Medications used for stroke

TAP (recombinant tissue plasminogen activator, activase, alteplase)

Dose for intravenous administration - 0.9 mg/kg (not more than 90 mg)

Aspirin

Prescribed at a dose of 325 mg/day in the form of a tablet in a coating that dissolves in the intestine. The dose is reduced to 75 mg/day if severe gastrointestinal discomfort occurs.

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Ticlopidine (Ticlid)

The usual dose is 250 mg, administered orally 2 times a day with food. A clinical blood test with platelet count and white blood cell count is performed before the start of treatment, then every 2 weeks for the first 3 months of treatment. Subsequently, hematological testing is performed according to clinical indications.

Clopidogrel (Plavice)

Prescribed orally at a dose of 75 mg once a day

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Aspirin/dipyridamole extended release (apreiox)

1 capsule of the drug contains 25 mg of aspirin and 200 mg of delayed-release dipyridamole. Prescribed 1 capsule 2 times a day

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Heparin

Intravenous administration of heparin in full dose is carried out under control of partial thromboplastin time (during treatment this indicator should be increased by 2 times compared to the control). The best control of the level of anticoagulation is provided by continuous infusion of heparin using an infusion pump at a rate of 1000 units per hour.

In patients without established cerebral infarction, heparin is administered as a bolus in a dose of 2500 to 5000 units to achieve a more rapid effect. Partial thromboplastin time should be measured every 4 hours until the indicator stabilizes. Due to the risk of intracranial hemorrhagic complications in patients with infarctions, the infusion is started without an initial bolus. The risk of hemorrhagic complications is greatest immediately after the bolus is administered. Since the anticoagulant effect occurs quickly after intravenous administration of the drug, therapy should be carefully monitored and individualized as much as possible to minimize the risk of hemorrhagic complications. In the absence of a therapeutic effect in the first 4 hours, the infusion rate should be increased to 1200 units per hour.

Warfarin (Coumadin)

Therapy is carried out under the control of the International Normalized Ratio (INR), which is a calibrated analogue of prothrombin time. In patients with a high risk of stroke (for example, in the presence of an artificial heart valve or recurrent systemic embolism), the INR is brought to a higher level (3-5). In all other patients, the INR is maintained at a lower level (2-3).

Treatment is started with a dose of 5 mg/day, which is maintained until the INR begins to increase. The INR should be monitored daily until it stabilizes, then weekly and finally monthly. Each time, the dose is adjusted by a small amount to achieve the desired INR value.

Warfarin is contraindicated in pregnancy because it can cause multiple fetal malformations and stillbirth. Since heparin does not cross the placental barrier, it should be preferred in cases where anticoagulant therapy is absolutely necessary during pregnancy.

Extreme caution should be exercised when prescribing warfarin to a patient with a bleeding tendency.

When using warfarin for a long time, it is important to consider the possibility of interactions with other drugs: the effectiveness of warfarin may be increased or decreased by certain drugs. For example, a number of drugs may affect the metabolism of warfarin or blood clotting factors. Since this effect may be temporary, repeated adjustments of the warfarin dose may be required when taking other drugs at the same time.

Drug interactions can lead to life-threatening situations, so the patient should inform the physician of any new drug he or she begins taking. Alcohol and over-the-counter drugs may also interact with warfarin, especially drugs containing significant amounts of vitamins K and E. Laboratory monitoring should be increased until the effect of the new drug is known and clotting parameters have stabilized.

Prospects for treatment with antiplatelet agents and warfarin

Although aspirin reduces the risk of stroke in patients who have had a previous stroke or TIA, many patients still have recurrent strokes despite treatment. Its low cost and favorable side effect profile make aspirin the drug of choice for long-term therapy in patients at high risk of stroke. Patients who cannot tolerate aspirin can be treated with ticlopidine or clopidogrel. If standard doses of aspirin are not tolerated, a combination of low-dose aspirin and extended-release dipyridamole can be used. Clopidogrel and the combination of aspirin and dipyridamole have advantages over ticlopidine due to their more favorable side effect profile.

In cases where recurrent ischemic strokes or TIAs occur during aspirin treatment, warfarin is often used in practice. However, this practice is based on the misconception that aspirin should necessarily prevent strokes. Since some patients are resistant to aspirin, it is more appropriate to switch them to clopidogrel or ticlopidine rather than warfarin.

Neuroprotection

There are currently no neuroprotective agents whose effectiveness in stroke has been convincingly proven. Although many drugs have demonstrated a significant neuroprotective effect in experiments, this has not yet been demonstrated in clinical trials.

