P3 PharmSci Exam 1 Opiates, Triptans, Alzheimers, Parkinsons
The magnitude and origin of pain are determined by what 3 things?
SSC, ACC, Thalamus
Describe the pathway of pain, starting with a hammer to your thumb: a pain-inducing blow to peripheral tissues will promote the release of ______________ that activate nerve fibers
Prostaglandin release from a painful blow to peripheral tissues will then activate:
afferent pain nerve fibers
Afferent pain fibers activated by prostaglandins at the site of injury send signals to what part of the spinal cord? What tract do these signals travel to upward toward the brain?
dorsal spinal horn, spinothalamic tract
Pain signals travel from the dorsal spinal horn up the spinothalamic tract to the thalamus. Where are they sent from here?
anterior cingulate cortex (ACC)
Why does it make sense that pain information would be relayed from the ACC to the somatosensory cortex (SSC) as well as the pre-frontal cortex?
somatosensory cortex is aptly named, but the pre-frontal cortex can give us context for the pain we are experiencing and emotional framework for it
What 4 structures are responsible to our cognition and emotional response to pain?
ACC, SSC, PFC, amygdala
An emotional response to pain is sent from the amygdala to the ____/____ which can then modulate ________________
periaqueductal grey area (PGA) and rostral ventral medulla (RVM) to modulate pain intensity
The periaqueductal grey area (PGA) and rostral ventral medulla (RVM) modulate pain signals from
afferent spinothalamic tracts
Activation of Mu opiate receptors inhibit GABAergic neurons leading to ____________ firing of the descending pain pathway in the PGA
Patient populations where the use of opiates for analgesia may result in severe respiratory depression include:
elderly, COPD, severely ill cardiac pts
What is considered the main site of analgesia in the brain?
When activated, a vanilloid receptor receptor will ______ firing of descending pain neurons to induce ____________
AM404 activates what receptors to induce analgesia?
Activation of Mu opiate receptors inhibits __________ neuron firing. What does this mean?
That is a very good fucking question which he answered 2 different ways
The descending pathway from the PGA projects into the _____ which then project to ______ to inhibit signals traveling this route.
RVM, ascending spinothalamic tract
Opiates work pre-synaptically to induce analgesia by:
preventing ascending pain signals into the brain via the spinothalamic tract and also via the PGA to reduce inflow of pain information from the spine itself at the dorsal spinal horn
Activation of what receptors causes respiratory depression?
Does activation of Kappa and nociceptors cause respiratory depression?
Mu receptor activated respiratory depression works in 2 ways:
_________ depressant effect at medullary respiratory control center which slows down ______
decreases the ventilatory response to ________ in the blood
direct, rate, CO2
CNS depressants exacerbate the respiratory depression caused by opiates. List 4 examples
general anaesthetics, sedating/hypnotic agents such as benzos, alcohol, 1st Gen antihistamines
What patient populations are most at risk for respiratory depression? Why is this so critical?
elderly and newborns
bc 100% opiate deaths are from profound respiratory depression
Opiates cause constipation. Describe the mechanism by which this occurs
activation of opiate receptors in myenteric plexus lead to decrease in longitudinal (forward) propulsion but increase in circular (non-propulsive) contraction, this leads to prolonged time in intestine which increases water reabsorption leading to harder/drier stools
Activation of inhibitory GABAergic neurons by opiates increases the inhibition of GABA; this increases the inhibition via GABA on excitatory neurons in the dorsal spinal horn decreases the overall (excitatory) spinal pain pathway
GABAergic neurons are tonically firing to reduce central sensitivity to pain. Increased firing of GABAergic neurons leads to decreased pain signals
descending pain signals communicate about the intensity of pain being interpreted in the brain. Increased pain perception in the brain leads to a stronger message being sent from the RVM to the spinal cord saying "less pain information plz" and decreases the signal being sent up the spinothalamic tract
Opiate activation of Mu receptors leads to inhibition of (inhibitory) GABAergic neurons in the PGA. This decrease in inhibition of GABAergic neurons in the PGA leads to a stronger signal being sent to the RVM, which is responsible for the inhibitory signal sent down to the spinal cord. This transmission from the RVM to the spinal cord serves to induce analgesia by modulation of the pain messages being sent to the brain via the afferent spinothalamic tract. The RVM is essentially saying to the excitatory neurons in the dorsal horn "we're experiencing a lot of pain up here, so we're going to to need you to tone it down please"
Opiate receptor activation constricts the sphincter of Oddi, which can lead to
Opiates cause ___________ of pupils from activation of Mu receptors in the oculomotor nucleus
It is known that opiates raise the cough threshold in the medulla. DXM is not an opiate but causes cough suppression. How?
