18. PERIPHERAL MUSCLE RELAXANT DRUGS

Question 1

Explain the nicotinic cholinergic receptor:

Answer 1

• Transmembrane ion-channel receptor
• Alpha units are the ligand (ACh) ocupation sites.
• ACh activates the influx of Na+ and efflux of K+
• Depolarizing agents act similarly to Ach.
• Nondepolarizing agents antagonise the ACh competively

Question 2

Classes of neuromuscular blocking agents:

Answer 2

• Depolarizing neuromuscular blocking agents (succinylcholine)
• Competitive (non-depolarizing) neuromuscular blocking agents (prototype: dtubocurarine/curare)

Question 3

What are the Uses of neuromuscular blocking agents?

Answer 3

By intravenous or systemic administration:
– Surgical anesthesia to obtain relaxation of skeletal muscle

– to minimize anesthetic use without compromising analgesia.

– To assist in intubation

– Corneal or retinal surgeries to obtain relaxation of extraocular muscles (cisatracurium)

– Therapy of spastic disorders

By topical administration:

– Mydriasis in birds (e.g. vecuronium)

Question 4

NEUROMUSCULAR BLOCKING DRUGS DO NOT PRODUCE ——-

Answer 4

ANALGESIA!!!!

Question 5

Mechanism of succinylcholine:

Answer 5

Mechanism:
-Stimulate opening of nicotinic ACh receptor channel and produce depolarization of the cell membrane;

• Succinylcholine persists at the neuroeffector junction and activates the nicotinic receptor channels continuously, which results in inactivation of voltage-gated sodium channels so that they cannot reopen to support further action potentials (sometimes called “depolarizing blockade”)

Question 6

Why is succinylcholine chloride used?

Answer 6

Used to facilitate intubation (mostly in humans); used illegally in bow hunting or „euthanasia”.

• In an emergency can be given IM, but slower and less predictable action.

Question 7

What can succinylcholine chloride cause?

Answer 7

• Bradycardia (atropine can prevent)
• hyperkalaemia
• increased intra-ocular and intragastric pressure
• anaphylaxis
• malignant hyperthermia in genetically predisposed subjects.
• Dogs, cattle, sheep sensitive; horses and pigs less.

Question 8

Depolarizing blocking agents: Phase 1

Answer 8

Phase I block

– depolarizing block of motor end-plate.

Phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.

Question 9

Depolarizing blocking agents: Phase 2

Answer 9

Phase II block – side effect, After repolarisation the membrane cannot easily be depolarized again

Question 10

Depolarizing agents: How is the onset of action?

Answer 10

rapid (1min)

Question 11

Depolarizing agents: How is the duration of action?

Answer 11

Duration of action - short; however may revert to phase II block

Question 12

Depolarizing agents: How is the effect?

Answer 12

The effect is rather predictable

Question 13

Depolarizing agents: termination of action?

Answer 13

Termination of action: metabolized by plasma pseudocholinesterase and liver

Question 14

Depolarizing agents: who is the initial metabolite?

Answer 14

Initial metabolite is succinylmonocholine, weaker, predominately competitive blocking action.

Question 15

Depolarizing agents: how is the effect on skeletal musle?

Answer 15

• fasciculation “muscle twitch” - weakness - paralysis

Question 16

Depolarizing agents: how is the effect on cardiovascular system?

Answer 16

Effect on cardiovascular system:

• increased blood pressure
• increased or decreased heart rate (due to stimulation of parasympathetic and/or sympathetic ganglia)
• Bradycardia occurs after repeated use more frequently (Atropine)

Question 17

By who is the activity of depolarizing agents enhanced?

Answer 17

Activity enhanced or potentiated by neostigmine and organophosphates (cholinesterase inhibitors), isoflurane.

Question 18

What are the undesirable side effects? (depolarizing agents)

Answer 18

• muscle fasciculation
• hyperkalemia

– Phase II block

– May trigger malignant hyperthermia in genetically susceptible patients (dyspnea, tremor and stiffness, extreme hyperthermia, and rapid postmortem rigor mortis)

– Muscarinic actions at high doses

Question 19

advantages of depolarizing agents?

