Medications Used for Stroke

TPA (recombinant tissue activator of plasminogen, activase, alteplase)

The dose for intravenous administration is 0.9 mg / kg (not more than 90 mg)

Aspirin

It is prescribed in a dose of 325 mg / day in the form of a tablet in a shell dissolving in the intestine. The dose is reduced to 75 mg / day with the appearance of severe gastrointestinal discomfort

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

Ticlopidine (ticlid)

Usual dose of 250 mg, is given orally 2 times a day with food. A clinical blood test with counting the number of platelets and determining the leukocyte formula is performed before the start of treatment, then every 2 weeks, the first 3 months of treatment. Further hematological examination is performed according to clinical indications

Clopidogrel (to the smelter)

Assign inside a dose of 75 mg once a day

[12], [13], [14]

Aspirin / dipyridamole with delayed release (apreioks)

1 capsule contains 25 mg of aspirin and 200 mg of sustained-release dipyridamole. Assign 1 capsule 2 times a day

[15]

Heparin

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

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

Warfarin (Coumadin)

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

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

Warfarin is contraindicated in pregnancy, as it can provoke multiple fetal development anomalies and stillbirth. Since heparin does not cross the placental barrier, in those cases where anticoagulant therapy is absolutely necessary during pregnancy, preference should be given to him.

Extreme caution should be observed when prescribing warfarin to a patient who is prone to bleeding.

With prolonged treatment with warfarin, it is important to consider the possibility of interaction with other drugs: the effectiveness of warfarin may increase or decrease under the influence of certain medications. For example, a number of drugs can affect the metabolism of warfarin or clotting factors. Since such an effect is temporary, with simultaneous administration of other drugs, it may be necessary to repeatedly correct the dose of warfarin.

Drug interactions can lead to life-threatening conditions, so the patient should inform the doctor about every new drug that he begins to take. Alcohol and over-the-counter products can also interact with warfarin, especially preparations containing significant amounts of vitamins K and E. Laboratory monitoring should be strengthened until the effect of the new drug becomes known, and blood coagulation indicators do not stabilize.

Prospects for treatment with antiplatelet agents and warfarin

Although aspirin will reduce the likelihood of stroke in patients who have suffered a stroke or TIA before, many patients, despite treatment, still have strokes. Low cost and favorable side effects profile makes aspirin the drug of choice for long-term therapy of patients at high risk of stroke. Patients who do not tolerate aspirin can be treated with ticlopidine or clopidogrel. With poor tolerability of standard doses of aspirin, a combination of small doses of aspirin and slow-release dipyridamole can be used. Clopidogrel and a combination of aspirin with dipyridamole have an advantage over ticlopidine, due to a more favorable profile of side effects.

In the event that on a background of treatment with aspirin there are repeated ischemic strokes or TIA, in practice often go to treatment with warfarin. However, this practice is based on the erroneous opinion that aspirin must necessarily prevent strokes. Since some patients are resistant to aspirin, it is more appropriate to transfer them to clopidogrel or ticlopidine, rather than to warfarin.

Neuroprotection

At present, there are no neuroprotective agents, the effectiveness of which in case of stroke would be convincingly proved. Although in the experiment, many drugs demonstrated a significant neuroprotective effect, it has not yet been demonstrated in clinical trials.

With cardiac ischemia, well-developed strategies exist that simultaneously restore perfusion and protect the myocardium from damage caused by inadequate energy supply. Methods of neuroprotection are also aimed at increasing the resistance of brain cells to ischemia and restoring their function after resumption of blood supply. Protective therapy for cardiac ischemia reduces the burden on the heart. Energy needs of the myocardium decrease with the appointment of funds that reduce pre- and postnagruzku. Such treatment contributes to the fact that the function of the heart lasts longer and allows to delay the development of energy insufficiency and cell damage. It can be assumed that in the case of cerebral ischemia, a reduction in energy requirement is also capable of protecting cells from ischemia and facilitating their recovery.

