Muscle Pharmacology: Muscle Relaxants and Stimulants

Question 1

Centrally-Acting Muscle Relaxants

Answer 1

Used For Muscle Spasm and Spasticity

• 2 groups that relax skeletal muscle
  
  • 1 group- localized muscle spasm
  • other groups-spasticity
• Produce effects through CNS
  
  • except dantrolene (acts solely on the muscle)
• Groups are not interchangable

Question 2

Muscle Spasm

Answer 2

• Involuntary contraction of muscle or group of muscles

Question 3

Treatment: Muscle Spasm

Answer 3

• Physical:
  
  • immobilization of affected muscle
  • cold compresses
  • whirlpool baths
  • Physical Therapy
• Drug Therapy
  
  • Analgesic anti-inflammatory (aspirin)
  • Centrally Acting muscle relaxants
    
    • Diazepam
    • Tizanidine

Question 4

Centrally Acting Muscle Relaxants:

MOA

Therapeutic Use

Answer 4

• MOA: Unclear- might be from sedative properties of the drugs or presynatpic action
  
  • Diazepam
    
    • enhane effects of GABA
  • Tizanidine
    
    • agonist-presynaptic alpha2 receptor
• Therapeutic use
  
  • relieve local muscle spasm
  • decrease local muscle pain
  • increase range of motion
  • no studies show one drug is better than another

Question 5

Centrally Acting Muscle Relaxants: Side Effects

Answer 5

• Generalized CNS depression
• Hepatic Toxicity
  
  • Tizanidine (Zanaflex) & Metaxalone (Skelaxin)
    
    • can cause damage
  • Chlorzoxazone (paraflex)
    
    • can cause hepatitis and necrosis
• Physical Dependence
  
  • Abstinence syndrome (addiction)

Question 6

Spasticity

Answer 6

• Movement disorder of CNS origin
• Common Cause:
  
  • multiple sclerosis
  • cerebral palsy
• Characteristics:
  
  • Increased muscle tone
  • Spasm
  • Loss of dexterity

Question 7

Drugs for Spasticity

Answer 7

• Baclofen (Lioresal)
  
  • acts in the CNS
• Diazepam (Valium)
  
  • Acts in the CNS
• Dantrolene (Dantrium)
  
  • acts directly on smooth muscle

Question 8

Baclofen

Answer 8

• Aka: Lioresal
• Acts in the Spinal Cord (CNS)
• Suppresses hyperactive reflexes
• MOA: Unknown
  
  • may mimic th action of GABA on spinal neurons
• Therapeutic Uses:
  
  • Multiple Sclerosis, spinal cord injury, cerebral palsy
    
    • NOT with stroke
  • Decreases flexor and extensor spasms
  • Suppresses resistance to passive movement
  • no direct effect on skeletal muscle
• Adverse Effects
  
  • no antidote for overdose
  • Gradual withdrawal over 1 to 2 weeks
    
    • abrupt intrathecal withdrawal-rhabdomyolysis (destruction of skeletal muscle)
  • CNS Depressant
  • GI symptoms (Nausea, constipation)
  • Urinary Retention

Question 9

Diazepam

Answer 9

• Aka Valium
• Member of the benzodiazepine family
  
  • only one approvd to treat spasticity
• MOA
  
  • acts in the CNS
  • mimics action of GABA
• Adverse Effect:
  
  • sedation

Question 10

Dantrolene

Answer 10

• aka Dantrium
• MOA:
  
  • acts directly on skeletal muscle
  • suppresses the release of calcium from the Sarcoplasmic reticulum (SR)
• Therapeutic uses:
  
  • spasticity associated with multiple sclerosis, cerebral palsy, spinal cord injury
  • Malignant hyperthermia
    
    • fatal condition baused by combo of succinylchoine and general inhalation anesthetics
• Adverse effects
  
  • hepatic toxicity
  • muscle weakness
  • drowsiness
  • Diarrhea
  • Acne-like rash

Question 11

Centrally Acting Muscle relaxants: Other agents

Answer 11

• Gapapentin (Neurontin) and Pregabalin (lyrica)
  
  • antiepileptic drugs
  • some promise
• Progabide (Gabrene)
  
  • mimics action of GABA at both receptor populations
  • not approved in US
• Glycine
  
  • inhibitory amino acid neurotransmitter
• Idrocilamide (Talval) and Riluzole (Rilutek)
  
  • glutamate antagonists
  • might be useful in ALS
  • Talval not available in US

Question 12

Neuromuscular Drugs: Types

Answer 12

• Non-depolarizing Antagonists
• Depolarizing Antagonists

Question 13

Non-depolarizing Neuromuscular Blocking Drugs

Answer 13

• d-Tubocurare;
• (-nium)
  
  • pancuronium
  • Vecuronium
  • rapacuronium
  • Rocuronium
  • cisatracurium
  • atracurium
  • mivacurium
• Competitive inhibition of ACh binding at nAChR (Nm) receptor
  
  • stabilizing blockade
• Rapid muscle weakness followed by flaccid paralysis
• Curare
  
  • 1st in class
  • least selective bc it also produces some ganglionic blockade and induces release of histamine

Question 14

Depolarizing Neuromuscular Blocking Drugs

Answer 14

• Acetylcholine
  
  • pure agonist of nicotonic receptor
• Succinylcholine
  
  • ideal bc composed of 2 Ach
  • Nicotinic receptor requires 2 Ach
• Nicotine
  
  • pure agonist of nicotinic receptor

Question 15

Depolarizing Neuromuscular Blocking Drugs: How does it work

Answer 15

• Acetylcholine, Succinylcholine and Nicotine
  
  • inhibit the activation of the neuromuscule nicotinic receptor
• Similar to Desensitization
  
