Overview

Physiology review

Excitation:

• Skeletal muscle cell contraction requires stimulation by an action potential (AP) from somatic motor neurons.
• Nerve signal arrives at the synaptic knob → release of acetylcholine into the synaptic cleft
• Binds and activates ion channels on the motor end plate of the muscle fiber → creates a wave of depolarization known as an AP
• The AP propagates in all directions throughout the sarcolemma.

Excitation-contraction coupling:

• The AP stimulates voltage-dependent dihydropyridine (DHP) receptors:
  • Mechanically tethered to ryanodine receptors present on (and remain closed) the Ca⁺²-release channels in the sarcoplasmic reticulum (SR)
  • Stimulation of the DHP receptors moves the ryanodine receptors → opening of Ca⁺²-release channels in the SR
• Ca²⁺ floods out of the SR into the sarcoplasm → binds to troponin on the thin filaments (actin)
• Troponin-tropomyosin complex changes shape → allows binding of actin and myosin
• Cross-bridge cycling occurs → sarcomere shortens → muscle contraction

Function and classification

Spasmolytics can be divided based on where and how they exert their effects:

• Centrally acting:
  • Function: prevent nerve signal transmission from the brain or spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord via:
    • Enhancing inhibition
    • ↓ Excitation
  • Includes:
    • CNS depressants
    • GABA agonists
    • Alpha-2 agonists
    • Cyclic antidepressants
• Peripherally acting:
  • Function: act directly on skeletal muscle to reduce muscle contraction
  • Example: dantrolene

CNS Depressants

Medications in this group

• Carisoprodol
• Methocarbamol

Mechanism of action

• The mechanism of action is unclear.
• CNS depression results in skeletal muscle relaxation.
• No direct effect on the contractile mechanism of skeletal muscle

Pharmacokinetics

• Absorption: oral
• Distribution:
  • Cross the blood–brain barrier
  • Cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
• Metabolism: hepatic
  • Carisoprodol: via cytochrome P450 (CYP)2C19 to the active metabolite
  • Methocarbamol: via dealkylation and hydroxylation
• Excretion: urine

Indications

• Relief of pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain associated with acute musculoskeletal conditions (muscle spasms)
• For short-term use
• Usually used as an adjunct to other pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain relievers (e.g., acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen, NSAIDs)

Adverse effects

• CNS depression
• Blurred vision
• Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Drug dependency and withdrawal symptoms (carisoprodol)

Contraindications and precautions

• Carisoprodol should not be taken if there is a history of acute intermittent porphyria.
• Use with caution in individuals with hepatic or renal impairment.

Drug interactions

• Enhanced CNS depression can occur with (list is not exhaustive):
  • Alcohol
  • Barbiturates
  • Cannabinoid products
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
  • Metoclopramide
  • Ropinirole
  • Sedatives
• Strong CYP2C19 inducers: ↑ carisoprodol effect
• Strong CYP2C19 inhibitors: ↓ carisoprodol effect

Agonists of GABA receptors

Medications in this group

• Baclofen
• Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (such as diazepam)

Mechanism of action

Baclofen:

• GABA_B receptor agonist:
  • Opens postsynaptic inward-rectifier K⁺ channels
  • Closes presynaptic Ca²⁺ channels
  • Inhibits adenylyl cyclase
• ↓ Excitatory neurotransmitter release and inhibition of spinal motor neurons

Diazepam:

• Binds to the γ subunit of the GABA_A receptor → enhances the binding of GABA in the pocket between the α and β subunits of the receptor
• ↑ Frequency of chloride channel opening → ↑ chloride influx → inhibits AP

Pharmacokinetics

Pharmacokinetics of baclofen:

• Absorption:
  • Rapid, oral absorption
  • Can also be given intrathecally
• Distribution:
  • Does not readily cross the blood–brain barrier
  • Crosses the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
• Metabolism: hepatic
• Excretion:
  • Urine (primary)
  • Feces (minor)

Indications

Baclofen:

• Management of muscle spasticity originating from:
  • Spinal cord injury (e.g., multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis)
  • Cerebral injury (e.g, cerebral palsy Cerebral palsy Cerebral palsy (CP) refers to a group of conditions resulting in motor impairment affecting tone and posture and limiting physical activity. Cerebral palsy is the most common cause of childhood disability. It is caused by a nonprogressive CNS injury to the fetal or infant brain. Cerebral Palsy, traumatic brain injury)
• Temporary adjunctive therapy for muscle spasms or musculoskeletal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Diazepam:

• Temporary adjunctive therapy for:
  • Muscle spasms
  • Spasticity
• Neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome (adjunctive therapy)
• Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (acute management)

Adverse effects

• Urinary retention
• Hypotonia and muscle weakness
• Nausea and vomiting
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• CNS depression
• Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
• Respiratory depression (more likely with diazepam)
• Seizure (baclofen)
• Withdrawal effects with abrupt discontinuation

Contraindications and precautions

Baclofen should be used with caution in individuals with:

• Urinary retention
• Psychiatric disorders (e.g., psychotic disorders, schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia)
• Renal impairment
• Seizure disorder

Diazepam:

• Contraindications:
  • Untreated open-angle glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis
  • Severe respiratory impairment
  • Severe hepatic impairment
• Use with caution:
  • Psychiatric conditions (e.g., depression, anxiety)
  • Renal impairment
  • Respiratory conditions

