Opiate Analgesics Flashcards
General therapeutic strategies for chronic pain:
1) relief of pain
2) Delay or arrest of disease process
What is prototype opioid drug?
morphine
What level of pain are opioids used to treat?
moderate to severe pain
Opioids historically used for:
euphoria analgesia sedation relief from diarrhea cough suppresion
opium definition -
- greek for “juice”
- the exudate from poppy seeds containing 20 bilogically acting components including morphine and codeine
Opiate definition -
drug extracted from the exudate of the poppy
opioid definition:
natural or synthetic drug that binds to opioid receptors producing its agonist effects
narcotic definition:
term used to characterize pharmacological compounds used to treat moderate to severe pain
Only two natural opioids that come directly from poppy?
morphine and codein
endogenous opioids?
endorphins
enkephalins
dynorphins
All other non-natural opioids are prepared from?
- morphine
- other precursor compounds
Three endogenous opioid receptors:
1) Mu -two types: Mu1 & Mu2
2) Kappa (k)
a) supraspinal and spinal analgesia
b) little or no respiratory depression
c) little or no dependence
d) dysphoric and general psychomimetic effects
3) Delta-
a) modest supraspinal and spinal analgesia
b) little addictive potential
c) modulation of hormone and neurotransmitter release
d) may regulate Mu receptor activity
**Two types of Mu receptors and effects:
a) Mu1-outside spinal cord= responsible for central interpretation of pain - supraspinal analgesia
b) Mu2-located throughout CNS-brainstem and spinal cord=responsible for supraspinal and spinal analgesia, respiratory depression, constipation, physical dependence and euphoria
general pharmacokinetics for all opioids:
ABSORPTION
- well absorption from GI tract
- first pass effect (morphine)
- low oral bioavailability (low oral:parenteral ratio)
general pharmacokinetics for all opioids:
METABOLISM
- hepatic - primary process- glucuronidation
- *-Morphine –> morphine-6-glucuronide (M6G = even more active than morphine!); M3G
- heroin and codein both metabolized to morphine
general pharmacokinetics for all opioids:
LATENCY TO ONSET
- transdermal >12hr
- oral 15-30 min
- intranasal 2-3min
- intravenous 15-30 sec
- pulmonary inhalation 6-12 sec
What is morphine 6 glucuronide?
metabolite of morphine = even more active than morpine
MOA for opioids?
hit Mu receptors
What kind of receptor is Mu?
Gi/Go coupled
MOA at the receptor level:
Mu receptor - Gi/Go coupled
1) inhibition of adenylyl cyclase = dec production of cAMP
2) reduced opening of presynaptic voltage gated Ca channels =in **loss of intracellular Ca and dec release of neurotransmitters
3) Inc postsynaptic opening of K channels = loss of intracellular K and neuronal hyperpolarization (less firing)
Mechanism of analgesia - ascending pain paths:
1) inh of afferent pain transmission-block pain impulse from the periphery to the brain
2) peripheral effects-activate opioid receptors on distal ends of primary afferent (sensory) neurons decreasing their activation and excitability
3) Dorsal horn of the spinal cord-
a) presynaptic=opioids block release of pain mediating neurotransmitters from primary afferent neurons via inhibition of Ca channels=reduction in incoming pain signaling
b) postsynaptic=opioids inhibit activation of 2nd afferent neurons via inc K conductance that leads to hyperpolarization
c) activate GABA (inhibitory) neurons in the spinal cord leading to reduced activation of teh secondary afferent neurons
**Mechanisms of analgesia- descending pain paths
-Opioisd block inhibitory GABAergic interneurons (disinhibition) = enhanced inhibition of nociceptive processing in the spinal cord and overall pain relief
Descending pathways regulate/lower our pain subconsciously!
