Pharmacodynamic interactions additivity

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

In addition to the numerous pharmacokinetic interactions seen with the maintenance immunosuppressants, there also exists the possibility for pharmacodynamic interactions. An in-depth review of pharmacodynamic interactions with maintenance immunosuppressive agents goes beyond the scope of this chapter. 

Knowledge of which mechanism of delayed toxicity is operating in specific cases cannot usually be gained from the animal test or from epidemiology studies additional studies of ADME, and of pharmacodynamic interactions of the chemical with cellular components, are necessary to understand mechanisms of delayed toxicity. Some mechanisms are discussed in the following to illustrate the value of this kind of study. 

Pharmacodynamic Interactions. Sometimes medications interact pharmacody-namically. If two medications produce similar side effects, then those effects can be additive. This can be advantageous. For examples, coadministering two antidepressants that relieve depression in different ways can be more effective than either medication alone. However, added effects can be problematic. If two medications that each produce drowsiness are coadministered, then the combination may produce intolerable daytime sedation. 

Pharmacodynamic interactions generally involve additive, synergistic or antagonistic effects of drugs acting on the same receptors or physiological systems. These interactions are more difficult to classify than those with a pharmacokinetic basis. They are fairly common but may not always be recognised. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

Research on drug interactions with zolpidem and zaleplon is limited, but any drug with CNS depressant effects could potentially enhance the CNS depressant effects of zolpidem and zaleplon through pharmacodynamic interactions. In addition, zolpidem is primarily metabolized by CYP 3A3/4, and zaleplon is partially metabolized by CYP 3A3/4. Thus, inhibitors of these enzymes may increase blood levels and the toxicity of zolpidem. 

Pharmacodynamic interactions take place at the site of drug action. When two or more drugs with similar pharmacological effects are administered together, an additive or synergistic effect is usually seen. 

Common pharmacodynamic interactions involve the additive anticholinergic or antidopaminergic effects of antipsychotics. Thus, concomitantly administered antiparkinsonian agents (e.g., benztropine) may increase the chances of toxicity (e.g., delirium) while dopamimetic agents (e.g., levodopa) may counteract the antipsychotic or neurotoxic effects of these agents. 

MAOIs have the most serious pharmacodynamic interactions of any antidepressant class. As discussed earlier, they can cause a hypertensive crisis and the serotonin syndrome. They potentiate the hypertensive effects of most sympathomimetic amines, as well as tyramine, which is the reason for the avoidance of over-the-counter preparations containing such agents, in addition to the tyramine-free diet ( 508, 509). The serotonin syndrome occurs most often when MAOIs are used in combination with SSRIs and venlafaxine but it can also occur when MAOIs are used with tryptophan, 5-hydroxytryptophan, and some narcotic analgesics. In addition, MAOIs can also significantly potentiate the sedative and respiratory depressant effects of narcotic analgesics. 

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). 

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). 

Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents. 

The possibility of a pharmacodynamic interaction between risperidone and serotonin re-uptake inhibitors has been discussed (258-260). Published cases of amelioration and deterioration have perpetuated the debate. Amelioration was observed in four patients with depression that had responded inadequately to selective serotonin re-uptake inhibitors by the addition of risperidone 1 mg bd (n = 2) or 0.5 mg at night (n = 2) (261). 

Pharmacodynamic interactions may also be relevant to patients with liver disease. These generally occur when two drugs having the same pharmacological effect are given together and cause additive or synergistic effects. It is often the additive adverse effects that need to be taken into consideration in patients with liver disease, for example sedation or constipation in patients predisposed to encephalopathy. 

Pharmacodynamics describes the effect(s) of a drug on the human body, which is primarily determined by its concentration at the site of action (which in turn depends on its pharmacokinetics). The nature of change at target sites or receptors depends on the state of these sites, for example whether they are affected by disease states. Pharmacodynamic interactions may result in excessive therapeutic effects, diminished therapeutic effects or additive adverse effects (e.g. adding together two drugs that prolong the Q-T interval). 

For instance/ the interaction between cerivastatin and gemfibrozil/ which has resulted in cases of severe rhabdomyolysiS/ is likely due to the inhibition of cerivastatin metabolism by gemfibrozil (i.e./ pharmacokinetic interaction)/ in addition to the propensity of both drugs to cause skeletal muscle toxicity (i.e./ pharmacodynamic interaction) (13-15). 

A particular feature of minoxidil is excessive hair growth (7), which occurs in about 70% of patients who take oral minoxidil, usually within 2 months of the start of therapy. Severe hypertrichosis, unacceptable even to men, has comphcated the otherwise successful antihypertensive treatment of six patients after renal transplantation, for which ciclosporin was also used. Since hypertrichosis has also been described with ciclosporin, there may be an additive pharmacodynamic interaction (8). 

Pharmacokinetic and pharmacodynamic interactions between caffeine 250 mg and phenylpropanolamine 25 mg have been investigated in six healthy subjects in a double-blind, placebo-controlled study. Coadministration of caffeine and phenylpropanolamine produced an additive increase in blood pressure, not attributable to a pharmacokinetic interaction and despite the fact that phenylpropanolamine attenuated the responses of adrenaline and renin to caffeine (17). 

Drug interactions with hawthorn are theoretically possible with cardioactive medications, but have not been documented (2). In addition, the flavonoid constituents have been shown to have inhibitory and inducible effects on the cytochrome P-450 enzyme system, making other drug interactions possible (20). However, an in vivo study of a potential pharmacokinetic interaction of digoxin and hawthorn demonstrated that concurrent administration had no effect on digoxin pharmacokinetics, suggesting that the two could be safely administered together from a pharmacokinetic point of view (21). However, one must be mindful of additive effects and a potential pharmacodynamic interaction. 

More recently Brochot et al. [89] reported an extension of the isobolographic approach to interaction studies for convulsant interaction among pelloxacin, norfloxacin, and theophylline in rats. Their contribution is unique in that they started out by explaining pharmacodynamic interactions for two drugs, but then extended the approach to derive an isobol for three drug interaction. In addition they included Bayesian analysis and developed a population model with Markov chain Monte Carlo methods. 

Response Surface Model A dose-response surface is an extension of dose-response lines (isobols) to three dimensions. In this representation there can be a dose-response surface representing additivity and surfaces above and below suggesting deviation from additivity. Tam et al. [90] studied the combined pharmacodynamic interactions of two antimicrobial agents, meropenem and tobramycin. Total bacterial density data, expressed as CFU (colony forming units), were modeled using a three-dimensional surface. Effect summation was used as the definition of additivity (null interaction hypothesis) and the pharmacodynamic model was assumedi to take the functional form... 

Combinations of drugs often are employed to therapeutic advantage when their beneficial effects are additive or synergistic or because therapeutic effects can be achieved with fewer drug-specific adverse effects by using submaximal doses of drugs in concert. Combination therapy often constitutes optimal treatment for many conditions, including heart failure see Chapter 33), hypertension see Chapter 32), and cancer see Chapter 51). This section addresses pharmacodynamic interactions that produce adverse effects. 

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