Pharm Week 1
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. What would you like to do?
Who has a say in the type of anesthesia performed?
The patient, the anesthetist, and the surgeon
What is the stress response of surgery due to?
- activation of the HPA axis and SNS which causes an increase in:
- cortisol, catecholamines, and cytokines
What are the consequences of the stress response to surgery?
- tachycardia, hypertension, increased metabolism, hypercoagulability, decreased immune function
- which can cause: periop ischemia, infarction, clots, arrhythmias, and delayed wound healing
What are the major characteristics of anesthesia?
- a reversible state mediated by the CNS that produces:
- -immobility in the face of noxious stimuli
- also: LOC, analgesia, suppression of autonomic reflexes, and muscle relaxation
What would an "ideal anesthetic" do?
- -induce anesthesia smoothly and rapidly
- -permit rapid recovery
- -have a wide margin of safety
- -have no adverse effects
In general, how does a chemical synapse work?
- -these are most of the synapses in the CNS
- -presynaptic neuron secretes NT
- -NT acts on receptor proteins on membrane of postsynaptic neuron
- -can be excitatory or inhibitory (in terms of its affect on the postsynaptic membrane and its permeability)
Where does an excitatory or inhibitory NT exert its effects?
On the POST-synaptic membrane
What's a synapse?
The junction between neurons
What is the amount of NT released dependent on?
It's directly dependent on the number of calcium ions that enter the presynaptic membrane thru voltage gated calcium channels
When is calcium released in the presynaptic membrane?
It's released when the action potential depolarizes the presynaptic membrane, at this time Ca++ channels open, and Ca++ flows into the pre-synaptic terminal
How are NT released?
The action potential depolarizes the presynaptic membrane and causes vesicles containing NT to empty into the synaptic cleft.
Why does the presynaptic knob need mitochondria?
To generate ATP to make new NT
What happens after a NT is released?
The released NT causes immediate change in the permeability characteristics of the post-synaptic membrane. This results in either excitation or inhibition of the post-synaptic neuron based on effect on ion channels.
What are the 2 types of ion channels that NT can open? What ions are characteristic of each?
1) cationic (+), mostly Na+, some K+, and Ca++
2) anionic (-), mostly Cl-
categorized by what type of ion (+ or -) can go thru
How can K+ ion have an inhibitory effect?
When K+ ion leaves the cell, it takes its positive charge with it, leaving a negative charge inside
What part of the body do anesthetics act on to cause immobility?
- spinal cord
- -actions here underlie the determination of MAC (MAC= amt of anesthetic which does not cause movement in response to a painful stimuli in 50% of patients)
- -specific location may be the motor neuron
What role does anethesia have on the reticular activating system?
- It inhibits information transfer thru the brain stem.
- RAS is responsible for arousal.
What role does anethesia have on the cerebral cortex?
- -Interferes with integration and storage of information and memory and awareness
- -This effect can be measured with a surface EEG (BIS monitor)
What specific site is responsible for "anesthesia"?
None, there isn't one specific site that is responsible for the general term "anesthesia"
How can anesthesia affect synaptic transmission presynaptically?
- -can alter NT release-can alter NT reuptake following release
How can anesthesia affect postsynaptic NT action?
It can alter the binding of the NT to the receptor sites
What are examples of voltage gated channels? How do they work?
Open and close according to the electrical potential difference across the membrane.
Ex: Na+ and K+ gates
What types of transport are carrier proteins responsible for?
facilitated and active transport
What are characteristics of channel proteins?
- -highly selective as to what ion can pass, not just based on size
- -open and close either by voltage gating (electrical potential difference) or ligand gating
What is the major characteristic of a ligand gated channel?
Involves a chemical or NT that binds with the channel protein
What is the Nernst Potential (AKA Goldman Equation)?
Accounts for 2 factors that affect the net rate of diffusion, 1) concentration gradient and 2) electrical potential gradient
-Calculates the voltage taking Na+, Cl-, and K+ into account
-Fundamental to action potential in all nerves and cardiac and skeletal muscle
What is the significance of the diffusion potential of an ion?
