OPIOID Agonist /Anta Flashcards
Opioid, Greek word for
Juice
Narcotic
Greek work for Stupor
Term opioid include
opioid agonists
opioid antagonists
opioid agonist-antagonists.
Opioid- unique
Provide analgesia without loss of touch, proprioception or consciousness
Antagonists
Binds to a receptors site and blocks and agonists from binding
One opioid associated with loss of touch
lidocaine
Semisynthetic opioids
- From modified Morphine molecule
- Codeine
- Heroin
- Hydromorphone
- Oxycodone
Hydropmorphone is _____times more potent than morphine
EIGHT
Synthetic Opioids
Fentanyl Sufentanil Alfentanil Remifentanil Methadone Meperidine Tramadol
Mechanism of action
• Opioids in ionized state bind strongly at the
anionic opioid receptor site
• Only levorotary forms of the opioid exhibit
agonist activity
Mechanism of action (read)
Opioids- agonists at stereospecific opioid receptors
Presynaptic and post synaptic sites (inhibit
neurotransmitters)
In CNS-
Principally the brainstem and spinal cord
In peripheral tissues
Opioid receptors on primary afferent neurons
These opioid receptors on primary afferent neurons are
activated by 3 endogenous peptide opioid receptor ligands:
Enkephalins
Endorphins
Dynorphins
Opioids mimic these endogenous ligands & bind to opioid
receptor and modulate pain
Mechanism of opioid Principle effect
Principle effect of opioid receptor activation is ⇩
neurotransmission
Decrease largely due to presynaptic inhibition of
Ca++ channels= ⇩ neurotransmitter release
Acetylcholine
Dopamine
Norepinephrine
Substance P
Serotonin
Postsynaptic inhibition of evoked activity may
also occur
Presynaptic opioid receptors
G coupled protein receptor
• Leads to ⇩intracellular cAMP concentration, ⇩ Ca+
+ ion influx and inhibits the release of excitatory neurotransmitters (Glutamate,substance P)
Mu 1 receptors
- Mu1 – produces analgesia (Supraspinal & spinal)
- Euphoria
- Low abuse potential
- Miosis
- Urinary retention
- Hypothermia
Agonists of Mu 1
Endorphins
Morphine
Synthetic opioids
Antagonists of Mu 1
Naloxone
• Mu2 –responsible for
- Analgesia (spinal)
- Hypoventilation
- physical dependence (addiction)
- Constipation- marked
Mu2 Agonists
Endorphins
Morphine
synthetic Opioids
Mu2 antagonists
Naloxone
Receptors
Mu, Delta and Kappa
• All 3 classes couple to G proteins and
subsequently inhibit adenyl cyclase, ⇩
conductance of voltage gated calcium channels or
open potassium channels
• All of these effects = ⇩ neuronal activity
• Mu or morphine receptors are principally
responsible for supra spinal and spinal analgesia
POSTSYNAPTIC OPIOID RECEPTORS
• G protein coupled receptor- all opioid receptors
• Antagonize Adenyl cyclase
• ⇩ cAMP
⇧ K channels
resting membrane potential is more negative
Makes it more difficult for the neuron to propagate a
signal
Kappa receptors responsible for ?
Kappa Receptors • Analgesia (supraspinal & spinal) • Sedation • Dysphoria • Low abuse potential • Miosis • Diuresis Antagonist Naloxone
Kappa agonists
Agonists
Dynorphins- cause inhibition of neurotransmitter release via type N calcium channels which results in analgesia
• Less respiratory depression, but may cause diuresis and dysphoria
• High intensity painful stimulation may be resistant to the analgesic
effect of kappa receptors
• Opioid agonist-antagonists often act principally on kappa receptors
Kappa antagonist
Naloxone
• Delta Receptors
Analgesia (supraspinal & spinal) • Antidepressant effects • Physical dependence • Ventilatory depression • Constipation- minimal • Urinary retention • May modulate the activity of the Mu receptor
Delta agonists
- Responds to the endogenous ligand enkephalin
* No Delta selective agents, but several are being researched
Neuraxial Opioids
Epidural or subarachnoid/spinal/intrathecal
space
• Opioid receptors (principally Mu) are in
substantia gelatinosa of the spinal cord
- Opioids given neuraxial, rather than IV or
regional local anesthetics injection, are
not associated with _______
sympathetic nervous system denervation
skeletal muscle weakness
Loss of proprioception
Epidural dose is __________times ____dose
Analgesia is dose related and specific for visceral rather than somatic pain is 5-10 times subarachnoid dose
⇩ MAC for volatile anesthetics
Clinicians must evaluate patient for contraindications to epidural injection
Duramorph ______– epidural
Duramorph_______—spinal
3-5 mg
0.1-0.3mg
Know Coagulation status
To prevent epidural hematomas
Epidural administration
• <1mm from spinal cord, separated by 2 meninges
• Dura and Arachnoid
•
• Opioids placed in the epidural space undergo
uptake into the epidural fat, systemic absorption (epidural
veins), or diffusion across the Dura (mu receptors on
spinal cord)into the CSF
What penetrates the Dura mater faster?
