Lecture 16, 17 - OPIOIDS Flashcards
Endogenous opioid receptor subtypes:
Mu receptor
The first opioid receptor to be discovered
It is the primary receptor for endogenous opioids called beta-endorphin and enkephalins
-helps regulate the body’s response to pain and other stuff
Endogenous Opioid Receptor Subtypes:
Delta
Enkephalins ( spinal analgesia )
Endogenous Opioid Receptor subtypes:
Sigma
N-allylnormetazocine (more psychotomimetic effects; sedation)
Define Narcotic, Opium, Opiate, Opioid
Narcotic - opium, its derivatives, semi-synthetic substitutes
Opium-dried powder mixture of 20 alkaloids
Opiate - derived from opium
Opioid - all substances with morphine-like properties
Opioid receptors are GPCRs…
When activated, they decrease __________ production
Which causes a __________ in calcium coming in from inhibition of voltage-gated calcium channels
This results in activation of __________ channels, which leads to hyperpolarization
The hyperpolarized state causes inhibition of neuronal signaling which in the is case inhibits ____________
decrease adenyl cyclase
decrease in calcium influx from inhibition of voltage-gated calcium channels
Activates Potassium channels
Inhibits pain transmission
Mu 1 vs Mu2
Mu1- most endogenous naturally-occurring or synthetic opioids = supraspinal analgesia
Mu2 - morphine (M2s need this) = respiratory depression or hypotension
K - kappa
Ketocyclazocine and dynorphin = **spinal analgesia, sedation, miosis (constriction)
Drugs that attach to Mu have these clinical effects:
Analgesia
Depression
euphoria
physical dependence
Respiratory depression
Sedation
Drugs that attach to Delta receptors have these clinical effects:
Analgesia
Inhibit dopamine release
Modulation of mu receptor
Drugs that bind to Kappa (k) have these clinical effects:
Analgesia
Diuresis
Dysphoria
Mu-Receptor Binding Affinities
the lower the value of (Ki), the Higher the binding affinity for the u-receptor
What is a partial agonist ?
A mixed agonist/antagonist!
If you give an agonist then the partial agonist, the partial agonist will act like an antagonist in this situation
-less of a dose-response curve, less ceiling effects, less addictive potential
-able to reduce effect of full agonist
What is an example of partial agonist?
Buprenorphine on Mu receptor
Nalbuphine on Kappa receptor
Butorphanol, Nalbuphine, and Pentazocine are all antagonist on Mu receptor, while also agonists on sigma, and agonist on kappa except for Nalbuphine which is partial on kappa
Facts on BUTORPHANOL vs morphine
BUTORphanol is 5x more potent than morphine and causes 50% less nausea/vomiting than morphine
-if given intranasally, it can cause a headache
FACTS on most High Yield Opioids
Morphine
Dextrmethorphan
Codeine
Hydrocodone/Oxycodone
Methadone
Meperidine
Tramadol
morphine - has many formulations (PO/IV/Sub-Q)
Dextromethorphan - D-isomer of morphine, L-isomer is NMDA antagonist
Codeine - natural opiate, MOST PRESCRIBED !! , low potency !! So do not use for severe pain
-perceived frequency of nausea/vomiting
hydrocodone combinations with acetaminophen: Norco, Vicodin, Lorcet
oxycodone combinations
With acetaminophen — Percocet
With ASA — Percodan
methadone - used to treat severe ongoing pain (due to cancer) = good for neuropathic pain
-stigma of heroin maintenance, must write ‘for pain’ in some states
Acute half life: 15 h first degree, 55h second degree
Chronic half life: 24 h
Methadone -liver metabolism prolonged by grapefruit juice
Meperidine (demerol) = causes tachycardia not bradycardia like the others!! Renally cleared.
tramadol - dual mechanism of action: Mu-agonist and serotonin/NE re-uptake inhibitor; less abuse potential so non-scheduled opioid
potential with long term use of high doses of tramadol causes physical dependence and withdrawal syndrome.
