Centrally Acting

Antispastic Drugs

Introduction

A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone

used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.

Muscle Relaxants classified as:

1.Neuromuscular Junction Blockers

1.1. depolarizing

1.2. Nondepolarizing muscle relaxant

2.Spasmolytics

1.Neuromuscular Junction BlockersCan be;

1.1. Depolarizing

1.2. Nondepolarizing Muscle Relaxants

Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity.

Important for induction of muscle paralysis as part of preoperative general anesthesia.

2.Spasmolytics Spasmolytics, also known as "centrally acting" muscle relaxants

Used to alleviate musculoskeletal pain and spasms and to reduce spasticity

Both neuromuscular blockers and spasmolytics are often called muscle

relaxants

It is often associated with cerebral palsy, multiple sclerosis, and stroke.

The generation of the neuronal Signals in motor neurons that cause muscle contractions are dependent on the:

balance of synaptic excitation and

inhibition the motor neuron receives

What is muscle spasm?

Muscle spasms is defined as an involuntary muscular contraction

A painful muscle spasm is typically referred to as a muscle cramp

Spasticity is defined as a muscle tone disorder characterized by hyperactive tonic stretch reflexes

thought to arise from an imbalance of excitatory and inhibitory neurotransmitters

Spasmolytic agents generally work by either enhancing the level of inhibition, or reducing the level of excitation

Inhibition is enhanced by mimicking or enhancing the actions of endogenous inhibitory substances, such as GABA

The mechanisms underlying clinical spasticity appear to involve not only the stretch reflex arc itself but also

Higher centers in the central nervous system (ie, upper motor neuron lesion), with damage to descending pathways in the spinal cord resulting in hyperexcitability of the alpha motoneurons in the cord.

Baclofen

Baclofen has commonly been used for its muscle relaxant effects in the treatment of spasticity

Baclofen is as effective as diazepam in reducing spasticity

Causes much less sedation

Mechanism Of Action

Acts as a GABA agonist at GABAB receptors in the brain and spinal cord

Potassium Ion Conductance

Hyperpolarization

calcium ion influx

Release of excitatory neurotransmitters

substance P

Baclofen also inhibits neural function presynaptically

Reducing the in both the brain and spinal cord

It may also reduce pain in patients by inhibiting the release of substance P in the spinal cord, as well

Studies have confirmed that intrathecal administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration

Partial tolerance to the effect of the drug may occur after several months of therapy, but can be overcome by upward dosage adjustments to maintain the beneficial effect

Pharmacokinetics

Metabolized in the liver and excreted in the urine

Baclofen can be administered orally as well as intrathecally

Baclofen is rapidly and effectively absorbed after oral administration

It is lipophilic and able to penetrate the blood-brain barrier

Approximately 35% of the drug is excreted unchanged in the urine and feces

side effects Common are weakness, sedation, and dizziness

At higher doses, baclofen can cause seizures, ataxia, and hallucinations

Abrupt withdrawal should be avoided because it can precipitate

seizures and hallucinations

Diazepam

The benzodiazepines, such as diazepam, interact with the GABAA receptor in the central nervous system

Its action in reducing spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection

While it can be used in patients with muscle spasm of almost any origin

Produces sedation in most individuals at the doses required to reduce muscle tone

Tizanidine

Clonidine and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity.

Tizanidine is an agonist at α2 adrenergic receptor

Reduces spasticity at doses that result in significantly less hypotension

than clonidine

Neurophysiologic studies show that it depresses excitatory feedback from

muscles that would normally increase muscle tone, therefore minimizing spasticity

Several clinical trials indicate that tizanidine has a similar efficacy to other spasmolytic agents, such as diazepam and baclofen, with a different spectrum of adverse effects

Tizanidine is a centrally acting muscle relaxant that, through its alpha-2

adrenergic agonist properties

Thought to prevent the release of excitatory amino acids by suppressing polysynaptic excitation of spinal cord interneurons

Even though tizanidine’s pharmacologic effect is similar to another alpha-2 agonist like clonidine, but

