Chapter 15: Pharmacology in Critical Illness

Medication errors and adverse drug reactions (ADRs) occur more frequently in critically ill patients due to complex polypharmacy, frequent off-label drug use and multiorgan dysfunction. Requests to provide “STAT” doses during emergent situations further complicate this issue. Clinicians require an adequate knowledge of drug pharmacokinetics (PK) and pharmacodynamics (PD) to ensure safe and effective drug use in intensive care units (ICUs).

PK describes the movement of a drug through the body including the processes of absorption, distribution, metabolism, and elimination. PD describes the physiologic effects once the drug reaches the site of action. Most PK data are derived from healthy volunteers or from stable patients with specific disease states and may not be applicable to critically ill patients. Failure to anticipate significant changes in PK and PD in critical illness may contribute to suboptimal patient management.

Volume of distribution (Vd) and clearance (CL) are the 2 most important PK parameters for appropriate drug dosing. Initial loading dose (LD) is determined by Vd whereas maintenance dosing (MD) is determined by CL. Alterations of Vd and CL can occur during critical illness. These changes may result in an increased pharmacologic effect and/or undesired toxicity. The following provides a brief review focusing on general principles related to drug PK and changes that can occur during critical illness. All discussion is based on a one-compartment model using first-order PK principles.^1,2,3,4,5,6

Absorption of medications from the gastrointestinal (GI) tract during critical illness is frequently low due to shunting of blood flow to support vital organs. Poor peripheral perfusion also impairs systemic absorption from muscles and subcutaneous tissues. Thus, intravenous (IV) administration is usually preferred for patients in shock. However, oral administration may be considered once patient is hemodynamically stable and enteral feeding is tolerated. Medications such as antihypertensive agents can be titrated to the effect and provide smooth blood pressure coverage when given orally as compared to the intravenous alternatives. Some antimicrobial agents, such as cotrimoxazole, quinolones, linezolid, fluconazole, and voriconazole, have excellent oral bioavailability and can safely be given enterally once the infection is under control.

Vd is calculated by dividing the amount of drug in the body by the plasma concentration. Drug distribution in the body depends on blood flow, body composition, and plasma protein binding (PPB). In general, drugs that have high PPB stay mainly in the intravascular space and have a small Vd (Table 15–1). Lipophilic drugs have a large Vd because they tend to diffuse into the tissue and have a low plasma concentration. Vd can be used to determine the LD required to achieve a desired serum drug concentration (Cp_desired) by using the following equation (Equation 15–1):

After appropriate fluid resuscitation, patients in septic shock and other forms of multiorgan dysfunction tend to have both greatly increased intra- and extravascular fluid volume. This can increase the Vd for hydrophilic medications significantly. Thus, much higher initial dose (LD) is required to achieve a desired therapeutic effect for a hydrophilic drug such as vancomycin and aminoglycosides. Lipophilic drugs have larger Vd and their Vd is usually not affected by the fluid shift.

PPB may affect the Vd and the therapeutic effect of a drug. Only free or unbound drugs can be readily distributed into tissues and thus have pharmacologic effect. Albumin and alpha 1-acid glycoprotein (AAG) are 2 primary proteins. Acidic drugs, such as phenytoin, bind to albumin whereas basic drugs, such as lidocaine, bind to AAG. The increased vascular permeability and protein catabolism seen in critically ill patients can result in decreased albumin concentrations. Thus, increased free plasma concentration for acidic drugs. AAG, an acute phase reactant, is increased in critically ill patients, thus, decreasing the free plasma concentration of basic drugs. Metabolic abnormalities, uremia, and drug interactions may further displace a drug from PPB. Warfarin, a drug frequently avoided in ICU patients, is 99% PPB with only 1% free drug responsible for its therapeutic effect. A displace of 1% PPB can double its free drug in the plasma and cause excessive anticoagulation. Meanwhile, phenytoin is approximately 90% bound to albumin and can be displaced in uremia. It is important to recognize that these patients frequently have a low measured total phenytoin level with adequate free phenytoin level (1-2 μg/mL) for therapeutic effect. Equations have been proposed to account for increased free plasma phenytoin in patients with hypoalbuminemia (Equation 15–2) and uremia (Equation 15–3).

C_measured and C_adjusted: measured and adjusted phenytoin concentrations.

