Pharmacology and the Anesthetic Care Plan (Lecture 1)

PATIENT!!

• 1. Chronic Medications-_{what to continue day of surgery, if the diagnosis is 'controlled' with the medication}
• 2. Choice of Anesthetic-_{type of anesthetic directed at patient, surgeon, and anesthetist choices/preferences, specific choice of anesthetic must remain goal directed}

• 1.Chronic Medications
• a. Which meds to continue day of surgery
• b. Need for pre-operative fine tuning (if pt. comes to preoperative assessment with high blood pressure, and needs anti-HTN adjusted- refer to PCP)

• 2. Choice of Anesthetic
• a. Type of Anesthesia- goal directed
• 1) Patient- wants comfort throughout; have a sense of what they want
• 2) Surgeon-have a sense for what they want; what they’re comfortable with
• 3) Anesthetist- careful to make decision based on science, not preference
• b. Specific Choice of Agent- opioid,
• NMB, induction agent, local for spinal, Inhaled

Want to consider Patients history, Duration of the Agent v. Duration of Surgery, Side effects of the agent/technique, Contraindications to the agent/technique, Availability of the Agent

• -psychological._{most common is loss of control, fear of mutilation, pain, and death}
• -Tissue Injury-_incision
• -Intravascular volume changes
• -Anesthetic agents_{-cause vasodilation and fluid status changes}
• -Pain**
• -Organ Manipulation**

**Pain and Organ manipulation can lead to stimulation of the autonomic nervous system  (think vagal stimulation)

The stress response is the activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system

• Stimulation of the stress response results in the increase of: 
• 1. cortisol
• 2. catecholamines
• 3. cytokines

Tachycardia, hypertension, increased metabolism, hypercoagulability, decreased immune function

Morbidities associated with the stress response: perioperative ischemia/infarction, arrythmias, thrombosis, infection, and delayed wound healing

Anesthesia is the REVERSIBLE state mediated by the CNS that produces IMMOBILITY and AMNESIA. (along with unconsciousness, analgesia, suppression of autonomic reflexes, and relaxation of muscle)

Anterograde: amensia from the time you give the drug on

Retrograde: amensia preceeding the stimulus (we can't control this)- typical result in head injuries

• Induce anesthesia smoothly and rapidly
• Permit rapid recovery
• Wide margin of safety
• No adverse effects
• Low cost
• Patient is "street ready"- go home safely/quickly with no PONV

• 1. CHEMICAL
• 2. ELECTRICAL

• Chemical: 
• -most CNS synapses are chemical
• -dependent on the release of NT from 1 neuron that then affects the next
• -presynaptic neuron secretes NT (like Epi, Ach, Norepi)
• -NT acts on receptor proteins on membrane of post synaptic neuron
• -May be excitatory or inhibitory- depends on how it effects the postsynpatic membrane

• Electrical:
• -NOT the same as voltage gated channels
• -Gap junctions permit free moments of ions from one cell into another
• -Found mostly in cardiac and smooth muscles

Chemical

FALSE!!

• 1. Action potential spreads over the presynaptic terminal/knob
• 2. Membrane depolarizes
• 3. Depolarization causes vesicles to empty into the synaptic cleft
• 4. NT is released from the vesicles
• 5. The release of NT causes a change in permeability of the postsynaptic terminal
• 6. The change in permeability leads to either excitation or inhibition depending on the characteristics of the channel

A. the amount of neurotransmitter released into the synapse is directly related to the number of CALCIUM ions that enter the presynaptic terminal. 

This is true because: the presynaptic terminal contains a large amount of voltage gated calcium channels, when an action potential depolarizes it causes the calcium channels to open- so that the calcium will flow into the terminal and the neurotransmitter will flow out.

• Cell powerhouse!
• -generates new ATP to make new neurotransmitters

• 1. Cationic
• 2. Anionic

• Cationic
• -only allows positive ions to move through 
• -mostly conduct sodium and calcium, but can conduct some K⁺ too. 
• -lined with anions so that it will draw the + charges through them 
• -any NT that opens channels and allows cations to move in is EXCITATORY

• Anionic
• -only allows negative ions to move through
• -any NT that allows anions (like chloride) to move in is considered INHIBITORY due to its effect on the action potential

• TRICK QUESTION!
• -There isn't one- anesthetic action is a culmination of many different things

We think the synapse itself is the most likely target of anesthetic action because anesthetics can disrupt synaptic transmission at various locations within the synapse.

• 1. Spinal Cord
• -MAJOR focus of our anesthetics is the spinal cord (where the idea of MAC comes from)
• -immobility
• -action here underlies determination of MAC
• -specific location may be the motor neuron

• 2. Reticular Activating System
• -involved in arousal behavior
• -inhibit information transfer through the brain stem

• 3. Cerebral Cortex
• -site for storage, integration, and retrieval of information
• -memory and awareness interference
• -alteration of corticol electrical activity: BIS MONITOR (monitors changes in the surface EEG)

• Alters NT release
• Alters NT reuptake following release

Alters binding of NT to receptor sites

• 1. Channel Proteins
• 2. Carrier Proteins

• 1. Channel Protein: 
• -act by simple diffusion
• -transports water soluble, small molecules
• -ex. Sodium

• 2. Carrier Protein:
• -act by facilitated diffusion or active transport
• -provides a means for substances to bind and get moved into the cell

• FALSE. 
• Both channel and carrier protein channels are highly selective to what they allow to cross the membrane (ions/molecules)

NO! 

