Antihistamines pharmacokinetics

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a... 

Pharmacokinetics Dimenhydrinate has a depressant action on hyperstimulated labyrinthine function. The precise mode of action is not known. The antiemetic effects are believed to be caused by the diphenhydramine, an antihistamine also used as an antiemetic agent. 

Mechanism of Action A propylamine derivative antihistamine that competes with histamine for histamine receptor sites on cells in the blood vessels, gastrointestinal (GI) tract, and respiratory tract. TAerapfiMtic Effect Inhibits symptoms associated with seasonal allergic rhinitis such as increased mucus production and sneezing. Pharmacokinetics Well absorbed after PO and parenteral administration. Food delays absorption. Widely distributed. Metabolized in liver. Primarily excreted in urine. Not removed by dialysis. Half-life 20 hr. 

Mechanism of Action An antihistamine and anticholinergicthat competes for H,-receptor sites on effector cells of the G1 tract, blood vessels, and respiratory tract. The anticholinergic action diminishesvestibular stimulation and depresses labyrinthine function. Therapeutic Effect Prevents symptoms of motion sickness. Pharmacokinetics Well absorbed following PO administration. Metabolized in liver. Excreted in urine. Half-life Unknown. 

Mecfianism of Action A long-acting nonsedating antihistamine that competes with histamine for Hj-receptor sites on effector cells. Therapeutic Effect Prevents allergic responses mediated by histamine, such as rhinitis, urticaria, and pruritus. Pharmacokinetics ... 

Mechanism of Action A phenothiazine that acts as an antihistamine, antiemetic, and CNS-antipsychotiC typical hypnotic. As an antihistamine, inhibits histamine at histamine receptor sites. As an antiemetic, diminishes vestibular stimulation, depresses labyrinthine function, and acts on the chemoreceptor trigger zone. As a sedative-hypnotic, produces CNS depression by decreasing stimulation to the brainstem reticular formation. Therapeutic Effect Prevents allergic responses mediated by histamine, such as rhinitis, urticaria, and pruritus. Prevents and relieves nausea and vomiting. Pharmacokinetics ... 

In the treatment of children and adolescents with anxiety disorders clinicians have a wide variety of pharmacologic options beyond the antidepressants (Shader and Greenblatt, 1995 Lydiard et ah, 1996 Riddle et ah, 1999). The benzodiazepines (BZs), with their favorable safety profile and quick onset of action, are attractive alternatives for the treatment of acute anxiety. While the clinical effectiveness of buspirone has not been proven in children, buspirone is used alone or in combination with other drugs in the treatment of anxiety disorders. The antihistamines are often used to treat insomnia and may reduce acute mild agitation. Zolpidem (Ambien) is occasionally used for its sedative properties. This chapter reviews the structure, proposed mechanisms of action, pharmacodynamic principles, and pharmacokinetic principles of these drugs. 

Quetiapine is metabolized by hepatic CYP 3A3/4. Concurrent administration of cytochrome P450-inducing drugs, such as carbamazepine, decreases blood levels of quetiapine. In such circumstances, increased doses of quetiapine are appropriate. Quetiapine does not appreciably affect the pharmacokinetics of other medications. Pharmacodynamic effects are expected if quetiapine is combined with medications that also have antihistaminic or a-adrenergic side effects. Because of its potential for inducing hypotension, quetiapine also may enhance the effects of certain antihypertensive agents. 

Effects of solvation on zwitterion formation between methylamine and fom-aldehydewere studied by various solvation methods. The SM2/AM1 model predicted the expected zwitterionc minimum while SM3/PM3 failed to do so [127]. Calculations were performed with the use of AMSOL to account for solvation effects in the study of molecular properties and pharmacokinetic behavior of ce-tirizine, a zwitterionic third-generation antihistaminic. Results indicated that the folded conformation remains of low energy not only in vacuo but also in water solution [128]. 

