• Atracurium Besylate
• Cisatracurium Besylate
• Mivacurium Chloride
• Pancuronium Bromide
• Rocuronium Bromide
• Vecuronium Bromide

MOA

• Competitive Antagonist at the nicotinic receptor
• Causes skeletal muscle relaxation to complete paralysis (small muscles first)

Uses

• Tracheal intubation
• Duratin surgery and during mechanical ventilation

Side Effects

• Tachycardia, increased cardiac output
• Flushing, decreased peripheral vascular resistance
• Side effects of blocking nicotonic receptors on autonomic ganglia depends on sympathetic or parasympathetic tone (vasodilation, tachycardia)

• Nicotinic receptor is a ligand-gated ion channel
• 5 subunits
• Receptor has two binding sites for ACh (delta-alpha and alpha-beta)
• When ACh binds, Na+ moves into the cell resulting in depolarization
• Action potential is produced and Ca2+ is released from sarcoplasmic reticulum 
• Muscle contracts

MOA

• Succinylcholine binds to nicotinic receptors and opens the Na+ channel
• Phase I -- succinylcholine causes sustained muscle fiber depolarization
• Phase II -- the muscle fiber then repolarizes but is not responsive to acetylcholine or succinylcholine (desensitization)
• Flaccid paralysis follows and drug is hydrolyzed

Uses

• Adjunct to surgical anesthesia
• Facilitates intubation

Side Effects

• Hyperkalemia
• Malignant hyperthermia (muscle rigidity, hyperthermia)
• Negative inotropic and chronotropic effects on heart

• Baclofen
• Diazepam
• Tizanidine

• Spinal cord (reflex arc) -- reduce stretch reflex
• Higher brain centers -- activate descending pathways that inhibit motor neurons that synapse directly with muscle

• The spindle senses muscle length (stretch)
• Ia afferent nerves become activated and send action potential to spinal cord
• The efferent nerves (motor neurons) become activated and send action potentials to the muscle fibers causing muscle contraction
• CNS Acting Drugs inhibit the stretch reflex

• Descending inhibitory neurons from the brain stem reduce basal alpha motor neuron activity (regulates muscle tone)
• When this descending inhibitory neuron activity is damaged, increased muscle tone results
• CNS Acting Drugs activate descending inhibitory pathways

MOA

• GABA analogue
• A selective GABA-B receptor agonist
• Hyperpolarizes excitatory neurons in the brain and spinal cord (K+ efflux)
• Reduces Ca2+ conductance in the presynaptic terminal
• Has muscle relaxant and analgesic properties

ADRs

• Somnolence
• Increased seizure activity

MOA

• Allosteric agonist at GABA-A receptor
• Increases Cl- conductance
• Enhances descending inhibitory input to the alpha motor neurons
• Suppresses reflex arc

ADRs

• Somnolence
• Tolerance

MOA

• Agonist of alpha2 presynaptic receptors
• Reduces adrenergic input to alpha motor neurons
• No effect on spinal cord reflex

ADRs

• Hypotension
• Asthenia

• Binds to presynaptic vesicles
• Inhibits ACh release

MOA

• Binds to ryanodine receptor
• Inhibits Ca2+ release from sarcoplasmic reticulum

Uses

• Treatment for malignant hyperthermia

• Direct activation of nociceptors by thermal, chemical, or mechanical stimulation --> the neuron reaches threshold and produces an action potential
• Thermal, mechanical, and chemical stimulus concurrently causes nearby cell damage --> damaged cells may leak potassium into the extracellular space and release bradykinin, serotonin and prostaglandins, all of which promote production of action potentials in nociceptors
• As a result of the first two steps, this is the "pain" signal conduction to the CNS
• Activated neurons release mediators (substance P, calcitonin gene related peptide) that lower neuron activation threshold --> this results in vasodilation of nearby blood vessels and mast cell degranulation (releases serotonin and histamine)

Fiber Types: Aδ

Presence of Myelin, Diameter, Conduction Velocity, Function

Myelin

Yes

Diameter

Intermediate

Velocity

Intermediate

Function

First pain, Temperature

Fiber Types: C (dorsal root)

Presence of Myelin, Diameter, Conduction Velocity, Function

Myelin

No

Diameter

Small

Velocity

Slow

Function

Second pain, Temperature

• Three states of the Na+ channel exists -- resting, activated, inactivated
• Local anesthetics (LA)bind to the activated and inactivated states
• When LAs bind the activated state, Na+ current is decreased
• Binding of LAs to the inactivated state stabilize the inactivated state
• Each time the neuron produces an action potential, more LA is bound to the Na+ channels causing more blockage of current

