Indirectly Acting Cholinergic Agonists (Cholinesterase Inhibitors) Flashcards
What does AChE do?
catalyzes the hydrolysis of Ach into choline and acetic acid
**Indirectly, what do cholinesterase inhibitors do?
ChE inhibitors act INDIRECTLY as Ch agonists
What are the two distinct types of endogenous Ch?
(true) AChE and Butyrylcholinesterase (pseudoChE)
AChE D & F?
Distribution: neurons, motor end plate, RBC
**Function: hydrolysis of ACh liberated in synaptic cleft or in neuroeffector transmission
(Booty)BuCh D & F?
D: plasma (glial cells, liver)
F:hydrolyze certain exogenous drugs, eg SUCCINYLCHOLINE
How do AChE Inhibitors bind?
Competitively to the active sites
What are the FOUR clinically used AChE REVERSIBLE Inhibitors
- NEOSTIGMINE
- EDROPHONIUM
- PHYSOSTIGMINE
- DONEPEZIL
**NEOSTIGMINE
- 4$ poorly penetrates BBB
- Inhibits ACh, direct stim effect on nicky R at skeletal mu endplate
- used to REVERSE neuromu blockade
- tx of myasthenia gravis
- side effects: due to excessive ACh action at peripheral musky and Nicky R
**EDROPHONIUM
- inhibits ChE and stimulates Nicky R
- very rapid onset of action BUT short duration (10-15 mins)
- dx of myasthenia gravis or make a differential dx between progression of myasthenic weakness and a cholinergic crisis (i.e. excessive ACh) due to cholinesterase toxicity
What happens with excessive ChE inhibition ?
causes neuro.mu block resulting in mu weakness which can mimic and be mistaken for myasthenia gravis progression.
**PHYSOSTIGMINE
-crosses BBB, takes longeylong time to geti inactivated by plasma ChE.
-counteracts DELIRIUM with excess ANTI-Ch activation
-side effects related to increased ACh at musky or nick R
Ci: asthma, cardiac insufficiency, and gut obstruction
**DONEPEZIL
- tx of Alzheimer’s dz
- reversible inhibitor of AChE in the CNS
- HIGH F, long t1/2=1x/day po
**What are the epic IRREVERSIBLE inhibitors of ChE?
Organophosphate used as insecticides and toxic nerve gases.
What is the mechanism of OPP?
- phosphorylates the esteratic site on the AChE molecule.
- **phosphorylated enzyme becomes a stable complex with time
- exhibit SEVERE toxicity–>cholinergic crisis; common agent in nerve gases
What are the 8 tissues/systems affected by the toxicity of OPP?
- skin
- visual
- urinary
- respiratory
- digestive
- skeletal muscle
- CV
- CNS
Skin OPP
(S)weating (diaphoresis)…S
Visual OPP
(L)acrimation, (M)iosis, blurred vision, accomodative spasm
Lauren McClusky is a blind crybaby.
Urinary OPP
(U)rinary frequency and incontinence
Respiratory OPP
Increased bronchial secretions {(B)ronchorrea}, bronchoCONSTRICTION, weakness or paralysis of respiratory muscles
Digestive OPP
(S)alivation; increased gastric, pancreatic, and intestinal secretion; increased tone and motility in gut {(G)astric distress}, abdominal cramps, vomiting, (D)iarrhea
SGD…some good D will wreck your tummEEE
SkelMu OPP
Fasciculations, weakness, paralysis (depolarizing block)
CV OPP
(B)radycardia (due to musky predominance), decreased CO, hypOtension; effects due to ganglionic action and activation of adrenal medulla also possible
(B) eats by less CO hypO
CNS OPP
Tremor, anxiety, restlessness, disrupted concentration and memory, confusion, sleep disturbances, desynchronization of EEG, convulsions, coma, circulatory and respiratory depression
Tx of severe OPP poisoning
- Mechanical ventilation to counteract effects on NMJ
- suction of oral secretions
* *3. ATROPINE to protect from systemic musky effects
* *4. Reactivation of the alkylphosphorylated AChE with Pralidoxime Chloride (2-PAM) (the phosphate is transferred to 2-PAM)
**What is an example of an OPP and what is it clincally used for?
ECHOTHIOPHATE is used clinically to produce long-term miosis in the tx of open angle glaucoma.
OPP synopsis (SLUDGE DUMBBELS)
Salivation Lacrimation Urination Defecation Gastrointestinal distress Emesis
Diarrhea Urination Miosis Bradycardia Bronchorrea Emesis Lacrimation Salivation
