A Rational Ordering of the Actions of Antipsychotic Drugs Glenn Schwarcz, MD Washington, DC Most major actions of the antipsychotic drugs stem from one of the four antagonistic functions common to all these drugs. Antidopaminergic activity in the mesolimbic system results in the primary desired effect, control of psychosis. Antidopamin­ ergic activity also occurs in other brain areas. Dopamine blockade in the nigrostriatal pathway results in extrapyramidal symptoms and tardive dyskinesia. Blockade in the tuberoin- fundibular tract of the hypothalamus causes elevated circulating prolactin. Central H, histaminic receptors are also blockaded by these drugs, causing sedation. The anti-alpha adrenergic activity of the antipsychotics results in orthostatic hypoten­ sion, and antimuscarinic activity results in the atropinic pic­ ture commonly seen with these drugs. The mnemonic “the anti-fours” is used to order the four major pharmacological effects: anti-dopaminergic, anti-H, histaminic, anti-alpha ad­ renergic, and anti-muscarinic. Among the most complex and theoretically de­ and dibenzoxazepines (eg, loxapine)—are similar manding medications in all of medicine are the enough in their main actions to be considered as phenothiazine-type antipsychotics. Their diverse one class. They will therefore be referred to as the and seemingly unrelated actions can overwhelm antipsychotics, as that is their best appreciated the novice as well as the experienced physician. action. This article presents an organized approach to rationally understanding the pharmacology of these medications. Although it is clear that the The "Anti-Fours" structures and minor or idiosyncratic side effects While there are numerous less frequent and of some of the antipsychotics may vary, all of the idiosyncratic side effects of the antipsychotics, major classes—phenothiazines, butyrophenones, their main actions can be broken up into four thioxanthenes, dihydroindolones (eg, molindone), major antagonistic functions, which can be nick­ named the “anti-fours.” These are (1) anti­ From the Department of Psychiatry, Howard University dopaminergic, (2) anti-H, histaminic, (3) anti-alpha School of Medicine, and St Elizabeth's Hospital, Washing­ adrenergic, and (4) anti-muscarinic. These four an­ ton, DC. Requests for reprints should be addressed to Dr. Glenn Schwarcz, O'Malley Division, St Elizabeth's Hospital, tagonistic actions constitute the crux of the action Washington, DC 20032. of all antipsychotics (Table 1). 0094-3509/82/020263-05$01.25 ® 1982 Appleton-Century-Crofts THE JOURNAL OF FAMILY PRACTICE, VOL. 14, NO. 2: 263-267, 1982 263 ACTIONS OF ANTIPSYCHOTIC DRUGS Table 1. The "Anti-Fours" Pharmacological Action Clinical Picture Anti-dopaminergic: In the m esolim bic system Antipsychotic activity In the nigrostriatum Extrapyramidal side effects and tardive dyskinesia In the hypothalam ic High prolactin syndrome with tuberoinfundibular tracts amenorrhea, galactorrhea, and gynecomastia Anti-Hi histaminic Sedation Anti-alpha adrenergic Orthostatic hypotension Anti-muscarinic Atropinic side effects Antidopaminergic elderly people, which causes primary Parkinson’s disease. Typical symptoms include rest tremor, It is well known that all drugs used to treat psy­ masked facies, shuffling gait, and muscular rigid­ choses block dopamine. It does not follow that ity. Other extrapyramidal effects of antipsychot­ dopamine overactivity is the cause of schizophre­ ics, such as akathisia and acute dystonia, are nia, although that very hypothesis, the dopamine thought to be due to diminished dopamine trans­ theory of schizophrenia, has been espoused.1 It mission in the striatum. The acute dystonias in­ may be that dopamine blockade is only indirectly clude acute spasms of muscle groups occurring related to amelioration of psychosis. Neverthe­ early (hours to days) in treatment. Examples are less, as the dopamine theory of schizophrenia is spasm of neck muscles (torticollis), of extraocular the most consistent and scientifically supported muscles (oculogyric phenomenon), of the mastica­ etiological theory of schizophrenia, the primary tory muscles (trismus), and of the back muscles antipsychotic action of antipsychotics may be en­ (opisthotonos). Clinical observation suggests that visioned by postsynaptic dopamine blockade. the less-sedating piperazine phenothiazines more Dopamine is actually blocked in three areas in often cause dystonias. In contrast, the more- the brain, giving three distinct actions common to sedating aliphatics, like chlorpromazine, tend to all antipsychotics. cause parkinsonism. In recent years, much attention has been fo­ cused on late-appearing choreoathetoid movements Dopamine Blockade in the Mesolimbic System of the tongue, mouth, and