CNS I Pharm - Migraines/Opioids Flashcards
MIGRAINES
Cause of Migraines?
Altered brainstem activity leads to inflammation and activation of sensory nerves, mainly the trigeminal nerve (main nerve innervation for meninges and cranial vessels). These nerves then release neuropeptides (CGRP) that act to relax vascular smooth muscle (vasodilation) and promote capillary permeability and leakage of proteins, which further irritates the sensory nerves.
Drug of choice for mild migraines?
NSAIDs –> Ibuprofen, aspirin, acetaminophen or combinations (Excedrin = Aspirin + Aceta + Caffeine)
Caffeine has a vasoconstrictive action –> remember that vasodilation is a central problem)
Mechanism for Triptans
Vasoconstriction –> Structurally similar to 5HT and act at the 5HT1B/D receptor (Gi coupled) –> this makes them very selective
Gi receptor review –> lower cAMP –> lower PKA –> dephosphorylate MLCK (increases MLCK activity) –> increase phosphorylation of MLC –> vasoconstrict
Also inhibit the release of vasodilatory peptides from sensory nerve terminals (CGRP)
Often combined with NSAIDs
Sumatriptan
Rapid Onset, especially for SC injection or nasal spray; short half-life, metabolized by MAO; indicated for rapid migraine relief
Frovatriptan
Slower onset and longer half-life; reduce migraine recurrence; metabolized by the liver
GOOD FOR MENSTRUAL MIGRAINES
Side Effects of Triptans
Contraindicated in those with coronary or cerebrovascular disease, or UNCONTROLLED HTN
DO NOT take with ERGOTS within 24 hours –> too much constriction
MAO inhibitors should not be taken with SUMATRIPTAN (wouldn’t break it down!)
Taking with SSRI creates risk for SEROTONIN SYNDROME
Mechanism of Ergots
“messy drugs”
VERY POTENT vasoconstrictors with very high affinity
Non-selective 5HT receptor agonist
Partial alpha adrenergic receptor agonist/antagonist
Generally LESS EFFECTIVE than triptans, but may be useful in patients that are unresponsive to them
—-> GI absorption is "erratic" with ergots: sublingual or parenteral preps only
Ergotamine and Dihydroergotamine
Sublingual tablet that is LONG LASTING (24 hour vasoconstriction)
Therapeutic doses –> 5HT1B/D receptor agonist like triptans, AS WELL as an ALPHA PARTIAL AGONIST (even more constriction)
–> At high doses, alpha antagonist
Nausea/Vomiting
Dihydroergotamine is an IM, SC or nasal spray
Side Effects of Ergots
Contraindicated in those with coronary or cerebrovascular disease, or UNCONTROLLED HTN
Contraindicated in pregnancy
Inhibit CYP3A4 (drug interactions
DO NOT USE WITH BETA BLOCKERS OR TRIPTANS (excessive vasoconstriction)
Migraine Prophylaxis
Need to limit the use of triptans and ergots if having frequent migraines (can add triptans or NSAIDs for acute/breakthrough migraines)
BETA BLOCKERS are first line for prophylaxis (Propranolol and Timolol)
Seems to work after a few weeks (unclear mechanism)
Cost-effective for continuous treatment, relatively safe
NOT FOR USE IN PATIENTS WITH DECOMPENSATED HEART FAILURE AND ASTHMA, as expected
Anti-epileptics and tricyclics can be useful, but have way more side-effects
Preventing Nausea
METOCLOPRAMIDE
Treats the gastric stasis associated with nausea by speeding up gastric movement (this is also an effect of caffeine)
Appears to exert its effects via activity at the D2 receptors (D2 receptor antagonist)
What migraine drug is safe in pregnancy?
SUMATRIPTAN
All ergots are contraindicated, NSAIDs cannot be used in 3rd trimester
A vs. C Fibers
A Fibers mediate "first pain" – the initial pain when touching a hot stove or stepping on a nail; mediate the “pull away” reflex –> these fibers are thinly myelinated
C fibers –> “second pain” –> dull burning and persistent pain associated with injured or inflamed tissue –> these are unmyelinated
Where are opioid receptors found?
Brain, SC, peripheral nerves, GI tract and immune cells
Their expression in nociceptive nerve endings make them great analgesic targets
–> Expression in the gut and immune cells is responsible for their side effects!