Highly lipid soluble and low molecular weight
penetrate Dura faster
CSF concentration of sufentanyl (1000xx more lipid soluble)peaks in about ____, fentanyl in about ______
Morphine only _____cross the dura to the CSF
If drugs is poorly lipid soluble
• CSF concentration of Sufentanil peaks in about 6
minutes, fentanyl in about 20
• Morphine peaks in 1-4 hours in CSF
• Morphine only 3% crosses the Dura to the CSF
• Poorly lipid soluble will have slower onset and longer
duration of action
LUMBAR INJECTION
Most common location for epidural is in lumbar
spine
• Epidural space largest in the lumbar region
• Spine is most perpendicular in lumbar region
• Spinal cord ends at L-1
LUMBAR EPIDURAL
Most common location for epidural is in lumbar
spine
• Epidural space largest in the lumbar region
• Spine is most perpendicular in lumbar region
• Spinal cord ends at L-1
NEURAXIAL OPIOIDS
After epidural injection fentanyl blood levels peak
________
_________ peaks faster
• Morphine blood levels peak in _________
After epidural injection fentanyl blood levels peak
in 5-10 minutes
• Sufentanil peaks faster
• Morphine blood levels peak in 10-15 minutes
• Epidural administration of morphine, fentanyl and
sufenta produce opioid blood levels similar to
blood levels by IM injection of equal dose
• Epinephrine with opioid will decrease systemic
absorption but won’t decrease diffusion of
Morphine into the CSF
• Epidural administration of morphine, fentanyl and
sufenta produce opioid blood levels similar to
blood levels by IM injection of equal dose
• Epinephrine with opioid will
decrease systemic absorption but won’t decrease diffusion of Morphine into the CSF
Subarachnoid (intrathecal) lipid soluble opioids
fentanyl
• Rapidly absorbed in spinal cord
Subarachnoid (intrathecal) morphine + epinephrine
- Increase the block density
- Decreases intravascular absorption
- Prolongs duration of action of lipid soluble local anesthetics
- doesn’t alter duration of highly protein bound LA
Subarachnoid (intrathecal) water soluble (morphine)
- Doesn’t get absorbed intravascular
- Floats in CSF –movement to brainstem
- May cause delayed apnea
• Side effects of neuraxial ( Epidural and Spinal)
opioids
- Pruritus
- Nausea/vomiting
- Urinary retention
- Depression of ventilation
- Sedation
- CNS excitation
- Viral reactivation
- Neonatal morbidity
- Sexual, ocular, GI, and Thermoregulation dysfunction
- Water retention
PRURITUS
MAY GIVE BUPRENEX< (WILL TREAT PRURITIS AND NOT REVERSE ANALGESIA EFFECT)
• Side effects are caused by the opioid in the CSF
or systemic circulation
• Side effects are
dose dependent
Pruritus
• Nausea/vomiting
• Urinary retention
• Respiratory depression
Most common SE with neuroaxial opioids
Pruritus-
usually localized-face, neck, upper thorax
Usually within a few hours of injection
Likely R/T cephalad migration in CSF
Can relieve with opioid antagonist (BUPRENEX)
URINARY RETENTION
Urinary Retention
• Most common with young males, R/T interaction
of opioid receptors in the sacral spinal cord
• This interaction promotes inhibition of sacral
parasympathetic nervous system outflow and
causes detrusor muscle relaxation and ↑ in max
bladder capacity -> bladder retention
• Morphine can cause marked
detrusor relaxation in 15 min and can last up to 16 hours
• Most serious side effect OF OPIOIDS
OCCURS IN _____PATIENTS
