Opioid Analgesics I & II Flashcards
Describe the structure of morphine and what accounts for the variation in potency/efficacy/solubility etc
it’s a five ring structure; variation is due to chemical radicals and modifications at positions 3,6, and 17
What is considered to be an endogenous opioid peptide?
endorphins! they inhibit responses to painful stimuli; their precursor has commonality w/ACTH, MSH, b-LPH; modulate GI, endocrine and autonomic function and have rewarding (addictive) properties (runner’s high!)
How do opioids act on opioid receptors?
They are agonists to the receptors that: inhibit release of substance P, inhibit ascending transmission from the dorsal horn, activate pain control circuits descending from midbrain
What type of receptors are opioid receptors and what is the signaling process?
GPCR: G proteins bind–>activates GTP–> effector protein activated–>inhibits adenyl cyclase –>activates K currents and suppresses voltage gated Ca currents
What are the different opioid receptor subtypes?
Mu: MOST IMPORTANT, most prescribed
Delta: analgesia but doesn’t cross BBB
Kappa
Nociception opioid receptor
What are the general effects/side effects of opioids?
analgesia, mood alteration/reward, neuroendocrine, miosis, convulsions, depressed respiration, antitussive (cough), nausea/emesis, GI effects, GU (urinary retention), skin (vasodilation/urticaria)
How are opioids absorbed? metabolized? excreted?
Absorbed: GI (sublingual, oral, rectal)
Metabolized: significant first pass metabolism in liver; then conjugation w/glucuronic acid in liver
Excreted: by kidney
What is the Cmax for oral, SC/IM, IV admin of opioids? When is steady state achieved?
Oral: 1h; SC/IM: 30 min; IV: 6m
steady state for all routes of administration = 1 day except for immediate release (3-5hrs)
What are the major metabolites of morphine?
morphine-6-glucuronide: active metabolite with higher potency
morphine-3-glucoronide: little receptor affinity (so most analgesia comes from m-6 metabolite)
Why is codeine considered a weak analgesic?
it has low receptor affinity, and the analgesia that does result is only from the 10% of the drug that gets demethylated to morphine
What happens to people that cannot convert codeine to morphine?
they have issues with CYP2D6 thus they cannot convert the drug and have side effects without analgesia
What is the most commonly used opioid for antitussive effects (cough suppression)
Codeine
What type of drug is Tramadol and what is it’s MOA?
synthetic codeine analog and weak Mu agonist; its demethylated form is more potent
MOA: analgesia from inhibition of NE and serotonin reuptake
What type of pain does Tramadol treat?
good for mild to moderate pain, less effective for severe pain (but also less constipating)
What’s everything you should know about Fentanyl?
1) very potent with very long 1/2 life
2) much more lipid soluble than morphine
3) delayed effect and toxicity/overdose common
4) transdermal patch useful for longterm Rx (ensure adherence to skin)
5) may not be as effective if patient is very thin
6) wait a week between dose changes
What is everything you should know about Methadone?
1) extended duration of action (don’t change dose more than 1x/wk)
2) it’s 90% bound to plasma proteins thus has gradual accumulation in tissues
3) used to treat chronic pain and heroin addicts
4) overdoses common
What type of drug is Oxycodone? what derivative of this drug has widespread abuse and overdose associated with it?
1) very effective potent oral analgesic
2) oxycontin–>it’s long acting extended release
Why is Meperidine no longer used?
metabolite toxicity (normeperidine)
Which two drugs are analogs to Meperidine that treat diarrhea and what is their MOA?
Diphenoxylate and Loperamide
MOA: slows peristalsis via opioid receptors in intestine, and possibly decreases GI secretion
What is the opioid antagonist used to treat opioid toxicity and how is it administered?
Naloxone – continuous infusion (parenteral) because oral admin is almost completely metabolized by the liver; note that it can also induce withdrawal symptoms…
What opioid antagonist is approved for treatment of alcoholism?
Naltrexone
What is the caution with acetaminophen usage?
Note that many opioids come in combo w/acetaminophen and patients may already be taking acetaminophen. Physicians forget to ask –>inadvertently take too much
When would you use breakthrough dosing
if patient is going to physical therapy/being active and needs an IMMEDIATE (not extended) release opioid for short term relief; can give 5-15% of normal total 24hr dose and only after Cmax is reached
Why are mixed agonist-antagonists not recommended?
the antagonists compete w/the agonists to cause withdrawal; analgesic ceiling effect; and high risk of psychomimetic adverse effects
What is the mechanism of tolerance in opioid drugs?
due to modification of opioid receptors which may involve phosphorylation or receptor internalization
What is meant by abstinence syndrome?
When someone who is physically dependent has abrupt withdrawal from the drug and experiences agitation, abdominal pain, nausea/vomiting, diarrhea, *yawning, piloerection)
What is meant by equianalgesic dosing?
converting to alternative routes of delivery or between different opioids to maintain state of analgesia (leaving hospital, insurance change, etc)
What are the common side effects of taking opioids? What are the uncommon side effects?
Common: constipation, dry mouth, N/V, sedation, sweats
Uncommon: bad dreams/hallucinations, dysphoria/delirium, myoclonus/seizures, pruritus/urticaria, respiratory depression, urinary retention
What can be used to treat the following side effects: sedation? respiratory depression? urticaria/pruritus?
1) psychostimulant like methylphenidate
2) naloxone
3) nonsedating antihistamines (fexofenadine, loratidine)
What two side effects of opioids to people usually continue to have (ie, don’t develop tolerance to)?
Pupillary constriction and constipation
What works and doesn’t work for treating constipation associated with opioid use?
diet and bulk forming agents (ie metamucil) don’t work; tx with stimulant laxative, stool softener, pro kinetic agent, osmotic laxative
Who are at the highest risk for opioid overdose
Patients that see multiple doctors (typically involved in drug diversion)
