Pharmacology notes

1. Myasthenia Gravis
vishwas

2. Introduction
 Most common primary disorder of
neuromuscular transmission
 Usually due to acquired immunological
abnormality
 Also due to genetic abnormalities at
neuromuscular junction.

3. History
 In 1862, Willis described a disease with
fluctuating weakness that varied
throughout the day.
 Erb described the classic signs of
Myasthenia gravis in 3 patients &
recognized that fluctuating weakness
differed from that seen in other
diseases.
 In 1893, Goldflam provided a
comprehensive description of the
disease
 In 1895, Jolly used the term “
Myasthenia Gravis Pseudoparalytica”

4. Epidemiology
 Most common age of onset :
women : 2nd & 3rd decades
men : 5th & 6th decades
 < 40 yrs , females are affected 2 to 3
times as often as males.
 Later in life, incidence is higher in
males.
 Of pts with thymomas- is a tumor,
majority are older ( 50 – 60 yrs ) &
males.

5. Clinical Presentation
 c/o specific muscle weakness rather &
not of generalized fatigue.
 2/3rd – ocular motor disturbances,
ptosis
or diplopia
 1/6th – oropharyngeal muscle
weakness
difficulty in chewing, swallowing
or talking
 10 % - limb weakness

6. Clinical Presentation
 Severity of weakness fluctuates during
the day
least severe in the morning & worse
as the day progresses, especially after
prolonged use of affected muscles.
 Patient usually gives h/o
 Worsening of ocular symptoms while
reading, watching television, driving.
 Worsening of jaw muscle weakness
on prolonged chewing – meat / chewy
candy.

7. Clinical Presentation
 Also give h/o :
 Frequent purchase of new eyeglasses
to correct blurred vision
 Avoidance of foods that became
difficult to chew or swallow
 Cessation of activities that require
prolonged use of specific muscles.

8. Clinical Presentation
 Course of disease is variable but often
progressive.
 Symptoms fluctuate over a short
period & then become more severe for
several years ( Active Stage )
 Followed by a period in which
fluctuations in strength still occurred (
Inactive Stage )
 After 15-20 yrs, weakness becomes
fixed & most severely involved
muscles become atrophic ( Burnt-out

9. Ocular manifestations :
 Weakness of levator palpebrae &
extraocular muscles – initial
manifestation in ½ cases.
 Ocular palsies, ptosis-dropping of one
or both upper eyelids, usually
accompanied by weakness of eye
closure – always myopathic & not
neuropathic in origin
 Diplopia- due to asymmetric weakness
of muscles in both eyes.

11. Ocular manifestations :
 Sustained upgaze for 30 or more
seconds – induce / exaggerate ptosis &
uncover myasthenic motor weakness.
 Lid-twitch sign : twitching of upper eyelid
appears a moment after the patient
moves the eyes from downward to
primary position
 After sustained upward gaze, 1or more
twitches are observed with closure of
eyelids.

12.  Unilateral painless ptosis without
ophthalmoplegia or pupillary
abnormality.

13. Ocular manifestations :
 Combined weakness of extraocular
muscles, levators & orbicularis oculi
combined with
 Normal pupillary response to light
 Normal accomodation
is virtually diagnostic of myasthenia.
 Bright light aggravates ocular signs
 Cold ( application of ice pack ) improves
them.

14. Oropharyngeal manifestations
:
 Voice may be nasal after prolonged
talking
 Weakness of laryngeal muscles –
hoarseness
 Frequent choking due to difficulty in
swallowing & chewing after eating for
a while.
 Characteristic facial appearance

15. Rest smiling
 At rest, b/l lid ptosis,
downward curve of
corners of mouth,
giving pt a sad
appearance
 Smiling: myasthenic
snarl – resulting from
upward movement of
medial portion of
upper lip & horizontal
contraction of
corners of mouth

16. Oropharyngeal manifestations
:
 Jaw weakness – shown by manually
opening the jaw against resistance,
which is not possible in normal people.
 Patient holds
jaw closed with thumb under chin,
middle finger curled under nose/lower
lip
index finger extended up the cheek
producing studious appearance.

