opiods Flashcards
what are opiods
substances, natural and synthetic, that bind to opioid receptors and produce an agonist effect
Opiods can be divided in terms of their chemical structure as follows
Phenanthrenes
Benzylisoquinolines
Opiod classification are?
Naturally occuring
semisynthetic
synthetic.
NAturally occuring opiod is
Morphine
Semisynthetic opiod(Analogs of Morphine) is
Heroin
Hydromorphone
Codeine
Name the Synthetic Opiods classes and their examples
1.Morphinan derivatives Levorphenol, butorphenol(these are used for Withdrawals)
2.Diphenyl derivatives
Methadone
3.Benzomorphans
Phenazocine, Pentazocine
4.Phenylpiperidines
Meperidine, Fentanyl, Alfentanil, Sufentanil, Remifentanil
OPiod classification and E.g–according to their agonist Agonist Activity
Agonist.
Partial agonist
Ie: buprenorphine: regardless of the dose the cannot produce full mu receptor effects like morphine.
Mixed agonist/antagonist
Ie: nalbuphine where agonist at one receptor, kappa and antagonist at mu reversing resp depression
Antagonist: ie: naloxone
OPiate receptors are stimulated by what kind of substances.
Endogenous substances
3 endogenous substances identifies in 1973 are
enkephalins
endorphins
dynorphins
What is the mechanis,m of action of synthetic opiods
Antinociceptive, inhibiting excitatory neurotransmitters ie. substance P
synthetic opioids mimic action of endogenous opioids by binding to opioid receptors
name the 3 types of opiod receptors
mu, kappa, and delta
Mu subtype are ? and where are they found in the body
MU 1,2,3
Primarily found in the Brain and SPinal Cord
ALl enogenous and Exogenous agonist act on Mu receptors T/F?
T
Mu-1 Receptor characteristics
*Bradycardia
*Analgesia
*Supraspinal (to a lesser degree spinal) analgesia
Hypothermia
*Miosis
*Urinary retention
*Spinal
*Euphoria
Low Abuse potential
*All endogenous and synthetic opioid agonists act on these receptors
Fentanyl can act here
Mu-2 receptor characteristics
Constipation (marked)
Hypoventilation
Physical dependence
Spinal analgesia
All endogenous and exogenous agonists act on these receptors
fentanyl can act here
Kappa Receptor characteristics
Low Abuse potential Miosis Supraspinal spinal analgesia Sedation Dynophines only Dysphoria Diuresis
Only dynorphins act on these receptors
Delta receptor characteristics are ?
Constipation (minimal) Hypoventilation Physical dependence Supraspinal and spinal analgesia Urinary retention spinal Enkaphalines
Only enkephalins act on these receptors
Memorize slide 15
Do IT NOW
Whats the mech of Action for opiod
Net effect- Increased potassium conductance Calcium channel inactivation Both Decrease in neurotransmitter release
Activation of receptors either
- directly decreases neurotransmission or
- inhibits the release of excitatory neurotransmitters ie Substance P
state opiods Pharmacokinetic characteristics and state how it affects mechanism of crossing,binding and
Onset .
Weak bases
Only unionized & unbound opioids can diffuse from blood to target tissue thus…
Higher % unionized the higher diffusible fraction and the faster the onset
Higher % unbound the faster the onset
Increase dose of opiods if acidotic pt.
Decrease dose if alkalotic pt.
Slide 20 Memorise Pharmacokinetics of Opiod Agonist
Memorise
what are the Factors that can Alter Pharmacokinetics & dynamics of Opioids
Age
*Neonates show decrease rate of elimination d/t immature cyp P450
- Elderly show greater brain sensitivity to the drug
- Weight- dose based on lean body mass not actual weight in kg
- Renal failure
- Hepatic failure
Base on ideal body weight.
Reduce dose and extend time between doses for renal and liver failure
What is the difference in Mechanism of Action Between Spinal analgesic and Supraspinal analgesic
Spinal analgesic effects produced by receptor activation in spinal cord and dorsal root ganglian
Supraspinal analgesia produced by receptor activation in periaquaductal/periventricular gray matter in brain
Spinal in substantia gelatenosa: Direct stimulation of these receptors produces intense analgesia from inhibition of substance P release
Supraspinal in hypothalmus, amygdala. Believed that stimulation of these receptors reduce the transmission of nociceptive information from peripheral nerves into the spinal cord and up the neuraxis.
