Opoids & analgesia

Question 1

The clinical pharmacokinetics of alfentanil can be estimated by “4”. Compared to fentanyl:

Answer 1

alfentanil has 4x faster onset,
is 1/4th as potent,
and lasts about 1/4th the duration.

Question 2

Alfentanil, onset and offset?

Answer 2

has a pKa of 6.5 meaning that it is primarily non-ionized at physiologic pH (approximately 90%) which allows it to move across membranes very rapidly providing a very fast onset and offset with a bolus dose.

It has a significant protein binding and has a modest clearance.

It can be used as an infusion and has a context-sensitive half time that is better than fentanyl but worse than remifentanil.

It is metabolized by the CYP3A4 and 5 system in the liver which shows considerable variability amongst patients and thus response can be highly variable

Question 3

Alfentanil volume of distribution compared to fentanyl ?

Answer 3

Alfentanil has a smaller volume of distribution than fentanyl and morphine, owing to a lower Lipid solubility

Question 4

Opioid induced biliary colic can be relieved by

Answer 4

Atropine, papaverine, and nalaxone

The biliary smooth muscle contraction is prevented by efferent inner action which inhibited by activation of opioid receptors

Question 5

Opioids that exhibit some NMDA antagonist are

Answer 5

Methadone
Tramadol 
Propoxphene (not available in US)

Question 6

The safest analgesic opioids for ESRD patients is ..

Answer 6

Remifentanil is an ultra-short acting opioid analgesic that is metabolized independent of the kidneys by plasma esterases.

Additionally, fentanyl and methadone would be options in ESRD.

Fentanyl is relatively safe when used in patients with end stage renal disease (ESRD) because of its rapid redistribution, lack of metabolites, and unchanged free fraction. However, because remifentanil is metabolized independent of the liver and kidneys, it is considered ideal for patients with renal failure.

Methadone needs little adjustment in ESRD

Question 7

Why patients on hydrocodone will may need increase dosage if they recently started on SSRI

Answer 7

SSRI inhibits CYP(2D6) which reduces the activation of pro drugs like hydrocodone to hydromorphone

Question 8

Pro-drug opioids and there active metabolites

Answer 8

Codeine -> morphine
Hydrocodone -> hydromorphone
Oxycodone -> oxymorphone

Converted by the C-P450 system (specifically CYP2D6)

Question 9

Ketorolac effect on kidney?

Answer 9

Ketorolac can decrease GFR, especially when administered for greater than 5 days, via inhibition of afferent renal artery vasodilation

Question 10

Opioids can cause tachycardia are?

Answer 10

Morphine -> Tachycardia may occasionally be seen with morphine administration as histamine release can cause transient hypotension with reflexive tachycardia.

Meperidine -> because of its atropine-like drug effects and weak local anesthetic properties. At standard analgesic doses, meperidine is associated with hemodynamic stability. However, high doses cause hypotension and tachycardia. The hypotension is likely attributed to histamine release. In addition, high concentrations of meperidine decrease cardiac contractility, an effect resistant to naloxone. This is due to the local anesthetic effects of meperidine.

Question 11

Why it is recommended to remove fentanyl patches before surgery if patient on it?

Answer 11

Removal of fentanyl patches is recommended because physiologic changes that occur during an anesthetic alter drug release from the patch. The initial peripheral redistribution of blood flow during a general anesthetic increases skin perfusion (and transiently skin temperature), both of which are known to increase fentanyl uptake from the patch. Fentanyl patches are particularly sensitive to heat; delivery can more than double in the presence of heat. Care must be taken with active warming devices, since if placed on or very near a patch they can significantly increase fentanyl delivery and cause unintentional perioperative overdoses.

Generally, patches should be removed prior to an anesthetic and an equipotent intravenous infusion (e.g. morphine or fentanyl) be started and carefully titrated to effect. For minor or short surgeries, a patch may be left in place.

Question 12

Fentanyl patch onset? peak effect?

Answer 12

The median time to peak plasma fentanyl concentration is approximately 30 hours following placement of a transdermal fentanyl patch. Onset is approximately 6-8 hours after placement.

Question 13

Opioid likely to prolong the QT interval?

Answer 13

Methadone can produce or worsen a preexisting prolonged QT interval, which can lead to the lethal arrhythmia, torsades de pointes. This risk is increased with concurrent use of CYP3A4 inhibitors.

Question 14

The … of an opioid is a prime determinant of the onset and duration of action of the drug as it affects how easily the drug is able to cross cellular (lipid) membranes.

Which opioid has the lowest pKa and therefore has the highest fraction of nonionized drug at physiologic pH, makes it the most lipid soluble?

Answer 14

lipid solubility

In addition to a drug’s chemical composition, one of the most important physicochemical characteristics relating to lipid solubility is the fraction of the drug that is in a nonionized form. Ionized drugs are polar and do not readily pass through cell membranes whereas nonionized drugs are significantly more lipid soluble (often 103-104 times more soluble). The pKa of a drug refers to the pH at which it exists in equal parts of ionized and nonionized forms. An opioid with a pKa less than physiologic pH (~7.4) will have a much greater nonionized fraction whereas an opioid with a pKa >7.4 will have a greater ionized fraction.

