Flashcards in Opioids (Dr. E's Lecture) Deck (71):
What does the word "opioid" refer to?
all substances, natural and synthetic, that bind to opioid receptors and produce an agonist effect
What are the naturally occurring opioids?
What are the Semisynthetic opioids?
Analogs of morphine
Heroin, Hydromorphone, Codeine
What are the 4 subdivisions of the synthetic (exogenous) opioids?
1. Morphinan derivatives
2. Diphenyl derivatives
What are the synthetic opioids of morphinan derivatives?
What are the synthetic opioids of Diphenyl derivatives?
What are the synthetic opioids of Benzomorphans?
What are the synthetic opioids of Phenylpiperidines?
how does a partial agonist work?
regardless of the dose the drug cannot produce full mu receptor effects like morphine
How do agonist/antagonists work?
agonist at one receptor, kappa and antagonist at mu reversing respiratory depression
What are the 3 endogenous agonists?
Enkephalins, Endorphins, Dynorphins
Opioid receptors are activating pain _____________ systems. which are?
-Inhibiting excitatory Neurotransmitters (ie substance P)
Where are mu receptors primarily?
in the brain and spinal cord
Tell me all about the mu-1 receptor
-Supraspinal (and spinal to lesser degree)
-Bradycardia (direct central vagal activity)
-All endogenous and synthetic agonists act on these receptors
Tell me all about the mu-2 receptors
-Spinal analgesia (and some supraspinal)
-all endogenous and synthetic agonists act on these receptors
tell me about the kappa receptor
-Supraspinal and spinal analgesia
-Only DYNORPHINS act on these receptors
-some agonist/antagonist such as Butorphenol also act there
Tell me about the delta receptor
-Supraspinal and spinal analgesia
-Only ENKEPHALINS act on these receptors
In a nutshell, tell me all of the effects of Mu-1
-sedation, prolactin release
-Indifference to environmental stimulus
-low abuse potential
In a nutshell, tell me all of the effects of Mu-2
-possible growth hormone release
-inhibition of peristalsis
-Can cause physical dependence
In a nutshell, tell me about the effects of Kappa
-possible resp. depression
-psychotomimetic reactions (hallucinations, delirium)
-diuresis (inhibition of vasopressin release)
-low abuse potential
In a nutshell, tell me about the delta receptor
-modulate mu receptor activity
What type os receptor is the opioid receptor?
G protein coupled- G-alpha-i and G-alpha-o
What are the effects of an opioid binding to the receptor? (4)
-(+) K channel inward rectifier (increases outward K flow to hyperpolarize cell)
-(-) decreases conversion of adenyl cyclase to cAMP
-(+) MAPK cascade: 1. gene expression and 2. Phospholipase A2 (production of prostaglandins and leukotrienes)
-(-) Voltage-dependent Ca channel (N-type)->suppression of neurotransmitter release (sub. P)
What is the MOA of the opioids on the receptors?
-opioid receptors exist on the peripheral ends of primary afferent neurons
-activation of receptors either
1. directly decreases neurotransmission or
2. inhibits the release of excitatory neurotransmitters (ie. Substance P)
What are the pharmacokinetic features of the opioids regarding the onset of action?
-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
Why does morphine have a slower onset of action?
because its % nonionized at physiologic pH is only 23%
Why does Alfentanil have a very rapid onset of action?
b/c it has a high % unionized (89%) at pH 7.4
What are the pharmacokinetic features of the opioids regarding the volume of distribution?
-Vd= dose of drug at time 0/ plasma [ ] b4 elimination occurs
-Larger Vd equates to a longer duration of action
-Vd related to lipid solubilty (1st, most important parameter), protein binding (2nd), (and 3rd molecular size/structure)
-higher lipid solubility=Larger Vd, longer DOA!
~more lipid soluble the more potent these drugs are
-Redistribution and fast termination of effect b/c of drug redistributing to other sites and is gone from the effect sites
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of MORPHINE?
E 1/2L= 1.7 - 3.3hr
o/2 partition coe= 1
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of MEPERIDINE?
% nonionized= 7
protein binding= 70%
Vc= 0.6 l/kg
o/w partition coe= 21
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of METHADONE?
Vc= 0.15 l/kg
E 1/2L= 23hr
o/w part/coe= 115
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of FENTANYL?
Protein binding= 84%
E1/2 L= 2 - 4 hours
o/w partition/coe= 820
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of SUFENTANIL?
% nonionized= 20
Protein binding= 93%
Vc= 0.1 l/kg
Vd= 2 L/kg
Clearance= 12 ml/kg/min
E 1/2 L= 2-3 hours
o/w partition/coe= 1750
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of ALFENTANIL?
% non-ionized= 89
Protein binding= 92
Vc= 0.12 l/kg
Vd= 0.6 L/kg
Clearance= 5 ml/kg/min
E 1/2 L= 1-2 hours
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of REMIFENTANIL?
Protein binding= 93%
Vc= 0.1-0.2 l/kg
E 1/2 L= 0.1-0.3 hrs
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of BUTORPHANOL?
