Local anesthetics and Muscle Relaxants Flashcards Preview

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Flashcards in Local anesthetics and Muscle Relaxants Deck (27)
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General structure of local anesthetic?

Lipophilic group (aromatic ring) connected to an intermediate chain (ester or amide) to an ionizable group (usually tertiary amine). -- the ester link (ex what is in procaine) are more probe to hydrolysis compared to amide links therefore have a shorter duration of action.

Local anesthetics = weak bases (pK b/t 8.0-9.0) -- therefore at the normal physiological pH, most of the anesthetics will be in the cationic form (charged). - this protonated form is the most active form at the receptor site, but the uncharged form is more lipophilic therefore is important for penetration through membranes

Ester-lined - metabolized in tissue and plasma by esterases (pseudoesterases)

Amide-linked -degraded by liver microsomal cyt P450


Why are vasoconstrictors administered with anesthetics?

Vasoconstrictors (usually epinephrine) are usually administer with local anesthetics as it prolongs and enhances the local action preventing absorption to the blood stream, retains the drug at that area, and promotes increased neuronal uptake.

Epinephrine also acts on a2-receptors inhibiting release of substance P.
AE pf vasoconstrictors - delayed wound healing, tissue edema, necrosis

Side note: cocaine constricts blood vessels by potentiating the action of NE therefore preventing its own absorption


MOA of local anesthetics.

1. binds to receptors near the intracellular end of the channel
2. binding blocks VG sodium channels
3. sufficient concentration of the local anesthetic applied to the nerve fiber abolishes action potential


What are the different short, intermediate and long-actiging local anesthetics?

short-acting = procaine, chloroprocaine

intermediate-acting = lidocaine, mepivacaine, prilocaine

Long-acting = tetracaine, bupivacaine, etidocaine, ropivacaine


Toxicity of local anesthetics?

CNS stimulation - restlessness, tremor preceeding clonic convulsions [convulsions are usually the most serious toxic reaction due to high doses so when you know you are giving high doses, premedicate with benzodiazepines]

CNS depression follows stimulation - respiratory failure

PNS - toxic to nerve tissue

CV system - block sodium channels and depress cardiac pacemaker activity, excitability and condition
[all local anesthetics other than cocaine cause arteriolar dilation leading to hypotension -- cocaine may cause vasoconstriction, HTN and cardiac arrhythmias] -- BUPIVACAINE IS THE MOST CARDIOTOXIC

Allergic reaction - related to ester anesthetics b/c they are converted to PABA derivates and many people are allergic to them

Blood -- large doses of prilocaine may lead to accumulation of the metabolite o-toluidine which is capable of converting hemoglobin to methemoglobin


Systemic adverse effects of local anesthetics with increasing plasma concentration?

Drowsiness → parasthesias in mouth and tongue → tinnitus, auditory hallucinations → muscular spasms → seizures → coma → respiratory arrest → cardiac arrest


Drug interactions with local anesthetics?

Procaine hydrolyzed to PABA which inhibits sulfonamide action -- so do not administer large doses of procaine if pt is on sulfonamide drug


Neuromuscular blockers vs Spasmolytics?

Neuromuscular blockers - causes paralysis [medications can be antagonists (non-depolarizing) or agonists (depolarizing)] -- quarternary ammoniums that are highly polar but poorly soluble in lipids therefore do not cross BBB -- administer via IV or IM

Spasmolytics - manage spasticity [medications can be chronic or acute]


Non-depolarizing blockers?

Benzylisoquinolines - tubocurarine (prototype), atracurium, cistracurium, mivacurium

Ammonio steroids - pancuronium, rocuronium, vecuronium


Depolarizing blockers?

Succinylcholine -- two ACh molecules linked end-to-end


MOA of non-depolarizing blockers?

Competitive antagonists that can be overcome by increasing the concentration of ACh in the synapse -- via neostigmine or edrophonium [AChEI] -- Tubocurarine is the prototype

There is initial non-depolarizing blockers causing motor weakness followed by complete flaccid skeletal muscle that is inexcitable to stimulation.


MOA of depolarizing blockers?

Agonist nicotinic receptors that binds causing depolarization of the muscle, but since it is not metabolized effectively by AChE, it remains on the receptor causing it to become unresponsive resulting in flaccid paralysis.
Rapid onset of blockade -- less than a minute and lasts for 5-10 minutes.


Short, intermediate and long acting non-depolarizing blockers?

Short- acting - Mivacurium -- liver excretion

Intermediate acting - Atracurium, Cisatracurium, Rocuronium, Veruronium

Long-acting - Tubocurarine, Pancuronium -- kidney excretion


Metabolism of Altracurim?

