opioid analgesics Flashcards
plant sources of opiods
poppy- source of morphine, codeine
Animal sources of opiods
- Enkephalins- modulatory neurotransmitters at synapses derived from pro-enkephalin. Tyr-Gly-Gly-Phe opiod motif. Rapidly broken down by peptidases so only act at short distances. 2. endorphins- neurotransmitters and heurohormones. Derived from proopiomelanocortin. Beta-endorphin is most active. 3. Dynorphin- derived from prodynorphin. Dynorphin A is most active. K selective. 4. Endomorphins- variation of opiod ligand motif (Tyr-Pro-Trp/Phe-Phe). Mu receptor selective 5. Nociceptin: regulates pain and related to true opiods but binds to distinct receptors.
Where are endorphins found
hypothalamic neurons and pituitary
antagonist of opiods
naloxone
opiod receptors- classes, structures, locations, where opiods bind
classes: Mu, delta and kappa. 65% homology. All are coupled to G proteins Gi and Go. Distributed throughout the CNS and PNS. Exogenous opiods bind to transmembrane domains, endogenous opiods binds both transmembrane and extracellular domains. receptor dimerization and desensitization mechanisms might further determine differences in ligand specificity and response for different receptor subtypes
Mu receptor-pharmacological response, endogenous agonists, agonist drugs
analgesia (central) and respiratory depression, Beta-endorphin , morphine
delta receptor-pharmacological response, endogenous agonists, agonist drugs
analgesia, Met/Leu-enkephalin plus Beta endorphin, do drugs in clinical use
kappa receptor-pharmacological response, endogenous agonists, agonist drugs
spinal analgesia, dynoprhin 1-17, pentazocine
Sigma receptor- unique properties
not a true opioid receptor. Actually is a binding site on the NMDA (glutamate) receptor that is a target for some opiate type drugs (dextramethorphan) as well as dissociative agents (ketamine, phencyclidine)
where are opiod receptors found
analgesia: periaqueductal gray (descending pain), medulla nuclei (side effect-respiratory depression), spinal cord dorsal horn (ascending pain). limbic and motor CNS regions: amygdala, hippocampus, striatum (affective response to pain). “reinforcement” regions in CNS: ventral tegmentum, nucleus accumbens (addiction-abuse). gut: myenteric plexus (side effect-constipation).
Opiod receptor mechanisms
- decrease neuronal excitability (hyperpolarization). 2. direct inhibition of pre synaptic VG calcium channels, activation of potassium channels (GIRK) and inhibition of neurotransmitter release. 3. inhibition of cAMP synthesis.
List major actions of opiods
- inhibition of transmission in pain pathways 2. reduce subjective response to pain
How do opiods inhibit transmission in pain pathway
- Inhibition of spinal cord/ascending pain pathway:
inhibition of presynaptic excitatory neurotransmitter release from primary afferent terminals in dorsal horn of the spinal cord (substance P, glutamate, others?) and
inhibition of excitatory postsynaptic spinothalamic “ascending” output neurons. 2. Activation of descending pain pathway: activation of “descending” inhibitory output systems in the medulla, periaqueductal gray, and locus coeruleus; mediated by 5-HT and NE - Inhibition of spinal cord/ascending pain pathway:
inhibition of presynaptic excitatory neurotransmitter release from primary afferent terminals in dorsal horn of the spinal cord (substance P, glutamate, others?) and
inhibition of excitatory postsynaptic spinothalamic “ascending” output neurons. 2. Activation of descending pain pathway: activation of “descending” inhibitory output systems in the medulla, periaqueductal gray, and locus coeruleus; mediated by 5-HT and NE - Inhibition of spinal cord/ascending pain pathway:
inhibition of presynaptic excitatory neurotransmitter release from primary afferent terminals in dorsal horn of the spinal cord (substance P, glutamate, others?) and
inhibition of excitatory postsynaptic spinothalamic “ascending” output neurons. 2. Activation of descending pain pathway: activation of “descending” inhibitory output systems in the medulla, periaqueductal gray, and locus coeruleus; mediated by 5-HT and NE - Inhibition of spinal cord/ascending pain pathway:
inhibition of presynaptic excitatory neurotransmitter release from primary afferent terminals in dorsal horn of the spinal cord (substance P, glutamate, others?) and
