Opiates + NSAIDS Flashcards
Opioid agonists
- natural alkaloids
- synthetic opioids
Natural alkaloids –> morphine + codeine
Synthetic opiods
- meperidine
- fentanyl, sufentanil, alfentanil, remifentanil
- methadone
Opioid agonists - basic principles
Act at stereospecific opioid receptors
- presynaptic and post synaptic sites in the CNS
- principally brainstem and spinal cord
- activation of opioid receptors on primary afferent neurons
- affinity for receptors correlates with potency
The same receptors are normally activated by endogenous peptides = endorphins –> opioids mimic endorphins
Opioid receptor locations + roles
Brain
- periaqueductal gray matter in the brainstem
- amygdala
- corpus striatum
- hypothalamus
Spinal cord –> substantia gelatinosa
Roles
- Involved with pain perception
- Integration of pain impulses-
- Pain responses
Sites of opioid drug action
- thalamus
- PAG
- rostral ventral medulla
- dorsal horn
- peripheral tissue
Opioid receptor activation and mechanism
Activation
- results in decrease in neurotransmission
- largely by presynaptic inhibition of NT release –> ach, dopamine, NE, substance P
Mechanism
- Pre-synaptic –> Mu is a g-protein coupled receptor = inhibits adenylyl cyclase
- activation results in decreased conductance of voltage gated calcium channels –> decreased transmitter release –> prevents pain transmission - Post synaptic –> activation of Mu receptor increases K outflow postsynaptically = hyperpolarizes the membrane potential –> prevents excitation and prolongation of action potential = decreased neuronal activity
Classification of opioid receptors
3 classes of opioid receptors = mu, delta, kappa
- these receptors function as a pain suppression system
Mu receptors –> most important
- underlie most analgesia
- some unwanted effects = respiratory depression, GI, euphoria, depression, constipation, physical dependence, sedation
Delta receptors –> contribute to analgesia
Kappa receptors –> contribute to spinal analgesia
- unwanted side effects = constipation, miosis, psych, sedation
Opioid effects - CNS
- Analgesia –> acts on dorsal spinal cord, PAG, dorsal raphe nucleus, limbic system
- sedation
- respiratory system –> normally if the CO@ is too high or O2 is too low, a signal is sent to the brainstem to stimulate ventilation –> this is blunted by narcotics
- –> dose dependent depression
- –> direct depressant effect on brainstem ventilation centers
- –> loss of CO2 responsiveness
- –> retain hypoxic drive
Opioid effects
- antitussive (cough suppression)
- muscle rigidity
- miosis
Antitussive –> by effects on medullary cough centers
- D-methorphan, codeine
Muscle rigidity –> related to actions at opioid receptors and interaction within corpus striatum and substantia niagra - inhibit DA release
- large doses
- rapid injection
Miosis –> due to excitatory action at edinger-westphal nucleus
- no tolerance to this effect
- antagonized by atropine
Opoid effects
- cardiovascular system
- Nausea and emesis
Myocardium is generally unaffected in normal individuals
Hypotension occurs due to
- bradycardia from decreased central sympathetic tone
- increased activity over vagal nerves
- direct depressant effect on SA node
- histamine release
Nausea and emesis –> caused by direct stimulation of CTZ in 4th ventricle
- due to opioid dopamine agonism
Opioid effects - GI
Stomach and intestines
- decreased peristalsis, increased sphincter tone (decreased Ach)
- constipation –> delayed passage allows for water reabsorption = constipation
- gallbladder –> sphincter of oddi narrowing + increased biliary pressure
Opioid effects
- GU
- skin
- placenta
GU
- increased tone and peristalsis of ureter
- tone of vesicle sphincter is enhanced
- urinary retention
Skin
- histamine release
- cutaneous vasodilation
- urticaria
Placenta –> not a barrier for transfer
- neonatal ventilatory depression can occur
- neonatal dependence is a possibility
Morphine
Prototype opioid agonist
- analgesia, euphoria, sedation
- modifies pereception of noxious stimulation
- no longer perceived as pain
- onset –> 15-30 minutes
- peak effects (blood to brain) –> 45-90 min
- duration –> 4 hours
- delay in penetrance of BBB –> so analgesic and ventilatory effects may not correlate with initial high plasma levels
