Kaplan + Sadock's Synopsis of Psychiatry, 11e

912

Chapter 29: Psychopharmacological Treatment

Table 29.1-1 Glossary of Receptor Drug Interactions

Receptor Interaction Definition

Examples and Comments

Agonist (full agonist)

A drug or medication that binds to a specific receptor producing an effect identical to that usually produced by the neurotransmitter affecting that receptor. Drugs are often designed as receptor agonists to treat a variety of diseases and disorders in which the original neurotransmitter is missing or diminished. A compound that binds to a receptor that blocks or reduces the action of another substance (agonist) at the receptor site involved. Antagonists that compete with an agonist for a receptor are competitive antagonists. Those that antagonize by other means are noncompetitive antagonists. A compound that (even when fully occupying a receptor) possesses affinity for a receptor, but elicits a partial pharmacological response at the receptor involved. Partial agonists are often structural analogs of agonist molecules. If neurotransmitter concentrations are low, partial agonists may behave as an agonist. This is why these medications are sometimes called mixed agonists. An inverse agonist is an agent that binds to the same receptor as an agonist for that receptor but produces the opposite pharmacological effect.

Full agonists include opioids such as morphine, methadone, oxycodone, hydrocodone, heroin, codeine, meperidine, propoxyphene, and fentanyl. Benzodiazepines act as agonists at the GABA receptor complex. Flumazenil is a competitive benzodiazepine receptor antagonist. It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/ benzodiazepine receptor complex. It is the purest antagonist synthesized. Drugs used in the treatment of schizophrenia block dopamine 2 receptors. Examples of opioid antagonists include naltrexone and naloxone. Buprenorphine is a partial agonist that produces typical opioid agonist effects and side effects, such as euphoria and respiratory depression, but its maximal effects are less than those of full agonists like heroin and methadone. When used at low doses buprenorphine produces sufficient agonist effect to enable opioid-addicted individuals to discontinue the drugs with fewer withdrawal symptoms. Several inverse agonists are currently in clinical development. One particular example is R015-4513, which is the inverse agonist of the benzodiazepine class of drugs. R015-4513 and the benzodiazepines both utilize the same GABA binding site on neurons, yet R015-4513 has the opposite effect, producing severe anxiety rather than the sedative and anxiolytic effects associated with benzodiazepines. Cannabinoid inverse agonists have been found to reduce appetite, the opposite of the craving effect associated with cannabis. (thioridazine [Mellaril]). Overall, the risk of life-threatening side effects with psychotropics is low. Drugs that carry such a risk should be monitored more closely, and the prescribing physician should take into account whether the potential clini- cal benefits justify the additional risk. Any drug with a serious risk, as reflected in a black box warning, is generally used less extensively than would otherwise be the case. In the case of haloperidol (Haldol) and other dopamine receptor antagonists, long-term complications, such as tar- dive dyskinesia, have been well documented. Emerging evi- dence also suggests that the use of dopamine antagonists is associated with a small increase in the risk of breast cancer and that this is related to larger cumulative doses. In cases in which serious risk is associated with a drug, closer medi- cal monitoring of medication treatment is warranted. Because the most widely used psychotropics, such as the SSRIs and serotonin-dopamine antagonists, have only been in use since the 1980s or 1990s, there is less certainty about long-term effects, but no evidence indicates that side effects are not merely extensions of those already evident during initial ther- apy. It should also be kept in mind that most drugs used in the treatment of chronic medical disorders have not been in use

Antagonist

Partial agonist

(mixed agonist)

Inverse agonist

GABA, g -aminobutyric acid. (Table by Norman Sussman, M.D.)

persistent, side effects include dry mouth that is associated with noradrenergic reuptake inhibition or antimuscarinic activ- ity. Some side effects appear later in treatment ( late-appearing side effects ) and, sometimes, may be just the opposite of adverse events early in treatment. For example, patients may typically lose weight during early treatment with SSRIs, only to find, over time, a reversal occurs, so that they gain weight. Similarly, early activation or agitation may be followed by constant fatigue or apathy. Because most data about new drugs come from short- term studies, generally 8 weeks in duration, early-onset side effects are overrepresented in product information and descrip- tions of newly marketed information. It is essential that clini- cians follow the letters to the editor sections of journals and other sources of information to update their understanding of the true side effect profile of a drug. Adverse effects differ in their impact on compliance and potential to cause harm. Depending on a patient’s threshold of tolerance for a side effect and the impact on quality of life, side effects can lead to drug discontinuation. Examples of serious side effects include agranulocytosis (clozapine), Stevens-Johnson syndrome (lamotrigine [Lamictal]), hepatic failure (nefazo- done [Serzone]), stroke (phenelzine [Nardil]), and heart block