Weak to moderate glutamate antagonist with strong chirality to activate opiate receptors
How do opiates cause nausea and vomiting? Why is it more common in ambulatory patients?
activation of vestibular complex and chemoreceptor trigger zone
Opiate induced euphoria occurs in what pathway?
mesolimbic dopaminergic pathway
The mesolimbic dopaminergic pathway extends from the ______ to the ______
ventral tegmental area (VTA) to the nucleus accumbens (reward center)
Opiate Mu receptor activation inhibits GABAergic inhibitory effects in the VTA. This leads to increased mesolimbic dopaminergic firing and __________
How does short term tolerance to opiates occur?
uncoupling of G proteins which decreases signal of agonist binding to receptor, and internaliztion of the receptor/antagonist complex via beta-arrestin
What are the outcomes of opiate tolerance in short term administration
degradation of Mu receptor, recycle receptor back to cell surface
What are the effects of long term opiate administration?
fewer Mu receptors translated on cell surface means fewer place for opiates to bind and decreased effect, upregulation of factors that increase pain response (nociceptor, glutamate NMDA receptors)
Do long term opiate users develop tolerance to miosis and constipation?
What are 3 effects that opiate users develop rapid tolerance to? Minor tolerance?
analgesic an euphoric effects, emesis
Opiate dependence is manifested by physical and psychological dependence, will lead to _____________ if therapy is halted
What is the mechanism of long term opiate dependence?
it literally changes your neural pathways (long term potentiation) through activation of glutamate NMDA receptors; alters the synapses in the mesolimbic and mesocortical DA pathways and in the hippocampus (memory) and pre-frontal cortex (executive functioning)
How do you treat withdrawal induced by cessation of drug?
antagonist or partial agonist administration (ex. Naloxone)
Opiate withdrawal induces an increase in cAMP, excitatory glutamate and cytokines, sensorimotor and autonomic outflow. What physical symptoms will this cause in the patient?
agitation, hyperthermia, HTN, dysphoria, diarrhea
What distinguishes dependence from addiction to opiates?
craving to procure and use more drug despite negative consequences
Place the opiates in increasing analgesic potency:
morphine, codeine, hydocodone, fentanyl, dilaudid
codeine < hydrocodone <morphine < dilaudid <fentanyl
What functional groups greatly increase the potency of morphine-like agents?
-OH group at position 14, a carbonyl at position 6 (oxidation of -OH group there in C=O), removal (reduction) of 7-8 double bond
What SAR is REQUIRED for opiate activity
-OH group at position 3
addition of alkyl groups to -OH decreases activity
What are the only 2 N-substituents tolerated on opiate agonists?
N-methyl an N-phenylethyl
What types of N-substituents will make a compound an opiate antagonist?
N-allyl, N-cyclopropylmethyl, N- cyclobutylmethyl
Which N-substituent gives Kappa full or partial agonist activity?
Which CYP enzyme should be considered in opiate metabolism?
3-O-demethylation of codeine by CYP 2D6 does what? Does this matter?
converts 10% of codeine to morphine, yes it is therapeutically necessary
Oxycodone undergoes N-demethylation by 3A4 to
Morphine-3 and Morpine-6-glucuronides are formed in the liver and are excreted __________. Where else are these glucuronides formed?
renally, in the brain
Morphine-6-glucuronide is _______ potent than morphine
M3G and M6G have longer half lives than morphine in the brain. What can this tell us?
higher levels of M6G can indicate chronic use
Do renally compromised pts need adjusted doses of opiates?
Heroin, diacetylmorphine is a _________. It is converted in the liver to 6-acetyl morphine by a specific _____________
Is 6-acetylmorphine more potent than morphine? why? How does this factor into addition?
yes, ester is more lipophilic, more drug is taken up into brain leading to increased euphoria
Nalbuphine and butorphanol are both Mu ___________. Which has full Kappa agonist activity and which has partial?