Thanks to the creation of a model of cerebral ischemia on tissue culture, it was possible to establish factors determining the sensitivity of neurons. It is curious that these factors are similar to those that are important for the sensitivity of the heart muscle.

Resistance to damage is determined by the ability to preserve and restore cellular homeostasis. The main tasks of the cells are maintaining ionic gradients and oxidizing the cellular "fuel" to generate energy. It is suggested that the NMDA receptor plays a key role in the development of ischemia, since the ion channel contained in it passes through the massive ion current through an open current. Moreover, as shown in the figure, this channel is permeable for both sodium and calcium. The energy produced by mitochondria in the form of ATP is consumed by Na ⁺ / K ⁺ ATPase, which pumps out sodium ions from the cell. Mitochondria perform a buffer 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 mediator systems and energy supply processes.

The complex structure of the NMDA receptor is presented in the form of three numbered sections. Section 1 is the binding zone with the ligand-excitatory neurotransmitter glutamate. This site can be blocked by competitive receptor antagonists, for example, APV or CPR. Site 2 is the binding zone inside the ion channel. If this area is blocked by a non-competitive antagonist, for example, MK-801 or a cestat, the movement of ions through the channel ceases. Section 3 is a complex of modulator sites, including a binding site with glycine and polyamines. A region sensitive to oxidation and reduction is also described. All three of these areas can be the target for neuroprotective agents, the gradient of the concentration of a whole series of ions, the violation of the calcium gradient seems to be the most important factor that causes damage to the cell. The condition for maintaining the integrity of cellular structures is also strict control over the course of oxidative processes. The disturbance of oxidation-reduction homeostasis with the development of oxidative stress is the most important factor of cell damage. It is suggested that oxidative stress is most pronounced during reperfusion, but cellular is homeostasis is also disturbed 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, the maintenance of calcium homeostasis and measures to limit the production of free radicals can weaken the damage of cells in brain ischemia.

Compound and NMDA receptors.

One of the most important factors of damage to neurons are excitatory amino acids, of which glugamate (glutamate) is of the greatest importance. Excitatory effect is also provided by other endogenous compounds, including aspartic acid (aspartate), N-acetyl-aspartyl-glutamic acid and quinoline acid.

Pharmacological and biochemical studies have identified four major families of receptors for excitatory amino acids. Three of these are ionotropic receptors, which are ion channels whose state is modulated by the interaction of the receptor with the ligand. The fourth type is the metabotropic receptor, which is coupled to the system of the second mediator with the help of G-protein.

Of the three ionotropic receptors, the family of NMDA receptors (N-methyl-D-aspartate) has been extensively studied. This type of receptor can play a key role in neuronal damage, since its ion channel is permeable for both sodium and calcium. Since calcium plays a leading role in the development of cellular damage, it is not surprising that the blockade of NMDA receptors has a neuroprotective effect in the experimental model of cerebral ischemia in laboratory animals. Although there is evidence that blockade and other ionotropic receptors of excitatory amino acids are able to provide 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 the functioning of the brain, it can be assumed that drugs blocking the receptors of these substances will have numerous, and possibly very serious side effects. Preclinical and clinical trials show that although these drugs have a negative effect on cognitive functions and cause a sedative effect, they are generally relatively safe, possibly because the receptors of excitatory amino acids outside the CNS are extremely few.

In the case of the heart muscle, to increase the resistance of myocytes to damage, it is sufficient to reduce the workload. To this end, very radical measures can be taken, similar to those used to protect the heart during transplantation. However, this approach has a limit, since the load should not be reduced to a level where the function of the heart may suffer. In the brain, there is no need to completely block all the exciting systems and call someone in order to protect the 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 reducing perfusion resulting from occlusion of the artery.

