Mediator antihistamine activity

Alkylation of the monobenzhydryl derivative of piperazine ( ) with the same alkylating agent gives oxatomide (59), after removal of the protecting group.This agent shows antihistaminic activity as well as some mediator release inhibiting activity, a... 

Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. 

The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations rather than from scientific knowledge of the neurobiological basis of psychosis or the mechanism of action of effective antipsychotic agents. Thus, the fist antipsychotic drugs were discovered by accident in the 1950s when a putative antihistamine (chlorpromazine) was serendipitously observed to have antipsychotic effects when tested in schizophrenic patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action. 

Sensory nerves contain no acetylcholine and the chemical mediator involved in the simplest unit of central nervous activity, the monosynaptic reflex, is not known. For this reason, some considerable attention has been paid to the pharmacological activity of extracts of sensory nerves, which have been shown to contain three substances of potential neuropharmacological significance—ATP, substance P (a polypeptide) and histamine. They have been reviewed at length elsewhere and little need be added here, since it now seems likely that neither ATP nor substance P will be shown to have neurohumoral functions. However, some psychotropic drugs have antihistamine activity and a brief statement is therefore necessary concerning the present status of histamine. 

Mediator release inhibitors with antihistamine activity Several agents which are both antihistamines and inhibitors of mediator release have also been reported (Figure 12). An early compound of this type was Schering 15,280 (C, azanator) (76). Three other compounds (Cl, Cll and ClII) have subsequently been reported (TJ-SI). The most advanced of these is ketotifen (Cl) which is structurally related to azanator. It is orally active in man at 1 mg (b.i.d.) (Z7) and has been marketed by Sandoz in Switzerland. Two other potent, orally active compounds in the rat PCA procedure are Janssen s oxatomide (7 ,79) and Boehringer Mannheim s BM 15,100 (S0>S1)- These compounds combine the properties of mediator release inhibition with antihistamine activity. 

Figure 12. Some agents with combined inhibition of mediator release and antihistaminic activity...

Many of these drugs have effects that are not mediated by Hi-receptors (Table 38.2). The antimuscarinic activity of several first-generation Hj-blockers may account for their effectiveness in combating motion sickness and their limited ability to suppress parkinsonian symptoms. The phenothiazines have some capacity to block a-adrenoceptors, whereas cyproheptadine Periactin) is an antagonist at serotonin receptors. Diphenhydramine Benadryl), pyrilamine (Ryna), and promethazine Phen-ergan) are effective local anesthetics. Many second-generation antihistamines also have been found to inhibit the non-histamine-mediated release of various... 

Cromolyn sodium inhibits mast cell degranulation. As a result its main mode of action is to prevent mediator release and its subsequent clinical manifestations. There is no evidence of antihistamine, anti-inflammatory, or vasoconstrictive activity. Absorption is poor. 

Muscarinic effects, mediated by acetylcholine, the primary transmitter of the autonomic nervous system ganglia, are inhibited by the anticholinergic effects exerted by antihistamines. Anticholinergic side effects include dry mouth, urinary retention, blurred vision, and constipation. Because first-generation antihistamines also distribute into the CNS, sedation is a prominent side effect. The development of second-generation antihistamines, such as loratadine and fexofenadine, lack anticholinergic activity and do not distribute into the CNS (Table 31-1). Hence, they are not typically associated with sedation and do not possess antiemetic properties. 

The concept of an endogenous mediator of increased permeability was supported by the classical studies of Lewis on histamine. The increase in vascular permeability is a biphasic process, the earlier transient stage, in some species at least, resulting from the release of histamine. After suitable mild inflammatory stimuli, the tissue oedema may often be inhibited by anti-histaminic drugs. In a limited sense, therefore, antihistaminic drugs may be regarded as having anti-inflammatory activity, but they are not discussed in detail in this review. 

The anticholinergic effects of the antihistamines can synergize with the increased sympathetic activity mediated by the drug, and a hypertensive crisis or other cardiovascular event can result. 

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