Anesthesia Pharm Lecture 1
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. What would you like to do?
What is the ideal anesthetic? (4 things)
- Induce anesthesia smoothly & rapidly
- Permit rapid recovery
- Wide margin of safety
- No adverse effects
2 types of CNS synapses
chemical and electrical
THE ANESTHETIC CARE PLAN IS ______
SPECIFIC NOT _____ SPECIFIC
- THE ANESTHETIC CARE PLAN IS PATIENT
- SPECIFIC NOT PROCEDURE SPECIFIC
What are some pharmacological issues for the anesthesia care plan?
- Chronic medications
- a.Which meds to continue day of surgery
- b.Need for perioperative “fine-tuning” 2.
- Choice of anesthetic
- a.Type of anesthesia – goal directed
- b.Specific choice of agent – also goal directed
What are the causes of surgical stress? (there are six)
- 1. Psychological
- 2. Tissue injury
- 3. Intravascular volume changes
- 4. Anesthetic agents
- 5. Pain
- 6. Organ manipulation
Explain the stress response of surgery
- Activation of hypothalamic-pituitary-adrenal axis
- & sympathetic nervous system
- Resulting in:
- -Increased metabolism
- - Hypercoagulability
- - Decreased immune function
- (Peri-op ischemia infarcation, arrhythmia, thrombosis, infection & delayed wound healing)
What do we want out of anesthesia?
Unconscious, immobility, amnesia, no pain, no infection, rapid recovery, no PONV, safe, confidence, no anxiety
Eger says what two major things are involved in "anesthesia"
- immobility & amnesia
- *for inhaled anesthetics
Eger states: Anesthesia is the reversible statemediated by the central nervous system that produces: (six things total)
- Immobility in the face of noxious stimuli
- Suppression of autonomic reflexes
- Relaxation of muscles
Anesthesia provides ______grade amesia
antegrade-can not give retrograde
Most CNS synapses are ______ synapses
Explain how chemical synapses work
Presynaptic neuron secretes neurotransmitter
Neurotransmitter acts on receptor proteins on membrane of postsynaptic neuron
Chemical synapses can be _______ or ______
excitatory or inhibitory
How do electrical synapses work?
Gap junctions permit free movement of ions from 1 cell to another
Where are electrical synapses found?
Found mostly in cardiac and smooth muscle
GABA is an _______ neurotransmitter
The mechanismby which most IV anesthetics work is via _______
Are electrical synapses the same as voltage gated channels?
The presynaptic terminal holds what two things?
Presynaptic terminal contains vesicles that hold NT and the mitochondria. The mitochondria generates ATP to make new NTs. So when the action potential spreads over the presynaptic terminal the membrane depolarization causes those vesicles to empty into synaptic cleft
The post synaptic terminal has what? _____ ______
receptor proteins. As NT is released into synaptic cleft, it changes in permeability characteristic in post synaptic membrane leading to excitation (Na+ channel opens an Na moves through) or inhibition (depending on characteristics of the channel or receptor of the NT).
Presynaptic membrane contains a large number of voltage gated ___ channels
Presynaptic membrane contains a large # of voltage gated Ca+ channels. When action potential depolarizes the presynaptic membrane, Ca+ channels open, so that Ca+ will flow into terminal. The reason this is important, is that the amount of NT that’s released is directly related to the # of Ca+ ions that enter presynaptic terminal.
Explain neurotransmitter release
Action potential depolarizes the presynaptic membrane & causes vesicles containing neurotransmitter to empty into the cleft
Released neurotransmitter causes immediate change in permeability characteristics of the post-synaptic membrane causing either excitation or inhibition of the post-synaptic neuron based on effect on ion channels
Cation channels, conduct mostly _____ but some do conduct ___ & ____ ions as well.
Cation channels, mostly conduct Na+ ions but some do conduct Ca+ and K+ ions as well. Structures such that lines w/anions (negative charge) which draws the + charges through them. So any NT that as it opens channel that allows cations to pass is excitatory
Any channel that allows anions like ____ to pass is ______.
Any channel that allows anions (Cl-) to pass is inhibitory
Name the THREE anesthetic sites of action in the Central Nervous System
- Spinal Cord
- Reticular Activating System
- Cerebral Cortex
Anesthetics act on the spinal cord producing _____
Actions of the anesthetic on the ____ ____ underlie the determination of the MAC
What is the specific location in the spinal cord that the anesthetic acts upon?
May be the motor neuron
How do anesthetics act on the Reticular Activating System?
