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Pharm I > Anticholinesterases > Flashcards

Anticholinesterases Flashcards

1
Q

The basis for specificity differences between AChE and butylrylcholinesterase

A
  1. Acyl pocket of the active center
  2. The choline subsite of the active center
  3. The peripheral anionic site
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2
Q 
A. Reversible inhibitors
------------------
NON COVALENT
Short-acting in general
(simple alcohol?)
A

Edrophonium (4): quaternary structure facilitates renal elimination, volume of distribution is limited.

Tacrine (higher affinity for AChE)

Donepezil

-bind with higher affinity to the active center.

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3
Q

Edrophonium

A
  • Quaternary
  • Reversible
  • Activity limited to peripheral nervous system synapses
  • Short duration of action, more rapid renal elimination
    1. Used in diagnosis of myasthenia gravis and other diseases of the neuromuscular junction
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4
Q

Tacrine

Donepezil

A

-Tertiary
-Higher affinity for AChE
-More hydrophobic and readily cross the blood-brain barrier => inhibit AChE in the CNS.
-Longer duration of action due to partitioning into lipid and higher affinities for AChE
==============
Oral treatment of Alzheimer’s disease (other drugs: Rivastigmine, Galantamine)

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5
Q 
B. Drugs have a carbamoyl ester linkage
---------------
Half-life 15-30min
COVALENT binding
Long half-time of AChE inhibition
A

Physostigmine (tertiary)
Neostigamine (quaternary)

  • Hydrolized by AChE but much more slowly than ACh.
  • Carbamoyl moiety resides in the acyl pocket => more stable than acetyl enzyme.
  • Sequestration of the enzyme in its carbomoylated form, precludes the enzyme-catalyzed hydrolysis of ACh for extended periods of time. (duration of inhibition by the carbamoylating agents is 3-4h)
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6
Q

Physostigmine

A

-Tertiary
-Alkaloid obtained from the Calabar or ordeal bean (perennial plant found in tropical West Africa)
-First therapeutic use of the drug in 1877
-Treatment of glaucoma, once/day
——————————-
Absorption, Fate and Excretion
-Absorbed readily from the GI tract, subcutaneous tissue and mucous membranes. => may result in systemic effects (pressure on the inner canthus can prevent absorption from the nasal mucosa)
-Parentally administered physostigmine is largely destroyed within 2 hours. (mainly hydrolytic cleavage by plasma esterases). Renal excretion plays only a minor role in its elimination.
——————–
Available as an injectable, ophthalmic ointment药膏 and ophthalmic solution

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7
Q

Neostigamine

A
  • Quaternary ammonium derivative
  • Equal or greater potency to physostigmine
  • Introduced into therapeutics in 1931
  • Stimulant action on the GI tract, subsequently reported to effective in treatment of myasthenia gravis symptoms.
  • Available as ophthalmic solution, for oral use and parenteral injection
  • enhance GI contraction and secretion (different effects in different conditions.)
  • Used to treat Myasthenia Gravis
  • To reverse paralysis induced by nicotinic ACh receptor for treating anticholinergic poisoning during or after surgery.
  • Absorbed poorly after oral administration => larger doses (15-30mg or more) needed than by the parenteral route (0.5-2mg)
  • Destroyed by plasma esterases
  • Quaternary aromatic alcohols and parent compounds are excreted in the urine (HL 1-2h)
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8
Q

Pyridostigmine

A

-Quaternary
-Close congener (analog) that is also used to treat Myasthenia Gravis
-Oral or parenteral use
———————–
-Absorbed poorly after oral administration => larger doses (15-30mg or more) needed than by the parenteral route (0.5-2mg)
-Destroyed by plasma esterases
-Quaternary aromatic alcohols and parent compounds are excreted in the urine (HL 1-2h)
========================
P.S. Ambenonium chloride is available for oral use

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9
Q

Demecarium

A
  • Miotic agent
  • Increased anti-ChE potency and duration of action
  • Two neostigmine molecules connected by a series of ten methylene groups
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10
Q

Rivastigmine

A
  • Tertiary
  • Carbamoylating inhibitor with High Lipid Solubility (readily cross the BBB, longer duration of action)
  • Approved for Alzheimer’s disease treatment.
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11
Q

2 R groups (R1 and R2)
X group (the leaving group)

A

-Highest risk of toxicity agents are highly lipid-soluble liquids
-Many have high vapor pressures
——————————————————-
Echothiophate (only one used clinically)

