Opioid Analgesics 2 Flashcards

Morphine
Terms Definitions
Pentazocine
-weak μ-antagonist-κ-agonist: responsible for analgesic activity-actions similar to morphine-like opioids with respect to analgesia, sedation, respiratory depression-because of antagonist activity, increased doses do not cause proportionate depression of respiration-high doses increase BP and HR-may precipitate withdrawal in μ-opioid dependent patient
What drug is demerol?
meperidine
Methadone
μ-agonist with morphine-like activityprolonged use gives rise to tolerance-used for relieve of chronic pain and treatment of opioid abstinence and dependence-oral efficacy
Methadone
Mechanism: better bioavailability than morphine, longer T1/2, less withdrawalClinical Use: superior to morphine, moderate to sever pain, replacement therapy for opiate addiction
 
 
 
Nalbuphine, Pentazocine
mixed agonist/antagonist opioid
 
Kappa receptor agonist = spinal analgesia, dysphoria
 
Mu receptor antagonist = precipitation of w/drawl
 
 
 
Meperidine
Full agonist opioid, like morphine/heroin
 
Characteristics: also antimuscarinic (no miosis, tachycardia, no GI/GU/ gallbladder spasm)
 
Active metabolite (normeperidine) a serotonin reuptake inhibitor that can cause seizures
 
 
 
Codeine
Partial agonist opioid
 
Cough suppressant, analgesia, used in combo w/ NSAIDS
What is buprenorphine derivied from?
thebaine
meperidine
μ-agonist, actions similar to morphinedecreased constipation and urinary retention problems
dextromethorphan
cough suppressant-no analgesic or addictive properties-acts centrally to increase threshold for coughing with no drowsiness or GI disturbances-does not act through opioid receptors
respiration
-depresses respiration due to decreased sensitivity of brain stem to increases in Pco2 and H+ (dec. chemical sensory drive)-main stimulus for breathing becomes hypoxia-effect increased by concurrent use of other CNS -active drugs (alcohol, barbiturates, benzodiazepines)-voluntary breathing not blocked
Pentazocin
Mechanism: partial my agonist, powerful kappa agonist, 1/2 to 1/5 as potentClinical Use: analgesicSide Effects: less respiratory depression, higher dysmorphic effect (anxiety, nightmares, hallucination), increase BP and HR
 
 
 
Naloxone, Naltrexone 
Antagonists of opioids
 
Naloxone (IV) reversal for respiratory depression
 
Naltrexone (PO) decrease craving for EtOH and used in opiate addiction
What is dysphoria?
a feeling of fear
What gene polymorphism leads to different metabolism of codeine?
CYP2D6
miosis
due to excitation of the parasympathetic nerve innervating the pupil->pathognomonic of opioid use (can use to check if patient is using meds)
GI tract effects
-decreases propulsive peristalsis, leading to constipation-suppresses awareness of bowel stimuli-tone of anal sphincter is increased
Codeine
-analgesic efficacy due to conversion to morphine - polymorphisms in cytochrome P450 isoform CYP2D6 can affect metabolism-dispensed alone or in combination with aspirin or acetaminophen
tolerance
develops to analgesia and respiratory depression, but not to constipation and pupillary miosispatient will need higher dosesrelapses in abusive drug use can die from respiratory effects - no longer tolerant but take dose they took while using
endogenous opioids
endogenous pain suppressing system1. enkephalins2. endorphins3. dynorphins
Fentanyl
80x more potent than morphinepatch for cancer patients
Propoxyphene
less effective than codeinemild to moderate painless abuse liability than codeine
Miperidine
Mechanism: shorter duration of action than morphoneClinical Use: obstetrical analgesia; less spasmogenic, less constipation/micturition, and less respitory depression than morphine
 
 
 
Presynatpic/postsynaptic inhibition of opioid analgesics  
through Gi coupling
 
presynaptic = dec. in Ca2+ influx --> substance P release/ inhibits release of NT)
 
postsynaptic = inc. K+ efflux --> hyperpolarization
What are the four mild-moderate opioid agonists of this lecture?
CHOP
 
codeine
hydrocodone
oxycodone
prropoxyphene
What are the two opioid antagonists discussed in this lecture?
naloxone
naltrexone
What ethnicity has slow metabolism of codeine?
caucasians
naltrexone
used in long-term management of opioid addiction - the long duration (24 hrs) of action serves as a safety valve after detox for patients with high motivation to remain opioid free
neuropathic pain
results from injury to peripheral nerves
Morphine
Mechanism: mu opioid receptor opens K and less Ca -> adenylate cyclase inhibition -> reduced transmitter releaseDorsal horn has opioid receptors that gate nociceptive input (these receptors receive input from 5-HT and NE)Clinical Use: analgesia without loss of consciousness, continuous dull pain better relieved than sharp intermittent, cough suppressionSide Effects: prominent physical dependence (less severe than ethanol, barbiturates, and some BDZs), cross tolerancerespiratory depression (even low dose), resulting BP fall, constriction of pupils (miosis) useful for abuse diagnosis, hypotension only in hypovolemic patients, nausea, constipation, epigastric pain, and micturition
How is emesis exacerbated in using morphine?
standing up
What is the use for dextromethorphen?
antitussive (cough supressant)
What illegal drug is inactive but can be converted to morphine easily?
heroin
What are the 5 strong opioid agonists in this lecture?
morphine
fentanyl
heroin
methadone
merperidine
meperidine toxicity
-large, repeated doses can lead to excitatory syndrome: hallucinations, tremors, muscle twitches, dilated pupils, hyperreflexia, convulsions - due to accumulation of normeperidine-half-life of normeperidine is 20 hrs while meperidine is 3-not drug of choice for prolonged pain
visceral pain
results form injury to visceral organs - vaguely localized with a diffuse aching quality
NSAIDs + opiates
analgesic effects are additivein some situations NSAIDs may be more analgesic
What two locations on the morphine molecule are important for its metabolism and analgesia?
3,6 hydroxyl groups
What are the nine effects of morphine?
analgesic (Euphoria)
respiratory depression
miosis
GI depression
Urinary retention
Cardiovascular (orthostatic hypertension)
Sphincter of Oddi contraction
Antitussive
Emesis
 