inhibition of excitatory postsynaptic spinothalamic “ascending” output neurons. 2. Activation of descending pain pathway: activation of “descending” inhibitory output systems in the medulla, periaqueductal gray, and locus coeruleus; mediated by 5-HT and NE
How do opiods reduce subjective response to pain
- inducement of tranquility, euphoria. 2. patients report “feeling pain”, but the response to the pain is lessened. 3. possible involvement of limbic system, locus coeruleus, and ventral tegmentum
How do opiods compare to other analgesics (ie. NSAIDs)
more efficacious but more dangerous (respiratory depression)
Do opiods affect conciousness
No, they eliminate pain without altering other sensations or conciousness
Which type of pain do opiods work better on
Opioid drugs relieve dull, constant pain better than sharp, intermittent pain Opioid drugs reduce nociceptive pain, but do not alter neurogenic pain
Are opiods antipyretics
- Opioid drugs are not antipyretics, but can be combined with antipyretics such as acetomenophen, aspirin, or ibuprofen (i.e. Vicodin®, Percocet®, Percodan®)
- Know the medical circumstances in which opioids are indicated
pain associated with malignancy: chronic use , painful diagnostic procedures: in combination with other drugs such as local anesthetics and tranquilizers (benzodiazapines), post-operative pain, obstetrical anesthesia, patient-controlled analgesia (PCA), cough (lower doses) : separable from analgesic actions
behavioral effects of opiods
euphoria (Mu receptors), dysphoria (kappa receptors, high dose, hallucinations), sedation/lethargy/confusion (common, CNS depression), behavioral excitation (sign of acute toxicity)
Opioid actions on brainstem nuclei
respiratory depression, nausea and vomiting (biphasic-activates at low dose, suppresses at high dose at chemoreceptor trigger zone), cough suppression (symptomatic relief, codeine or non-analgesic opiates like dextromethorphan), pupillary constriction (miosis due to excitation of edinger-westphal nucleus)
How do opioids induce respiratory depression
Due to a decrease in sensitivity to CO2 in brain stem respiratory centers. increase in blood CO2 levels leads to cerebral vasodilation, vasodilation can exacerbate head injury (ICP increased), opioid drugs contraindicated in case of suspected head injury, use opioid drugs with caution in any case of compromised respiratory function (e.g. asthma, emphysema, severe obesity etc.)
Due to a decrease in sensitivity to CO2 in brain stem respiratory centers. increase in blood CO2 levels leads to cerebral vasodilation, vasodilation can exacerbate head injury (ICP increased), opioid drugs contraindicated in case of suspected head injury, use opioid drugs with caution in any case of compromised respiratory function (e.g. asthma, emphysema, severe obesity etc.)
Due to a decrease in sensitivity to CO2 in brain stem respiratory centers. increase in blood CO2 levels leads to cerebral vasodilation, vasodilation can exacerbate head injury (ICP increased), opioid drugs contraindicated in case of suspected head injury, use opioid drugs with caution in any case of compromised respiratory function (e.g. asthma, emphysema, severe obesity etc.)
Opiods effects on smooth muscle
GI: constipation (decreased secretions and gastric motility, increased tonus of sphincters, very little tolerance to GI effects). Biliary tract: constriction of spincter of Oddi causing 10-fold increase in biliary pressure. Ureter and bladder: increased tonus and contraction (urinary retention, rapid tolerance develops)
Opiods used for anti-diarrheal or induced constipation
low abuse potential (Schedule IV) due to poor water solubility.Only act locally in GI tract. Not absorbed into bloodstream. a. diphenoxylate b. loperimide (Imodium-AD®, non-prescription). C. Alvimopan-antagonist (new drug that counters constipation from abd surgery and opiod therapy)
Treatment of biliary pain
best treated with opioid + smooth muscle relaxant (e.g. atropine) otherwise opioid may make pain worse.
Allergic response to opioids
severe allergic responses may include: 1. anaphylaxis is rare, but possible, especially with i.v. administration.
- usually symptoms resemble mild allergy (respond to antihistamines). a. itching b. urticaria c. local vasodilation d. headache 3. can sometimes exacerbate asthmatic symptoms 4. peripheral vasodilation and decreased blood pressuresevere allergic responses may include: 1. anaphylaxis is rare, but possible, especially with i.v. administration.