Respiratory Depression • Occurs in about 1% of patients • May occur within minutes or hours later Early depression occurs within 2 hours Most likely due to systemic absorption
Respiratory Depression
Late depression occurs > ______ after injection
due to ___________
All reports of clinically significant delayed depression is due to morphine
No respiratory depression after 24 hours
Late depression occurs > 2 hours after injection
due to cephalad migration of opioid in CSF and
interaction with receptors in the ventral medulla
All reports of clinically significant delayed depression is due to morphine
No respiratory depression after 24 hours
Increases risk of Respiratory depression
• Respiratory depression
• Increased risk with concomitant use of IV opioid or
sedative
• Coughing may affect movement of CSF and ↑risk of
depression of ventilation
Ventilatory depression risk is increased with:
High opioid use low lipid solubility of opioids Concomitant IV opioid/ sedative use, lack of opioid tolerance, advanced age, Increased intrathoracic pressure
Diagnosis of respiratory depression
What does it decrease
All leads to ______eventual _______
• Decreasing RR • Decreasing MV • Causes decreased SpO2 reading - Increased somnolence (hypercarbia) - May see increased Blood pressure - All leads to apnea - Eventual cardiopulmonary arrest
Opioids Side effects sedation
Sedation
• Dose related with all opioids especially sufentanil
• Mental status changes i.e. paranoid psychosis, catatonia,
hallucinations can occur- reversible with Naloxone
Opioids side effects CNS excitation
Most likely due to cephalad migration in CSF->
interaction with non-opioid receptors in brainstem and
basal ganglia-> block glycine or GABA inhibition
Tonic skeletal muscle rigidity is rare with neuraxial
Opioids side effects: Viral Reactivation
Link between OB patients and reactivation of herpes
virus with epidural morphine use
Miscellaneous side effects
• PRESERVATIVE FREE OPIOIDS (and Local Anesthetics) ONLY
- Sustained erection
- Miosis, nystagmus and vertigo- (after morphine)
- Delayed gastric emptying
- Inhibiting shivering- may cause ↓ temp
- Oliguria, water retention leading to peripheral edema
- Spinal cord damage
Duramorph is good because it is
PRESERVATIVE FREE
MORPHINE Intro Produces? Better for what type of pain? Works best if\_\_\_\_\_\_ In absence of pain may cause \_\_\_\_\_\_\_
Opioid that all other opioids are compared to
• Produces- analgesia, euphoria, sedation and ↓
concentration
• Morphine is better for dull pain than sharp
• Works best if given prior to painful stimulus
• In absence of pain may cause dysphoria rather than
euphoria
• Effective against visceral as well as skeletal muscles and
joints
• Water soluble molecule
• Morphine peak effect
• _________– rapid onset
• IM for peak effect
Oral morphine-
IV-15-30 minutes
45-90 minutes
absorption from GI tract is limited
For morphine, plasma does not correlate with
Clinical effect.
Morphine Pharmacokinetics
• Only a small percentage gains access into the
CFS (<0.1%)
• Reasons of poor penetration into the CNS include:
poor lipid solubility, high ionization at
physiological pH, protein binding, rapid
conjugation with glucuronic acid
• Hyperventilation will make the blood more
alkaline and ↑ non-ionized fraction and ↑ passage
into the CNS
• Respiratory acidosis (hypoventilation) will do what?
