Myoglobinuria; Rhabdomyolysis

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MYOGLOBINURIA - RHABDOMYOLYSIS

Myoglobinuria
Malignant hyperthermia
General features
Pathophysiology
Specific causes

Myoglobinuria: Acquired causes
Compartment syndromes
Drugs
Hypokalemia
Idiopathic recurrent
Infections
Ischemia
Mitochondrial
Muscle overactivity
Neuroleptic malignant syndrome
Other: Occasional myoglobinuria
Polymyositis: Anti-MAS syndrome
Serotonin syndrome
Snake venoms
Thyroid: Hyper or Hypo
Toxins
Trauma

Myoglobinuria: Familial causes
Acyl-CoA Dehydrogenase (VLCAD)
Carnitine Palmitoyltransferase II (CPT2)
Central core
Familial Recurrent Rhabdomyolysis
Glycogen metabolism disorders
Hypokalemic periodic paralysis
King-Denborough syndrome
Malignant hyperthermia (MHS) loci
MHS1: Ryanodine Receptor; 19q13
MHS2: Na⁺ channel (SCNA4); 17q11
MHS3: Ca⁺⁺ channel (CACNL2A); 7q21
MHS4: 3q13
MHS5: Ca⁺⁺ channel (CACNA1S); 1q32
MHS6: 5p
CPT2: 1p32
Marinesco-Sjögren
Mitochondrial
Myoadenylate deaminase deficiency
Sickle cell anemia

Other familial causes

MYOGLOBINURIA: General features¹²

Myoglobinuria: General pathology
- Necrosis, especially acute, of muscle fibers (rhabdomyolysis)
- Release of muscle components into circulation
- Most common causes: Drugs & Alcohol
Mechanisms of muscle injury
- Rise in free intracellular calcium: Due to
  - Damage to muscle sarcolemma
  - Failure of energy supply within muscle cell
- Activation of calcium-dependent neutral proteases & phospholipases
  - Destroys myofibrillar, cytoskeletal, and membrane proteins
  - Lysosomal digestion of muscle fiber contents ensues
Typical clinical features
- Muscle
  - Weakness: Proximal > Distal
  - Discomfort: Pain; Tenderness
  - Swelling
  - May be asymptomatic
- Renal: More severe cases
  - Dysfunction
  - Urine: "Tea-colored"
- General
  - Fever
  - Leukocytosis
- More likely hereditary etiology
  - Rhabdomyolysis on minimal exertion or fasting
  - Family history
  - Multiple episodes
Common causes
- Adults: Non-recurrent myoglobinuria
  - Alcohol & Drug abuse
  - Compression of muscle: Acute; Prolonged immobility
  - Seizures
  - Multiple contributing factors
- Children: Non-recurrent myoglobinuria
  - Trauma
  - Nonketotic hyperosmolar coma
  - Viral myositis,
  - Dystonia
  - Malignant hyperthermia
- Recurrent myoglobinuria: Metabolic & Hereditary disorders
  - Most common: Myophosphorylase; CPT II; Idiopathic
Predisposing factors
- Increased age
- Exercise: Progressive exercise produces Fatigue & Myalgia
- Fasting
- Hypokalemia
- High ambient temperatures
- Toxins & Drugs
- Genetic
Time course
- Early: Pigment in urine may occur immediately or with delay up to 24 hours
- Late: Severe rhabdomyolysis may be followed by fibrosis & contractures
Complications
- Compartment syndrome
  - Muscles in closed space swell & become ischemic
  - May require fasciotomy
- Renal failure with acute tubular necrosis: Due to
  - Ferrihemate toxicity: Dissociates from globulin below pH 5.6
  - Tubular obstruction: Precipitation of myoglobin casts
  - Alterations in glomerular filtration rate
  - Myoglobin toxicity: Treatment is Volume expansion
    - Mannitol or Normal saline: Maintain urine output at 200 to 300 ml/hr
  - Hypotension
  - Crystal formation: Alkalinize urine with Na bicarbonate
  - Protease release from muscle: Avoid nephrotoxic agents
- Hyperkalemia
  - Due to: Muscle breakdown; Renal failure
  - Treatment: Calcium gluconate; Diuresis
- Hypocalcemia: Due to binding by damaged muscle & hyperphosphatemia
- Hypercalcemia
  - Due to: Release from muscle; Reduced renal excretion
  - Treatment: Diuresis
- Hyperphosphatemia & Tissue calcification
  - Due to: Release of organic & inorganic phosphates from muscle
  - Treatment: Diuresis
- Disseminated intravascular coagulopathy
Laboratory
- Urine dip stick (benzidine)
  - Positive: Myoglobin; Hemoglobin; Hematuria
  - Negative: Porphyria
- Myoglobin
  - Urine
    - Precedes rise in CK
    - Visible pigmentation with level > 1 g/L
    - Testing: Radioimmunoassay; Use urine fresh & neutralized
    - Urinalysis pattern: Albumin & Heme with Few RBCs
  - Serum
    - Normal levels: 3 to 80 μg/L
    - Rhabdomyolysis: High
- Serum CK
  - Very high: Up to hundreds of thousands
  - Half life: 1 to 3 days
- Serum lactate
  - Glycogenoses: No rise with exercise
  - Mitochondrial disorders: Rise with minimal exercise
- Serum carnitine: Low in β-oxidation disorders, especially during attack
- Muscle biopsy: Required for diagnosis in most hereditary disorders
  - Pathology: Scattered muscle fiber necrosis & degeneration
  - Metabolic analysis: Perform at least 1 month after episode
    - Biopsies performed near time of rhabdomyolysis will give spurious biochemical results
- MRI with gadolinium enhancement: Increased signal; T₂ > T₁
Treatment
- Maintain airway & circulation
- Prevent acute tubular necrosis
  - Normal saline IV: 10 to 15 mL/kg; Continue if adequate urine output
  - Isotonic Sodium bicarbonate
  - Mannitol: 0.3 to .05 g/kg IV; Monitor K⁺
  - Furosemide: 40 to 80 mg IV initially; Up to 200 mg total
- Treat other complications
  - Hyperkalemia
  - Disseminated intravascular coagulation
- Treat specific underlying condition: Diet; Ribose; Riboflavin; Carnitine