- usually symptoms resemble mild allergy (respond to antihistamines). a. itching b. urticaria c. local vasodilation d. headache 3. can sometimes exacerbate asthmatic symptoms 4. peripheral vasodilation and decreased blood pressuresevere allergic responses may include: 1. anaphylaxis is rare, but possible, especially with i.v. administration.
- usually symptoms resemble mild allergy (respond to antihistamines). a. itching b. urticaria c. local vasodilation d. headache 3. can sometimes exacerbate asthmatic symptoms 4. peripheral vasodilation and decreased blood pressure
Cardiovascular effects of opiods
Usually minimal at therapeutic doses. Indirect effects: 1. decrease in cardiac work load 2. inhibition of baroreceptor reflex possibly leading to orthostatic hypotension 3. Use opioids with caution in cases of hypovolemia due to decreased blood pressure.
Cario/pulmonary uses of opiods
MI: fentanyl and morphine good for analgesia, alleviating apprehension, decreasing cardiac load. Pulmonary edema associated with cardiac dysfunction: alleviation of dyspnea.
- Know the medical circumstances in which opioids are contraindicated.
Head injury (ICP increases due to cerebral vasodilation), compromised respiratory function (emphysema, asthma, sleep apnea, severe obesity), hypovolemia (decreased BP), shock (makes worse), histamine release, hypothyroidism, impaired hepatic function (elderly, infants, alcoholics)
2.List categories of drugs which interact with opioids
CNS depressants, Phenothiazines (antipsychotics), MOAIs and tricyclic depressants
How do CNS depressants interact with opioids
CNS depressants: 1. Barbiturates: additive or synergistic CNS depression. 2. can increase metabolism of some opioids (e.g. meperidine).
How do antipsychotics interact with opioids
Phenothiazines (antipsychotics): 1. Used to increase opioid analgesia, but also increases respiratory depression. 2. Can also increase hypotensive effects of opioids. 3. Some can reduce analgesic actions of opioids.
How doMAOIs/ tricyclic antidepressants interact with opioids
MOAIs and tricyclic depressants: 1. Increase respiratory depression through unknown mechanisms. 2. Can induce CNS excitation, delirium and seizures. 3. However, combination therapies using antidepressant 5HT and NE reuptake inhibition and opiate agonist activities may be useful in chronic pain treatment by potentiating the inhibitory descending pain pathway (example: Tramadol)
Opioid absorption
Methadone and codeine are readily absorbed from GI. Opioids are more effective if given parenterally due to first pass hepatic metabolism. IV is most rapid.
Opioid rapidity increases with what?
lipid solubility and abuse potential (ie heroin is very fast)
effects of epidural or intrathecal opioids
–administration produces profound analgesia at the level of the spinal cord while limiting respiratory depression
opioids distribution
1/3 morphine is bound to proteins with therapeutic doses. small quantities of morphine actually cross BBB vs. heroin or codeine.
Opioid metabolism
Morphine: major pathway is conjugation with glucuronide in liver. Morphine-6-glucuronide is a major metabolite of morphine that is 100 times more potent- may be main analgesic. Following glucuronidation morphine is excreted in urine.
List opioid phenanthrenes and where they act
Agonists at Mu receptors: Morphine (schedule II), Heroin (schedule I), Codeine ((Schedule II alone or Schedule III in Tylenol 3®), Oxycodone (Oxycontin® and in Percodan®, Percocet®; Schedule II), Hydrocodone (in Vicodin®; Schedule III), Tramadol (Ultram®)
use of morphine
widely used to relieve severe pain post-operatively and in acute trauma (IV/IM). Also available in oral sustained release form (MS Contin®) for chronic pain treatment
uses of codeine
most commonly used opioid analgesic. 10% metabolized to morphine by CYP2D6, but 10% of caucasians are deficient in this pathway, so not an effective analgesic for everyone.
a. often combined with acetaminophen (Tylenol 3®) or aspirin. b. often prescribed as an antitussive
c. less potent than morphine (analgesia limited by toxicity at high doses) d. high oral bioavailability most commonly used opioid analgesic. 10% metabolized to morphine by CYP2D6, but 10% of caucasians are deficient in this pathway, so not an effective analgesic for everyone.
a. often combined with acetaminophen (Tylenol 3®) or aspirin. b. often prescribed as an antitussive
c. less potent than morphine (analgesia limited by toxicity at high doses) d. high oral bioavailability
use of hydrocodone
atitussive, weak analgesic
Where does tramadol act
acts at mu receptors but also blocks monoamine uptake to potentiate descending pain pathway.
