Flashcards in Lecture 3 - NSAIDs and Opioids Deck (27):
- what is the natural ligand to opioid receptors ?
- where in the brain are opioid receptors found?
Natural Ligand: Endorphins
Locations of Receptors:
Brain -- PAG, Amydala, Hypothalamus, corpus stiratum
Mu Opioid Agonists --
what is the mechanism of action of most opioid agonists ?
Receptors are both pre and post synaptic:
• Pre synaptic: When Mu agonist binds, decreased conductance of voltage gated calcium channels/less likely for the vesicles to merge and release contents to synaptic cleft
• Post Synaptic level -- Increase in K conductance; hyperpolarization of the post synaptic membrane; less likely to reach action potential
what are the three different classes of opioid receptors? which is most likely to cause side effects?
• Mu -- the workhorse for pain relief; also most of the associated unwanted side effects from these drugs (respiratory depression, for example)
• Kappa -- contribute to spinal analgesia; also some unwanted side effects such as constipatin, miosis, sedation
Delta -- contribute to analgesia
Opioid agonist effects/side effects at the CNS level?
Respiratory System -- Dost dependent depression (depressant effect on brain stem ventilation centers; loss of CO2 responsiveness)
Opioid agonist effects/side effects at the cardiovascular level?
-- describe the potential mechanisms for this
Bradycardia -- from decreased central sympathetic tone
Increased activity of vagal nerves --
Depressant at the SA node
Histamine Release -- vasodilation; decreased preload via venous pooling
Opioid agonist effects/side effects at the GI level?
constipation -- decreased peristalsis; increased sphincter tone; more water resorption
Nausea and Vomiting -- direct stimulation of chemo-receptor trigger zone on the 4th ventricle
side of effects of Mu agonists at the level of the GU, skin and placenta?
• The GU -- increased tone and peristalsis of the ureter; tone of vascular sphincter is enhanced; urinary retention
• The Skin -- histamine release, cutaneous vasodilation, urticaria
• Placenta -- No a barrier for transfer; neonatal ventilator depression or even neonatal dependence is a possibility
what three factors influence ability of a drug to cross the BBB
Lipid Solubility (higher lipid solubility, the easier the cross)
Drug is un bound to protein
- - mechanism?
be careful giving this drug to patients with....
CNS Penetraton -- poor -- delay in the crossing BBB
• Onset -- 15 to 30 minutes;
• Peak effect: (Blood to brain); 45-90 minutes
• Duration: 4 hours
Metabolism via the Liver
15-25% M6G Metabolite -- still active; prolonged effects in the body;
Excreted via the kidneys
Becareful giving to patients with Renal insufficiency
• Meperidine (Demerol)
- potency compared to morphine/
- side effects?
- Clinical uses?
- Synthetic opioid agonist that also has anti-muscarininc effects
- 10% as potent as morphine
- duration - 2-4 hours
- Metabolism: Normeperidine, which can cause clonus and seizures
- Side effcts: Antimuscarinics effects, histamine release, decreaed myocardial contractility
- Only current clinical use: Post operative shivering
Potency compared to morphine? why?
onset vs dduration?
100x more potent that morphine -- more lipid soluble, fast onset, long context sensitivehalf life
Fast onset --
Short duration -- redistributes quickly bc of thoses same properties
no active metabolites
No histamine release
which two opioid agonists can cause histamine release?
- potency compared to fentanyl
- duration ?
10x more potent than fentayl
very fast Onset
Short duration (rapid redistribution)
No active metabolites
Used for intra-operative infusions
- potency compared to fentayl
- Chemical structure? what is the significance of this?
Similar potency to fentanyl
Ester linkage -- metabolised by estase in the blood stream
therefore can be used in patients with liver or kidney failure
No toxic metabolites
Peak effect - 1 minute
extremely short, and very predictable, duration
considerations of dosaging?
Mu opioid agonist; also an NMDA receptor Antagonist; both help with pain modulation
• Used for chronic pain; used for weaning off heroin
• Half-life is unpredictable (16-120 hours?)
• The drug can accumulate; can result in respiratory arrest
• Have to start off on small doses;
• Hydromorphone (dilaudid)
- potency compared to morphine?
• 5x a potent as morphine
• Same side effect profile as morphine
• Safer in renal failure patients
Mixed Drugs: Opioid receptor agonists/Antagonists --
what are they ?
Mechanism? (which receptors)
who are they used for?
• Butorphanol, nalbuphine, buprenorphine
Partial agonists at one receptor (eg Mu)
Competitive antagonist at another (Delta, Kappa)
Advantages -- good analgesic, but avoid some of the side effects, such as respiratory depression
• Generally reserved for patients who cannot tolerate pure agonist
what are they?
• High affinity for opioid receptor ---
• Will displace the agonist; used for rescue
side effects: Withdrawal; increased SNS activity; such as pain perception, tachy, HTN
Duration -- 30-45 minutes
Metabolized in theliver
Mechnaims -- COX Inhibtion
Therapeutic profile -- Analgesia, anti-inflammatory, anti-pyretic, Synergistc effect with opioids
what is the mechanism of anti-pyresis of NSAIDs
IL1 and IL6
NSAID side effect profile
COX 1 -- GI mucos, renal parenchyma, platelets
COX 2 - pain and inflammation
Bleeding, Gastric Ulceration, Renal dysfunction,
Allergic Rx, Asthma, Hepatocellular injury, Tinnitus
• Non Selective COX Inhibition -- -
- what are they
ASA, Ibuprofen, Naproxen, Acetopminophen, Ketorolac
COX 2 selective inhibitor
- most often used clinically for...
- benefits ?
○ Especially arthritis
○ Post-operative pain
- ○ Crosses BBB
○ Highly lipophilic
○ Lacks inhibition of platelet aggregation
○ Decreased GI side effects
- therapuetic profile
- side effects?
Analgesic, Anti-pyretic, Anti-inflammatory
Side effcts -- GI upset, dyspepside, bleeding, alergic rxn
• Ibuprofen, Naproxen
- therapeutic profile
- side effects
benefit of naproxen over ibu?
○ Analgesic, antipyretic, anti-inflammatory
○ Side effects:
GI irritation, dyspepsia, etc. but less than aspirin
Naproxen -- longer half life; can take BID
- primary side effect?
HEPATOTOXIC --- NAPQI, treat with NAC