AP test 2 Flashcards
Nociception Comprised of four components:
–Transduction – process by which a noxious stimuli (e.g., heat, cold, mechanical distortion) is converted to an electrical impulse in sensory nerve endings.
––Transmission - conduction of these electrical impulses to the CNS with the major connections for these nerves being in the dorsal horn of the spinal cord and thalamus with projections to the cingulate, insular, and somatosensory cortices.
Modulation - process of altering pain transmission. It is likely that both inhibitory and excitatory mechanisms modulate pain (nociceptive) impulse transmission in the PNS and CNS.
Perception - mediated through the thalamus acting as the central relay station for incoming pain signals and the primary somatosensory cortex serving for discrimination of specific sensory experiences.
Note that pain can occur without one or more of these steps (e.g. phantom limb pain)
Nociceptors
- Specialized cells and nerve endings that respond to thermal, chemical, and mechanical stimuli
- C-fiber afferents (unmyelinated and have the slowest conduction) transmit burning pain and sustained pressure
- Type I fibers (some Aβ and some Aδ) are myelinated and referred to as polymodal fibers
- Transmit thermal, chemical, and mechanical stimuli
- Type II fibers (some Aδ fibers with slower conduction) transmit initial pain responses to heat
- Other fibers (some myelinated and some not) transmit chemical and cold stimuli to the CNS
Nociception pic
Nociceptive Signal Transduction - Pain Receptor Schematic
Nociceptor Activity
Calcitonin gene-related peptide (CGRP) and Substance P (SP) released from some sensory nerves as a means of pain transmission
SP is a undecapeptide that acts at Neurokinin-1 receptors (NK-1) which are widely distributed in the brain and found in specific areas associated with pain processing in the amygdala, hypothalamus, and periaqueductal gray
SP is not “substance pain”, P actually stands for powder
SP found with glutamate in primary afferents that respond to painful stimuli
Attempts made but no good NK-1 receptor pain relievers
Nociceptor Activity - Gi/o receptor system responsible for many types of inhibitory actions at pain receptors
- Causes receptor hyperpolarization by increasing potassium conductance
- Endorphin, cannabinoid and acetylcholine receptors
Nociceptor Activity - Transient V receptor-1 (TVR1)
- Transient V receptor-1 (TVR1)
- AKA Capsaicin or Vanilloid receptor
- Provides sensations of scalding heat and pain
- Receptor similar to NMDA receptor
Nociception - NMDA Receptor – Primary Pain Afferent Receptor pic
Sensitization of Nociceptors
Peripheral neurons can be sensitized for pain transmission by many inflammatory mediators
Chronic pain occurs when inflammatory effects do not resolve leading to hyperalgesia due to sensitization
Allodynia is the perception of pain from normally non-painful stimuli and is a response to sensitization
Nociceptor sensitization induced by peripheral inflammation
Nociception- Dorsal Horn Synapse
CNS Pain Structures -CNS locations of incoming (afferent) pain stimuli
CNS Pain Tracts
Dorsal Horn
Dorsal Horn Pain Inputs
Gate Theory of Pain
Pain information is transmitted to the brain if the gate is open but not if the gate is closed by inhibitory stimulation
Rubbing skin stimulates additional mechanical inputs which inhibit the gate through Aβ fibers and diminishes pain transmission to the brain
Gate Theory Modulation
A Brief History of the Opioids
- Opium resin isolated from Papaver somniferum.
- First known use: ~100AD.
- Morphine isolated in 1806.
- Other major alkaloids include Codeine and Papaverine.
- Synthetic congeners such as Meperidine ~1940’s.
Opioid Terminology
Morphine named after the Greek God of sleep, Morpheus.
Opium comes from Greek word meaning juice.
Opiates refers to agents derived from opium.
Opioids covers all agents acting on morphine receptors, including antagonists.
Natural, semisynthetic, and synthetic agents.
Narcotic named from the Greek word for stupor. While frequently used to refer to opioids, this is a much broader term.
Opioid Receptors
Four (?) major families (m, d, k, Nociceptin). All belong to the G protein-coupled class of receptors. Endogenous ligands for these receptors are peptides with varying affinities for each receptor type. Most opioid receptor activity is inhibitory, decreasing intracellular cAMP, however very low doses are actually excitatory (increases intracellular cAMP).
Opioid Receptor Activation
Opioid Receptor Locations
m-Receptor: Mainly found in the brainstem and medial thalamus. Some located in spinal cord.
k-Receptor: Mainly in the dorsal horn of the spinal cord and some in the brainstem medullary reticular formation.
d-Receptor: Mainly in the limbic system.
Opioid Receptor Functions
m-Receptor: analgesia, respiratory depression, euphoria, miosis, physical dependence, decreased GI motility.
k-Receptor: supraspinal analgesia, sedation, dysphoria (psychoses).
d-Receptor: analgesia (spinal?).
