B10 NMJ blockers

Question 1

About Neuromuscular blocking agents

Answer 1

Act locally, at the level of the neuromuscular junction, to produce muscle paralysis1. Non-depolarizing agentsCompetitive antagonists at skeletal muscle Ach nicotinic receptors (NM); parenteral administrationIndications:- Prolonged relaxation for surgical procedures- Relaxation of respiratory muscles to facilitate mechanical ventilation in ICU patients- Epileptic seizure (convulsion) not responding to antiepileptics- Intoxication with certain drugs (theophylline, amphetamine)2. Depolarizing agents- Agonist at skeletal muscle Ach nicotinic receptors (NM); may stimulate ganglionic nicotinic Ach receptor (NN) and cardiac muscarinic Ach receptors (M3)- Phase I ??membrane depolarizes, resulting in an initial discharge that produces transient contraction (fasciculations/twitch), followed by flaccid paralysis- Phase II ??membrane repolarizes, but receptor is desensitized to the effect of Ach (succinylcholine is still bound to the receptor)

Question 2

Neuromuscular blocking agents : Non-depolarizing agents : 4

Answer 2

D tubocurarine(B10), Atracurium(B10), Cisatracurium(B10), Mivacurium(B10)

Question 3

D tubocurarine(B10)

Answer 3

isoquinolineIntermediate-acting (25-45 min’)Renal mechanism- Histamine release (hypotension)- Prolonged apnea (muscle weakness)

Question 4

Atracurium(B10)

Answer 4

isoquinolineIntermediate-acting (25-45 min’)Spontaneous metabolism- Histamine release (hypotension)- Muscle spasm (muscle weakness)

Question 5

Cisatracurium(B10)

Answer 5

isoquinolineIntermediate-acting (25-45 min’)Spontaneous metabolism- Histamine release (hypotension)- Prolonged apnea (muscle weakness)

Question 6

Mivacurium(B10)

Answer 6

isoquinolineShort-acting (10-15 min’)Pseudocholinesterase (metabolism)- Histamine release (hypotension)- Prolonged apnea (muscle weakness)

Question 7

Neuromuscular blocking agents : Non-depolarizing agents: 4 s

Answer 7

Pancuronium(B10), Rocuronium(not in the list), Vecuronium(not in the list), Pipecuronium(B10)

Question 8

Pancuronium(B10)

Answer 8

Long-acting (60-180 min’)Renal metabolism- M2-inhibition (tachycardia)- NE reuptake inhibition

Question 9

Rocuronium(not in the list)

Answer 9

Intermediate-acting (25-45 min’)Hepatic metabolism- Prolonged apnea (muscle weakness)

Question 10

Vecuronium(not in the list)

Answer 10

Intermediate-acting (25-45 min’)Hepatic metabolism- Prolonged apnea (muscle weakness)

Question 11

Pipecuronium(B10)

Answer 11

Long acting (60 180 minutes)renal metabolism

Question 12

Neuromuscular blocking agents : 1 depolarizing agents:

Answer 12

Succinylcholine(B10)

Question 13

Succinylcholine(B10) (suxamethonium)

Answer 13

-Selective agonist of the Nm receptor receptor and the acetylcholinesterase doesnot metabolize it- Parenteral- Duration of action 5 min’- Rapid metabolism by pseudocholinesterase in the blood then in liver- Surgical procedures where a rapid onset and brief duration is needed (intubation, endoscopy, ECT)- Side effects: arrhythmias(mainly bradycardia), hyperkalemia, transient increased intra-abdominal and intraocular pressure, postoperative muscle pain, Malignant hyperthermia (highlighted in the lecture)

Question 14

About Spasmolytic agents

Answer 14

Act centrally, at the level of the CNS, to reduce abnormal muscle tone caused by neurologic/muscle end-plate disease (causing spasm and associated muscle pain). The goal is to reduce excessive skeletal muscle tone without reduction of strength; reduced muscle spasm results in reduction of pain and improved morbidity.

Question 15

4 Spasmolytic agents

Answer 15

Diazepam(A25, A33,B9), Baclopen(B9), Tizanidine(B9), Tolperisone(B9)

Question 16

Diazepam(A25, A33,B9)

Answer 16

GABAA agonist- Increases interneuron inhibition of primary motor afferents in spinal cord- Hepatic metabolism- Duration of action 12-24 h’- Chronic spasm due to cerebral palsy, stroke, spinal cord injury- Acute spasm due to muscle injury- Side effects: CNS depressant actions, tolerance, dependent liability

Question 17

Baclopen(B9)

Answer 17

GABAB agonist- Pre- and postsynaptic inhibition of motor output in the spinal cord- Oral, intrathecal- Spasm due to cerebral palsy, multiple sclerosis, stroke- Side effects: sedation, weakness,

Question 18

Tizanidine(B9)

Answer 18

α2 agonist- Pre- and postsynaptic inhibition of reflex motor output in the spinal cord- Oral- Renal and hepatic elimination- Duration of action 3-6 h’- Spasm due to multiple sclerosis, stroke, amyotrophic lateral sclerosis- Side effects: weakness, sedation, hypotension, hepatotoxicity (rare), rebound hypertension upon abrupt withdrawal

Question 19

Tolperisone(B9)

Answer 19

• Poorly understood inhibition of muscle stretch reflex in spinal cord and brain stem ??reduction of muscle reflexes- Mechanism involved inhibition of Na+ and Ca2+ channels- Oral- Acute spasm due to muscle injury- Not used in chronic spasm- Side effects: sedation, confusion, ocular effects, strong anti-muscarinic effect

Question 20

2 Direct-acting muscle relaxants

Answer 20

Dantrolene(9), Botulinum toxin(B9)

Question 21

Dantrolene(9)

Answer 21

• RyR1 antagonist ??Blocks Ca2+-release channels in the sarcoplasmic reticulum of skeletal muscle ??reduces actin-myosin interaction- IV, oral- Duration of action 4-6 h’- Malignant hyperthermia (IV)- Spasm due to cerebral palsy, spinal cord injury, multiple sclerosis (oral)- Side effects: muscle weakness, hepatotoxicity

Question 22

Botulinum toxin(B9)

Answer 22

• Prevents synaptic exocytosis through inhibition of SNARE fusion proteins in presynaptic nerve terminals ??flaccid paralysis- Direct injection into muscle- Duration of action 2-3 months- Upper and lower limb spasm due to cerebral palsy, multiple sclerosis- Cervical dystonia- Migraine- Overactive bladder- Hyperhidrosis- Cosmetics