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Analgesic Drugs: Mechanisms, Migraines, & Antirheumatics
Terms in this set (43)
what's going on with pain?
PNS nociceptors sense injurious stimuli (whether mechanical, thermal, chemical, or inflammatory) and respond "polymodally" --> they neurotransmit the message up the spinal cord (using Glutamate and Substance P) --> signal gets relayed to the brain --> brain provides cognitive, emotional, and deliberated motor responses to the nociception
*extreme injury (nociceptor hyperexcitation) can also trigger the "spinal motor reflex" which moves faster by its own pathway
what does beta-endorphin do to act against pain?
- MOA: it is the strongest endogenous agonist of the Mu Opioid Receptor [MOR] that acts as a neuroinhibitory peptide --> mediates euphoria and analgesia, and spinal cord and PNS nociception
- result: peaceful/calm euphoria and analgesia
T/F: beta-endorphin is the main endorphin and main analgesic target
true! it acts on neuroinhibitory Gi-coupled MORs ("Mu or MOR for Morphine")
examples of when the Beta-Endorphin mechanism is naturally evoked:
during the "runners high" and during detachment from extreme physical trauma in emergency "fight or flight" situations (+NE and Adr)
what are some other neuroinhibitory opioid receptors besides beta-endorphin?
Mu-, Kappa-, and delta- opioid receptors
- bring "short-lived" endorphin agonists enkephalin, B-endorphin, and Dynorphin
what are the 4 important circuits for endorphin analgesia?
1. endorphin euphoria and pain irrelevancy
2. endorphin analgesia
3. endorphin local spinal analgesia
4. endorphin systemic anti-nociception
major benefit of the endorphin analgesia circuits:
mediate temporary extreme analgesia, particularly upon emergency/bad wounding
- lessens pain and makes it irrelevant during sympathetic nervous system-mediated "fight-or-flight" emergencies
- binds the inhibitory Mu-opioid receptor (MOR)
- this endogenous and short-term relief of pain can be reproduced long-term by opioids
how is local Algesia sensed/transmitted through the body?
nociceptor nerve axonal conduction at voltage-gated Na+ channels along Nodes of Ranvier (can block this conduction with local anesthetics)
define neuropathic Algesia (neuralgia)
damage to peripheral nociceptors, or to spinal or crainial nerves
- can lessen this with neuroinhibitory analgesics, which include many anti convulsive neuroinhibitor drugs like THC and CBD
what causes trigeminal neuralgias?
tooth, jaw, and face pain jolts mediated by damaged PNS trigeminal nerve (cranial nerve V)
- the dendrites from facial nociceptors' extend up cranial nerve V to the ganglion near the base of the brain and can cause trigeminal-mediated migraine
- nerve pressure (e.g. aneurysms) or demyelination/scarring (from age or MS) cause inappropriate firing, felt as jolts of pain
how can someone know a trigeminal ganglionic migraines is coming on?
sometimes preceded by visual "aura" from brain vasoconstrictive 5-HT (causing the aura) and then consequent inflammatory ACh and Substance P are released
the release of what chemical causes the actual pain of the headache?
calcitonin gene-related peptide (CCRP) is released, which causes the brain meninges to vasodilate (lasts 4-72 hours)
summary: first there is a VASOCONTRICTION phase causing the aura, followed by a VASODILATION phase causing the pain of the headache
what pathway/RXN is stimulated by injury that mediates the perception of pain?
define inflammatory algesia, hyperalgesia, and allodynia:
prostaglandins released by damaged cells cause local vasodilation, edema, and the release of inflammatory cytokines that act on local + distant nociceptors to trigger pain
- can even trigger pain from non-painful stimuli (allodynia) and cause supersensitive pain (hyperalgesia)
which drugs are taken to decrease the effects of this pathway?
