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About Nivalin

Anticholinesterase activity of nivalin (galantamine hydrobromide)

Nivalin reversibly inhibits brain, erythrocyte, muscle and serum cholinesterase. The effect on brain cholinesterase is 10-12 times stronger than the effect of physostigmine due to the penetration of nivalin through the blood-brain barrier. Galantamine hydrobromide (nivalin) inhibits muscle cholinesterase more strongly than pyridostigmine bromide and less than neostigmine bromide. The anticholinesterase activity of nivalin is manifested in concentrations of 10-7 g/ml.

Effect of nivalin on neuromuscular transmission

Nivalin prolongs the action of acetylcholine on the postsynaptic membrane and its accumulation in the synaptic cleft, resulting in increased intensity and time of transmission of the nerve impulse to muscle tissue. The strength of muscle contraction and its duration increases. The manifestation of this effect depends on the concentration of nivalin, respectively, on its plasma concentration.

Fig.2. A. Presynaptic membrane, axon terminal button, where acetylcholine (ACh) is synthesized, captured and released through synaptic vesicles, fragments of choline and acetate of hydrolyzed ACh are reabsorbed

B. The synaptic cleft, in which ACh is released, reaches the postsynaptic membrane (B) and upon contact with receptors, transmission occurs, and is subsequently hydrolyzed by acetylcholinesterase (AChE). Nivalin (“N”) competitively and reversibly blocks AChE.

Nivalin (galantamine hydrobromide) as an antagonist of non-depolarizing neuromuscular blocking agents

Nivalin finds its first clinical application in anesthesiological practice as a means of antagonizing the effect of non-depolarizing neuromuscular blockers - d-tubocurarine, galamine, pancuronium bromide, aloferin, diplacin, etc. By blocking acetylcholinesterase, nivalin allows acetylcholine to displace the neuromuscular blocker from the receptors of the postsynaptic membrane and restore neuromuscular transmission.

The antagonizing effect appears within 20-30 s from the moment of application of Nivalin. It is stable for 30-60 min. No recurarization phenomena are observed.

Nivalin has a milder and more manageable effect than neostigmine: a wider therapeutic index, weaker cardiotoxicity and a weaker manifestation of muscarinic, parasympathomimetic effect

Nivalin is convenient and suitable for use by both children and older adults.

Nivalin and depolarizing neuromuscular blockers

Nivalin enhances the neuromuscular blockade caused by depolarizing blockers (succinylcholine)!

Once depolarized by the corresponding muscle relaxant, the postsynaptic membrane continues its depolarization, i.e. it remains in this state, maintained by accumulated acetylcholine under the influence of nivalin.

Nivalin is not used if depolarizing neuromuscular blockers have been used!

Galantamine hydrobromide and its effect on the smooth muscles of the gastrointestinal tract

Nivalin stimulates the muscles of the gastrointestinal tract. It increases the tone and frequency of smooth muscle contraction. Activates peristalsis. This phenomenon caused by nivalin is a frequently sought-after necessity, as it is manageable through flexible dosing capabilities, as well as neutralization with parasympathicolytics (atropine) (4).

Fig.3. Places where nivalin acts along the reflex arc path: A. Anterior horn of the spinal cord - motor ganglia; B. Efferent, motor axon, which has a neuromuscular synapse at the end (B); D. Afferent pathway

Galantamine and its effect on the muscles of the bladder and ureters

Nivalin tones the detrusor muscles of the bladder and reduces the threshold of irritability by 15-20 times. Nivalin increases the potential for myoelectric stimulation of the detrusor function of the bladder.

Nivalin increases the tone and peristalsis of the ureters, thereby facilitating the outflow of urine.

Nivalin and neurotransmission in the upper segment of the cervical sympathetic ganglia

Nivalin prolongs, intensifies and increases the amplitude of the postganglionic potential. It leads to a slight weakening of negative post-potentials.

Nivalin antagonizes the blocking effect of hexamethonium on the synaptic neurotransmission of nerve impulses in the superior cervical sympathetic ganglia.

Galantamine hydrobromide and its effect on glomus caroticum

Nivalin increases the sensitivity of acetylcholine hemoreceptors in the glomus carotidum. Stimulates the afferent impulses of the Hering nerve and hence breathing.

Nivalin antagonizes the blocking effect of curare-like non-depolarized agents on the glomus carotidum.

Nivalin has a direct effect on acetylcholine-mediated hemoreceptors in the glomus carotidum. Experimental data have shown that it enhances the irritant effect of nicotine and potassium cyanide on the carotid glomus (5).

Nivalin exhibits this effect in concentrations of 5 x 10-7 – 10-4g/ml.

NIVALIN AND THE ADRENAL GLANDS

Effect (galantamine hydrobromide) of nivalin on the medulla of the adrenal glands

Nivalin stimulates acetylcholine-mediated neurotransmission of the splanchnicus nerve to chromaffin cell receptors in the adrenal medulla. The stimulating effect is also manifested through the bloodstream. As a result, adrenaline is released.

The effect of nivalin on the adrenal cortex

Experimental data have shown that subcutaneous administration of nivalin significantly increases the concentration of 17-hydroxycorticosteroids in the blood (6). The effect is realized through the pituitary-adrenal system and stimulation of peripheral cholinergic structures, and it is assumed that the effect on ACTH has a leading role (7).