In cardiac ischemia, there are well-developed strategies that simultaneously restore perfusion and protect the myocardium from damage caused by insufficient energy supply. Neuroprotective methods are also aimed at increasing the resistance of brain cells to ischemia and restoring their function after restoration of blood supply. Protective therapy in cardiac ischemia reduces the load on the heart. The energy requirements of the myocardium are reduced by prescribing agents that reduce pre- and afterload. Such treatment helps to preserve cardiac function longer and delay the development of energy insufficiency and cell damage. It can be assumed that in cerebral ischemia, a decrease in energy requirements can also protect cells from ischemia and promote their recovery.

By creating a tissue culture model of cerebral ischemia, it became possible to establish the factors that determine neuronal sensitivity. Interestingly, these factors are similar to those that are important for cardiac muscle sensitivity.

Resistance to injury is determined by the ability to maintain and restore cellular homeostasis. The main functions of cells are to maintain ion gradients and oxidize cellular "fuel" to obtain energy. It is assumed that the NMDA receptor plays a key role in the development of ischemia, since the ion channel it contains allows a massive current of ions to pass through when open. Moreover, as shown in the figure, this channel is permeable to both sodium and calcium. The energy produced by mitochondria in the form of ATP is consumed by Na ⁺ /K ⁺ ATPase, which pumps sodium ions out of the cell. Mitochondria perform a buffering function with respect to calcium ions, which can affect the energy status of the cell. The figure does not reflect many potentially important interactions between sodium, calcium, second messenger systems, and energy supply processes.

The complex structure of the NMDA receptor is represented by three numbered regions. Region 1 is the binding site for the ligand, the excitatory neurotransmitter glutamate. This region can be blocked by competitive receptor antagonists, such as APV or CPR. Region 2 is the binding site within the ion channel. If this region is blocked by a noncompetitive antagonist, such as MK-801 or cerestat, the movement of ions through the channel stops. Region 3 is a complex of modulatory regions, including the binding site for glycine and polyamines. A region sensitive to oxidation and reduction has also been described. All three of these regions can be targets for neuroprotective agents. The concentration gradient of a number of ions, disruption of the calcium gradient appears to be the most important factor causing cell damage. Strict control over the oxidative processes is also a condition for maintaining the integrity of cellular structures. Disruption of redox homeostasis with the development of oxidative stress is the most important factor in cell damage. It is assumed that oxidative stress is most pronounced during reperfusion, but cellular homeostasis is also disrupted by ischemia itself. Free radicals, the increase in the level of which is characteristic of oxidative stress, arise not only in the process of mitochondrial oxidative reactions, but also as a by-product of intracellular signaling processes. Thus, maintaining calcium homeostasis and measures to limit the production of free radicals can reduce cell damage in cerebral ischemia.

Eputamate and NMDA receptors.

One of the most important factors in neuronal damage are excitatory amino acids, of which glutamic acid (glutamate) is the most important. Other endogenous compounds also have an excitatory effect, including aspartic acid (aspartate), N-acetyl-aspartyl-glutamic acid, and quinolinic acid.

Pharmacological and biochemical studies have identified four major families of excitatory amino acid receptors. Three of these are ionotropic receptors, which are ion channels whose state is modulated by receptor-ligand interactions. The fourth type is a metabotropic receptor, coupled to the second messenger system via a G protein.

Of the three ionotropic receptors, the NMDA (N-methyl-D-aspartate) receptor family has been studied most intensively. This receptor type may play a key role in neuronal injury, since its ion channel is permeable to both sodium and calcium. Since calcium plays a leading role in the development of cellular injury, it is not surprising that blockade of NMDA receptors has a neuroprotective effect in an experimental model of cerebral ischemia in laboratory animals. Although there is evidence that blockade of other ionotropic excitatory amino acid receptors can have a protective effect in tissue culture and experimental models of stroke, only NMDA receptor antagonists are currently undergoing large-scale clinical trials. Given the important role of excitatory amino acids in brain function, it can be expected that drugs that block receptors of these substances will have numerous and, possibly, very serious side effects. Preclinical and clinical trials indicate that although these agents have negative effects on cognitive function and cause sedation, they are generally relatively safe, perhaps because there are very few excitatory amino acid receptors outside the CNS.

