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Flashcards in General and local anesthetics Deck (19):
1

Mechanism of action for inhaled general anesthetics 1

-Cause loss of consciousness, immobility, amnestic and analgesic effects (highly lipid soluble)
-The sites of action for general anesthetics include brainstem-hypothalamus/thalamus (control of sleep and attention) and the cerebral cortex (loss of consciousness)
-Suppressing the thalamus alters sensory and motor information going to/from the brain

2

Mechanism of action for inhaled general anesthetics 2

-Molecular targets: potentiation of GABAA and Gly receptor activity (causing hyperpolarization) as well as inhibition of glutamate and NMDA receptors (prevents glutamate binding to NMDA-> no depolarization)
-Also will inhibit Ca, Na, and K channels (causes hyperpolarization of neurons)
-Overall the increased inhibitory transmission and decreased excitatory transmission provide the general effects of anesthesia (multiple site hypothesis)

3

Pharmacokinetics/dynamics of inhaled general anesthetics 1

-Uptake: vaporized drug passes thru alveolar-arterial membrane into the blood stream
-Partition coefficient: the ratio of amount of drug in blood: amount of drug in gas (blood/gas)
-The partial pressure of the gas will equilibrate w/ the partial pressure in the brain, the objective is to achieve a constant brain partial pressure of the inhaled anesthetic (distribution)
-At equilibrium the CNS partial pressure equals the blood partial pressure which equals the gas partial pressure

4

Pharmacokinetics/dynamics of inhaled general anesthetics 2

-Solubility of a gas will affect the partition coefficient (how fast a drug will become equilibrated in the blood)
-A lower solubility means a lower partition coefficient (more drug in the gas form), and this means faster induction of the drug
-A low partition coefficient means less anesthetic needs to be dissolved in blood before Palveoli equilibrates w/ Parterial
-Thus, a higher partition coefficient means slower induction

5

Pharmacokinetics/dynamics of inhaled general anesthetics 3

-Potency: minimum alveolar concentration (MAC) means the concentration required to suppress movement in 50% of pts
-Want lowest MAC possible
-Metabolic profile of drugs is negligible, b/c elimination thru the pulmonary system is responsible for recovery from anesthetized state (as Pcns begins to fall)

6

Side effects of inhaled general anesthetics

-All cause CNS obtundation, decrease cerebral metabolic rate, increase cerebral blood flow via vasodilation
-The drugs w/ MAC greater than 1 will increase ICP
-All are myocardial depressants, they decrease mean arterial pressure due to drop in vascular resistance
-They all increase respiratory rate and decrease tidal volume
-However at higher concentrations ventilation slows
-Decrease in respiratory systemic resistance causes decreased pulmonary tone and bronchodilation

7

Intravenous general anesthetics

-These have a rapid onset and short duration of action
-All of them except for one (ketamine) affect the GABA receptor in some way (decrease rate of GABA dissociation or enhance affinity)
-Ketamine works by blocking the NMDA receptor
-Overall these also cause generalized hyperpolarization of neurons
-They are also highly lipophilic and easily cross the BBB

8

Pharmacokinetics and dynamics of IV general anesthetics

-They have a very short T1/2, mostly due to a combination of redistribution and metabolism
-The agents move from sites that are highly perfused (like brain) to areas less perfused in peripheral compartments, followed by normal metabolism/elimination
-They are metabolized by hepatic nzs followed by renal elimination

9

Actions of IV general anesthetics on different parts of the body

-The ones that act on GABA receptors affect the body in the same ways as the volatile general anesthetics
-This includes CNS depression (decrease metabolic rate but increase vasoconstriction instead of vasodilaiton), cardiac depression, eventual respiratory depression, analgesia
-The NMDA-acting drug (ketamine) is different, it causes vasodilation in brain, increases metabolic rate and increases ICP, it stimulates the CV system (hypertension and tachycardia), and it decreases RR

10

Inhaled general anesthetics

-Sevoflurane
-Desflurane
-Isoflurane
-Nitric oxide

11

IV general anesthetics

-Isopropylphenols (propofol)
-Barbiturates
-BZDs
-Phencyclidine (ketamine)

12

Local anesthetics mechanism of action 1

-Local anesthetics inhibit voltage-gates Na channels to block Na conductance (either esters or amides: esters have 1 "i" in name, amides have 2)
-The agents must be inside the cell to achieve their effect, they also must be protonated (charged)
-How lipid soluble the agents are and their pKa directly affect how well they act
-The ideal drug is one w/ a pKa close to 7.4 (physiologic pH) so that 1/2 the drug is protonated and 1/2 isn't
-Most local anesthetics have pKa higher than 7.4 and thus most of the drug is protonated (pH lower than pKa-> majority of compound is protonated)
-Therefore the drug is active but cannot get into the cell

13

Local anesthetics mechanism of action 2

-Diffusion into the cell requires the non-protonated form, but activity requires the protonated form
-The lower the pKa the faster the onset of action b/c more of the drug will be not protonated and thus can pass thru the membrane
-To solve this inject bicarbonate in w/ the drug to increase the pH closer the the pKa so more of the drug is deprotonated and can pass into the cell
-But once in the cell the drug needs to be protonated so that it can be active
-Potency is not related to pKa (only time of onset is)

14

Manifestation of inhibiting Na channels

-Interruption of transmission of motor, autonomic, and sensory impulses
-Results in paralysis, autonomic blockade, and sensory anesthesia
-Local anesthetics affect nerve fibers differently, according to their size, function, and presence or absence of myelin
-Large neurons have faster nerve conduction, and generally are myelinated

15

Classification of nerve fibers

-Type A: myelinated, large, fast, many functions
-Type B: myelinated, small, medium speed, preganglionic (autonomic)
-Type C: unmyelinated, small, slow, dull pain, temp, touch
-Order of being affected by local anesthetics: C->B->A
-Small fibers get anesthetized first

16

Pharmacokinetics of local anesthetics

-Injected IV or into a nerve plexus, systemic absorption is affected by binding to plasma or tissue proteins (prolongs onset and duration of action)
-The site of injection, dose, and pharmacokinetic properties of the drug all affect the rate of absorption of the drug
-Coadministration of the drug w/ a vasoconstrictor can minimize the absorption of the drug into the blood stream
-Amide local anesthetics are metabolized by CYP450
-Ester local anesthetics are metabolized by plasma cholinesterases (shorter duration of action)

17

Pharmacodynamics of local anesthetics

-There must be 50% of action potential decrease to see loss of function
-Diffusion of the drug will reach the outer nerve bundle prior to diffusion into the core of the nerve bundle
-The core contains the nerve fibers that innervate distal areas
-Thus the onset of the drugs occurs in the proximal tissues initially

18

Coadministration of drugs w/ local anesthetics

-Addition of epinephrine (vasoconstrictor) will decrease systemic absorption of local anesthetics
-The overall effect is to prolong duration of action, decrease metabolism and prevent systemic toxicity
-Addition of bicarbonate increases the pH to allow the drug to become deprotonated to a greater degree so they can enter the cell faster (decreases duration of onset)

19

Toxic effects of local anesthetics

-Systemic toxicity usually due to inadvertent vascular injection, but diffusion from tissue injection sites may occur
-CNS toxicity: facial tingling/numbness, restlessness, virtigo, tinnitus, slurred speech, hypoxia, metabolic acidosis, hemodynamic instability
-CV toxicity: profound hypotension and myocardial depression (impairs the conduction of cardiac myocytes due to Na channel blockade)
-Rx: lipid resuce via lipid emulsion which enables a "lipid sink" to extract lipophilic anesthetic molecules to reduce their plasma concentration

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