AP test 2

Question 1

Nociception Comprised of four components:

Answer 1

–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)

Question 2

Nociceptors

Answer 2

• 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

Question 3

Nociception pic

Answer 3

Nociceptive Signal Transduction - Pain Receptor Schematic

Question 4

Nociceptor Activity

Answer 4

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

Question 5

Nociceptor Activity - Gi/o receptor system responsible for many types of inhibitory actions at pain receptors

Answer 5

• Causes receptor hyperpolarization by increasing potassium conductance
• Endorphin, cannabinoid and acetylcholine receptors

Question 6

Nociceptor Activity - Transient V receptor-1 (TVR1)

Answer 6

• Transient V receptor-1 (TVR1)
  
  • AKA Capsaicin or Vanilloid receptor
  • Provides sensations of scalding heat and pain
  • Receptor similar to NMDA receptor

Question 7

Nociception - NMDA Receptor – Primary Pain Afferent Receptor pic

Answer 7

Question 8

Sensitization of Nociceptors

Answer 8

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

Question 9

Nociceptor sensitization induced by peripheral inflammation

Answer 9

Question 10

Nociception- Dorsal Horn Synapse

Answer 10

Question 11

CNS Pain Structures -CNS locations of incoming (afferent) pain stimuli

Answer 11

Question 12

CNS Pain Tracts

Answer 12

Question 13

Dorsal Horn

Answer 13

Dorsal Horn Pain Inputs

Question 14

Gate Theory of Pain

Answer 14

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

Question 15

Gate Theory Modulation

Answer 15

Question 16

A Brief History of the Opioids

Answer 16

• 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.

Question 17

Opioid Terminology

Answer 17

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.

Question 18

Opioid Receptors

Answer 18

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).

Question 19

Opioid Receptor Activation

Answer 19

Question 20

Opioid Receptor Locations

Answer 20

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.

Question 21

Opioid Receptor Functions

Answer 21

m-Receptor: analgesia, respiratory depression, euphoria, miosis, physical dependence, decreased GI motility.
k-Receptor: supraspinal analgesia, sedation, dysphoria (psychoses).
d-Receptor: analgesia (spinal?).

Question 22

Endogenous Opioids

Answer 22

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.

Question 23

Opioid Receptor Homology

Answer 23

~65% homology exists among m, d, k.
Open circles are AA’s that differ among each receptor type.

Question 24

Opioid Receptor Distribution

Answer 24

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.

Question 25

Opioid Receptor Interactions

Answer 25

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.

Question 26

*_Partial Agonist/Antagonist pic_*

Answer 26

Question 27

Opioid MOA

Answer 27

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

Question 28

*_Central Opioid Effects_*

Answer 28

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.

Question 29

*_Therapeutic Opioid Uses_*

Answer 29

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).

Question 30

*_Opioid Analgesia_*

Answer 30

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.

Question 31

Major Opioid Side Effects (starts opioids part 2)

Answer 31

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.

Question 32

*_ADME of the Opioids_*

Answer 32

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.

Question 33

Opioid SAR

Answer 33

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(?)

Question 34

Opioid SAR (miller pic)

Answer 34

Question 35

Opioid SAR pic 2 miller

Answer 35

Question 36

Opioid Agonists (long list)

Answer 36

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)

Question 37

*_Morphine_*

Answer 37

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.

Question 38

Heroin

Answer 38

Diacetylmorphine. Semisynthetic, and easily prepared from morphine. Approximately twice as potent as morphine, but much more lipid-soluble. Enters CNS rapidly, causing quick euphoria. Not approved for clinical use due to high addiction liability.

Question 39

Codeine

Answer 39

Only one tenth the analgesic potency of morphine. Little risk of addiction or respiratory depression. Partially converted to morphine in the body, which is thought to account for the analgesic component. Potent antitussive in the parent form.