Site of action of opioids:
1) periaqueductal gray area - midbrain-activates enkephalin releasing neurons that projects to the raphe nuclei in the brainstem
2) Rostral ventral medulla -brainstem-nuceus raphe magnus; serotonergic projections to the dorsal horn of the spinal cord
3) Locus ceoruleus-pons in brainstem-noradrenergic projections to the dorsal horn of the spinal cord
General pharmacological effects of opioids: ANALGESIA
**-reduce both sensory and affective aspects of pain
both spinal and supraspinal (u,k,delta) sites
General pharmacological effects of opioids: EUPHORIA
- *-pleasant floating sensation with reduced anxiety and distress
- more common in abuse situations
General pharmacological effects of opioids: SEDATION
- -drowsiness and lethargy, cognitive impairment and sense of tranquility
- more prominent effect in elderly
General pharmacological effects of opioids: RESPIRATORY DEPRESSION
-**inh of brainstem respiratory mechanism (less sensitivity to pCO2 tension
General pharmacological effects of opioids: MIOSIS
*-constriction of pupis (pin point pupils)
Do not use opioids with what presenting patient condition
head trauma-bc inc cerebral vasodilation due to increased pCO2 since body is not sensitive to pCO2 tension anymore with drug
General pharmacological effects of opioids: COUGH SUPPRESSION:
- suppression of cough center
* -action is predominantly via the brainstem chemoreceptor trigger zone
Other pharmacological effects of opioids: EMESIS:
- nausea and vomiting
- **-directly stimulate chemoreceptor trigger zone in brainstem
- effect reduced with continued use
Other pharmacological effects of opioids: GI:
- ***CONSTIPATION
- increased tone and decreased motility
- *Relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle
Other pharmacological effects of opioids:RENAL:
- inc tone of muscle in bladder and ureters
- enhanced release of ADH
- urinary retention
Other pharmacological effects of opioids: UTERUS:
diminished force of contractions in labor
Other pharmacological effects of opioids: CARDIOVASCULAR:
- -hypotension - dec symp tone
* -bradyvcardia- decreased preload and afterload
Other pharmacological effects of opioids: HISTAMINE RELEASE:
-*stimulates mast cell degranulation and release of histamine = utricaria (hives), itching, diaphoresis, and vasodilation
- Main therapeutic indication for opioids?
Analgesia! - mod to severe pain that is constant in duration
**Therapeutic indications for opioids?
- 1) analgesia (acute post surgical/trauma pain; post MI pain; severe inflammatory and neuropathic pain; cancer)
- 2) anesthetic (pre-med/adjunct to general anasthetic)
- 3) cough suppresant (codeine, dextromethorphan)
- 4) diarrhea (loperamide)
- 5) acute pulmonary edema (reduce intense panic and anxiety)
opioids side effects/toxicities:
- -sedation
- -respiratory depression
- -nausea and vomit
- -beh restlessness
- -seizures
- -hypotension
- -constipation
- -increased intracranial pressure
- -urinary retention
- -utricaria
usual first step to managing a side effect or toxicity for opioids?
switch opioids!
*Opioids - Drug interaction:
- *-CNS depressants - esp respiratory
- *-MES liver metabolism enzymes
- *****-MAOI - CONTRAINDICATION MOST ASSOCIATED WITH MEPERIDINE - USE CAUTION! hyperpyrexic (inc in body temperature) reaction including hypertension
- *-mixed agonist-antagonist
- *-antagonist
**Which opioid should never be used with MAOIs?
**meperidine!
strong agonist for severe pain opioids - list drugs?
- morphine
- hydromorphone
- oxymorphone
- methadone
- meperidine
- fentanyl
- levorphanol
- sufentanil
- heroin
moderate agonist for moderate pain opioids?
- codeine
- hydrocodone
- oxycodone
- propoxyphene
- tramadol
Mixed Agonist/Antagonists for moderate pain opioids?
- buprenorphine
- butorphanol
- balbuphine
- pentazocine
- nalbuphine
Opioid antagonist drugs?
- naloxone
- naltrexone
- nalmefene
morphine -
- belongs to which category of opioids?
- hits what receptor
- strong opioid agonsit
- prototype stong Mu agonist
fentanyl -
- belongs to which category of opioids?
- solubility
- hits what receptor?
- strong opioid agonsit
- strong lipophilic Mu agonist
meperidine
- belongs to which category of opioids?
- what is it?
