Analgesia (1) Flashcards
What are the major groups of analgesics?
narcotics (all opiate drugs acting on central and peripheral opiate receptors) and non-narcotics (various mechanisms, including NSAIDs)
What are the major opiate agonists?
alfentanil, sufentanil, remifentanil
codeine
fentanyl
hydrocodone
hydromorphone
methadone
meperdine
morphine
oxycodone
oxymorphine
tramadol
What are the major opiate partial agonists?
butorphanol
buprenorphine
nalbuphine
pentazocine
What are the major opiate antagonists?
naloxone
naltrexone
methylnaltrexone
What are the NMDA receptor antagonists?
ketamine
dextromethorphan
What are the TCAs?
amitriptyline
nortriptyline
imipramine
desipramine
What are the anticonvulsants?
gabapentin
lamotrigene
carbamazepine
pregabalin
What are the major endogenous opiod peptides?
enkephalins, endorphins, and dynorphins
Enkephalins, endorphins, and dynorphins are derived from what?
large precursor proteins, POMC (endorphins), preproenkephalin, and preprodynorphin via trypsin-like enzyme activity
Where are POMC producing cells located in the CNS?
predominantly in the arcuate nucleus of the hypothalamus and the NTS. These areas project neurons widely to limbic and brainstem areas and to the spinal cord.
POMC expression also occurs:
in the anterior and intermediate lobes of the pituitary and in pancreatic islet cells
Circulating beta-endorphin is derived predominantly from where?
pituitary where it is released
Where is proenkephalin peptides found?
Proenkepahlin peptides are present in areas of the CNS involved in the processing of pain info, for ex. the spinal trigeminal nucleus and perqiaquductal gray area in the spinal cord
They are also found in areas invovled in affective behavior such as the amygdala, hippocampus, and the frontal cerebral cortex, areas involved in motor control, such as the caudate nucleus and the globus pallidus, those involved in modulation of autonomic control, such as the medually oblongata, and neuroendocrine function, such as the median eminence.
Circulating proenkephalins are derived from where?
adrenal medulla and exocrine glands of the stomach and intestine
Dynorphins are widely distributed in the CNS, frequently being coexpressed with other opiod peptides
Anatomic sites for therapeutic intervention of pain
Notice how NSAIDS primarily modulate initial signal transduction, Na+ channel blocks (local anesthetics) block signal conduction in nociceptive fibers, opiods, antidepressants, and antiepileptic drugs and a2-adrenergic agonists all modulate transmission of pain sensation in the spinal cord by decreasing the signal relayed, and opiods also modulate the central perception of painful stimuli
Describe peripheral pain signaling
Free nerve endings generate an AP that propagates to the the dorsal horn via Adelta and C fibers. The AP activates presynaptic voltage-gated Ca+ channels in the dorsal horn, leading to calcium influx and subsequent synaptic vesicle release. Neurotransmitters include glutamate, CGRP, and substance P, and they bind postsynaptically, while stimulation of ionotropic glutamate receptors leading to fast postsynaptic depolarization, and slow depolarization for the others.
What things inhibit Ca+ entry to the presynaptic dorsal horn during pain relay?
nor (acting via a2-receptors), GABA (via GABAb receptors), and endogenous opiates, endorphin and encephalin
How do nor (acting via a2-receptors), GABA (via GABAb receptors), and endogenous opiates, endorphin and encephalin all inhibit pain relay postsynaptically?
they increase the K+ conductance, causing hyperpolarization of the cell to interrupt pain signaling
T or F. So, opiate analgesics work both pre- and postsynaptically to inhbit pain propagation
T. Activation of both pre- and post synaptic u-opiod receptors by descending and local-circuit inhibitory neurons inhibit central relaying of nociceptive stimuli. Recall, in the presynaptic terminal, u-opiod receptor activaiton decreases calcium influx and postsynaptically, it increases outward K+ conductance to hyperpolarize
What are the main opiod receptor subtypes?
mu (u, OP-3), delta (OP-1), and kappa (k, OP-2)
What are the functions of mu (OP-3) receptors?
supraspinal and spinal analgesia; sedation; decrease respiration; decrease GI transit
modulation of hormone and neurotransmitter release
What opiods bind most to mu receptors?
endorphins > enkephalins > dynorphins
What are the roles of delta opiod receptors?
supraspinal and spinal analgesia
modulation of hormone and NTM release
What opiods bind most to delta receptors?
enkephalins > endorphins > dynorphins
What are the roles of k opiod receptors?
supraspinal and spinal analgesia; psychotomimetic effects
decrease Gi transit
What opiods bind most to kappa receptors?
dynorphins >> endorphins and enkephalins
Note that the green box represents complete OP-3 agonists, while the red drugs with +- are partial agonists to mu receptors (aka OP-3), and nalbuphine is the only listed mu receptor antagonist .
What opiods also bind to other receptor subclasses?
Pentazocine, Nalbuphine, and Butorphanol all bind positively to Kappa receptors
Buprenorphine negatively binds to delta and kappa receptors
What are the most commonly abused opiates?
hydrocodone, oxycodone, hydromorphone, and oxymorphone
Note the mechanism of methadone (blocks NMDA receptors) and Tramadol (NE and 5-HT reuptake blockers)
What is a very important point about mixed OP-3 agonist/antagonists (i.e. pentazocine, butorphanol)?
these drugs can precipitate withdrawal in an opiate addict or in someone receiving full-agonist opiates for a legit medical reason
Through effects upon the OP-2 receptor, these drugs are also associated with the production of dysphoria (a state of unease or generalized dissatisfaction with life.)
