Opioids and NSAIDs

Question 1

How do opioids work/where do they work?

Answer 1

Opioid Agonists act on both Pre-synaptic and Post-synaptic GPCR in brainstem, SC, and brain

Pre-synaptic = decrease Adenyl Cyclase and decrease VG Ca2+ channel conductance and therefore decrease vesicular release of Ach, DA, NE, and Substance P (primarily from primary afferent neurons like C/Delta/Alpha fibers going into SC)

Post-synaptic = Increased K+ outflow and hyperpolarization of neurons to prevent signal propogation

Question 2

What are the unwanted effects from Mu receptor activation? Delta? Kappa?

Answer 2

Mu: Respiratory depression, GI (constipation from less Ach release pre-synaptically), Euphoria, Sedation, Dependence

Delta - analgesia and that’s it!

Kappa - Constipation, Miosis (antagonized with Atropine) and Psychotomimesis, sedation

Question 3

How do opioids cause respiratory depression?

Answer 3

Decrease CO2 responsiveness in Brainstem ventilation center and so CO2 can go high but blunted reflex to breath it off….however maintain hypoxic drive

Question 4

What Opioids act on the Medullary Cough center?

Answer 4

Dextromethorphane and Codeine

Question 5

Why can rapid injections/bolus of some opioids cause muscle rigidity?

Answer 5

Especially Fentanyl rapid bolus

*Rigidity of chest muscle wall makes it hard to ventilate*

Causes decreased DA release from Corpus Striatum and Substantia Nigra causing PArkinsonian-like rigidity

Question 6

What are the CV effects of opioids?

Answer 6

Myocardium generally unaffected but can cause Hypotension several ways:

1) decrease HR bc decrease sympathetic tone response from pain and increasing parasympathetic
2) Bradycardia from Direct Depression effect at SA node from inhibition of NE release
3) HISTAMINE RELEASE causing vasodilation and loose preload as blood pools in periphery (2 that cause histamine release)

Question 7

What are the 2 Opioids that cause Histamine release?

Answer 7

Morphine and Meperidine

Question 8

What are the GI effects of Opioid agonists?

Answer 8

Decreased Ach release leads to:

• decreased peristalsis and increased spincter tone
• delayed emptying causes increased water resporption leading to constipation –> Give with stool softeners
• Gall Bladder - Increase biliary pressure and colicky pain when eat

- N/V = acts on DA receptors in CTZ 4th ventricle

Question 9

What are the GU effects of opioid agonists?

Answer 9

Increased tone of ureters but much more increased tone of bladder sphincter leading to Urinary Retention

Question 10

What are the important pharmacokinetics of morhine? Metabolism of Morphine?

Answer 10

Onset 15-30 min and Lasts about 4 hours

**Delayd BBB Penetrance bc poorly lipid soluble and very ionized and so Analgesic and Ventilatory effects don’t correlate with plasma levels* *

Histamine Release!

Metab - conjugated with glucuronic acid (10% bile and 90% urine) 2 metabolites: M3G (inactive) and M6G (Active - acts on Mu receptors and can increase negative side effects)

CAUTION in RENAL FAIILURE PATIENTS - can have increased ventilatory depression from M6G not being cleared

Question 11

Important things to know about Meperidine? Uses? Metab?

Answer 11

1/10 x potent as morphine BUT has local anesthetic features from Amide/Ester

Atropine derivative and so has anti-muscarinic effects: Tachycardia!!! and Mydriasis (abused by doctors a lot bc of dilated pupils)

Cuases **Histamine Release! **And large doses decrease Myocardial Contractility

Metabolized in Liver to Nor-Meperidine which can cause Myoclonus and seizures and so BAD for RENAL FAILURE patients – seizures

Lasts 2-4 hrs and used in low doses for Post-Op Shivering (kappa rec)

Question 12

Fentanyl - unique features and when to use?

Answer 12

MORE potent than Morphine

Rapid onset and short duration

No active Metabolites

HEMODYNAMICALLY STABLE - no changes in myocardium or histamine!

Question 13

Compare and contrast Fentanyl derivatives - name them, actions/uses, and anything else about them

Answer 13

1) Sulfentanil (MORE potent than fentanyl!):

-Rapid onset but longer duration and used as infusion for smoother wakeup emergence and easy extubation….Ex. Exploratory Laparotomy

2) Alfentanyl (1/5-1/10x potent as Fentanyl):

• FAST onset bc 90% ionized and Fast offset
• cleared by Liver CYP3A so no problem in Renal Failure
• good for short procedures bc no lingering sedation (ex. placing nerve block in leg)

3) Remifentanyl (equally potent fentanyl):

• FAST onset and offset (1 min on and off in 6 min)
• Easy to titrate and predict, fast offset so minimal respiratory depression
• good to use if want to move out of OR fast or for Neuro-monitoring to wake pt up
• **UNIQUE ESTER LINKAGE and so hydrolyzed by plasma esterase and GOOD FOR LIVER AND KIDNEY PATIENTS!

Question 14

Methadone - what’s unique about it and how is it really used?

Answer 14

Mu Agonist AND NMDA Antagonist

LONG ACTING 16-20 hours but takes a while to reach steady state and there’s prolonged activation after repetitive doses

2 Clearance Times: first 4-5 hours for analgesic and second 20 hours for other neg side effects therefore dosing every 5 days!

