Autonomic drugs: Cholinesterase inhibitors Flashcards
cholinesterase inhibitors effects
profound effects skeletal muscle, autonomic system and brain
what are the two binding sites on cholinesterase enzyme important for drug action?
anionic
esteratic
why hydrolysis acetylcholine?
AChE
-block parasympathetic system and somatic system
how is the anionic site formed?
by ring systems of Trp and Phe binds ACh
how is the esteratic side formed?
by Ser, His, and Glu hydrolyses ester
ACh is hydrolysed
rapidly
25,000 molecules/sec
is the inhibitor neostigmine hydrolyzed?
Yes, but carbamate portion remains on the Ser to block further hydrolysis for a few hours
edrophonium
- simple quarternary alcohol, no ester, lasts for 2 days
- binds to anionic site
- duration few mins, must inject, can’t take orally
- organophosphate block AChase
medical use of cholinesterase inhibitors?
Alzheimer’s
- most common cause of dementia in old age
- improper processing beta amyloid protein-> beta-amyloid 42, toxic
- loss of cholinergic neurons in brain
- treated with donepezil
ACh inhibitors neostigmine used to
increase GI activity postoperatively
- quaternary but effective p.o.
- no CNS effects
Myasthenia gravis
skeletal muscle weakness
- autoimmune loss receptors
- loss 2/3 receptors-> symptoms
- more common in women
- neostigmine effective: increase in muscle strength
drugs used for MG
- edrophonium for diagnosis, injection and short duration of action (sometimes neostigmine used)
- pyridostigmine p.o. for treatment: longer duration of action than neostigmine
important amino acids in AChE
- Glu237
- Phe338
- His440
- Ser203
- Trp86
catonic cholinesterase inhibitors
act on anionic site
- edrophonium 4N
- donepezil 3N
carbamate ester cholinesterase inhibitors
rivastigmine 3N
physostigmine 3N
neostigmine 4N
pyridostigmine 4N
insecticides
chlorpyrifos
malathion: specific for insects
- non medical cholinesterase inhibitors
- block cholinesterase
- block esteratic site
nerve gases
soman
toxicicty from cholinesterase
asphyxia
four factors for asphyxia
bronchoconstriction
increased secretions: can drown in own secretion
skeletal muscle paralysis
CNS depression: at a high dose
Acronym for symptoms
DUMBELS Diarrhea Urination Muscle weakness, miosis Bronchoconstriction Excitation Lacrimation Seizures, sweat, salivation
treatment of toxicity
because increasing acetylcholine in body:
- atropine: block parasympathetic
- For skeletal muscle: pralidoxime (2-PAM) (Protopam)
- blocks anionic site from quaternary charge
Therapy quickly
May require prolonged therapy
what does atropine not help with in toxicity
skeletal muscle paralysis
-PAM does
what does Pralidoxime not help with in toxicity
CNS depression
-quaternary, won’t get to brain
Malathion for pediculosis capitis
common in school children
- person contact transmision
- vector for typhus, trench fever, relapsing fever
- small ovoid gray nits (ova) and mature lice both respond to malathion
what are pyridostigmine and edrophonium also used to diagnose?
distinguish between MG and cholinergic crisis
- too much ACh-> get weakness
- MG: edrophonium will make them feel better
- cholinergic: edrophonium will make worse because already too much drug there
Acronym for parasympathetic
SLUG
Salivation, Lacrimation, urination, GI