decrease non ionized portion but may lead to
higher CNS concentrations due to ↑ cerebral blood
flow due to the ↑ carbon dioxide levels
Morphine accumulates
accumulates rapidly in the kidneys, liver
and skeletal muscles and unlike fentanyl does not
undergo significant first pass effect into the lungs
Principle pathway is
Conjugation with glucuronic acid
in hepatic and extra hepatic sites, mainly the kidneys
• Principle metabolites of Morphine
• Morphine -3-glucuronide (75-80%)Pharmacologically
inactive
• Morphine-6-glucuronide (5-10%)-pharmacologically activemore potent and longer duration of action than morphine
MAO inhibitors and Morphine
Inhibit formation of glucuronide metabolites
Leads to exaggerated effects(morphine doesn’t break down)
ELIMINATION ON MORPHINE
• Elimination of morphine glucuronide may be
impaired in renal failure, leading to
accumulation of metabolites and unexpected
respiratory depression with small doses
Formation of glucuronide conjugates may be
impaired by
MAOI’s, which may cause exaggerated effects of morphine
Morphine elimination half time
________in plasma concentration of morphine after _______Is principally due to ________
Amount in urine?
Decrease in plasma concentration of morphine
after initial distribution is principally due to
metabolism
• Only a small amount of unchanged drug is
excreted in urine
• Plasma concentrations are higher in the elderly
• Clearance of morphine is
↓ in the first 4 days of life making neonates more sensitive to respiratory depression
Morphine in women vs men
Greater analgesic potency and slower speed of
onset in women
• Higher postoperative opioid consumption in men
CV and morphine
•
high doses (1mg/kg IV) to supine
normovolemic patient is unlikely to cause a direct
myocardial depression or hypotension
Morphine and position changes
what is it caused by?
Change from supine to standing may cause hypotension and syncope
• Caused by impairment of compensatory sympathetic
nervous system response
• Decrease in vasomotor tone leads to decreased preload,
cardiac output and blood pressure
- CV
* ↓ BP can occur due to morphine induced______or _________
bradycardia or histamine release
Bradycardia with morphine due to
↑ activity over vagal nerves, stimulation of vagal nuclei in the medulla, also depressant effect on SA node and slowed conduction through AV node
• Opioids given prior to induction _______heart rate during exposure to volatile anesthetics (VA) with/without surgical stimuli
• Histamine release and hypotension can be minimized by
limiting the rate of administration to_____
may slow
5mg/minute IV,
maintain pt supine and well hydrated
Morphine \_\_\_\_\_\_\_\_\_\_\_\_produces substantial histamine release and a ↓ in BP & SVR • Response varies among patients •\_\_\_\_\_\_\_\_\_\_\_\_\_minutes does not cause histamine release, neither does
1mg/kg over 10 minutes
Fentanyl 50mcg/kg over 10
sufentanil
Give ______ AND*** _______to prevent
changes in BP and SVR ? Does it prevent histamine release?
Pretreatment with H1, H2 blockers does not
prevent histamine release but does
CV and morphine
• Morphine does not sensitize the heart
to catecholamines or predispose to dysrhythmias as long as hypercarbia or
arterial hypoxemia doesn’t result from ventilatory
depression
Rise CO2
is a stiumulus to breathe
Patient with narcotics does not respond
All opioids cause a dose dependent depression of
ventilation
• Primarily due to_________
• Depression of ventilation characterized
- agonist effect at Mu 2 receptor leading to a direct depressant effects on brainstem ventilation centers
- by ↓ responsiveness to CO2.