Question 40

*_Oxycodone (Oxycontin)_*

Answer 40

Approximately twice as potent as morphine as an analgesic. High euphoric liability. Available in a 160 mg. extended release tablet, which is widely abused (“Hillbilly Heroin”). Many deaths linked to chewing the extended release form

Question 41

Levorphanol

Answer 41

Very potent synthetic morphine analgesic congener (5X). Less constipating and longer lasting.

Question 42

Dextromethorphan (Bromfed-DM)

Answer 42

A dextro-rotary isomer, which means it has no analgesic activity, but is an effective antitussive.

Question 43

Meperidine (Demerol)

Answer 43

Most widely used synthetic congener. Only one-tenth the mg. potency of morphine as an analgesic, and has a shorter duration of action. Frequently abused since it does not cause miosis, thus is hard to detect abuse. Metabolized to Normeperidine, a CNS stimulant. Decreased renal function can allow metabolite build-up, and potential seizures. Contraindicated with MAOI therapy.

Question 44

*_Methadone (Dolophine)_*

Answer 44

Same analgesic potency as morphine. Causes much less sedation than morphine. Longer duration of action, due to slower elimination. This explains its use to counter withdrawal symptoms.

Question 45

*_Propoxyphene (Darvon)_*

Answer 45

## Footnote Structurally related to Methadone, but less than one-tenth as potent per mg. Properties similar to other Opioid analgesics. Questions have been raised concerning it’s benefit in dose strengths found in most products. (Now DC’ed)

Question 46

*_Fentanyl (Sublimaze)_*

Answer 46

Chemically related to Meperidine. Approximately 80X as potent an analgesic as Morphine (similar potency among it’s other effects also). Main advantage is it’s short half-life of redistribution (12.5 min.). Often combined with other agents for anesthesia such as neuroleptics. **Sufentanil (Sufenta) (800X), Remifentanil (Ultiva) (80X), and Alfentanil (Alfenta) (20X)** have similar uses. Used also for continuous epidural and transdermal analgesia.

Question 47

*_Remifentanil (Ultiva)_*

Answer 47

Selective m-receptor agonist. Differs from other fentanyl derivatives by having an ester-linkage. Causes **short duration of action due to hydrolysis by non-specific esterases.** This allows an agent of short duration that can be more carefully titrated to needs and allows rapid recovery. Commonly used as an adjunct for induction and/or maintenance in pediatric patients

Question 48

Etorphine (Immobilon, M99)

Answer 48

Veterinary-use only 1000X morphine potency Used as a large animal immobilizer (elephants) Toxic to humans, one drop on skin can be fatal Dihydroetorphine used in China as a painkiller, it appears to be less addictive(??)

Question 49

Opioid Antagonists

Answer 49

Have receptor affinity but no intrinsic activity. Act by blocking m receptors mainly (some k blockade also). Blocks analgesic, respiratory, euphoric, miosis, hypotension, and smooth muscle actions of the Opioids and endogenous b-endorphin and enkephalins. Used clinically to reverse opioid-induced respiratory depression and in the treatment of “addicts”. Naloxone is a pure antagonist (mostly m) normally given IV. Naltrexone (Revia) is similar, but has a longer half-life, and can be given orally. Used mainly to treat alcoholics by decreasing ethanol intoxication pleasure. Methylnaltrexone (Relistor) is a quat and thus ionized and used for peripheral opioid antagonism. No CNS withdrawal effects. Use is to control N&V from opioid agonists Almivopan (Entereg) is an oral m selective peripheral antagonist approved for post-op ileus.

Question 50

*_Partial Opioid Agonists_*

Answer 50

Buprenorphine (Buprenex) shares structural components of Codeine and Naltrexone. High affinity for m receptors, and elicits a weaker maximal response than other agonists (but still good analgesia). Therefore it has less abuse potential, and has been used to counteract Heroin and Morphine addiction without causing full-blown withdrawal symptoms. Slow dissociation from receptors increases duration (8 hrs) and limits use of Naloxone to reverse. Used for moderate to severe pain, can also be used epidurally Can displace other m receptors agonists (antagonistic action) and can precipitate withdrawal reaction.