Alfentanil has the lowest pKa of all of the listed drugs with a pKa of 6.5. At a physiologic pH of 7.4, approximately 89% of the drug will be in its nonionized form.

Question 15

How is it fentanyl has faster onset of action and shorter duration of action then morphine but yet it has longer elimination half-live than morphine? (The elimination half-lives ~3-6 hours for fentanyl and ~2-3 hours for morphine).

Answer 15

The duration of effect of opioids determined by lipid solubility. Morphine has a longer onset time and duration of action because it has a more difficult time crossing and then leaving the blood-brain (or blood-spinal cord) barrier due to a lower lipid solubility. By contrast, the more lipid-soluble fentanyl has a shorter onset and duration of action since it readily crosses, and leaves, the blood-brain barrier.

Question 16

MoA of Buprenorphine? and why its a great DOC for opioid addicts?

Answer 16

It is a partial μ-agonist and κ-antagonist with 25-40 times the potency of morphine.

There are ceiling effects, particularly for respiratory depression, at high doses (This offers a degree of safety against abuse potential and respiratory depression.).

Cessation of buprenorphine is typically associated with only mild withdrawal symptoms.

Question 17

Which epidural opioid associated with increased risk of NV?

Answer 17

Use of epidural hydrophilic opioids (e.g. morphine) is associated with a increased risk of nausea and vomiting and possibly pruritus compared to epidural use of lipophilic opioids (e.g. fentanyl) .

Question 18

The only opioid metabolized via hydrolysis by plasma esterases? and what its half-life?

Answer 18

Remifentanil.

Since remifentanil’s short duration of action is due to metabolism instead of redistribution, a 60 minute or 600 minute infusion will have the same elimination half-life of 10-20 minutes.

All other opioids are metabolized in the liver. Opioids are first biotransformed in the liver by phase I reactions involving the cytochrome P450 system (oxidative and reduction reactions) and then phase II reactions (conjugation). The metabolized and conjugated opioids are then renally excreted.

Question 19

The most potent opioid used ever?

Answer 19

Carfentanil
It is used in veterinary medicine and may require special protective gear to prevent absorption. It has been found as an additive in street drugs (e.g. heroin), resulting in overdose death. It is also suspected as being used in the 2002 Moscow theater hostage crisis. Since it is not used in humans, no metabolism data are available.

Question 20

Difference of opioid antagonist In half life.

Nalaxone
Naltrexone
Nalmefene

Answer 20

Nalaxone-> competitive inhibitor of all opioid receptors but has highest affinity to mu-receptors (t1/2 is one hour)

Naltrexone-> linger t1/2 with 8-12 hours. Only PO used for blocking effect of euphoric heroin.

Nalmefene-> t1/2 8.5 hours

Question 21

Nalaxone receptor affinity? Onset and duration? Side effects?

Answer 21

Naloxone has the greatest affinity for the µ-receptor but also has some activity at the δ- and κ-receptors.

Onset of action for intravenous naloxone is 1-2 minutes and duration of action is 30-60 minutes.

Side effects include increased heart rate, increased blood pressure, and potentially pulmonary edema. These effects are mediated by an increase in resultant pain and sympathetic stimulation. Hypothermic patients receiving naloxone for opioid reversal can experience a two or three-fold increase in oxygen consumption with the resultant increase in cardiac output and stress on the cardiovascular system.

Question 22

Morphine improves coronary perfusion through

Answer 22

a reduction in preload and a reduction in end-diastolic pressures (EDP) in the ventricles.

Question 23

prodrug opioid?

Answer 23

Codeine is an opiate prodrug whose effects are primarily dependent on metabolism to morphine, which requires the cytochrome P450 enzyme CYP2D6.

Question 24

Why Nalbuphine does not lead to increasing respiratory depression above 30 mg in adults?

Answer 24

Nalbuphine is a mu antagonist and kappa opioid receptor agonist which exhibits a plateau effect for respiratory depression. (plateau or ceiling effect).

Question 25

At what ketamine dose will be responsive to reversal naloxone ?

Answer 25

At higher doses (full-anesthetic or induction doses, 1-2 mg/kg IV), proportionally more of the analgesic properties of ketamine are due to opioid receptor binding. This dose-dependent difference is demonstrated by response to naloxone administration. Naloxone does not reverse analgesia produced by low ketamine doses, but can attenuate analgesia from higher doses.

Question 26

Chronic opioid therapy has a profound effect on the adrenal and gonadal axes leading to …

Answer 26

increased prolactin levels, and decreased testosterone, estrogen, cortisol, luteinizing hormone, and follicular stimulating hormone (FSH).

Question 27

Opioid that is optimal for neuropathic pain treatment?

Answer 27

Opioid use for treating chronic pain is controversial. Methadone, however, is effective for chronic pain since in addition to its opioid analgesic effects, it has NMDA and serotonin reuptake antagonistic properties. The NMDA receptor antagonism also makes methadone effective for neuropathic pain.