Answer 19

Advantages - short duration of action, little histamine release

Question 20

Competitive - nondepolarizing - neuromuscular blocking agents: Mechanism:

Answer 20

Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (sometimes called “nondepolarizing blockade”)

Question 21

What are some Competitive neuromuscular blocking agents: GROUPS

Answer 21

-BENZYLISOQUINOLINE group

A-MINOSTEROID group

-OTHERS: gallamine

Question 22

BENZYLISOQUINOLINE group:

Answer 22

• d-tobocurarine
• Atracurium (imp)
• Cisatracurium (imp)
• Mivacurium Metabolism in blood plasma Histamine release

Question 23

AMINOSTEROID group

Answer 23

• Pancuronium
• Vecuronium
• Rocuronium Metabolism in liver

No histamine release

Question 24

Classification of the agents based on their duration of action:

Answer 24

Ultra-short duration:

-Gantacurium

Short duration: Mivacurium

-Chandonium

Intermediate duration:

• Atracurium
• Cisatracurium
• Fazadinium
• Rocuronium
• Vecuronium

Long duration:

• Doxacurium
• Dimethyltubocurarine
• Pancuronium
• Pipecuronium
• Laudexium
• Gallamine

Question 25

Effect of competitive blockers on cardiovascular system

Answer 25

• Decreased blood pressure - due to histamine release (benzylisoquinolines)
• Increased heart rate (baroreceptor reflex)
• Coagulability of blood decreased (due to release of heparin from mast cells)

Question 26

Competitive neuromuscular blocking agents – long acting

Answer 26

d-tubocurarine (BI)
- slight hypotension and tachycardia; histamine (HA) release (problem in asthma), excretion via urine (in kidney disease delayed); Long-acting. Limited use.

-Gallamine (O)
tachycardia and hypertension; no HA release (only in very large doses); Long-acting. Crosses placental barrier. Frequently used in human surgery.

-Pancuronium (AS)
long-acting; slight tachycardia and hypertension. Metabolism in liver, elimination via urine. Liver and kidney disease prolongs its effect.

Question 27

Competitive neuromuscular blocking agents benzylisoquinolines: • Atracurium (BI)

Answer 27

• Atracurium (BI) (ATRACURIUM BESILATE KALCEKS® 10 mg/ml inj., TRACRIUM ® 10 mg/ml inj.) - intermediate-acting; - safe in liver and kidney disease (metabolism in plasma); - bradycardia may occur during surgical manipulations, esp. ophthalmologic, or laparoscopy (treat with atropine or glycopyrrolate); - precipitates in alkaline pH; - can cause HA release at higher doses. Probably most used in veterinary medicine.

Question 28

Competitive neuromuscular blocking agents - benzylisoquinolines • Cisatracurium (BI)

Answer 28

Cisatracurium (BI) (CISATRACURIUM KALCEKS ® 2 mg/ml inj.) – R-cis isomer of atracurium; 3X potency; immediate onset of action; intermediate-acting; metabolism in plasma; used in ophthalmologic surgeries.

Question 29

Competitive neuromuscular blocking agents - benzylisoquinolines • Mivacurium (BI)

Answer 29

• Mivacurium (BI) – short acting, succinylcholine alternative developed for human use; HA release, hypotension can occur; meatabolism in plasma (esterases)

Question 30

Competitive neuromuscular blocking agents -aminosteroids • Rocuronium (AS)

Answer 30

• Rocuronium (AS) (ESMERON® inj., ROCURONIUM KALCEKS® inj.) Due to very fast onset of action is a succinylcholine alternative developed for human use. intermediateacting; metabolism in liver; excretion with bile; lack of CV or HA-releasing effects but may cause anaphylactic reaction quite frequently.

Question 31

Vecuronium (AS) -

Answer 31

Vecuronium (AS) - intermediate-acting; lack of CV or HA-releasing effects; drug of choice when CV stability required; metabolism in liver; excretion with bile and urine; Causes mydriasis in birds.

Question 32

Competitive blockers

Answer 32

Action antagonized by cholinesterase inhibitors (neostigmine, pyridostigmine, edrophonium), or tetanic stimulation (a 50-Hz electrical stimulation given for 5 seconds) • The muscarinic side-effect of neostigmine has to be controlled with Atropine.