Neuro Domain - Pharmacy of Pain Flashcards
Nociceptive Pain
Via activation of peripheral nociceptors (mechanical, chemical, thermal sensory stimuli)
Inflammatory Pain
associated with tissue damage and resulting infiltration of immune cells; SENSITIZATION of nociceptors either peripherally or centrally
Neuropathic Pain
associated with damage to CNS or PNS
TRPV1
receptor channel on peripheral sensory afferent terminal (nerve ending)
Hyperalgesia
increased response to noxious stimuli (aka “pain” stimuli hurts even more… like a needle poke feeling like a gun shot)
Allodynia
pain response to innocuous stimulus (aka “pain” from something that normally wouldn’t be painful like a gentle touch)
Sensitization
repeated exposure to a stimulus results in progressive amplification of a response… occurs in inflammatory pain!
Central sensitization
increased membrane excitability and synaptic efficacy and reduced inhibition
peripheral sensitization
reduced threshold and amplification in responsiveness of nociceptors
Role of microglia in sensitization of nociceptors
primary peripheral nociceptor afferents come back to dorsal horn and activate microglia… the microglia then release pro-inflammatory cyto/chemokines that modulate pain by
1) enhancing pre-synaptic release of neuroTs
2) enhancing post-synaptic excitability
Nerve sprouting in sensitization
when fibers from touch receptors synapse on dorsal horn neurons that normally only receive nociceptive input! (allodynia?)
(Substance P + Glutamate)-combo in sensitization
COMBINED release of substance P + Glutamate from primary afferents in dorsal horn causes excessive activation of NMDA receptors
TrkA receptors in sensitization
Nerve growth factor (NGF) and tumor necrosis factor (TNF) released by injured tissue is picked up by TrkA receptors in nerve terminals and retrogradely transported to DRG cell bodies causing altered gene expression!
Role of Nerve growth factor in sensitization (2 of em)
NGF increases production of Substance P and converts non-nociceptive neurons to nociceptive neurons!!! (phenotypic change!)
ALSO influences expression of “nociceptive-specific” sodium channel “Nav 1.8” in DRG
Nav 1.8
sodium channel that is specific to nociceptive neurons in DRG!!!
Capsaicin
TRPV1 agonist… thus it activates TRPV1 nerve terminals and “depletes/exhausts” the supply of Substance P so that other painful stimuli have a decreased outcome
Ambroxol
selectively blocks Nav 1.8 channels.
used to treat oral and pharyngeal cavities
(lidocaine and mexiletine are also thought to work this way which is why some dentists use lidocaine)
Ketamine (aka “special K”)
NMDA receptor antagonist
when used in combination with opioids, may decrease tolerance to opioids!
Gabapentin/Pregabalin
Anti-Convulsant
GABA analogues (GABA is an inhibitory NeuroT)
acts on V-gated CALCIUM channels
treatment of **“neuropathic & inflamm pain” **like fibromyalgia (old people have it… and old people need “calcium” for their bones)
Carbamazepine
Anti-Convulsant
blocks V-gated SODIUM channels
Gold-standard for treating trigeminal neuralgia
Valproic Acid (Valproate)
Anti-Convulsant
blocks V-gated SODIUM channels
Treatment of Migraines
Topiramate
Anti-Convulsant that potentiates GABA transmission
MOA: block V-gated SODIUM channels AND blocks AMPA/kainate Glutamate receptors
Treatment of migraines
Amitriptyline, desipramine etc.
