Skeletal Muscle Relaxants Overview

Skeletal Muscle Relaxants

• Skeletal Muscle Relaxants are categorized into CNS Muscle Relaxants and Neuromuscular Blocking Drugs.
• CNS Muscle Relaxants include Diazepam, Baclofen, Carisoprodol, Cyclobenzaprine, and Tizanidine.
• Neuromuscular Blocking Drugs include non-depolarizing blockers (like Tubocurarine, Benzylisoquinolines, aminosteroids) and depolarizing blockers (like Succinylcholine).
• Neurotoxins, like botulinum toxin, interfere with calcium influx, impacting acetylcholine release.

Neuromuscular Junction

• The neuromuscular junction involves a cholinergic motor neuron, motor end-plate, vesicles, and mitochondria.
• Acetylcholine vesicles are crucial for signal transmission.

Non-Depolarizing Agents

• At low doses, these drugs bind to nicotinic receptors, competing with acetylcholine.
• Approximately 70% of acetylcholine receptors must be blocked for a clinical effect.
• This prevents depolarization at the end-plate, inhibiting muscle contraction.

Non-Depolarizing Agents: Mechanism of Action

• Non-depolarizing agents at lower doses block acetylcholine binding to receptors, competing with it.
• They directly inhibit muscle contraction leading to relaxation.
• To achieve a clinical effect, around 70% of ACh receptors are blocked.

Overcoming Non-Depolarizing Agent Action

• Increasing acetylcholine in the synaptic cleft can overcome the blockade.
• This is achieved by inhibiting the breakdown of acetylcholine (e.g., Neostigmine, Physostigmine, Edrophonium).
• Anesthesiologists utilize this to shorten blockade or manage overdoses.

Non-Depolarizing Agents: High Doses

• At high doses, the drugs block ion channels at the end-plate.
• This further weakens transmission and reduces the effectiveness of acetylcholine esterase inhibitors.

Skeletal Muscle Actions

• Different muscles display varying sensitivity to blockade.
• Small, fast-contracting muscles are paralyzed initially.
• Respiratory muscles are the last to be affected and first to recover.

Pharmacokinetics

• Skeletal muscle relaxants are often administered intravenously.
• Many cross the blood-brain barrier poorly. They are often not metabolized in the liver.
• They are eliminated in the urine, either unchanged or after some metabolism.

Atracurium

• Atracurium undergoes spontaneous degradation, releasing histamine and potentially causing a drop in blood pressure, flushing, and bronchoconstriction.
• It's metabolized to laudanosine, potentially leading to seizures in some cases.
• Cisatracurium is a safer alternative with similar pharmacokinetics because of reduced histamine release.

Vecuronium and Rocuronium

• Vecuronium and Rocuronium are acetylated in the liver.
• Clearance can be prolonged in liver impairment.
• They can be excreted unchanged in bile.
• They differ in onset, duration, and recovery time.

Non-Depolarizing Agents: Summary

• Therapeutic Use: Adjuvant drugs in surgical anesthesia.
• Pharmacology: Given via injection, not orally absorbed, doesn't cross the blood brain barrier, often not metabolized.
• Adverse effects: Tubocurarine can release histamine, potentially causing blood pressure drops, wheezing, and skin reactions.

Drug Interactions

• Cholinesterase inhibitors decrease the efficacy of non-depolarizing agents.
• Aminoglycoside antibiotics can diminish acetylcholine release, potentially amplifying non-depolarizing action.
• Calcium channel blockers can enhance non-depolarizing responses by reducing acetylcholine release.
• Halogenated anesthetics can strengthen neuromuscular blockage and increase the effectiveness of non-depolarizing agents.

Depolarizing Agents

• Succinylcholine is the primary depolarizing agent.
• Its mechanism of action is similar to acetylcholine, acting by depolarizing the muscle membrane.
• Two distinct phases:
  • Phase 1: Brief depolarization causing muscle twitching
  • Phase 2: Continued occupation of the receptors after depolarization, causing prolonged block.

Depolarizing Agents: Additional

• It's insensitive to potassium (K+) and electrical stimulation.
• The effect is amplified by acetylcholine esterase inhibitors.
• It paralyzes skeletal muscles initially more than respiratory muscles.