Mu antagonists, Nalbuphine - full, Butorphanol - partial
___________ is a partial Mu agonist (100x more than morphine)
What is the SAR for mixed opiate agonists/antagonists?
morphine nucleus, N-substituent
When would you want to use nalbuphine over morphine and why?
in pts with compromised respiration, up to 30 mg of nalbuphine will cause no more respiratory depression than 10 mg of morphine
Dose response curve between morphine and buprenorphine??
All _________ opiates are Mu agonists. These include meperidine (demerol), fentanyl, tramadol, tapentadol, and antidiarrheals loperamide and diphenoxylate
Remifentanil is a "soft drug" which means:
it has an ester and can only be administered parenterally
How is sulfentanil so much more potent than fentanyl?
ether makes it way more lipophilic
What keeps the antidiarrheals loperamide and diphenoxylate out of the brain despite having Mu agonist structure?
The fact that fentanyl is extremely lipophilic means it can be administered via ____________
What 2 synthetic Mu agonists have SRI effects?
meperidine and tramadol
What is required to give tramadol its analgesic effects instead of SRI?
Global drug interactions issues exist for what 2 CYPs an their associated drugs?
2D6: codeine, tramadol
3A4: oxy/hydrocodone, fentanyl
In migraines, triggers spark:
cortical spreading depression (CSD)
CSD leads to activation of __________ nuclei and nociceptive/sensory afferents leading to pain
What can increase the perception of pain in migraine?
meningeal and dura arterial vasodilation
What are the 4 main migraine triggers?
bright/flashing lights, lack of sleep, food, allergies
Type of aura characterized by bright squiggly line
If aura occurs with migraine it means there is CSD in the
CSD is a depolarization of the cerebral cortext. What 3 ion channels are affected?
inward Na/Ca, outward K
What is thought to be the PRIMARY cause of pain in migraine?
the release of calcitonin-gene related protein (CGRP) from trigeminal nuclei
Meningeal arterial dilation in migraine is mediated by the release of nitric oxine from
degranulation of mast cells
Agonists of serotonin 5HT 1b/d receptors:
What are 4 examples of migraine prevention drugs?
gabapentin (neurontin), pregabalin (lyrica), topiramate (topamax), amytriptyline
This agent has the same mechanism to treatment of migraines as triptans
IgG G2 subclass MAB used to treat migraine via CGRP receptor antagonism. Major ADE is constipation
The structure of triptans have a __________ nucleus
The SAR for triptans includes what 3 things?
indole nucleus (required), must have an H-bond 1-3 atoms from ring starting at the 5 position, basic aliphatic N 2 carbons away from ring
Why does it not matter than naratriptan's 3-position aliphatic N is more than 2 carbons away?
because the N is on a ring in chair position which makes it sit roughly no more distance away
What is the mechanism by which Alzheimers occurs?
B-amyloid proteins which are regularly released by neurons are not degraded and begin to form plaques which accumulate at the synaptic cleft and block transmission of NT's. When these signaling at the synapses is blocked it triggers an immune response and leads to inflammation. Blocking glutamate pre-synaptic uptake results in sustained NMDA receptor activation and excitotoxicity.
The microtubules that form the connection of the soma of a neuron to the synapse are held together by Tau proteins. In Alzheimers patients, the Tau protein does not bind the microtubules which then start to separate from organized bundles. The culmination of the loss of microtubule connection between neurons, and the accumulation of defective Tau protein filaments kills the neuron and ultimately leads to the formation of a neurofibrillary tangle. This is why Alzheimers patients have such a marked reduction in gray matter
it is thought that the B-amyloid proteins form plaques, and tau proteins cause neurofibrillary tangles
Which neuronal tracts are disproportionately affected in Alzheimers?
cholinergic (decrease in muscarinic, nicotinic receptors, decrease in acetyltransferase which makes ACh, ultimately decreased choline uptake
What is the backbone of Alzheimers treatment?
augmentation of cholinergic transmission
There are 3 steps to increase cholinergic transmission in alzheimers treatment:
creation of ACh from choline via acetyltransferase
acetylcholinesterase (responsible for clearing ACh from synaptic cleft)
increased pre-synaptic update of choline
How does AChE work?
there is a serine-containing hydrolytic site proximal to the ACh binding site that "steals" the acetyl group from ACh and releases choline and (separately) the acetyl group in the form acetate
Carbamylation is the process of:
adding a compound with N and C