Drugs Affect The Central Nervous System By

Drugs Affect The Central Nervous System By – Now that we’ve covered stimulants, it’s time to move on to drugs that have opposing effects. In this chapter, we will examine a variety of depressants and learn how they alter neurotransmission to reduce central nervous system activity. We will begin with an overview of the GABAA receptor which is the molecular target of a heterogeneous group of CNS depressants ranging from alcohol to barbiturates to benzodiazepines and others.

As you would expect from the name, depressants are the opposite of stimulants. CNS depressants are drugs that reduce neuronal activity in the brain. Because of this, they are sometimes referred to as “downers”, as opposed to the term “uppers” used for stimulants. Although there are many different types of depressants, many target the same site of action:  the GABA receptor. We already recognized GABA as the most abundant inhibitory neurotransmitter in the CNS. Therefore, before we discuss any specific drugs, it is worth taking a closer look at this receptor and how different depressants interact with it.

Drugs Affect The Central Nervous System By

Drugs Affect The Central Nervous System By

Remember from Chapter 4 that γ-aminobutyric acid (GABA) is the brain’s main inhibitory neurotransmitter. This is because GABA targets GABA receptors, promoting hyperpolarization of the postsynaptic cell. This inhibits the postsynaptic cell from firing and releasing other neurotransmitters such as glutamate or norepinephrine. As a result, increasing GABA activity will generally decrease the activity of other neurons and transmitters.

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There are two subtypes of GABA-sensitive receptors. The first type is the GABAA subtype. GABAA receptors are ionotropic receptors or ligand-gated ion channels. When they are activated, chloride ions (Cl-) flow into the cell, increasing the negative charge inside the neuron. In comparison, GABAB receptors are inhibitory metabotropic or 7TM GPC receptors. The G proteins are coupled to potassium channels. The efflux of potassium ions (K+) increases the negative charge inside the cell. Therefore, there are two different mechanisms by which the two GABA receptor subtypes cause hyperpolarization and neuronal inhibition. To review this information, you may find it helpful to watch this short video:

GABAA receptors consist of five protein subunits that surround the central chloride ion pore. The most common type of GABAA receptor has two α-subunits, two β-subunits and one γ-subunit, as seen in the diagram below. The primary binding site, also known as the orthosteric site, is where GABA normally binds to the receptor. The classical GABAA receptor is part of what is called the GABAA chloride channel receptor complex.

There are two orthostatic or primary binding sites on the chloride channel that interact with molecules of GABA. There are additional multiple allosteric sites that bind ligands other than GABA. This name should be familiar to you as we covered it in Chapter 4. To refresh, ligands that bind to these sites are called allosteric modulators. It changes the functionality of the orthostatic site without competing for the same site.

Many depressants are allosteric modulators of the GABAA receptor. When they bind to the receptor, they change its conformation so that GABA has greater efficacy at the orthosteric site. Because they increase efficiency, they are known as positive allosteric modulators. Positive allosteric modulators do not increase the amount of GABA present in the synapse like reuptake inhibitors or activate the receptor on their own, as in the case of direct agonists. Instead, they change the conformation of the receptor so that it is more responsive to GABA binding. There are allosteric binding sites for several ligands, including benzodiazepines, barbiturates, and neurosteroids. So far, an allosteric site where ethanol acts is not known, although the inhibitory effects of ethanol are ultimately mediated by the GABAA receptor.

Drugs Affecting The Central Nervous System

Many types of drugs have depressant effects. Perhaps the most well-known depressant is alcohol. Because of its significance and certain unique characteristics, the entirety of the next chapter is devoted to it. Apart from alcohol, we will also find sedatives and hypnotics in this category. Sedatives calm anxiety and agitation, while hypnotics induce sleep. Since they share similar functions and many sedatives produce hypnotic effects at higher doses (and vice versa), they are usually referred to as a single class of drug, sedative-hypnotics.

Sedative hypnotics include barbiturates, benzodiazepines, and non-benzodiazepines (such as Z drugs). We will discuss some of these in more detail during Unit 4 on psychotherapeutic drugs, but for this chapter we will focus on barbiturates. Other types of drugs have sedative effects through action on the GABA receptor, such as γ-hydroxybutyrate (GHB), another drug we will cover in this chapter.