It possesses only a fraction of its blood pressure–lowering effect

OTHER CENTRALLY ACTING - SPASMOLYTIC DRUGS

Gabapentin

An antiepileptic drug that has shown considerable promise as

a spasmolytic agent in several studies involving patients with multiple sclerosis

Pregabalin

is a new analog of gabapentin that may also prove useful

Progabide and glycine

Have also been found in preliminary studies to reduce spasticity

Progabide is a GABAA and GABAB

agonist and has active metabolites, including GABA itself

Glycine

Is another inhibitory amino acid neurotransmitter

It appears to possess pharmacologic activity when given orally and readily passes the blood-brain barrier

Idrocilamide and riluzole

Newer drugs for the treatment of amyotrophic lateral sclerosis

Have spasm-reducing effects, possibly through

Inhibition of glutamatergic transmission in the CNS

Spasmolytic Drugs

Side Effects

Because of the enhancement of inhibition in the CNS

most spasmolytic agents have the side effects

Sedation

Drowsiness and

Dependence with long-term use

Several of these agents also have abuse potential, and their prescription is strictly controlled!!!

The most commonly used muscle relaxant for non spasticity-related

muscle pain

Structurally, it resembles tricyclic anti-depressants(TCAs)

Its therapeutic effect is centrally mediated and carries no direct peripheral

action on the affected muscles

Its main pharmacologic action occurs at the brainstem and spinal cord levels and is partially explained by a depressant effect on the descending serotonergic neurons

Cyclobenzaprine

Methocarbamol

It is a centrally acting muscle relaxant that suppresses spinal polysynaptic reflexes and has no direct effect on skeletal muscle

Orphenadrine

Structurally related to diphenhydramine and carries relativelystrongeranticholinergic and weaker sedative properties

Its exact mechanism of action is unknown

Common side effects include drowsiness and dizziness, followed by other central nervous system effects such as agitation, hallucinations, and euphoria

Quinine

Antimalarial, antipyretic, analgesic, and muscle relaxant effects

Prescribed for the Rx of nocturnal leg muscle cramps

Increase the refractoriness of muscle and to decrease the excitability of the neuromuscular endplate

Metaxalone

Metaxalone is a centrally acting muscle relaxant with an unknown mechanism

It is metabolized in the liver and excreted through the kidneys in the form of metabolites

Carisoprodol

Carisoprodol is still a commonly prescribed muscle relaxant that should caution owing to the

Potentially addictive properties of its main metabolite, meprobamate

Carisoprodol produces its muscle relaxant effect by depressing the interneuronal activity at the

Spinal cord level aswell as in the descending tracts of the reticular formation

It is not recommended in the pediatric age population

These neurotoxins exert their pharmacologic effect at the neuromuscular junction (NMJ)

Prevent the calcium-dependent release of acetylcholine

Producing a state of temporary drug-induced denervation

The therapeutic effect can take up to 1 week to take place fully and can last up to 3 months, at which point repeat injections can be considered

Caution should be exercised in using appropriate botulinum dosing to avoid functionally limiting muscle weakness

Diazepam has commonly been used in the treatment of muscle spasm especially in the acute setting

It belongs to a group of compounds called benzodiazepines

known for their potent anxiolytic, sedative, as well as muscle

Mechanism of action

Their main mechanism of action is through central potentiation

of the inhibitory g-aminobutyric acid (GABA) effect through presynaptic

Facilitation of GABA release

Antispastic drugs are principally used for the treatment of spasticity observed

in disease states with upper motor neuron pathology such as

Stroke

Spinal cord injury

Traumatic brain injury, and

Multiple sclerosis

All but two of these agents exert their clinical effect through centrally mediated mechanisms

Dantrolene reduces muscle spasms by inhibiting the release of calcium from the sarcoplasmic reticulum and does not directly affect the CNS

Because dantrolene tends to produce greater muscle weakness than baclofen,

It should not be the first-line agent for patients who are capable of

ambulation