Local anesthetics and Muscle Relaxants

Question 1

General structure of local anesthetic?

Answer 1

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

Question 2

Why are vasoconstrictors administered with anesthetics?

Answer 2

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

Question 3

MOA of local anesthetics.

Answer 3

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

Question 4

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

Answer 4

short-acting = procaine, chloroprocaine

intermediate-acting = lidocaine, mepivacaine, prilocaine

Long-acting = tetracaine, bupivacaine, etidocaine, ropivacaine

Question 5

Toxicity of local anesthetics?

Answer 5

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

Question 6

Systemic adverse effects of local anesthetics with increasing plasma concentration?

Answer 6

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

Question 7

Drug interactions with local anesthetics?

Answer 7

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

Question 8

Neuromuscular blockers vs Spasmolytics?

Answer 8

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]

Question 9

Non-depolarizing blockers?

Answer 9

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

Ammonio steroids - pancuronium, rocuronium, vecuronium

Question 10

Depolarizing blockers?

Answer 10

Succinylcholine – two ACh molecules linked end-to-end

Question 11

MOA of non-depolarizing blockers?

Answer 11

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.

Question 12

MOA of depolarizing blockers?

Answer 12

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.
**Succinylcholine

Question 13

Short, intermediate and long acting non-depolarizing blockers?

Answer 13

Short- acting - Mivacurium – liver excretion

Intermediate acting - Atracurium, Cisatracurium, Rocuronium, Veruronium

Long-acting - Tubocurarine, Pancuronium – kidney excretion

Question 14

Metabolism of Altracurim?

Answer 14

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.

Question 15

Metabolism of mivacurium?

Answer 15

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.

Question 16

Metabolism of rocuronium?

Answer 16

• most rapid onset of all the non-depolarizing blockers

- can be alternative to succinylcholine for rapid sequence intubation

Question 17

Metabolism of Succinylcholine?

Answer 17

• 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

Question 18

AE of non-polarizing blockers?

Answer 18

• 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)

Question 19

AE of succinylcholine (depolarizing blockers)?

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

• 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

Question 22

Contraindications to depolarizing blocker administration?

Answer 22

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

Question 23

How do you reverse non-depolarizing neuromuscular blockade?

Answer 23

• neostigmine or edrophonium -AChE inhibitor

- atropine or glycopyrrolate - used concomitantly to prevent bradycardia

Question 24

Uses of neuromuscular blockers?

Answer 24

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

Question 25

Drugs for chronic spasms that act in CNS?

Answer 25

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

Question 26

Drugs for chronic spasms that act on skeletal muscle?

Answer 26

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

Question 27

Drugs for acute spasms?

Answer 27

• 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