Examples of tricyclic anti-depressants
can manage pain by activating endogenous opioid system by activating the descending 5-HT (serotonin) pathway
Name 4 strong opioid receptor agonists
1) morphine
2) Methadone
3) Meperidine
4) Fentanyl
Methadone
slightly more potent than morphine and equally efficacious
- bioavailability exceeds morphines
- tolerance and abstinence develop slower than morphine
- used to treat opioid tolerance and dependence
- Can also block NMDA and monoaminergic reuptake transporters (thus explaining ability to relieve difficult-to-treat pain)
Meperidine
1/10th potency of morphine and LESS efficacious
pronounced anti-shivering vs other opioid analgesics
may accumulate in kidney with renal insufficiency
Fentanyl
One of the most widely used opioid analgesics
100X more potent then morphine as an analgesic
highly lipophilic with high first pass rate
***can cause muscle rigidity thus should use neuromuscular blocking agent in conjunction
Name 2 Partial/Weak opioid receptor agonists
1) oxycodone
2) codeine
codeine
1/10 analgesic of morphine (from which it is synthesized)
converted to morphine by CYP 2D6
-used as an antitussive
Oxycodone
Used in combo with acetaminophen (percocet) or aspirin (percodan) for oral use
used in controlle-release tablets (oxycontin)
*major drug of abuse
Name 2 opioid receptor mixed agonist-antagonists
1) nalbuphine
2) buprenorphine
nalbuphine
strong MOP antagonist and KOP agonist
**parenteral use only
respiratory depression a problem, and difficult to reverse with naloxone
buprenorphine
partial MOP agonist but antagonist at DOP & KOP
- used in management of opioid dependence
- admin sublingually to avoid first pass effect
as effective as methadone in detoxification of heroin abusers and may be safer also reduces craving for alcohol but costs 10X as much as methodone
Tramadol
NON-opioid analgesic
- synthetic codeine analog
- major MOA = inhibition of serotonin reuptake transporter
Name 2 opioid receptor antagonists
1) naloxone
2) naltrexone
Naloxone
competitive antagonist at MOP, DOP, & KOP
rapidly blocks agonist effects of morphine! (ie reverses resp. depression, coma etc)
Major use is to treat an acute overdose of opioid analgesics *given IV
Naltrexone
Competitive antagonist at MOP, DOP, & KOP
subject to rapid first pass metabolism
blocks effects of heroin for up to 48 hours (thus longer lasting than naloxone)
***used to help prevent relapse in chronic alcoholics; may act by releasing Beta-endorphins
MOA of local anesthetics
Blockade of voltage-gated sodium channels (unmyelinated, small nerve fibers are more susceptible to the effect aka those like A-delta and C-fibers for pain)
Also have a higher affinity for more active nerve fibers vs those at rest
Name 5 local anesthetics listed
1) Cocaine (ester-like)
2) Tetracaine (ester-like)
3) Bupivacaine (amide-like)
4) Lidocaine (amide)
5) Mepivacaine (amide)
Name the 5 major goals of a generalized Anesthetic
1) analgesia
2) muscle relaxation
3) stable CV and resp. function
4) amnesia
5) loss of consciousness
MOA of general anesthetics (inhaled and IV)
GABA-A mediated inhibition… they don’t need to bind to GABA-A receptors as “agonists” but simply sensitize the GABA-A receptors to endogenous GABA which leads to an influx of chloride ions and thus hyperpolarization preventing nociceptive action potential formation
What are the 2 general anesthetics that are exceptions to GABA-A mediated inhibition and name their MOA
1) Ketamine
2) Nitric Oxide
Work by inhibiting the glutamate-gated cation channel in NMDA receptors
Neural pathways blocked during anesthesia
even low [ ] of anesthetics inhibit transmission of nociceptive input to neurons in substantia gelatinosa in dorsal horn and in the spinothalamic tract neurons
How do general anesthetics cause sedation?
Via suppression of reticular activating system of the brainstem
How are anesthetics similar to sleep?
anesthia modulates endogenous sleep regulating pathways such as the ventrolateral preoptic nucleus and tuberomammillary nuclei.
How do anesthetics cause amnesia?
via actions in the hippocampus
definition of Minimum alveolar concentration (MAC)
the avleolar concentration of anesthetic such that 50% of patients do not move in response to a noxious stimulus
what does blood:gas coefficient measure and why is it important?
it is a measure of solubility of a gas… the higher the number, the easier the gases dissolve in the blood.
A higher solubility also means a less rapid increase of partial pressure in the arteries thus there won’t be a big change in arterial tension. (low solubility results in a fairly rapid increase in arterial tension)
What are the 2 differences between induction and recovery phases of anesthesia?
1) You can enhance movement of anesthesia into lungs by increasing the concentration of drug into the air the pt. is breathing… but in recovery, manipulation of concentration of drug cannot be altered
2) In recovery you can have variations of arterial tension in different tissue whereas in induction the arterial tension due to anesthetic is zero (as it hasn’t entered yet)
Name 4 inhaled anesthetics and one fun fact about them
1) desflurane (increase HR)
2) Isoflurane (increase HR)
3) Sevoflurane (no change in HR and is a bronchodilator thus is DOC for pts with pulmonary probs) also commonly used in ped. pts.
4) Nitric oxide – usually combined with others not used on its own
Name 4 IV general anesthetics with fun facts and speed of onset
1) Ketamine (CV stimulant; increased cerebral blood flow) –moderately rapid post-op illusions and vivid dreams aka emergence phenomena*
2) Midazolam(benzodiazepine) – CV stability – SLOW onset
3) Propofol – RAPID induction and maintenance only with less post-op nausea
4) Thiopental (barbituate) – standard induction; CV depressant. rapidly crosses the BBB