Question 51

Mixed Opioid Agonist/Antagonists

Answer 51

Nalorphine (Nalline) (US – Veterinary use only) is a m receptor antagonist and a weak agonist at k receptors. While it blocks m receptor-mediated analgesia and euphoria, it also stimulates k induced analgesia and sedation. Large doses may cause dysphoria and hallucinations. Pentazocine (used with Naloxone to limit abuse) and Nalbuphine have similar actions, but are stronger k mediated analgesics.

Question 52

Tramadol (Ultram)

Answer 52

Newer analgesic with structural similarities to Opioids and NSAIDs. Both the parent compound and an active metabolite have moderate affinity for m receptors and weak k and d affinity, thus, their analgesic effect is not entirely reversed by Naloxone. Also acts to block re-uptake of serotonin and norepinephrine in central synapses, which then decreases pain information transmission in the brain. Racemic mix, different enantiomers responsible for each action. Analgesic strength similar to Codeine-Acetaminophen agents. Can cause dizziness, sedation, seizures and hallucinations. Less addiction liability than other opioid agonists. Nausea and vomiting common, limiting perioperative use. Reported increased risk of bleeding if taken with Warfarin. Avoid in epilepsy due to epileptogenic effects.

Question 53

Opioid Abuse

Answer 53

High abuse potential due to euphoria and sedative effects. Rapid tolerance development means higher and higher doses requires to achieve same euphoria. Physically and psychologically addictive. Many “addicts” only continue to take the opioids to avoid the uncomfortable withdrawal symptoms. Proper addiction therapy often requires years of psychological therapy as well as pharmacologic therapy (ex.- Methadone). More prescription abuse than illicit substances. In 2011 -2012, Opana (oxymorphone) ER became the single largest cause of prescription deaths in US. Total overdose deaths in US (2016) were more than all deaths in Vietnam war (\>60,000). Most due to opiates. Rapid Detox – Anesthesia + Opioid Antagonist for 6-8 hours.

Question 54

Opioids in Anesthesiology

Answer 54

Spinal analgesia/anesthesia. Pre-op use to decrease pre-surgical pain, surgical pain, and to provide mild sedative effects. Use allows the amount of general anesthetic required to be decreased. Surgical adjuvant. Can be used alone in some cases, or provided with lower doses of other agents such as anesthetics, muscle relaxants, neuroleptics (neuroleptic anesthesia: butyrophenone i.e. droperidol – a D2 blocker with antiemetic properties + opioid i.e. fentanyl + nitrous oxide), etc.

Question 55

Future Therapeutic Possibilities

Answer 55

Use of peptide-type opioid receptor agonists for pain relief. These are being designed to target specific receptor sub-types. Transplantation of adrenal medullary chromaffin cells (which secrete opioid peptides) into the spinal subarachnoid space to provide long-term pain relief to chronic pain sufferers without exogenous opioid SE’s.

Question 56

Nonopioids Analgesics *_Nonopioid Analgesic Classes_*

Answer 56

NSAIDS – inhibit enzyme (Cycloxygenase) responsible for prostaglandin and thromboxane systnesis. Acetylsalicylic acid (Aspirin) - similar to NSAIDS but irreversible inhibitor of COX Acetaminophen (Tylenol) – similar to NSAIDS but are not anti-inflammatory. Also believed to inhibit COX but not in periphery. Probably in CNS. Cannabinoids – act through specific receptors. All are Gi/0 type receptors. CB1 found in brain and spinal cord, CB2 receptors mainly in immune system. Research weak. CBD (cannabidiol) oil questionable.