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12
Q

Echothiophate

A
  • Quaternary ammonium organophosphorus compound used clinically. (limited to opththalmic administration)
  • Postitively charged, not volatile and doesn’t readily penetrate the skin.
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13
Q

Quaternary Ammonium Group

A
  • Absorbed poorly from the GI tract, across the skin, and are excluded from the CNS by BBB
  • They act preferentially at the neuromuscular junctions of skeletal muscle (exert their action both as anti-ChE agents and as direct agonists => elicit cholinergic effect, can stimulate Ch receptors directly)
  • Have comparatively less effect at autonomic effector sites and ganglia.
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14
Q

More Lipid Soluble Agents

A
  • Well absorbed after oral administration and across skin
  • Have ubiquitous effects at both peripheral and central cholinergic sites.
  • Have actions on autonomic effector cells and on CNS cortical and subcortical sites. (receptors are largely of the muscarinic type and actions are blocked by atropine)
  • Have actions on autonomic ganglia (nicotinic and muscarinic receptors)
  • May be sequestered in lipids for long time
  • Volatile agents are transferred readily across the alveolar membrane.
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15
Q

Sites of action of anti-ChE agents of therapeutic importance

A

a. CNS, eye (conjunctival hyperemia, miosis, block of accommodation reflex but is transient, elevated intraocular pressure), intestine, and the neuromuscular junction of skeletal muscle
b. Other actions are of toxicological consequence.

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16
Q

GI

A

Neostigmine

  • enhance gastric contractions
  • increases the secretion of gastric acid
  • effects different (after bilateral vagotomy => effects on gastric motility are greatly reduced; patients with marked achalasia and dilation of the esophagus => lower portion of the esophagus is stimulated, can cause a salutary increase in tone and peristalsis)
  • Atony produced by muscarinic receptor antagonists or prior surgical intervention (augment motor activity of the small and large bowel, especially colon.)
17
Q

Neuromuscular Junction

A
  • Intra-arterial injection of neostigmine evokes an immediate contraction of skeletal muscle.
  • Increase residence time of ACh in the synapse; allows for lateral diffusion and rebinding of the transmitter to multiple receptors.
  • Successive stimulation of neighboring receptors to the release site in the endplate => results in a prolongation of the decay time of the endplate potential. Destroy endplate depolarization and the action potential development synchrony.
  • Blockade occur due to depolarization caused by sufficient inhibition of AChE, may result in antidromic firing of the motoneuron.
  • Neostigmine is not effective against the skeletal muscle paralysis caused by succinylcholine.
18
Q

Other Sites

A

Secretory glands/Gastric glands:

  • low doses of anti-ChE augment secretory responses to nerve stimulation
  • higher doses increase the resting rate of secretion.

Bronchioles and ureters:
-increase contraction of smooth muscle fibers, ureters may show increased peristaltic activity.

CV:
-bradycardia
-higher doses cause a fall in blood pressure.
at Ganglionic level:
-Normal level: accumulation of ACh initially is excitatory and nicotinic receptors.
-Higher conc: ganglionic blockade ensues as a result of persistant depolarization.
-Opposite effects of ACh accumulation: excitatory action on the parasympathetic ganglion cells => reinforce diminished CO. effects on sympathetic ganglion cells would lead to enhanced CO
=Combined effcts lead to an INCREASED heart rate with severe ChE inhibitor poisoning.

19
Q

Treatment of Acute Anti-ChE intoxication

A
  1. Atropine
    - Effectively antagonizes the actions at muscarinic receptor sites. (increased tracheobronchial and salivary secretion, antagonizes the bronchoconstriction and bradycardia)
    - Larger doses are required to get appreciable concentrations of atropine into the CNS.
    - Virtually without effect aginst the peripheral neuromuscular effects.
    - ——————————————
  2. Can be reversed by pralidoxime (2-PAM)
    - Cholinesterase reactivator, early treatment is very important
    - Must be regarded as a supplement to the administration of atropine, continue atropine and pralidoxime for a week or longer when with severe toxicities from the lipid-soluble agents.
20
Q

