Opioids (Dr. E's Lecture) Flashcards Preview

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1
Q

What does the word “opioid” refer to?

A

all substances, natural and synthetic, that bind to opioid receptors and produce an agonist effect

2
Q

What are the naturally occurring opioids?

A

Morphine

3
Q

What are the Semisynthetic opioids?

A

Analogs of morphine

Heroin, Hydromorphone, Codeine

4
Q

What are the 4 subdivisions of the synthetic (exogenous) opioids?

A
  1. Morphinan derivatives
  2. Diphenyl derivatives
  3. Benzomorphans
  4. Phenylpiperidines
5
Q

What are the synthetic opioids of morphinan derivatives?

A

Levorphenol

Butorphenol

6
Q

What are the synthetic opioids of Diphenyl derivatives?

A

Methadone

7
Q

What are the synthetic opioids of Benzomorphans?

A

Phenazocine

Pentazocine

8
Q

What are the synthetic opioids of Phenylpiperidines?

A
Meperidine
Fentanyl
Alfentanil
Sufentanil
Remifentanil
9
Q

how does a partial agonist work?

A

regardless of the dose the drug cannot produce full mu receptor effects like morphine

10
Q

How do agonist/antagonists work?

A

agonist at one receptor, kappa and antagonist at mu reversing respiratory depression

11
Q

What are the 3 endogenous agonists?

A

Enkephalins, Endorphins, Dynorphins

12
Q

Opioid receptors are activating pain _____________ systems. which are?

A
  • Antinocioceptive

- Inhibiting excitatory Neurotransmitters (ie substance P)

13
Q

Where are mu receptors primarily?

A

in the brain and spinal cord

14
Q

Tell me all about the mu-1 receptor

A
  • Analgesia
  • Euphoria
  • Supraspinal (and spinal to lesser degree)
  • Miosis
  • Bradycardia (direct central vagal activity)
  • Urinary retention
  • All endogenous and synthetic agonists act on these receptors
15
Q

Tell me all about the mu-2 receptors

A
  • Hypoventilation
  • Physical dependence
  • Spinal analgesia (and some supraspinal)
  • Constipation (marked)
  • all endogenous and synthetic agonists act on these receptors
16
Q

tell me about the kappa receptor

A
  • Supraspinal and spinal analgesia
  • Dysphoria
  • Sedation
  • Miosis
  • Only DYNORPHINS act on these receptors
  • some agonist/antagonist such as Butorphenol also act there
17
Q

Tell me about the delta receptor

A
  • Supraspinal and spinal analgesia
  • Hypoventilation
  • Physical dependence
  • Constipation (minimal)
  • urinary retention
  • Only ENKEPHALINS act on these receptors
18
Q

In a nutshell, tell me all of the effects of Mu-1

A
  • supraspinal
  • bradycardia
  • euphoria
  • sedation, prolactin release
  • hypothermia
  • catalepsy
  • Indifference to environmental stimulus
  • miosis
  • urinary retention
  • low abuse potential
19
Q

In a nutshell, tell me all of the effects of Mu-2

A
  • spinal
  • bradycardia
  • resp. depression
  • euphoria
  • pruritis
  • dopamine turnover
  • possible growth hormone release
  • miosis
  • inhibition of peristalsis
  • n/v
  • urinary retention
  • Can cause physical dependence
20
Q

In a nutshell, tell me about the effects of Kappa

A
  • Supraspinal, spinal
  • possible resp. depression
  • sedative dysphoria
  • psychotomimetic reactions (hallucinations, delirium)
  • miosis
  • diuresis (inhibition of vasopressin release)
  • low abuse potential
21
Q

In a nutshell, tell me about the delta receptor

A
  • supraspinal, spinal
  • modulate mu receptor activity
  • Resp. depression
  • Urinary retention
  • pruritis
  • physical dependence
22
Q

What type os receptor is the opioid receptor?

A

G protein coupled- G-alpha-i and G-alpha-o

23
Q

What are the effects of an opioid binding to the receptor? (4)

A
  • (+) 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)
24
Q

What is the MOA of the opioids on the receptors?

A
  • 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)
25
Q

What are the pharmacokinetic features of the opioids regarding the onset of action?

A

-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

26
Q

Why does morphine have a slower onset of action?

A

because its % nonionized at physiologic pH is only 23%

27
Q

Why does Alfentanil have a very rapid onset of action?

A

b/c it has a high % unionized (89%) at pH 7.4

28
Q

What are the pharmacokinetic features of the opioids regarding the volume of distribution?

A

-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

29
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of MORPHINE?

A
pKa= 7.9
%nonionized= 23
Protein binding=35%
Vc=0.23 L/kg
Vd=2.8 L/kg
Clearance=15.5 ml/kg/min
E 1/2L= 1.7 - 3.3hr
o/2 partition coe= 1
30
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of MEPERIDINE?

A
pKa= 8.5
% nonionized= 7
protein binding= 70%
Vc= 0.6 l/kg
Vd=2.6 l/kg
Clearance=22.7 ml/kg/min
E1/2L= 3-5hrs
o/w partition coe= 21
31
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of METHADONE?

A
pKa= 9.3
% nonionized=NA
Protein binding=85%
Vc= 0.15 l/kg
Vd=3.4 l/kg
Clearance=1.6 ml/kg/min
E 1/2L= 23hr
o/w part/coe= 115
32
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of FENTANYL?

