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
CODEINE
Is a PRODRUG of MORPHINE
There is a methyl substitution at the 3rd hydroxyl of morphine –> remember that the hydroxyl was imp for binding –> lower potency than morphine!
Gets converted (demethylated) to morphine via CYP2D6 –> Only 10-15% gets demethylated so it is 10-15% as POTENT (better bioavailability); inhibit and block codeine’s effect (won’t metabolize)
So we need 8x as much codeined to achieve morphine’s effect (parenteral); need 4x to achieve the same oral dose
Relatively weak opioid, frequently COMBINED WITH NSAIDs (aspirin or acetaminophen)
HEROIN
Has 2 acetyl groups at the 3rd and 6th carbons (no hydroxyl groups ) so it has NO EFFECT AT OPIOID RECEPTORS
More lipophilic so it can rapidly enter the CNS where it is then deacetylated into morphine and binds at the opioid receptors – 2-3x more potent than morphine
EUPHORIC effects!! Rapidly metabolized, fast acting, DRUG OF ABUSE
HYDROMORPHONE and OXYMORPHONE
Ketone group at 6th C –> higher liposolubility than morphine; crosses BBB faster
6-10x MORE POTENT THAN MORPHINE!!!! Similar side effect profile
Oxy has an additional hydroxyl group
HYDROCODONE/OXYCODONE
Ketone and Ketone+hydroxyl group substitutions
Both more potent than oral codeine; Hydro = 6-8x more potent, oxy is 8-9x more potent (about that of morphine)
Used in combo with aceta or aspirin (Oxy + aceta = Percoset, Oxycontin = sustained release oxy
Demethylated into Hydro and Oxymorphone…more potent derivatives
CYP2D6 metabolism –> blocking this will NOT block the analgesia (unlike codeine!)
FENTANYL
100x more potent than morphine!!!!
Extensively used in anesthesia because of its RAPID ONSET AND TERMINATION (IV has peak analgesia at 5 minutes, morphine is 15 min)
SPINAL ADMINISTRATION – HIGHLY lipophilic so it just stays put and doesn’t spread rostrally (remember, morphine is VERY hydrophilic)
Transdermal patch – great for long term severe pain, like chronic cancer pain
Lollipop and lozenges – useful for breakthrough pain (faster - buccal mucosa)
SUFENTANIL is 1000x more potent than morphine!
LEVORPHANOL
~5x more potent than morphine
Metabolized very slowly (unlike fentanyl)
Half life of 12-16 hours!!!! (morphine = 4-5)
FEWER SIDE EFFECTS (less N/V!)
METHADONE
Equipotent to morphine; LONG HALF LIFE 15-40 hours!
Slow kinetics = LESS euphoria –> useful in heroin detoxification and maintenance treatment of opioid addicts
D-isomer blocks NMDA receptors –> ONLY OPIOID USEFUL FOR TREATING NEUROPATHIC PAIN!!**
L-Isomer is responsible for the analgesia
PROPOXYPHENE
Related structurally to methadone; 1/2 the potency of codeine when given orally
Used less frequently because of TOXICITY with repeated doses (buildup of metabolites)
MEPERIDINE
1/6 as potent as morphine
Side effects similar to morphine if given at equipotent doses
Not often used due to toxicity –> BUILDUP OF BYPRODUCTS CAN CAUSE CONVULSIONS; especially problematic because the metabolite has a longer half life than the drug itself!!!!
TRAMADOL
Synthetic codeine analog
Partial mu receptor agonist with inhibition of NE and 5HT reuptake
As effective as morphine for mild to moderate pain
SInce it is only a partial agonist, there is a CEILING EFFECT ON ITS ANALGESIA
Much less likely to experience resp depression or develop addiction
LOPERAMIDE
(Imodium)
Poorly penetrates CNS, therefore LACKS euphoria or analgesia
Retains constipating effects - Very effective against diarrhea!!!!! So is Diphenoxylate
PENTAZOCINE
Full kappa agonist, PARTIAL MU agonist
1/5 as potent as morphine
Ceiling effect on resp depression
Kappa causes patients to have PSYCHOMIMETIC effects (hallucinations)
Mu can precipitate WITHDRAWAL
BUPRENORPHINE
Partial agonist at MU RECEPTORS
ANTAGONIST at KAPPA (no hallucinations)
Similar potency to morphine
NALOXONE
Competitive ANTAGONIST AT ALL OPIOID RECEPTORS
Derived from oxymorphone (has a methyl nitrogen substitution –> binds to receptors, but makes them antagonistic to the opioid effects); more selective for MU subtype
Antagonizes the effects of RESP DEPRESSION, euphoria, sedation, miosis, GI effects, analgesia
Useful for OVERDOSES
Also PRECIPITATES WITHDRAWAL
MUST be given IV or it is completely metabolized before any effect seen
VERY short acting (completely metabolized in 30-60 min); So OD on morphine (4-5 hr half life) –> give every 30 minutes for 4 hours!
No effects when administered alone, only to reverse opioids
NALTREXONE
More potent ANTAGONIST than naloxone and CAN BE TAKEN ORALLY
NOT for overdose because of its long duration!!! More pain and withdrawal
GOOD PROPHYLACTIC DRUG because of the long half life
METHYL NALTREXONE
Blocks PERIPHERAL OPIOID RECEPTORS and DOES NOT CROSS BBB!!!!!!!
Thus, useful for treating CONSTIPATION and other opioid GI effects
12% of Caucasians
Have polymorphisms at the MU RECEPTOR so will have reduced potency/variable responses to the drugs
Withdrawal
Physical dependence is the ALTERING of the Homeostatic Set Point for NT that occurs after long term use
Because of this change in set point, if a patient has been chronically taking a drug and stops using it ABRUPTLY or begins an antagonist –> withdrawal
After chronic use, body has adapted and become physically dependent on these drugs operating at a new set point!
