Intro to Narcotics Flashcards
Non opiate drug examples
local anesthetics, GABA agonists non N-methylD asparate (NMDA) antagnists, COX inhibitors corticosteroids
Antidepressants are useful in treating chronic pain because
they increase the availability of serotonin or norepi in pain modulating descending pathways
NSAIDs
ibuprofen
aspirin
acetominophen
NSAID action
non specific COX inhibitors, peripheral and spinal
COX 2 inhibitor example and action
celecoxib
COX 2 selective inhibitor
Peripheral and spinal
Opioids example and action
morphine
mu receptor agonist
supraspinal and spinal
Anticonvulsants example and action
Gabapentin
Na+ channel block
alpha2delta subunit of Ca+ channel
supraspinal and spinal
Tricyclic antidepressants example and action
amitryptiline
inhibits uptake of serotonin and Norepi (therefor prolongs the effect of these)
Opium contains
Morphine (10-15%)
Codeine (1-3%)
Thebaine (1-2%)
Opioid receptors in the brain
expressed in many parts of the brain, cerebellum, nucleus accumbens and hypothalamus
many of the regions are involved in pain perception, emotion, reward and addiction
Opioid activity in the brainstem
can affect breathing by quieting neurons that control respiration
respiratory depression is serious side fx and commonly sited in case of opioid overdose
opioid receptors in the spinal cord
Pain transmission in the dorsal horn is dampened by opioids.
This a useful and intended target for pain treatment
Opioid receptors in the periphery neurons
opioid drugs can bind pain sensing neurons and curb nociceptive messages
Opioid receptors in the intestines
expressed in neurons regulating peristalsis
inhibition of these cells can lead to constipation
Examples of pain pathways
afferent neuron - AS (alpha delta neurons) (fast and myelinated) and C fiber (slow, visceral, unmyelinated)
Dorsal root & ganglia
Substantia gelatinosa
Contralateral Spinothalamic tract - Neospinal (sharp) and Paleospinal (dull)
Supraspinal thalamic nuclei that project to the cortex
Gate theory
cutaneous sensory input activate inhibitory interneurons or descending projections release various NTs: GABA, NE or endogenous opioids
These NTs bind to presynapse of afferent pain fibers and inhibit Ca+ channels leading to reduced vesicle release
They bind post synaptically and signal via G proteins to cause K+ efflux or Cl- influx (both of which hyperpolarize)
Descending control of pain
PAG –> Nucleus Raphe Magnus and Lateral tegmental nucleus —> excitatory to Enkephalin neurons in Lamina 2 (sub gelatinosa) —> inhibit Spinothalamic tract
4 step model of Pain
Transduction, transmission, perception, modulation
acute stimulation in form of noxious input, impulses to thalamus and cortex. Cortical and limbic structures in brain are involved in awareness and interpretation of pain. Pain is inhibited or facilitated by mechanisms in the ascending and descending pathways
Physiology of Endogenous Opioids
released by pituitary gland and hypothalamic neurons in response to pain, stress, exercise and labour
- act to relieve pain and anxiety
- asso. with feelings of euphoria, increased appetite and enhancement of immune response
- “runner’s” high = increased release during long, strenuous exercise and results in euphoria and increased pain threshold
- play a role in social bonding
Examples of endogenous opioids
proorphanin
prodynorphin
proenkephalin
POMC - beta endorphins
What produces POMC? what is it a precursor for?
…
Beta endorphin
31 AA
tyr-gly-gly-phe-met (Met Enkephalin) , replace met with Leu for Leu enkephalin
the Leu sequence is seen in number of endogenous opioids
Analgesia
stimulation of AS (alpha delta) and C afferents can stimulate release of endogenous opioid beta endorphin from hypothalamus
Dynorphin released from PAG
Analgesia pathway
Transmission cell sends spinoreticular tract to RF which sends to hypothalamus. Hypothalamus (B endorphin) –> PAG —-> Raphe nucleus (serotonin) —-> via Dorsolateral tract acts on Enkephalin interneuron which releases enkephalin on the transmission cell
From transmission cell receives from (As and C fibers)
enkephalin interneuron from transmission cell
Endorphin is selective for
mu opioid receptors
How do opioid receptors work?
decrease synaptic transmission
binding activates G proteins that, in turn, activate potassium channels (neuronal membrane hyperpolariztion) inhibit voltage operated calcium conductance and neurotransmitter release
Dynorphin is co released with
Orexin
neuropeptides that modulate neurotransmitter action
Endorphins
Mechanism of Action of Endorphins
directly stimulate opioid receptors on the pre and post synaptic membranes rapidly degraded peptidases each binds a different opioid receptor -B endorphin and endomorphin (mu) -enkephalin (delta) -dynophin (kappa)
Nociceptin receptor
ORL-1
synthetic agonists for mu receptors
Morphine
codeine
heroin
synthetic agonists for kappa opioid receptor
pentazocine
oxycodone?
What receptor Naloxone not an antagonist for?
ORL-1
What type of receptors are opioid receptors?
G protein receptors
B-FNA is an antagonist for?
Mu receptor
Natrindole is an antagonist for?