MYOGLOBINURIA: Specific causes

Malignant Hyperthermia

Malignant Hyperthermia - Central Core Disease (MHS 1)
l Ryanodine Receptor (RYR1) ; Chromosome 19q13; Dominant
King-Denborough Syndrome
l Autosomal Dominant
Other Malignant Hyperthermia loci
l Chromosome 17q11.2-q24; Dominant (MHS 2)
- Same Sodium channel gene (SCN4A) as in hyperkalemic periodic paralysis
l Chromosome 7q21-q22; Dominant (MHS 3)
- Calcium channel, Skeletal muscle, Voltage-dependent, L-type, α-2 peptide (CACNL2A)
l Chromosome 3q13.1; Dominant (MHS 4)
l Chromosome 1q32; Dominant (MHS5)
- L-type Calcium Channel, α1_S subunit (Dihydropyridine Receptor)
- Same gene as Hypokalemic periodic paralysis
- Different gene location: Arg1086His
  - Mutation in cytoplasmic loop betweeen S3 and S4
  - ? region that interacts with ryanodyne receptor
l Carnitine Palmitoyltransferase II; Chromosome 1p32; Dominant
l Chromosome 5p; Dominant (MHS6)
l Autosomal Dominant
Malignant hyperthermia susceptibility

Glycogen metabolic disorders

Myophosphorylase - McArdle's
l Chromosome 11q13.1; Recessive
- Muscle pain after short intense exercise
- Persistent proximal weakness in teens & 20's
Phosphofructokinase
l PFK-M; Chromosome 1cen-q32; Recessive
- Muscle cramps & Myoglobinuria after vigorous exercise; Second wind
- Late-onset with fixed myopathy in some patients
- Fatal infantile cases reported
Other glycogenoses

Fatty acid oxidation

Carnitine Palmitoyltransferase II
l Chromosome 1p32; Recessive
- Myoglobinuria after moderate sustained exercise
Acyl-CoA Dehydrogenase deficiencies
Electron transfer flavoprotein (ETF) deficiency
Ketoacyl CoA thiolase deficiency
Trifunctional enzyme deficiency

Mitochondrial disorders

Cytochrome c Oxidase (COX) deficiency
- Cytochrome c Oxidase, Subunit I
- Cytochrome c Oxidase, Subunit III
Cytochrome b deficiency (Complex III)
Mitochondrial DNA deletions: Multiple
Point mutations
- tRNA Phenylalanine (A606G)
  - Muscle with many COX negative fibers
- tRNA Leucine (A3243G)
Coenzyme Q₁₀ deficiency
Krebs cycle
- Succinic Dehydrogenase + Aconitase
- Lipoamide dehydrogenase

Familial: Other disorders with occasional myoglobinuria

Hypokalemic periodic paralysis
Duchenne & Becker Dystrophy
Brody myopathy
Familial Recurrent Rhabdomyolysis
Fingerprint body disease
G6PDH deficiency
LGMD 2I
Marinesco-Sjögren
Miyoshi myopathy: Occasional
Myoadenylate deaminase deficiency
Myotonias
Multicore disease
Cylindrical spiral (Myofilamentous) myopathy
Schwartz-Jampel
Sickle cell anemia: Myonecrosis; Sterile abscesses

Drugs & Toxins

Toxins
- Intravenous
  - Cocaine: Ischemia due to vasoconstriction
  - Heroin
- Ingestion
  - Haff disease: Fish ingestion (US - Buffalo fish; Northern Europe - burbot)
  - Mushrooms: Amanita phalloides; Tricholoma equestre (T. flavovirens)
  - Small birds that have previously eaten water hemlock (Conium maculatum)
  - Ethanol
  - Monensin
  - Chromium picolinate
  - Kidney beans
  - Peanut oil
- Venoms
  - Snake
    - Cobra; Coral; Viper; Rattlesnake
    - Toxin action: Muscle membrane damage
  - Insect
    - Hornet
    - Redback spider
    - Wasp
    - African bee
  - Blowpipe dart poison
- Environmental exposure
  - Chlorophenoxy insecticides
  - Pentaborane
  - Toluene: Membrane damage
Medications: Direct effects on muscle
- Amiodarone
- Emetine
- e-Amino Caproic Acid (Amicar)
- Lipid lowering agents
  - Clofibrate
  - Statins
    - Lovastatin; Simvastatin; Pravastatin; Fluvastatin; Atorvastatin; Cervistatin
    - Especially with concurrent: Cyclosporine A, Danazol, Erythromycin, Gemfibrozil, Niacin...
- Isoniazid
- Lamotrigine
- Nicotinic acid
- Pentamidine
- Propofol
- Proton pump inhibitors
- SSRI + Irinotican
- Temazepam (Intra-arterial; Gel form): Rhabdomyolysis due to local limb ischemia
- Valproate: Patients with CPT2 deficiency
- Vasopressin: Ischemia
- Zidovudine
  - Pathology: Ragged red muscle fibers
Drugs & toxins producing muscle overactivity
- Amphetamines
- Hemlock
- Loxapine
- LSD
- Mercuric chloride
- Phencyclidine
  - Pathology: Myofibrillar architectural changes
- Strychnine
- Tetanus
- Terbutaline
- Also see
  - Neuroleptic Malignant Syndrome (NMS)
  - Serotonin syndrome
Hypokalemia

Other drugs & toxins associated with rhabdomyolysis¹⁸

Acetaminophen
Amoxapine
Anticholinergics
Azathioprine
Baclofen
Barbiturates
Benzodiazepines
Butyrophenones
Caffeine
Carbon Monoxide
Chloral hydrate

Chlorpromazine
Corticosteroids (Myosin loss)
Daptomycin
Fenfluramine
Glutethimide
Hydroxyzine
Ketamine
Lysergic acid diethylamide
Methanol
Morphine
Phencyclidine

Phenothiazines
Phenytoin
Proton pump inhibitors
Salicylate
Serotonin antagonists
Succinylcholine
Sympathomimetics
Theophylline
Trimethoprim-sulfamethoxazole
Vasopressin
Vincristine

Hypokalemic myopathy & Rhabdomyolysis

Causes
- Pharmacologic
  - Diuretics & Laxatives: Thiazides
  - Amphotericin (Renal tubular acidosis)
  - Lithium
  - Gossypol
  - Licorice
  - Methylxanthines: Caffeine; Theophylline
  - Laxative abuse
- Toxic
  - Aldosterone-like: Licorice (Glycyrrhizic acid); Carbenoxolone (Glycyrrhetinic acid)
  - Barium
  - Ethanol
  - Cottonseed oil (with low dietary K⁺)
  - Volatile substances: Toluene
- Thyroid hormone
Hypokalemia: Clinical syndromes
- Painless proximal weakness
- Periodic paralysis
- Hypokalemia: Myoglobinuria
Treatment
- Potassium: Up to 20 mEq per hour i.v.
- Removal of underlying cause of hypokalemia

Muscle Trauma

Acute (minutes): Crush
Chronic (hours): Due to sedation
- Alcohol
- Opiates
- Sedatives
Overactivity
- Exercise: Military training; Bodybuilding
- Drugs
- Hyperthermia
Compartment syndromes
Heat stroke: Often with exertion