Symptoms of withdrawal –> sadness, anxiety, diarrhea (opposite of opioid effects)
Addiction
NOT the same as physical dependence of withdrawal
Behavioral pattern characterized by COMPULSIVE DRUG USE, FIXATION with OBTAINING and USING IT
Tolerance and dependence are PHYSIOLOGICAL responses and are NOT predictors of addiction (T and D are seen in all patients)
Treating addiction to opioids?
10-15% of physicians experience addiction to alcohol and drugs!
Since FENTANYL and HEROIN are so rapidly acting, they are more prone to euphoric effects/addiction
Use long lasting opioids like METHADONE to wean off – weak euphoria, long effect
When weaned successfully, use NALTREXONE TO PREVENT RELAPSE (no analgesia or euphoria while still occupying receptors!)
Codeine and potency
CODEINE is 8-9x LESS POTENT THAN MORPHINE (good number to know!!!)
So we need 8-9x HIGHER DOSE just to reach the same effect as morphine
Nociceptive vs. Neuropathic Pain
Nociceptive –> results from the activation of nociceptors and is TRANSMITTED along nerves (Somatic - damage to normal tissue; inflammation, localized or Visceral = damage in the organs due to compression, dissension, ischemia, etc)
NEUROPATHIC pain –> Damage to nerves themselves; causes them to misfire, resulting in pain; basically neuronal hyper excitability. Burning, electric shock, sharp, etc. (Diabetic neuropathy, Herpes Zoster, Phantom limbs)
Treating Neuropathic Pain W/O Opioids
TCAs –> inhibit the reuptake of 5HT and NE, inhibiting pathways involved in the pain process; cause anti-cholinergic effects, so not well tolerated –> AMYTRIPTYLINE
5HT-NE reuptake Inhibitors –> Act in the same way, but do NOT have the anticholinergic effects; DULOXETINE
Anticonvulsants –> treat epilepsy, which obviously is hyperexcitability of neurons (just like neuropathic pain!)
PREGABALIN & GABAPENTIN (watch with
renal failure)
CARBAMAZEPINE and VALPROIC ACID (not used usually for neuropathic pain)
What is the one opioid with neuropathic efficacy?
METHADONE
Transdermal Fentanyl Patch
Very useful for CHRONIC, SEVERE PAIN –> can’t use for acute pain
Fun fact! If patient has a FEVER, the blood vessels are dilated, which increases the emptying of the patch in the skin –> lasts for less time!
When switching between opioids…
Want to make sure the dose of the new drug is LOWER than the equianalgesic dose to protect against non-cross tolerance –> while cross tolerance is very real, it doesn’t necessarily mean it always happens. So if you are one one drug for a while, maybe tolerance developed, but when switching to a NEW drug, start at a lower-than-equianalgesic dose because maybe less drug will produce the same effect!
Switching is very common
Can fentanyl be given orally?
NO!
Naloxone vs. Naltrexone
Both reverse opioid effects, but ONLY NALTREXONE can be given orally; naloxone would be metabolized way too fast and not have an effect!
Which opioid has the LONGEST half-life?
METHADONE! 35-190 hours!
What else is unique about this opioid?
NEUROPATHIC pain
And, it is 50% excreted by the LIVER (most are metabolized by liver, excreted by kidney)
When are OPIOID ANTAGONISTS used?
Naloxone, Naltrexone, Methyl Naltrexone (for cancer patients)
For OD and RESP DEPRESSION
If a patient who has never experienced opioids, or is not on them currently, there will be NO EFFECT
Giving them to a patient who was OD or on opioids and got Resp Dep. means the PAIN WILL COME BACK
What are good agents for NEUROPATHIC PAIN?
First line = Pregabalin or TCAs (Amytriptyline)
Gold Standard for Cancer pain?
MORPHINE (cheap!!)
Transdermal Fentanyl Patch (expensive!)
Should we use long-acting/extended release forms sublingually?
NO! Too much, too fast = OD
If patients are severely out of breath…
Give Opioids! Normal clinical doses DON’T cause respiratory depression; good for calming breathing and decreasing anxiety
How does opiate withdrawal present?
Autonomic symptoms –> sweating, pilo-erection, chills, excessive lacrimation, nausea, cramps, vomiting, diarrhea, tachycardia, HTN, anxiety, restlessness, FREQUENT YAWNING!
Withdrawal is VERY RARE and RARELY DEADLY!
Gold Standard for long-term OPIOID ADDICTION?
METHADONE!!! No euphoria, slow action, long half-life
What about treating the short-term GI symptoms (Diarrhea after stopping Opioids)?
LOPERIMIDE or DIPHENOXYLATE (No CNS analgesia/euphoria, but maintain the GI effects of opioids (constipation))
WHO 3-Step Ladder
1 = Mild = ASA, Acetaminophen, NSAIDs +/- Adjuvants (TCAs, Anticonvulsants, SNRI)
2 = moderate = Acet/Codeine, A/hydrocodone, A/Oxycodone, Tramadol +/- Adjuvants
3 = SEVERE = Morphine, Hydromorphone, Methadone, Fentanyl, Oxycodone +/- Adjuvants
PO/IV Ratios of: Morphine, Hydromorphone, Oxymorphone
Morphine –> 3:1
Hydromorphone –> 5:1
Oxymorphone –> 10:1
Make sure when switching that the dose of the new drug is LOWER than the equianalgesic dose to protect against CROSS-TOLERANCE
