How esketamine works
Esketamine primarily has analgesic, narcotic and antidepressant effects. It can also stimulate the circulation and increase saliva production, for example.
Analgesic and narcotic effects of esketamine.
Esketamine mediates its main effect by blocking the so-called N-methyl-D-aspartate receptors (NMDA receptors for short) and reversibly switching off consciousness.
NMDA receptors are docking sites of the endogenous messenger glutamate. They are found primarily in the central nervous system (brain and spinal cord). As a nerve messenger, glutamate is involved in signal transmission in the nervous system. By blocking NMDA receptors, esketamine prevents glutamate from docking. This results in various effects known as dissociative anesthesia:
- Amnesia: The affected person does not remember afterwards the period of time when esketamine was effective, e.g. the anesthesia or the surgery.
- Pain relief (analgesia): Esketamine has a strong analgesic effect even at low doses.
- Extensive preservation of protective reflexes and respiratory control: Protective reflexes such as the eyelid closure reflex are not or hardly impaired. In addition, the patient continues to breathe independently despite anesthesia.
Antidepressant effect of esketamine
The antidepressant effect of esketamine is probably also based on the blockade of NMDA receptors. The body reacts to the blockade of these glutamate docking sites by temporarily releasing more of the nerve messenger – a glutamate excess results.
In this way, esketamine counteracts the disturbed neurotransmitter metabolism in the brain that physicians suspect is behind depression.
It also blocks docking sites in brain regions that correspond to a so-called anti-reward system. Activating docking sites in these areas triggers the symptoms of hopelessness, listlessness and listlessness that occur in depression. Esketamine inhibits this process, thereby alleviating the signs of depression.
As a further effect, esketamine presumably inhibits the reuptake of messenger substances such as noradenalin and serotonin: these mediate their effect after they have been released by a nerve cell and bind to docking sites of a neighboring nerve cell. As soon as they are reabsorbed into the cell of origin, their effect ends.
Other effects of esketamine
Esketamine also triggers other effects in the body:
- Activation of the cardiovascular system: esketamine increases blood pressure and heart rate. This may be desirable (e.g., in volume-deficiency shock after severe blood loss) or undesirable (e.g., in hypertension).
- Dilation of the airways (bronchodilation): Esketamine blocks acetylcholine receptors. This prevents the neurotransmitter acetylcholine from exerting its effect. As a result, the airways relax and widen.
- Local anesthesia: Esketamine blocks sodium channels, resulting in a local anesthetic effect – pain sensation and transmission are inhibited.
- Increased saliva production (hypersalivation).
Absorption, breakdown and excretion
If esketamine is used in the form of a nasal spray (for depression), the active ingredient reaches the bloodstream via the nasal mucous membranes. The antidepressant symptoms then subside after just a few hours – faster than with other antidepressants.
Enzymes in the liver break down esketamine. In patients with liver dysfunction, physicians may therefore reduce the dose of active ingredient. The kidneys excrete the breakdown products of esketamine in the urine.
Ketamine
Like esketamine, the similar ketamine is used in anesthesia medicine and pain management. Esketamine (or S-ketamine) is the so-called S-enantiomer of ketamine. This means that the two molecules have the same chemical structure, but behave as mirror images of each other (like right and left gloves).
The molecules are also referred to as left-handed (S-enantiomer: esketamine) and right-handed (R-enantiomer: ketamine) – depending on the direction in which they rotate linearly polarized light.
Because of these advantages, esketamine is predominantly used nowadays instead of ketamine.
How esketamine is used
Esketamine is available as a solution in ampoules that a doctor can administer directly into the vein (intravenously) or into the muscle (intramuscularly). It is possible to administer it as an injection or as an infusion over a longer period of time.
As a rule, physicians give 0.5 to 1 milligram of esketamine for anesthesia when administered intravenously and two to four milligrams when administered intramuscularly – in each case per kilogram of body weight. Depending on how long the anesthesia is to last, doctors inject half the dose every 10 to 15 minutes or administer a continuous infusion.
For pain management or local anesthesia, a lower dose of 0.125 to 0.5 milligrams of esketamine per kilogram of body weight is sufficient.
The state of dissociative anesthesia can be unpleasant for patients. For this reason, physicians usually combine esketamine with drugs from the benzodiazepine group. This can prevent dissociations and unpleasant waking phases.
Esketamine possibly impairs the ability to react. Alcohol can intensify this effect. Therefore, after anesthesia with esketamine, patients should not operate cars or machines and should not drink alcohol for at least 24 hours. After outpatient procedures under esketamine, patients ideally go home only if accompanied.
Esketamine as a nasal spray
The exact dosage depends on the age of the patient. Treatment is started with 28, 56 or 84 milligrams of esketamine and continued twice a week for four weeks. If further treatment is necessary, patients receive the nasal spray at the appropriate dosage every one to two weeks.
Blood pressure monitoring is performed prior to application and approximately 40 minutes thereafter. After use, patients remain under medical supervision for follow-up until they are stable enough again.
If the symptoms of depression improve with the esketamine nasal spray, patients should generally continue to use it for at least another six months. The treating physician regularly reviews the dosage and adjusts it if necessary.
For psychiatric emergencies, patients receive 84 milligrams of esketamine twice a week for four weeks.
When is esketamine used?
- Anesthetic inductions for general anesthesia: esketamine acts rapidly and shuts down consciousness before the patient is given another narcotic to inhale.