17.  Neck flexors are weaker than neck
extensors
 Bulbar weakness is prominent
 Limb weakness is often proximal &
asymmetric
 Tendon reflexes are unaffected

18. Clinical Presentation
 I Ocular myasthenia ( 15-20% )
 II A. Mild, generalized myasthenia with
slow progression; no crises;
drug responsive ( 30% )
 II B. Moderately severe generalized
myasthenia; severe skeletal &
bulbar
involvement but no crises;
drug response –less
satisfactory(25%)

19. Clinical Presentation
 III. Acute fulminant myasthenia;
rapid progression of severe
symptoms
with respiratory crises & poor drug
response; high incidence of
thymoma;
high mortality ( 15% )
 IV. Late severe myasthenia;
symptoms
same as III; resulting from
steady progression over 2 years

20. Congenital Myasthenic
Syndromes
type Clinical features genetics treatment
SLOW
CHANNEL
MOST COMMON
WEAK
FOREARM
EXTENSORS
AUTOSOMAL
DOMINANT
QUINIDINE
LOW AFFINITY
FAST CHANNEL
PTOSIS AUTOSOMAL
RECESSIVE
3,4-DAP,
ANTI AChE
SEVERE AChR
DEFICIENCIES
VARIABLE
SEVERITY
TYPICAL MG
FEATURES
AUTOSOMAL
RECESSIVE
ANTI AChE
? 3,4-DAP
AChE
DEFICIENCY ABSENT
PUPILLARY
RESPONSE
- WORSE WITH
ANTI AChE
DRUGS

21. Pathophysiology
 Decrease in number of available
AChR at postsynaptic muscle
membrane due to antibody mediated
autoimmune attack.
 Postsynaptic folds are flattened or
simplified.
So, although ACh is released normally,
it produces small endplate potentials
that may fail to trigger muscle action
potential.
Failure of transmission at many NMJs

23. Pathophysiology
 Decreased efficiency of
neuromuscular transmission
 combined with presynaptic rundown
 results in activation of fewer & fewer
muscle fibres by successive nerve
impulses
 & hence increasing weakness /
myasthenic fatigue

25. INVESTIGATIONS

26. Anticholinesterase Test /
Edrophonium Chloride ( Tensilon )
Test
 Positive in > 90 % of patients with MG
 Initially 2mg Edrophonium IV given,
response monitored for 60 sec
- if definite improvement of muscular
weakness occurs, it is + & test is
terminated.
 If no change, additional 8mg IV is
given in 2 parts ( 3mg & 5 mg ) , if
improvement is seen within 60 sec
after any dose, no further injections
are given.

27. Anticholinesterase Test /
Edrophonium Chloride ( Tensilon )
Test
 10 mg of Edrophonium does not
weaken normal muscle & occurrence
of weakness indicates neuromuscular
transmission weakness.
 IM Neostigmine can be used ( infants
& children )
 False positive in neurologic disorders
like Amyotropic lateral sclerosis

28. Antibodies to AChR , MuSK :
 Anti-AChR Radioimmunoassay :
 85 % positive in generalized MG
 50 % positive in ocular MG
 Presence of Anti-AChR antibodies is
virtually diagnostic
 But negative result does not rule out
MG

29. ELECTROMYOGRAPHY

30. Repetitive Nerve Stimulation
 Decrement > 15 % at 3Hz is highly
probable.

31. Single Fiber
Electromyography
 Most sensitive clinical test of
neuromuscular transmission & shows
increased jitter in some muscles in
almost all pts with MG.
 It is confirmatory but not specific
 Pts with mild / purely ocular muscle
weakness may have increased jitter
only in facial muscles.
 When jitter increases, EMG should be
done.

32. JITTER
 Single fibre needle generally records from a single
muscle fibre, because the muscle fibre in a motor
unit are randomly destributed.
 It is possible, to position the needle so as to record
from 2 or more muscle fibre of the same motor unit.
 A pair of single muscle fibre potentials that
recorded trigering potential and slave potential.
 The time interval between these two potentials
varies from one discharge to another is known as
jitter.

33. CT / MRI
 For ocular MG : Do CT / MRI to
exclude
intracranial lesions

34. Disorders associated with
Myasthenia gravis
 Disorders of thymus : thymoma,
hyperplasia
 Other auto-immune disorders :
Hashimoto’s Thyroiditis
Graves’ Disease
Rheumatoid Arthritis
SLE

35. Disorders / Circumstances that
worsen Myasthenia gravis
 Emotional upset
 Systemic illness ( especially viral
respiratory infection )
 Hypothyroidism
 Hyperthyroidism
 Pregnancy
 Drugs

36. Drugs
 D-pencillamine ( never use )
 Succinylcholine, D-tubocurarine, other
neuromuscular blocking agents
 Quinine, Quinidine, Procainamide
 Aminoglycosides – Gentamycin,
Kanamycin, Neomycin, Streptomycin
 Beta blockers
 Calcium channel blockers
 Magnesium salts
 Iodinated contrast agents