• Opioids depress cough by effects on the
medullary cough centers, codeine greatest effect
Ventilation and morphine
3 things increase
Dose dependent depression of ciliary activity • ⇧ airway resistance • ⇧ bronchial smooth muscle contraction • ⇧ Histamine release
Hypoventilation =
⇧ CBF & ⇧ ICP
Opioids in absence of ___________decrease ____and _____
Caution in head injury pt due to effects on
wakefulness, producing miosis, ventilation depression
and associated __________
Opioids in absence of hypoventilation ⇩ CBF ⇩ICP
Caution in head injury pt due to effects on
wakefulness, producing miosis, ventilation depression
and associated ↑ in ICP, also BBB integrity could be
impaired resulting in ↑ sensitivity to opioids
Rapid IV administration of opioids can cause
• Risk greatest with _____then ___then
skeletal muscle rigidity, especially the abdomen and thoracic area- leading to difficult ventilation
Fentanyl then remifentanil, then morphine
Sufentanil may cause ______-and ________
Laryngospasm & ⇧ difficulty to ventilate
• Opioids can cause
Equal analgesic doses of opioids ↑ bile duct pressure above pre drug levels • Fentanyl 99% • Morphine 53% • Meperidine 61%
spasm of biliary smooth muscle,
resulting in ↑ intrabiliary pressure associated with
epigastric distress and biliary colic
a. During cholangiogram spasm may be misdiagnosed as a stone- __________may reverse opioid induced biliary smooth muscle spasm
b) Naloxone may _________
Glucagon (2mg IV)
b)also reverse spasm but will also reverse
analgesia
Opioids can produce spasms of the___________
• Delayed passage =
• Morphine was once used to treat diarrhea
GI tract, causing constipation, biliary colic & delayed
gastric emptying
↑ water absorption = ↑ constipation
• Morphine ____peristaltic contraction _____tone of pyloric sphincter, ileocecal valve and _____sphincter
↓ propulsive peristaltic contraction and ↑ tone of pyloric sphincter, ileocecal valve and anal sphincter
What causes opioids induced N/V/D? (most important)
Opioid induced N/V are caused by direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle
Morphine may also cause N/V by
↑ GI secretions and delaying passage of intestinal contents
Morphine can cause urinary retention by
↑the tone and peristaltic activity of the ureter
• Giving an anticholinergic can reverse these effects
• Urinary retention
Morphine and skin
• Morphine causes cutaneous blood vessels to dilate,
causing skin of the face, neck and upper chest to become flushed and warm
• Changes in cutaneous circulation are in part caused by
histamine release
• Histamine is responsible for_____and_____ at the injection site
urticaria and erythema
Chronic opioid use by the mom may result
in physical dependence (intrauterine addiction)
Administration of naloxone may cause life
threatening
neonatal abstinence syndrome
IMPORTANT: Drugs interactions with some opiods? what exaggerates ventilatory depression?
Ventilatory depression effects of some opioids may be exaggerated by: • amphetamines • phenothiazine • MAOI • TCA’s
Cross tolerance develops between all opioids
• Tolerance can occur without physical dependence but
the reverse does not seem to occur
• Tolerance usually takes _____with analgesia
doses of Morphine
• Repeated use causes compulsive desire
(psychological) and continuous need (physiologic) for
drug
2-3 weeks
• Tolerance develops to_____, ______, ________, _____ and ______ but not to effects on______and _______
analgesia, euphoric, sedative,
depression of ventilation and emetic effects
Miosis and constipation
WITHDRAWAL of opioids
• Initial symptoms include (6)
and Later symptoms include
• Yawning, diaphoresis, lacrimation, or coryza, insomnia
and restlessness
Abdominal cramps, nausea, vomiting and
diarrhea reach their peak in 72 hours and decline
over the next 7-10 days
Abrupt withdrawal of opioids leads to_______
Prevention?
increases in sympathetic nervous system
Prevention
Clonidine diminishes transmission in sympathetic pathways in the CNS and may help prevent withdrawal symptoms
What is the Principal manifestation of OVERDOSE?
_________ which may lead to apnea
• Pupils are______ and ______ unless severe
hypoxemia is present which results in mydriasis
Skeletal muscles are may occur
• Pulmonary edema commonly occurs
depression of ventilation
Slow breathing frequency
symmetric and miotic
flaccid and airway obstruction
• Triad of ______. _______ and _______should
suggest opioid overdose
Miosis, hypoventilation and coma
Treatment of Overdose Treatment
- Ventilation?
• Opioid antagonist
• If no response after______- question diagnosis
• Continuous infusion for adults __________
Caution- opioid antagonist to treat opioid
overdose may cause
Mechanical ventilation
Naloxone 0.4-2mg every 2-3 minutes as needed
10mg
Adults up to 0.8mg/kg/hr
acute withdrawal
MEPERIDINE is a ______Agonist at
• Synthetic opioid agonist at mu and kappa opioid
receptors
• Structurally similar to atropine and produces a
mild atropine like antispasmodic effect
What are analogues of Meperidine?
