Historical prototype: Physostigmine
Physostigmine is an alkaloid isolated from the plant Physostigma venenosum (Calabar bean). Being a tertiary amine, it readily crosses the blood-brain barrier (BBB) and exerts a pronounced central effect. At high concentrations, the drug is capable not only of accumulating the neurotransmitter but also of directly stimulating cholinergic receptors.
Historically, physostigmine was used in two main areas:
- Toxicology: served as a classic antidote for poisonings by centrally acting anticholinergics (specifically, henbane and atropine intoxication).
- Ophthalmology: was used to manage acute attacks of angle-closure glaucoma. By causing miosis (pupil constriction), the drug effectively facilitates the outflow of aqueous humor, surpassing pilocarpine in potency. However, its use was limited due to a serious drawback: powerful contraction of the iris induces intense pain in the eyes and supraciliary arches.
Physostigmine became the starting point for creating a whole class of drugs for treating neurodegenerative diseases, although it is not used for dementia itself due to its overly short duration of action and numerous peripheral side effects.
Pathophysiology and treatment of Alzheimer's disease
The pathogenesis of Alzheimer's disease is based on progressive atrophy of neurons in the cerebral cortex and subcortical structures. Cholinergic neurons are affected first, leading to a sharp decrease in acetylcholine concentration. The main pharmacological strategy is to compensate for this deficit using anticholinesterase agents.
The evolution of drugs for treating dementia has gone through several stages:
- Tacrine (Cognex): one of the first drugs, its use is now strictly limited. Its main drawback is severe hepatotoxicity and an abundance of adverse reactions.
- Modern generation: galantamine (Reminyl), rivastigmine (Exelon), donepezil (Aricept).
Modern agents are characterized by high selectivity. They inhibit acetylcholinesterase predominantly in brain tissues (especially rivastigmine), minimally affecting the enzyme in skeletal muscles and internal organs. Due to this, they have a more favorable safety profile: no hepatotoxicity and fewer peripheral effects.
Regimen:
- Donepezil is prescribed once daily.
- Galantamine and rivastigmine — twice daily.
- Rivastigmine is also available as a transdermal therapeutic system (patch) acting for 24 hours.
Such symptomatic therapy improves cognitive functions (memory, attention, speech) and partially mitigates the manifestations of dementia.
Features of Galantamine and Ipidacrine
Galantamine (Nivalin) is a snowdrop alkaloid that has found wide application outside of dementia therapy. It is actively used in neurology to treat skeletal muscle paralysis (sequelae of poliomyelitis, spastic forms of cerebral palsy), and is also administered subcutaneously for myasthenia gravis. In internal medicine, it helps manage intestinal and urinary bladder atony. In anesthesiology, the drug is administered intravenously as an effective antagonist of curariform muscle relaxants (nondepolarizing type).
Ipidacrine (Neuromidin) possesses a unique dual mechanism:
- Exhibits mild anticholinesterase activity.
- Blocks potassium channels on neuronal membranes, which facilitates depolarization and significantly improves nerve impulse conduction.
Ipidacrine acts in both the central and peripheral nervous systems. The spectrum of its indications includes polyneuritis, myasthenic crises, bulbar paralysis, intestinal atony, and uterine inertia.
Toxicology and side effects
The effects of anticholinesterase agents that penetrate the CNS are strictly dose-dependent. While low doses have a favorable stimulating effect (accelerating reflexes, improving attention), high doses lead to severe intoxication: generalized seizures develop, progressing to coma, and fatal respiratory center depression.
Typical side effects include gastrointestinal disorders (nausea, vomiting, diarrhea) and neurological symptoms (headache, dizziness).
Carbamate poisoning (agricultural insecticides) Carbamates are easily absorbed through the skin and mucous membranes. The clinical picture of intoxication is identical to organophosphate (OP) poisoning, but is milder and resolves faster because cholinesterase inhibition is reversible.
Rescue principles: Unlike OP poisonings, cholinesterase reactivators are not used — they are pointless due to the short-lived bond between the toxin and the enzyme. The main emergency treatment is atropine, which competitively displaces excess acetylcholine from its binding to M-cholinergic receptors.
Briefly: answers to topical questions
What are the absolute and relative contraindications to the use of anticholinesterase agents?
Contraindications to the use of anticholinesterase agents are conditions in which vagus nerve stimulation or increased muscle tone is hazardous. A division into absolute and relative contraindications is not provided in the sources.
- CNS — epilepsy, Parkinson's disease.
- Cardiovascular system — angina pectoris, cardiac conduction disorders.
- Respiratory system — bronchial asthma.
- Gastrointestinal tract — peptic ulcer disease of the stomach and duodenum.
Which drugs belong to the group of cholinesterase reactivators?
Cholinesterase reactivators include drugs categorized by their ability to cross the blood-brain barrier:
- Dipiroxim and Alloxime are quaternary ammonium compounds. They poorly cross the BBB and eliminate predominantly peripheral effects.
- Isonitrosine is a tertiary amine. It readily penetrates the CNS, eliminating both peripheral and central effects.
What are the pharmacokinetic features and differences between donepezil and rivastigmine?
Pharmacokinetic and pharmacological features of the drugs:
| Characteristic | Donepezil | Rivastigmine |
|---|---|---|
| Selectivity of action | Inhibits acetylcholinesterase predominantly in the brain | Selectivity of action is especially pronounced; inhibits acetylcholinesterase predominantly in the brain |
| Duration of action | Long duration of action | Long duration of action |
| Dosing regimen | Once daily | Twice daily |
| Dosage forms | Dosage forms are not specified in the sources | Oral forms and a transdermal patch system |
| Features of transdermal administration | Not specified | When using the patch, the effect lasts for 24 hours; transdermal administration ensures the substance enters the bloodstream bypassing the liver |
Mechanism of action of ipidacrine — "Double hit on the synapse": enzyme block (AChE) + membrane potassium channel block.
Class and exam questions
Why is physostigmine, which reduces intraocular pressure more strongly than pilocarpine, rarely used for glaucoma?
The drug causes excessively strong contraction of the iris. This leads to marked pain in the eyes themselves and the superciliary arch area, which limits its use.
What is the advantage of modern drugs for Alzheimer's disease over historical physostigmine and tacrine?
Modern agents (donepezil, rivastigmine) have a prolonged duration of action and selectively block the enzyme specifically in the central nervous system, reducing peripheral side effects. In addition, unlike tacrine, they do not cause severe liver damage (hepatotoxicity).
Why are cholinesterase reactivators contraindicated in poisoning by carbamate insecticides?
Carbamates form a reversible and short-term bond with acetylcholinesterase. The enzyme rapidly restores its activity on its own, so specific therapy is limited to the use of atropine to block M-cholinergic receptors.
What else to study on this topic
- Structure and permeability of the blood-brain barrier for drugs
- Comparative characteristics of reversible and irreversible acetylcholinesterase inhibitors
- Mechanisms of cholinergic deficit development in Alzheimer's disease
- Interaction of anticholinesterase agents with nondepolarizing muscle relaxants
- Pharmacodynamics of atropine as a universal M-cholinergic blocker
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