Ischemia

Vascular occlusion
Hemangioma steal syndrome: Focal exertional rhabdomyolysis²
Sickle cell trait
Cocaine
Calciphylaxis

Infections

Viral: Influenza A & B; Coxsackie; Herpes; Adenovirus; HIV-1
Bacterial: Streptococci; Salmonella; Staphylococci; Typhoid; Legionella; Clostridia; E. coli
Rickettsia: Mediterranian tick typhus
Hyperthermia related

Immune myopathy

Polymyositis: Anti-MAS syndrome
Polymyositis: Occasional
Dermatomyositis: Occasional

Malignant Hyperthermia Syndromes (MHS)¹

General features
Pathophysiology

Hypokalemic periodic paralysis
MHS loci
MHS1: Ryanodine Receptor; 19q13
MHS2: Na⁺ channel (SCNA4); 17q11
MHS3: Ca⁺⁺ channel (CACNL2A); 7q21
MHS4: 3q13
MHS5: Ca⁺⁺ channel (CACNA1S); 1q32
MHS6: 5p
CPT2: 1p32
King-Denborough syndrome
Occasional MH

Malignant hyperthermia: General features
- Inheritance: Commonly autosomal dominant
- Epidemiology
  - Species affected: Humans; Pigs; Turkeys; Cats; Dogs; Horses
  - Frequency with triggering anesthetics: Children 1:15,000; Adults 1:62,000
  - World-wide occurrence: All racial groups
  - Age
    - Most common: Children & Young adults
    - Rare: Infants
    - Reduced frequency: After 50 years of age
  - May have prior exposure to triggering anesthetic without developing MH
  - Most patients asymptomatic before developing MH syndrome
  - High serum CK: Not sensitive or specific as screening test
- Triggers
  - Full episodes: General anaesthesia
    - Inhalational agents (potent); Halothane; Sevoflurane; Desflurane
    - Muscle relaxant: Succinylcholine
    - Not Xenon
  - Milder MH: Exercise in hot conditions; Neuroleptic drugs; Alcohol; Infections
  - Safe agents
    - Barbiturates
    - Epinephrine/Norepinephrine
    - Etomidate
    - Ketamine
    - Local anesthetics
    - Narcotics
    - Nitrous oxide
    - Nondepolarizing muscle relaxants
- Clinical features
  - Onset
    - Time: During anesthetic to 24 hours after
    - Sudden rise in end tidal CO₂ or core temperature
    - Trismus
  - Skeletal muscle
    - Rigidity
    - Weakness
    - Rhabdomyolysis
  - Autonomic: Sympathetic hyperactivity
    - Hyperventilation (Tachypnea)
    - Tachycardia
    - Hemodynamic instability
    - Hyperhidrosis
  - General
    - Fever: May have delayed onset
    - Cyanosis
  - Late features
    - Edema: Muscle; Brain
    - Cardiac arrest
    - Renal failure
    - Disseminated intravascular coagulation
  - Poor prognosis
    - Fulmanent onset
    - Late diagnosis
- Laboratory
  - Hypermetabolism
    - Increased oxygen consumption
    - Rising CO₂
  - Lactic acidosis
- Diagnostic tests
  - Halothane contracture test
    - Muscle exposed to 3% halothane
    - Positive contracture response: > 0.7 grams
    - Requires fresh muscle
  - Caffeine contracture
    - Muscle exposed to increasing caffeine concentrations from 0.5 mM to 32 mM
    - Positive contracture response: > 0.7 grams at caffeine < 2 mM
- Treatment: Dantrolene
  - Initial dose: 2.5 mg/kg
  - Total dose: 10 mg/kg
  - Avoid, if possible: During obstetric labor & delivery
- External link: UCLA
Malignant hyperthermia: Pathophysiology
- General cascade of events
  - Increased cytosolic Ca⁺⁺
  - Muscle hyperactivity & hypermetabolism
  - Rhabdomyolysis & Fever
- Pathophysiology of malignant hyperthermia (Postulated)
  - Increased tendency for calcium release from sarcoplasminc reticulum (SR)
    - Probably produced by defective ryanodine receptor
    - Dantrolene prevents or inhibits this tendency
  - Triggering agent produces rapid abnormal increase in cytoplasmic calcium
  - Muscle ATP is depleted by activity of
    - Muscle contractile apparatus
    - SR calcium reuptake pump
  - Aerobic metabolism increases to replace ATP
    - Heat & CO2 produced as a byproduct
  - Calcium accumulates in mitochondria: Failure of aerobic metabolism
  - Anaerobic metabolism increases
    - Lactic acidosis
- Pathogenic mechanisms & related symptoms
  - Elevated myoplasmic Ca⁺⁺
    - Muscle spasms: Masseter; Generalized
    - Heat production
    - Hypermetabolism
    - Rhabdomyolysis
  - Rhabdomyolysis
    - Muscle pain
    - Myoglobinuria: May cause Renal failure
    - Cardiac arrhythmia
    - Serum: Increased Creatine kinase (CK) & K⁺
  - Hypermetabolism
    - Tachycardia
    - Acidosis
    - ATP depletion
    - Hypoxemia
    - Heat production
- Compensatory mechanisms
  - Heat loss
  - Sympathetic hyperactivity: Increased circulating catecholamines
  - Increased cardiac output
  - Increased ventilation
MHS1: Malignant Hyperthermia - Central Core Disease
l Ryanodine Receptor (RYR1) ; Chromosome 19q13; Dominant
- Genetics
  - Ryanodine receptor mutations
    - ~30 Point mutations identified
    - Patient frequency: RYR mutations found in
      - 50% of MH families
      - 20% of all MH patients
    - Mutation locations: 50% between exons 39 to 46
    - Mutation types
      - Most are missense mutations
      - Deletion of Glu2347: Large evoked contraction tension by electrical stumulus in absence of drugs₅
  - Malignant hyperthermia is allelic with
    - Central core disease
    - Porcine malignant hyperthermia
      - Recessive Arg615Cys mutation (Same as human Arg614Cys)
      - 4% to 9% of human MH also at this locus
  - Correlations of mutations with in vitro contracture test
    - Strong: Caffeine threshold & tension values
    - None: Halothane threshold and tension values
- Clinical features
  - High fever
  - Muscle rigidity: All pigs; 75% of humans
    - Isolated trismus: May be early sign
  - Cardiovascular: Tachycardia; Dysrhythmias; Hypotension
  - Laboratory
    - Increased pCO2
    - High lactate & acidosis: pH may be < 7
    - CK
      - During episode: Very high (up to 100,000)
      - Elevation correlates
        