A
pKa= 8.4
% nonionized=8.5%
Protein binding= 84%
Vc= 0.85l/kg
Vd= 4L/kg
Clearance= 13ml/kg/min
E1/2 L= 2 - 4 hours
o/w partition/coe= 820
33
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of SUFENTANIL?

A
pKa= 8.0
% 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
34
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of ALFENTANIL?

A
pKa= 6.5
% 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
o/w= 130
35
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of REMIFENTANIL?

A
pKa= 7.26
non-ionized= 58% 
Protein binding= 93%
Vc= 0.1-0.2 l/kg
Vd=0.39 l/kg
Clearance=41 ml/kg/min
E 1/2 L= 0.1-0.3 hrs
o/w= NA
36
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of BUTORPHANOL?

A
pKa= 8.6
% 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
o/w= 140
37
Q

What is the pKa, %non-ionized, Protein binding(%), Vc, Vd, Clearance, E 1/2 life (hr), partition co-ef (o/w) of NALBUPHINE?

A
pKa= 8.71
nonionized= NA
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
o/w= NA
38
Q

What are the factors altering pharmacokinetics and dynamics of Opioids?

A
  • 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
  • Renal failure
  • Hepatic failure
39
Q

How should you dose opiates?

A

to IBW!

40
Q

Spinal analgesia vs. supraspinal analgesia

A

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

41
Q

What are the periop CNS effects of opioids?

A
  • Analgesia
  • Euphoria
  • Drowsiness/Sleep
  • Respiratory depression
  • miosis
  • Nausea- direct activity on CTZ
  • Does NOT produce amnesia or anesthesia
  • Modest decrease in ICP
  • Decrease CBF
  • Advantages of opioids in neuroanesthesia (hemodynamic and cerebrovascular instability)
42
Q

What are the periop CV effects of opioids?

A
  • No impairment in CV function
  • dose dependent bradycardia
  • Tachycardia with Meperidine
  • Myocardial depression with meperidine
  • Decrease CO and BP
  • Vasodilation
43
Q

What are the periop ventilatory effects?

A
  • dose dependent respiratory depression
  • decrease compliance in chest wall
  • constriction of pharyngeal and laryngeal muscles
  • Hypercarbia, Hypoxia
44
Q

What are the periop skeletal muscle effects?

A
  • 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
45
Q

What are the periop Renal/GI/Liver effects?

A
  • 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)
46
Q

What can morphine and demerol cause that no other opioids cause?

A

Histamine release!

47
Q

What are the nontherapeutic effects of opioids?

A
  • 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
48
Q

Tell me about respiratory depression and opioids?

A

-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!

49
Q

What are the factors increasing magnitude/duration of opioid induced Respiratory depression?

A
  • increased dose
  • intermittent bolus vs. cont. infusion
  • speed of injection
  • concurrent admin with other anesthetics~synergistic effects
  • decreased clearance
  • age
  • Alkalosis-increase unionized fraction increases brain penetration of drug
  • Secondary peaks in plasma levels from reuptake of opioid from muscle, fat, lung, and intestine
50
Q

What are the neuroaxial effects of opioids/ how is this happening?

A
  • 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
51
Q

What are the SE of neuraxial opioids?

A
  • Pruritis
  • N/v
  • Urinary retention
  • Ventilatory depression
52
Q

Give me facts about Hydromorphone.

A
  • 5x more potent than MSO4
  • Derivative of MSO4
  • Rapid elimination and redistribution
  • Q 4hr dosing needed
  • More sedation but less euphoria than MSO4
53
Q

What is an agonist/antagonist?

A
  • 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
54
Q

Give me the order of potencies from highest to lowest of the opioids.

A

Sufentanil > Remifentanil > Fentanyl > Alfentanil > Dilaudid > Nubain > MSO4 > Demerol

55
Q

What is the additional bolus dose of Sufentanil?

A

2.5 - 10 mcg

56
Q

What is the additional fentanyl bolus dose?

A

25 - 100 mcg

57
Q

What is the additional bolus dose of Alfentanil?

A

5 - 10 mcg/kg

58
Q

What is the additional bolus dose of Remifentanil?

A

0.1 - 1 mcg/kg

59
Q

What is the loading dose of Alfentanil?

A

25 - 100 mcg/kg

60
Q

What is the loading dose of Sufentanil?

A

0.25 - 2 mcg/kg

61
Q

What is the loading dose of Fentanyl?

A

4 - 20 mcg/kg

62
Q

What is the loading dose of Remifentanil?

A

1 -2 mcg/kg

63
Q

What is the maintenance infusion rate of Alfentanil?

A

0.5 -2 mck/kg/min

64
Q

What is the maintenance infusion rate of Sufentanil?

A

0.5 - 1.5 mcg/kg/hr

65
Q

What is the maintenance infusion rate of Fentanyl?

A

2 -10 mcg/kr/hr

66
Q

What is the maintenance infusion rate of Remifentanil?

A

0.1 - 1mcg/kg/min

67
Q

What is the dose of Meperidine iv?

A

50 - 100 mg IV

68
Q

What is the dose of Fentanyl?

A

1 -3 mcg/kg

69
Q

What is the dose of Remifentanil?

A

1 -2 mcg/kg

70
Q

What is the dose of Alfentanil?

A

10 -20 mcg/kg

71
Q

What is the dose of Sufentanil?

A

0.1 - 0.3 mcg/kg