Alb: patient's albumin levels in g/dL.

As explained above, a patient with a serum albumin of 2 g/dL will only need a measured phenytoin level between 5 and 10 μg/mL to maintain a therapeutic effect. In the presence of uremia, a measured level between 3 and 6 μg/mL may be adequate. Although only supported by limited data, these equations are useful in ICU setting to guide dosage adjustment. Monitoring free phenytoin concentration may be impractical due to rapid changes in serum albumin levels and slow laboratory turnaround times.

CL measures drug removal from the body by all elimination pathways, including metabolism and excretion. To maintain therapeutic effect, the amount of drug removed during the dosing interval should be replaced as maintenance dose. In critically ill patients, both hepatic and renal CL is usually reduced. However, in early stage of septic shock, a compensatory hyperdynamic phase accompanied by an increase in cardiac output and organ perfusion may result in increased drug clearance. Appropriate dosage adjustment is critical to provide the desired effect while minimizing toxicity. Serum creatinine (SCr) and urine output are frequently monitored to estimate the extent of renal dysfunction. However, changes in SCr lag behind changes in actual renal function during acute kidney injury and recovery. Also, extensive muscle injury or drug interactions (ie, concurrent trimethoprim) may cause elevated SCr unrelated to renal dysfunction. Monitoring the trend of organ dysfunction for proactive dosing adjustments is recommended. Maintenance dose for medications mainly cleared renally should be reduced in patients with oliguria or anuria, while prompt dosing increase is imperative with renal recovery. Various dosing guidelines are available based on the estimated creatinine clearance (CrCl) using Cockroft-Gault equation (Equation 15–4):

It is important to know that this estimate is not reliable in patients with acute changes in SCr or very low SCr. In addition to estimated CrCl, extent of dose reduction should be based on the trend in renal function, and the indication for therapy. This is especially important to avoid inadequate dosing of antibiotic therapy. MD adjustment can be done by either dose reduction or interval extension. Dosing for many cardiovascular drugs (ie, antihypertensive and inotrope agents), analgesics and central nervous system (CNS) depressants can be initiated conservatively and titrated to desired effect based on clinical assessment. It is also important to remember that toxic or active metabolites (ie, of opiates and benzodiazepines) may also accumulate in patients with renal dysfunction; close monitoring is required when an extended duration of therapy is indicated. Goal-directed sedation and sedation vacations are probably the most useful approaches to avoid excessive sedation in ICU patients with multiorgan failure.

Metabolism may be affected by decreased hepatic blood flow, altered PPB, decreased hepatic enzyme activity, and other metabolic abnormalities seen in critically ill patients. Concurrent renal and cardiac dysfunction further complicates this issue. Acute hepatic dysfunction usually does not affect drug metabolism significantly. Extent of hepatic dysfunction cannot be quantified for dosage adjustment in acute or chronic liver failure. Dosing for medications that require hepatic metabolism should be initiated conservatively and titrated to the effect based on risk and benefit assessment. Concurrent or excessive use of hepatotoxic agents such as acetaminophen should be avoided whenever possible.

Half-life (T_1/2), the time required for plasma drug concentration (Cp) to reduce by 50%, is determined by Vd and CL as shown in Equation 15–5:

T_1/2 is increased with a decrease in CL, or an increase in Vd. Under normal circumstance, 4 to 5 half-lives are required for serum drug concentrations to reach steady state after a therapy is started. It may take much longer for an ICU patient to reach steady state due to rapid changes in CL and Vd. When a drug regimen is discontinued, it also takes 4 to 5 half-lives for a drug to be cleared from the plasma compartment. Dosing strategy is frequently determined by the T_1/2. For drugs with long T_1/2 (such as amiodarone with a T_1/2 of 1 month or longer with chronic use) initial LDs are required to achieve a more rapid therapeutic response. On the other hand, aminoglycosides (AGs) have a short T_1/2 of 1 to 2 hours in patients with normal renal function. Serum concentration would approach 0 before the next dose for once-a-day AG regimen. This dosing approach utilizes the concentration-dependent killing effect of AG to enhance bactericidal action while lowering the risk of nephrotoxicity. The postantibiotic effect of AGs allows for continued bacterial killing even when trough concentrations of 0 are reached.

