Indirectly Acting Cholinergic Agonists (Cholinesterase Inhibitors)

Question 1

What does AChE do?

Answer 1

catalyzes the hydrolysis of Ach into choline and acetic acid

Question 2

**Indirectly, what do cholinesterase inhibitors do?

Answer 2

ChE inhibitors act INDIRECTLY as Ch agonists

Question 3

What are the two distinct types of endogenous Ch?

Answer 3

(true) AChE and Butyrylcholinesterase (pseudoChE)

Question 4

AChE D & F?

Answer 4

Distribution: neurons, motor end plate, RBC

**Function: hydrolysis of ACh liberated in synaptic cleft or in neuroeffector transmission

Question 5

(Booty)BuCh D & F?

Answer 5

D: plasma (glial cells, liver)
F:hydrolyze certain exogenous drugs, eg SUCCINYLCHOLINE

Question 6

How do AChE Inhibitors bind?

Answer 6

Competitively to the active sites

Question 7

What are the FOUR clinically used AChE REVERSIBLE Inhibitors

Answer 7

1. NEOSTIGMINE
2. EDROPHONIUM
3. PHYSOSTIGMINE
4. DONEPEZIL

Question 8

**NEOSTIGMINE

Answer 8

• 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

Question 9

**EDROPHONIUM

Answer 9

• 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

Question 10

What happens with excessive ChE inhibition ?

Answer 10

causes neuro.mu block resulting in mu weakness which can mimic and be mistaken for myasthenia gravis progression.

Question 11

**PHYSOSTIGMINE

Answer 11

-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

Question 12

**DONEPEZIL

Answer 12

• tx of Alzheimer’s dz
• reversible inhibitor of AChE in the CNS
• HIGH F, long t1/2=1x/day po

Question 13

**What are the epic IRREVERSIBLE inhibitors of ChE?

Answer 13

Organophosphate used as insecticides and toxic nerve gases.

Question 14

What is the mechanism of OPP?

Answer 14

• 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

Question 15

What are the 8 tissues/systems affected by the toxicity of OPP?

Answer 15

1. skin
2. visual
3. urinary
4. respiratory
5. digestive
6. skeletal muscle
7. CV
8. CNS

Question 16

Skin OPP

Answer 16

(S)weating (diaphoresis)…S

Question 17

Visual OPP

Answer 17

(L)acrimation, (M)iosis, blurred vision, accomodative spasm

Lauren McClusky is a blind crybaby.

Question 18

Urinary OPP

Answer 18

(U)rinary frequency and incontinence

Question 19

Respiratory OPP

Answer 19

Increased bronchial secretions {(B)ronchorrea}, bronchoCONSTRICTION, weakness or paralysis of respiratory muscles

Question 20

Digestive OPP

Answer 20

(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

Question 21

SkelMu OPP

Answer 21

Fasciculations, weakness, paralysis (depolarizing block)

Question 22

CV OPP

Answer 22

(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

Question 23

CNS OPP

Answer 23

Tremor, anxiety, restlessness, disrupted concentration and memory, confusion, sleep disturbances, desynchronization of EEG, convulsions, coma, circulatory and respiratory depression

Question 24

Tx of severe OPP poisoning

Answer 24

1. Mechanical ventilation to counteract effects on NMJ
2. 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)

Question 25

**What is an example of an OPP and what is it clincally used for?

Answer 25

ECHOTHIOPHATE is used clinically to produce long-term miosis in the tx of open angle glaucoma.

Question 26

OPP synopsis (SLUDGE DUMBBELS)

Answer 26

Salivation
Lacrimation
Urination
Defecation
Gastrointestinal distress
Emesis

Diarrhea
Urination
Miosis
Bradycardia
Bronchorrea
Emesis
Lacrimation
Salivation