Question 57

Centrally Acting Nonopioid Analgesics A2

Answer 57

a2-Adrenergic Agonists Act to decrease NE release in multiple pathways including pain pathways in the CNS. They do this by stimulating pre-synaptic a2 receptors which act to block vesicle fusion and NE release from pre-synaptic terminal. Major effect on pain is on sympathetic preganglionic neuronal activity. Clonidine: partial a2 receptor agonist. Neuraxial use effective for cancer and non-cancerous pain and post-op pain. Co-administration with local anesthetics shown to potentiate effects. Also used synergistically with opioids Black-box warning for neuraxial administration in obstetrics due to maternal hemodynamic instability. Dexmedetomidine: more potent a2 receptor agonist Fewer systemic and hemodynamic side effects than clonidine May be associated with demyelination following epidural dosing

Question 58

Centrally Acting Nonopioid Analgesics - Acetylcholinesterase Inhibitors (AChEI’s)

Answer 58

Neostigmine Blocks metabolism of acetylcholine in synapse. Intrathecal administration shown to allow released ACh to continue to stimulate muscarinic receptors producing minor pain relief. Used as an adjunct to other such as intrathecal local anesthetics and opioids Side effect profile is high and may outweigh small benefit

Question 59

*_Centrally Acting Nonopioid Analgesics- Anethetics ketamine_*

Answer 59

Anesthetics Ketamine Analgesic in both anesthetic and subanesthetic doses Mechanism is via noncompetitive inhibition of NMDA receptors of secondary afferent neurons in the dorsal horn of the spinal cord. Neuraxial administration with or without local anesthetics has been shown to be effective for post-op pain relief. Use sterile, preservative-free solution. Acts synergistically with opioids. Side effects include sedation, headache, and transient burning back pain during administration, and risk of psychotic reactions. Benefits are the lack of cardiovascular SE’s and respiratory depression

Question 60

Centrally Acting Nonopioid Analgesics- benzodiazepines - midazolam

Answer 60

Benzodiazepines Midazolam Acts at GABAA receptors, enhancing inhibition and blocking pain transmission Believed to act in the dorsal horn due to large concentration of GABAA receptors in that area (Lamina II). Also have some activity at opioid receptors by stimulation release of endogenous opioids. No neurotoxic effects from neuraxial administration proven.

Question 61

Centrally Acting Nonopioid Analgesics - conopeptides- ziconotide

Answer 61

Conopeptides Ziconotide (Prialt) 25 amino acid polypeptide derived from conotoxin (from marine snail) A selective antagonist of neuronal (N-type) voltage-gated calcium channels found in presynaptic nerve terminals in the dorsal horn. Use acts to block nerve transmission by blocking NE release. Acts as a sympatholytic and decreases both mean and systolic BP if given IV but minimal effect given IT. Only currently FDA approved nonopioid for IT use to treat neuropathic pain. Side effects are very common (\>90%) and include dizziness, confusion, ataxia, memory impairment, suicide ideations. High costs and SE’s limit use.

Question 62

Centrally Acting Nonopioid Analgesics- GABA agonists- Baclofen

Answer 62

GABA Agonists Baclofen (Lioresal) A GABAB agonist. Acts via a G-protein system to activate potassium channels and hyperpolarizing internal membrane. Has inhibitory effects like GABAA but by different mechanism. Acts in lamina II and III of dorsal horn presynaptically to inhibit depolarization and decrease calcium entry which decreases afferent pain transmission. Intrathecal administration shown to be effective in treating chronic pain syndrome from MS and complex regional pain syndrome. Also used for back pain (with root compression) as well as spasticity from disorders such as cerebral palsy. Use with Bupivocaine shown to decrease opioid use after some surgery. Common SE’s include sedation, drowsiness, nausea, headache, and weakness. Rare but more serious SE’s such as rhabdomyolysis and multiple organ failure has been reported.

Question 63

*_Centrally Acting Nonopioid Analgesics - other (weaker proof of benefit)_*

Answer 63

Others (weaker proof of benefit) Ketorolac (NSAID) Gabapentin Magnesium Sulfate Calcitonin Adenosine Octreotide Tramadol Droperidol

Question 64

Peripheral Nervous System (intro)

Answer 64

Most drugs either have a direct effect on the peripheral nervous system or a side effect on the system. Any alteration in normal function could be life-threatening to the individual. Proper understanding is critical to access potential side effects seen to therapeutic treatments.

