Opioid Drugs Flashcards
What receptor is the site of most opioid drug action in the CNS? Where do the endogenous opioids bind?
Mu receptor
Most endogenous opioids bind delta and kappa receptors
What are the functions of the delta and kappa receptors?
Delta - site of enkephalin binding, mediate analgesia, but less so than mu receptors
Kappa - analgesia with psychotomimetic effects -> partial agonist drugs can bind this strongly
Why are there such diverse effects of opioid receptors?
They use alternative splicing, they have many possible combinations due to receptor dimerization, and they undergo biased agonism
What is biased agonism?
Activation of the receptor via one ligand mediates different effects than activation by another opioid (slightly different signalling pathways and cascades carried out by binding the same receptor)
What are the best described effects mediated by opioid signal transduction at the cellular level?
- Closing of voltage gated Ca channels on presynaptic nerves -> prevent release of NT
- Opening of K channels on postsynaptic neurons -> hyperpolarize
How is morphine absorbed and why is it not taken orally?
Absorbed well by all routes, not taken orally due to extensive first pass metabolism
What is the purpose of sustained-release morphine formulations and what is the safeguard? What is this called?
They are long-acting. Safeguard is typically naltrexone in a capsule, which if crushed would lead to free opioid antagonist. This is called a diversion system.
How is morphine eliminated and what condition should it be avoided in?
Eliminated via kidneys and bile, most often by glucuronidation to an active metabolite.
Avoid in patients with renal insufficiency -> can lead to decreased clearance and possible OD
What are the analgesic effects of morphine? When is it used surgically, and can you get tolerance?
Pain relief without loss of general sensory. The pain is still reported but it affects people less.
Surgically -> used in combination with other drugs for multimodal analgesia
Can get tolerance with chronic use, and even hyperalgesia can develop
How does morphine affect mood / cognition? Where does it act?
Euphoria and tranquility, acts in locus coeruleus, mesolimbic dopamine pathway, and nucleus accumbens which all mediate pleasure and awakeness
How do the effects of morphine differ between normal, pain-free individuals and combat-injured soldiers?
Normal people: often unpleasant, causes difficulty thinking, drowsiness, nausea
Combat-injured: reduced risk of PTSD
What is a classic sign of morphine OD / abuse which does not develop tolerance, and why?
Miosis
Due to excitation of parasympathetic innervation to the pupil
How does morphine inhibit cough?
Depresses cough reflex mediated by medullary cough center, at levels much lower than what would cause respiratory depression
How does morphine-mediated respiratory depression occur? Who is this important in?
Morphine decreases the response to CO2 via brain stem, which is important in patients with COPD on other CNS depressants
Why should morphine be avoided in head trauma?
Increased pCO2 can cause to cerebrovascular dilation and subsequent increased intracranial pressure
Who is most likely to vom from morphine?
Patients who are new to morphine and standing up (vestibular component to this).
Effect is mediated via area postrema chemoreceptor, and tolerance develops rapidly
What are the cardiovascular effects of morphine usage? How does this relate to one of its usages?
Peripheral vasodilation / reduced peripheral resistance. This can cause orthostatic hypotension and thus
fainting upon standing
Used for patients with dyspnea due to acute pulmonary edema associated with LV heart failure. Good in a palliative care setting.
What is the biggest quality of life concern with chronic opioid use and how is this combatted?
Constipation, due to decreased propulsive contractions and increased water reabsorption
-> proactive use of stool softeners and laxatives
What do opiates do to urinary output and labor?
Urinary output - decreased, a problem in the elderly
Uterus - prolongs labor
What systemic skin effect do opiates cause?
Itching -> not completely understood
What is heroin?
The potent, rapid-acting morphine, made into morphine rapidly by deacetylation in vivo
What painkiller is used in opioid tolerant cancer patients? How does it differ from morphine? What else is it indicated for?
Oxycodone -> more orally active than morphine
Also indicated in combination with NSAIDS for moderate-severe acute pain, but NOT chronic back pain
What is done to prevent oxycodone being used a drug of abuse?
Crush resistant, forms a viscous gel which is hard to inject or snort when crushed
What is the most widely prescribed opioid in the US and its indications?
Hydrocodone
Severe pain, also as an anti-tussive (cough)
What is the controversy surrounding hydrocodone?
FDA approved a long-active hydrocodone without tamper resistance, and also in combination with an antihistamine for coughing. Easily abused.
New formulations which are tamper-resistant have been approved
How does fentanyl differ from morphine, and why might it be preferable?
It is 80-100x more potent, and it has NO active metabolites so it is better in renal failure
-> also a short duration of action, control via IV infusion
What are the indications for fentanyl?
