P4

• Muscle Relaxant Drugs


  A drug which affects skeletal muscle function and decreases the muscle tone
• Types of Muscle Relaxant Drugs

  • Neuromuscular Blockers
  • Spasmolytics
• Neuromuscular Blocker


  Drugs that block neuromuscular transmission at the neuromuscular junction causing paralysis of the affected skeletal muscle

  
• Spasmolytics


  Drugs which relieve spasms of smooth muscle, can act centrally to reduce elevated muscle tones or spasticity
• Types of Neuromuscular Blocking Drugs

  • Depolarizing
  • Non-depolarizing

  
• Depolarizing Neuromuscular Blockers


  Act by depolarizing the plasma membrane of the skeletal muscle fiber, causing persistent depolarization which makes the muscle fiber resistant to further stimulation by acetylcholine
• Non-depolarizing Neuromuscular Blockers


  Competitive acetylcholine antagonists that bind directly to nicotinic receptors on the postsynaptic membrane, blocking the binding of acetylcholine
• Non-depolarizing Neuromuscular Blockers by Duration of Action

  • Long (>35 mins): Tubocurarine, Pancuronium, Pipecuronium
  • Intermediate (20-40 mins): Atracurium, Cisatracurium, Vecuronium
  • Short (10-20 mins): Mivacurium, Rapacuronium, Rocuronium

  
• Tubocurarine


  Prototypical non-depolarizing neuromuscular blocker, has slow onset and long duration of action, side effects include hypotension

  
• Mechanism of Action of Non-depolarizing Neuromuscular Blockers

  Competitive antagonists at nicotinic receptor sites, compete with acetylcholine, effects are reversible with cholinesterase inhibitors
• Pharmacokinetics of Neuromuscular Blockers

  • Must be administered intravenously, metabolized and excreted differently depending on the specific drug, exhibit rapid initial distribution and limited volume of distribution
• Skeletal Muscle Paralysis


  Net effect of non-depolarizing neuromuscular blockers, proceeds from muscle weakness to flaccidity and inexcitability, recovery proceeds in the opposite direction

  
• Cardiovascular Effects


  Non-depolarizing blockers can cause hypotension due to histamine release and autonomic ganglionic blockade, pancuronium causes tachycardia
• Succinylcholine


  The only depolarizing neuromuscular blocker used clinically, resembles acetylcholine in chemical structure

  
• Non-depolarizing neuromuscular blockers


  Cause skeletal muscle paralysis, proceeding from muscle weakness to flaccidity and inexcitability to stimulus

  
• Paralysis


  1. Starts in the small muscles, proceeding to the trunk muscles and lastly on the diaphragm

  2. Recovery proceeds in the opposite direction

  
• Cardiovascular effects of non-depolarizing neuromuscular blockers

  • Hypotension can be significant with administration of tubocurarine, metocurine and mivacurium
  • Pancuronium administration causes tachycardia and must be avoided in patients with a history of arrhythmias
• Succinylcholine


  Depolarizing neuromuscular blocker of choice, with rapid onset and very short duration of action
• Mechanism of action of succinylcholine

  1. Binds to postsynaptic cholinergic receptors on the motor end plate, causing rapid depolarization, fasciculation and flaccid paralysis

  2. Paralysis usually takes place approximately 1 minute after administration and lasts approximately 7 to 12 minutes
• Metabolism of succinylcholine


  • Metabolized by plasma pseudocholinesterases
  • Prolonged neuromuscular blockade may occur in patients with pseudocholinesterase deficiency
• Phases of depolarizing block

  • Phase 1: Muscular fasciculations or muscle twitches while depolarizing the muscle fibers
  • Phase 2: Desensitizing block, with tetanic fade and characteristics of a non-depolarizing block
• Pharmacokinetics of succinylcholine


  • Metabolism by plasma cholinesterases
  • Duration of 5-10 minutes
  • Termination by diffusion away from the neuromuscular junction

  
• Dibucaine number test


  Used to detect genetic variance in plasma cholinesterase enzyme function

  
• Effects of succinylcholine

  1. Transient muscle fasciculation (chest & abdomen)

  2. Paralysis proceeds from the arm and leg muscles, the facial and pharyngeal muscles, and eventually the respiratory muscles

  3. Recovery from paralysis happens in the opposite direction

  
• Cardiovascular effects of succinylcholine

  • Stimulates all autonomic cholinoceptors (nicotinic and muscarinic)
  • Low dose: (-) inotropic & chronotropic effects
  • High dose: (+) inotropic & chronotropic effects
  • Can cause bradycardia and hypotension
• Other effects of succinylcholine

  • Hyperkalemia
  • Increased intraocular pressure
  • Increased intragastric pressure
  • Muscle pain/myalgia
• Train of four (TOF) count


  • Most common method to monitor extent of neuromuscular blockade
  • Provides information on patient's recovery from neuromuscular blockade

  
• Monitoring neuromuscular blockade


  • Train of four count
  • Double burst pattern
  • Post tetanic potentiation
• Train of four ratio (TOFR)

  • Ratio of the amplitude of the fourth twitch to the first twitch
  • TOFR <0.9 indicates residual neuromuscular blockade
• Reversal of neuromuscular blockade

  Commonly achieved with neostigmine and anticholinesterase, or sugammadex

  
• Drug interactions with succinylcholine

  • Anesthetics (augmentation)
  • Antibiotics (potentiation)
  • Local anesthetics/antiarrhythmics (potentiation)
  • Other neuromuscular blockers (potentiation)
• Other uses of neuromuscular blockers

  • Facilitate tracheal intubation and reduce muscle tone during surgery
  • Assist ventilator care in ICU patients
• Spasmolytic drugs


  Work by enhancing inhibition or reducing excitation of motor neurons
• Stretch reflex arc


  • Drugs can modulate excitatory or inhibitory synapses to reduce hyperactive stretch reflex
• Centrally-acting spasmolytic drugs


  • Baclofen
  • Diazepam
  • Tizanidine
  • Cyclobenzaprine
  • Chlorzoxazone
  • Carisoprodol
  • Methocarbamol
  • Chlorphenesin
  • Orphenadrine

  
• Baclofen


  • Derivative of GABA, primarily used to treat spasticity
  • Acts by binding to and activating GABAB receptors, inhibiting release of excitatory neurotransmitters
• Baclofen


  A derivative of gamma aminobutyric acid (GABA), primarily used to treat spasticity
• Conditions Baclofen is used to treat


  • Spinal cord injury
  • Spastic diplegia
  • Multiple sclerosis
  • Amyotrophic lateral sclerosis (Lou Gehrig's disease)
  • Trigeminal neuralgia
• Baclofen


  • Shown to be as effective as diazepam in uncomplicated alcohol withdrawal syndrome
  • Has reduced abuse & dependence potential compared to Gamma Hydroxybutyrate (GHB) which has similar mechanism of action
• Mechanism of action of Baclofen

  1. Binds to and activate GABAB receptors

  2. Inhibit release of excitatory neurotransmitters