Question 65

Peripheral Nervous System - physiology

Answer 65

Physiology PNS broken down into two major components: Somatic nervous system controls skeletal muscles Autonomic nervous system controls other bodily functions required for life further subdivided into: Sympathetic nervous system Parasympathetic nervous system

Question 66

Peripheral Nervous System - somatic nervous system

Answer 66

Somatic Nervous System Provides CNS and reflexive control of skeletal muscles. Muscle fibers divided into “motor units”, which are innervated by a single nerve fiber with axonal branches going to individual muscle fibers in the motor unit. The number of muscle fibers in each motor unit varies with the amount of control needed by the body (ex.- fine control in the fingers due to small number of muscle fibers per motor unit). Nerve fibers leave spinal cord from all levels and do not synapse until reaching motor end plate. Nerve fibers are myelinated for rapid conduction. Transmitter at motor end plate is acetylcholine and receptor type is nicotinic (N1 type [old term], neuromuscular nAChR).

Question 67

Peripheral Nervous System- autonomic nervous system

Answer 67

Autonomic Nervous System Critical in maintenance of body homeostasis. Regulates hormonal secretions from various glands as well as tone and motility of smooth muscles throughout the body. Most tissues (except skeletal muscles) innervated by at least one branch of the ANS. Many tissues innervated (or serviced) by both branches (sympathetic and parasympathetic) which serves as a positive and negative control system. Each tissue has a normal ‘predominant tone’ which is controlled mainly by the symp or p-symp system, and the other system may over-ride that normal tone.

Question 68

Somatic NS notes

Answer 68

Muscle fibers many fibers together not single in a long muscle – make up a motor unit small group of fibers that all work together at same time in the unit… a general muscle is made up of 1000s of units- has a never fiber that goes to it… nerve branches off doe not have to go to other fiber gap juctions can stimulate muscle next to it so you do not technically have branches to every one. Need fine control fingers dexterities small number of motor fibers in each unit. Quads large massive muscle do not need that kind of control not as many motor units. Remember do not synapse - muscle in toes fibers that go to them come all they way from spinal cord no synapses in process- very long axons. Myelinated- more rapid transmition across nodes of randvi N1 and N2 some old material and testing material – nicotinic receptor N1 at some point people mixed it up

Question 69

Peripheral Nervous System

Answer 69

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.

Question 70

Peripheral Nervous System- parasympathetic nervous system -

Answer 70

Parasympathetic Nervous System Mainly controls sedentary functions. Exits spinal column from cranio-sacral regions. Synapses at ganglia close to innervated tissue. Approximately 1:1 ratio of incoming to outgoing fibers provides fine control. Neurotransmitter at both pre-ganglionic (N2, neuronal nAChR) and post-ganglionic (M) sites is acetylcholine. notes- Parasympathetic- relaxed- digest, lower BP, so on rest and digest HR homeostatic controls - post and pre uses acetylcholine. Incoming and outgoing 1:1 fine control keep in mind sympathetic is very different

Question 71

Peripheral Nervous System- sympathetic nervous system

Answer 71

Sympathetic Nervous System Mainly controls ‘fight-or-flight’ responses. Exits spinal column from thoraco-lumbar regions. Synapses at ganglia (paravertebral chain) that lies close spinal cord. Approximately 1:10 to 1:100 ratio of incoming to outgoing fibers provides wider (not fine) control. Neurotransmitter at pre-ganglionic synapse is acetylcholine (ganglionic nAChR), whereas post-ganglionic synaptic transmitter is norepinephrine (mostly). NOTES- Fight or flight- massive sympathetic see everything in body sympathetic BP up vasoconstriction skin- pupils dilated to see – far vision, blood flow cutanious vasoconstriction- bleeding out and shunts to muscle and more glucose in blood stream – crisis management Para- exit sacrial Sympathetic from the thoraco-lumbar We find many nerve fibers exiting for one going to ganglia – massive nonspecsific – like sounding alarm in body everyone hears it large number of locations at same time. – most part get everyone ready for crisis – not thought as fine control 99% of neurotrassmiter is nerepinepherine

Question 72

Peripheral Nervous System -sympathetic nervous system cont.