Not all CNS depressants are sedative-hypnotics. Inhalants, which we will also explore, have no sleep-inducing effects. At the same time, some drugs produce sedative effects through mechanisms other than the GABA receptor. Antihistamines, one such example, act on histamine receptors and cause drowsiness as a side effect. Although we will not explore this in this chapter, keep this in mind.

Drugs Affect The Central Nervous System By

The first depressants we will discuss are barbiturates. Barbiturates are powerful sedative-hypnotic drugs that were widely used in the early 1900s. Although its use has declined in recent decades, it remains an illustrative example of how depressants affect neurotransmission.

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Barbiturates are derived from barbituric acid, which was first synthesized in 1864 by the Bayer Company. No use was found for it until 1903 when German chemists discovered the sedative-hypnotic effects of its derivative compounds. The first barbiturate, barbital, was marketed by Bayer under the name Veronal® that year, and barbiturate use steadily increased in the first half of the 20th century.

Barbiturates were frequently used to induce sleep in psychotic patients and were prescribed to treat insomnia and anxiety. They were also shown to reduce the number and intensity of seizures—a first since no other drugs were effective in treating epilepsy at the time—and began to see popular use as anticonvulsants. In 1912, Bayer produced another barbiturate, phenobarbital, which is still used to treat epilepsy today.

Dependence and overdose were identified as serious problems soon after the drug was synthesized. Despite this, barbiturates continued to be prescribed until the 1950s and 1960s, when increased reports and greater visibility of barbiturate abuse led to significant change. Perhaps the most famous case of barbiturate overdose was Marilyn Monroe’s death in 1962. By 1970, barbiturates were considered controlled substances, and doctors prescribed them at much lower doses.

Currently, most barbiturates are classified as Schedule III controlled substances, although some types, such as phenobarbital, are Schedule IV instead. Barbiturates have mostly been replaced with benzodiazepines and Z drugs for the treatment of insomnia and anxiety because they have fewer problems with dependence and overdose. They remain in use as anticonvulsants, general anesthetics and antagonists to the effects of certain stimulants.

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Barbiturates are usually classified according to their duration of action. Long-acting barbiturates such as phenobarbital have low lipid solubility and are slowly absorbed. In exchange for a delayed onset (about 1 hour), effects can last up to 12 hours. This makes them useful as anticonvulsants as less doses are needed to maintain the level of drug in the body.

Intermediate and short-acting barbiturates such as pentobarbital and secobarbital have moderate lipid solubility. They are absorbed more quickly and have an onset of action of about 30 minutes, but their effects do not last as long as phenobarbital (up to 8 hours). Its faster onset means it is most commonly used as a sedative-hypnotic.

Ultra-short-acting barbiturates such as thiopental have the highest lipid solubility of all barbiturates. Time to action can be only minutes, although effects only last about half an hour. Drugs such as these are more suitable to serve as general anesthesia for short surgical procedures.

Drugs Affect The Central Nervous System By

Because they are weak acids, barbiturates are readily absorbed after oral administration. Other routes include rectal or intravenous. The method chosen depends on the intended use and recipient. Ultra-short-acting barbiturates are usually administered by IV, while long-acting anticonvulsant medications can also be taken by suppository.

Drugs And Synapses

Barbiturates are positive allosteric modulators of GABAA receptors. By binding to areas other than the orthosteric site of the receptor, they increase GABA activity. In particular, they increase the amount of time the chloride ion channel remains open when GABA binds to the receptor. At high concentrations, barbiturates can also bind to the main site as direct agonists.

At the same time, barbiturates are also antagonists against certain glutamate receptors. Remember that glutamate is an excitatory neurotransmitter. By blocking these glutamate receptors—NMDA, AMPA, and kainate—barbiturates further reduce CNS activity. This accounts for the strong effects of barbiturates compared to other sedative-hypnotics. Thus, barbiturates not only increase inhibition but also block excitation.

The effects of barbiturates are dose dependent. At lower doses they produce sedation and hypnosis. But higher doses can cause deeper and deeper stages of depression—anesthesia, coma, and even death. These effects tend to follow each other as you increase the dose (see figure below):

Intermediate-acting barbiturates used as sedative-hypnotics can induce sleep. Specifically, they decrease the time required to fall asleep, increase the time spent asleep, and decrease the occurrence of rapid eye movement (REM) sleep.

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A negative effect of barbiturates on sleep is the ability of repeated drug treatment to interfere with rapid eye movements

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