Part 2. Cholinesterase Inhibitors

Question 1

Basic Pharmacology of Indirect-Acting Cholinomimetics (Cholinesterase Inhibitors):

Answer 1

• Pharmacodynamic actions almost identical to Direct- Acting Cholinomimetics
• Primary difference between indirect-acting agents agents is chemistry and PK

Question 2

What is the basic structure of cholinesterase inhibitors?

Answer 2

1) Simple alcohols with quaternary ammonium group (edrophonium)
2) Carbamic acid esters of alcohols (carbamates)with quaternary or tertiary ammonium groups (neostigmine)
3) Organic derivatives of phosphoric acid (organophosphates, e.g., echothiophate)

Question 3

ADME of Carbamate Cholinesterase Inhibitors:

Answer 3

• Quaternary carbamates poorly absorbed from conjunctiva, skin, and lungs due to quaternary amine
• Much higher oral vs parenteral dose required
• CNS distribution negligible
• Carbamates stable in water but readily metabolize via esterase-catalyzed hydrolysis (including AChE)

Question 4

What carbamate cholinesterase inhibitor is well absorbed and used topically in the eye? Why is it well absorbed?

Answer 4

Physostigmine; it has a tertiary amine

Question 5

ADME of Organophosphate Cholinesterase Inhibitors:

Answer 5

• Organophosphates readily absorbed via all routes (except ecothiophate)
  
  • are widely distributed throughout the body including the CNS
  • are less stable in water than carbamates
• Thiophosphates are readily and rapidly absorbed but must be metabolically oxidized to the corresponding active organophosphate
• Alternate pathways in mammals and birds metabolize malathion to inactive nontoxic compounds

Question 6

MOA of Reversible AChE Inhibition:

Answer 6

• Quaternary alcohols (edrophonium) reversibly bind to the AChE active site blocking access to ACh – electrostatic vs covalent bond (2 – 10 minutes)
• Carbamate esters undergo the same two-step hydrolysis as ACh

Question 7

MOA of Irreversible AChE inhibitors:

Answer 7

• Same as for reversible AChE Inhibition
• Difference = Covalent phosphorus-enzyme bond is extremely stable to hydrolysis
• Rate of hydrolysis of phosphorylated enzyme is much slower (100s of hours)

Question 8

What is Enzyme Aging?

Answer 8

• Cleavage of one or more phosphoester bonds while AChE is phosphorylated
• If this happens, enzyme is much less likely to hydrolyze phosphoester bond to the enzyme and MUCH LESS LIKELY TO REGENERATE ENZYME

Question 9

What is an antidote to Irreversible AChE Inhibitors?

Answer 9

• pralidoxime chloride

- MUST BE ADMINISTERED WITHIN A FEW HOURS OF ORGANOPHOSPHATE EXPOSURE (due to enzyme aging)

Question 10

Pharmacodynamics of AChE Inhibitors:

Answer 10

• Prominent effects seen in cardiovascular system, GI system, eye, and skeletal muscle neuromuscular junction
  • CNS:
  • low concentrations – alerting response (lipid soluble drugs)
  • high concentrations – convulsions, coma, respiratory arrest
  • Eye:
  • similar to direct acting cholinergic drugs

Question 11

PD of AChE Inhibitors on cardiovascular system:

Answer 11

• Increase activity of parasympathetic and sympathetic ganglia supplying the heart
• Activate ACh receptors on cardiac (M2) and vascular smooth muscle cells (M3)
• Heart – parasympathetic effects predominant

Question 12

Net Cardiovascular Effects of AChE Inhibitors:

Answer 12

• Modest bradycardia; decrease cardiac output; increase PVR and increase blood pressure
• At toxic doses:
  
  • marked bradycardia, significant  cardiac output; hypotension

Question 13

PD of Neuromuscular Junction:

Answer 13

• Low concentrations: prolong and intensify effects of endogenous ACh
• Higher concentrations: fibrillation of muscle fibers or fasciculation of entire motor unit
• Very high concentrations: depolarizing blockade followed by non depolarizing blockade

Question 14

physostigmine:

Answer 14

• Alkaloid from Physostigma venosum (calabar bean)
• Tertiary amine is lipophilic and can cross blood-brain barrier
• Elimination t1/2 ≈ 1 - 2 hours
• Rx of glaucoma; overdose of compounds with anticholinergic effects (e.g., atropine; tricyclic antidepressants); investigated for potential utility in Alzheimer’s