  • Administer succinylcholine
  • Muscle Fasciculations
    
    • • initial depolarization (muscle contraction) followed by increasing weakness–>flaccid paralysis
  • Densensitization
    
    • end plate is repolarized but not able to be activated by agonists
  • Phase I block of voltage-gated channels will be enhanced by AChE inhibitors which will reverse late Phase II Block

Question 16

Depolarizing vs Nondepolarizing Neuromuscule Blockers

Answer 16

• Nondepolarzing NM blockers
  
  • bind to the active site (ligand binding site)
  • compete with the natural ligand
• Depolarizing NM blockers
  
  • bind to the activated site, and opens the channel
  • causes preliminary muscle fasciculations and leaves the channel in an open state

Question 17

Neuromuscular Blocking Agents: Therapeutic use

Answer 17

• Relax skeletal muscle during surgery
• Permit reduction in anesthetic dose
• Assist with orthopedic procedures
• Facilitate procedures involving skeletal muscle
  
  • intubation
  • endoscopy
  • laryngoscopy
  • ECT

Question 18

Neuromuscular Blocking Agents: Adverse Effects

Answer 18

• Prolonged Apnea
  
  • genetic disorder when you cant metabolize Succinylcholine
• Hyperkalemia
  
  • excessive potassium release
• Malignant Hyperthermia
  
  • increase in body core temp
  • antidote-dantrolene

Question 19

Agents the produce Neuromuscular Contraction

Answer 19

• Nicotinic (Nm) Receptor Agonists
• Indirect Acting Cholinomimetic Drugs
  
  • inhibit Acetylcholinesterase (AChE)
  • 2 families
    
    • Reversible
    • Irreversible

Question 20

Acetylcholinesterase (AChE)

(Agent that produces muscle contraction)

Answer 20

• Enzyme: Serine Esterase
  
  • contains 2 active sites:
    
    • Anionic Site
      
      • binds the cation portion=uncharged
      • attracts the molecule
    • Esteratic Site
      
      • business end
      • ester linkage is hydrolyzed by nucleophilic attack
  • Hydrolysis regenerates free enzymes
• Enzyme Inhibitor Classes:
  
  • inhibit cholinesterase
    
    • increase or eliminate metabolism of Acetylchoine
  • 2 families
    
    • Reversible
      
      • Carbamate
      • Competitive
    • Irreversible
      
      • Organophosphates

Question 21

Cholinesterase: Competitive Inhibitors

Answer 21

• Drugs:
  
  • Endrophonium (Tensilon)
  • Donepezil (Aricept)
    
    • used in Alzheimers
  • Galantamine (Reminyl)
• Compete with ACh at the anionic site
• contains no ester linkage so not hydrolyzed/metabolized
• inhibition=reversible

Question 22

Cholinesterase: Carbamate Inhibitors

Answer 22

• Drugs: (-stigmine)
  
  • Physostigmine, Pyridostigmine, Neostigmine, Rivastigmine)
  • Carbaryl
  • Propoxur
  • Aldicarb
• Contain Carbamyl ester that is hydrolyzed to carbamylate enzyme
• Carbamyl moiety is slowly released
  
  • causes long lasting but reversible inhibition
• Physostimine & Rivastigmine
  
  • CNS permeable
  • Alzheimers Disease

Question 23

Cholinesterase: Irreversible Inhibitors

Answer 23

• Drugs
  
  • DFP (Isoflurophate)
  • Echotiophate
  • Parathion
  • Tabun (GA)
  • Sarin (GB)
  • Soman (GF)
  • VX (10x more potent than G-series
  • Novichok-5

Question 24

Effects of Cholinesterase Inhibition

Answer 24

• Concentration dependent
  
  • low concentration enhances cholinergic transmission
  • High concentration block cholinergic transmission
• Classes of effects
  
  • Muscarinic receptor
    
    • stimulation of organs
  • Nicotinic Recptor
    
    • stimulation followed by antagonism of ganglionic and neuromuscular receptors
  • Stimulation of BOTH in the CNS only if substance crosses BBB
• Organ System:
  
  • Cardiovascular
    
    • Bradycardia
    • Decreased Cardiac Output
    • Hypotension
  • Respiratory System
    
    • Bronchoconstriction
    • Increased secretion
    • Paralyzed diaphgram
  • GI Tract
    
    • increased tone, motility, secretions
  • Skin
    
    • increased sweating
  • Eye
    
    • miosis
    • near accommodation
  • CNS
    
    • tremore
    • anxiety
    • confusion
    • convulsions
    • coma

Question 25

Cholinesterase Inhibitors: Therapeutic Use

Answer 25

* Atony of GI tract and Urinary Bladder * loss of muscle strength * Glaucoma * Myasthenia Gravis * effects of competitive neuromuscular blocking agents * in combo with muscarinic receptor antagonist * Alzheimers (increases adverse cardio events) * Treatment of Atrophine poisoning

Question 26

Cholinesterase Inhibitor Poisoning: Treatment

Answer 26

* Atropine * block the muscarinic receptor * Pralidoxime (2-PAM) * reactivate the enzyme * effective at the neuromuscule junction * not effective against Novichok agents * Respiratory Support