Nivalin and electrophysiology of afferent nerve impulses

In small doses, nivalin causes acceleration of fast potentials and the manifestation of slow potentials.

In large doses, the effect of nivalin develops in two phases - an inhibition phase followed by a stimulation phase.

Nivalin (galantamine hydrobromide) and the cardiovascular system

Nivalin potentiates the effect of acetylcholine on the heart, which is reflected in moderate negative inotropism, which manifests itself at concentrations from 10-5 - 10-3g/ml. At higher doses, the heart rhythm changes in two phases: after an initial slowdown, acceleration is observed. The electrocardiogram shows a moderate prolongation of the PQ interval and an increase in T wave voltage.

Nivalin has a moderate hypotensive effect in small and medium doses, potentiating the cardiac and peripheral vascular effect of acetylcholine. At higher doses, a two-phase effect appears: after an initial decrease in blood pressure, an increase is observed, which is explained by the effect of nivalin on the central nervous system, adrenal medulla, sympathetic ganglia and postganglionic parasympathetic injection into the heart muscle.

Nivalin has no cardiotoxic effect over a wide dose range. All unwanted effects are quickly neutralized by atropine.

Nivalin (galantamine hydrobromide) and the central nervous system

Nivalin crosses the blood-brain barrier due to the presence of a tertiary nitrogen atom. This gives it the opportunity to demonstrate its anticholinesterase activity at all levels of the central nervous system, where acetylcholine transmission of nerve impulses occurs.

The effect of nivalin on the spinal cord and medulla oblongata

Nivalin increases the bioelectrical activity of the spinal cord and medulla oblongata. The frequency and amplitude of biopotentials of postganglionic fibers increase. Nivalin intensifies efferent impulses in motor nerves.

Nivalin stimulates all mono- and polysynaptic reflexes of the spinal cord.

The effect of Nivalin at the level of the spinal cord and medulla oblongata is determined twice: by direct action and by a reflex-descendant pathway from the brain.

Effect of nivalin on the brain

Conditioned reflexes, as a classic model of higher nervous activity, are exposed to nivalin.

Nivalin shortens the latent period and time of conditioned reflexes.

. In experiments with animals, it was found that nivalin normalizes the function of certain levels of higher nervous activity, disrupted due to the use of psychopharmacological drugs (8).

Nivalin eliminates disturbances in the conditioned reflex arc caused by anticholinergics. Electroencephalographic recording of the bioelectric activity of the brain showed that Nivalin affects the levels of the ascendant activating system of the reticular formation of the mesencephalon, the ventral and dorsal part of the hippocampus. At these levels, changes in neuronal cells have been histologically established, which proves that nivalin interferes with their metabolic activity (9).

Nivalin (galantamine hydrobromide) and its effect on phagocytosis

Experimental data have shown that nivalin activates phagocytosis, which leads to improved cellular immunity. This mechanism is believed to be driven by the effects of nivalin on the central and autonomic nervous system via acetylcholine and other neurotransmitters (10).

Pharmakinetics of Nivalin

Instructions for use NIVALIN® tablets

Galantamine, as a cholinesterase inhibitor, has a vagotonic effect on the sinoatrial node and AV node, which can cause bradycardia and AV block. The drug should be used with extreme caution in patients with supraventricular conduction disorders, as well as when used simultaneously with other drugs that significantly reduce heart rate. In such patients, more frequent monitoring of heart rate (pulse) is necessary.

As a result of its cholinomimetic effect, galantamine may increase gastric secretion and cause gastrointestinal side effects. A higher risk exists in patients with a history of peptic ulcer disease, during the recovery period after gastric surgery and in patients concomitantly taking NSAIDs. When treating such patients with galantamine, monitor for symptoms of active or occult gastrointestinal bleeding.

Galantamine should be used with caution in patients with chronic obstructive pulmonary disease.

The use of galantamine is not recommended in patients with urinary retention or after recent prostate surgery.

Cholinomimetics may potentiate the effect of succinylcholine-type neuromuscular blockers during anesthesia.

When treated with cholinesterase inhibitors, including galantamine, a decrease in body weight may be observed in some cases. In such cases, it is necessary to monitor the patients' body weight.

The tablets contain wheat starch as an excipient, which may contain gluten in small amounts, safe for people with celiac disease (gluten enteropathy).

The tablets contain lactose as an excipient, which should be taken into account when prescribing to patients with galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption.

Impact on the ability to drive vehicles and operate machinery

Nivalin® may cause drowsiness and dizziness, especially at the beginning of treatment. In these cases, it is recommended to avoid driving vehicles and working with machines until the symptoms disappear.

Preclinical safety data

Preclinical data do not indicate any particular risk to humans based on conventional pharmacological testing for safety, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

In a study of the chronic toxicity of galantamine when taken orally in doses of 0.25, 0.5; 1 mg/kg body weight; s/c - 0.125, 0.5 mg/kg body weight for 6 months in mature Wistar rats, no biometric, biochemical, hematological and morphological deviations from normal parameters are observed. The processes of pregnancy and childbirth proceeded normally. No statistically significant deviations were established in comparison with the control group, with the exception of increased physical activity for approximately 2 hours after administration of higher doses. The doses used are equivalent to the average therapeutic daily doses used in humans, divided into single, double and quadruple doses respectively.

Studies of galantamine using mutagenicity tests show no evidence of mutagenic potential.