How to prescribe meds:
Effective concentration (EC50)
Equianalgesic doses
EC50 = the concentration which produced 50% of the maximum response
Decrease EC50 = increased potency
Equianalgesic doses
**-morphine PO:IV ratio = 3:1 **
**- 30 mg PO to 10mg IV **
** 3-4 hours duration **
**-codeine 180-200mg PO; 4 hours duration **
*if you need a drug to cross the BBB, administer it ICV (intracerebroventricular) at 1/3000 of the dose
What are the adverse effects of opioid use?
constipation, addiction, respiratory depression, paradoxical hyperalgesia
Schedule I
Schedule II
Schedule III
Schedule IV
Schedule V
Schedule I
high potential for abuse; not accepted medical use in the US (heroin, LSD, marijuana, meth)
Schedule II
high potential abuse which may lead to severe or high incidence psychological and/or physical dependence, high risk for addiction/abuse (Hydromorphone (DILAUDID), methadone, meperidine, oxycodone, fentanyl, morphine, opium, codeine, hydrocodone, cocaine, amphetamines**
Schedule III
less potential for abuse than I and II and abuse may lead to moderate and/or low physical dependence or high psychological dependence (Tylenol w codeine, Buprenorphine, ketamine, benzphetamine)
Schedule IV
low potential for abuse relative to III (Xanax, Valium, ativan)
Schedule V
**even lower potential, consist of preparations containing limited quantities of certain narcotics
Opioid effect on GABA?
Inhibits the release of gaba
Causing euphoria
Allows dopaminergic neurons to fire more vigorously
What are the two types of fibers that pain signals arrive from?
What type of pain is specific to each?
Pain signals arrive in the spinal cord from
A-delta fibers —> myelinated
And
C fibers —> unmyelinated
A-delta = sharp pain
C fibers = dull, achy pain
What is the MOA of Opioid agonists?
Binding opioid receptors and inhibiting neurotransmitter release of substance P which reduces nerve excitability and alters pain perception
Effect of opioids on the eyes
Most opioids cause pupillary constriction,
EXCEPT for meperidine which causes mydriasis
General Physiological effects of opioids
Nausea, cough suppression, respiratory depression, hypotension, constipation, urinary retention, bile duct spasm
Effects of opioids on the heart
Most opioids cause Bradycardia
EXCEPT meperidine which can cause tachycardia
In the presynapse phase of Opioid MOA, what is inhibited and what does that result in?
Presynapse inhibits calcium influx which
reduces release of glutamate, substance P, and catecholamines
What are some symptoms of opioid withdrawal?
Opposite of its actions: bradycardia, smooth muscle spasms ….
Tachycardia
Reversal of smooth muscle spasms: diarrhea, vomiting, cramps abd pain
cutis anseriunus or goosebumps!
distinguishing features of opioid agonists
Codeine
Heroin
Meperidine
Diphenoxylate & Loperamide
Fentanyl
Methadone
Tramadol
Naloxone
Buprenorphine
Codeine = used for cough and pain
Heroin = quickly cross the BBB and is hydrolyzed into morphine
Meperidine = CAN NOT be used with MAO inhibitors due to risk of serotonin syndrome (sweating, hypotension, vomiting) , seizures and arrhythmias. CAN be used in obstetrics bc does not cause respiratory depression in the baby
Diphenoxylate & Loperamide = derivatives of meperidine that are only active in the GI tract, so good tx for diarrhea!
Fentanyl = is 80x more potent than morphine
Methadone = Used to prevent symptoms of withdrawal with reduced drug cravings, longer duration of action than Morphine
!Tramadol = weak opioid agonist AND SNRi, risk for physical dependence and prolonged withdrawal period (lasts longer than most opioids)
Naloxone = pure antagonist firstline for tx of opioid overdose, immediate onset of action
- methylnaltrexone blocks peripheral Mu receptors without affecting the CNS, used to tx opioid induced constipation
Buprenorphine = **mixed - agonist at kappa, antagonist at Mu. Good for management of addiction due to high affinity for Mu receptors but can reverse effects of withdrawal due to partial agonism WITHOUT EUPHORIA
