Nervous System Pharm Flashcards
1
Q
Ionic Permeability of Nerve Cells
A
- Nerve cell membrane = lipid bilayer so impermeable to ions
- Overcome by ion channels (ion selective pores in membrane)
- More Na++ / Cl- outside cell and more K+ in cell
- Maintained via Na/K pump - 3 Na+ out and 2 K+ in using ATP hydrolysis
- Also ion channels that are open at rest are mainly permeable to K+ (passive diffusion)
2
Q
Action Potential (3 steps)
A
- 1- Depolarization: Excitatory input to dendrites —> voltage-gated Na+ channels open (rapid kinetics)
- Moving toward Na+ equilibrium potential
- 2- Repolarization: soon after, slower voltage-gated K+ channels open and Na+ channels become inactive and close
- Moving toward K+ equilibrium potential
- 3- After Hyperpolarization: undershoot below resting membrane potential b/c K+ channels still open
3
Q
How is resting membrane potential maintained?
A
- Passive diffusion of ions through channels down conc gradient - eventually opposed by electrostatic force as charge builds up
- Equilibrium Potential = voltage when net flow of ion is 0 b/c passive diffusion countered by electrostatic force
- Resting Membrane Potential = weighted combo of all ions in cell
- Mainly based on the open K+ channels at rest (passive diffusion)
4
Q
Refractory Period
A
- Na+ channels spont deactivate when membrane is cont depolarized (by loop in intracellular domain that plugs the channel)
- Na+ channels take tome to recover from inactivation SO…period of time when membrane is not able to generate another AP
- Limits frequency at which APs can be generated AND prevents APs from bouncing back at nerve terminal
5
Q
Multiple Sclerosis
A
- Demyelinating disease
- Can effect motor, somatosensation, vision, speech, etc
- Might be autoimmune? NO cure but given immune suppressants
6
Q
EEG and EMG
A
- even though individual APs are always the same magnitude, you can measure the summation/ensemble of APs to diagnose pathology
- EEG - meas electrodes in head (seizures)
- EMG - meas how many muscle fibers are firing simultaneously via electrode in muscle
- Normal - consistent magnitude
- Abnormal- waxing/waning
7
Q
How do action potentials propagate?
A
- Action potential opens more Na+ channels as it moves down axon
- B/c myelin inc resistance (inc length constant) and dec capacitance (dec time constant- faster)
- Node of Ranvier have local pockets of more Na+ channels to maintain AP
- “Saltatory conduction”
8
Q
Different Local Anesthetic Structures
A
- Aniline or benzoic acid linked to tertiary amine via ester or amide bond
- Esters hydrolyzed in plasma by esterase so short-lived
- Procaine - ester linkage (less stable and shorter action) Novocaine®- Amide bond more stable and longer lasting
- Lidocaine Xylocaine®
- Amide bond more stable and longer lasting
9
Q
Impact of pH on local anesthetics
A
- Dec pH (more acidic environment) —> less conc of neutral form/more protonated form—> less effective LA
- How is pH lowered?
- Constricted infection
- If use acidic vehicle to deliver LA to low perfused area like spinal cord
10
Q
General Mechanism of Local Anesthetics
A
Na Channel Gating
- Stabilize inactive form of ion channels…inability to produce action potential
- DO NOT BLOCK CHANNEL ITSELF
- Bind to the wall of the channel pore —> conformational change
11
Q
Use-dependent v use-independent action
A
- The charged form gives use-dependent inhibition while the neutral form gives use-independent inhibition b/c must get INTO cell to work/bind
- Use-dependent = the more channels are open; the more effective the drug inhibition is because must enter via channel to bind
- Use-independent= channel does not have to be open b/c drug goes through membrane (permeable) to bind
12
Q
Proximal v Distal Nerve Block
A
- Drug permeates nerve from outside so affects mantle first
- Proximal -early block
- Distal - delayed- block
13
Q
Passive Propagation
A
- If smaller diameter the diffusion of Na+ cannot span the width of the bolus of drug; if larger diameter the Na+ can diffuse and bridge the gap of the bolus
- Dep on space constant - This Na+ diffusion to create downstream AP is “passive propagation”
14
Q
Differential Blockade
A
- specificity of blockage depends on which axons are blocked first
- Small diameter, shorter length (2-3 nodes) and mantle (periphery) blocked before core
- Order: Pain, cold, warmth, touch, deep pressure, motor
15
Q
Side Effects of Local Anesthetics
A
- Safety- if end up in bloodstream they will have effects all over body b/c Na+ channels all over body
- Numb tongue, light-headed, visual/auditory disturbances, muscular twitching, unconscious —> seizures (no GABA inhibition)—> coma —> resp arrest —> CVS depression
16
Q
Basic Features of Synapses
A
- Synapse- space b/n neurons - pre-synaptic and post-synaptic terminal
- Synaptic vesicles- transport neuroT in synapse
- Active zone- specialized cell membrane region on pre-synaptic membrane where synaptic vesicles cluster
17
Q
NMJ - What Receptors Do They Use?