Perioperative cns Effects of Opiods
Analgesia Euphoria Drowsiness/sleep Respiratory depression Miosis Nausea- chemoreceptor trigger zone
Does not produce amnesia or anesthesia
Modest decrease in ICP
Decrease CBF
Advantages of opioids in neuro-anesthesia
Hemodynamic stability
Cerebrovascular stability
what are the Perioperative Cardiovascular Effects
of opiods
No impairment in CV function
Dose dependent bradycardia
Tachycardia with meperidine
Myocardial depression with meperidine
Decrease CO and BP
Vasodilation
Dose dependent brady from vagal stimulation
Decrease in CO and BP from vasodilation from histamine release with morphine and demerol. Venodilation decreases BP and CO with other opioids.
what are the Perioperative Ventilatory effects of opiods
Dose dependent respiratory depression
Decrease compliance in chest wall
Constriction of pharyngeal and laryngeal muscles
Hypercarbia, hypoxia
what are happens to resp rate and TV at low doses of opiods
Decrease RR with increased Vt (low doses)
What happens to RR and TV at High opiod doses
Decrease RR and Vt (high doses)
What happens to Ventilatory drive with opiods
Decrease hypoxic ventilatory drive
What happens to resp response curve with opiods
Ventilatory response curve reduced and shifted to right
Compare resp depression per onset and duration btwn Morphine and fentanyl
Peak onset of respiratory depression is slower for morphine than fentanyl
Respiratory depression produced by morphine lasts longer than fentanyl
what are the factors that increase the magnitude/Duration of opiod-induced resp Depression
Increased dose
Intermittent bolus vs. cont. infusion
Speed of injection
Concurrent admin with other anesthetics
Synergistic effects
Decreased clearance
Age(Baby and elderly reduce dose pls)
Dont give drugs fast.
Alkalosis- increase unionized fraction increases brain penetration of drug
Secondary peaks in plasma levels from reuptake of opioid from muscle, fat, lung and intestine
Opiod perioperative skeletal muscle effect
Skeletal muscle rigidity- Laryngeal muscles Inhibition of GABA Increase in dopamine Can make ventilation difficult or impossible
Opiods PerioperativeRenal/GI/Liver Effects
Increase peristaltic and tone of ureters
Urgency
Blocked catecholamine release and cortisol
Spasm of sphincter of Oddi with increase in biliary pressure
Constipation-decrease GI motility
Prolonged gastric emptying
What are causes and characteristics of Pruritic effects with opiod
Cause unknown
Histamine release most probable cause with some
Occurs primarily on face particularly nose
“fentanyl nose itch”
Opiods Neuraxial effects and what determines diffusion into CSF
Opioids placed in epidural space may undergo uptake into
fat
systemic absorption
diffusion into CSF
Penetration into CSF depends upon lipid solubility
More lipid soluble, quicker peak CSF concentration
What is the mechanism of Cephaladad migration
Drugs that do not penetrate csf or get into circulation are not lipid soluble.They travel Cephalad into the brain.
Cephalad movement of opioid in the CSF depends on lipid solubility
Highly lipid soluble will be limited in migration by uptake into the spinal cord ie. fentanyl
Whereas less soluble opioid will remain in CSF for transfer to cephalic location ie. morphine
Fentanyl penetrates csf and gets into circulation
Mso4 does not get absorbed at much..
Cephalad migration more pronounced with less lipollic drugs like morphine
What does vascular absorption into epidural space depend on per opiods
Vascular absorption of opioid from epidural space depends on lipid solubility
More lipid soluble, quicker peak concentrations of opioid will be in blood
…in fact…effects may be due to systemic absorption rather than CSF
What are the side effects of Neuraxial opiods
Pruritis-most common Nausea/vomiting Urinary retention Ventilatory depression More rapid with lipophilic agents Delayed with less lipophilic (6-12hrs)
Morphine characteristics and effects
Causes bradycardia via direct stimulation of vagus nerve
Inhibition of SA node as well
Metabolized by liver
Active metabolite: morphine-6-glucuronide (M6G) > potency than MSO4
Kidneys play a key role in the extrahepatic metabolism of morphine
Renal failure will have effects due to M6G
Meperidine characteristics and effects
Structurally similar to atropine, exhibits muscarinic effects
Also similar to local anesthetics-blocks Na Channels
Potent at alpha-2 receptors agonist effects
DOA 2-4 hours
Produces same amount of euphoria, sedation and analgesia as morphine
Normeperidine: active metabolite lasting 3 days, ½ as potent-CNS stim-szs reported
Used to treat postop shivering-kappa and alpha-2 receptors activity
1/10th as potent as morphine
Direct cardiac depressant
Alpha 2 agonist
Normeperidine last long time
Seizures
Hydromorphone characteristics and effects
5 X more potent than MSO4 Derivative of MSO4 Rapid elimination and redistribution Q 4 h dosing needed More sedation but less euphoria than MSO4
Fentanyl characteristics and effects
More lipid soluble than morphine with shorter DOA - 75% of initial dose undergoing first pass pulmonary uptake.
Rapid redistribution to inactive tissue sites as fat, skeletal m. and lungs.
Multiple IV doses or cont. infusion produces progressive saturation of inactive tissue.
Plasma concentration does not decrease rapidly and DOA is prolonged-(secondary to peak in plasma levels.
Fentanyl produces secondary peak in plasma levels. This is due to immobilization of sequestered drug form inactive tissue sites. Accumulates with multiple doses.
Clinically impression that fentayl shorter DOA than MSO4 but can have longer DOA if infusion or multiple doses.
