Anticholinesterases Flashcards
Mechanism of action of AChE Inhibitors
There are 3 classes of anti-ChE agents.
3 distinct domains on the AChE constitute binding sites for inhibitory ligands and form the basis for specificity differences between AChE and butyrylcholinesterase:
1. the acyl pocket of the active center.
2. the choline subsite of the active center
3. the peripheral anionic site
Therapeutic uses: Topical application of cholinesterase inhibitors to the cornea of the eye decreases intraocular pressure by facilitating the outflow of aqueous humor.
Edrophonium
Quaternary drug-Edrophonium activity is limited to the PNS synapses.
It has moderate affinity fir AChE
Reversible inhibitor of acetylcholinesterase.
Noncovalent inhibitor-interacts by reversible and nonequivalent associated with the active site in AChE.
Binds to the choline subite in the active center.
Brief duration of action: QUATERNARY STRUCTURE facilitate renal elimination.
Volume distribution is limited.
Its short duration of action makes edrophonium useful in the diagnosis of muscle weakness like myasthenia graves.
Urinary or GI motility agent.
Glaucoma
Serious side effects: seizure, bronchospasm, cardia arrhythmia, bradycardia, cardiac arrest/
Other adverse effects: hypotension or hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis.
Contraindications (a certain instance in which a drug should not be used because it may be harmful): Mechanical intestinal or urinary obstruction, concomitant choline ester or depolarizing neuromuscular blocker use, CV disease.
Therapeutic uses:
-Edrophonium has also been used for terminating attacks of paroxysmal supra ventricular tachycardia.
Donepezil
Reversible inhibitor of acetylcholinesterase
Binds with higher affinity to the active center.
Clinical application in mild to moderate Alzheimer’s disease and dementia.
Side effects: diarrhea, nausea, vomiting, cramps, anorexia, vivid dreams.
Produces modest symptomatic benefits in Alzheimers disease.
Higher affinity for AChE than Edrophonium-Donepezil is more hydrophobic and readily crosses the BBB (TERTIARY); it inhibits AChE in the CNS,
Donepezil has a longer duration of action due to partitioning into lipid and its higher affinities for AChE.
Oral preparation for Alzheimer’s disease.
Well tolerated in single daily doses.
Usually at night and can be increased if well tolerated.
Tacrine
Reversible inhibitor of acetylcholinesterase.
Binds to the choline subsite in the active center.
Used in mild to moderate Alzheimer’s disease and dementia.
Side effects: diarrhea, nausea, vomiting, cramps, anorexia, vivid dreams.
Contraindication: Associated liver function test abnormalities.
Produces modest symptomatic benefits in Alzheimer’s disease.
High affinity for AChE than Edrophonium-Morei hydrophobic and readily crosses the BBB (TERTIARY STRUCTURE); it inhibits AChE in the CNS.
Longer duration of action due to partitioning into lipid and its higher affinities for AChE.
Oral preparation for Alzheimer’s disease.
High levels of hepatotoxicity limits utility of this drug.
Most of the time liver function returns to normal
Alanine aminotransferase levels high; return to normal upon discontinuing drug.
Neostigmine
Has a carbamoyl ester linkage.
Quaternary amine
“Reversible” carbamate inhibitor
Equal or greater potency than physostigmine.
It is hydrolyzed by AChE, but much slower than ACh.
The carbamoyl moiety of neostigmine resides in the acyl pocket.
Methylcarbamoyl AChE and dimethylcarbamoyl AChE (half life for hydrolysis is 15-30 minutes) formed.
It is far more stable than the acetyl enzyme.
Sequestration (form a stable compound with that is no longer available for reaction) of the enzyme in its carbamoylated form; precludes (prevents) the enzyme-catalyzed hydrolysis of ACh for extended periods of time.
The duration of action of the carbamoylating agents is 3-4 HOURS!
Used to treat urinary or GI motility agent, glaucoma, NMJ diseases such as myasthenia gravis.
Serious side effects: seizure, bronchospasm, cardia arrhythmia, bradycardia, cardiac arrest.
Other side effects: Hypotension or hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis.
Contraindications: Mechanical intestinal or urinary obstruction, concomitant choline ester or depolarizing neuromuscualr blocker use, CV disease.
Used in chronic treatment of myasthenia gravis because it is a long acting cholinesterase inhibitor.
Neostigmine also has direct cholinergic effect at Nm receptors.
-Effects at the GI TRACT: Enhances gastric contractions, increases the secretion of gastric acids.
-After a bilateral vagotomy (remove part of vagus nerve), the effects of neostigmine on gastric motility are greatly reduced.