Depolarizing Agents: Therapeutic Use

• Depolarizing agents are used as adjuvants in surgical anesthesia.
• They act quickly, meaning they can be given by infusion in short bursts.
• Malignant hyperthermia: Some patients exhibit this syndrome when these agents are administered with halothane.

Succinylcholine

• Induces skeletal muscle paralysis.
• The paralysis sequence differs from non-depolarizing drugs; respiratory muscles are paralyzed later than others.
• It causes a transient muscle twitching before muscle blockage.
• It continuously maintains depolarization at the end-plate, leading to a loss of electrical excitability.
• It has a shorter duration of action than non-depolarizing agents.
• It mimics acetylcholine in action but diffuses at a slower rate which leads to prolonged depolarization.

Succinylcholine: Additional

• Low doses have negative ionotropic/chronotropic effects (weakening).
• High doses produce opposite effects (strengthening).

Unwanted Effects:

• Bradycardia is preventable with atropine.
• Hyperkalemia can arise in patients with burns or trauma, potentially causing arrhythmias and cardiac arrest.
• Intraocular and intragastric pressure can increase due to skeletal muscle contraction.
• Malignant hyperthermia: rare, inherited condition, caused by Ca++ channel defects resulting in muscle spasms and fever. Treated by cooling the body and using dantrolene.
• Prolonged paralysis can occur due to factors affecting cholinesterase activity (genetic variants, anticholinesterase drugs, and liver dysfunction).

Dantrolene

• Dantrolene acts directly on skeletal muscles, reducing the activity of excitation-contraction coupling.
• It's helpful in treating malignant hyperthermia induced during use of depolarizing agents.
• Administered orally, but absorption is limited to around one-third of the intravenous dose.
• Half-life is roughly 6–8 hours.
• Repeated dosing after 10 minutes.

Baclofen: Overview

• Baclofen acts through GABA B receptors in the spinal cord.
• It increases potassium conductance, reducing calcium influx, and reducing activity of excitatory neurotransmitters (like aspartate and glutamate).
• Baclofen also acts by reducing substance P in the spinal cord.
• It is considered a less sedative agent.

Baclofen: Additional Information

• It inhibits monosynaptic and polysynaptic reflexes.
• Hyperpolarization of afferent terminals may occur when it is used.
• Speeds nerve activity within the spinal cord.
• It acts on excitatory transmitters.

Baclofen: Characteristics

• Rapid and complete oral absorption.
• Half-life of 3-4 hours.
• May worsen seizures in epileptics.

Baclofen: Dosage

• Optimal dose is determined by titration, starting at low doses (e.g. 5mg tid) and gradually increasing.
• Maximum daily dose of 80 mg is generally recommended.
• Titration schedules are often used in patients.

Baclofen: Side Effects

• Potential side-effects include sedation, drowsiness, muscle weakness, ataxia, anxiety, tachycardia, hallucinations.
• It may cause increased seizures in some patients.
  • Pregnancy risk, including possible teratogenicity.
  • Side effects like blurred vision or double vision, convulsions, shortness of breath, slow or troubled breathing, and vomiting.

Tizanidine: Overview

• Tizanidine is an alpha-2 adrenergic receptor stimulator.
• It's used for treating skeletal muscle spasticity, acting by reducing presynaptic activity of motor neurons, via reduction in excitatory neurotransmitters (e.g., glutamate, aspartate).

Tizanidine: Dosage

• Initial dose: 4 mg orally every 6 to 8 hours (maximum three doses in 24 hours).
• Dose may be increased by 2 to 4 mg steps to optimize effect and tolerance.
• Maintenance dose: 8 mg orally every 6 to 8 hours (maximum three doses in 24 hours).
• Maximum dose: Up to 36mg per day.

Tizanidine Presentations:

• Available in 2mg and 4mg tablets.

Individual Drug Presentations

• Specific tablet strengths and dosing schedules are provided for each drug mentioned.

Other topics

• This document also includes details of elimination mechanisms, clearance rates, potency, and pharmacodynamic characteristics for a variety of muscle relaxants.