[Misco arc Loratadine (Claritin) J ng Longer action | Cetirizine (Zyrtec) fees is | eeeerraSeceeeee| SceceeseSceceeseee cs cceceesea | id, no data found, ‘These agents are rapidly absorbed following oral administration, with peak blood concentrations occurring in 1-2 hours. They are widely distributed throughout the body, and the first-generation drags enter the central nervous system readily. Some of them are extensively metabolized, primarily by microsomal systems in the liver. Several of the second-generation agents are metabolized by the CYP3A4 system and thus are subject to important interactions when other drugs (such as ketoconazole) inhibit this subtype of P450 enzymes. Most of the drugs have an effective duration of action of 4-6 hours following a single dose, but meclizine and several second-generation agents are longer-acting, with a duration of action of 12-24 hours. The newer agents also are considerably less lipid-soluble and enter the central nervous system with difficulty or not at all. Many Hy antagonists have active metabolites. The active metabolites of hydroxyzine, terfenadine, and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively). Pharmacodynamics Histamine Receptor Blockade 11; receptor antagonists block the actions of histamine by reversible competitive antagonism at the 1; receptor. They have negligible potency at the Hy receptor and little at the Hs receptor. For example, histamine-induced contraction of bronchiolar or gastrointestinal smooth musele can be completely blocked by these agents, but the effects on gastric acid secretion and the heart are unmodified. Actions Not Caused by Histamine Receptor Blockade ‘The first-generation H; receptor antagonists have many actions not ascribable to blockade of the actions of histamine. The large number of these actions probably results from the similarity of the general structure (Figure 16-2) o the structure of drugs that have effects at muscarinic cholinoceptor, a-adrenoceptor, serotonin, and local anesthetic receptor sites, Some of these actions are of therapeutic value and some are undesirable. Sedation, A.common effect of first-generation H, antagonists is sedation, but the intensity of this effect varies among chemical subgroups (Table 16-2) and among patients as well. ‘The effect is sufficiently prominent with some agents to make them useful as "sleep aids" (see Chapter 64: Therapeutic & ‘Toxic Potential of Over-the-Counter Agents) and unsuitable for daytime use. ‘The effect resembles that of some antimuscarinic drugs and is considered very unlike the disinhibited sedation produced by sedative-hypnotic drugs. Compulsive use has not been reported. At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than sedation. At very high toxie dose levels, marked stimulation, agitation, and even convulsions may precede coma. Second-generation H, antagonists have little or no sedative or stimulant actions. These drugs (or their active metabolites) also have far fewer autonomic effects than the first-generation antihistamines