If time Neuropharmacology

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If time Neuropharmacology
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Drugs that affect AP generation/conduction

• Tetraethylammonium anion (TEA?)
• blocks K channels
• does not prevent AP, but prolongs duration and
  abolishes afterhyperpolarization
• not used clinically
• Tetrodotoxin (TTX)
• blocks Na channels irreversibly not used
  clinically
• 2nd most potent naturally-occurring toxin know to
  man (lethal at doses
• from puffer fish (watch out for Fugu--a sushi
  made from the fish)
• closely related drug found in California
  salamanders
• attenuates spike or blocks AP altogether

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Tetrodotoxin or TTX (FYI only)
Puffer fish (Tetraodon sp.) Fugu
California newt (sp. sierrae)
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Drugs that affect AP generation/conduction (cont.)

• Local anesthetics (novocaine, lidocaine, etc.)
• blocks Na channels reversibly
• used clinically for anesthesia inject around
  nerve prevents nerve conduction
• nerve conduction returns after drug washes
  away, dilutes into extracellular volume, and
  eventually metabolized and/or excreted
• Extracellular Ca dependence
• outer leaflet of membrane often composed of
  charged phospholipids (e.g., phosphatidyl serine
  PS)
• screened by Ca (elevated Ca at membrane
  surface)
• hypocalcemia Ca replaced by Na, so ? ENa
• ? in threshold potential results in
  hyperexcitability

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Drugs that affect AP generation/conduction (cont.)

• Hyperkalemia
• depolarizes all resting cells
• closes h gates
• critical in monitor serum K in patients
• clinical use of high serum K
• execution of condemned criminals
• third IV solution infused

shift in Vm
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Drugs that affect synapses

• Curare (d-tubocurarine) blocks nicotinic-type
  ACh receptors
• skeletal-muscle neuromuscular junctions
• causes complete paralysis
• analogs used clinically (induce paralysis during
  surgery)
• curare itself used for hunting from large vines
  in Amazon rain forest (So. American natives)
• not toxic if taken p.o.

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Drugs that affect synapses (cont.)

• Atropine blocks muscarinic-type ACh receptors
• heart, glands, some muscles (e.g., iris of eye)
• causes heart rate, dry mouth, dilation of
  pupil
• used clinically as antidote for ACh-ase
  inhibiting drugs
• From Belladonna (beautiful woman) plant (also
  called Deadly Nightshade)
• named for Atropos -- one of Greek fates
  (mythology) who cut the thread of life.

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Drugs that affect synapses (cont.)

• Hemicholinium blocks choline uptake in presyn.
  terminal
• causes ? ACh synthesis, hence ? quantal content
• not used clinically
• Black-widow spider venom uncouples
  Ca-dependent synaptic release
• uncontrollable release of all transmitter,
  depleting terminal of vesicles
• not used clinically
• Botulinus toxin (BOTOX) irreversibly blocks
  synaptic release of vesicles at cholinergic
  synapses (e.g., NMJ)
• similar to action of tetanus toxin (GABA
  synapses)
• causes paralysis at affected synapses
• clinical uses tremors, nervous twitches,
  cosmetic

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Drugs that affect synapses (cont.)

• Cholinesterase inhibitors blocks hydrolysis of
  ACh at cholinergic synapses
• causes huge amplitude EPPs with long duration,
  effectively paralyzing muscle can stop heart due
  to huge increase in ACh
• atropine is antidotal, but only for muscarinic
  (e.g., heart)
• clinical use treatment of myasthenia gravis
  autoimmune disease attacking ACh receptors
  (physostigmine, neostigmine)
• industrial use insecticide (malathion)
• chemical warfare nerve gas (sarin) -- among
  most toxic substances known to man

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Compound AP
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Compound (extracellular) AP
stimulate here w/ Taser-like device
?V
time
?V
time
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?V
time
?V
time
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Compound AP

• Measured with two skin electrodes along axon
• Measures extracellular PD -- not Vm
• due to electrotonic currents flowing outside
  nerve
• biphasic response as APs propagate past
  electrodes
• Response of entire nerve -- not single neuron
• Amplitude of response
• ?V to fraction of mV
• dependent on number of neurons conducting APs

Recording elect.
Stimulating elect. (like Taser)
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Compound AP Ulnar Nerve Conduction

• Velocity 0.30 m/0.0046 sec 65 m/sec
• Ignore amplitude! Gain 1000!
• What about shape and duration?

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Clinical utility of compound AP

• Locate peripheral nerve block
• Assessing peripheral nerve blocks
• Compare AP amplitude from maximal nerve
  stimulation distal to site of injury with that
  proximal to site of injury
• Amplitude ratio reflects fraction of conducting
  axons
• Measuring conduction velocity
• MS and ALS (a/k/a amyotrophic lateral sclerosis
  or Lou Gehrigs disease)
• Demyelination ? ? velocity