List phenylpiperidine opioids and where they act
Agonists at Mu receptors: Meperidine (Demerol®; Schedule II), Loperimide (Imodium®) and diphenoxylate, Fentanyl and relatives: extremely potent piperidines (Schedule II),
uses of meperidine
severe pain. a. faster onset and offset than morphine
b. decreased biliary spasm c. decreased constipation
d. not antitussive e. toxic metabolites (normeperidine) cause CNS excitation, limits use to short-term such as
painful diagnostic procedures. f. Slower development of tolerance. g. frequently abused by physicianssevere pain. a. faster onset and offset than morphine
b. decreased biliary spasm c. decreased constipation
d. not antitussive e. toxic metabolites (normeperidine) cause CNS excitation, limits use to short-term such as
painful diagnostic procedures. f. Slower development of tolerance. g. frequently abused by physicians
loperimide uses
anti-diarrheal
Fentanyl uses
a. 100 times more potent than morphine used in peri-operative and post-operative pain management (IV administration) b. very short duration of action (1 hr vs. 4-6 hr for morphine) c. used as adjuncts to surgical anesthesia (fast, short-acting; no histamine release)
d. requires mechanical ventilation at high doses to due to severe respiratory depression. e. However, also available in sustained release transdermal patches (Durgesic®), oral lozenges (Fentanyl Oralet®) and lollipops (Fentanyl Actiq®) giving slower routes of administration in treatment of chronic pain.a. 100 times more potent than morphine used in peri-operative and post-operative pain management (IV administration) b. very short duration of action (1 hr vs. 4-6 hr for morphine) c. used as adjuncts to surgical anesthesia (fast, short-acting; no histamine release)
d. requires mechanical ventilation at high doses to due to severe respiratory depression. e. However, also available in sustained release transdermal patches (Durgesic®), oral lozenges (Fentanyl Oralet®) and lollipops (Fentanyl Actiq®) giving slower routes of administration in treatment of chronic pain.
List phenylheptamine opioids and where they act
Agonists at Mu receptors: Methadone
Methadone uses
opioid maintenance therapy for addiction, suppresses withdrawal symptoms
. Mixed Agonist/Antagonists and Partial Agonist opioids and where they act
Buprenorphine: Partial mu agonist. Pentazocine: (in Talwin-NX® [NX=naloxone, antagonist not orally available but limits abuse by injection]): A agonist, antagonist
Buprenorphine actions
Partial u agonist that can precipitate mild withdrawal, can cause analgesia and can partially antagonize the effects of morphine. Long acting
Pentazocin actions
A appa agonist, u antagonist, spinal analgesia with less respiratory depression. Can also precipitate withdrawal in people dependant on u agonists
Butorphanol actions
A appa agonist, u antagonist more potent than morphine and pentazocine. Combined in a nasal spray (Stadol®) for postoperative pain and migraine
Nalbuphine actions
A appa agonist, u antagonist
List opioid antagonists
–Naloxone (Narcan®- competitive antagonist, short duration), Naltrexone (Revia®- longer duration, used in alcoholism), Alvimopam (Entereg ®)
What is tolerance
•A decreased response to a drug as a result of previous exposure. The need for an increased dose of a drug to produce the same pharmacological effect.
Factors involved in tolerance
high frequency, high dose, long duration
When is tolerance seen with normal therapeutic doses
–Significant levels of tolerance not commonly seen over 2-3 weeks of normal use at normal therapeutic doses
Which opioid effects develop tolerance, and which ones don’t
No GI tract; No pupil constriction; Yes analgesia; Yes respiratory depression; Yes euphoria
What is cross tolerance
Tolerance can “generalize” to similar drugs such as all m agonists
What causes tolerance
opioid receptor desensitization
What is dependence
Physical: The continued use of a drug to maintain a normal physiological state. The continued use of drug to prevent withdrawal. Psychic: The continued desire or craving for a drug (addiction).
Symptoms of withdrawal
•flue like: Dilated pupils, insomnia, restlessness, yawning, rhinorrhea, sweating, diarrhea, nausea, cramps, chills
drug used to treat withdrawal due to sympathetic overflow
clonidine (alpha2-adrenergic agonist)