Pralidoxime

A

-Available in the US as a parenteral formulation
-Oxime (RCH=NOH) is oriented proximally to exert a nucleophilic attack on the phosphorus. Phosphoryloxime is formed leaving the regenerated enzyme.
-Dependency of velocity o freactivation of phosphorylated AChE by oximes => certain phosphorylated AChEs can undergo a fairly rapid process of “aging” and become resistant to reactivators.
-Oximes are not effective in antagonizing more rapidly hydrolyzing carbamoyl ester inhibitors.
-**Pralidoxime itself has WEAK ANTI-ChE ACTIVITY **
(not recommended for the treatment of overdosage with neostigmine or physostigmine or poisoning with carbamoylating insceticides such as carbaryl)

21
Q

Paralytic Ileus and Atony of the Urinary Bladder

A

-Direct parasympathomimetic agents are employed for the same purpose.
-Relieves abdominal distension and acute colonic pseudoobstruction
-Treat atony of the detrusor muscle of the urinary bladder
————————–
Situations when neostigmine should not be used:
-Intestine or urinary bladder is obstructed
-Peritonitis腹膜炎
-Viability of the bowel is doubtful
-Bowel dysfunction results from inflammatory bowel disease.

22
Q

Glaucoma and other ophthalmologic indications

A

Echothiophate
-used in advanced glaucoma
-may be associated with the production of CATARACTS.
===============
Other ophthalmologic conditions:
-Accomodative esotropia (斜眼) and myasthenia gravis in just the extraocular and eyelid muscles. (Anti-ChE employed locally)
-Adie (or tonic pupil) syndrome, results from dysfunction of the ciliary body, perhaps because of local nerve degradation. (Low concentration of Physostigmine decrease the blurred vision and pain).
-Breaking adhesions between the iris and the lens or cornea. (Short-acting anti-ChE agents in alternation with a mydriatic drug such as atropine.)

23
Q 
Myasthenia Gravis 
(autoimmune response, complement-mediated lysis of junctional folds in the endplate, enhanced receptor degradation)
A
  • Anti-ChE agents produces no improvement in most congenital myasthenic patients.
  • Edrophonium test for evaluation of possible MG (2mg rapid injection)
  • Pyridostigmine (30-60mg 3-6H, has sustained-release tablets for 6-8H, limited use for bedtime), neostigmine (7.5-15mg, 2-4H) and ambenonium (2.5-5mg, 3-8H): increase the response of myasthenic muscle to repetitive nerve impulses (primarily by the preservation of endogenous ACh even though you don’t have enough receptors). Optimal SINGLE ORAL DOSE of an anti-ChE agent is determined empirically to record baseline. After 1 HOUR or longer in the basal state, drug is given again. with 1/1.5x amount.
24
Q

Prophylacis in Cholinesterase Inhibitor Poisoning

A

Pyridostigmine

  1. Pretreatment with Pyridostigmine: reduces the incapacitation and mortality associated with nerve agent poisoning (ex. Soman). First large-scale administration of pyridostigmine to humans. Long-term: low incidence of Persian Gulf War syndrome
  2. Pyridostigmine has been approved by FDA
    - prophylaxis against soman, an organophosphate that rapidly ages.
25
Q

Intoxication by anticholinergic drugs

A

Many drugs have central and peripheral anticholinergic activity.

  • Atropine and other muscarinic agents, many other drugs.
  • Reversal of the central anticolinergic syndrome produced by these drugs => physostigmine is potentially useful in reversing the central anticholinergic syndrome.
26
Q

Alzheimer’s Disease Therapy
(deficiency of intact cholinergic neurons)

Tacrine
Donepezil
Rivastigmine
Galatamine

A
  1. Tacrine
    - FDA approved in 1993
    - Used in mild to moderate AD
    - High incidence of hepatotoxicity limits the utility of this drug.
  2. Donepezil
    - Approved for clinical use recently
    - 5-10mg daily oral doses (improved cognition and global clinical function in the 21- to 81- week intervals)
    - Drug delayed symptomatic progression of the disease for periods up to 55 weeks.
    - Side effects: Largely attributable to excessive cholinergic stimulation: nausea, diarrhea and vomiting.
  3. Rivastigmine
    - Long-acting carbamoylating inhibitor.
    - Recently approved for use in the US and Europe
    - Efficacy, tolerability, and side effects are similar to those of donepezil.
  4. Galatamine
    - AChE inhibitor,
    - Recently approved by the FDA.
    - Side effect profile similar to those of donepezil and rivastigmine

Pharm I (6 decks)

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