- local anesthesia (local anesthesia)
- short, painful procedures such as dressing changes or burns
- rapid pain relief (analgesia), especially in emergency medicine
- pain relief during artificial respiration (intubation)
- status asthmaticus (very severe form of asthma attack)
- Caesarean section
Esketamine nasal spray is used for depression when other therapies have not been sufficiently effective. Sufferers use the nasal spray in combination with another antidepressant.
In addition, physicians use the nasal spray together with oral antidepressants to quickly relieve symptoms of moderate to severe depression. In these psychiatric emergencies, esketamine is used only for a short period of time.
What are the side effects of esketamine?
This side effect occurs particularly in young adults. This effect is less frequent in older patients and children. To mitigate the unpleasant side effect, doctors usually administer a sedative and sleeping pill (e.g. from the benzodiazepine group such as midazolam) in addition to esketamine.
The disturbances of consciousness after waking up usually subside after one to two hours.
After administration of the nasal spray, it may be helpful not to close the eyes during visual sensations (seeing colors, shapes, tunnels), and to avoid bright lighting and excessive stimuli such as loud music.
Esketamine activates the cardiovascular system. The heart beats faster (tachycardia), blood pressure increases. Patients often have increased oxygen consumption.
To prevent nausea and vomiting, do not eat for at least two hours before using esketamine nasal spray. You should also not drink anything for at least 30 minutes beforehand.
Patients also often complain of visual disturbances. They see blurred or double. In addition, intraocular pressure often rises.
Occasionally, the patient’s muscles stiffen or twitch (tonic-clonic spasms) or eye tremors (nystagmus) occur.
If esketamine is used during procedures or examinations in the upper respiratory tract, children in particular often suffer from muscle twitching or have easily triggered and strong reflexes (hyperreflexia). This increases the risk that the laryngeal muscles will spasm (laryngospasm). In this case, doctors administer so-called muscle relaxants. These are active substances that relax the muscles.
When should esketamine not be used?
Esketamine should not be used in the following cases:
- if you are hypersensitive to the active substance
- in case of uncontrolled high blood pressure
- during pregnancy, if the woman suffers from pre-eclampsia or eclampsia (forms of pregnancy poisoning) or has an increased risk of uterine rupture or umbilical cord prolapse
- If she has had an aneurysm, heart attack or cerebral hemorrhage within the past six months
- untreated hyperthyroidism or thyrotoxic crisis (acute metabolic derailment due to hyperthyroidism)
- @ concomitant use of xanthine derivatives, e.g. theophylline (drugs used to treat bronchial asthma and COPD)
For some pre-existing conditions, medical professionals will check whether esketamine is appropriate before using it. These include:
- chest tightness (angina pectoris)
- Heart failure (congestive heart failure)
- increased intraocular pressure or increased intracranial pressure
- Alcohol Abuse
These interactions may occur with esketamine
Esketamine is broken down by a specific enzyme system (CYP3A4 system) in the liver. So-called enzyme inhibitors inhibit this system, preventing esketamine from being broken down. This causes its blood level to rise, increasing its effect and any side effects.
These inhibitors include macrolide antibiotics, drugs for fungal infections, and grapefruit (as juice or fruit).
Conversely, so-called enzyme inducers can accelerate the breakdown of esketamine. As a result, a higher dose of esketamine is necessary to achieve the full effect. These enzyme inducers include drugs for epilepsy such as phenytoin or carbamazepine, and the herbal antidepressant St. John’s wort.
If patients take drugs that increase blood pressure and heart rate, esketamine can enhance this effect. Such drugs include:
- Thyroid hormones
Sedatives (mainly from the benzodiazepine group) reduce the unpleasant waking phase after esketamine application. However, they prolong the duration of action of the drug. Therefore, the physician may adjust the dosage of esketamine.
The simultaneous use of centrally depressant substances (benzodiazepines, opioids or alcohol) may also increase the sedative (sedative) effect of esketamine. Therefore, do not drink alcohol the day before or after treatment or on the day of treatment itself.
Barbiturates such as phenobarbital (used to treat epilepsy, among other conditions) may prolong the patient’s recovery period. The same applies to the strong painkiller fentanyl.
Some muscle-relaxing drugs (muscle relaxants) such as suxamethonium have a longer effect when esketamine is given at the same time.
Tell your doctor about any other medications or supplements you are taking.
Even babies and toddlers can receive esketamine as an injection or infusion. The so-called feeling of dissociation is not yet very pronounced in children – esketamine is therefore better tolerated in this age group. Physicians often use the active ingredient before painful procedures in children.
Esketamine nasal spray is not approved in Germany, Austria and Switzerland for patients under 18 years of age.
Esketamine during pregnancy and breastfeeding
Doctors use esketamine during cesarean sections because the active ingredient has a circulatory stabilizing effect. It reaches the placenta quickly. A single application to induce anesthesia does not affect the unborn child. However, repeated administration may cause an inhibitory effect of esketamine on the child.
Some diseases during pregnancy also preclude use with esketamine. You can read more about this under Contraindications!
Esketamine during breastfeeding does not require a break from breastfeeding. The woman may therefore breastfeed her child as soon as she has regained sufficient strength after the anesthetic.
In general, esketamine is used in pregnancy and breastfeeding at the lowest possible dosage if its use is absolutely necessary and there are no more suitable alternatives.
How to obtain medicines containing esketamine
Medicines containing the active ingredient esketamine are available on prescription in Germany, Austria and Switzerland. As a rule, the drugs are administered by healthcare professionals in emergency services, clinics and doctors’ offices.
