Part 2. Cholinesterase Inhibitors Flashcards
Basic Pharmacology of Indirect-Acting Cholinomimetics (Cholinesterase Inhibitors):
- Pharmacodynamic actions almost identical to Direct- Acting Cholinomimetics
- Primary difference between indirect-acting agents agents is chemistry and PK
What is the basic structure of cholinesterase inhibitors?
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)
ADME of Carbamate Cholinesterase Inhibitors:
- 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)
What carbamate cholinesterase inhibitor is well absorbed and used topically in the eye? Why is it well absorbed?
Physostigmine; it has a tertiary amine
ADME of Organophosphate Cholinesterase Inhibitors:
- 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
MOA of Reversible AChE Inhibition:
- 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
MOA of Irreversible AChE inhibitors:
- 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)
What is Enzyme Aging?
- 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
What is an antidote to Irreversible AChE Inhibitors?
- pralidoxime chloride
- MUST BE ADMINISTERED WITHIN A FEW HOURS OF ORGANOPHOSPHATE EXPOSURE (due to enzyme aging)
Pharmacodynamics of AChE Inhibitors:
- 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
PD of AChE Inhibitors on cardiovascular system:
- 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
Net Cardiovascular Effects of AChE Inhibitors:
- Modest bradycardia; decrease cardiac output; increase PVR and increase blood pressure
- At toxic doses:
- marked bradycardia, significant  cardiac output; hypotension
PD of Neuromuscular Junction:
- 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
physostigmine:
- 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
neostigmine (Prostigmin):
- Quaternary amine thus no CNS activity
- Elimination t1/2 ≈ 15 – 90 minutes
- Postoperative abdominal distension & urinary retention, myasthenia gravis, reversal of neuromuscular blockade
pyridostigmine (Mestinon):
• 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)
donepezil (Aricept):
- 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
revastigmine (Exelon):
• 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
galantamine (Razadyne):
• 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
echothiophate iodide (Phospholine Iodide):
- 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
Toxicity of Direct-Acting Muscarinic Agonists:
- Overdosage - predictable signs of muscarinic excess –
extension of the pharmacological actions - Treatable with competitive muscarinic receptor blockade (e.g., atropine)
Toxicity of Cholinesterase Inhibitors:
- 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
What are signs of toxicity of AChE Inhibitors?
- Muscarinic signs are followed by CNS involvement along with peripheral nicotinic effects:
* Cognitive disturbances, convulsions and coma
* Depolarizing neuromuscular blockade
What is the treatment for AChE Inhibitor toxicity?
- Maintain vitals
- Decontaminate
- Atropine (to control muscarinic effects)
- Pralidoxime to combat AChE aging
What can be used for prevention of AChE Inhibitor chemical warfare?
• Autoinjector syringes with pyridostigmine and atropine (pyridostigmine protection limited to peripheral nervous system)
What happens with chronic exposure to organophosphates?
• 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
