Antagonist Medications

Mechanism of Action

All psychotropic drugs are characterized by the type of neurotransmitter system on which they [Page 29]work. For example, drugs that decrease activity at dopamine receptors are known as dopamine antagonists; those that decrease activity at serotonin receptors are known as serotonin antagonists, and so on.

Further, antagonists can be broadly divided into two categories—those that bind to and work directly at the postsynaptic receptor, and those that decrease activity at these receptors by acting remotely. Drugs falling into the former category are known as direct antagonists, while those in the latter are known as indirect antagonists. All psychoactive drugs, however, exert their effects by influencing one or more steps in the neurotransmission process. The following is a description of common sites of action:

• Neurotransmitter synthesis: Drugs that decrease the amount of neurotransmitter synthesized in the presynaptic neuron function as antagonists by decreasing the amount of neurotransmitter available for release into the synaptic cleft.
• Storage in vesicles: Neurotransmitters cannot be released into the synaptic cleft unless they are first stored in vesicles. Drugs that inhibit storage, or that cause stored neurotransmitters to leak out of the vesicles prior to release, also decrease the amount of these chemicals available for release into the synaptic cleft.
• Neurotransmitter release: Drugs that inhibit the release of neurotransmitters by the presynaptic neuron decrease action at postsynaptic receptors. Therefore, they are classified as antagonists.
• Autotransmission: Autoreceptors are found on presynaptic neurons, and bind neurotransmitters released from the cell on which they are located. This provides feedback to the presynaptic cells and modulates the amount of neurotransmitter synthesized presynaptically. Drugs that enhance function at autoreceptors cause less neurotransmitter to be synthesized, thereby decreasing the amount released from the presynaptic neuron.
• Reuptake: Reuptake is the process by which neurotransmitters in the synaptic cleft are returned the terminal bouton of the presynaptic cell. Drugs that enhance this process increase the amount of neurotransmitters removed from the synapse, thereby decreasing the amount available in the synaptic cleft that may interact with postsynaptic receptors.
• Enzymatic degradation: This is a process by which neurotransmitters or drugs are broken down by enzymes, thereby inhibiting their ability to act postsynaptically. Drugs that promote enzymatic degradation, therefore, function as antagonists.

Treatment of Substance Abuse

Antagonist medications have a variety of clinical applications, including in the treatment of substance abuse and psychological disorders. Naloxone and naltrexone are pure opioid antagonists that bind directly to opiate receptors. They are used to treat overdoses of drugs that function as opiate agonists (e.g., heroin, morphine). The former is a short acting drug that is not well absorbed gastrically; therefore, it is administered intravenously. The latter has a longer duration of action and can be administered orally. In the presence of opiate agonists, both drugs compete for and preferentially bind to opiate receptors, while exerting no effects of their own. Administration of naloxone or naltrexone prevents death due to respiratory depression caused by opiate intoxication.

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