        Best with rhabdomyolysis
        Less well with fever & acidosis
      - Resting CK: Mild elevation
  - Triggering agents
    - Halothane (volatile anesthetics)
    - Succinylcholine & carbachol (depolarizing agents)
  - Diagnosis
    - Gene testing
    - Caffeine contracture test (only on fresh muscle)
  - Treatment
    - Dantrolene: 2 mg/kg i.v. q 5 minutes to a total of 10 mg/kg
    - Hyperventilation; Sodium bicarbonate; Cooling
    - Discontinue anesthesia
    - Maintain urine output: 2 ml/kg/hr
    - Avoid calcium, Calcium antagonists, beta blockers
- External link: Gasnet
Other Malignant Hyperthermia loci
- General
  - MHS2
    l Chromosome 17q11.2-q24; Dominant
    - Same Sodium channel gene (SCN4A) as in hyperkalemic periodic paralysis
  - MHS3
    l Chromosome 7q21-q22; Dominant
    - Calcium channel, Skeletal muscle, Voltage-dependent, L-type, α-2 peptide (CACNL2A)
  - MHS4
    l Chromosome 3q13.1; Dominant
  - MHS5
    l Chromosome 1q32; Dominant
    - L-type Calcium Channel, α1 subunit (Dihydropyridine Receptor)
    - Same gene as Hypokalemic periodic paralysis
    - Different gene location: Arg1086His
      - Mutation in cytoplasmic loop betweeen S3 and S4
      - ? Region that interacts with ryanodyne receptor
  - MHS6
    l Chromosome 5p; Dominant
  - MHS Other
    l Autosomal Dominant
- King-Denborough Syndrome
  l Autosomal Dominant
- Other: Occasional familial MH

King-Denborough Syndrome

l Autosomal Dominant, or Sporadic

From: A Connolly MD

Nosology (Other name): King syndrome¹⁰
Epidemiology
- Male preponderance (4:1)
Clinical
- Age of ascertainment: 2 to 14 years
- Malignant hyperthermia (94%)
  - Triggered by heat or anesthesia
- Weakness (90%)
  - Proximal
  - Symmetric
  - Mild
  - Delayed motor development
  - Scapular winging
  - Myopathy often not present in other family members
- Tendon reflexes: Often reduced
- Skeletal abnormalities: Noonan syndrome-like
  - Short stature (90%): < 5th percentile
  - Chest: Pectus carinatum/excavatum
  - Spinal curvature
    - Onset: 1st decade
    - Kyphosis, Scoliosis or Lumbar Lordosis
  - Dislocating shoulders
  - Vertebral fusion
  - Pes cavus
  - Contractures
- Faces
  - Dysmorphic: Malar hypoplasia
  - Low-set ears
  - Micrognathia
  - Eyes: Ptosis; Strabismus
- Cryptorchidism
- Intelligence: Usually normal (80%)
- Not present: Congenital heart disease
Laboratory
- Serum CK: High (63%) or High normal at rest
- EMG: Myopathic
- Muscle: Non-specific
  - Myopathic, mild
  - Some with few Type 2A muscle fibers
Differential diagnosis
- MHS 1
- Other malignant hyperthermia

Ethanol-Induced Myopathies

Myopathy syndromes
- ? Association with malnutrition
- Acute necrotizing myopathy
  - History of
    - Chronic alcohol intake; Binge drinking
    - Prior pain & swelling of muscles
  - Predominantly males
  - Onset: Heavy alcohol intake; Acute withdrawal; Seizure
  - Clinical
    - Myalgias
    - Cramps
    - Weakness
      - Proximal
      - May be localized to quadriceps or gastrocnemius
    - Duration: 1/2 to 6 months
  - Laboratory
    - Associated metabolic disorders: Low K⁺; Low PO₄
    - Serum CK: High
    - Urine: Myoglobinuria
  - Pathology: Scattered necrotic muscle fibers
- Hypokalemia: Painless acute weakness
- ? Chronic myopathy
  - Muscle wasting
  - Proximal weakness
  - Muscle pathology: Type II atrophy; Moth-eaten muscle fibers
- ± Associated cardiomyopathy
  - Cobalt intoxication in beer drinkers
  - Beriberi heart disease
  - Chronic alcoholic
    - Males < 50 years
    - Long history of alcohol intake
    - Congestive heart failure
    - Prognosis: 40% mortality over 3 years%
- Anti-MAS antibody associated myositis
Pathology
- Muscle fiber necrosis & regeneration: Segmental
- Tubular aggregates
- Separation of myofibrils
Also see: Alcoholic neuropathy

Monensin-Induced Rhabdomyolysis¹¹

Drug Properties
- Sodium-selective carboxylic ionophore antibiotic
- Facilitates the transmembrane exchange of sodium for other protons
- Sodium: Increased intracellular concentration.
- Used by
  - Poultry and pig producers: Anticoccidial action
  - Cattlemen: Changes rumen microbial population, increasing feed efficiency
Toxicity
- Overdose
  - Human: 500 mg
  - Animals: 2 to 25 mg/kg
- Epidemiology
  - Common in animals
  - Human: 1 case reported
- Clinical Syndrome
  - Onset: 6 hours; Nausea
  - Myalgias
  - Weakness
  - Myoglobinuria
  - Renal failure
  - Cardiac failure
- Laboratory
  - Serum CK: Very high
  - Pathology
    - Skeletal & cardiac muscle fiber necrosis
    - Swelling of mitochondria & Sarcoplasmic reticulum
  - Lactate production: Increased
  - Hyperkalemia: Late