• Fentanyl, Sufentanil, alfentanil and remifentanil
• Principle pharmacologic effects of Meperidine resemble
morphine
Meperidine pharmacokinetics
1/10 as potent as morphine
Duration of action 2-4 hours, which is shorter
then morphine
In equal doses causes as much
sedation, euphoria, depression of ventilation, nausea and
vomiting as morphine
Meperidine Metabolism
Hepatic metabolism is extensive, 90% metabolized to normeperidine (demethylation) and meperidinic acid (hydrolysis)
• More acidic urine can speed elimination
• Decreased renal function-⇧ risk for seizure
Primary route of elimination of Meperidine? what is dependent on ?
Urine excretion ; pH
If urinary pH <5 than up to
25%of meperidine is eliminated unchanged in the urine
_______can lead to accumulation of normeperidine–> increase risk of ______
Decrease renal function : Seizures
Only narcotic to cause Mydriasis
Demerol (because of anticholinergic side effect)
Metabolite Normeperidine what is the half time
Elimination Half time of 15 hours
• Pt with renal failure half life may be >35 hoursc
Normeperidine is ______as potent as meperidine as an
analgesi
½
Normeperidine causes CNS stimulation-
toxicity manifests as myoclonus and seizures- most likely during prolonged meperidine administration as during PCA, especially with renal function
Meperidine half time
3-5 hours
Meperidine protein binding and elderly
PB 60%
• Elderly have decreased protein binding and
increased plasma concentrations of free drug and
increased sensitivity to the opioid
Meperidine may be effective in suppressing post
operative
shivering that may cause increases in metabolic o2 consumption
IV meperidine causes a massive
release of histamine
therefore is usually given IM
• Anti-shivering effects of meperidine may be due
to
stimulation of kappa receptors (10% of drugs activity)
Meperidine is a potentt
• Not useful to treat diarrhea, no antitussive effects
alpha 2 agonist-this might contribute to the anti-shivering effect
• Clonidine is more effective at
reducing post op shivering
Side effects of meperidine
Orthostatic Hypotension
Hypotension _______, ______and ________ than with morphine
more frequent and more profound, more ventilatory depression
• Meperidine given to pts on antidepressants
(MAOI, fluoxetine) may cause
Serotonin syndrome aka serotonin toxicity
Serotonin Syndrome Symptoms are-
Autonomic instability with htn, tachycardia, diaphoresis, hyperthermia,
confusion, agitation, hyperreflexia
• Severe cases- coma seizures, coagulopathy and
metabolic acidosis may develop
Fentanyl Structurally related to______________
meperidine
100 times more potent than morphine
75% of initial fentanyl dose undergoes_______
• Effect site equilibration time is
first pass pulmonary uptake- limits the initial amount of
drug that reaches the systemic circulation
6.4 minutes
• If multiple Iv doses or continuous infusion are
given inactive sites
become saturated
FENTANYL METABOLISM
• Metabolized by N-demethylation, producing
norfentanyl, which is structurally related to normeperidine
• <10% fentanyl is excreted unchanged in urine
Norfentanyl is excreted in the_____and
detectable for
urine ; 72 hours after a single IV dose
• Fentanyl metabolites–_________pharmacological
action
minimal
• Elimination half time of Fentanyl is _____than morphine and reflects a _________due to__________
Greater; larger Vd due to greater lipid solubility
Fentanyl in elderly
↑ elimination half time is D/T a ↓ in clearance, due to ↓ hepatic blood flow, ↓ albumin production and ↓ hepatic enzyme activity
FENTANYL CONTEXT SENSITIVE HALF
TIME
As duration of continuous infusion ↑ past 2 hours, the
context-sensitive half time of fentanyl becomes greater
then sufentanil
All opioids show a __________with initiation of CPB
• ↓ in plasma concentration is greater with fentanyl d/t a
↓ in plasma concentration; significant portion of the drug will adhere to the cardiopulmonary bypass circuit
• The ↓ is least with opioids with
a large Vd (alfentanil, sufentanil) and have a more stable
plasma concentration
Fentanyl Clinical Uses
Analgesia
Low dose 1-2 mcg/kg IV for analgesia
• 2-20 mcg/kg IV as an adjunct to inhaled anesthetics to blunt tachycardia and htn associated with laryngoscopy or sudden change in level of surgical stimulation
**Hallmark of fentanyl
STABLE HEMODYNAMICS profile
Lack of Histamine release
Lack myocardial depression effects
High dose of fentanyl
• High dose 50-150mcg/kg have been used alone
to produce surgical anesthesia
• CV effects of fentanyl
• No histamine release-no dilation of venous vessels to
cause hypotension
• Carotid sinus baroreceptor reflex control of heart rate is
depressed by fentanyl
• Bradycardia more prominent than with morphine
Fentanyl and muscle
CHEST WALL RIGIDITY
Difficult to differentiate myoclonus from muscle rigidity.