Channel proteins are HIGHLY selective! It is not just the size of the ion or molecule that dictates passage... Potassium channels are potassium specific. They allow dehydrated potassium to pass because the filter is lined with carbonyls (C=O) which will pull off the H₂O molecule and allow the potassium ion to pass- because sodium is smaller it will not come into contact with the carbonyls (C=O) and therefore will not pass.

• Voltage-gated channels: 
• -opening/closing occurs due to the electrical gradient 
• -ex. Na channel

• Ligand-gated channels:
• -chemical or NT binds with channel protein 
• -ex. Ach channel

A. CHANNEL!

• Aquaporins depend on ADH secretion. They allow more H₂O to pass through the very narrow opening, water molecules must pass single file
• -Number of aquaporins depend on physiologic requirements and are directly related to the secretion of ADH by the hypothalamus released by the posterior pituitary

Molecules/Particles will move from high concentration to less concentrated portions

Overarching charge on inside/outside of cell will cause movement of the oppositely charged ion. 

For instance, if the inside of the cell is move positive, negative ions from the ECF will move intracellularly, regardless of the concentration gradient (Typically the Nernst potential will provide a balance between the two gradients)

The Goldmann Equation

C. Both electrical and concentration gradients contribute to the action potential

-94 mV- diffusion will stop even if a concentration gradient still exisits

+61 mV

The diffusion potential is the electrical potential difference between the inside and the outside of the cell that opposes net diffusion (that would ordinarily occur because of the concentration gradient)

• 1. Polarity of the electrical charge of each ion
• 2. Permeability of the membrane to each ion
• 3. Concentration Gradient of each Ion across the membrane

Before depolarization, the resting membrane potential is -90 mV and the activation gate on the voltage gated sodium channel is closed

A stimulus occurs that causes the -90 mV to move closer to 0, for example to -50 mV. 

Following the move to -50 mV the activation gate will flip open and subsequently there is a rapid influx of sodium ions into the cell

Membrane potential may overshoot (to +20 for example) and shortly after the inactivation gate will close slowly so that no more sodium can get into cell

Potassium voltage gated channels open and potassium moves out of cell to help repolarize the cell (and bring the membrane potential back to resting)

When the cell is "polarized"

Typical value is -70 to -90 mV (inside of cell relative to outside of the cell)

KNaATPase Pump and Potassium leak Channels

ATPase pump moves 3 sodium ions out of the cell for every 2 potassium ions moved into the cell.

• Happens when membrane becomes suddenly permeable to sodium ions- making the cell more positively charged
•  
• Occurs following the membrane potential- when the threshold reaches -50mV

Occurs after cell membrane becomes increasingly permeable to potassium

K moves outside of cell returning the negative charge inside cell

Yes... but by increasing the stimulus strength, will increase the depolarization and reaches threshold to stimulate the action potential

Inhibition causes hyperpolarization of the resting membrane (making the mV -110 instead of -90)- so a stimulus that would've otherwise reached threshold won't anymore... THIS IS HOW ANESTHETICS WORK!

• 1. Depressing excitatory potential
• 2. Enhancing inhibitory potential 

Thereby inhibiting action potentials in the CNS

typically increase permeability 

ex. Acetylcholine attaches to its receptor and causes increased permeability of the membrane to sodium (Sodium will move intracellullarly)

Usually reflect selective increase to permeability to potassium and chloride ions. 

Will have the same effect of making inside of the cell more negative because taking + charges out of the cell and moving - charges into the cell.

Glutamate

GABA

Ach, Norepi, Epi, Endorphins, Glycine, Serotonin, GABA, Glutamate

• 1. Voltage Gated Ion Channels
• 2. Ligand Gated Ion Channels
• 3. Transmembrane Modulators

• -can be for both cations and anions
• Sodium
• Potassium
• Calcium
• Chloride

• Nicotinic Cholinergic Receptors- found in NMJ and ganglia
• Amino Acid Receptors
• GABA
• NMDA (N-methyl-D-aspartate)- MOA Ketamine

• Adrenergic Receptors (alpha/beta)
• Muscarinic Cholinergic (end organ)
• Opioid
• Serotonin
• Dopamine

• Gamma amino butyric acid
• 

GABA

Throughout the CNS: cortex, cerebellum, spinal cord, and basal ganglia

TRUE

Chloride- makes cell hyperpolarized

GABA receptors

Almost all inhaled and IV drugs rely on chloride shift from GABA

NO. GABA transmission helps to counteract excitatory NTs

No, because it's polarized

POTENCY OF INHALED ANESTHETIC IS DIRECTLY CORRELATED TO LIPID SOLUBILITY

Proposes that all inhaled gases share component at a molecular level that causes the anesthetic effect

• 1. Only applies to gases and volatile liquids- because olive oil:gas partition CoE can't be determined for liquids (IV drugs)
• 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**

**think non-immobilizers as example

Oil-Gas Partition CoE

Proposes anesthetics act by disrupting the structure or dynamic properties of the lipid portion of nerve membranes

inhalation agents don't have a predominant structure-function relationship

Unitary Hypothesis

agents expand lipid bilayer beyond the critical volume

disrupt ion channels

Fluidization theory, Lateral Phase Separation Theory

Eger proposed that anesthetics produce anesthesia by an action on 2 sites separated by a distance of 5 angstroms

-maximum potency is achieved with a molecule that is 4 carbons long have 2 active sites attached at each end

• 1. Healthy, no meds, no comorbidities
• 2. Smoker, HTN but well controlled
• 3. Uncontrolled HTN, ischemic heart disease, fragile DM
• 4. Unstable patient
• 5. Die with or without surgery
• 6. Organ Donor

Adding an E- emergency case