Coenzyme Q₁₀ Deficiency ²³

General: Coenzyme Q₁₀ (Ubiquinone 50)¹³
- Highest levels in heart, Kidney & liver
- Cellular: Located in many organelles in addition to mitochondria
- Distributes electrons between dehydrogenases and cytochrome segments of respiratory chain
- Large excess compared to other components of respiratory chain
  - Kinetically compartmentalized pool: Redox status regulates activity of dehydrogenases
  - Allows protons to be extruded from the matrix to the intermembrane space
- Can act as pro- or anti-oxidant
- 9 genes required for synthesis
- Coenzyme Q₁₀ deficiency disorders
  - Inheritance: Usually recessive or sporadic
  - Clinical syndromes
    - Infantile & Childhood
      - Encephalopathy: COQ2; PDSS2
      - Encephaloneuropathy + Multisystem disorder: PDSS1
    - Ataxia
      - Ataxia: Aprataxin
      - Ataxia + CoQ₁₀ deficiency
      - Ataxia + Hypogonadism
      - Ataxia: CABC1
    - Myopathy
      - Myopathy, Myoglobinuria & CNS
      - Myopathy: ETFDH
      - Statin toxicity
Myopathy, Myoglobinuria + CNS disorder
- Onset: Childhood
- Clinical features
  - Exertional fatigue
  - Myoglobinuria
    - Recurrent
    - Preciptiated by fever, convulsions, mild to moderate exercise
  - Weakness
    - Proximal
    - May occur without other systemic features
  - CNS: Seizures; Cognitive impairment
- Muscle pathology
  - Ragged red fibers
  - Prominent lipid accumulation
  - Coenzyme Q₁₀ levels < 50% of normal
- Treatment: Coenzyme Q₁₀ 150 to 200 mg qd
Myopathy²²
l Electron transfer flavoprotein dehydrogenase (ETFDH) ; Chromosome 4q32-qter; Recessive
- Genetics
  - Mutations: Missense
  - Allelic with: Glutaricaciduria, Type II (MADD)
- Clinical: Isolated myopathy
  - Onset: Childhood to 4th decade
  - Weakness
    - Limbs: Proximal; Legs & Arms
    - Trunk & Anterior neck
    - Symmetric
  - Other muscle symptoms
    - Fatigue
    - Cramps
    - Myalgia
  - Tendon reflexes: Reduced
  - Course
    - Sub-acute exacerbations: May occur in Childhood or Pregnancy
    - Long term: Slowly progressive
  - Other systemic
    - Usually normal
    - Occasional: Elevated liver enzymes
- Laboratory
  - Serum CK
    - High: 1000 to 5000
    - May return to normal after treatment
  - EMG: Myopathic
  - Muscle pathology
    - Muscle fibers with mitochondrial proliferation: SDH+
    - Lipid: Increased
    - Respiratory chain
      - Complexes I & II + III: Severely reduced
      - Complex IV (COX): Moderately decreased
      - Citrate synthase: High
    - Coenzyme Q₁₀ levels: Reduced
    - Tandem mass spectrometry: Multiple acyl-CoA deficiency
- Treatment
  - Coenzyme Q₁₀ 150 to 500 mg per day
  - Riboflavin: 100 mg/day
Coenzyme Q₁₀ deficiency syndrome: Infantile-childhood encephalopathy & Nephrotic syndrome
l COQ2 ; Chromosome 4q21-q22; Recessive
- COQ2 Mutation
  - Homozygous missense: Tyr279Cys
  - Causes defect in CoQ₁₀ synthesis: Blocks ubiquinone synthesis
- COQ2 protein
- Onset
  - Age: 1st year
  - Nystagmus
  - Nephrotic syndrome
- Clinical: Neurological
  - Hypotonia
  - Weakness
  - Psychomotor delay & regression
  - Seizures
  - Tremor
  - Severe: If untreated, rapidly fatal
- Clinical: Other
  - Nephrotic syndrome: Corticosteroid-resistant
- Laboratory
  - Serum CK: Normal
  - Serum & CSF lactate: Normal or High
  - Muscle pathology
    - SDH: Mild mitochondrial proliferation
    - Complex I + III & II + III deficient
    - Complex II + III deficiency repaired by decylubiquinone
  - Hyperglycemia
- Treatment
  - Coenzyme Q₁₀ (30 mg/kg per day po)
  - Improved CNS but not renal function
Coenzyme Q₁₀ deficiency syndrome: Infantile encephalomyopathy & Nephrotic syndrome ²⁰
l PDSS2 ; Chromosome 6q21; Recessive
- Genetics: PDSS2 gene
- Onset
  - Age: Infancy
  - Hypotonia
  - Pneumonia
- Clinical
  - Hypotonia
  - Poor feeding
  - Episodic vomiting
  - Seizures: Focal with secondary generalization
  - Cortical blindness
  - CoQ₁₀ treatment: No benefit
- Laboratory
  - Nephrotic syndrome
  - Serum lactate: High
  - Muscle
    - Increased subsarcolemmal mitochondria
    - No COX- muscle fibers
    - Complex I activity mildly reduced: Others normal
    - Complex II + III activity: Reduced; Increased by decylubiquinone
    - CoQ₁₀ reduced
Coenzyme Q₁₀ deficiency syndrome: Encephaloneuropathy & Multisystem disorder ²¹
l PDSS1 ; Chromosome 10p12.1; Recessive
- Epidemiology: Single family
- Genetics
  - Mutation: Homozygous D308E
- Clinical
  - Deafness: Onset 1-2 years
  - Encephalopathy: Mental retardation, Mild
  - Optic atrophy
  - Polyneuropathy: Tendon reflexes absent
  - Obesity & Bulemia
  - Livedo reticularis
  - Valvulopathy: Aortic and mitral regurgitation
  - Macrocephaly
- Laboratory
  - Plasma lactate: Mildly high
  - Muscle biopsy: Mitochondrial aggregates
Coenzyme Q₁₀ deficiency syndrome: Childhood-onset cerebellar ataxia
- See: Aprataxin mutation (AOA1)
- Clinical
  - Ataxia
  - Seizures
  - Muscle weakness
  - Mental retardation
  - Pyramidal tract signs
  - Peripheral neuropathy
Also see
- Ataxia, recessive
- Mitochondrial disorders
- AOA1: Secondary CoQ₁₀ deficiency

Familial Recurrent Rhabdomyolysis

l Autosomal Recessive

Clinical features
- Attacks:
  - Often not related to exercise
  - Triggered by upper respiratory infections
- Onset in young children < 5 years

l ? Autosomal Dominant

Also see: Idiopathic recurrent myoglobinuria

Neuroleptic Malignant Syndrome (NMS)

Drugs
- Butyrophenones; Lithium; Phenothiazines; Pimozide; Promethazine; Thioxanthines
- Dopamine agonist withdrawal
Pathophysiology
- Probably caused by heat generated by muscle rigidity & tremor
- Heat production amplified by sarcolemmal depolarization & muscle contraction
Onset
- Days to weeks after initiation of drug
- Encephalopathy
Clinical
- Muscle
  - Rigidity
  - Rhabdomyolysis
- CNS: Extrapyramidal signs; Altered consciousness; Seizures
- Other neural: Dysarthria & Dysphagia; Oculogyric crises
- Systemic: Autonomic instability
  - Hyperthermia: > 38°C
  - Cardiac: Blood pressure lability; Tachycardia
  - Incontinence
  - Tachypnea
  - Hyperhidrosis
- Disease course: Resolution in
  - 2 weeks withshort acting drugs
  - 4 weeks with depo drugs
Associations
- Often not familial
- Age: Any age; Most often young adults
- Precipitating factors
  - Psychoactive drugs
    - Within 1 week for short-acting & 4 weeks for long-acting
    - Lithium; Haloperidol; Phenothiazines; or especially combinations
    - High doses of neuroleptics
  - Cytochrome P4502D mutation (Allele CYP2D6J)
    - Homozygous
    - Poor hepatic metabolism of drugs associated with NMS
  - General: Dehydration; Exhaustion; Organic brain damage
Lab
- Serum CK
  - Transient increase in 2/3
  - Levels: Usually 2,000 to 15,000
- Leukocytosis
- Hyponatremia: Some patients
- CSF: Normal
Treatment
- Medication: Bromocriptine; Dantrolene; Amantadine
- Cooling to < 38°C
- Supportive care: Hydration; Reduce fever
- Discontinue predispoasing drugs