Drug interactions

Enhanced CNS depression can occur with (list is not exhaustive):

• Alcohol
• Barbiturates
• Cannabinoid products
• Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
• Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
• Metoclopramide
• Ropinirole
• Sedatives

Alpha-2 Agonists

Medications in this group

• Tizanidine
• Clonidine (also an alpha-1 agonist)

Mechanism of action

• Stimulate presynaptic alpha-2 adrenergic receptors → ↓ norepinephrine release
• Inhibit spinal motor neurons → ↓ muscle tone and spasticity

Pharmacokinetics

Pharmacokinetics of tizanidine:

• Absorption:
  • Tablets: Food increases peak plasma concentrations and the extent of absorption.
  • Capsules: Food decreases peak concentration but increases the extent of absorption.
• Distribution:
  • Crosses the blood–brain barrier
  • Protein binding: approximately 30%
• Metabolism:
  • Extensive 1st-pass effect
  • CYP1A2
• Excretion:
  • Urine (primary)
  • Feces (minor)

Indications

• Management of spasticity (including spasticity associated with multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis, stroke, or spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord injury)
• Can be used as temporary adjunctive therapy for muscle spasm or musculoskeletal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Adverse effects

• Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
• Bradycardia
• CNS depression
• Xerostomia
• Muscle weakness
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• ↑ Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
• Rebound symptoms after abrupt discontinuation

Contraindications and precautions

• Contraindications: concurrent therapy with potent CYP1A2 inhibitors (tizanidine)
• Use with caution in individuals with:
  • Severe renal or hepatic impairment
  • Cardiovascular disease (clonidine)
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension

Drug interactions

• CYP1A2 inhibitors ↑ tizanidine concentration (and risk of adverse effects):
  • Cimetidine
  • Ciprofloxacin
  • Fluvoxamine
• Enhanced CNS depression can occur with (list is not exhaustive):
  • Alcohol
  • Barbiturates
  • Cannabinoid products
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
  • Metoclopramide
  • Ropinirole
  • Sedatives
• ↑ Risk of hypotension:
  • ACE inhibitors
  • Beta-blockers
  • Other antihypertensives
• ↑ Risk of bradycardia:
  • Beta-blockers
  • Midodrine
  • Terlipressin

Cyclic Antidepressants

Medications in this group

Cyclobenzaprine is the main drug in this group.

Mechanism of action

• Similar structure as that of tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
• Acts centrally within the brainstem to inhibit somatic motor activity
• The exact mechanism is unclear but may include the inhibition of serotonin (5-HT2) receptors.
• Also has anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs properties

Pharmacokinetics

• Absorption: orally absorbed
• Distribution:
  • Crosses the blood–brain barrier
  • Protein binding: approximately 93%
• Metabolism:
  • Hepatic
  • Via the CYP system:
    • CYP3A4
    • CYP1A2
    • CYP2D6
• Excretion: urine and feces

Indications

Cyclobenzaprine can be used as a temporary adjunctive therapy for:

• Muscle spasms and musculoskeletal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
• Temporomandibular joint dysfunction
• Note: Cyclobenzaprine is ineffective in spasticity due to cerebral or spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord pathologies.

Adverse effects

• Anticholinergic effects:
  • Xerostomia
  • Mydriasis
  • Tachycardia
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Urinary retention
• CNS depression
• Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome
• Muscle weakness

Contraindications

• Concurrent therapy with monoamine oxidase (MAO) inhibitors → ↑ risk of serotonin syndrome
• Hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
• Heart block or arrhythmias → cyclobenzaprine slows cardiac conduction via blockade of fast Na⁺ channels
• Acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
• Acute heart failure

Drug interactions

• Serotonergic medications → ↑ risk of serotonin syndrome
• Enhanced CNS depression can occur with (list is not exhaustive):
  • Alcohol
  • Barbiturates
  • Cannabinoid products
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
  • Metoclopramide
  • Ropinirole
  • Sedatives

Peripherally-acting Spasmolytics

Medications in this group

Dantrolene is the only drug in this group.

Mechanism of action

• Acts directly on skeletal muscle (does not affect cardiac or smooth muscles)
• Binds to ryanodine receptors in the SR → blocks Ca²⁺ release
• ↓ Concentration of intracellular Ca²⁺ → ↓ excitation-contraction coupling → ↓ skeletal muscle contraction

Pharmacokinetics

• Absorption: well absorbed orally
• Distribution:
  • Crosses the blood–brain barrier (poorly)
  • Crosses the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
• Metabolism:
  • Hepatic
  • Oxidative and reductive pathways
  • Active metabolite: 5-hyroxydantrolene
• Excretion: urine and feces

Indications

• Chronic spasticity associated with upper motor neuron disorders
• Malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia
• Neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome

Adverse effects

• CNS depression
• Muscle weakness
• GI discomfort
• Hepatotoxicity
• Respiratory insufficiency
• Photosensitivity
• Phlebitis (at the site of IV administration)

Contraindications and precautions

• Contraindications: active liver disease
• Use with caution: individuals with impaired respiratory function

Drug interactions

Enhanced CNS depression can occur with:

• Alcohol
• Antidepressants
• Barbiturates
• Cannabinoid products
• Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
• Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
• Metoclopramide