Specific PD considerations Medications with long T_1/2 do not always have a long duration of action. This is especially true for CNS depressants including opioids, benzodiazepines, and barbiturates. These agents are highly lipid soluble and have a rapid onset of action after an IV dose. However, disproportion to the relatively long T_1/2, the duration of action is frequently short lived secondary to a rapid decline of CNS concentration after a rapid redistributed into peripheral “lipid-rich” tissues. Clinical experience has shown that the effect and duration of these medications also depends heavily on the past exposure history of the patient. Patients with chronic use of alcohol, opioids, and benzodiazepines tend to develop tolerance to these agents and require much higher doses and more frequent dosing for the required sedative or analgesic effect. Receptor desensitization and/or downregulation may be responsible for this observation. In these patients, medications with long T_1/2, such as diazepam and chlordiazepoxide may still accumulate after repeated doses. This is the rationale of repeating the doses of benzodiazepines until the patient is calm in the acute management of alcohol withdrawal. At this stage, enough benzodiazepine accumulates in the tissue (adipose) to sustain adequate concentration in the CNS. Further doses may be used less frequently and as needed for recurrent symptoms of delirium tremens (DT). The amount accumulated in the tissue will serve as a drug depot to support a slow benzodiazepine taper and complete DT management. It is also important to recognize that all benzodiazepines will have longer duration of action and longer half-lives once the agent is accumulated in the tissue. Thus, a short-acting agent, such as midazolam, may have a long-lasting sedative effect with prolonged use.

Because of increased multiple-drug resistance infections, some specific PD-based antibiotic dosing approaches have been advocated. Aminoglycoside antibiotics have concentration-dependent killing and a pronounced postantibiotic effect. Once-daily AG regimens (gentamicin and tobramycin: up to 7 mg/kg; amikacin: up to 20 mg/kg) can achieve high peak serum concentrations with better bactericidal effect than the same dose divided into multiple doses per day. Beta-lactam antibiotics, such as piperacillin/tazobactam, have time-dependent killing. Maintaining serum beta-lactam concentrations above the minimum inhibitory concentration (MIC) during the dosing interval can achieve better antibacterial activity. When piperacillin/tazobactam is administered as an extended infusion over 4 hours, compared to a 30-minute bolus infusion, serum concentration can be maintained above the MIC for a greater proportion of time during the dosing interval.

Renal Replacement Therapy

In addition to intermittent hemodialysis (IHD), continuous renal replacement therapy (CRRT),^7,8,9 especially continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF), is often provided to ICU patients with acute and chronic kidney injury. Removal of solutes and fluid from blood through semipermeable membranes occurs by means of either diffusion and/or convection during RRT. While IHD utilizes diffusion for clearance, CVVH utilizes convection and CVVHDF utilizes a combination of both. Small molecules (MW < 1000 Da) are removed effectively by IHD with conventional hemofilters (small pores). Modern high-flux membranes (large pores) utilized in CRRT are permeable to large molecules (30,000-50,000 Da) and therefore, most drug molecules. The characteristics of high-flux hemofilters and the continuous, prolonged nature of CRRT result in efficient solute removal and enhanced drug clearance. In general, the relative extent of drug removal in CRRT is CVVHDF greater than CVVH greater than IHD. However, the extent of CRRT clearance still depends on specific physiochemical properties of the drug and how CRRT is prescribed and delivered. Compared to IHD or patients with renal failure, drugs that are normally cleared by the kidney may require a much higher dose during CRRT. Drugs with a high Vd (> 1 L/kg), high PPB (> 80%), and predominant nonrenal clearance may need no dose adjustment due to poor CRRT removal.

Only unbound and water-soluble drug molecules are removed effectively during CRRT. It is evident that an increase in unbound fraction secondary to changes in systemic pH, plasma protein concentrations, organ function, and drug interactions can contribute to increased CRRT elimination. Another potential mechanism for solute removal during CRRT is “adsorption.” The clinical significance of drug adsorption to the dialysis circuitry and membrane is unclear. Many published data are available to guide proper drug dosing in CRRT. However, these dosing recommendations have been derived from diverse patient populations in which different modes of CRRT were prescribed. Other clinical and patient variables, such as interruptions or inconsistency of CRRT delivery, fluid overload, and residual renal function, may also affect drug clearance. Thus, dosing in patients requiring CRRT needs to be individualized. Drugs such as analgesics, sedatives, and cardiovascular agents can be dosed based on clinical response. Therapeutic drug monitoring (TDM) is available for some antiepileptics, antimicrobials, and cardiovascular agents. The turnaround time for TDM should be short enough for the monitoring to be clinically relevant.

