This document summarizes key events in neuromuscular transmission and discusses different types of neuromuscular blocking drugs used in surgery. It describes how non-depolarizing drugs like tubocurarine work competitively at nicotinic receptors to block acetylcholine, while depolarizing drugs like succinylcholine mimic acetylcholine's action. The document also discusses cholinesterase inhibitors and their use in treating myasthenia gravis by inhibiting breakdown of acetylcholine in the neuromuscular junction.

1. Miastenia Gravis actualización Dr. Juan Lozano

2. Thomas Willis (1621-1675), English physician, published a book, De anima brutorum (1) in 1672 in which he wrote about "a woman who temporarily lost her power of speech and became 'mute as a fish. '"(1) This has been interpreted as being the first written description of myasthenia gravis. Thomas Willis was born in Great Bedwin, a Wiltshire village in England. He graduated from Oxford University Legion with a Bachelor of Medicine in 1646. In 1660 he was appointed Sedleian Professor of Natural Philosophy at Oxford and given the M.D.(2)

3. Her first patient, 'Mrs. M.', had had intermittent weakness for 14 years and had been admitted to St. Alfege's Hospital about 2 months prior to the treatment given by Dr. Walker because of an exacerbation. Mrs. M's muscle power was restored about 30 mins after the hypodermic injection of physostigmine sulphate (gr. 1/60) --- the effect lasted up to 4 hours. The case was written up in the Lancet 2nd June 1934, pp. 1200-1 and was also reported in the local newspaper The Kentish Mercury on 15th March 1935. Dra. Mary Walker

4. Paciente de la Dra Walker 'Mrs. M.' before (left image) and after (right image) injection of physostigmine. Before - patient cannot raise left eyelid. After - eye is fully open. These photos were reproduced from a cine film and appeared in reverse (right for left) in The Lancet 1934 (i) 1200-1. They are reproduced here with correct orientation.

5. GENTE FAMOSA CON MG David Niven Aristotle Onassis Sir Lawrence Olivier Phil Silvers (actor - Sgt. Bilko) "Sleepy" (© Disney) of Snow White and the Seven Dwarfs was supposedly based on a friend of Walt Disney who had MG

7. Julie Long artista Jerry lewis

8. Epidemiología Incidencia: 10 x millón x año Prevalencia: 14 x 100,000 habitantes Se estima que en los Estados Unidos hay 70,000 personas con Miastenia Gravis.

9. Miastenia Gravis En la persona joven predomina en la mujer En la persona anciana predomina en el hombre.

10. Miastenia Gravis Es universal. No es Hereditaria. No es contagiosa. No tiene preferencias estacionales. Afecta todas las edades.

11. Unión neuromuscular

12. Edad de inicio 2a. y 3a. década en la mujer. 7a. y 8a. década en el hombre Los hombres son mas afectados que las mujeres.

13. Miastenia Gravis Datos Clínicos Debilidad. B) Fatigabilidad.

14. Miastenia Gravis La debilidad es el síntoma cardinal de la Miastenia Gravis

16. Síntomas Iniciales Ptosis o diplopía en 2/3 de los pacientes Dificultad para la masticación, deglución o para hablar en 1/6 de los pacientes. En un 10% hay debilidad localizada

17. Miastenia Gravis La Pupila nunca se afecta en la Miastenia Gravis.

22. DEBILIDAD FATIGABLE

24. Crisis Miasténica La crisis ocurre cuando un paciente experimenta debilidad muscular que compromete la función respiratoria Puede ser miasténica o colinérgica Es una urgencia neurológica

26. Procedimientos Diagnósticos Prueba del Tensilón Es positiva en mas del 90% de los pacientes Puede ser positiva en otras enfermedades Precaución. Paciente hospitalizado. Prueba de Neostigmina

28. Prueba de Tensilón Paciente hospitalizado Canalizado.examen completo. Sv. Atropina Equipo de paro

29. Despues de tensilón Prueba de tensilón Antes de tensilón

30. Anticuerpos Antireceptores de acetilcolina Presentes 85% MG Generalizada. 55% MG ocular. No predicen la severidad Su presencia ante datos clínicos confirma el diagnóstico. Su ausencia no excluye el Dx.

31. Procedimientos Diagnósticos Electromiografía. Estimulación repetitiva EMG de fibra Única

32. Clasificación Clínica Generalizada Neonatal Congénita Juvenil Adulto leve, mod. y severa Ocular - Juvenil y del Adulto

35. Steinert Kearn-sayre

36. tratamiento 1.- anticolinesterásicos. 2.- esteroides. 3.- inmuno supresores. 4.- plasmaferesis 5.- inmunoglobulina. 6.- timectomia

37. Dosis equivalentes de anticolinesterasicos Dosis (mg) y vía Oral IM IV Jarabe Neostigmina 15 Neostigmina 1.5 0.5 Mestinon 60 2 0.7 60 mg 5 ml Mestinon Timespan 90 - 180 Ambenomio 7.5

38. Anticolinesterásicos toxicidad y efectos secundarios Muscarínicos Músculo liso Cólicos-diarrea Nausea,vómito Miosis pupilar Broncoespasmo Glandulas Sialorrea,diaforesis Nicotínicos Musculoesqueletico s Fasciculaciones Espasmos musculares debilidad

