Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.1 General Principles of Psychopharmacology

In cases in which suicide is a major concern, an attempt should be made to verify that the medication is not being hoarded for a later overdose attempt. Random pill counts or asking a family member to dispense daily doses may be help- ful. Some patients attempt suicide just as they are beginning to recover. Large quantities of medications with a low therapeutic index should be prescribed judiciously. Another reason to limit the number of pills prescribed is the possibility of accidental ingestion of medications by children in the household. Psy- chotherapeutic medications should be kept in a safe place. Physicians who work in emergency rooms should know which drugs can be hemodialyzed. The issues involved are com- plex and are not based on any single chemical property of the drug. For example, it is generally presumed that drugs with low protein binding are good candidates for dialysis. Venlafaxine, however, is only 27 percent protein bound and is too large as a molecule dialyzed. Hemodialysis is effective for treating over- dose of valproic acid. Pharmacokinetics Pharmacokinetic drug interactions are the effects of drugs on the plasma concentrations of each other, and pharmacodynamic drug interactions are the effects of drugs on the biological activities of each other. Pharmacokinetic concepts are used to describe and predict the time course of drug concentrations in different parts of the body, such as plasma, adipose tissue, and the central nervous system (CNS). From a clinical perspective, pharmacokinetic methods help explain or predict the onset and duration of drug activity and interactions between drugs that alter their metabolism or excretion. Pharmacogenetic research focuses on finding variant alleles that alter drug pharmacokinetics and pharmacodynamics. Researchers are attempting to identify genetic differences in how enzymes metabolize psychotropics, as well as CNS pro- teins directly involved in drug action. Likely, identification of patient genotypes will facilitate prediction of clinical response to different types of drugs. Most clinicians need to consult charts or computer programs to determine when potential interactions may occur and, if so, how clinically relevant they may be. Whenever possible, it is preferable to use a medication that produces minimal risk of drug interactions. Also, it is recommended that prescribers know the interaction profiles of the drugs they most commonly prescribe. Examples of pharmacokinetic interactions include one drug increasing or decreasing the concentrations of a coadministered compound. These types of interactions can also lead to altered concentrations of metabolites. In some cases, there may also be interference with the conversion of a drug to its active metabo- lite. Enormous variability exists among patients with respect to pharmacokinetic parameters, such as drug absorption and metabolism. Another type of interaction is represented by inter- actions involving the kidney. Commonly used medications, such as angiotensin-converting enzyme (ACE) inhibitors, nonsteroi- dal anti-inflammatory drugs (NSAIDs), and thiazides, decrease renal clearance of lithium, increasing the likelihood of severe elevations of lithium. Drug interactions can occur pharmacoki- netically or pharmacodynamically. Pharmacogenetics is being used to study why patients differ in the way they metabolize drugs. In patients who are ultrarapid

known pharmacologic properties, and most likely represent a genetically based abnormal sensitivity to a drug. A paradoxi- cal response represents the manifestation of a clinical effect the opposite of what is expected. In March 2007, the FDA reported dissociative-like states associated with certain sedative hypnot- ics. These included behaviors such as sleepwalking, binge eat- ing, aggressive outbursts, and night driving of which the patient was unaware. Table 29.1-2 lists the drugs required to have warn- ing labels for that effect. Therapeutic Index Therapeutic index is a relative measure of the toxicity or safety of a drug and is defined as the ratio of the median toxic dose to the median effective dose. The median toxic dose is the dose at which 50 percent of patients experience a specific toxic effect, and the median effective dose is the dose at which 50 percent of patients have a specified therapeutic effect. When the thera- peutic index is high, as it is for haloperidol, it is reflected by the wide range of dosages in which that drug is prescribed. Conversely, the therapeutic index for lithium is quite low, thus requiring careful monitoring of serum lithium levels in patients for whom the drug is prescribed. Overdose Safety in overdose is always a consideration in drug selection. Almost all of the newer agents, however, have a wide margin of safety when taken in overdose. By contrast, a 1-month supply of TCAs could be fatal. The depressed patients they were used to treat are the group most at risk to attempt suicide. Because even the safest drugs can sometimes produce severe medical compli- cations, especially when combined with other agents, clinicians must recognize that the prescribed medication can be used in an attempt to commit suicide. Although it is prudent to write non- refillable prescriptions for small quantities, this practice passes along increased copay costs to the patient. In fact, many phar- macy benefit management programs encourage the prescribing of a 3-month supply of medication.

Table 29.1-2 Sedative Hypnotics Cited by the U.S. Food and Drug Administration

Drug

Manufacturer

Zolpidem (Ambien/Ambien CR) Butabarbital (Butisol Sodium) Pentobarbital and carbromal (Carbrital)

Sanofi Aventis

MedPointe Pharmaceuticals

Parke-Davis

Flurazepam (Dalmane) Quazepam (Doral) Triazolam (Halcion) Eszopiclone (Lunesta) Ethchlorvynol (Placidyl) Estazolam (Prosom) Temazepam (Restoril) Ramelteon (Rozerem) Secobarbital (Seconal)

Valeant Pharmaceuticals Questcor Pharmaceuticals

Pfizer

Sepracor

Abbott Abbott

Tyco Healthcare

Takeda

Lilly

Zaleplon (Sonata)

King Pharmaceuticals