Acute post-op pain: patient controlled analgesia via transdermal iontophoresis -> press button to stimulate electrical current
Surgical anesthesia for multimodal analgesia
Acute hospitalized severe pain
What are the fentanyl delivery routes for opioid-tolerant patients?
Trandermal patch left on for 2-3 days
Also: Lozenges, sublingual tablets, and nasal sprays for breakthrough pain
What can increase and decrease the plasma levels of fentanyl?
Increase - CYP3A4 inhibitors like macrolides, azole antifungals, and grapefruit juice
Decrease - CYP3A4 inducers like carbamazepine, phenytoin
What is methadone and why does it have to be carefully titrated? Who is it used in
A long halflife full mu agonist - used in patients with opioid addiction to get their fix without the high
Needs to be carefully titrated because it can prolong the QT interval
How is methadone similar to fentanyl?
Has no active metabolites, so it can be used in patients with renal problems
It’s almost like the opposite drug in terms of halflife
What is the oral bioavailability and action of codeine alone?
It has good oral bioavailability because it is not glucuronidated as easily as morphine
Before any metabolism, it is a weak agonist of opioid receptors and does have some modest analgesic effect + antitussive activity (think of codeine barcode)
How does codeine’s metabolism affect its activity? When is this dangerous / what is the contraindication?
Codeine is metabolized to morphine via CYP2D6 demethylation.
Dangerous for CYP2D6 rapid metabolizers who can thus have a morphine overdose due to extra CYP2D6.
because of this fear, it is contraindicated in children
What two groups are likely to respond poorly to codeine?
- Individuals lacking CYP2D6 - get no morphine
- Individuals taking CYP2D6 inhibitors - i.e. fluoxetine
There are thus large individual differences in its activity
Name the drug which is a partial agonist at mu receptor, and dissociates slowly from the receptor leading to long duration of action and poor reversal via naloxone?
Buprenorphine - the blue print near the tapering flags from the pool in sketchy
What is the approved use of buprenorphine?
Opiate dependence -> less risk for OD due to partial agonist, especially in combination with naloxone
Secondarily: moderate-severe pain via injection or patch
What are the mixed agonist drugs which are not used and why not?
nalBU-PHINe, BUtor-PHanol, PENTAzocine
think of blue-phin bar (buprenorphine is also a partial agonist)
Less reversible, less analgesia, more respiratory depression, and most psychotomimetic effects
What is Tramadol and what do its parent and daughter compounds do?
A synthetic codeine derivative - think of the tram in sketchy
Parent compound: SNRI - think of the N/S compass on the tram
Daughter compound: Codeine derivative which is active
Requires metabolism from parent to daughter compound for analgesia
What are the indications for tramodol?
Less physically dependent opioid, seeing more use for chronic acute pain
What are the side effects of concern for tramodol?
- Increased frequency of seizures
2. Serotonin syndrome
What are the contraindications for tramodol?
Other CYP2D6 / CYP3A4 inhibitors - increase seizure risk by limiting metabolism and increasing SNRI activity
Other antidepressants - serotonin syndrome
Patients with seizure history
Children - same reason as codeine
List the opioid receptor antagonists.
- Naloxone - No lax zone -> rapid ending of effects
- Naltrexone - No tricks zone -> cannot do heroine with this
- Methylnaltrexone
- Naloxegol
How does naltrexone differ from naloxone?
Naltrexone has the same receptor blocking profile, but naloxone is used acutely for OD whereas naltrexone is used to prevent relapse, especially in once monthly injection (highly politicized treatment for opiate addicts)
What is methylnaltrexone used for?
Opioid-induced constipation for patients in palliative care -> useful because it doesn’t cross BBB and block analgesia
What is naloxegol and what is it used for?
Pegylated naloxone metabolite used for treatment of opioid-induced constipation in chronic pain patients
What opioid drugs are used exclusively for treatment of diarrhea?
These have poor gut absorption, local action
- Loperamide (Imodium) - lope-eared rabbit
- Diphenyoxylate - think dolphin-oxylate fountain
What is dextromethorphan used for? Contraindication?
An isomer of a full-agonist opiate - little orphan cough drops
used in combination with quinidine for chronic cough in lower airway, as well as pseudobulbar affect
Contraindicated in children
What is the PD profile of dextromethorphan?
Very strange
- > NDMA antagonist - NMDA camel
- > Sigma-1 receptor antagonist
- > SNRI
Why are opioids of concern in the elderly?
Polypharmacy, poor clearance via kidneys, and many surgeries to merit their use -> constipation, balance issues (fainting upon standing), impaired cognition
Has opioid use in pregnancy changed recently? What are its potential effects?
Yes -> 5 fold increase due to drug abuse and weight gain-associated back pain
Effects: Neural tube defects, neonatal withdrawal syndrome