What cardiac effects does pentazocine have?
increased HR and BP
What can't an individual become tolerant to with respect to morphine's effects?
GI depression and miosis
δ-morphine receptor
1. much less is known2. main barrier to clinical utility is that most of the δ-receptor agonists are peptides and do not cross the BBB
somatic pain
results from injury to tissues - bones joints, muscleslocalized and sharp in quality
At what location does morphine have its antitussive effect?
at the pulmonary receptors
What type of pain is caused by tissue damage?
nociceptive pain
What three effects are seen in morphine's GI actions?
increases anal sphincter tone
decreases peristalsis --> diarrhea
decreases awareness to GI stimului
How do morphine and naloxone differ in molecular structure?
the 17 position
What is the cardiovascular effect (hypertension) of morphine due to?
vasodilation secondary to histamine release
biliary colic
can cause spasm of lower end of the common bile duct (sphincter of Oddi), causing increased pressure within the biliary tract-morphine can intensify pain in patients with pre-existing biliary colic so know cause of pain before administration
morphine receptor mechanism of action
-morphine binds to a specific receptor-binding is stereospecific and involves 3 binding sites-regions of highest binding are associated with the limbic system, cortex, and brainstem-opiate receptors are concentrated within pain and reward pathways-work both presynaptically and postsynaptically -receptors are G-protein coupled and activation reduces Ca++ influx during AP, leading to less neurotransmitter release from nociceptive primary afferents
How is the respiratory drive supressed with the use of morphine?
the central chemoreceptors lose senstivity causing the respiratory system to respond to peripheral hypoxia at the carotid body instead; therefore the respiratory system will not activate at the higher levels of CO2 and you become acidotic
What are the three signs of a morphine overdose?
pinpoint pupils
coma
depressed respiration
How does morphine cause emesis?
it crosses into CTZ center to stimulate nausea/vomit
What three general areas of the brain does morphine bind to?
limbic system
reward system
pain pathway
intensity of withdrawal syndrome
1. half-life of drug: short - intense but brief, long - prolonged but less intense2. degree of physical dependence3. methadone, meperidine, codeine qualitatively the same but less intense than morphine withdrawal
codeine molecular structure
methoxy group on C3 - can be taken orally
ADME of opioids
A: absorbed well IM, SC, and oral and nasal mucosaD: rapid from blood into highly perfused tissues, less to brain bc of BBBM: first pass in liver inactivates many opioids (undergoes conversion to polar entity) E: polar metabolites excreted in urine
mechanism of increased intracranial pressure
dec. respiration -> inc. pCO2 -> arteriolar dilatation ->inc. CSF pressure
What side effect does increased doses of pentazocine not induce when compared to morphine?
decreased respiratory drive is not seen with pentazocine
What is true of the ADME of opioids?
absorbed well by all routes
Distributed to all metabolic tissues (less in the brain)
Metabolized by liver (glucoronidation)
polar compound after glucoronidation is excreted
How does morphine cause analgesia?
by euphoria (making one feel well and tranquil)
What are two uses for naloxone?
it is used for reversal of overdose and used to determine if a suspected individual is abusing opioids (will cause an acute withdrawal syndrome for up to 2 hours in a positive abuser)
What do opioids do to secondary neurons?
they hyperpolarize them to reduce the transmission
What opioid drugs have been associated with ototoxicity?
some of the mild-moderate opoids most specifically vicodin (hydrocodone+acetaminaphin)
What happens when you change the 3 or 6 hydroxyl groups of the morphine structure?
decreases its metabolism by the liver
What is normeperidine and how is it produced?
it is the product of N-demethylation of meperidine
What unique type of patients can you not give pentazocine in due to a side effect?
cardiac patients b/c it increases work of the heart
Why does morphine not have very good oral efficacy?
because it is greatly reduced by first pass in the liver by glucoronidation
What is the reason behind given Talwin-NX?
In giving oral talwin NX you are given pentazocine with a small does of naloxone.  So when you take talwin-NX orally, the naloxone is metabolized by first pass and has not antagonistic effect.  However, if you were to abuse the drug and change its form to enable it to be injected, you would not have the benefit of first pass and it would induce a withdrawal symptom
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