NSAIDs, CNS prostaglandin blockers, and other anti-inflammatory drugs like DMARDs (disease-modifying anti rheumatic drugs)
one more time- what is allodynia?
pain in response to normally NON-painful stimuli
what are the 2 different kinds of inflammatory algesia?
normal inflammatory algesia or autoimmune inflammatory algesia
NORMAL inflammatory algesia
damaged cells' PhosphoLipase A2 converts membrane lipids to arachidonic acid, from which COX1 and COX2 then synthesize prostaglandins that diffuse from the damaged cells
- prostaglandins trigger local vasodilation, edema, and inflammatory and pyretic (fever-inducing) cytokines, which act on local nociceptors neurons to cause nociceptor firing (algesia) and aggravate nociceptor firing severity (i.e. hyperalgesia and allodynia)
AUTOIMMUNE inflammatory algesia
inflammation can arise not only from injury and infection, but also from autoimmune cells attacking normal body cells
how do local anesthetics inhibit the normal saltatory conduction of pain?
- normally, depolarization "leaps" down cytoplasm between unmyelimated Nodes of Ranvier's voltage-gated Na+ channels (very fast)
- however, smaller-diameter nociceptor fibers can't depolarize (fire) when channels are blocked by local analgesics, so then there is NO nociception
what are neuropathic algesias?
when there is damage to peripheral nociceptors, spinal nerves, or cranial nerves --> causes algesia and dysesthesia (abnormal excess sensation)
sources of damage to peripheral nociceptors, spinal nerves, or cranial nerves in neuropathic algesias:
- pressure on nerves from impacts, spinal-disc or muscle compressions, tumors, edema, surgical scarring, swollen joints and tendons, aneurysms, or abnormal vasodilation (migraine)
- neurolocal disorders
- nerve-demyelinating diseases
- amputation and consequent supersensitization or somatosensory topographic redirection of denervated spinal cord/brain neurons (e.g. phantom-limb algesia or dysesthesia)
what are some ways you can alleviate phantom-limb pain?
by rubbing the "mirrored" and or "remapped" body area
what are the 4 migraine drug classes?
1. cerebral vasoconstrictors
2. cerebral vasodilators
3. cerebral preventatives of vasoconstriction
4. cerebral preventatives of vasodilation
MOA of cerebral vasoconstrictors:
REVERSE migraine attack's final acute vasodilation and pain (ex. sumatriptan)
MOA of cerebral vasodilators:
PREVENT migraine attack's initial vasoconstriction and/or final acute vasodilation and pain (ex. propranolol)
MOA of preventatives of vasoconstriction:
PREVENT neurotransmitter triggers of attack's initial vasoconstriction (ex. divalproex, topiramate, and botox)
MOA of preventatives of vasodilation:
PREVENT neuromodulator trigger of attack's final vasodilation and pain (ex. erenumab)
which drug is taken to stop an ongoing migraine attack?
- a migraine reversing drug that is a serotonin (5-HT1) receptor agonist
- reverses the cerebral/meningeal vasodilation that causes pain via vasoconstriction of 5HT1D receptors
- acts for 2hr
- contraindicated in CAD patients
which drug is used as a migraine-preventive drug that is also a beta-receptor antagonist (beta-blocker) used in hypertension?
- prevents migraines by sympatholytic calming of triggers like stress and high BP
- prophylactic vasodilation of brain meningeal blood vessels to reduce initial vasoconstriction and later acute vasodilation --> prevents it from even coming on in the first place!
-- > also used for heart arrhythmias, hypertension, golf yips, and stage freight
which drug is a migraine-preventive drug that is also a neuroinhibitory anticonvulsant?
- increases GABA levels and blocks BOTH voltage-gated Na+ channels and low-threshold T-type Ca2+ channels
- prevents migraine's initial transmitter triggers
- side Fx= is a teratogen (causes IQ loss in fetuses), hair loss, hepatotoxic
"Divalproex bad for fetus"
his example question: "which algesia or analgesia mechanism is often treated with drugs that are also used as anticonvulsants?"
*Divalproex is the anticonvulsant med that is also used to treat trigeminal neuralgia migraines
which drug, similar to Divalproex, is a migraine-preventive drug that is also a neuroinhibitory anticonvulsant?
- blocks voltage-gated fast Na+ channels, inhibits Glu AMPAr, and enhances GABAr
- used to prevent migraines
Topiramate (just recognize the name Topiramate along with Divalproex and know that neuralgia drugs are also anticonvulsants)
which drug is a "migraine trigger-blocking" drug that gets transported up sensory dendrites to the trigeminal ganglionfrom skin injection sites on the head but can cause paralysis of face and head muscles if too much injected near muscles?