As a general rule, a proper LD is usually required for an agent with a long T_1/2 to achieve therapeutic plasma levels rapidly. This initial dose is determined largely by the Vd of the drug and need not be adjusted in CRRT. However, Vd might be increased significantly in ICU patients as described in the PK section. Using vancomycin as an example, a regular or even higher LD (25 mg/kg or more) should be administered initially. Subsequent MDs require modification based on the PK and PD characteristics, and CRRT clearance. For medications such as most beta-lactam antibiotics that are renally cleared, 50% to 100% of the regular MD has been recommended for patients undergoing CRRT. It is important to recognize that aggressive antibiotic dosing during CRRT along with proper monitoring is always preferred to underdosing in patients with septic shock, especially within the first few days of therapy. The nurse in charge of the CRRT delivery should also document the actual delivery of CRRT and must inform the physicians and pharmacists if any significant interruptions of CRRT occur. This information should be communicated every 6 to 8 hours, if not more often, to ensure timely dosing adjustment. This rule should also be followed when CRRT is discontinued or a different CRRT mode is prescribed.

Plasmapheresis and Therapeutic Plasma Exchange

These are automated extracorporeal apheresis techniques designed to remove or reduce the concentration of large-molecular-weight substances such as immunoglobulins and autoantibodies from the plasma. This treatment may increase drug CL. During the process, plasma proteins are removed. Drugs with a small Vd and/or high PPB, such as basiliximab, ceftriaxone, and propranolol, may be removed significantly and supplemental doses may be required at the completion of plasmapheresis. Another approach to retain drug efficacy is to schedule the plasmapheresis toward the end of the dosing interval, allowing the regular dose to be administered at the completion of the session.¹⁰

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO)^11,12 is an advanced life support system to provide support for patients with respiratory and/or or cardiac failure who have failed conventional management. ECMO may influence PK through hemodilution (increased Vd) as well as by binding or sequestration of drugs in the ECMO circuit. Significant sequestration of opioids (fentanyl, morphine), benzodiazepines (diazepam, lorazepam, midazolam), nitroglycerin, propofol, and antimicrobials (ampicillin, cefazolin, voriconazole) has been reported. This sequestration can lower serum drug concentrations and potentially reduced the therapeutic effect. There is limited data available to guide dosing adjustment in adult patients. Most of the data have been derived from pediatric populations. Decreased serum levels of gentamicin, heparin, phenobarbital, phenytoin, and vancomycin have been reported in neonates maintained on ECMO. It is important to note that children supported by ECMO require a relative larger volume (compared to their body size) to prime the circuit and blood transfusion is frequently utilized to maintain acceptable hemoglobin levels. Although pediatric data may not be applicable to adults, higher LD and MD may be needed to maintain therapeutic levels in adult ICU patients requiring ECMO support. Proper monitoring to guide dose adjustment is essential. Serum drug monitoring is not possible for many drugs used in ICU. Tailoring therapy to the individual clinical response is often a more practical approach.

Dosing Adjustment in Obese Patients

Most recent reports indicate that 12% to 37% of ICU patients are obese. Obesity presents unique challenge because only limited PK data are available to guide dosing. Many drug investigations either exclude or do not include enough obese patients for data extrapolation. In general, both Vd and CL of drugs are altered by obesity. Lipophilic medications are distributed to adipose tissue and a larger dose is required to achieve therapeutic serum or tissue levels. Loading doses of lipophilic agents, such as phenytoin, should be based on the actual body weight followed with MD adjusted based on serum concentrations. Also, higher doses of sedatives and opioids (most are lipophilic) are usually required initially for the desired sedative or analgesic effect. However, obese patients are also at increased risk for drug accumulation after prolonged infusion or frequent dosing. Thus, proper dose titration to goal or patient response is essential. More hydrophilic medications with smaller Vd and limited distribution to adipose tissue may be dosed based on adjusted weight as per Equation 15–6.¹³

*See Equation 15–4 for ideal body weight.

