Opioids Flashcards
What are the key pharmacological effects of mu receptors?
Analgesia
Respiratory depression
Reward
***Constipation also mu mediated
What are key pharmacological effects of delta receptors?
Analgesia
Affective disorder (Anxiety)
**Also Seizures
What are key pharmacological effects of kappa receptors?
Analgesia
Dysphoria
Psychomimetic effect
***Also Diuresis
What are the endogenous opioid peptides that act at mu receptors?
B-endorphin
Endomorphin 1 and 2
What are the endogenous opioid peptides that act at delta receptors?
Met-Enkephalin
Leu-Enkephalin
What are the endogenous opioid peptides that act at kappa receptors?
Dynorphin peptides
Mu receptors are how many amino acids?
398
Delta receptors are how many amino acids?
372
Kappa receptors are how many amino acids?
380
Where do antagonists bind?
Extracellular tail
Where do agonists bind?
Extracellular domain
All opioid receptors are coupled to what proteins?
Gi and Go
What is the result of opioid receptor binding?
INHIBITION. ALWAYS.
Activation of opioid receptors induces G-proteins to:
Inhibit adenylyl cyclase activity (Gi) - decreases cAMP
Activate receptor-operated K+ channels (Gi) - Increases K+ leaving the cell, hyperpolarizes it, less action potentials
Suppress voltage-gated Ca2+ currents (Go) - influx of Calcium also hyperpolarizes
Analgesia is the result of what receptor(s) in what area(s)?
Mu, Kappa, Delta
Spinal cord, PAG, Thalamus, Cortex, Limbic system
Respiratory depression is the result of what receptor(s) in what area(s)?
Mu
Medulla
Reward is the result of what receptor(s) in what area(s)?
Mu and delta in the striatum increase reward
Kappa in striatum decrease reward
Pupil constriction is the result of what receptor(s) in what area(s)?
Mu and Kappa receptors
Edinger-Westphal nucleus
Cough relief is the result of what receptor(s)?
Dextramorphan receptors! Not opioid receptors, but opioids can bind to it
Nauseant and emetic effects are due to what receptor(s) in what area(s)?
Mu
Chemoreceptor Trigger Zone
Sedation is due to what receptor(s) in what area(s)?
Mu and Kappa
Inhibition of the locus ceruleus
Describe the pain pathway
Dorsal root ganglia (Delta and Kappa, few Mu)
Substantia gelatinosa - incoming pain signals (hyperpolarize these cells to decrease pain signals)
Spinal cord ventral horn (Dynorphin interneurons synapse on spinothalamic axons)
Thalamus (Spinothalamic neurons connect cortex to limbic system, also have input to PAG and RAS)
Descending pathways from PAG, Locus ceruleus (NE) and Raphe nuclei (5HT) - serve to inhibit incoming pain activity in primary afferent arteriole
How can Kappa agonists be used against addiction? Why aren’t they used?
There are kappa receptors on the PRESYNAPTIC TERMINAL (test Q!) of dopamine receptors to inhibit release. So you have inhibition of dopamine release and you lose inhibition of inhibiting dopamine release.
This leads to dysphoria, which can lead to depression. Patients would rather be in pain.
What effects do opioids have on the CV system?
Nothing directly
Histamine indirectly causes vasodilation and CO2 blunting reflex of vasoconstriction
What effects do opioids have on bronchial smooth muscle?
Constriction bc histamine
Contraindication in asthmatics
What effects do opioids have on urinary bladder smooth muscle?
Mu agonists decrease voiding and increase ADH
K agonists at kidney increase voiding and indirectly decrease ACTH to increase urination rate
What effects do opioids have on the GI tract?
Mu agonists decrease gastric acid secretions in the biliary tract, food concentrates so it’s harder to pass (CONSTIPATION!)
Decreases GI transit
What effects do opioids have in the uterus?
Decrease oxytocin
Increase labor time
What effect do opioids have on muscular rigidity?
Mu, kappa, delta receptors in the NIGROSTRIATAL TRACT all contribute
Increase muscle rigidity, easier to cut thru in surgery
But delta agonism - too far can cause seizures!
What effect do opioids have on skin?
Indirect effect - histamine release increases flushing and increases pruitus/itching
What effect do opioids have on the immune system?
Complex - all 3 receptors found
Mu decreases cytotoxic activity (morphine)
or increases cytotoxicity (in cell culture)
Increases speed and replication of viruses - bad with HIV!
What effect do opioids have on the endocrine system?
Mu receptors in the hypothalamus inhibit gonadotropins
Chronic use influences homeostasis
Antagonists have no effect on the side effects of opioids except which ones?
Feeding and prolactin/growth hormone secretion
Antagonists will decrease feeding and decrease secretion
Onset of action of opioids is determined by….
route of admin (mostly parenteral) lipid solubility (usually high - crosses BBB faster)
What chemical change decreases likelihood of metabolism?
Methylation of C3 on morphine ring
Describe protein binding of morphine
Significantly protein bound - 1/3 of morphine is bound to protein for distribution, but there is rapid departure in highly vascularized areas
How is morphine metabolized?