extremities, known as The limbic system and its midbrain connections tardive dyskinesia. The social and cosmetic unde­ are the seat of emotion and behavior. Specifically, it sirability of these movements is underscored by is dopamine blockade in this locality that is thought the knowledge that the syndrome is irreversible in to act against the symptoms of schizophrenia. many cases, even after the medications are with­ drawn. Theoretically, tardive dyskinesia is oppo­ site to parkinsonism and the dystonias because too Dopamine Blockade in the Nigrostriatal System much striatal dopamine, not too little, is its cause. Dopamine of the extrapyramidal system is Initially, postsynaptic dopamine blockade by likewise blockaded by all antipsychotics. De­ antipsychotic medications decreases striatal dopa­ creased dopamine transmission in the substantia mine. However, years of denervation lead to two nigra causes parkinsonism, similar to idiopathic compensatory mechanisms. First, new receptors dopamine degeneration in the substantia nigra of grow de novo postsynaptically. Second, feedback 264 THE JOURNAL OF FAMILY PRACTICE, VOL. 14, NO. 2, 1982 ACTIONS OF ANTIPSYCHOTIC DRUGS loops cause increased presynaptic dopamine re­ antidepressants is due to their H, antihistaminic lease. The net result is increasing dopamine activ­ action.2 The tricyclic antidepressants are struc­ ity that eventually overcomes drug blockade and turally very similar to the phenothiazines. They results in a high dopamine state in the striatum. were, in fact, originally synthesized in an attempt When dopamine activity becomes excessive in the to find a more effective phenothiazine. caudate nucleus, the choreoathetosis of tardive It should be appreciated that phenothiazines are dyskinesia results. Dopamine inhibits the caudate, true antihistamines.3 They are one of the five basic which itself is an inhibitory nucleus. Excessive structural classes of antihistamic drugs, the proto­ dopamine inhibition of the caudate causes disin- type in general clinical use being promethazine hibition of movements normally suppressed, with (Phenergan). Promethazine is identical to chlor­ resulting choreoathetosis. This resembles the cho­ promazine except that the three-carbon bridge be­ reoathetosis of Huntington’s disease, in which idi­ tween the tricyclic B-ring nitrogen and the amine opathic caudate degeneration similarly disinhibits side chain moiety is replaced by a two-carbon normally suppressed movements. bridge in the nonpsychoactive antihistamine pro­ The situation in the striatal disorders is actually methazine. The three-carbon bridge is necessary more complicated because it is not absolute for antipsychotic activity, occurring in all of the dopamine deficiency or excess that causes the ex- psychoactively efficacious phenothiazines. trapyramidal signs; rather, it is a change in the The necessary structure for antihistaminic ac­ dopamine-acetylcholine ratio. Thus, if the cholin­ tivity is a substituted ethylamine.3 The phenothia­ ergic system is diminished to the same extent as zine structure, with the tricyclic ring linked to the the dopaminergic system, as by benztropine side-chain ethylamine, is a perfect example of this (Cogentin), parkinsonism and dystonias will not antihistamine structure. How H, antihistamines occur. Likewise, if the cholinergic system can be depress the central nervous system and cause se­ enhanced by physostigmine, cholinergic activity dation is not understood from a structure activity temporarily rises to match the enhanced dopamine viewpoint,3 but it is well established that they do activity of tardive dyskinesia, and the choreoathe­ cause sedation, as anyone with hayfever knows. tosis transiently disappears. In this light, anticho­ Thus, by recognizing that phenothiazines, the pro­ linergic drugs worsen the low acetylcholine-high totype antipsychotics, are antihistamines, their dopamine balance and worsen tardive dyskinesia. sedative action can easily be appreciated and con­ ceptualized. Dopamine Blockade in the Tuberoinfundibular System Dopamine, blocked in these tracts in the hypo­ Anti-Alpha Adrenergic thalamus, causes the well-known rise in prolactin The adrenergic blocking action of antipsychot­ induced by all antipsychotic drugs. Since dopa­ ics is well documented as causing orthostatic hy­ mine causes tonic inhibition of prolactin, blocking potension. The low-potency antipsychotics, such dopamine allows dysinhibition and tonic release as chlorpromazine (Thorazine) and thioridazine of prolactin. This results in galactorrhea, gyneco­ (Mellaril), are especially potent in this activity and mastia, amenorrhea, and the libidinal disturbances in causing orthostasis.4 Since alpha receptor stim­ well known with antipsychotics. ulation causes