Since most antimicrobial agents are hydrophilic, adequate blood concentrations may be achieved at the usual recommended doses. However, more aggressive antibiotic dosing approaches may be indicated based on the severity of the infection and the safety profile of the agent chosen. Again, with limited data to support dosing, seeking assistance from an experienced clinical pharmacist is recommended. Close monitoring for drug efficacy and toxicity is essential in the management of obese ICU patients.

Therapeutic Drug Monitoring

Serum drug concentrations of some medications may need to be monitored to ensure therapeutic effect without excessive toxicity (Table 15–2). Timing of a blood sample in relation to previous dose influences the interpretation of a drug concentration measurement. As a general rule, TDM should be done when steady state has been reached (after 4-5 half-lives). Check a peak level “immediately” after a LD is rarely justified. To confirm if a LD is adequate or further LD is needed, the level should be checked after the completion of the distribution phase. Most drugs, such as vancomycin and aminoglycosides, have a distribution phase of 30 to 60 minutes after IV administration. Digoxin is an exception to this rule. The distribution phase of digoxin is prolonged and a level (if indicated) should be drawn at least 4 to 6 hours after an IV dose or 6 to 8 hours after an oral dose. Otherwise, the measured serum digoxin level will be falsely high and misleading. Although a peak level may be required for some medications (ie, AGs), most drug levels should be checked as steady-state troughs just before the next dose is due. These trough levels represent the lowest level in the blood which can be used to guide dose adjustment based on clinical assessment. If trough monitoring is not feasible, another approach is sampling blood for drug levels consistently during a dosing interval after the completion of distribution phase. This means drawing a level at the same time of the day when such monitoring is indicated. The trend of serum drug concentration changes can then be used to guide MD adjustment. After a target level is achieved, drug levels only need to be rechecked as clinically indicated such as in patients with acute changes in organ function, suspected toxicity, or clinical failure. Also, it is important to allow at least 2 to 4 hours to elapse after any form of renal replacement therapy before sampling blood if a drug level is indicated. This is to allow redistribution of the drug from other tissues into the intravascular space. Otherwise, a falsely low level may lead to unnecessary dosing increase. The extent of this rebound of serum concentration after dialysis is more significant for a drug with a larger Vd and/or after prolonged therapy secondary to increased tissue drug accumulation.

Adverse Drug Events

Adverse drug events (ADEs)^14,15,16,17 are defined as harm or injury caused by the use of a drug. These events can occur at any stage in treatment. Approximately 25% of ADEs are either unpredictable or caused by an allergic reaction. The rest ADRS (> 70%) are dose related or predictable based on pharmacologic characteristics. Critically ill patients are at high risk for ADEs because of their organ dysfunctions as well as the complexity of the medications they are prescribed. Acute renal failure in ICU patients has been linked to increased morbidity/mortality, length of stay, and cost. Up to 20% of all cases of renal failure in ICUs may be associated with drug toxicity. The benefit of using any nephrotoxic agent (Table 15–3) in ICU patients needs to be weighed against the risk. Patients should be monitored carefully and evidence-based preventive measures should be provided whenever possible. Efforts should also be directed to minimize the exposure to other potential causes of renal injury. Adequate hydration with isotonic fluid and maintenance of renal perfusion are crucial for reducing renal toxicity associated with many agents including acyclovir, amphotericin B, radiocontrasts, and sulfonamides. Aggressive diuretic therapy should be used with caution when a patient is maintained on a therapy with known nephrotoxicity. If drug-induced renal failure is suspected, the therapy should be discontinued whenever possible. Medication profiles should be reviewed for proper dose adjustment while renal supportive care is provided. Many drugs used in ICU have been associated with prolongation of the QT interval (Table 15–4). Amiodarone and methadone are the 2 most frequently reported drugs to cause prolonged QT interval and torsades de pointes based on the data from the Food and Drug Administration (FDA) Adverse Event Reporting System (January 2004 to December 2007). Patients receive concurrent medications with QT prolongation potential should be monitored properly. Clinical decisions about drug discontinuation should be made based on the extent of QT prolongation. The risk of developing torsades de points is significantly increased in patients with QT intervals of greater than 500 msec.