39. Glucocorticoides Efectos secundarios a largo plazo Gastrointestinales Nausea,vómitos, Gastritis, ulceras Dermatologicos ac né, hirsutismo Cushing Endocrino s: Hiperglucemia Hipokalemia . Inmunológicos : Inmunodepresión. Hematológicos : petequias Cardiovascular HAS edema Oftalmológicos : Cataratas Glaucoma Psicológicos: Depresión Insomnio. Otros: Aumento de peso

40. Azatioprina Efectos secundarios Gastrointestinales Nausea,vómitos,diarrea Ulceras,malestar Hematológicos Leucopenia, anemia Trombocitopenia. Hepático Enzimas Hepáticas elevadas Inmunológico Mayor susceptibilidad a infecciones Neoplásico Incrementa el riesgo para linfoma

41. Timectomia No se practica en la MG ocular. No se realiza después de los 60 años (a menos que haya timoma). Requiere preparación. Mejores resultados en mujeres jóvenes. Se prefiere abordaje transesternal.

42. TIMOMA

43. Terapias emergentes Micofenolato de mofedetilo tacrolimus

45. El que alguien toque mi vida es un privilegio, Tocar la vida de alguien es un honor, Pero el ayudar a que otros toquen sus propias vidas Es un placer indescriptible! Rubén Darío

51. Major Events in Neuromuscular Transmission Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction (1). Depolarization of the axon terminal causes an influx of Ca 2+ (2) which triggers fusion of the synaptic vesicles (3) and release of neurotransmitter ( Acetylcholine ; ACh) (4). ACh diffuses across the synaptic cleft and binds to post-synaptic ACh receptor (AChR) located on the muscle fiber at the motor end-plate (5). Binding of ACh to AChRs opens the channels causing an influx of Na (5), depolarization of the sarcolemma that travels down the t-tubules (6) and ultimately causes the release of Ca 2+ from the sarcoplasmic reticulum - CONTRACTION. Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) (7).

52. Two main Types of Neuromuscular Blocking Drugs Nondepolarizing (competitive) Depolarizing

53. Mechanism of Action of Nondepolarizing Neuromuscular Blocking Drugs

54. Non-depolarizing (competitive). Prototype of Non-depolarizing is tubo curarine (new generation: pancuronium and gallamine). Mechanism of Action : In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh. At higher does they can block prejunctional Na channels thereby decreasing ACh release. Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors).

55. Nondepolarizing Agents Therapeutic Use: Adjuvant drugs in surgical anesthesia Pharmacology: Must be given by injection because they are poorly absorbed orally. Do not cross the BBB. Generally excreted unchanged (i.e. not metabolized). Adverse Effects: Tubocurarine causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. Newer generation don’t.

56. Drug Interactions: Cholinesterase Inhibitors decrease the effectiveness of nondepolarizing agents Aminoglycoside antibiotics (e.g. streptomycin) decrease ACh release by competing with Ca 2+ – increase action of nondepolarizing drugs Calcium channel blockers increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs) Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by 1) decreasing excitability of motoneurons, 2) increasing muscle blood flow, and 3) decreased kinetics of AChRs (increase action of nondepolarizing drugs)

57. Depolarizing Agents

58. Depolarizing Agents Prototype of d epolarizing agent is succinylcholine (only depolarizing drug in clinical use). Mechanism of Action : Similar action to ACh, but longer acting. Phase 1 : Membrane is depolarized by opening AChR channels causing brief period of muscle fasciculation. Phase II : End-plate eventually repolarizes, but because succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate. Because of the mechanism of action of depolazing drugs is similar to ACh, their blocking effects are augmented by AChE inhibitors.

59. Depolarizing Agents Therapeutic Use: Adjuvant drugs in surgical anesthesia Pharmacology: Duration of action is short (several minutes) because it is rapidly broken down by plasma cholinesterases (must be administered by continuous infusion) Adverse Effects: When administered with halothane some genetically susceptible people (inherited autosomal dominant condition) experience malignant hyperthermia. Treatment: rapid cooling of the body and dantrolene

60. Cholinesterase Inhibitors

61. Cholinesterase Inhibitors Examples: Neostigmine, edrophonium. Mechanism of Action : Inhibit acetylcholinesterase Therapeutic Use: Antidote for nondepolarizing blockers Treatment of myasthenia gravis (neostigmine) Diagnosis of myasthenia gravis (edrophonium)

62. Myasthenia Gravis

63. Myasthenia Gravis is an autoimmune Disease that is characterized by a decrease in number of AChR Because there are fewer AChR to bind to the end plate potentials (EPPs) are smaller. With smaller EPPs the “ safety factor” is reduced there is less chance that the post-synaptic muscle fibres will be activated

64. Note: The amplitude of the end plate-potential is directly related to the amount of ACh that binds to the post-synaptic AChRs.

65. Myasthenia Gravis

66. Adverse Effects Actions of generalized cholinergic activation (muscarinic and nicotinic). Abdominal cramping Diarrhea Flushing (transient redness of the face and neck) Increased salivation Miosis (contraction of the pupils) Incontinence Bronchospasms (can exacerbate bronchial asthma)

67. Malignant Hyperthermia Dantrolene (interferes with EC coupling by decreasing Ca exflux from the SR

68. Diazepam (A Benzodiazepine that probably f acilitates the actions of GABA A in the CNS) Baclofen (GABA B agonist – note error in your handouts) Primarily used in the treatment of spastiticy associated with spinal cord injury Spasmolytic Drugs