Question 15

neostigmine (Prostigmin):

Answer 15

• Quaternary amine thus no CNS activity
• Elimination t1/2 ≈ 15 – 90 minutes
• Postoperative abdominal distension & urinary retention, myasthenia gravis, reversal of neuromuscular blockade

Question 16

pyridostigmine (Mestinon):

Answer 16

• Structurally similar to neostigmine
• Lacks CNS activity
• Orally effective
• Longer duration of action and fewer side effects than neostigmine and better choice for myasthenia gravis
• Adjunct for prophylaxis of soman exposure (military)
• Parenteral administration for nondepolarizing neuromuscular
agents (i.e., block ACh at skeletal neuromuscular junction)

Question 17

donepezil (Aricept):

Answer 17

• Nonclassical, centrally acting, reversible AChE inhibitor
• Mild to moderate AD & dementia (1997)
• Highly selective for AChE vs butyrylcholinesterase
• Higher affinity for brain AChE vs peripheral AChE (and vs tacrine) • Little to no potential for hepatotoxicity
• Elimination t1/2 is 70 – 140 hrs (subjects > 55 years)
• Metabolized by CYP2D6 & CYP3A4 to cis-N oxide and glucuronidation
• 6-O-desmethyl metabolite (activity = parent) represents 11% of the dose

Question 18

revastigmine (Exelon):

Answer 18

• Centrally selective arylcarbamate (approved in 2000 for
AD)
• Elimination t1/2 = 1.4 – 1.7 hrs but inhibits AChE up to 10 hrs
• Referred to as a pseudo-irreversible AChE inhibitor
• Low hepatic toxicity
• rapidly & extensively hydrolyzed by cholinesterase in the CNS
• Minimal CYP450 involvement

Question 19

galantamine (Razadyne):

Answer 19

• Alkaloid found in plants such as the daffodil (family
Amaryllidaceae)
• Does not inhibit butyrylcholinesterase
• Crosses the bbb (tertiary amine)
• Mild to moderate AD & dementia (2001)
• Used as an anticurare agent in anesthesia (ex. USA)
• Binds to nicotinic receptors resulting in dual cholinergic action
• 75% metabolized by CYP2D6 & CYP3A4 to normethyl, O- desmethyl, and O-desmethylnormethyl metabolites (and other minor metabolites) – not associated with hepatotoxicity
• Elimination t1/2 in 5.7 hrs

Question 20

echothiophate iodide (Phospholine Iodide):

Answer 20

• Only irreversible AChE inhibitor for treatment of glaucoma and strabismus (topical)
• Effective in reducing intraocular pressure for up to 4 weeks
• Last resort treatment due to cataractogenic potential
• Not used systemically

Question 21

Toxicity of Direct-Acting Muscarinic Agonists:

Answer 21

• Overdosage - predictable signs of muscarinic excess –
  extension of the pharmacological actions
• Treatable with competitive muscarinic receptor blockade (e.g., atropine)

Question 22

Toxicity of Cholinesterase Inhibitors:

Answer 22

• A direct extension of pharmacological actions (like the direct acting cholinomimetics)
• Major source pesticides (agriculture, home, veterinary)
• Can develop rapidly or slowly and persist
• Chemical warfare agents (soman, sarin, VX) rapid onset due to concentration

Question 23

What are signs of toxicity of AChE Inhibitors?

Answer 23

• Muscarinic signs are followed by CNS involvement along with peripheral nicotinic effects:
  * Cognitive disturbances, convulsions and coma
  * Depolarizing neuromuscular blockade

Question 24

What is the treatment for AChE Inhibitor toxicity?

Answer 24

• Maintain vitals
• Decontaminate
• Atropine (to control muscarinic effects)
• Pralidoxime to combat AChE aging

Question 25

What can be used for prevention of AChE Inhibitor chemical warfare?

Answer 25

• Autoinjector syringes with pyridostigmine and atropine (pyridostigmine protection limited to peripheral nervous system)

Question 26

What happens with chronic exposure to organophosphates?

Answer 26

• Delayed neuropathy associated with neuron demyelinaton • “Intermediate syndrome” - nerve toxicity appearing 1-4 days post exposure to organophosphate insecticides -muscle weakness related to AChE inhibition