Serotonin syndrome

Precipitating factors
- Serotonergic agents: SSRIs (Prozac, Zoloft, Paxil, Luvox, Irinotican), Wellbutrin (Bupropion), Tryptophan
- Tricyclic antidepressants
- Often with MAO inhibitors
- Other: Amphetamines; Ecstasy; Nefazodone; Venlafaxine
Onset: Minutes to hours after increasing dosage of serotonergic agent
Clinical
- Fever
- CNS: Altered mental status; Hypomania; Seizures
- Autonomic dysfunction: Hyperhidrosis; Blood pressure lability; Tachycardia; Mydriasis; Flushing
- Movement disorders: Myoclonus; Shivering; Tremor; Rigidity
- Muscle: Rhabdomyolysis
- Hyperreflexia
- GI: Diarrhea
- Respiratory: Tachypnea; Respiratory failure
Lab
- Serum CK: May be high but lower than neuroleptic malignant syndrome
- Leukocytosis
Treatment
- Medications: Cyproheptadine; Mehtysergide
- Stop offending agent

Haff disease*

Fish ingestion
- US
  - Buffalo fish (Ictiobus cyprinellus)
  - Fish from Mississippi river
- Northern Europe (Baltic, Russia & Scandinavia): Burbot
Rhabdomyolysis: Onset 6 to 24 hours after ingestion
Toxin: Unknown; Heat resistant

Mushroom intoxication

Amanita phalloides⁸
- Clinical features
  - Hepatic failure
  - Encephalopathy
  - Myopathy
- External link
Tricholoma equestre⁷
- Onset
  - After ingestion at several consecutive meals
  - Myalgias & Fatigue: 1 to 3 days after ingestion
- Clinical features
  - Rhabdomyolysis: 1 week after ingestion
  - Other signs
    - Nausea
    - Facial erythema
    - Profuse sweating
  - Course
    - Early: Progressive myalgias
    - Late: Resolution over ~ 2 weeks
- Laboratory
  - EMG: Complex & Myotonic activity; No fibrillations
  - Serum CK: Very high
  - Hyperthermia
  - Muscle biopsy: "Nibbled" myofibrils; Edema
- External link

Pentaborane

Uses: Rocket fuels; Semiconductors; Catalysts
Exposure: Inhalation; Ingestion; Skin
Clinical: High dose
- Cardiac: Depression; Hypotension; Bradycardia
- Metabolic acidosis
- Muscle: Rhabdomyolysis; High CK; Myoglobinuria
- Neurologic: Encephalopathy
Laboratory
- EEG: Slowing; Seizures
- CT: Cerebral edema followed by brain atrophy
Treatment: ? Catecholamines; Pyridoxine
Prognosis: High mortality; Residual cognitive defects

e-Amino Caproic Acid (Amicar)

Use: Inhibits fibrinolysis
Onset of myopathy
- Up to several weeks afer treatment with high dose (30 g/day)
- Tenderness & weakness in proximal muscles
Clinical syndrome
- Necrotizing myopathy: Weakness & Muscle tenderness
- Rhabdomyolysis
Symptoms improve after discontinuation of treatment
Mechanisms of disease
- ? Production of carnitine deficiency: Competes with lysine for carnitine synthesis
- Ischemia

Lipid lowering agent myopathies⁴

Fibrates
General syndromes
Myotoxins
Statins

General clinical syndromes
- Frequency of myopathy: 1 to 6 in 10,000
- Risk factors
  - Female gender
  - Increased age
  - Exercise
  - Diseases: Renal; Liver; Diabetes; Hypothyroidism; Debilitated status
  - Surgery or Trauma
  - Excessive alcohol intake
  - ? Mitochondrial disease¹⁷
  - Concurrent medications & dietary factors
  - Statin drug property
    - Lipophilicity
    - Higher drug dose
    - Low serum protein binding
  - CoQ2 gene polymorphisms
- Onset
  - Usual: 2 to 3 months after starting lipid-lowering drug
  - Range: 2 days to 2 years
  - Myalgias
  - ? Serum CK elevation before symptoms
- Clinical features
  - Myalgias
    - Type of discomfort: Pain; Cramp sensation; Muscle tenderness
    - Pain: Present at rest; Increased with exercise
    - May occur with normal CK
    - Progress to myoglobinuria unless drug stopped
  - Weakness
  - Myoglobinuria
  - Recovery: Days to months after stopping drug
- Laboratory
  - Serum CK
    - Myopathy: High; < 1% of patients taking statins
    - Myalgias: May be normal
  - Pathology: Scattered necrotic muscle fibers
Fibric acid derivatives (Fibrates)
- Specific drugs: Clofibrate; Bezafibrate; Ciprofibrate; Clofibrate; Gemfibrozil
- Primary metabolism: Renal
- Epidemiology
  - Frequency: 6 cases per 10,000 patients
  - Relative risk of myopathy in fibrate users vs controls: 42x⁶
- Increased risk
  - Renal failure
  - Nephrotic syndrome
  - Drugs: Probenecid; Furosemide; Statins
- Onset: After 2 to 3 months of treatment
- ± Associated cardiomyopathy
- Biochemistry
  - Reduced Fatty acid & Branched chain amino acid oxidation
  - Reduced Carnitine palmitoyl transferase activity

HMG-CoA Reductase Inhibitors (Statins)⁹

Drugs: All statins associated with myopathic disorders
- Lovastatin; Simvastatin; Pravastatin; Fluvastatin; Atorvastatin; Cervistatin
- Relative risks: Increased incidence of myopathy when
  - Compared to controls ⁶: 8x
  - Higher statin doses used
  - Statins are given with drugs that inhibit metabolism in liver
    - Gemfibrozil, Niacin, Cyclosporine; Azoles; Diltiazem; Erythromycin; Colchicine
  - Organ failure: Hepatobiliary dysfunction; Renal failure
  - Cytochrome P450 polymorphisms with reduced activity: Except pravastatin & rosuvastatin
  - Hypothyroidism
Toxins: Red yeast rice (Monascus purpureus)¹⁶
- Contains monacolin K (identical to lovostatin)
- High CK (asymptomatic) developed in transplant patient also taking cyclosporine

