Altered Pharmacodynamics

Most literature reports of pharmacodynamic botanical-drug interaction involve the anticoagulant warfarin, likely because it has therapeutic end points such as the INR and PT, which are routinely closely monitored. In addition, most botanicals possess anticoagulant and/or antiplatelet activities, and their combined use with warfarin provides a good example of pharmacodynamic interaction with additive pharmacological effect. 

The similar pharmacological profile of selective serotonin reuptake inhibitors and St. John s wort would suggest the potential of a pharmacodynamic interaction due to an additive effect. A case of concurrent use of sertraline and St. John s wort, resulting in mania, was reported for a patient with a history of depression who was prescribed sertraline and who also took St. John s wort against medical advice (58). A similar potentiation of serotonergic effect was reported by Gordon (49). 

Miscellaneous Central Nervous System Acting Drugs 

Ephedra (ma huang) is a popular botanical incorporated into a variety of formulations for weight loss, energy or performance enhancement, and symptomatic control of asthma. A pharmacodynamic interaction leading to a fatality has been reported with concurrent use of caffeine and ephedra (62), possibly as a result of additive adrenergic agonist effect of the ephedrine alkaloids and caffeine on the cardiovascular system and the CNS (63). Ephedra was recently withdrawn from the market (64). 

In a brief report, a potential interaction between curry and chlorpropamide, leading to reduction in chlorpropamide dose in a 40-year-old woman was attributed to the garlic and karela components of this complex mixture (70). Garlic reportedly can lower blood glucose. However, there was no information provided regarding the estimated amount of garlic intake in this patient. To date, there are no formal studies that confirm the initial clinical observation or evaluate the likely mechanism. 

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Tolerability" should not be confused with the term "tolerance", which describes the diminution in effects of a drug on prolonged exposure. Tolerance may be due to increased clearance because of autoinduction of the enzymes that metabolise the drug, such as occurs with some antiepileptic drugs, for example, carbamazepine. Tolerance may also result from altered pharmacodynamics, which is common with drugs acting on the CNS. 

Pravastatin is less dependent on biliary excretion, a smaller percentage is protein boimd, and it is hydrophilic. Therefore, it would be the statin least likely to exhibit altered pharmacodynamics in this patient. However, it has been reported to cause increases in transaminases and should be used with caution and with appropriate monitoring. The drug should be started at a low dose, e.g. 10 mg at night, and then adjusted according to the patient s clinical response. 

Genetic factors account for some ADRs due to either altered pharmacokinetics or by altering tissue responsiveness. Altered metabolism of drugs occurs due to differences in hydrolysis, acetylation, and hepatic oxidation of drugs. Altered pharmacodynamic reactions could be either an exaggerated response or a... 

Different subpopulations may react differently to drugs, due to a variety of reasons affecting metabolism. Factors that could influence patient susceptibility include multiple drug therapies, multiple disorders and severity of disease, types of drugs prescribed, altered pharmacokinetics, pharmacogenetics, altered pharmacodynamics and the age of the population treated (Nolan and O Malley, 1988). 

Patients with AD are more sensitive to antipsychotic side effects than other patient groups. Increased sensitivity to antipsychotic side effects in the elderly appears to be the result of altered pharmacodynamics rather than altered pharmacokinetics. Particularly problematic side effects are extrapyramidal side effects, postural hypotension caused by a-adrenergic blockade, and anticholinergic effects, including increased confusion, urinary retention, constipation, and dry mouth. For a more detailed description of antipsychotic side effects see Chap. 66 on schizophrenia. Overall, fewer side effects are seen with tlie newer atypical antipsychotics, making them a preferred choice for treatment of psychosis or aggression in the AD patient. Effective doses of antipsychotic medications are much lower than those typically used to treat schizophrenia (see Table 63-8). The rule of thumb is to start low and go slow. ... 

Over 4 decades, between 1960 and 2000, the development of new antibiotics used well characterized basic structures for partial synthetic modifications, primarily to overcome resistance by increasing the pharmacodynamic properties and, secondarily, to improve the pharmacokinetic profile of older compounds. However, bacteria rapidly responded by acquiring additional genetic alterations either as mutations or by accumulating resistance genes as part of mobile genetic elements ( integrons) on transferable resistance plasmids. 

Ciraulo DA, Sands BE, Shader RI Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 145 1501-1506, 1988b Ciraulo DA, Barnhill JG, Ciraulo AM, et al Parental alcoholism as a risk factor in benzodiazepine abuse a pilot smdy. Am J Psychiatry 146 1333-1335, 1989 Ciraulo DA, Antal EJ, Smith RB, et al The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol 10 27—32, 1990 Ciraulo DA, Sarid-Segal O, Knapp C, et al Liability to alprazolam abuse in daughters of alcoholics. Am J Psychiatry 153 956-958, 1996 Ciraulo DA, Barnhill JG, Ciraulo AM, et al Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone. J Clin Pharmacol 37 64-73, 1997... 

BEIs apply to 8 hr exposures, five days a week. However, BEIs for altered working schedules can be extrapolated on pharmacokinetic and pharmacodynamic bases. BEIs should not be applied, either directly or through a conversion factor, to the determination of safe levels for non-occupational exposure to air and water pollutants, or food contaminants. The BEIs are not intended for use as a measure of adverse effects or for diagnosis of occupational illness. 

Within the medical community it has been acknowledged that elderly patients often respond to drug therapy differently from their younger counterparts. Aside from alteration of various pharmacokinetic and pharmacodynamic processes, elderly patients tend to suffer from a number of chronic conditions and, thus, have more complex dosage regimens. Additionally, a variety of physical limitations prevalent among the elderly may hinder their ability to self-administer medication. 

J. Roberts and N. Turner, Pharmacodynamic basis for altered drug action in the elderly, Clin. Geriatr. Med., 4, 127 (1988). 

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