Inhibit information transfer through brain stem. Involved in arousal
How do anesthetics act upon the Cerebral Cortex?
Memory & awareness
Alteration of cortical electrical activity (can see changes in EEG --BIS monitor)
TRUE or FALSE. Some anesthetic effects contribute to specific site of action but not one site is responsible for general term of anesthesia. Anesthesia is more than 1 single effect.
How do anesthetic agents disrupt synaptic transmission?
- Presynaptic Action:
- Alter neurotransmitter release
- Alter reuptake of neurotransmitter following release
- Postsynaptic Action:
- Alter the binding of the neurotransmitter to receptor sites
Name the characteristics of the channel proteins
- Highly selective
- Not just size of ion or molecule
- Open & close via “gating”
Explain how the K+ channel is highly selective.
- It’s because the filter is lined with carbonyl structure. The carbonyl oxygen has lone pair of electrons, & this lines the selectivity of K+ channel, the presence of carbonyl oxygen will effectively pull on water and allow dehydrated
- K to pass. Na+ is smaller and it doesn't come into contact with carbonyl oxygen and Na+ can’t pass through the channel.
TRUE or FALSE. Na+ is smaller than K+ so it must be able to fit through the K+ channel.
FALSE! Anatomic # of K+ is 19 and mass is 39, Na+ is 11 and 22. Na+ is smaller than K+. Even w/size discrepancy, Na being smaller, K+ channels won’t allow Na+ ions to pass because there is selectivity filter on K+ channel.
How do Na+ channels work?
Na+ channel is lined w/amino acids (protein channel), Amino acids have a negative charge to them. Negative charge of AA effectively pulls the + charge of Na+ ions through the pore and away from their attached water molecules
How do voltage gated channels work?
Occurs according to electrical potential difference across the membrane basis of opening and closing of Na+ and K+ gates. Na+ gate opens when membrane potentials (difference between outside and inside of cell) reaches a level and that’s when depolarization begins.
Explain how ligand gated channels work
Chemical (or NT) binds w/channel protein. Ex: Ach
Net Diffusion depends on what two things
Concentration gradient and electrical potential gradient
The _____ potential takes both concentration and electrical potential
- This is really fundamental to action potential in all nerves and cardiac muscle contraction
_____ is the point at which diffusion (via concentration gradient) of K+ stops because the inside of the cell has become too negative.
-94mV (this is aka the membrane potential)
The diffusion potential is:
the electrical potential difference in inside and outside of cell that opposes net diffusion because of a concentration gradient
____ is the point at which Na+ will stop diffusing into the cell (via concentration gradient) because the inside of the cell has become too positive
+61mV (this is aka the membrane potential)
The resting membrane potential depends on what three things
- Polarity of electrical charge of each ion
- Permeability of membrane to each ion
- Concentration gradient of each ion across membrane
The diffusion potential can be explained by the ____ equation which gives the calculated voltage incorporating Na, K, and Cl.
Nernst or Goldman equation
The key to action potential is the permeability of the membrane to ___ & ___ changes (very quickly)
Na+ & K+
During normal nerve transmission,___ ion doesn't change much. Stimulation of GABA receptor by our anesthetics, will change permeability to ___ ion
How does the cell remain more negative in relation to the outside
That negative potential is maintained by Na/K ATPase pump and also by K+ leak channels. (So again mostly Na and K responsible for maintaining resting membrane potential)
What type of voltage gated channel has two gates and is critical to the action potential? What are the two gates?
Na+. Activation gate (outside) and inactivation gate (inside)
Which voltage gated channel has a single gate?
The resting membrane potential is at -90mV and a stimulus moves the membrane potential towards zero (say -50mV), the two gates of ___ will open and what will happen?
Na+, rapid influx of Na+ into cell, the ↑ voltage inside the cell causes the inactivation gate to close (slower process than opening of activation gate). This halts Na ions from going into the cell, that inactivation gate, won’t open again until membrane potential (charge inside of cell) gets back to resting.
What happens with the K+ voltage gated channel duing the action potential
K+ channel (voltage gate) is closed during resting phase of action potential. When depolarization occurs, when membrane potential less negative (influx of Na+) the K+ channels will open. Two things happen to help repolarization, Na+ cant come in anymore, and K+ can leave. That helps return the charge on inside of membrane back to resting.
Name the THREE parts of the action potential
- Resting membrane potential
Even after repolarization of the action potential, the ions are in the wrong place (K+ outside and Na+ in). What helps to correct these ions to normal concentrations?