In the case of cardiac muscle, reducing the workload is sufficient to increase the resistance of myocytes to injury. Quite radical measures, similar to those used to protect the heart during transplantation, can be taken to this end. However, this approach has its limits, since the workload should not be reduced to a level that would compromise cardiac function. In the brain, it is not necessary to completely block all excitatory systems and induce coma in order to protect neurons from ischemia. Of course, the goal is not to make neurons invulnerable to ischemia, but rather to increase their resistance to the negative effects of decreased perfusion resulting from arterial occlusion.

There is a large body of evidence from tissue culture and animal models that glutamate receptor antagonists increase the resistance of neurons to ischemic injury. Initial animal studies were based on creating global ischemia, simulating cardiac arrest. In this case, perfusion was reduced to very low levels for a short time (less than 30 min). In this case, the damage is limited to the most sensitive areas of the brain and is most noticeable in the hippocampus. A feature of this model is the delayed nature of neuronal damage: hippocampal neurons appear intact for several days after ischemia and only subsequently undergo degeneration. The delayed nature of the damage leaves the possibility of rescuing neurons for some time by blocking glutamate receptors. In this model, it was shown that ischemia is accompanied by a sharp increase in extracellular glutamate levels. High glutamate levels may play an important role in the initiation of neuronal injury. However, its adverse effects may also persist during the recovery period, since glutamate receptor antagonists provide a protective effect even when administered several hours after the ischemic episode.

A more adequate model of the processes occurring during a stroke is focal ischemia, which is created by blocking one of the vessels. Glutamate receptor antagonists have proven effective in this model as well.

It is likely that ischemic injury to neurons in the penumbra occurs slowly against the background of low perfusion, metabolic and ionic stress caused by the action of excitatory amino acids, which increases the sensitivity of tissues to ischemia and aggravates the energy deficit. Repeated depolarization of neurons recorded in the penumbra and associated with ion movements and pH shifts may contribute to the damage of ischemic tissue.

It is important to determine the duration of the period from the onset of symptoms during which it makes sense to start treatment. It is known that thrombolytic therapy should be carried out as early as possible. Otherwise, the risk of hemorrhagic complications increases sharply, negating all the achievements of reperfusion. However, the duration of the "therapeutic window" for neuroprotective agents has not yet been determined. In an experiment, the duration of the period during which it is possible to reduce neuronal damage depends on the model and severity of ischemia, as well as on the neuroprotective agent used. In some cases, the drug is effective only if it is administered before the onset of ischemia. In other cases, damage can be reduced if the drug is administered within 24 hours after exposure to ischemia. The clinical situation is more complex. Unlike standard conditions in an experimental model, the degree of vessel occlusion in a patient can change over time. There is also a risk of expansion of the ischemic zone during the first few days after the stroke. Thus, delayed therapy may rather protect areas that will be damaged in the near future, rather than promoting the restoration of already damaged areas.

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Neuroprotective agents

When protection is considered in the context of metabolic stress, it becomes clear why such diverse agents can attenuate ischemic cell injury in tissue cultures or experimental animals. A number of substances with putative neuroprotective effects are currently undergoing clinical trials, including phase III trials.

Cerestat

Cerestat is a non-competitive NMDA receptor antagonist. The drug was recently tested in a phase III study, but it was suspended. The main side effects associated with NMDA receptor blockade were drowsiness and psychotomimetic action. It should be recalled that phencyclidine (a psychoactive substance that causes abuse) and ketamine (a dissociative anesthetic) are also non-competitive NMDA receptor antagonists. One of the most important problems associated with the development of NMDA receptor antagonists is determining the dose that produces a neuroprotective but not psychotomimetic effect.

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Querven (nalmefene)

Querven is an opioid receptor antagonist that has already been used by clinicians to block the effects of opioids. The opioid receptor antagonist has a neuroprotective effect in animal models of stroke, possibly due to its ability to inhibit the release of glutamate.

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Downtime (lubeluzole)

The mechanism of action of prosynap remains unknown, although it has been shown to attenuate tissue culture damage mediated by glutamate receptor activation.

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Citicoline (cytidyl diphosphocholt)

The action of citicoline does not appear to be related to inhibition of glutamatergic transmission. Citicoline is a natural substance that serves as a precursor in the process of lipid synthesis. Pharmacokinetic studies show that after oral administration, it is metabolized mainly into two components - cytidine and choline. In rats, orally administered citicoline alters the lipid composition of the brain. In recent clinical trials conducted to test the neuroprotective properties of the drug, the drug was ineffective when administered within 24 hours of the onset of symptoms.

Recent double-blind, placebo-controlled clinical trials in stroke patients also failed to demonstrate neuroprotective activity of the GABA receptor agonist clomethiazole.

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