats

142
Q

Torb Use

A

o Can be used clinically to control mild to moderate pain if appropriate doses administered and relatively short DOA considered
 Not effective/adequate for severe pain
o More efficacious antitussive than morphine or codeine

143
Q

Torbutrol Tablets

A

FDA approved antitussive in dogs

144
Q

Other Uses of Torb

A

o Also used as antiemetic - used to prevent chemotherapy-induced emesis in dogs

145
Q

AEs Butorphanol

A

o AE similar to morphine, but occur with less severity
 Less dysphoria at clinical doses, +/- less CNS excitement vs full MOR in horses, cats
 Large doses, as with other opioids, likely to induce ataxia, excitement, dysphoria

146
Q

Butorphanol in Horses

A

o Admin of 0.1mg/kg to nonpainful horses produced increased locomotor activity, reduction in GI motility
 Total dose administered, presence/absence of pain likely contributes to development of adverse effects in horses
 Horses in particular: adverse CNS effects likely DT large peak plasma concentrations as CRIs assoc with fewer CNS effects
 May decrease GI motility  ileus, colic, GI effects also depended on portion of GIT studied
 Effective analgesic in both visceral pain models and for colic surgery, particularly when combined with an a2 R agonist

147
Q

Butorphanol, P-glycoprotein and MDR1

A

speculated to cause more profound, prolonged sedation in dogs with MDR1 gene mutation
 No well-designed studies performed
 Conservatively recommended that dogs heterozygous for MDR1 mutation should be given reduced dose (25% or less), homozygous dogs administered doses (30-50%) than that recommended for normal dogs

148
Q

Nalbuphine

A

o MOR antagonist, KOR agonist (similar to torb)
o Not currently a DEA scheduled drug, occasionally used in veterinary species
o Potency, PK, duration of effect of nalbuphine similar to morphine
 Analgesic effects expected to be less
o Efficacy likely to be sufficient for mild, +/- moderate pain
 Lacks extensive analgesic studies

149
Q

AE Nalbuphine

A

generally mild; panting, nausea, vomiting, CNS stimulation if admin rapidly IV or in higher doses to horses

150
Q

Dosing Nalbuphine

A

dogs, cats: 0.25-1mg/kg IM, SC, IV

151
Q

Pentazocine

A

o MOR antag, KOR ag rarely used in veterinary species
o Mild to moderate pain
o DOE 1-3h
 One study: analgesic effects as long as those reported for morphine (4h)
 Following ortho sx in dogs, morph, bup, and pentazocine all assessed as providing adequate analgesia

152
Q

Tramadol

A
  • Centrally acting analgesic that elicits effects through several different mechanisms
    o Humans: primary analgesic effect DT metabolism of tramadol to O-desmthyltramadol (M1) –> acts as full MOR agonist
     Additional effects can occur DT activity of both tramadol and M1 as serotonin and NE reuptake inhibitors
     Studies in humans: without formation of O-desmthyltramadol (M1), tramadol has little effect
153
Q

Metabolism of Tramadol in Horses, Dogs

A

do not make substantial amounts of O-desmthyltramadol (M1) –> analgesic effects weak at best
* Plasma concentrations following 7d continuous PO admin reduced to only 33% of those reached on day 1, further suggesting poor analgesic choice in dogs for chronic administration without p monitoring and dose adjustments
* 5-10mg/kg PO q8: provide tramadol concentrations within ranges achieved in humans

154
Q

Metabolism of Tramadol in Cats

A

Produce substantial amt of O-desmthyltramadol (M1)
* Likely an effective analgesic
* Bitter taste: routine PO admin difficult
* 1-2mg/kg PO q8-12h expected to produce O-desmthyltramadol (M1) plasma concentrations clinically effective in humans but control clinical trials not yet published

155
Q

Injectable Form of Tramadol

A

 Bioavailability higher, recommended dosing range 2-4mg/kg

156
Q

Tramadol and Serotonin Syndrome

A

RISK!

 Do not combine with: meperidine, tricyclic antidepressants (amitriptyline, clomipramine), or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine) DT risk of serotonin syndrome
 When severe, serotonin syndrome can present as fever, seizures, muscle tremors/fasciculations, hyperthermia, salivation, rarely death

157
Q

Toxicity of Tramadol in Dogs

A

restlessness, unsteady gait, reduced spontaneous activity, mydriasis, salivation, vomiting, tremors, convulsions, cyanosis, dyspnea

158
Q

Opioid Antagonists

A
  • Primary indication for admin: reversal of severe opioid-related adverse effects or reversing sedation after non-painful procedure
  • Safety margin of opioids = very large, life-threatening adverse effects, even with substantial overdoses = rare if supportive measures instituted
  • DOE of antagonists < agonists –> multiple doses may need to be admin
  • Admin to painful animal may result in adverse CV sequelae, presumably DT unmitigated pain from reversal of both exogenous and endogenous opioids
    o Admin to effect vs predetermined dose
159
Q

Nalbuphine, butorphanol as opioid R antagonists

A

reverse MOR effects but maintain some analgesia DT kappa agonism

160
Q

Naloxone

A

–primarily as MOR antag, but antagonistic effects also at KOR, DOR
–Can elicit convulsions DT GABA antag actions, not usually clinical consideration
–High doses: antagonize central effects of opioid agonists, may cause animal to experience acute pain, associated SNS stimulation with serious consequences = tachycardia, hypertension, pulmonary edema, cardiac arrhythmias

161
Q

Admin of Naloxone

A

o Best to admin by careful titration
 Multiple doses may be needed DT short DOA
 Dose range: 0.001-0.04mg/kg IV diluted, repeat q1-2min until desired effect achieved

162
Q

Other Effects of Naloxone

A

effects as Toll-like 4 (TLR4) R antag
 R appears to be stimulated by morph, resulting in allodynia at some doses
 Low-dose naloxone can block TLR4 allodynia assoc with morph admin in rodent models of peripheral nerve injury

163
Q

Naltrexone

A

o Opioid antag at MOR, DOR, KOR
o Often admin to reverse sedative effects of carfentanil in wildlife, zoo animals
 Would be effective in reversing opioids as well
o DOA 2x longer than naloxone
 Desirable in wildlife, zoo animals where repeat dosing not possible

164
Q

Dosing of Naltrexone with Carfentanil

A

100mg per 1mg carfentanil administered with typically one quarter of the dose administered IV, remainder admin subcutaneously

165
Q

Methylnaltrexone

A

o Quaternary derivative of naltrexone
o Only acts peripherally DT greater polarity, lower lipid solubility (excluded from CNS)
o Primary indication: controlling GI SE including ileus w/o affecting analgesic effects
 Some beneficial use in preventing GI motility problems assoc with opioid use
 Costly, further studies needed

166
Q

Low Dose Naltrexone, Naloxone

A

admin to humans prior to/after sx to reduce potential for SE (ie constipation, urine retention) without interfering with analgesia but SE not as common as in dogs and cats

Boards: Pharmacology (9 decks)

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