- strong opioid agonsit
- active metabolite of morphine
methadone
- belongs to which category of opioids?
- how long do effects last?
- what is it used for?
- strong opioid agonsit
- long duration
- tx patients with opiate addiction
sufentanil
- belongs to which category of opioids?
- solubility
- hits what receptor?
- strong opioid agonsit
- strong lipophilic Mu agonist - even more potent that fentanyl - extended action
Codeine
- belongs to which category of opioids?
- how used/combo with what?
- usually used for?
- prototype moderate opioid agonist
- used in combo with acetominophen and others
- used as an antitussive
oxycodone
- belongs to which category of opioids?
- used in what kind of cases?
- moderate opioid agonist
- used for breakthrough pain such as post-surgery
hydrocodone
- belongs to which category of opioids?
- how is this prepped for use?
- moderate opioid agonist
- only available combined with acetaminophen, NSAIDS, etc
Other opioid agonist: Dextromethorphan:
-used for
cough suppresant
Other opioid agonist: Diphenoxylate: use for?
-antidiarrheal agent
Other opioid agonist: Loperamide: used for?
-antidiarrheal agent
Other opioid agonist: tramadol: receptors??
Mu agonist plut 5-HT/NE uptake inh
Buprenorphine
- which class of opioid?
- hits which receptors?
- mixed agonist-antagonist
- partial activators of Mu receptors and block kappa receptors
butorphanol
- which class of opioid?
- hits which receptors?
- mixed agonist-antagonist
- activate kappa receptors and block or partially activate mu receptors
nalbuphine
- which class of opioid?
- hits which receptors?
- mixed agonist-antagonist
- activate kappa receptors and block or partially activate mu receptors
pentazocine
- which class of opioid?
- hits which receptors?
- mixed agonist-antagonist
- activate kappa receptors and block or partially activate mu receptors
which mixed agonist/antagonists activate kappa receptors and block or partially activate mu receptors
pentazocine
nalbuphine
butorphanol
What are the two antitussive opioids?
codeine
dextromethorphan (
What is an advantage of which mixed agonist/antagonists that activate kappa receptors and block or partially activate mu receptors?
provide adequate analgesia with less risk of side effects and addiction
Cons for mixed agonist-antagonist drugs?
more psychotropic effects - hallucinations
**potency of hydromorphone compared to morphine?
**7-10x more potent analgesic!!
- *fentanyl
- what strength opioid is it?
- special thing about this drug?
- *-strong!!
* **-available as transdermal patch = Duration is 72 hours (compared to 1-2 hours duration if oral)
Codine potency related to morphine?
-why is codeine better in some aspects?
-codeine is much LESS potent than morphine
- less euphoria
- lower abuse potential
- rare physical dependence
BUT can produce significant sedation
opioid antagonists are generally used for?
name the drugs?
opioid overdose!
- naloxone
- naltrexone
- nalmefene
**acute opioid overdose need to give what drug? Why?
naloxone - if given IV reverses respiratory and CNS depression within 30 seconds!!! But short duration of action (not maintenance - use naltrexone for maintenance)
**What drug is used as maintenance drug for addicts in treatment programs? Why?
naltrexone - duration of action is much longer than naloxone (which is used for acute opioid overdose and duration of action is super short relatively)
What effect of opioids is the leading cause of opiate dependence and abuse?
Euphoria - reward pathway (DA-pathway) - addiction
Primary drug used to treat opioid addiction?
methadone - development of withdrawl symptoms are slower and not as bad with methadone but still sucks
acute opioid drug actions:
withdrawal symptoms?
Withdrawl symptom just opposite of opioid effects:
- analgesia–>pain/irritability
- respir depression–>hyperventil
- euphoria–>dysphoria/depression
- relaxation/sleep–> restlessness/insomnia
- tranquilization–>fear/hostiity
- dec BP–>inc BP
- constipation–>diarrhea
- pulillary constriction–>dilation
- hypothermia–>hyperthermia
- dry of secretion–>lacrimation,runnynose
- reduced sex drive–>spontaneous ejaculation
- flushed/warm skin–> chills/gooseflesh
