Skeletal muscle relaxants

SKELETAL MUSCLE RELAXANTS
│
├── Peripherally acting
│   │
│   ├── At neuromuscular junction
│   │   ├── Nondepolarizing blockers: vecuronium, rocuronium, atracurium
│   │   └── Depolarizing blocker: succinylcholine
│   │
│   ├── Directly on skeletal muscle
│   │   └── Dantrolene
│   │
│   └── At cholinergic nerve terminal
│       └── Botulinum toxin
│
└── Centrally acting
    │
    ├── Antispasticity drugs for UMN lesions
    │   ├── Baclofen
    │   ├── Tizanidine
    │   └── Diazepam
    │
    └── Drugs for acute painful local muscle spasm
        ├── Chlorzoxazone
        ├── Methocarbamol
        ├── Cyclobenzaprine
        ├── Carisoprodol
        ├── Orphenadrine
        └── Metaxalone

Important distinction: Neuromuscular blockers cause paralysis, not analgesia, unconsciousness, or sedation. They are used during anesthesia and ventilation, not for routine muscle spasm.

A. Peripherally acting skeletal muscle relaxants

1. Flow chart: mechanisms

A. Nondepolarizing neuromuscular blockers
Rocuronium / vecuronium / atracurium
        ↓
Competitive blockade of Nm nicotinic receptors
at motor end plate
        ↓
ACh cannot produce end-plate depolarization
        ↓
No muscle action potential
        ↓
Flaccid paralysis

B. Depolarizing neuromuscular blocker
Succinylcholine
        ↓
Nm receptor agonist at motor end plate
        ↓
Persistent depolarization of end plate
        ↓
Initial fasciculations
        ↓
Voltage-gated Na+ channels remain inactivated
        ↓
Flaccid paralysis

C. Direct skeletal muscle relaxant
Dantrolene
        ↓
Acts on RyR1 calcium-release channel
in skeletal-muscle sarcoplasmic reticulum
        ↓
↓ Release of Ca2+ from sarcoplasmic reticulum
        ↓
↓ Cytosolic Ca2+
        ↓
↓ Actin-myosin interaction
        ↓
↓ Force of skeletal-muscle contraction

D. Botulinum toxin
Injected into selected muscle
        ↓
Enters presynaptic cholinergic nerve terminal
        ↓
Cleaves SNARE proteins
        ↓
Prevents vesicular release of acetylcholine
        ↓
No end-plate depolarization
        ↓
Local, reversible chemical denervation
        ↓
Relaxation of injected muscle

2. Table: peripherally acting drugs

B. Centrally acting skeletal muscle relaxants

1. Flow chart: general mechanism

Upper motor neuron lesion
(spinal cord injury, multiple sclerosis, cerebral palsy, stroke)
        ↓
Loss of descending inhibitory control
        ↓
Hyperexcitable spinal reflexes and α-motor neurons
        ↓
Increased muscle tone + hyperreflexia + spasms
        ↓
Centrally acting skeletal muscle relaxants
        ↓
Increase inhibitory transmission or decrease excitatory transmission
in brain and spinal cord
        ↓
Reduced spinal motor-neuron activity
        ↓
Reduced spasticity and painful muscle spasms

2. Individual mechanisms in flow charts

Baclofen

Baclofen
        ↓
GABAB receptor agonist in spinal cord
        ↓
Presynaptic inhibition of excitatory transmitter release
and postsynaptic hyperpolarization
        ↓
↓ Spinal reflex activity
        ↓
↓ Spasticity and flexor/extensor spasms

Diazepam

Diazepam
        ↓
Facilitates GABAA receptor action
        ↓
↑ Frequency of Cl- channel opening
        ↓
Neuronal hyperpolarization
        ↓
Enhanced inhibitory transmission in spinal cord
        ↓
↓ Polysynaptic reflexes and muscle spasm

Tizanidine

Tizanidine
        ↓
Central α2-adrenergic receptor agonist
        ↓
↓ Release of excitatory amino acids
from spinal interneurons
        ↓
↓ Excitatory polysynaptic spinal reflexes
        ↓
↓ Muscle tone and spasticity

Cyclobenzaprine and other antispasmodics

Cyclobenzaprine / methocarbamol / chlorzoxazone /
carisoprodol / orphenadrine / metaxalone
        ↓
CNS depressant action, mainly brainstem and spinal cord
        ↓
Reduced somatic motor activity and reflex muscle spasm
        ↓
Relief of acute painful musculoskeletal spasm

3. Table: centrally acting drugs

Quick exam comparison table

One-line memory aids

• Baclofen = B for GABA-B agonist.
• Tizanidine = T for alpha-2 agonist that reduces Tone.
• Diazepam = enhances GABA-A action.
• Dantrolene = decreases calcium release from skeletal-muscle RyR1.
• Botulinum toxin = blocks ACh release.
• Nondepolarizing blockers = Nm receptor antagonists.
• Succinylcholine = Nm receptor agonist causing persistent depolarization.

Skeletal muscle relaxants: brief

Classification

Skeletal muscle relaxants
│
├── Centrally acting
│   ├── Baclofen
│   ├── Tizanidine
│   ├── Diazepam
│   └── Cyclobenzaprine, methocarbamol, chlorzoxazone
│
└── Peripherally acting
    ├── Dantrolene
    ├── Botulinum toxin
    └── Neuromuscular blockers
        - Succinylcholine
        - Rocuronium, vecuronium, atracurium

Centrally acting drugs

Drug acts on brain/spinal cord
        ↓
↓ Spinal reflex activity and motor-neuron excitation
        ↓
↓ Muscle spasm and spasticity

Peripherally acting drugs

Dantrolene
        ↓
Blocks RyR1 calcium release from sarcoplasmic reticulum
        ↓
↓ Intracellular Ca2+
        ↓
↓ Actin-myosin contraction
        ↓
Muscle relaxation

Key point

• Centrally acting drugs: used mainly for spasticity and painful muscle spasm.
• Peripherally acting drugs: used for surgery/intubation, malignant hyperthermia, or focal spasticity.
• Dantrolene is the drug of choice in malignant hyperthermia.