A large amount of evidence has been obtained on tissue cultures and experimental animals, according to which antagonists of glutamate receptors increase the resistance of neurons to ischemic damage. Initial animal studies were based on the creation of a global ischemia simulating cardiac arrest. At the same time perfusion for a short time (less than 30 minutes) was reduced to a very low level. In this case, the damage is limited to the most sensitive parts of the brain and most noticeable in the hippocampus. The peculiarity of this model is the delayed nature of neuronal damage: hippocampal neurons within a few days after ischemia appear intact and only later degenerate. The delayed nature of the lesion leaves the possibility of rescuing neurons for a certain period of time with the help of a blockade of glutamate receptors. On this model it was shown that with ischemia there is a sharp increase in the level of extracellular glutamate. A high level of glutamate can play an important role in initiating neuronal damage. However, its adverse effect can also affect the recovery period, since glutamate receptor antagonists provide a protective effect even when administered several hours after the ischemic episode.

The model of focal ischemia, which is created by clogging one of the vessels, is more adequate to the processes arising in stroke. Antagonists of glutamate receptors proved to be effective on this model.

Probably, the ischemic damage of neurons in the penumbra zone is slow against a background of low perfusion, metabolic and ionic stress caused by the action of excitatory amino acids, which increases tissue sensitivity to ischemia and aggravates the energy deficit. Repeated depolarization of neurons recorded in the penumbra region and associated with ion transport and pH shifts may contribute to damage to the ishemicized tissue.

It is important to determine the length of the period from the onset of symptoms, during which it makes sense to begin treatment. It is known that thrombolytic therapy should be carried out as early as possible. Otherwise, the risk of hemorrhagic complications increases dramatically, negating all the achievements of reperfusion. However, the duration of the "therapeutic window" for neuroprotective drugs has not yet been determined. In the experiment, the length of the period during which it is possible to reduce neuronal damage depends on the model and severity of the 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 prescribed within 24 hours after exposure to ischemia. The clinical situation is more complicated. Unlike the standard conditions of the experimental model, in a patient the degree of occlusion of the vessel can vary with time. There is also a risk of expanding the ischemic zone during the first few days after a stroke. Thus, the delayed therapy may rather protect the zones that will be subjected to ischaemia in the near future, rather than contribute to the restoration of already damaged areas.

[16], [17], [18], [19], [20], [21], [22], [23], [24]

Neuroprotective agents

If we consider protection in the context of metabolic stress, it becomes clear why such different agents can weaken ischemic damage to cells in tissue cultures or in experimental animals. At present, a number of substances with presumed neuroprotective action undergo clinical trials, including Phase III.

CERESTAT

CERESTAT is a noncompetitive NMDA receptor antagonist. The drug was relatively recently tested in a Phase III study, but it was suspended. The main side effects associated with the blockade of NMDA receptors were drowsiness and psychotomimetic effects. It should be recalled that phencyclidine (a psychoactive substance that causes abuse) and ketamine (a dissociative anesthetic) are also noncompetitive NMDA receptor antagonists. One of the most important problems associated with the development of NMDA receptor antagonists is the determination of a dose that has a neuroprotective effect, but not a psychotomimetic effect.

[25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]

Cerven (nalmefene)

Cerven is an opioid receptor antagonist, which has already been used by clinicians to block the effects of opioids. An opioid receptor antagonist has a neuroprotective effect on stroke models in experimental animals, possibly due to its ability to inhibit the release of glutamate.

[38], [39], [40]

Downtime (lubeluzole)

The mechanism of action of prosinup remains unknown, although it is shown that it weakens tissue tissue damage, mediated by the activation of glutamate receptors.

[41]

Citicoline (cytidil diphosphoholt)

The effect of citicoline, apparently, is not related to the inhibition of glutamatergic transmission. Citicoline is a natural substance serving as a precursor in the synthesis of lipids. Pharmacokinetic studies show that after ingestion in the process of metabolism, it basically breaks down into two constituent parts - cytidine and choline. In rats, the citicoline administered inside changes the lipid composition of the brain. In recent clinical trials to verify the neuroprotective properties of the drug, the drug administered no later than 24 hours after the onset of symptoms was ineffective.

In recent double-blind, placebo-controlled clinical trials, patients with stroke also failed to demonstrate the neuroprotective activity of the clonamiazole GABA receptor agonist.

[42], [43], [44], [45], [46], [47], [48], [49], [50], [51]