K leak channels and Na/K ATPase pump
Explain this photo
- The effect of stimulation on the action potential The first excitatory stimulus causes
- transient depolarization
- Then increasing the stimulus strength
- increases the depolarization to reach threshold
Explain this photo
- Effect of inhibition on the action potential
- A similar suprathreshold stimulus causes depolarization beyond threshold
- Inhibition then prevents the second excitatory stimulus from reaching threshold
Explain how GABA works as an inhibitory NT
Causes hyperpolarization from ion perspective is usually an increase in membrane permeability to Cl- ions. Cl- ions are more likely to be outside of cell than inside, but if the membrane becomes selectively more permeable to Cl- ions (GABA) then Cl- goes into cell, make potential -110 (more negative than -90) then the usual stimulus will not stimulate an action potential because it did not get to threshold.
Major excitatory neurotransmitter in CNS
Major inhibitory neurotransmitter in CNS
What are the four voltage gated ion channels
What are the THREE types of transmembrane proteins involved in cell communication?
- Voltage Gated Ion Channels (both cations and anions)
- Ligand Gated Ion Channels
- Transmembrane Receptors
What are the Four ligand gated ion channels?
- Nicotinic cholinergic receptors (NMJ & ganglia)
- Amino acid receptors
- N-methyl-D-aspartate (NMDA)
What are the five transmembrane receptors?
- Adrenergic receptors (alpha, beta)
- Muscarinic cholinergic (end organs)
What ligand gated ion channel does Ketamine act on?
Estimated that ___ of the synapses in the brain are GABAergic
____ receptor is a prime anesthetic target
GABA is located where?
Located throughout CNS, the cortex, the basal ganglia, the cerebellum and the spinal cord.
Why can't we just give GABA as our anesthetic?
Can't cross the BBB
Except ______, almost
all anesthetics (injected or inhaled) enhance Cl-
ions through a GABA receptor.
Ketamine (it acts on NMDA)
What is the Meyer-Overton Rule?
Potency of inhaled anesthetics is directly correlated with lipid solubility
Implication is that anesthesia results from dissolved anesthetic molecules at hydrophobic sites (anesthetic target/receptor is hydrophobic)
What are two limitation of the Meyer-Overton Rule?
Only applies to gases & volatile liquids because the olive oil:gas partition coefficients can’t be determined for liquids (so not for IV meds)
Olive oil is a poorly characterized mixture of oils
What are the FOUR key points of the Meyer Overton Rule?
- 1. Correlation between lipid solubility & anesthetic potency
- 2. Lipid solubility measured as the oil:gas partition coefficient
- 3. Anesthetic potency measured as minimum alveolar concentration (MAC)
- 4. Anesthetics act by disrupting the structure or dynamic properties of the lipid portion of nerve membranes
TRUE or FALSE.
Some lipid soluble compounds are convulsants
inhalation agents don’t have a predominant structure-function relationship
all inhalation agents share a common mechanism of action at the molecular level (Meyer-Overton)
Critical volume hypothesis:
anesthetics bind to hydrophobic sites in lipid bilayer and expand the membrane beyond a critical volume
Disruption of membrane form: disrupt
ion channels, etc. (includes what two theories?)
- Fluidization theory
- Lateral phase separation theory
5-Angstrom theory (Eger) states....
Anesthetics produce anesthesia by an action on 2 sites separated by a distance of 5 angstroms
Maximum potency achieved with a molecule that is 5 carbons long (5 angstroms); having 2 active sites at each end
What are the surgical considerations for the anesthetic plan? (5 of them)
- Length of surgery
- Position needed
- Muscle relaxation requirements
- Blood/fluid loss
- Pain scale
The pre-anesthesia assessment decides the ASA status. What are the 5 levels of ASA?
- ASA 1: healthy, no comorbidities, no meds, etc.
- ASA 2: smoker or controlled HTN. Co-morbidities are well controlled.
- ASA 3: co-morbidities but not so controlled. Beyond HTN but has ischemic heart disease or perhaps a more fragile diabetic
- ASA 4: patient is sick patient who is unstable
- ASA 5: probably going to die w/ or w/out surgery
If the case is an emergency it is ASA what?
ASA __-E (add E onto the end)
TRUE or FALSE. If you need invasive monitoring due to the surgical procedure, you should probably put them in before induction
FALSE. If patient is ok, you can wait until after. If you need invasive monitoring because the patient is sick, need to put it in BEFORE induction
What would you like to do?
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