How do opioids work/where do they work?
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
What are the unwanted effects from Mu receptor activation? Delta? Kappa?
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
How do opioids cause respiratory depression?
Decrease CO2 responsiveness in Brainstem ventilation center and so CO2 can go high but blunted reflex to breath it off....however maintain hypoxic drive
What Opioids act on the Medullary Cough center?
Dextromethorphane and Codeine
Why can rapid injections/bolus of some opioids cause muscle rigidity?
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
What are the CV effects of opioids?
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)
What are the 2 Opioids that cause Histamine release?
Morphine and Meperidine
What are the GI effects of Opioid agonists?
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
What are the GU effects of opioid agonists?
Increased tone of ureters but much more increased tone of bladder sphincter leading to Urinary Retention
What are the important pharmacokinetics of morhine? Metabolism of Morphine?
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*
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
Important things to know about Meperidine? Uses? Metab?
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)
Fentanyl - unique features and when to use?
MORE potent than Morphine
Rapid onset and short duration
No active Metabolites
HEMODYNAMICALLY STABLE - no changes in myocardium or histamine!
Compare and contrast Fentanyl derivatives - name them, actions/uses, and anything else about them
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!
Methadone - what's unique about it and how is it really used?
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
Hydromorphone - uses?
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
What opioid agonists are bad to use in Renal Failure?
GOOD to use in Renal??
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
What are the Mixed Opioid Agonist/Antagonists and when do you use them?
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
What are the opioid Antagonists? How are they used? What happens wiht them?
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
What is codeine?
Converted to morphine in the liver by CYP2D6
just methylated morphine
What prostaglandin is the main meidator of pain?
What prostaglandin is Vasoprotective and good for your heart?
How do NSAIDs work? What are they used for?
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
What are the bad effects of NSAIDs?
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
DO NOT USE IN ASTHMATICS - increase LT pathway for bronchospasm
MI- block PGI2 vasoprotective effects and more likely to get MI or stroke (COX2)
Aspirin - uses, metab, side effects
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
Propionic Acid Derivatives: uses and side effects
Ibuprogen and Naproxen
They are analgesic, antipyretic and antinflammatory
RENAL TOXICITY!!! in patients with pre-existing disease but otherwise milder side effects than aspirin
Acetaminophen - uses, mechanism, clearance, toxicity
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
KETORLAC (aka?) used for, mechanism, metabolism, toxicity
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
What is the COX2 selective Inhibitor? What's it used for? What's different about it?
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