Cholinesterase Flashcards Preview

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Flashcards in Cholinesterase Deck (24):
1

Cholinesterase catalyses the hydrolysis of ___ to ___ and ____

ACh, acetate and choline

2

Two forms of ChE are

1. AChE
2. Butyrylcholinesterase (pseudocholinesterase)

3

Location of AChE

Membrane-bound, at all cholinergic synapses + red cells

4

Location of butyrylcholinesterase

Usually a soluble enzyme (sometimes membrane-bound) found in plasma, liver + other tissues

5

How does substrate specificity differ for 2 ChE's

AChE is specific for ACh and closely similar esters. BuChE is rather unspecific + faster hydrolysis for butyrylcholine than for ACh; can hydrolyse many other esters e.g. procaine, suxamethonium, cocaine

6

Inhibitor specificity

mainly selective for AChE

7

BuChE is controlled by an ____ gene with ____

Autosomal, several alleles

8

Those with mutant - low/reduced BuChE show 2 things:

1. Greatly reduced rate of hydrolysis of some drugs - imp. in anaesthesia (suxamethonium)
2. Reduced sensitivity of enzyme to inhibiton by dibucaine

9

Outline dibucaine number test

Normal range 70-90 (percentage enzyme inhibition by 10^-4 M dibucaine)
- Heterozygotes 50-70 without abnormal suxamethonium sensiticity
- Homozygous 10-20 - extremely sensitive to suxamethonium

10

ChE has 2 sites:

1. Catalystic site (esteratic) containing a reactive serine OH group
2. Anionic site - binds cationic quaternary ammonium group of ACh

11

Enzymatic hydrolysis involves:

1. binding of ACh at 2 sites
2. Transfer of acetyl group to serine OH
3. Dissociation of choline spontaneous hydrolysis of acetylated serine OH

12

Number of ACh hydrolysed at 1 active site/second

10^4

13

transmitter (ACh) released at NMJ is normally hydrolysed in less than

1 ms

14

Short-acting anticholinesterases

e.g. Endrophonium - quaternary NH4 but no group complementary to esteratic site
- act competitively - bind anionic site by ionic bond

15

Medium/ long acting reversible anticholineserases

e.g. neostigmine, eserine
- most clinically imp.
- both sites bound - forms ester bond with serine OH of esteratic site

16

When is spontaneous hydrolysis much slower?

When serine OH is bound to neostigmine rather than acetyl group + enzyme molecule inactivated for several mins

17

Excamples of long-acting (irreversible) anticholinesterases

e.g. dyflos, parathion, ecothiopate + organophosphate compounds

18

Long-acting (irreversible) anticholinesterases mech

Phosphorylate serine OH. Hydrolysis of phosphorylated enzyme = slow + recovery requires synthesis of new enzyme
If ecothipate (few hour recovery)
-> most organophosphates have no quaternary group = inhibit many serine enzymes besides ChE

19

Peripheral effects of inhibtion

Parasympathetic - fall in IC pressure
Nmj - restoration of transmission at junctions blocked by competitive blocking agens or in myasthenia gravis
-: high doses -: depolarising muscle block

20

Central effects of inhibitions

Mainly excitatory, agitation + convulsions followed by respiratory depression

21

Main uses of anticholinesterases

1. Glaucoma - eye drops (eserine/ organophosphate)
2. Myasthenia gravis - quaternary comp. (neostigme) don't reach brain, edrophonium used as a test
3. Reversal of competitive neuromuscular block after anaesthesia
4. Insectisides - organophosphate
5. AD symptoms - tacrine/ doneprezil cross BBB -: small effect, inconsistent + temp relief

22

Toxic effects of anticholinesterases

acute -> demyelination -> paraylsis + sensory loss -> enzyme loss in myelin synthesis

23

ChE reactivators

Oxime compounds e.g. pralidoxime which binds reversibly to anionic site -> oxime OH is at right distance to reach phosphate group + substitutes for serine OH

24

What are ChE reactivators used for

treatment of organophosphate poisoning -: early treatment essential