Answer 72

Sympathetic Nervous System Other neurotransmitters (dopamine, epinephrine) Adrenal Medulla acts as a giant ganglion Receives pre-ganglionic fibers, then outputs transmitter into bloodstream instead of a synapse. Provides a mechanism for affecting wide-ranging tissues. Stimulated by preganglionic Ach release from Sympathetic system Actually secretes epinephrine : norepinephrine in an 80:20 ratio.

Question 73

ANS Receptors

Answer 73

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.

Question 74

Ganglionic Blockers (intro)

Answer 74

Little use today (primarily experimental). Were used to control blood pressure, but very dangerous. Ganglia function is much more complex than the simple idea of a cholinergic nerve entering and acting on a ganglionic nicotinic receptor. Actually several receptors in ganglia. However, the rapid depolarization and passage of an EPSP is due to this nicotinic receptor (N2, ganglionic nAChR) (blocked by hexamethonium) in which Na+ rapidly enters via a ligand gated channel. Secondary receptors on the ganglia (muscarinic, adrenergic, and others) believed to amplify or suppress this signal. Only nicotinic ganglionic blockers can completely block the transmission through ganglia. Depolarizing type blockers initially stimulate the ganglia like ACh then block due to a persistent depolarization (i.e. nicotine). Other type of blockade (i.e., hexamethonium) doesn't stimulate the receptor. Acts by competing for ACh binding site only (non-depolarizing). Mecamylamine is a non-depolarizing blocker that acts at a secondary site (non-competitive) to decrease ACh binding (negative allosterism). Hexamethonium works a little differently, blocking the ion channel after it opens - like a plug. The actions of these compounds are often complex and unpredictable, especially the depolarizing type, for example, nicotine can increase heart rate by initial stimulation of the sympathetic ganglia or depressing the parasympathetic cardiac ganglia, and vice versa. Also, nicotine acts on chemoreceptors and the medullary centers which then send increased or decreased signals to the heart via compensatory responses. Nicotine also triggers release of epinephrine from the adrenal medulla which increases cardiac rate and blood pressure.

Question 75

Ganglionic Blockers- symptoms

Answer 75

Symptoms of ganglionic blockade, such as seen with hexamethonium include: increased bloodflow to the skin (warm and pink), decreased sweating, inhibited lacrimation and salivation, mydriasis and cycloplegia, decreased GI tone and motility, hypotension, urinary retention, constipation, and hypoglycemia. These symptoms are due to blockade of the predominant tone on each tissue, allowing the non-predominant autonomic effects to override and be expressed.

Question 76

Ganglionic Blockers (pic) (

Answer 76

nondominate tone

Question 77

Ganglionic Blockers - mecamylamine

Answer 77

Mecamylamine Originally used to treat severe and malignant hypertension, but much safer and better antihypertensives available today. Granted Orphan drug status by the FDA for treating specific nicotine-responding neurological disorders such as Tourette’s syndrome. Also shown to be useful in treating some cocaine and nicotine addictions. Crosses CNS easily, and acts to block nicotinic receptors in the brain, as well as at the ganglia. In the brain, this blockade tends to decrease dopamine and norepinephrine release from specific neurons as well as modulating neuroendocrine responses. At low doses, the CNS effects are seen with few peripheral side effects. Due to its potential peripheral activity, it should not be used in patients with a history of myocardial infarction, glaucoma, or any cerebrovascular disease (i.e. stroke). Avoid sudden discontinuation of use (rebound hypersensitivity effects possible). Use should also be avoided in pregnancy since the drug crosses the placenta well. Adverse reactions include: nausea and vomiting, anorexia, constipation, mydriasis, syncope, weakness and fatique, among others.