CAN OD TOO FAST AND CAUSE RESP ARREST

**Used for Chronic Pain and in Pts with Addicion **

Question 15

Hydromorphone - uses?

Answer 15

5x potent as morphine

Safer for patients in Renal Failure bc no active metabolites! So used more often then morphine

Used in both the OR and for Chronic Pain and in ICU

Question 16

What opioid agonists are bad to use in Renal Failure?

Liver Failure?

GOOD to use in Renal??

Answer 16

Renal Problems - do NOT use:

Morphine - M6G can cause ventil depression (hydromorphone safer)

Meperidine - Normeperidine can cause seizures

Methadone - already has long clearance times on its own

Liver Problems - do NOT use: **Alfentanyl **

SAFE for Renal Problems:

ALFENTANYL - Liver clearance CYP3A

REMIFENTANIL - ESTER Hydrolase clearance - **no problem in Kidney or Liver failure **

HYDROMORPHONE - safer than Morphine

Fentanyl, Sulfentanil = OK nc no active metabolites

Question 17

What are the Mixed Opioid Agonist/Antagonists and when do you use them?

Answer 17

Butorphanol, Nalbuphine, Buprenorphine

Bind to Mu receptors and Delta/Kappa as partial agonist and competitive agonists

ex. Agonist at my and antagonist at delta/kappa

Good for analgesia withi minimal side effects like resp depression and low potential for dependence

Use for pts who can’t tolerate the hard shit….pussys

Question 18

What are the opioid Antagonists? How are they used? What happens wiht them?

Answer 18

Naloxone - used for OD and Naltrexone -used for chronic use

Have high affinity for opioid receptor and displace agonist rapidly to reverse effects and precipitate withdrawal

*CV stimulation and Increased SNS activity with increased perception of pain*

- pts wake up in pain, tachypnic and tachycardic

Naloxone has short duration - 30-45 min and so need to watch pts closely to make sure that they dont Re-Narconize and start having neg side effects again

Metabolised in **LIVER **

Question 19

What is codeine?

Answer 19

Converted to morphine in the liver by CYP2D6

just methylated morphine

Question 20

What prostaglandin is the main meidator of pain?

What prostaglandin is Vasoprotective and good for your heart?

Answer 20

PGE2

PGI2

Question 21

How do NSAIDs work? What are they used for?

Answer 21

Block COX enzymes that convert AA to prostaglandins

COX1 - gastric mucosa protection, Renal parenchyma, platelets

COX2 - pain and inflammation

NSAIDS decrease peripheral nociceptors response to pain, cause anti-inflammation, anti-pyretic (less IL1 and IL6 and PG in hypothalamus)

Good for Mild to moderate pain, skeletal muscle inflammation, HA/Toochache, and post-op pain management to decrease opioid use

Question 22

What are the bad effects of NSAIDs?

Answer 22

Stop platelet aggregation (no thromboxane A2 from COX1)

Stop blood flow and PG mucosa protection in GI (Cox1)

Stop PG causing renal medulla perfusion - therefore get renal ischemia (COX1)

Can injure Liver

Allergic Responses!!

DO NOT USE IN ASTHMATICS - increase LT pathway for bronchospasm

Tinnitus

MI- block PGI2 vasoprotective effects and more likely to get MI or stroke (COX2)

Question 23

Aspirin - uses, metab, side effects

Answer 23

Used for low pain - small effective dose so after which you just get side effects

Antipyretic and Anti-inflamm as it irreversibly inactivates COX

Good oral absorption and metabolized in liver to Sialic Acid

BAD: Gi upset, dyspepsia, bleeding, tinnitus, and allergy

Question 24

Propionic Acid Derivatives: uses and side effects

Answer 24

Ibuprogen and Naproxen

They are analgesic, antipyretic and antinflammatory

RENAL TOXICITY!!! in patients with pre-existing disease but otherwise milder side effects than aspirin

Question 25

Acetaminophen - uses, mechanism, clearance, toxicity

Answer 25

NOT Anti-Inflammatory - but good antipyretic and analgesic for central pain

**Central Inhib of PG synthesis **

Randomly also good for joint pain?

NO Gi effects and No platelet aggregation

LIVER TOXICITY: NAPQI and tx with NAC

Question 26

KETORLAC (aka?) used for, mechanism, metabolism, toxicity

Answer 26

Ketorlac (aka Toradol) is a POTENT analgesic (30 mg IM = 10 mg morphine) with moderate anti-inflammatory effects

Good to use with opiates- potentiates their actions;

Lasts 5 hours

Metabolized by glucuronic acid conjugation in Liver

**No ventilatory or cardiac depression **

Effects: Stops platelet aggregation (bleeding), Bronchoconstriction in ASA sensitive patients, GI effects, Renal and Liver toxicity

Question 27

What is the COX2 selective Inhibitor? What’s it used for? What’s different about it?

Answer 27

Celecoxib

Used for Arthritis, Post-op pain and chronic pain

Orally taken and good absorption

Metabolized by Liver CYP450 but low first-pass hepatic extraction

BAD - blocks vasoprotectiveof PGI2 and so inreased risk MI and Stroke