- block's the ganglia's synaptic vesicle release of vasoconstrictive 5-HT and pro-inflammatory ACh and Substance P that trigger migraine attacks and pain
which "migraine vasodilation-block" drug
is a humanized monoclonal antibody (huMAb) that blocks brain calcitonin gene-related peptide receptor (CGPR) on meningeal vessels?
- prevents the trigeminal release of CGPR, which is what normally causes the final vasodilation and pain
- $7000/year, injected one a month (supposed to be very effective)
new topic. --> immunosuppressors
what is the main drug used for transplant rejection drug?
- uses T-cell specific rabbit or horse ATG infusions to prevent transplanted organ rejection
- suppresses T cell recognition of foreign organ antigens (but also impairs T-cell immunity to cancer and infections :(
Anti-Thymocyte Globulin, ATG
which drug is known as the "fetal rejection drug" and is used to prevent fetal Rhesus Disease? (prevent the immune attack from the mom to the baby)
an anti-D-immunoglobulin drug
how does the anti-D-immunoglobulin drug prevent the mom's body from attacking the fetus?
- a human blood serum donated by male Rh(D)-negative blood-donors previously exposed during prior surgeries to blood transfusions from Rh(D)-positive blood donors is injected into a pregnant Rh-negative mom with an Rh+ fetus to prevent her body from killing her Rh+ fetus
- the mom makes anti-anti-D antibodies that desensitize her anti-D antibodies that would have made B cells to attack her baby
which drug. is a transplant and autoimmunity drug/immuophilin ligand drug that is naturally derived from the parasitic fungus of scarab beetles?
- used to prevent transplanted organ rejection, marrow Graft vs. Host disease, and autoimmune disease symptoms (like RA, Sjogren's syndrome, dry mouth, and oral lichen planus)
- side Fx= can cause gingival hyperplasia
which drug is taken to prevent the onset of MS and reduce relapses by 30% in relapsing-remitting MS?
- an autoimmunity drug that inhibits autoimmune T-cells' brain infiltration (CNS)
- increases NK cells' anti-neuroinflammatory cytokine release
- can cause skin necrosis at the site of i.m. injection
Interferon-beta 1 a/b
"Interferon-beta 1 a/b 'interferes' with the onset of MS"
which drug MOA involves gold particles accumulating in body cells to treat rheumatoid arthritis?
- a Disease Modifying Anti-Rheumatic Drug (DMARD)
- derived from a gold-glucose
- impairs more metabolically-active cells like immune T-cells, thus is an immunosuppressant, but very delayed action (the gold particles must first accumulate in body cells)
- side Fx= chrysalis (the accumulation of gold in skin cellsccumulation of gold in skin cells, which after sun or laser-light exposure will turn skin patches to purple-brown/mauve color)
auro=gold, the "gold standard" for treating RA
what other uses for antimalarials (Hydroxychloroquine) were discovered during WWII?
they were found to also be immunosuppressive drugs that could alleviate autoimmune symptoms in vets with Lupus or RA (still doubles today as a DMARD to treat RA, Lupus, and other autoimmune disorders, including Sjorgren's disease)
- side-Fx of Hydroxychloroquine: retinal and cardiac toxic (need eye-screens and strict dosing)
which drug is a folate/folic acid antogonist that is the MOST popular RA drug now, and also used for treating Sjorgren's?
- an analog of antifolate cancer drug aminopterin that was effective and safe for RA in 1962, but unused for >20 years until the 1980s
- triggers T-cell apoptosis and releases adenosine, inhibiting inflammatory enzymes/cytokines/adhesins
*remember that rheumatoid arthritis drugs are also used to treat Sjorgren's!!
Methotrexate (an antimetabolite DMARD)
which drug is effective for RA but is also used to treat psoriatic arthritis, plaque psoriasis, Crohn's disease, and eczema?
- it is a "biological response modifier (BRM)" which means it works as a humanized monoclonal antibody (Mab)-style DMARD that selectively inhibits the TNF-alpha inflammatory cytokine
- now is a "generic" drug
- some pretty scary side-Fx = cancer, rare bacterial and fungal infections (all consequences of immunosuppression)
weird word...treats weird diseases..with some creepy side Fx
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