A
- Synapse b/n motor neuron and muscle fibers; ea fiber only has one NMJ but each NMJ can have multiple fibers
- Release neuroT acetylcholine
- Nicotinic acetylcholine receptors - ligand-gated ion channel; bind acetylcholine then release cations (Na and K); fast and transient
- Requires binding of 2 acetylcholine molecules to open channel
18
Q
Role of Ca++ in Synapse
A
Voltage-gated Ca2+ channels - trigger synaptic vesicle fusion
19
Q
Steps of Vesicle Release (3)
A
- Docking -filled w/ neuroT; dock at active zones w/in pre-synaptic membrane
- Priming- form protein complex w/ membrane to make them ready for exocytosis
- Fusion - Ca++ enters (channels open) —> fuse w/ membrane to exocytosis
20
Q
Steps of Vesicle Recycling (4)
A
- Endocytosis- internalized by clathrin-coated pits
- Translocation -shed coat, acidify, interior
- NeuroT uptake- loaded w/ neuroT via transporters that use proton-pump electrochemical gradient
- Translocation - moved back to active zone now that they’re filled
21
Q
Botullin and Tetanus Toxins
A
clostridial toxins; protease that cleaves proteins involved in vesicle docking so inhibit synaptic transmission (cleave SNARE proteins involved in vesicle fusion)
22
Q
Lambert-Eaton MS
A
- autoimmune attack of presynaptic Ca++ channels
- Symptoms improve when exercise - PTT
23
Q
Myasthena gravis
A
- immune attack of AChRs
24
Q
5 Properties of Neurotransmiters
A
- 1- synthesis (can be made by pre-synaptic cell or precursor)
- 2- release (calcium and activity dependent)
- 3- identity of origin (should have same effect exogenously)
- 4- pharm identity (drugs should still work exogenously on it)
- 5- termination of action (enzyme to degrade it or uptake mechanism)
25
Q
Acetylcholine Synthesis and Metabolism
A
- acetyl Coa + choline —> Ach + CoA (via choline acetyl transferase -ChAT)
- Limited by choline uptake
- Terminated by acetylcholinesterase
26
Q
Catecholamines Synthesis and Metabolism
A
- Tyrosine —> dopa —> dopamine
- Via tyrosine hydroxylase -rate limiting AND dopa decarboxylase - need Vit B6 )
- Dopamine —> norepinephrine (via dopamine-beta hydroxylase + absorbic acid and only INSIDE synaptic vesicle)
- Norepinephrine —> epinephrine (via PNMT)
- PNMT in cytoplasm so norepinephrine must leave vesicle to be converted
- Termination by receptors (DAT and NET) or degraded
- Receptors blocked by cocaine and amphetamines
- Monoamine oxidase - degrades catecholamines
27
Q
Neuropeptide Neurotransmission
A
Neuropeptides use large dense-core vesicle, do not use active zones and do not get recycled (must make new ones in soma); made in soma then transported to pre-synaptic terminal; usually takes mult APs to get them released
28
Q
Serotonin Synthesis and Metabolism
A
- Tryptophan —> 5-hydroxytryptophan —> 5-hydroxytryptamine (serotonin)
- Via tryptophan hydroxyls then L-AA decarboxylase
- Termination via reuptake by SERT
- Target of Prozac
- Also blocked by cocaine and amphetamines
29
Q
GABA Synthesis and Metabolism
A
- Glutamate —> GABA (via glutamic acid decarboxylase)
- OR alpha-ketogluterate —> GABA (via GABA transaminase)
- GABA terminated bu rapid uptake by presynaptic terminal and neighboring glial cells
30
Q
Post-Synaptic Potentials
A
- Dep on…# open channels, driving force and Vm (potential of membrane)
- Excitatory - drives neuron membrane pot toward AP threshold (EPSP)
- Increase the probability that a neuron generates action potentials
- Inhibitory - drives neuron membrane pot further from AP threshold (IPSP if hyper polarization)
- Decrease the probability that a neuron generates action potentials (not necessarily change potential)
- **Synaptic integration of EPSPs and IPSPs determines if AP is fired or not
31
Q
Pre-synaptic Inhibition
A
- can change amount of neuroT released
- Ex) release GABA on presynaptic terminal - decrease amount released
32
Q
Post-tetanic Potentiation
A
- intense stim of presynaptic terminal (inc Ca++) —> enhanced response to subsequent SMALL stim b/c there is more Ca++ then the channels can keep up with
33
Q
Long-term Potentiation
A
- stim minutes —> effects that last days or weeks; basis of learning and memory (more receptors, change gene expression, sprout new spines on dendrites, change morphology of synapses, etc)