• Procaine
• Benzocaine
• Tetracaine

• Lidocaine
• Prilocaine
• Bupivacaine
• Ropivacaine

Potency

Low

Duration

Short

Uses

Dental procedures

Important Considerations

Metabolized to para-aminobenzoic acid --> counteracts mechanism of sulfonamides

Potency

Hydrophobicity>Procaine, higher potency

Duration

Long

Uses

Spinal block

Important Considerations

PABA metabolite --> counteracts mechanism of sulfonamides

Limited to topical

Potency

Moderate

Duration

Medium

Use

Very common, infiltration anesthesia, peripheral nerve block, epidural, topical

Potency

Similar to lidocaine -- less CNS effects

Duration

Similar to lidocaine

Uses

Good choice when epinephrine is contraindicated

Important Considerations

Converstion of ferrous Fe (+2) to ferric Fe (+3) caused by prilocaine aromatic ring metabolite -- when iron is in ferric state, hemoglobin cannot carry O2 -- fetal circulation more prone to oxidative stress and slower to convert iron back to ferrous state

Potency

Very hydrophobic, high potency

Duration

Long

Use

Spinal, epidural, infiltration anesthesia and peripheral nerve block

Important Considerations

Cardiotoxicity -- S-enantiomer is less cardiotoxic

Potency

Very hydrophobic, high potency

Duration

Long

Use

Spinal, epidural, infiltration anesthesia and peripheral nerve block

Important Considerations

Less cardiotoxic than Bupivacaine

• Associated with wave of cortical spreading depression originating in the occipital lobe and then spreading toward frontal
• Most often described as visual changes

• Primarily a neurovascular disorder
• Results from dysfunction of the trigeminovascular system
• The disorder manifests as recurring attacks, usually lasting 4-72 hrs

• Potent vasodilator
• New target for migraine therapy

What Is It?

• A period of constriction of cerebral vessels (correlates with aura) followed by a reactive vessel dilation of the meningeal vessels
• Vessel dilation activates trigeminal sensory pathway (associated with head pain)

Problems with hypothesis

• Changes in blood flow similar in magnitude have been observed that do not result in head pain

What Is It?

• The initial factor involves neurons in the cerebral cortex
• A wave of neuron depolarization spreads over the cortex starting in the occipital love and proceeding toward the frontal lobe
• This is followed by depression of neuronal electrical activity and reduced blood flow is associated with migraine aura --> head pain follows

Problems with Hypothesis

• CSD can be induced in animal model by application of high extracellular K concentration, but this does not activate trigeminal afferent
• It is currently believed that CSD is associated with aura but is not required for subsequent migraine headache

• Activated trigeminal nerve releases neuropeptides onto meningeal vessels causing vasodilation
• Vasodilation causes inflammation (more neuropeptide release) and sensitization of trigeminal sensory nerves
• Pain impulses are transmitted to the trigeminal nucleus caudalis, thalamus, and to higher CNS pain centers (cortex)
• According to this hypothesis, vasodilatioon is not the cause of migraine but a consequence of trigeminal nerve activation

• CGRP and Substance P release from the activated trigeminal nerves
• Mast cells are also involved -- they are activated by the trigeminal nerve release of substance P -- the mast cells in turn release histamine
• CGRP will also stimulate the blood vessels directly and cause dilation indirectly through causing the endothelial cells to release NO and other vasodilation mediators

• 5-HT1B and 5-HT1D
• These receptors increase vasoconstriction of cerebral vessels, decrease vasoactive peptide release, and decrease the pain pathway

MOA

• Agonist at 5-HT1B -- constriction of cranial vessels
• Agonist activity at presynaptic 5HT1D -- inhibits cGRP
• Some pain transmission blockage (central action)

Uses

Treatment of acute moderate to severe migraine

ADRs

• Activation of 5-HT3 receptors in the CTZ
• Severe peripheral vasoconstriction caused by alpha1 receptor activation
• Rebound headache
• Epi reversal - Can antagonize the effects of epinephrine because it occupies the alpha receptor (high affinity) but does not activate the receptor

MOA

• Agonist at 5-HT1B -- constriction of cranial vessels
• Agonist activity at presynaptic 5HT1D -- inhibits cGRP
• Some pain transmission blockage (central action)

Uses

Nasal and injection formulations for acute migraine attack

ADRs

• Similar to ergotamine but much less severe
• Inhibitors of CYP3A4 (protease inhibitors, macrolide antibiotics, anti-fungals) increase serum DHE -- increases risk of severe peripheral and cerebral ischemia

• Triptans have more selective receptor interactions -- no activity at adrenergic or dopaminergic receptors
• Both have agonist activity at 5-HT1B and 5-HT1D
• Triptans have higher oral bioavailability

MOA

• 5-HT1B agonist -- constriction of intracranial blood vessels
• 5-HT1D agonist -- inhibition of vasoactive peptide release from trigeminal nerves
• Does NOT act on trigeminal nucleus caudalis -- does NOT cross BBB

Uses

Acute migraine attacks

ADRs

• Coronary artery constriction -- chest discomfort -- CI coronary artery disease

• Naratriptan
• Rizatriptan
• Zolmitriptan
• Almotriptan
• Eletriptan
• Frovatriptan

MOA

• Same as sumatriptan
• Additional action at central 5-HT1D receptors -- these receptors are found in the trigeminal nucleus caudalis and these drugs block transmission of pain signals to thalamus

Uses

• Treatment of acute migraine
• Greater clinical efficacy over sumatriptan

ADRs

• Tingling, sensation of warmth, nausea
• Can cause coronary artery constriction

Tubocurarine

Mivacurium