CNS penetration poor
- poor lipid solubility
- high degree of ionization
- protein binding
- rapid conjugation
Metabolism
- conjugation with glucoronic acid
- hepatic and extra hepatic sites –> 2 metabolites
- 75-85% M3G = inactive metabolite
- 15-25% M6G = active metabolite –> more potent than morphine
- metabolites removed principally in urine –> important if renal failure
- limited biliary excretion
M6G –> analgesia, respiratory depression due to action at mu receptors
- removal impaired in renal failure
- unexpected ventilatory depressant effects
Meperidine
Synthetic opioid agonist
- shares local anesthetic features
- structurally similar to atropine
Pharmacokinets
- 1/10 as potent as morphine
- duration 2-4 hours
- N-demethylated to normeperidine in liver
- Normeperidine –> myoclonus, seizures
- especially in renal impairment
Uses –> post operative shivering (stimulate kappa receptors
Meperidine - side effects
- large doses decrease myocardial contractility
- mydriasis, tachycardia –> due to atropine effects
- seizures
- histamine release
Fentanyl
Structurally related to meperidine
- 75-125 more potent than morphine
Pharmacokinetics
- more rapid but shorter duration than morphine
- greater lipid solubility
- rapid redistribution to inactive sites
Metabolites –> minimally active
No myocardial depression or histamine release
Sufentanil
5-10 times as potent as fentanyl –> greater affinity for opioid receptors
Lipophilic
- rapidly crosses BBB = fast onset CNS effects
- rapid redistribution
- extensive protein binding so smaller volume of distribution
Metabolism
- rapidly metabolized
- metabolites are inactive
Longer duration of analgesia
Alfentanil
Analogue of fentanyl –> 1/5 to 1/10 as potent
Rapid effect site equilibration (1.4 vs. 6 min for fentanyl)
- due to low pk, most is in non-ionized form –> readily crosses BBB
Rapid offset
- hepatic clearance –> renal failure does not effect clearance
Good for short lived stimuli
Remifentanil
Similar potency to fentanyl
Similar blood brain equilibration time to alfentanil
- Metabolized by tissue plasma esterases –> unaffected by liver or kidney failure
- inactive metabolites
Peak effect 1.1 minutes + rapid recovery
Elimination 1/2 time = 6 min
Titratable due to rapid onset/offset
Very easy to predict termination of drug effect
Methadone
Mu opiod agonist
- aslso NMDA receptor antagonist
Prolonged action after repeated doses
- due to binding to tissue protein and tissue accumulation
- prolonged and unpredictable half time ***
- drug can accumulate, resulting in negative side effects –> amount that it takes to reach peak effect varies from person to person
Hydromorphone
Derivative of morphine –> 5x as potent
- effective alternative to morhphine
- same side effect profile
- safer in renal failure patients
Opioid agonists/antagonists
Butorphanol, nalbuphine, buprenorphine
Bind mu receptors
- partial agonists at one receptor
- competitive antagonist at another
Advantages
- produce analgesia
- minimal ventilatory depression
- low potential for physical dependence
Generally resesrved for patients who cannot tolerate pure agonist
Opioid antagonists
Naloxone + naltrexone
High affinity for opioid receptor –> will displace the agonist
- potentially and rapidly reverses agonists effects if accidentally gave too much opioid –> results in decreased pain suppression as well
- precipitates withdrawal –> severity dependent on degree of dependence
- often CV stimulation due to increased SNS activity –> increased perception of pain
Naloxone
Nonselective antagonist at all 3 receptors
Uses
- treat opiate induced ventilatory depression
- treat opioid induced neonatal depression
- treat opioid overdose
Short duration
30-45 min due to removal from brain
Metabolized in liver -> t1/2 = 60-90 min
Side effects
- reversal of analgesia
- increased SNS activity –> tachy, htn, pulm edema, dysrhythmia
- can produce withdrawal in neonates
Why not just give everyone opiates
- negative side effects
- dependence can develop
- potential for abuse
Step wise pain treatment algorithm
Step 1 = mild pain –> simple analgesics = ibuprofen