Atracurium is inactivated by hydrolysis via nonspecific
plasma esterases and by a
spontaneous reaction. Because it is inactivated by plasma esterases, if the pt presents with renal failure, there is no increase in half life.
One major thing to watch out for with Altracurium metabolism is the metabolite Laudanosine, which leads to hypotension and
seizures. -- because of this, Cistracurium was created which is a sterioisomer of atracurium and forms much less laudanosine. Cistracurium also causes less histamine release and has therefore largely replaced atracurium in clinical practice.


Metabolism of mivacurium?

Mivacurium is the only nondepolarizing blocker
classified as short acting.It is inactivated by hydrolysis via plasma butyrylcholinesterase. It is not dependent on liver or kidney.


Metabolism of rocuronium?

- most rapid onset of all the non-depolarizing blockers
-can be alternative to succinylcholine for rapid sequence intubation


Metabolism of Succinylcholine?

-short duration of action due to hydrolysis of butyrylcholinesterase
-some pts have prolonged block by succinylcholine as they have abnormal variants of butyrylcholinetesrease
-treat these pts with mechanical ventilation until muscle function returns to normal


AE of non-polarizing blockers?

-hypotension due to histamine release and ganglionic blockade -- benzylisoquinolines

-tachycardia due to blockage of muscarinic receptors leading to arrhythmias -- ammonio steroids

-histamine release occurs esp with tubocurarine, mivacurium and atracurium -- administer anti-histamine before the NMJ blocker

-ganglion blockade - tubocurarine blocks nicotinic receptors of autonomic ganglia and adrenal medulla leading to hypotension and tachycardia

-blockade of cardiac M2 receptors - leading to tachycardia (esp with pancuronum - but even so, these cardiovascular effects as generally not a problem)


AE of succinylcholine (depolarizing blockers)?

Succinylcholine activates all autonomic cholinoceptors -- nicotinic and muscarinic.

-bradycardia - due to activation of muscarinic receptors-- can be prevented by thiopental, atropine, ganglionic blockers and non-polarizing muscle relaxants

-slight tendency to release histamine release

-muscle pain - major post-op complaint and due to damage produced by the unsynchronized contractions of adjacent muscle fibers

-hyperkalemia - due to loss of tissue potassium during depolarization -- esp a problem in pts with burns or trauma -- this may lead to cardiac arrest and circulatory collapse

-increased intraocular pressure - due to extraocular muscle contractions

-increased intragastric pressure - fasiculations increase intragastric pressure leading to emesis and aspiration of gastric contents

-malignant hyperthermia -- due to combination of succinylcholine and halogenated anesthetic -- tx with dantroline

-no CNS effects


What drug interactions need to be watched that may enhance neuromuscular blockade?

1. inhaled anesthetics - blocking properties
2. aminoglycosides -- sequester calcium?
3. tetracyclines


Effect of diseseas and aging on drug response to NMJ blockades?

-Myasthenia gravis - increases NMJ blockade
-advanced age - prolongs blockade probably due to decreased drug clearance
-pts with severe burns and UMN disease are resistant to non-depolarizing muscle relaxations due to proliferation of extra-junctional receptors


Contraindications to depolarizing blocker administration?

• History of malignant hyperthermia
• History of skeletal muscle myopathies.
• Major burns.
• Multiple trauma
• Denervation of skeletal muscle
• Upper motor neuron injury.


How do you reverse non-depolarizing neuromuscular blockade?

-neostigmine or edrophonium -AChE inhibitor
-atropine or glycopyrrolate - used concomitantly to prevent bradycardia


Uses of neuromuscular blockers?

1. adjuvants in surgical anesthesia to obtain relaxation of skeletal muscles
2. succinylcholine - endotracheal intubation during induction of anesthesia, also used during ECT


Drugs for chronic spasms that act in CNS?

1. Diazepam - facilitates GABAa receptor activation increasing frequency of Cl- channel opening
2. Baclofen - GABA agonist at GABAb receptors [CNS receptor that is a G-protein coupled receptor that is also inhibitory so when you activate it, you relax the skeletal muscle]
3. Tizanidine - a2 agonist in CNS


Drugs for chronic spasms that act on skeletal muscle?

1. Dantrolene - interferes with release of Ca2+ by binding to the ryanodine receptor in the SR of skeletal muscle -- also used in malignant hyperthermia
2. botulinum toxin


Drugs for acute spasms?

-prototype = cyclobenzaprine -- similar in structure to TCA which strong antimuscarinic side effects
-there are centrally acting drugs functioning at the brainstem that create relief of acute muscle spasm caused by local trauma or strain