Pharmacology

General features
- Primary metabolism: Hepatic
- HMG-CoA Reductase enzyme
  - Catalyzes formation of Mevalonic acid from HMG-CoA
  - Rate limiting step in cholesterol synthesis
  - Also plays role in synthesis of Ubiquinone & Isoprenylated proteins
- Statin toxicity
  - Direct effects on muscle metabolism
  - ? Association with coenzyme Q10 deficiency ¹⁵
  - Increased likelihood of effects: Inhibition of statin metabolism by interactions with other drugs
Statin Interactions
- Statin myopathy syndromes more common with associated interacting medications
- Mechanism of interaction: Often related to inhibition of statin metabolism
  - Most statins lipid soluble
    - Degradation: Hepatic & enteric systems
      - Most statins: Degradative enzyme is CYP3A4
      - Fluvastatin: Degradative enzyme is CYP2C9; Fewer drug interactions
    - Common drug interaction mechanism: Inhibit degradation of most statins by inhibition of CYP3A4
  - Exception: Pravastatin
    - Water soluble
    - Renal excretion
    - Fewer reports of interactions with Cyclosporin A

Statins: Metabolic interactions with other drugs

Metabolic enzyme
(Catabolic)

Statins

Drugs inducing
enzyme

Drugs inhibiting
enzyme

CYP3A4

Atorvastatin
Lovastatin
Simvastatin
Cerivastatin

Phenytoin
Barbiturates
Carbamazepine
Rifampin
Dexamethasone
Cyclophosphamide
Troglitazone
St John's wort

Antifungal
Ketoconazole
Itraconazole
Fluconazole
Antibiotic
Erythromycin
Clarithromycin
Azithromycin
Fusidic acid
Tricyclic antidepressants
Calcium channel blockers
Diltiazem
Verapamil
Mibefradil

Other
Amiodarone
Bezafibrate
Chlorzoxazone
Cholestyramine
Colchicine
Corticosteroids
Cyclosporin A
Danazol
Dicumarol
Digoxin
Fluoxetine
Fluvoxamine
Gemfibrozil
Grapefruit juice
Midazolam
Nefazodone
Niacin
Protease inhibitors
Sertraline
Tacrolimus
Tamoxifen
Venlaflaxine

CYP2C9

Fluvastatin
Rosuvastatin

Rifampin
Phenobarbital
Phenytoin
Troglitazone

Ketoconazole
Fluconazole
Sulfaphenazole
Warfarin

Statins: Drug interactions associated with rhabdomyolysis
	Fibrates	Warfarin	Digoxin	Macrolide antibiotics	Niacin	Antifungals	Cyclosporin
Atorvastatin	+	+	+	+		+	+
Cerivastatin	+	+	+	+			+
Fluvastatin	+	+	+
Lovastatin	+	+	+	+	+	+	+
Pravastatin	+	+	+	+	+		+
Simvastatin	+	+	+	+	+	+	+

Possible direct mechanisms underlying myopathy production by statins
- Mevalonic acid & farnesol formation: Inhibition in skeletal muscle
  - Causes reduced levels of cholesterol precursors
  - End result: Altered cell membrane permeability
- Mitochondrial
  - Reduced levels of ubiquinone: Might cause disturbances in cell energy production
  - Reduced synthesis of Coenzyme Q10: Association with lactic acidosis¹⁴
Inhibition of isoprenoid synthesis

Clinical myopathy syndromes
- Frequency of myopathic side effects
  - Overall frequency
    - 10% to 15%
    - Dose dependent
  - Myalgias
    - Frequency: 6% to 14%
    - Type of discomfort: Pain; Cramp sensation; Muscle tenderness
    - Pain: Present at rest; Increased with exercise
    - Present while taking drug & possible for several months after drug discontinuation
  - Myopathy: Frequency
    - Overall: ~1 in 10,000 patients; 0.02% to 2%
    - Monotherapy: 0.1% to 0.5%
    - ? Less common with Fluvastatin, Atorvastatin & Cervistatin
  - Rhabdomyolysis: 0.5%
- Myalgia
  - Most common syndrome
  - Distribution: Proximal or Diffuse
  - May occur with normal CK
- Myopathy
  - Weakness: Proximal > Distal, Symmetric
  - Often preceeds rhabdomyolysis
  - Rarely persists after discontinuation of drug
  - Early ultrastructural changes in lovastatin myopathy: Mitochondria & SR membranes
  - Fast twitch muscles more sensitive to lovastatin myopathy
- Rhabdomyolysis
  - Onset during drug administration: 3 Weeks to Months
  - Associated with weakness: Proximal > Distal
  - Serum CK
    - Very high
    - Rapid fall after drug discontinuation
    - Monitoring may not predict rhabdomyolysis
- Exercise intolerance
  - Frequency: Many athletes
  - May increase exercise induced muscle damage
- Increased CK: Statins
  - May increase resting CK by 50%
  - Exaggerate exercise-induced CK elevations (~1.9x)
- Other features
  - Arthralgias
  - Peripheral neuropathy
Serum CK
- CK level higher in more severe disorders
- Statins may predispose to high CK after exercise
Treatment
- Stop drug in all patients with weakness
- ? Coenzyme Q10 60 mg bid x 2 months
- Treat for rhabdomyolysis
- Monitor serum CK until normalized

Cocaine³

Source: Leaves of coca tree, Erythroxylon coca
Toxic exposure: IV; Nasal; Oral
Clinical syndromes
- CNS
- Myopathy
- Systemic
  - Renal failure
  - Cardiac: Infarction; Dysrhythmias
  - Pulmonary edema
  - Effects on fetus: Crosses placenta

Propofol

Use
- General anesthetic
- CNS sedative: Interacts with gamma amino butyric acid aminotransferase receptors
Rhabdomyolysis
- Skeletal ± Cardiac muscle
- In children & adults
- Onset
  - After prolonged infusion: 24 to 48 hours
- Prognosis: High mortality
Produces: Metabolic acidosis; Hypoxia

Proton pump inhibitors (PPI)¹⁹

Drugs: Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole, Rabeprazole,
Use: GI ulcer, reflux & hypersecretory disorders
Usual onset of toxicity: 1 to 10 weeks after drug use onset
Clinical myopathy syndromes
- Myalgias: 3% to 10%
- Rhabdomyolysis
- Myopathy
  - Weakness
  - Serum CK: High
  - Muscle: ? Inflammation
  - Course
    - Usually improves to normal after drug withdrawal
    - May recur with reinstitution of PPIs
- Dermatomyositis: Rash + Weakness + High serum CK
- High CK without symptoms
- Drug interactions
  - Statin
  - Clarithromycin
  - Methotrexate: Myalgias
Hyperhidrosis: Omeprazole, not other PPIs
- Intermittent: Episodes persist for minutes to hours
- Diffuse
- No clear precipitating factors
- Few other autonomic symptoms or signs