T or F. Pentazocine and Nalbuphine (partial OP-3 agonists) are useful for moderate pain but less effective than morphine for severe pain
T. Owing to a ceiling effect in both analgesia and respiraotry depressant effects
Butorphanol produces more sedaiton than nalbuphine at similar doses (considerd best suited for the relief of acute pain (e.g. postop) or as a nasal formulation for migraine tx.
In contrast to pentazocine and butorphanol, low doses of nalbuphine given to pts. with stable coronary artery disease do not produce an increase in cardiac index, pulmonary arterial pressure, or cardiac work, and systemic BP is not altered much
How are opiates given?
PO (peak analgesic effect at 1-1.5 hrs, or 3-5 hrs for extended release)
Transdermal- fentanyl patches provide 48-72 hrs of stable drug delivery (best for dysphagic pt. or if constipation is an issue)
Rectal
SC/IV- may employ a pt controlled analgesia device (PCA) (dose rate and max delivery/hr set by a nurse and locked to prevent tampering)
Intraspinal
How are opiates absorbed?
Note that morphine has bad oral bioavailability while codeine and oxycodone dont
Describe the distribution of opiates
- lipophilic
- weaking plasma protein binding
- easy transfer to tissues (high flow organs first): skeletal muscle serves as the main reservoir because of its greater relative bulk
- adipose tissue bloodflow limits accumulation (with continued drug delivery, however, opiates do accumulate which can act as a depot storage site and release drug slowly, once dosing is terminated)
Most opiates are eliminated via _____
urine (renal)
What are your best opiate options for those with renal failure?
hydromorphone and fentanyl
What are the major AEs of opiates?
-behavioral restlessnes, hyperactivity (in dysphoric rxns)
respriatory depression
N/V
increased intracranial pressure
postural hypotension accentuated by hypovolemia
constipation
urinary retention
itching around the nose, urticaria (more frequent with parenteral and spinal administration)
What are the classic symptoms of opiod OD?
respiratory depression
pinpoint pupils
coma
Opiates can produce CNS depression, so note that the presence of any concurrent depressant agent will worsen the situation. What are some concurrant CNS depressants to avoid when giving opiates?
- Sedative hypnotics (result in CNS depression, particularly respiratory)
- Antipsychotic tranquilizers (increased sedation; variable effects on respiratory depression; accentuation of CV effects (antimuscarinic and a-blocking actions))
- MAOIs (relative contraindication to all opiod analgesics b/c of the high incidence of hyperpyrexic coma; HTN all reported)
What is another isseu with opiate drugs?
tolerance (accompanied by the disappearacne of some of the AEs).
How does tolerance develop to opiates?
receptor activation by an agonist triggers not only receptor activation, but also desenitization. Receptor phosphorylation by the protein GRK increase receptor affinity for beta-arrestin- this enhances interaction between the two proteins and leads to internalization. Internalized receptors are then directed to early endosomes where they either recycle back to the membrane or are degraded.
Note the signficant difference between endogenous enkephalin recycling and that of exogenous morphine. Mainly:
for enkephaln, signaling can persist because of the relative balance between desensitization and resensitization. However, with morphine, there is a slow persistent desensitization and little recycling, favoring loss of activity and tolerance building
Another feature of chronic opiate use is hyperalgesia. Explain
Increased pain pperception (seen most with morphine, fentanyl, and remifentanil)- this could result in the physician increasing dose to compensate
What is the major problem with chronic opiod use (besides addiction)?
constipation (due to anticholinergic actions)- opiates lead to stasis, absorption of water, and hardening of stool. Therefore, those pts chronically using opiods should always be given a stool softener and/or laxative to prevent stool impacton from occurring.
Also a carefully titrated opiate antagonist can also relieve some of the constipative effects, although loss of pain relief occurs if the dose is too high
What predisposing factors suggest constipation will occur with chronic use of opiods?
advanced age, immobility, poor diet, intra-abdominal pathology, neuropathy, hypercalcemia, etc.
What opiate has less constipative effect?
transdermal fentanyl < oral sustained released morphine
How is the somnolence or mental clouding produced by opiates handled?
- opiod rotation- the use of another opiate with slightly different patterns of AEs
- the use of stimulants like metyhlphenidate, modafinil, dextroamphetamine
How is the N/V caused by opiates handled (note that N/V is most common following rapid admin of high dose opiates and is much less common when the dose is titrated up slowly over time)?
change the route of admin
How is the respiratory depression caused by opiates handled (note that this most often occurs due to drug abuse and is rarely a problem if dosing guidelines are followed)?
- withhold dosing
- opiod antagonist such as naloxone can be given to rapidly reverse (multiple administrations may be required to cause sustained reversal owing to drug half-life differences)
What are the risks of severe respiratory depression with opiates?
- given too quickly
- with sleep apnea syndrome (obesity, short neck, snoring)
- combined with sedative-hypnotic
Pruritis is another AE of opiates, occurring in about 2-10% of pts. What causes it?
Etiology unclear- not a true allergic rxn. Possibly a central action on mu receptors but distinct from the direct liberation of histamine from mast cells as seen with morphine (for ex., fentanyl, sufentanil, and oxymorphone are less likely to produce histamine release, yet they are still associated with pruritis)
How is pruritis caused by opiates tx?
Antihistamines (varying success)
low dose of opiod antagonist
What should you do if opiods cause contact dermatitis or systemic hypersensitivity?
switch to another alkaloid or semisynthetic opiod