Endogenous Opioids
Derived from precursor polypeptides.
Agents include the endorphins, dynorphins, and enkephalins.
All differ in chain length, but share same first few AA’s (61-65).
Endomorphines are newly discovered m-receptor selective tetrapeptides.
Act as neurotransmitters, neuromodulators, or neurohormones.
Body’s pain modulators.
Opioid Receptor Homology
~65% homology exists among m, d, k.
Open circles are AA’s that differ among each receptor type.
Opioid Receptor Distribution
Analgesia mediated via receptors located in the dorsal horn of the spinal cord, periaqueductal gray matter, and the thalamus.
Ventral brainstem receptors mediate effects on coughing, vomiting, respiration, and pupillary diameter.
Neuroendocrine functions controlled via the hypothalamus.
Mood and behavioral effects controlled by receptors mainly in the limbic system.
Peripheral m receptors associated mainly with the GI tract.
Opioid Receptor Interactions
Opioid ligands can interact with opioid receptors in four primary ways:
Agonist – bind to and activate receptor.
Antagonist – binds to the receptor but does not activate it.
Partial Agonist – binds to the receptor but produces less than maximal response.
Mixed Agonist/Antagonist – binds to more than one type of opioid receptor, acting as an agonist at one, and an antagonist at others.
Partial Agonist/Antagonist pic
Opioid MOA
CNS activity primarily in brainstem/spinal cord
Other activity on peripheral afferent neurons
Binds to receptors in ionized form
Primary action is decreased neurotransmission by presynaptic inhibition of neurotransmitter release (NE, ACh, DA, SubP)
Causes increased potassium conductance and/or calcium channel inactivation
Also some postsynaptic inhibition
Central Opioid Effects
Neuronal activity – decreased
Analgesia – raises pain perception threshold and increases pain tolerance.
Respiratory depression – decreases respiratory center sensitivity to CO2, and can lead to Cheyne-Stokes resp.
Mood alteration – produces a clouded state, which many describe as euphoria.
Sedation – level depends on specific agonist.
Miosis, nausea/vomiting, antitussive, and endocrine (inhibits LHRH secretion) effects
Histamine release – causes peripheral arteriole and venous dilatation, which can decrease blood pressure (sensitive individuals may enter shock following IV dose).
Venous dilatation – besides histaminic component, there is a direct opioid receptor action.
Smooth muscle contraction – biliary and bladder sphincter muscles.
Inhibition of ACh release – in mesentery, this decreases peristalsis, and causes constipation.
Therapeutic Opioid Uses
The most common opioid uses include:
Analgesia – both acute and chronic.
Pre-op sedation, anesthesia, epidural analgesia.
Diarrhea.
Cough suppression.
Opioid addiction withdrawal.
Opioid overdose (antagonist).
Opioid Analgesia
Mechanisms of opiate action in producing analgesia. Top left: Schematic of organization of opiate action in the periaqueductal gray. Top right: Opiate-sensitive pathways in PAG Mu opiate actions block the release of GABA from tonically active systems that otherwise regulate the projections to the medulla (1) leading to an activation of PAG outflow resulting and activation of forebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projections (4) which provide sensory input to higher centers and mood.
Bottom left: Schematic of primary afferent synapse with second order dorsal horn spinal neuron, showing pre- and post-synaptic opiate receptors coupled to Ca2+ and K+ channels, respectively. Opiate receptor binding is highly expressed in the superficial spinal dorsal horn (substantia gelatinosa). These receptors are located presynaptically on the terminals of small primary afferents (C fibers) and postsynaptially on second order neurons. Presynaptically, activation of MOR blocks the opening of the voltage sensitve Ca2+ channel, which otherwise initiates transmitter release. Postsynaptically, MOR activation enhances opening of K+ channels, leading to hyperpolarization. Thus, an opiate agonist acting at these sites jointly serves to attenuate the afferent-evoked excitation of the second order neuron.
Major Opioid Side Effects (starts opioids part 2)
Some normally considered side effects are beneficial in certain circumstances.
Orthostatic hypotension/syncope due to decreased sympathetic outflow from the CNS
Bradycardia due to increased vagal outflow
Respiratory depression.
Decreased cerebral blood flow and increased ICP.
Nausea and vomiting.
Hypothermia.
Constipation.
Histamine release and it’s effects.
Muscular rigidity due to inhibition of dopamine release in the striatum (Parkinson-like). This may cause ventilation difficulty due to laryngeal contraction and chest wall rigidity.
ADME of the Opioids
Most are well absorbed from GI tract.
Most undergo large first-pass metabolism following oral dosing.
Most distribute well. More lipid soluble agents reach higher CNS conc. faster.
Most cross placenta well, but fetus can not metabolize much, so conc. is high.
Metabolism varies among each compound, however all are metabolized to some extent.
Excretion mainly via renal and biliary mechanisms of metabolized forms.