MU receptor is pharmacologically relevant
Signal transduction at opioid receptors
Activation of G proteins (Gi, Go) leads to:
–> Inhibition of adenylyl cyclase –> less cAMP formation and protein phosphorylation (mu, delta, kappa)
–> suppression of voltage gated calcium currents causing decrease of NT release from presynaptic terminals (mu, delta, kappa)
–> Activation of receptor-operated K+ current resulting in membrane hyperpolarization and lowered excitability of postsynaptic neurons (mu)
How do opioids work for analgesia?
Bind primarily at MU receptors throughout regions of the BRAIN and SC that are involved in pain transmission and modulation
Reduce the transmission of pain AND remove the emotional component
What kind of pain do opioids help with?
CONTINUOUS DULL PAIN (what fiber type?!?!?!) –> severe pain can be reduced at sufficient doses
Despite SOME SEDATION, these effects occur w/o loss of consciousness
Pain relief is also SELECTIVE FOR NOCICEPTION (not touch or temp), because the MU RECEPTORS are PRIMARILY EXPRESSED ON C FIBERS responsible for chronic inflammatory pain (thus A fibers aren’t really affected)
Tolerance and Opioids
Is definitely seen; lose effectiveness as the body adapts to the drugs (need a higher dose for them to work) –> unknown mech, receptor mediated
CROSS TOLERANCE will occur between opioids working at the same receptor
What are some other effects of opioids?
Euphoria! Due to the drug’s activation of the DA reward pathways in the mesolimbic system; underlies the addictive properties
Sedation and anxiolysis –> mu receptor inhibition of NE release in the locus ceruleus
COUGH SUPPRESSION! Works at “cough center” of brainstem (Codeine is often used as an anti-tussive doses that are sub therapeutic for analgesia – D isomer of codeine analog = DEXTROMORPHAN –> found in many cough formulas)
Biggest side effect of opioids?
RESPIRATORY DEPRESSION!!! #1 cause of death from overdose
Opioids can get to the brainstem respiratory center, reducing responsiveness to the concentration of CO2 and effectively reducing the frequency of breathing
At high doses, the rate of breathing can DROP TO 3-4 BREATHS/MINUTE, decreasing respiratory volume, and generating an irregular pattern of breathing
While this normally does not happen, it is a common manifestation of MORPHINE OVERDOSE
Particularly pronounced WHEN COMBINED with other depressants (alcohol, barbiturates, benzos)
How can we avoid resp depression?
Well, first of all, it RARELY occurs in absence of underlying pulmonary problems and standard doses
Primarily mediated by MU RECEPTORS – administer opioids that work on other receptors or a mix of receptors
Develop TOLERANCE to this effect! Good! So we can avoid by slowly escalating doses of opioids
Other side effects?
Nausea/vomiting (area prostrema has opioid receptors)
Increase in vestibular sensitivity (vertigo?)
Constipation –> increase in intestinal tone, decreased motility/propulsion, dehydration of feces, intestinal spasm
as a result, these drugs treat diarrhea!
Orthostatic HYPOTENSION (peripheral vasodilation and decreased peripheral resistance)
Histamine release (itchy!)
MORPHINE
Prototypic opiod; HYDROPHILIC due to a hydroxyl group, so it has a SLOW PENETRATION INTO THE CNS
Hydroxy at C3 –> important for opioid receptor binding
Methyl group –> characteristic of morphine, important for ACTIVATION of the receptor
HIGH FIRST PASS (liver metabolizes 75%) so 25% oral bioavailability (lower than most opioids)
Oral and Injectable half life = 4-5 hrs
EPIDURAL and THECAL = up to 24 hours!!!
But thecal injects can SPREAD ROSTRALLY towards brain, so be careful
Metabolism of Morphine
High first pass
Conjugation of Morphine –> primarily occurs in the liver, but sometimes in brain/kidneys
GLUCURONIDATION occurs at the 3rd and 6th hydroxyl groups –> 60% of morphine goes to inactive Morphine-3-glucouronide
10% is converted to Morphine-6-glucouronide, which is active and 2x as potent
Remaining 30% unchanged and excreted
CAREFUL in renal insufficient patients as metabolites can accumulate in the liver