Has large volume of distribution secondary to more lipid soluble than MSO4 and plasma conc. maintained by slow reuptake from inactive tissue sites
Fentanyl Use and clinical significance
Used as analgesic adjunct for surgery.
As adjuvant to blunt stimulation of incision, laryngoscopy.
As sole anesthetic in large doses due to hemodynamic stability.
100 times more potent than morphine.
Wide range of doses given 1-20 mcg/kg
Lozenges (fent lollipop) 5-20mcg/kg 45 minutes prior to induction
Transdermal patch 75-100mcg/hour peak 18-24 hours left on for 72 hours
Sufentanyl characteristics and effects
Analogue of fentanyl
Twice as lipid soluble as fentanyl
Highly protein bound
Undergoes first pass pulmonary uptake
Rapidly metabolized in liver
Weakly active metabolite desmethylsufentanil
10 times more potent than fentanyl.
1,000 times more potent than morphine
What are the Sufentanil Clinical Significance
Used as adjunct for surgery and induction.
Compared to morphine and fentanyl produces quicker induction earlier emergence and earlier extubation.
Used as infusion for outpatient surgery.
what are the characteristics and effcts of Alfentanil
Analogue of fentanyl.
90% exists in unionized state= very rapid CNS onset (1.4 minutes compared to fentanyl, 6.8 and sufentanil, 6.2 minutes).
Highly protein bound
Despite more intense protein binding, alfentanil’s diffusible fraction is higher than that of fentanyl.
1/5th as potent as fentanyl 10-20 times more potent than morphine.
what are the Alfentanil Clinical Significance
Rapid onset is useful for blunting hemodynamic response to noxious stimuli.
Rapid effect due to 90% of drug in non-ionized form.
Used as infusion for outpatient surgery.
what are the characteristics and effects of Remifentanil
Chemically r/t fentanyl but unique d/t ester linkage.
Metabolized by tissue/plasma esterases (not pseudocholinesterases).
Rapid onset and duration.
Very small Vd, minimal accumulation in tissues, even with infusion.
Potency similar to fentanyl, 100 times more potent than morphine.
Used for Egg retrieval
Remifentanil Clinical significance
Used to blunt noxious stimulus.
Infusions for interm/long surgeries where rapid recovery is desired.
Such as-neurosurgery, O/P surgery
What are the MU antagonist and Partial agonist effects
Where else can they have a partial agonist effect
Mu antagonist/partial agonist, and partial agonist at kappa.
Analgesia with limited ventilatory depression and low probability of dependence.
Side effects sim. to opioid agonists.
May cause dysphoria-kappa receptors stimulation.
pentazocine, butorpheno, nalbuphine,
dezocine
what are the charateristics and effects of Nubain
Analgesic response equal to morphine. Works at kappa and sigma receptors. Antagonizes opioid induced respiratory depression while maintaining analgesia. No adverse CV problems. Reverses spasm of sphincter of Oddi.
Butorphenol (stadol)
characteristics and effects
Acts as agonist at kappa and weak antagonist or partial agonist at mu.
5 times more potent than morphine for analgesia.
Nasal spray for migraines
NAloxone Characteristics and effects
Pure opioid antagonist
Blocks receptor sites and reverses respiratory depression and analgesia
Competitive antagonist at mu, kappa, and delta
Duration of action less than most opioids
Titratable
must give slowly
Onset 1-2 minutes, reversal is does dependent.
What are the effcts of opiod reversal using Naloxone
Not benign.
Reversal of opioid effect you get tachy, HTN, ventricular dysrhythmais, severe pain also pulm edema.
Pulmonary edema in patients with CV disease.
Can induce pulmonary edema in healthy patients due to catecholamine release.
Reversal may cause hydrostatic pulm edema
Increase in sympathetic effects
Drug doses Slide 56
Pls review
SRFA and SFRA
How does Opioid receptor activation work to decrease pain
The principal effect of opioid receptor activation is a decrease in neurotransmission.8 This decrease in neurotransmission occurs largely by presynaptic inhibition of neurotransmitter release (acetylcholine, dopamine, norepinephrine, substance P), although postsynaptic inhibition of evoked activity may also occur
increased potassium conductance (leading to hyperpolarization), calcium channel inactivation, or both, which produce an immediate decrease in neurotransmitter
release
What is the principal manifestation of opioid overdose
depression of ventilation manifesting as a slow breathing frequency, which may progress to apnea
Whats is the triad of opioid overdose
Miosis, hypoventilation, and coma should suggest overdose with an opioid.
Tolerance develops to analgesic, euphoric, sedative, depression of ventilation, and emetic effects of opioids but not to their effects on what?
Miosis and bowel Motility
What are the symptoms of withdrawal per opiods
yawning, diaphoresis, lacrimation, or coryza. Insomnia and restlessness are prominent. Abdominal cramps, nausea, vomiting, and diarrhea reach their peak in 72 hours and then decline over the next 7 to 10 days.