-In patients with marked achalasia and dilation of the esophagus, the lower portion of the esophagus is stimulated by neostigmine; the drug can cause a salutary (beneficial) increase in tone and peristalsis.
-In atony produced by muscarinic receptor antagonists or prior surgical intervention, neostigmine augments motor activity of the small and large bowel (colon especially); propulsive waves are increased in amplitude and frequency and the movements of the investing contents is promoted.
Absorption, fate and excretion:
-Absorbed poorly after oral administration; larger doses are needed that by the parenteral route.
-Destroyed by plasma esterases; excreted in the urine
-Half life only 1-2 hours (short).
Available as an ophthalmic solution, for oral use and parenteral injection.
Duration of action to maintain a reasonably even level of strength: 2-4 hours.
Physostigmine
Drug that has a carbamoyl ester linkage.
“Reversible” carbamate inhibitor.
Tertiary amine.
Hydrolyzed by AChE, but slower than ACh.
The carbamoyl moiety resides in the acyl pocket.
Methylcarbamoyl and dimethylcarbamoyl are formed-these are far more stable than the ACh enzyme.
Half life for hydrolysis of dimethylcarbamoyl enzyme is 15-30 minutes.
There is sequestration of these enzymes in its carbamoylated form, which prevents the enzyme-catalyzed hydrolysis of ACh for extended periods of time.
The duration of inhibition by the carbamoylating agents is 3-4 hours!!
Used for the reversal of anticholinergic toxicity or induced paralysis in surgery.
Serious side effects: seizures, bronchospasm, cardiac arrhythmia, bradycardia, cardiac arrest
Other side effects: hypotension or hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis.
Contraindications: Mechanical intestinal or urinary obstruction, concomitant choline ester or depolarizing neuromuscular blocker use, CV disease.
The non-polar structure makes physostigmine useful for combating CNS anticholinergic toxicity (CAN CROSS THE BBB).
Absorption, fate and excretion:
-Absorbed readily from the GI tract, subcutaneous tissue and mucous membranes.
-Conjunctival instillation of solutions of the drug; this may result in systemic effects because it is so permeable to the BBB (tertiary compound).
-Pressure on the inner canthus (inner eye where the upper and lower eyelids meet) can prevent absorption from the nasal mucosa.
-Parenterally administer physostigmine: largely destroyed within 2 hours (quick); mainly by hydrolytic cleavage by plasma esterases, renal elimination plays a minor role in its elimination.
Therapeutic uses:
-Physostigmine with its shorter duration of action is useful in the treatment of intoxication by atropine and several drugs with anticholinergic side effects as well as the treatment of Friedreich’s or other inherited ataxias (the loss of full control of body movements).
-Available as an injectable, ophthalmic ointment and ophthalmic solution.
Organophosphorus inhibitors
DFP-diisopropylfluorophosphate
True hemisubstrates (enzyme inhibitor that acts as a substrate, but does not compete the catalytic cycle to regenerate active enzyme).
Resultant conjugate with active center serine
Phosphorylated or phosphorylated firms are extremely stable.
Tetrahedral in conformation; resembles the transition state formed in carboxyl ester hydrolysis.
Phosphoryl oxygen binds within the oxyanion hole of the active center.
Ethyl or methyl group in the phosphorylated enzyme-regernation of the enzyme takes several hours.
Secondary (DFP) or tertiary ally groups in the phosphorylated enzyme… further enhance the stability of the phosphorylated enzyme. significant regeneration of the enzyme is not observed; return of the AChE activity depends on synthesis of a new enzyme.
The stability of the phosphorylated enzyme is enhanced through “aging” due to the loss of one of the alkyl groups-ultimately irreversible for all purposes..
The organophosphorate and carbamoyl ester antiAChEs react covalently with serine, in the same manner as does ACh.
Reversible and irreversible are quantitative, it may happen but it takes a longer time; ACh is relatively fast reversal.
Absorption, fate and excretion:
-highest risk of toxicity agents are the highly lipid soluble liquids.
-Many have high vapor pressures.
Actions at Effector Organs
Transmitter ACh accumulates in the cleft because there is prevention of hydrolysis.
This enhances the response of ACh from cholinergic impulses.
Tertiary and quaternary ammonium Anti-ChE compounds might have additional direct actions at certain cholinergic receptor sites.
Examples: Effects of neostigmine on the spinal cord and NMJ-combination of both its anti-ChE activity and direct cholinergic stimulation.
Pyridostigmine
“Reversible” carbamate inhibitor
Close congener (same category) to Neostigmine and Physostigmine that is also used to treat myasthenia gravis.
Serious side effects: seizure, bronchospasm, cardiac arrhythmia, bradycardia, cardiac arrest.