- -Indicates at what electrical potential (in mV) diffusion will stop despite a concentration gradient
- -Ex: at -94 mV, K+ will stop diffusing out of the cell even though a concentration gradient remains
Is the electrical potential measured inside or outside the cell?
Where are the activation and inactivation gates of the Na+ channel located? (inside or outside)
Activation gate- outside
Inactivation gate- inside
In a voltage gated Na+ channel, which gate is open and which is closed at resting?
Activation gate is closed, inactivation gate is open.
What occurs in a Na+ channel with depolarization?
- -Inside is already negative due to K+ diffusing out due to the concentration gradient.
- -When the membrane potential becomes less negative due to some stimuli (threshold is reached), Na+ rushes into the cell as the activation gate opens
What is repolarization and how does it occur?
- Repolarization is the charge in the cell returning to resting (-90 mv)
- -Occurs after depolarization (when Na+ rushes in)
- -The increased voltage inside the cell (Na+) causes the inactivation gate to close (this is slower than the activation gate opening), Na+ can't enter the cell any longer
- -K+ channel opens, allows K+ to leave the cell
What happens after repolarization?
The cell returns to resting membrane potential, the Na+/K+/ATPase pump moves 3 Na+ out for every 2 K+ inside the cell
How is the resting membrane potential maintained and what is its normal value?
- -Normal value -90mV
- -Maintained by Na+/K+/ATPase pump and K+ leak channels
At RMP which voltage gates are open and which are closed?
Open- Na+ inactivation gate
Closed- K+ voltage gated channel and Na+ activation gate
What is another name for RMP?
What 2 ions are most important to action potential?
K+ and Na+, membrane permeability to each can change very quickly and thus both affect AP
What is hyperpolarization?
- -The inside of the cell becomes super negative, (ex: -110 mV)
- -A normal excitatory stimulus will not cause it to reach threshold
What can cause hyperpolarization? How?
- -An inhibitory NT such as GABA
- -GABA stimulation causes increased membrane permeability to Cl- ions
- -Cl- ions enter the cell and make it more negative
- -many anesthetics involve GABA
What are 2 mechanisms by which anesthetic agents can cause inhibition of the AP in the CNS?
- -Depress excitatory potentials
- -Enhance inhibitory potentials
What is the major excitatory NT in the CNS?
What is the major inhibatory NT in the CNS?
What happens to cell permeability when the membrane is exposed to an excitatory NT?
Increased permeability to Na+ (more Na+ can enter the cell)
What happens to cell permeability when the membrane is exposed to an inhibitory NT, such as GABA?
- Selective increase in permeability to Cl- and K+ (Cl- enters, K+ exits)
- -Result is that the inside of the cell is more negative
What are examples of ligand-gated ion channels?
nicotinic cholinergic receptors (NMJ and ganglia), amino acid receptors, GABA, and NMDA
T or F, all injected and inhaled anesthetic agents (except ketamine) have GABA influence?
What is the Meyer-Overton Rule (AKA Unitary Hypothesis)?
- -Attempts to provide an answer to the question, "why do diverse chemical structures cause anesthesia?"
- -Potency of inhaled anesthetics is directly correlated with lipid solubility (measured as oil:gas partition coefficient)
How is MAC calculated?
MAC = 150 / oil:gas partition coefficient
What are limitations to the Meyer-Overton Rule?
- 1) Only applies to gases and volatile liquids as an oil:gas partition coefficient can't be determined for liquids (IV agents)
- 2) Olive oil is a poorly characterized mixture of oils
- 3) Not all lipid soluble compounds are anesthetics
- 4) Some lipid soluble compounds are convulsants
T or F?
The Meyer-Overton Rule states that all anesthetics share the same MOA at the molecular level, that is, disrupting the structure or properties of the lipid portion of nerve membranes?
What are examples of channel proteins?
simple diffusion, K+ leak channels
What would you like to do?
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