% nonionized= 17
protein binding= 80%
Vc= 0.1 l/kg
Vd= 5 L/kg
Clearance= 38.6 ml/kg/min
E 1/2 L=2.65 hrs
What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of NALBUPHINE?
protein binding= NA
Vc= 0.45 l/kg
Vd= 4.8 l/kg
Clearance= 23.1 ml/kg/min
E 1/2 L= 3.7 hrs
What are the factors altering pharmacokinetics and dynamics of Opioids?
-AGE (neonates show a decrease rate of elimination d/t immature CYP450; Elderly show greater brain sensitivity to the drug)
-Weight- dose base on IBW
How should you dose opiates?
Spinal analgesia vs. supraspinal analgesia
Spinal analgesic effects produced by receptor activation in spinal cord and dorsal root ganglion
Supraspinal analgesia produced by receptor activation in periaquaductal/periventricular gray matter in the brain
What are the periop CNS effects of opioids?
-Nausea- direct activity on CTZ
-Does NOT produce amnesia or anesthesia
-Modest decrease in ICP
-Advantages of opioids in neuroanesthesia (hemodynamic and cerebrovascular instability)
What are the periop CV effects of opioids?
-No impairment in CV function
-dose dependent bradycardia
-Tachycardia with Meperidine
-Myocardial depression with meperidine
-Decrease CO and BP
What are the periop ventilatory effects?
-dose dependent respiratory depression
-decrease compliance in chest wall
-constriction of pharyngeal and laryngeal muscles
What are the periop skeletal muscle effects?
-skeletal muscle rigidity in chest, abdomen, jaw, and extremeties
-can make ventilation difficult or impossible
-high a/w pressures from increase intrathoracic pressures
-Glottic rigidity and glottic closure have been reported
What are the periop Renal/GI/Liver effects?
-increase UO- ADH release BLOCKED! but with urinary retention
-Blocked catecholamine release and cortisol
-Spasm of sphincter of Oddi with increase in biliary pressure
-Constipation- decrease GI motility
-Prolonged gastric emptying (can exacerbate N/V)
What can morphine and demerol cause that no other opioids cause?
What are the nontherapeutic effects of opioids?
-Decrease RR with increased Vt (low doses)
-Decrease RR and Vt (high doses)
-Decrease hypoxic ventilatory drive
-Ventilatory response curve reduced and shifted to right
Tell me about respiratory depression and opioids?
-Peak onset of respiratory depression is slower for morphine than Fentanyl (see it like 10-15 min to peak)
-Respiratory depression produced by morphine lasts longer than Fentanyl
Morphine peaks slower and lasts longer!
What are the factors increasing magnitude/duration of opioid induced Respiratory depression?
-intermittent bolus vs. cont. infusion
-speed of injection
-concurrent admin with other anesthetics~synergistic effects
-Alkalosis-increase unionized fraction increases brain penetration of drug
-Secondary peaks in plasma levels from reuptake of opioid from muscle, fat, lung, and intestine
What are the neuroaxial effects of opioids/ how is this happening?
-opioids given epidural or spinal have different onset, duration, but side effects as same drug given IV
-opioids placed in epidural space may undergo uptake into fat, systemic absorption or diffusion into CSF
-penetration into CSF depends upon lipid solubility
-more lipid soluble, quicker peak CSF concentration
-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
-Vascular absoprtion of opioid from epidural space depends on lipid solubility
-more lipid soluble, quicker peak concentrations of opioid will be in blood
What are the SE of neuraxial opioids?
Give me facts about Hydromorphone.
- 5x more potent than MSO4
-Derivative of MSO4
-Rapid elimination and redistribution
-Q 4hr dosing needed
-More sedation but less euphoria than MSO4
What is an agonist/antagonist?
-Mu antagonist and full or partial agonist at kappa
-bind to kappa receptors to produce agonist actions
-analgesia with limited ventilatory depression and low probability of dependence
-se similar to opioid agonists
-may cause dysphoria-kappa receptors stimulation
Give me the order of potencies from highest to lowest of the opioids.
Sufentanil > Remifentanil > Fentanyl > Alfentanil > Dilaudid > Nubain > MSO4 > Demerol
What is the additional bolus dose of Sufentanil?
2.5 - 10 mcg
What is the additional fentanyl bolus dose?
25 - 100 mcg
What is the additional bolus dose of Alfentanil?
5 - 10 mcg/kg
What is the additional bolus dose of Remifentanil?
0.1 - 1 mcg/kg
What is the loading dose of Alfentanil?
25 - 100 mcg/kg
What is the loading dose of Sufentanil?
0.25 - 2 mcg/kg
What is the loading dose of Fentanyl?
4 - 20 mcg/kg
What is the loading dose of Remifentanil?
1 -2 mcg/kg
What is the maintenance infusion rate of Alfentanil?
0.5 -2 mck/kg/min
What is the maintenance infusion rate of Sufentanil?
0.5 - 1.5 mcg/kg/hr
What is the maintenance infusion rate of Fentanyl?
2 -10 mcg/kr/hr
What is the maintenance infusion rate of Remifentanil?
0.1 - 1mcg/kg/min
What is the dose of Meperidine iv?
50 - 100 mg IV
What is the dose of Fentanyl?
1 -3 mcg/kg
What is the dose of Remifentanil?
1 -2 mcg/kg
What is the dose of Alfentanil?
10 -20 mcg/kg