Gonzalez MA, Estes KS. Pharmacokinetic overview of oral second-generation HI antihistamines. Int J Clin Pharmacol Ther 1998 36 292-300. 

Quinones-Torrelo et al. (1999 2001) have demonstrated a correlation of pharmacokinetic properties with results from micellar liquid chromatography. In this method micellar solutions of nonionic surfactants are used as the mobile phase in reverse-phase liquid chromatography. Interactions between the mobile and stationary phases are purported to correspond to the membrane/water interface of biological barriers as hydrophobic, steric, and electronic interactions are important for both. For a series of 18 antihistamines Quinones-Torrelo et al. (2001) showed that both volume of distribution and half-life values were better correlated with retention on these columns than with the classical log K, w descriptor. 

Quinones-Torrelo, C., Sagrado, S., Villanueva-Camanas, R.M., and Medina-Hernandez, M.J., Retention pharmacokinetic and pharmacodynamic parameter relationships of antihistamine drugs using biopartitioning micellar chromatography, J. Chromatogr. B, 761, 13-26, 2001. 

At times of physiological change, corresponding alterations can occur in pharmacokinetics. This can be reflected in variability in response and the need for dosage adjustment. Unusual, paradoxical pharmacodynamic differences can occur in children, for example. While antihistamines and barbiturates generally sedate adults,... 

Methods for Reducing Toxic Effects. Limited information is available on treatments to alleviate the symptoms of tetryl exposure. These include treatment of the dermatitis with calamine lotion and/or zinc oxide preparations, treatment of dermatitis and ocular irritation with aluminum acetate or boric acid compresses, and treatment of hypersensitivity-like symptoms (including severe dermatitis and asthma-like symptoms) with epinephrine or antihistamines (Bain and Thomson I 954 Bergman 1952 Cripps 1917 Eddy 1943 Ruxton 1917 Smith 1916 Troup 1946 Witkowski et al. 1942). The data on the pharmacokinetics of tetryl are also limited (Zambrano and Mandovano 1956). In order to develop mitigating agents, further studies are needed on its kinetics and mechanisms of action. 

Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTC interval. This can cause potentially dangerous interactions. In a double-blind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTC interval (27). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTC interval. This effect of nefazodone on... 

Paton DM, Webster DR. Clinical pharmacokinetics of HI-receptor antagonists (the antihistamines). Clin Pharmacokinet 1985 10 477-97. 

Desager JP, Horsmans Y Pharmacokinetic-pharmacodynamic relationships of Hj antihistamines. CUn Pharmacokinet 1995 5 419-432. 

Pharmacokinetics. Hj-antihistamines taken orally are readily absorbed. They are mainly metabolised in the liver. Excretion in the breast mUk may also be sufficient to cause sedation in infants. They are generally administered orally and can also be given i.m. or i.v. 

Example Pseudoephedrine hydrochloride (Actifed, Sudafed), phenylpropanolamine (Allerest, Dimetapp), phenylephrine HCK (Neo-Synephrine, Sinex), and pseudoephedrine (Actifed, Sudafed) frequently combined with an antihistamine, analgesic, or antitussive (anticough) in oral cold remedies Route Tablet, capsule, liquid Pregnancy category C Pharmacokinetic Absorbed by the GI tract, metabolized in liver and excreted in urine. Not removed by hemodialysis... 

Although drug interactions may occur through a variety of mechanisms, most occur because of pharmacodynamic or pharmacokinetic interactions. Common examples of pharmacodynamic interactions resulting in enhanced effect include the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative side effects (e.g., mood stabUizers, hypnotics, alcohol, antidepressants, anxiolytics, or antihistamines). 

While drug interactions based on pharmacokinetics do occur with sedative-hypnotics, the most common drug interaction is additive CNS depression. Additive effects can be predicted with concomitant use of alcoholic beverages, anticonvulsants, opioid analgesics and phenothiazines. Less obvious but equally important is enhanced CNS depression with many antihistamines, antihypertensives, and antidepressants of the tricyclic class. The answer is (A). 

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