Drug-Drug Interactions

Drug-drug interations (DDIs) are major contributors to ADEs but can easily be prevented or managed when identified in advance. It has been estimated that at least 11% of patients admitted to a general ICU may experience DDIs. Polypharmacy, altered organ function, and advanced age are risk factors identified. DDIs may contribute to adverse events and compromise patient care with increased morbidity, mortality, and health care cost. Most DDIs can be classified as PK or PD interactions. A PK interaction occurs when one drug alters the absorption, distribution, metabolism, or elimination of another agent. A PD interaction occurs when one agent enhances or antagonizes the pharmacologic action of another agent. Antibiotics and antithrombotic agents have frequently been implicated in DDIs. Drugs that are potent inhibitors or inducers of liver cytochrome P-450 enzyme system should be used with caution. Among many of the P-450 isoenzmes identified, CYP3A4 is involved in liver metabolism of up to 50% of medications. Protease inhibitors (ie, ritonavir), macrolides (ie, erythromycin), and triazoles (ie, fluconazole, posaconazole, voriconazole) are potent CYP3A4 inhibitors. Serious DDIs with significant toxicity may develop if any of these agents is initiated concurrently with a drug that is also a CYP3A4 substrate (ie, amiodarone, cyclosporine, tacrolimus, HMG-CoA reductase inhibitors). Warfarin, an agent with narrow therapeutic index, is metabolized by several CYP enzymes, especially CYP1A2, 2C9, 2C19, and 3A4. Rifampin, a potent inducer of CYP2C9, can result in decreased warfarin effect while CYP2C9 inhibitors (ie, amiodarone, sulfonamides, voriconazole, and metronidazole) can increase the effect of warfarin. Alternative medications with minimal or no DDI should always be considered. If this approach is not possible, most of the DDIs encountered clinically can be monitored with careful dosing adjustment. A multidisciplinary team approach, especially with the presence of a clinical pharmacist on rounds, may facilitate the detection, prevention, and resolution of potential DDIs. Potential DDIs should be evaluated at the time a medication is initiated or discontinued, especially if a high-risk medication (Table 15–5) is involved.

Medication Errors and Prevention

Medication errors (MEs) are a reality of medicine.^18,19,20 Harmful MEs are reported more frequently in the ICU than in the non-ICU setting. Although ME data are generally underreported, it has been estimated, that critically ill patients experience an average of 1.7 MEs per day, and many patients suffer a potential life-threatening ME during their ICU stay. Reduction of MEs is the focus of many hospital quality improvement programs. Several interventions have been shown to decrease MEs in the ICU. Improved medication safety can be accomplished by medication standardization (prophylaxis for venous thromboembolism and stress ulcer, standardized IV concentrations, etc.) computerized physician order entry, barcode technology, smart intravenous infusion devices, and medication reconciliation programs. “Medication reconciliation” has been incorporated into National Patient Safety Goal #3 as of July 2011. Patient's complete medication regimen should be reviewed at the time of ICU admission and transfer, and should be compared with the regimen being considered for the new setting of care. This process is to ensure consistencies in medication regimens and prevent possible harms from unintentional medication omissions or therapeutic duplicates. Elimination of situational risk factors, such as inadequate trainee supervision, excessive nurse and physician work hours or work load, and distractions from the work flow, can prevent MEs. In addition, multidisciplinary team approach with physicians, physician assistants, nurses, and pharmacists is essential to medication oversight and error interception.

1. Apply pharmacokinetic and pharmacodynamic knowledge to determine the best dosing approach for critically ill patients with rapidly changing multiorgan dysfunction.

2. Loading dose is required to achieve desired therapeutic response timely, especially for drugs with long T_1/2. Critically ill patients must receive adequate loading dose as indicated.

3. Loading (initial) dose is determined mainly by the volume of distribution – no dose adjustment is required in the presence of organ dysfunction.

4. Maintenance doses should be adjusted based on the extent and trend of organ dysfunction, as well as the clinical indication for the therapy—lower doses may be needed if organ function continues to deteriorate whereas higher doses may be indicated in the recovery phase of organ dysfunction.

5. Be proactive to avoid improper dosing for patients with rapidly changing organ function—look at the trend to maximize therapeutic effect while minimizing toxicity.

6. Prevent medication errors and adverse drug-drug interactions—review medication profiles when high-risk drugs with known toxicity or drug-drug interactions are initiated or discontinued.

7. Multidisciplinary team work is the key for safe and effective pharmacologic management.