Analgesic doses potentiates the effects of ________and _______the dose requirements of _______
Analgesic doses potentiate the effects of midazolam and decrease the dose requirements of propofol
• Marked synergism with opioid- benzodiazepine
combination with respect to hypnosis and
depression of ventilation
SUFENTANIL- SUFENTA
Structurally related to fentanyl
• 5-10 times more potent than fentanyl
• Greater affinity for opioid receptors than fentanyl
• Dose that produces seizures is 1000 times the
analgesic dose
Fentanyl vs sufenta on post op analgesia
• Less ventilatory depression than Fentanyl with
longer postoperative analgesia
SUFENTANIL PHARMACOKINETICS
Vd, Elimination half time
• Elimination half time is between fentanyl and alfentanil
• Vd and elimination half-time are ↑ in obese pt- r/t
highly lipid soluble
• <1% unchanged in urine
Effect site equillibration is
6.2 min similar to fentanyl
Protein binding of Sufentanyl
- Highly protein bound (92.5%) =low Vd
- Undergoes significant first pass pulmonary effect
- Undergoes significant liver metabolism
• Termination of action of Sufentanyl
• Context sensitive half time
• Lower than alfentanil for infusions up to 8 hours
• Sufentanil has a larger Vd than alfentanil
• May have a more favorable recovery profile than
alfentanil for longer procedures
redistribution
• Can accumulate over time
Clinical uses of Sufentanyl
More rapid induction, earlier emergence and earlier
extubation when compared to higher doses of fentanyl or
morphine
• Causes chest wall rigidity, N/V and bradycardia similar to
fentany
Alfentanyl: ALFENTA \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ •\_\_\_\_\_\_\_\_\_\_potent than fentanyl • 1/3 the duration of action of fentanyl • onset of action\_\_\_\_\_\_\_\_
Analogue of fentanyl
1/5-1/10 less
Rapid 1.4 min
For alfentanyl: Rapid effect site equilibration due
to low pKa90% of drug is non-ionized at physiologic pH
Pharmacokinetics of Alfentanyl
• Vd is 4-6 times smaller then fentanyl- lower lipid
solubility, higher protein binding than fentanyl
• Metabolized in liver by cytochrome P-450 3A
• Hepatic clearance of 96% from plasma in 60 min
• Clinical uses of Alfentanyl
• Rapid onset of action is useful when noxious
stimuli is acute but transient (laryngoscopy, retro
bulbar block)
• Useful for outpatient procedures
• Less N/V than fentanyl and sufentanil
• General anesthesia adjunct 5-15 mcg/kg IV q
5-20 minutes
• Caution with Parkinson’s pt in using ______ may cause
Alfentanyl; acute dystonia
Remifentanyl Selective_______________
• Similar potency to fentanyl
• 15-20 times more potent than alfentanil
• Effect site equilibration similar to alfentanil
• Only opioid not metabolized in the liver
• Not affected by renal failure
mu receptor opioid agonist
Only narcotic not eliminated by the liver
REMIFENTANYL (ALTIVA)
REMIFENTANYL Structurally unique- metabolism
ester linkage makes drug susceptible to hydrolysis by nonspecific plasma and tissue esterase’s
• Unique metabolism causes the following
characteristics of REMIFENTANYL
• Brevity of action
Rapid onset and short duration of action = precise and titratable effect
Non-cumulative effects
Rapid recovery after discontinuation of infusion
Pharmacokinetics of REMIFENTANYL
Onset, clearance, offset
• Very potent
Small Vd
Rapid onset (similar to alfentanil)
Reaches steady state in 10 minutes of infusion start
Rapid clearance (3L/min)
Low variability compared to other IV anesthetics relationship between infusion rate and opioid
concentration is less variable
Offset of Remifentanyl
Complete offset in 6-8 minutes after stopping infusion
Clinical use of REMIFENTANYL
Case where profound analgesic effect is desired
transiently (retro bulbar block)
• Long procedures when a quick recovery is desirable
• Short duration of action may be a disadvantage for
surgery with considerable post op pain
• Care must be taken not to stop infusion accidentally
• N/V, ventilation depression, ↓ HR and BP may occur
Anesthesia induction with remifentanyl?