37. Disorders that interfere with
therapy
 Tuberculosis
 Diabetes
 Peptic ulcer
 GI bleeding
 Renal disease
 Hypertension
 Asthma
 Osteoporosis
 Obesity

38. Investigations -
 CT /MRI of Mediastinum
 ANA –anti nuclear antibody, RA
Factor, Antithyroid antibodies
 Thyroid function tests
 Mantoux- for Tb
 Chest X Ray
 FBS, HbA1c
 Pulmonary Function Tests
 Bone densitometry

39. TREATMENT

40.  Based on natural history of disease in
each patient & predicted response to
specific form of treatment
 Treatment goals are individualized
 Successful treatment requires close
medical supervision & long term
followup
 Return of any weakness after a period
of improvement – to be taken as
heralding further progression.

41. Cholinesterase Inhibitors
 Pyridostigmine Bromide
initial dose 30 – 60 mg TID / QID
 Dose to be tailored according to pts
need
 Used as diagnostic test
 Early symptomatic treatment
 May be satisfactory chronic treatment
in some.
 Neostigmine, Mestinon,
Ambenonium chloride are also used.

42. Thymectomy - to remove the
thymus
 Recommended for most pts with MG
 Maximal favourable response occurs
2 - 5yrs after surgery
 Best response is seen in young
people operated early in the course of
disease
 But improvement can occur even after
30 yrs of symptoms.
 Improvement is also seen in
seronegative MG pts.

43. Corticosteroids
 Produce rapid improvement in many
pts
 Produce total remission / marked
improvement in > 75 % of patients
 Used as secondary treatment in who
do not respond to thymectomy /
immunosuppressive therapy
 Initial dose prednisone 15 – 25
mg/day increased until maximal
improvement is seen or upto 50 – 60

44. Immunosuppressants
 Produces marked & sustained
improvement in many
 Azathioprine – initially 50 mg OD,
which is increased in 50 mg/day
increments every 7 days to total of
150-200 mg/day
 Cyclosporine – initially 5-6 mg/kg/day
 Cyclophosphamide – IV 200 mg/day-
5days
150-200mg/day

45. Plasma exchange
 Produces rapid improvement
 Mainly used as adjunctive treatment
 As treatment in those who have not
responded to other forms of treatment

46. Ocular myasthenia
 Started on Cholinesterase inhibitors
 If unsatisfactory – prednisone is added
 Thymectomy in young

47. Generalized myasthenia
onset < 60 yrs
 High dose daily prednisone / plasma
exchange preoperatively
 Thymectomy in all
 Weakness + after surgery / recurs / no
improvement 12 months after surgery
– high dose daily prednisone,
cyclosporine / azathioprine

48. Generalized myasthenia
onset > 60 yrs
 Initially cholinesterase inhibitors
 If response is unsatisfactory –
add azathioprine
 If response is unsatisfactory –
add high dose prednisone or
substitute cyclosporine for
azathioprine

49. Thymoma
 Thymectomy in all cases
 Pretreated with high dose prednisone
with / without plasma exchange
 Postoperative radiation is used if
tumour resection is incomplete /
tumour is spread beyond thymic
capsule
 Small tumours – managed medically

50. Juvenile myasthenia gravis
 Onset of immune mediated MG < 20
yrs is referred to as Juvenile MG
 Female : male = 3 : 1
 When myasthenic symptoms develop
in childhood – determine if pt has
acquired form or genetic form that
does not respond to immunotherapy
 Cholinesterase inhibitors initially
 Later thymectomy can be done.

51. Seronegative myasthenia
gravis
 More likely male
 Have milder disease
 Ocular myasthenia, fewer thymomas,
less frequent thymic hyperplasia, more
frequent thymic atrophy

52. Myasthenic Crisis
 An exacerbation of weakness
sufficient to endanger life , usually
consists of respiratory failure caused
by diaphragmatic & intercostal muscle
weakness.
 Usually have precipitating event such
as infection (most common), surgery,
rapid tapering of immunosuppression

53. Cholinergic crisis
 Respiratory failure from overdose of
cholinesterase inhibitors
 It was more common before the
introduction of immunosuppressive
therapy
 Possibility that deterioration could be
due to cholinergic crisis is best
excluded by temporarily stopping the
anticholinesterase drugs.

54. Management
 Admit in intensive care unit
 Discontinue all cholinesterase
inhibitors
 Ventilate the patient
 Cholinesterase inhibitors should be
resumed at low doses & slowly
increased as needed
 Treat the intercurrent infection

55. reference
 Golwala
 devidson

56. THANK YOU