Glucoronidation in the liver to M6G (2x potency) and M3G (Inactive - does not bind opioid receptors but could actually induce pain…)
Both excreted in the urine
What are the indications of opioid use?
Acute pain (Best against dull, continuous pain)
Chronic pain (less effective)
Cough (DM binding site)
Diarrhea (mu receptors)
What are the contraindications of opioid use? (8)
Head injury (Stroke) Respiratory depression (COPD) Chronic pain (Long term opioid use - don't just keep increasing the dose) Pregnancy (threat of w/d for fetus) Allergy/asthma Impaired liver function (metab in liver) Renal disease (buildup of metabolites) History of opioidabuse
What drug interactions exist between opioids and CNS depressants?
Benzos, barbiturates, ethanol, etc
Increases sedation, euphoria, RESP DEPRESSION
Both PK and PD mechanism of action
What drugs should you NEVER give with an opioid?
MAO INHIBITORS!!!!!
What drug interaction exists between opioids and MAO inhibitors, antidepressants with mACh or H1 blockade?
Increase sedation and respiratory depression
Increase risk of seizures
Increase analgesia
Risk of serotonin syndrome (increase 5HT to the point it becomes excitatory)
Severe HTN (not sure why)
What drug interaction exists between opioids and antipsychotic agents with mACh or H1 receptor blockade?
Increases sedation and respiratory depression
Increases CV effects
What drug interaction exists between opioids and amphetamine?
Increase euphoria, increase analgesia
Decrease sedation
“Speed balling” Take opioid + heroin to increase euphoria
What drug interaction exists between opioids and NSAIDs?
Synergistic, increases analgesia
Some opioids are packaged with NSAIDs to decrease the dose of opioid necessary (ie Percocet)
What drug interaction exists between opioids and SSRI’s, NSSRI’s, and some atypical antidepressants?
They increase analgesia
What drug interaction exists between opioids and apha-2 agonists?
Helps treat spinal pain by decreasing transmission of pain as well as the analgesic property of the opioid
What are the symptoms of opioid overdose?
Stupor, coma (Mental clouding) Very low respiratory rate (2-4 breaths per minute) Symmetrical pinpoint pupils (miosis) Increased intracranial pressure (bad for stroke) N/V (Bad teeth) Constipation (Severe, lasts for days) Increased itching Increased urinary retention (mu) Postural hypotension
Define Tolerance, Physical dependence, and Withdrawal syndrome
Tolerance: Reduction in response to an opioid after repeated administration
Physical dependence: Require continued opioid administration to maintain normal function (shift in homeostasis)
Withdrawal syndrome: Only actual evidence of physical dependence; occurs when opioid administration in a physically dependent organism is abruptly discontinued
You do not know the degree of dependence until…
Either the drug is withdrawn or an antagonist is given
In dependence, there is a compensatory increase in…
neuronal cyclic AMP production, particularly in the locus ceruleus
What happens in morphine-dependent rats?
Basal adenylyl cyclase activity and cyclic AMP-dependent protein kinase activity are increased
Injection of cAMP in physical independence did what?
Potentiates the development of dependence and withdrawal symptoms
What is believed to be involved in the manifestation of withdrawal symptoms?
Opiods normally suppress adenylyl cyclase activity
When opioid is removed or an antagonist is given, there is no inhibitory influence on adenylyl cyclase activity.
At the onset of withdrawal, cyclic AMP levels are very high, and is believed ti be involved in the manifestation of withdrawal symptoms
What happens in the first 6 hours of heroin/mu agonist withdrawal?
Goose like flush Muscle spasm Pupil dilation Sweating Insomnia Anxiety Yawning Increased HR/BP Danger of tachycardia CRAVING
What happens in the 24-72 hours of heroin/mu agonist withdrawal?
Chills Diarrhea-SEVERE (need fluids) Sneezing Aching Nausea Vomiting Cramps
70% of patients fail at this point
What happens 7 days after heroin/mu agonist withdrawal?
Protracted withdrawal symptoms
What happens 6 months after heroin/mu agonist withdrawal?
Considerable anxiety, significant cravings, sense of feeling “not right”
Lasts for an unknown amount of time
What is the long term prognosis for heroin/mu agonist addiction?
Very poor
70% relapse in the first 72 hours
40% relapse even if they go through withdrawal under clinician care
Tolerance and dependence is highest in what receptor order?
Mu > Delta > Kappa
Abuse liability is highest in what receptor order?
Mu > Delta > Kappa
What is the abuse liability order for lipid solubility?
Worse for more lipid soluble
Fentanyl > Heroin > Meperidine > Morphine > Methadone
What are the treatment options for dependence?
“Cold turkey” ONLY for light abusers
Decrease dose for several days
Substitution detox - methadone, buprenorphine - decreases cravings
Long-acting opiate ANTAGONISTS - naltrexone - alleviates environmental cravings
Clonidine - activates alpha 2 adrenergic autoreceptors in LC (decreases NE hyperactivity to alleviate w/d symptoms but NOT cravings)