Opioid SAR
Two chemical classes of Opium Alkaloids:
Phenanthrenes
4 ring-system with a tertiary amine with pKa of >8.0, so mostly ionized at physiologic pH
Levo isomers more active
Morphine
Codeine - 1/10 morphine potency
Thebain - AKA paramorphine – CNS stimulant, can cause convulsions
Benzylisoquinolines
lack standard opioid activity
Papaverine – a smooth muscle relaxant – phosphodiesterase inhibitor, increases cAMP
Noscapine – antitussive and anticancer(?)
Opioid SAR (miller pic)
Opioid SAR pic 2 miller
Opioid Agonists (long list)
Morphine (MS Contin), Hydromorphone (Dilaudid), Oxymorphone (Opana)
Codeine (Tylenol w/ Codeine), Hydrocodone (Vicoprofen), Zohydro ER (Hydrocodone), Oxycodone (Oxycontin).
Heroin
Levorphanol
Dextromethorphan (Bromfed-DM) (from class otc cough suppress)
Meperidine (Demerol) (class- rigors)
Methadone (Dolophine) (class be familiar opioid addiction)
Propoxyphene (Darvon) (all DC’ed due to efficacy)
Fentanyl (Sublimaze)
Sufentanil (Sufenta)
Alfentanil (Alfenta)
Remifentanil (Ultiva)
Morphine
Natural alkaloid from Papaver somniferum.
Acts primarily at m receptors (some k).
Rapid tolerance development.
Agent by which all other opioid agonists are judged (activity set at “1”).
Used mainly for it’s analgesic properties.
Recent resurgence in the use of morphine over other agents for pain control.
Peripheral Nervous System
Synaptic is adrenergic receptor
Para preganglionic longer travel to ganglia not right next to spinal colum closer to the tissue. Muscarinic receptor and will talk about this later what that does.
ANS Receptors
Going to have to start learning these**
Understand how it affects each tissue- compound has autonomic sympathetic side effect if it has these side effects you should know potential side effects.
Ganglionic Blockers (pic) (
nondominate tone
Neuromuscular Blockers - pic
Anesthesia- block info neurons don’t work properly neuronal, local – nerve action potential stop signal no signal to motor endplate.
Succinylcholine neuromuscular blockers
Neuromuscular Blockers Normal Acetylcholine binding to neuromuscular nicotinic receptor
Have to have two acetylcholine molecules to allow to open channel
Quaternary amine goes to anionic binding site- - charge. Hydrogen boding force at other region- cause electron bonding
Neuromuscular blockers- Decamethonium binding to neuromuscular nicotinic receptor
neuromuscular blocker binding Vecuronium pic
Vecuronium- (amino-steroid) binding to neuromuscular nicotinic receptor
Sterioid nuclus **** look at structure
Neuromuscular Blockers •Mechanism of Action Two types:
Mechanism of Action
Two types:
1. Depolarizing blockers
These agents cause an initial stimulation (depolarization) of the receptor, followed by long-term blockade (due to keeping receptor depolarized, and not able to repolarize for re-stimulation).
Succinylcholine (Anectine) Used for many years. Its main benefit is its very short duration (1 - 2 minutes)
Decamethonium (not clinically used - experimental neuromuscular nicotinic blocker). It is comprised of a 10 carbon chain separating two tri-methyl amines (Quats). Compare this to hexamethonium, a ganglionic blocker with a 6 carbon chain between the two tri-methyl amines (Quats). This demonstrates the difference in physical layout of the two ACh sites on ganglionic and neuromuscular nicotinic receptors.
Neuromuscular blockers- nondepolarizing
Mechanism of Action Two types: 2. Non-Depolarizing blockers Agents in this class act as competitive antagonists of ACh at the neuromuscular junction. This blocks the ability of ACh to stimulate the muscle at the motor end plate, resulting in muscle weakness (at lower doses) or paralysis (at higher doses).
other neuromuscular blocker pic
Neuromuscular Blockers - Duration of action
Neuromuscular Blockers - special features- atracurium/mivacurium
Specific Features
Atracurium is metabolized by nonspecific serum esterases and spontaneous Hofmann elimination to produce laudanosine, a metabolite which may have CNS excitatory activity. It is also metabolized somewhat in tissues and a small amount eliminated unchanged. Cisatracurium is mainly metabolized by Hofmann degradation but due to greater potency and lower doses, laudanosine risks are limited.
Mivacurium is primarily metabolized by plasma esterases.
Hofmann Elimination is the spontaneous chemical deamination elimination that occurs in aqueous environments at specific temperatures and pH’s. With Atracurium, as the temperature and pH decrease, the rate of Hofman elimination decreases, and as the temperature and pH increases, so does the reaction rate. Due to this reaction and non-specific esterase degradation, the patient’s liver and renal function is not critical in their use.
Neuromuscular blockers Atracurium Metabolism
Atracurium Metabolism