Exertional Heat Stroke

Epidemiology
- Rare in women
- More common with type II muscle fiber predominance
Clinical syndrome
- Fever
- Encephalopathy: Delerium; Seizures; Coma
- Muscle: Rhabdomyolysis; Weakness
- Anhidrosis: Some patients
- Systemic: Hypotension; Multi-organ failure
Laboratory
- Lactic acidosis
- Hypoglycemia
- Disseminated intravascular coagulation
- Potassium: Variable; Hypokalemia promotes rhabdomyolysis
- Serum CK: Very high

Idiopathic Recurrent Myoglobinuria

Overall: Probably caused by multiple disorders
Genetics: May be Sporadic, Recesssive or Dominant
Onset triggers
- Exertion
  - More common
  - Male > Female
- Infection
  - Earlier onset
  - Male = Female
  - More frequent renal failure: Some with lipid myopathies
Laboratory
- Serum CK: High during attacks
- Muscle biopsy: Non-specific changes; Mildly abnormal to Myopathic

Compartment Syndromes

Definition & Features

Tissue damage: Pathogenesis
- Tissue pressure becomes greater than perfusion pressure (capillary)
- Location: Closed anatomic space
- Effects: Ischemia; Necrosis after 6 hours
Tissue damage: Clinical effects
- Functional impairment
  - Intracompartmental structures: Nerve; Muscle
  - Weakness
- Rhabdomyolysis: Renal failure
- Pain
  - Early: Out of proportion to examination
  - Induced by passive limb movement: Muscle stretch
  - Neural compression: Burning; Paresthesias
  - Tightness
- Swelling

General associations

Fracture: 69%; Long bones
Males: Up to 90%
Age: Mean < 35 years; Older in females
Hypotension
Bleeding disorder

Precipitating factors & Localization

Fractures
- Tibial shaft (diaphysis): Distal leg
  - Most common syndrome
  - 6% of tibial shaft fractures
  - Precipitants: Sports & traffic accidents
  - Compartment involved: Anterior most common; All may be involved
  - Nerve involved: Superficial peroneal
- Distal radius: Forearm
  - Frequency with radial fracture: 1%; More in younger patients
  - Associated with high-energy injury
Soft tissue injury
- Types
  - Trauma: High velocity; Stretch; Vigorous exercise; Crush
  - Envenomation
- Regions: Proximal arm or leg; Abdomen; Other
Vascular damage
- Penetrating injury
- Intra-arterial injection
Reduced compartment size
- Compression: Tight clothing; Casts
- Burns

Laboratory

Compartment pressure measurement: High
Serum CK: High
MRI: Increased T2 signal in muscle compartment

Treatment

Syndrome recognition: Within 6 hours
Fasciotomy
Manage rhabdomyolysis


Compartment syndrome: Deltoid muscle (MRI)

BIOLOGIC TOXINS: SNAKE & OTHER

Acetylcholine receptor (AChR) binding
Myotoxic
Phospholipase A₂ proteins

Myotoxic peptides

Crotalus: Crotamine ; Peptide c ; Toxin III; CAM-toxin
43 to 45 amino acid peptides cross-linked by 3 disulfide bridges
No enzyme activity
Mechanisms
- Interact with Na⁺ channels in sarcolemma & T-tubules
- Increase Na⁺ flux into muscle
- ? also disrupt membrane structure
Biologic activities on muscle after i.m. injection
1. Contracture for 1 to 3 hours
2. Vacuolation: Dilation of sarcoplasmic reticulum
3. Necrosis

Myotoxic phospholipase A₂ proteins: 2 groups

LD₅₀ > 1 mg/kg
- Myotoxic; Produce myoglobinuria
- Toxins: Pseudechis ; Bothrops ; Agkistrodon
- Biologic activities on muscle after i.m. injection
  - Lysis of muscle fiber membrane: Focal "delta" lesions
    - Basal lamina & satellite cells remain intact
    - May show selectivity for species & slow (oxidative) muscles
    - ? Hydrolytic activity of phospholipases A₂ necessary
  - Rapid necrosis: 1 to 3 hours
  - Phagocytosis: 1 to 2 days
  - Regeneration: 3 to 4 weeks
LD₅₀ < 1 mg/kg
- Act on presynaptic nerve terminal & myotoxic
  - Notexin ; Crotoxin ; Taipoxin ; Mojave toxin ; Ceruleotoxin; Micrurus corallinus
- β-bungarotoxin : Selective for presynaptic nerve terminal; Not myotoxic
  - Toxin type: Polypeptide; Homologies with proteinase inhibitors
  - Binds to K⁺ channels by B-chain
  - Internalized
  - Effects: Triphasic via internalized A-chain (phospholipase A₂ )
    - Inhibition of ACh release: Transient
    - Facilitation of ACh release: Transient
    - Necrosis of presynaptic axon: Permanent block of ACh release

Acetylcholine receptor (AChR) binding compounds: Toxins & Venom polypeptides

Block active site of AChRs
No morphologic damage to muscle or nerve
Different avidities & binding properties
Skeletal muscle types
- Target: Nicotinic AChRs containing
  - α 1-subunit: Amino acids 173-204; Skeletal muscle
  - α 7-subunit: Neuronal nicotinic
- Permanent AChR blockade
  - α-bungarotoxin
    - Snake: Bungarus multicinctus
    - Toxin: Polypeptide; 61-62 amino acids
    - Effect: Blocks ACh binding site on AChR
    - Also binds to neuronal membranes but no ACh blockade
  - Lophotoxin
    - Lactone from Pacific gorgonian sea coral Lophogorgia
    - Covalently binds to AChRs
    - No toxicity in humans documented
- Reversible AChR blockade
  - α-cobra toxin
    - Snake: Cobra; Naja naja
    - Toxin: Polypeptide; 71-74 amino acids
    - Effect: Blocks ACh binding site on AChR
      
      From Aquaviva
      Epipedobates tricolor
      
      Epibatidine
  - Erabutoxin
    - Snake: Sea snake; Laticauda semifasciata
    - Binds to NMJs & neuronal AChRs containing α7-subunit
    - Clinical: Weakness of EOM, Facial & Bulbar; Generalized ± Respiratory
  - Micrurus species: frontalis, lemniscatus, nigrocinctus
    - Weakness may be treated with anti-cholinesterase drugs
Neuronal types: Nicotinic AChR binding
- κ-bungarotoxin & κ flavotoxin
  - Toxin: Polypeptide; 66 amino acids
  - Snake: Bungarus multicinctus
  - Bind to AChRs containing alpha 3-subunit (especially α3-β2)
  - Effect: Blocks ACh binding site on neuronal AChRs
- Epibatidine
  - Skin of equadoran frog: Epipedobates tricolor
  - Toxin: Alkaloid; Molecular weight 210
  - Binds to α3 subunit of neuronal AChR: Cholinergic agonist
  - Anti-nociceptive effects
- ABT-594

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3/15/2008