Question 78

Neuromuscular Blockers -history

Answer 78

d-tubocurarine chloride was derived from a plant extract of Chondodendron Tomentosum. Curare is a plant alkaloid and has been used for centuries by South American Indians to kill wild animals to eat. Curare is also a generic historic term used extensively to describe an arrowhead poison capable of killing by causing skeletal muscle paralysis. Curare was first used in humans in 1932 for the treatment of tetanus and spasticity. In the 1940’s it was discovered that curare gave adequate skeletal muscle relaxation during operative anesthesia without using excessive amounts of general anesthetics. In addition to its use to promote skeletal muscle relaxation during surgery, tubocurarine has been used as an aid to mechanical respiration, to prevent trauma during electroconvulsive therapy and as an aid to the diagnosis of myasthenia gravis. Many other compounds have since been synthesized or identified as having curare-like properties, such as Succinylcholine, a unique neuromuscular blocker with depolarizing properties. Several synthetic neuromuscular blockers have been developed and utilized over the last 50 years such as pancuronium and several discontinued products. Newer, and currently available synthetic competitive nondepolarizing neuromuscular blocking agents with differing onsets or durations of action, metabolism, elimination, and side effects include atracurium, cisatracurium, rocuronium, and vecuronium.

Question 79

Neuromuscular Blockers - pic

Answer 79

Anesthesia- block info neurons don’t work properly neuronal, local – nerve action potential stop signal no signal to motor endplate. Succinylcholine neuromuscular blockers

Question 80

Neuromuscular Blockers Normal Acetylcholine binding to neuromuscular nicotinic receptor

Answer 80

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

Question 81

Neuromuscular blockers- Decamethonium binding to neuromuscular nicotinic receptor

Answer 81

Question 82

neuromuscular blocker binding Vecuronium pic

Answer 82

Vecuronium- (amino-steroid) binding to neuromuscular nicotinic receptor Sterioid nuclus \*\*\*\* look at structure

Question 83

Neuromuscular Blockers •**Mechanism of Action Two types:**

Answer 83

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.

