Antinausea and Antiemetic Actions Several first-generation Hy antagonists have significant activity in preventing motion sickness (Table 16-2). They are less effective against an episode of motion sickness already present. Certain 11; antagonists, notably doxylamine (in Bendectin), were used widely in the past in the treatment of nausea and vomiting of pregnancy (see below). Antiparkinsonism Effects Perhaps because of their anticholinergic effects (ef benztropine, Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders), some of the H; antagonists have significant acute suppressant effects on the parkinsonism symptoms associated with certain antipsychotic drugs. Anticholinoceptor Actions Many of the first-generation agents, especially those of the ethanolamine and ethylenediamine subgroups, have significant atropine-like effects on peripheral muscarinic receptors. This action ‘may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision. Adrenoceptor-Blocking Actions Alpha receptor-blocking effects can be demonstrated for many Hy antagonists, especially those in the phenothiazine subgroup, eg, promethazine. This action may cause orthostatic hypotension in susceptible individuals. Beta receptor blockade is not observed. Serotonin-Blocking Action Strong blocking effects at serotonin receptors have been demonstrated for some first-generation H antagonists, notably cyproheptadine. This drug is promoted as an antiserotonin agent and is, discussed with that drug group. Nevertheless, its structure resembles that of the phenothiazine antihistamines, and itis a potent H blocking agent. Local Anesthesia Many first-generation Hy antagonists are potent local anestheties. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to the conventional local anesthetic drugs. A small number of these agents also block potassium channels; this action is discussed below (see Toxicity). Other Actions Certain Hy antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other ‘mediators of inflammation. ‘This action is not due to Hy receptor blockade. ‘The mechanism is not understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few Hl antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain, The significance of this effect is not known,