Pharmacodynamic interactions

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. 

Ahmed SM, Banner NR, Dubrey S W Low cyclosporin-A level due to Saint-John s-wort in heart transplant patients (letter). J Heart Lung Transplant 20 795, 2001 

Breidenbach T, Hoffmann MW, Becker T, et al Drug interaction of St John s wort with cyclosporin (letter). Lancet 355 1912, 2000 

Callahan AM, Marangell LB, Ketter TA Evaluating the clinical significance of drag interactions a systematic approach. Harv Rev Psychiatry 4 153-158, 1996 

Durr D, Stieger B, Kullak-Ublick GA, et al St John s wort induces intestinal P-glycoprotein/MDRl and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 68 598-604, 2000 

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Drug-drug interactions Pharmacokinetic and/or pharmacodynamic interactions Pharmacokinetic and/or pharmacodynamic consequence of multiple drug therapy... 

Medications that have been used as treatment for anxiety and depression in the postwithdrawal state include antidepressants, benzodia2epines and other anxiolytics, antipsychotics, and lithium. In general, the indications for use of these medications in alcoholic patients are similar to those for use in nonalcoholic patients with psychiatric illness. However, following careful differential diagnosis, the choice of medications should take into account the increased potential for adverse effects when the medications are prescribed to alcoholic patients. For example, adverse effects can result from pharmacodynamic interactions with medical disorders commonly present in alcoholic patients, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (Sullivan and O Connor 2004). 

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

Pharmacodynamic interaction resulting in an increase in blood pressure possibly resulting in a hypertensive emergency or stroke avoid this combination. 

Pharmacodynamic interaction clonidine acts as an agonist at a2-receptors, and these TCAs block this receptor to varying degrees the result is an increase in blood pressure either avoid this interaction by choosing another antidepressant or increase the dose of clonidine. 

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. 

As the number of medications that a patient takes increases, so does the potential for DDIs. Disease severity, patient age, and organ dysfunction are all risk factors for increased DDIs. In general, DDIs can be broken down into two categories (1) pharmacokinetic interactions and (2) pharmacodynamic interactions. 

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. 

Use of a hERG blocker in a patient also taking drugs inducing electrolyte imbalance (e.g. risk of hypokalemia with diuretics) this is a pharmacodynamic interaction... 

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. 

Mechanism-based PK/PD models contain specific expressions to characterize the different stages between drug administration and clinical effects, namely target site distribution, target binding and activation, pharmacodynamic interactions. 

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. 

Bindschedler M., P. Degen, G. Flesch, M. de Gasparo, and G. Preiswerk (1997). Pharmacokinetics and pharmacodynamic interaction of single oral doses of valsartan and furosemide. European Journal of Clinical Pharmacology 52 371-378. 

PHARMACOKINETIC/PHARMACODYNAMIC INTERACTIONS AND THE CENTRAL SEROTONIN SYNDROME... 

Exogenous progesterone and benzodiazepines may have important pharmacodynamic interactions in that cognitive impairment to benzodiazepines may be enhanced with exogenous progesterone (Kroboth et al. 1985 McAuley et al. 1995). 

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. 

Risperidone is metabolized primarily by CYP 2D6 (Byerly and De-Vane 1996). Medications that inhibit this enzyme, such as many of the SSRls, cause increases in plasma risperidone levels. Pharmacodynamic interactions may occur when risperidone is combined with medications that share a similar physiological effect, such as orthostatic hypotension. 

Because rivastigmine is not hepatically metabolized, pharmacokinetic cytochrome P450-related drug interactions are not expected. However, the previously discussed pharmacodynamic interactions associated with other cholinesterase inhibitors may occur with rivastigmine as well. 

Once QSAR calculations have been used to optimize the pharmacodynamic interactions of the dmg molecule, the next step is to optimize the pharmacokinetic and pharmaceutical phases of dmg action. 

When an SSRI agent is used with a MAO inhibitor, a dangerous pharmacodynamic interaction may occur. The combination of increased stores of monoamine together with reuptake inhibition leads to a phenomenon termed serotonin syndrome. This syndrome, which arises from a marked increase in synaptic serotonin, is clinically... 

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

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