• Anesthesia induced with 1mcg/kg IV over 60-90 seconds
or with gradual initiation of infusion at 0.5-1.0 mcg/kg IV
for about 10 minutes, before a hypnotic prior to tracheal
intubation
OPIOID AGONIST USED POST OP
Half life _________
Mg dose = _______of aspirin
120mg IM
Codeine- similar to morphine Half life 3-3.5 hours • Effective anti-tussive at 15 mg dose • 60mg oral = to 650 mg of aspirin • 120 mg IM codeine = to 10mg morphine • Limited first pass hepatic effect due to methyl group for hydroxyl group- accounts for efficacy of oral codeine
Remifentanyl IV not recommended because
Significant histamine release
Hypotension
Codeine converts to
Morphine
Derivative of morphine
Remifentanyl
- 8 times more potent then morphine
- Shorter duration of action than morphine
- Used similar to morphine
- Side effects similar to morphine
TRAMADOL Centrally acting analgesic with a moderate affinity for the ______, ______ and________
• 5-10 times less potent analgesic than morphine
mu receptor, weak kappa and delta opioid receptor affinity
Tramadol actions
• Enhances function of spinal descending inhibitory
pathways by inhibition of neuronal reuptake of
nor epinephrine and serotonin and presynaptic
stimulation of serotonin release
• Dose 3mg/kg to treat moderate to severe pain
• Seizures reported with epilepsy and drugs that
lower the seizure threshold-antidepressants
Opiods agonist-antagonists
Bind to mu receptor and produce limited response
(partial agonist) or no effect (competitive
antagonist)•
Partial agonist at kappa and delta receptors
• Side effects- similar to opioid agonist- may cause
dysphoria
OPIOD AGONIST-ANTATONIST adv and disadv.
• Advantages- analgesia with low risk of depressed
ventilation, and physical dependence
• Disadvantage- has a ceiling effect
• Antagonist effects can attenuate
efficacy of subsequent doses of opioid agonist
Clinical use of OPIOID AGONIST and ANTAGONIST
• Used independently to produce limited level of analgesia
• Ceiling effect on analgesia and respiratory depression, ↑
dose has less profound effect
• Can use in combo with other agents- nitrous oxide,
benzodiazepines
• These combinations are NOT sufficient for surgical
anesthesia
Clinical use
•
Partially reverse an agonist
• Reverse unwanted effect of opioid without reversing all the analgesic properties
• Opioid agonist-antagonist will not remove all the analgesic properties
• Can result in onset of sudden pain which can evoke a severe sympathetic response leading to ↑ BP and HR
- Butorphanol-Stadol
* Nalbuphine-Nubain
OPIOD ANTAGONIST Naloxone- Narcan
• High affinity for opioid receptor which results in
displacement of agonist from receptor
• Antagonist does not activate receptor but
prevents an agonist from binding to it
Uses of Narcan
•
Treat opioid respiratory depression present in the
postoperative period
• Treat opioid respiratory depression in neonate
due to maternal administration of opioid
• Treat deliberate opioid overdose
• Treat side effects of itching associated with
neuraxial opioids- agonist-antagonist Nalbuphine
works well for this also
Dose of Narcan
Dose 1-4mcg/kg IV produces prompt reversal of
opioid induced analgesia and ventilation
depression
• Short duration of action so supplemental doses
may be needed or continuous infusion
• Metabolized in liver (high first pass effect)
Side effects of Narcan
what is related to dose and rte?
Administration over?
• N/V appear to be related to rate and dose given
• Administration over 2-3 minutes = ↓ N/V
• Fortunately vomiting occurs simultaneously with
awakening which allows for pt to protect their
airway