Delta receptor
In general, stimulation of opioid receptors result in
hyperpolarization of neurons
inhibition of NT release
Effects of mu receptors
analgesia relief of anxiety euphoria nausea constipation cough suppression dependence
Effects of delta receptor
like mu but less marked
Effects of Kappa receptor
Analgesia
aversion
Diuresis
Leu and Met enkephalin
short interneurons associated with pain pathways emotional behavior and motor control
what are endorphins co released with?
from pituitary with ACTH (Stress hormone)
Dynorphins are co localized with ….
vasopression, suggesting role in fluid homeostasis
in the spinal cord lowers pain threshold
Name opioid therapeutic for diarrhea
diphenoxylate
loperamide
Opioid for relief of cough
dextromethorphan
Treatment for opioid withdrawal
methadone
Treatment for opioid overdose
naltrexone
Treatment for constipation
methylnaltrexone
Treatment for postoperative ileus
alvimonpan
Narcotic analgesics
morphine codeine hydrocodiene oxycodone fentany
Mu opioid receptor
Main pharma site mu1 = analgesia mu2 = analgesia, respiratory depression Euphoria (m1), miosis, dependence (m2) sedation
Kappa opioid receptor
predominantly endogenous opiates
spinal analgesia
miosis
sedation dysphoria
Delta opioid receptor
analgesia
respiratory depression
dysphoria
state of unease or general dissatisfaction with life
Non opiate approaches: Transduction
nonsteriodal anti inflam. drug (NSAIDs) and cyclooxygenase (COX) 2 inhibitors - target the inflam. processes
Strong opioid agonists
Fentanyl Heroin - rapid brain entry increases abuse Meperidine - physician's drug of choice Methadone - withdrawal less severe Morphine - the original
Moderate opioids agonists
Codeine
Propoxyphene
Opioid antagonists
Naloxone-short acting must provide adequate breathing
Naltrexone
What limits narcotic analgesic clinical use?
induction of tolerance and dependence
which are influenced by their efficacy
Morphine is a _____ agonist
Full
- very potent analgesic
- High degree of dependence
Codeine/ Dextropropoxyphene
milder analgesia and dependence
lower first pass metabolism
Tramadol
weaker full agonist
less respiratory suppression
Methadone
full agonist for treating addicts
Mu opioid receptor (m1)
central analgesia miosis* bradycardia euphoria physcial dependence increased prolactin release inhibits Ach release*
Mu opioid receptors (m2)
Respiratory depression ** GI motility spinal analgesia GH release miosis* bradycardia
Kappa opioid receptor effects
central analgesia with k1 sedation ** disorientation, hallucinations depersonalization less miosis dysphoria ADH release - (diuresis) k1 Central analgesia
Delta opioid receptor
positive reinforcement of central analgesia
suppresses noxious thermal stimuli at spinal cord
enhances m agonists
Pharma action of Morphine
analgesia euphoria/sedation decreased respiration suppression of the cough reflex miosis emesis GI effects cardiovascular effects Hormones - CRH and ACTH, Gonadotropin releasing hormone
Tolerance develops to most of morphine’s effects, with the exception of
miosis
constipation
pruritis
What is different about codeine’s structure that reduces its first pass metabolism in comparison to Morphine?
The H on OH in Morphine is replaced by CH3 for codeine which makes it more resistant to glucuronidation
Morphine chemical structure
about four rings with O between two
Has two OH groups vulnerable to glucuronidation
N-CH3 group open to demethylation (minor)
Glucuronidation of the OH not subbed in codeine will increase potency of analgesia
Morphine mechanism of action
via activation of mu receptors and to lesser extent kappa
Analgesia: inhibition of ascending nociceptive info
activate descending pain control circuits
25% effective for oral vs. parenteral admin
Does morphine cross the BBB?
Yes but to a lesser extent that many opioids
Therapeutic uses for Morphine
acute pain (do NOT use in chronic malignant pain) dyspnea and pulmonary edema pre anesthetic medication open heart surgery to decrease fear in dying
Opioid analogs are designed after
morphine, thebaine, codeine
- simplification of morphine structure
- mod by addition to thebaine
Effects of Morphine on respiration
primary and continuous depression of respiration related to dose
- decrease in rate
- decrease volume
- decrease tidal exchange
Effects of morphine on N&V
stimulation of CTZ (?) in area postrema of medulla
sitmualtion by stretch receptors causes nausea and vomiting
has afferents from gut and ear
involved in motion sickness
Constipation as side effect from Morphine results from
increase in tone in stomach, small intestine and large intestine
decrease in mobility
decrease concentration of HCl secretion
altogether delays passage of food so more reabsorption of water
Tolerance to this effect does NOT occur
CV effects of Morphine
vasodilation which leads to decrease in BP
cause release of histamine
suppression of central adrenergic tone
suppression of reflex vasoconstriction
Morphine effects on the biliary tract
marked increase in pressure
10 fold over normal
due to contraction of sphincter of Oddi
Urinary bladder effects of Morphine
tone of detrusor muscle increased
feel urinary urgency
urinary retention due to increased muscle tone where sphincter closed off
Bronchial muscle effects of Morphine
bronchoconstriction
**is contraindicated in asthmatics, particularly before surgery
Uterine effects of Morphine
contraction uterus can prolong labour
Neuroendocrine effects of opioids
inhibit release of GnRH and CRF thus decreasing LH, FSH, ACTH and b-endorphin
as a result, decreased concentration circulating which leads to less testosterone and cortisol in plasma
-Thyrotropin is unaffected