Step 2 = moderate to strong pain, due to injury, medical procedures or break through pain –> combo analgesic painstop day-time contains both paracetamol and codeine
Step 3 = strong to severe pain due to serious injuries, diseases, cancer or major operations –> prescription meds
NSAIDs
- mechanism
- pharmacology and indications
Mechanism = COX inhibition
Pharmacology and indications
- mild to moderate pain
- musculoskeletal pain/inflammation
- headache/toothache
- post operative (decreased need for opioid management)
COX
Enzyme that synthesizes PGs from arachidonic acid –> mediates pain and inflammation
- protects gastric mucosa, maintains renal perfusion, causes platelet aggregation
COX 1 –> maintains gastric mucosa integrity, renal parenchyma + platelets
COX2 –> mediates pain and inflammation at sites of injury
NSAIDs block action of COX –> reduces production of PG mediators
- specifically PGE2
NSAID therapeutic profile
Analgesia
- peripheral inhibition of PG production
- decrease activation of peripheral nociceptors in response to pain
Antiinflammatory –> inhibition of COX
Anti pyretic
- inhibition of IL1 + 6 production of PGs in hypothalamus
- resetting thermoregulatory center, vasodilation, increased heat loss
Synergistic effect with opioids –> can decrease opioid use by 20-50%
- less nausea and vomiting
- absence of ventilatory depression
NSAID adverse effects
- inhibit platelet aggregation
- COX 1 needed for synthesis of TXA2 from PG - gastric ulceration –> PGs protect GI mucosa by maintaining mucosal blood flow, secreting mucus and bicarbonate
- renal dysfunction
- inhibiting PG synthesis leads to renal medullary ischemia
- PGs autoregulate renal blood flow - hepatocellular injury –> increased levels of transaminases
- allergic reaction
- asthma
- can trigger bronchospasm in asthmatics
- AA makes bronchoconstrictors since shunted from making PG - tinnitus
- MI –> reflexts COX2 suppression of PGI2 which is vasoprotective
NSAID classes
Non-specific COX inhibitors
- ibuprofen, naproxen, aspirin, acetaminophen, ketorlac
COX1 inhibition is responsible for many of the adverse side effects
COX2 selective inhibitors
- celecoxib –> better side effect profile
Non-selective COX inhibitors - salicylates
Salicylates (aspirin)
- analgesic –> for low intensity pain, small effective dose range, doses too high give toxic effects
- antipyretic
- anti-inflammatory –> irreversibly acetylates COX enzymes, prevents PG synthesis
- rapidly absorbed from small intestine
- metabolized in liver to salicylic acid
- side effects –> worst side effect profile
- -> GI upset, dyspepsia, bleeding, tinnitus, allergic reaction
Ibup
Non-selective COX inhibitors - Ibuprofen + naproxen
Propionic acid derivative
Analgesic, antipyretic, and anti-inflammatory –> due to inhibition of PG synthesis
- less GI irritation, dyspepsia, etc. than aspirin
- renal toxicity in patients with preexisting disease
- naproxen –> long elimination half life allows for BID dosing
Non-selective COX inhibitors - acetaminophen
Analgesic-anti-pyretic –> strong central inhibition of PG synthesis
- does not interact with platelets
- no GI irritation
- converted by conjugation and hydroxylation in liver to inactive metabolites
High doses of acetaminophen
- metabolized to NAPQ1 = hepatotoxic
- if glutathione stores are depleted, it can’t scavenge the metabolite and toxicity ensues
Tx with N-acetylcysteine –> antioxidant
- replacement for glutathione, acts as a scavenger
Non-selective COX inhibitors - ketorlac
- potent analgesic effects
- moderate anti-inflammatory effects
- potentiates actions of opioids
- ketorlac 30 mg IM = 10 mg morphine
- absence of ventilatory and cardiac depression
- max plasma concentration 45-60 min
- elimination half time = 5 hours
- hepatic metabolism
Side effects
- inhibits platelet aggregation
- bronchospasm in ASA sensitive patients
- GI irritation
- renal toxicity
- hepatic toxicity –> increased transaminases
Selective cox 2 inhibitors - celecoxib
analgesic, anti-inflammatory
- especially arthritis
- post-operative pain
well abosrbed from gi tract –> low first pass hepatic extraction
crosses BBB –> highly lipophilic
metabolized by cytp450
Lacks inhibition of platelet aggregation
decreased GI side effects
