Antispastics & Spasmolytic drugs that act centrally

Objectives

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Antispastics & Spasmolytic drugs that act centrally: Diazepam, Baclofen, Tizanidine, Dantrolene,

Types of skeletal muscle relaxants: 2 groups

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Neuromuscular blockers

Relax normal muscles (surgery and assistance of ventilation) Interfere with transmission at the motor end plate No central nervous system activity.

Used primarily as a part of general anesthesia • • •

Spasmolytics

Reduce spasticity Centrally acting (except dantrolene which act on the skeletal muscle) Used in a variety of neurologic conditions

Spasmolytic drugs

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Definition of muscle spasm (spasticity):

1. Increased muscle tone 2. together with muscle weakness It is often associated with cerebral palsy, multiple sclerosis, and stroke.

Centrally acting spasmolytic drugs

Drug

1- Diazepam 2- Baclofen 3- Tizanidine 4- Gabapentin

Mechanism

GABA receptor GABA receptors causing hyperpolarization by increasing potassium conductance Averse effects: drowsiness and increased seizure activity α 2 adrenoreceptor agonist

DIAZEPAM

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Benzodiazepines facilitate the action of γ-aminobutyric acid (GABA) in the central nervous system. Diazepam acts at GABA A synapses, and its action in reducing spasticity is at least partly mediated in the spinal cord

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Although diazepam can be used in patients with muscle spasm of almost any origin (including local muscle trauma), it produces sedation at the doses required to reduce muscle tone.

BACLOFEN

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Baclofen (p-chlorophenyl-GABA) was designed to be an orally active GABA-mimetic agent, its spasmolytic activity at GABA B receptors, this result in:

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hyperpolarization, probably by increased K+ conductance.

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inhibition of reducing calcium influx

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This will reduce excitation of spinal cords and reduce pain in patients with spasticity, perhaps by inhibiting the release of substance P (neurokinin-1) in the spinal cord.

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Baclofen is at least as effective as diazepam in reducing spasticity while producing less sedation. In addition, baclofen does not reduce overall muscle strength as much as dantrolene.

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Adverse effects:

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Drowsiness, tolerant to the sedative effect with chronic administration.

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Increased seizure activity has been reported in epileptic patients. Therefore, withdrawal from baclofen must be done very slowly.

TIZANIDINE

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Adverse effects, including drowsiness, hypotension, dry mouth, and asthenia.

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OTHER CENTRALLY ACTING SPASMOLYTIC DRUGS

Gabapentin

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It is an antiepileptic drug that has shown considerable promise as a spasmolytic agent in several studies involving patients with multiple sclerosis. Pregabalin

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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 GABA A and GABA B 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

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They are newer drugs for the treatment of amyotrophic lateral sclerosis that appear to have spasm-reducing effects, possibly through inhibition of glutamatergic transmission in the central nervous system.

Peripheraly acting spasmolytic drugs

Dantrolene:

Mechanism of action: Dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers • • Normal contraction involves release of calcium from its stores in the sarcoplasmic reticulum through a calcium channel Dantrolene interferes with the release of calcium through this sarcoplasmic reticulum calcium channel.

Cardiac muscle and smooth muscle are depressed only slightly, perhaps because the release of calcium from their sarcoplasmic reticulum involves a different process.

Dantrolene:

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Indications:

1- Muscle spasticity 2- Malignant hyperthermia: o Patients at risk for this condition have a hereditary impairment in the ability of the sarcoplasmic reticulum to sequester calcium.

o Following administration of one of the triggering agents (general anesthetics or succinylcholine) there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature. Treatment of malignant hyperthermia: 1.

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control acidosis and body temperature Reduce calcium release with intravenous dantrolene

Major adverse effects

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are generalized muscle weakness, sedation, and occasionally hepatitis.