Question 84

Neuromuscular blockers- nondepolarizing

Answer 84

``` 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). ```

Question 85

other neuromuscular blocker pic

Answer 85

Question 86

Neuromuscular Blockers - Duration of action

Answer 86

Question 87

Neuromuscular blockers - specific features- succinylcholine

Answer 87

Specific Features Succinylcholine (Anectine) Unique in its depolarizing mechanism and is also the shortest-acting (both onset and duration) neuromuscular blocker, with effective intubation conditions occurring within 60 seconds, and persisting for 2—3 minutes. Can cause transient sinus bradycardia accompanied by hypotension, cardiac arrhythmias, tachycardia, and possible cardiac arrest by increased vagal stimulation. Can cause also cause hyperkalemia. Pre-treatment with anticholinergic agents, e.g., atropine, may reduce the occurrence of bradyarrhythmia. Also possesses significant _histamine_-releasing properties.

Question 88

Neuromuscular blockers - special features- rocuronium +

Answer 88

Specific Features Rocuronium is classified as a short-acting(?), nondepolarizing agent and has been shown to be an effective alternative to succinylcholine for rapid sequence endotracheal intubation, due to it’s short onset and fairly short duration of action. Mivacurium has been re-offered after being off the market for several years. It is considered short-acting withy a longer onset time but shorter duration than Rocuronium. Intermediate-acting agents, Atracurium, Cisatracurium (Nimbex), and Vecuronium, have neuromuscular blocking effects for 30 to 60 minutes. The long-acting neuromuscular blocking agent, Pancuronium, has effects lasting from about 60 to 120 minutes. another slide- Specific Features Neuromuscular blockers differ in their mechanism for elimination and therefore the associated precautions for use in conditions which may impair drug elimination

Question 89

Neuromuscular Blockers - special features- atracurium/mivacurium

Answer 89

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.

Question 90

Neuromuscular blockers Atracurium Metabolism

Answer 90

Atracurium Metabolism

Question 91

Neuromuscular Blockers - special features- cont panc roc vec

Answer 91

Specific Features Renally eliminated agents include Pancuronium, which may require dosage reduction and careful monitoring in patients with renal impairment. Agents which are primarily excreted by hepatic metabolism or biliary excretion include Rocuronium and Vecuronium; these agents have precautions for use in patients with hepatic disease.

Question 92

Neuromuscular Blockers - special features histamine release

Answer 92

Specific Features Succinylcholine has moderate histamine-releasing properties. Atracurium and Cisatracurium(minimal) have mild to moderate histamine-releasing potential; histamine-release is generally dose-related. Agents with histamine-releasing properties have precautions for use in asthma or cardiac disease, and may be associated with increased cardiopulmonary adverse effects including flushing, hypotension, sinus tachycardia, and bronchospasm. Agents which lack significant histamine-releasing effects and do not block cardiac muscarinic receptors may be preferred in patients with compromised cardiovascular status, cardiac disease, or asthma. These agents include Rocuronium and Vecuronium.

Question 93

Neuromuscular blockers- adverse reactions

Answer 93

Adverse Reactions Prolonged neuromuscular blockade or paralysis may occur with the long-acting agent, Pancuronium, compared to the shorter-acting agents. Prolonged blockade can result in muscle paralysis, apnea, dyspnea, or respiratory depression. Patients at risk for prolonged neuromuscular blockade with neuromuscular blockers include those with conditions or receiving medications that impair neuromuscular function (e.g., myasthenia gravis) or potentiate the pharmacological actions of neuromuscular blockers (e.g., electrolyte imbalance). – Patients with myasthenia gravis are very sensitive to these agents and small doses should be used. In addition, conditions which impair elimination of the specific neuromuscular blocker (e.g., renal impairment, hepatic disease, pseudocholinesterase deficiency) may lead to drug accumulation and prolonged neuromuscular blockade, especially for the longer-acting agents. Significant drug interactions (e.g., lithium, calcium salts, magnesium salts, inhalational anesthetics, local anesthetics, certain antibiotics, quinidine, procainamide, lidocaine, and others) can potentiate neuromuscular blockade with the nondepolarizing agents. Tachycardia is most common with Pancuronium, due to blockade of muscarinic receptors. This problem may be enhanced by other conditions such as age, electrolyte imbalance, and renal or hepatic failure. Neuromuscular blocking agents with histamine-releasing properties (e.g., Atracurium, Cisatracurium (much less), and Succinylcholine) have precautions for use in asthma or cardiac disease, and may be associated with increased cardiopulmonary adverse effects including flushing, hypotension, sinus tachycardia, urticaria, wheezing, and bronchospasm. – In asthmatic patients treated with steroids and steroidal neuromuscular blockers (e.g., Vecuronium, Pancuronium) while on mechanical ventilation have experienced an acute myopathy lasting days to weeks. Phlebitis and pain has been reported with peripheral intravenous administration of non-depolarizing neuromuscular blockers Malignant Hyperthermia triggered by combination of certain anesthetics and neuromuscular blocking drugs. initiated by uncontrolled release of Ca++ from the sarcoplasmic reticulum in skeletal muscle. more commonly seen with depolarizing blockers given with an anesthetic, even though it has also been reported with succinylcholine alone or a volatile anesthetic alone

Question 94

Selective Relaxant Binding Agent

Answer 94

Sugammadex (Bridion) first in a new class known as SRBA’s designed as a reversal agent for Rocuronium also works fairly well with vecuronium and pancuronium structure is a complex cyclodextrin ‘cage’ with high lipophilicity that binds the neuromuscular blocker and allows removal. FDA approval granted 12/15/2015 after multiple rejections for allergic reactions.