Other side effects: hypotension of hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis.
Contraindications: Mechanical intestinal or urinary obstruction, concomitant choline ester or depolarizing neuromuscular blocker use, CV disease.
Used for the chronic treatment of myasthenia gravis (long duration).
Absorption, fate and excretion:
-Absorbed poorly after oral administration
-Destroyed by plasma esterases
-Excreted in the urine
-Half-life is only 1-2 hours (short)
Available for oral or parenteral use.
Duration of action to maintain a reasonably even level of strength: 3-6 hours.
Available in sustained release tablets-maintains patents for 6-8 hour periods.
Should be limited to use at bedtime.
180 mg: 60 mg released immediately and 120 mg released over several hours.
Demecarium
“Reversible” carbamate inhibitor
Miotic agent
Increased anti-ChE potency and duration of action.
Clinical applications in open angle glaucoma.
Serious side effects: Allergic reaction (shortness of breath, closing of throat, swelling of lips, face, or tongue, and hives), abdominal cramps or diarrhea.
Other side effects: burning, stinging or red eyes, headache or brow ache, decreased vision in poor light. Contraindications: pregnancy, active uveal (vascular tissue of eye) inflammation, angle-closure glaucoma.
Rivastigmine
“Reversible” carbamate inhibitor
Carbamoylating inhibitor with high lipid solubilities.
Readily crosses the BBB (TERTIARY STRUCTURE); longer duration of action.
Approved for treatment of mild to moderate Alzheimer’s disease and dementia.
Side effects: diarrhea, nausea, vomiting, cramps, anorexia, vivid dreams.
Produces modest symptomatic benefits in Alzheimer’s disease.
Rivastigmine affects both acetylcholinesterase and butyrylcholinesterase by forming a carbamoylate complex with the enzymes.
Oral preparation for Alzheimer’s disease.
Long-acting carbamoylating inhibitor.
Efficacy, tolerability, side effects are similar to that of Donepezil.
Echothiophate
Only organophosphorus compound that is used clinically.
Quaternary (positively charged)
Limited to ophthalmic administration
Not volatile and does not readily penetrate the skin.
Clinical applications in open angle glaucoma
Side effects: brow ache, uveitis (a form of eye inflammation), blurred vision.
Contrindications: active uveal inflammation, angle closure glaucoma.
Topical use, largely replaced.
Long-lasting cholinesterase inhibitor.
General considerations of Anti-ChE agents
The pharmacological properties of these agents can be predicted by knowing those loci where ACh is released physiologically by nerve impulses, the degree of nerve impulse activity, and the responses of the corresponding effector organs to ACh.
Potential Anti-ACh agent effects:
-Stimulation of muscarinic receptor responses at autonomic effector organs.
-Stimulation followed by depression or paralysis; all autonomic ganglia and skeletal muscles (nicotinic actions).
-Stimulation (with occasional subsequent depression) of cholinergic sites in the CNS.
Doses of anti-ChE agents
Toxic or lethal doses:
Most normal anti-ChE effects can be seen.
Smaller doses that are used therapeutically:
-Compounds containing a quaternary ammonium group-do not penetrate cell membranes really, are absorbed poor from the GI tract, across the skin, and are excluded from the CNS by the BBB.
Quaternary compounds act preferentially at the NMJ of skeletal muscle; they exert their action both as anti-ChE agents and as direct agonists; they have comparably less effect at autonomic effector sites and ganglia.
More lipid-soluble agents (tertiary):
-Are well absorbed after oral administration, have ubiquitous effects at both at peripheral and central cholinergic sites.
-May be sequestered in lipids for long time periods.
-Lipid soluble (not echothiophate) organophosphorus agents are well absorbed through the skin.
-Volatile agents are transferred readily across the alveolar membrane.
-Have actions on autonomic effector cells and on CNS cortical and subcortical sites (receptors are largely of the muscarinic type and blocked by atropine).
-Have actions on autonomic ganglia; nicotinic and muscarinic receptors.
SITES OF ACTION OF ANTI-CHE AGENTS OF THERAPEUTIC IMPORTANCE: CNS, eye, intestine, NMJ of skeletal muscle.
Anti-ChE effects at the EYE
Local application of anti-ChE agents to the conjuctiva
- causes conjunctival hyperemia (excess of blood in the vessels).
- causes miosis-apparent in a few minutes and can last several hours to days.
- blocks accommodation reflex with resultant focusing to near vision; block of accommodation is more transient, it disappears before termination of miosis.
- Usually decreases intraocular pressure when elevated as the result of facilitation of outflow of the aqueous humor.
