**1. Introduction**

120 Antihypertensive Drugs

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Scapa, E. (2001). Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. *Ther Drug Monit*, Vol.23, No.4, A potential drug-drug interaction (DDI) is related to the possibility of a drug to alter the effect of another drug simultaneously administered. It can occur before or after drug administration (Almeida et al., 2007). DDI are considered predictable and thus avoidable and manageable (Cruciol-Souza et al., 2006).

Many of these interactions have slow onset clinical manifestations that can be diagnosed as new diseases and handled wrongly (Correr et al., 2007). Drug interactions are estimated to occur between 3% and 5% in patients to whom few drugs are prescribed and 20% among those who use 10 to 20 drugs simultaneously (Ferreira Sobrinho et al., 2006). The incidence of drug interactions is directly proportional to the increase in the number of drugs prescribed (Matos et al., 2009). It is known that a prescription containing eight or more drugs will present at least one interaction (Almeida et al., 2007).

Drug interactions incidence in Intensive Care Unit (ICU) is higher than hospital rates in general probably due to patient disease severity admitted in this unit (Almeida et al., 2007). ICU patients usually need great number of administered drugs and they are under risk of 44.3% to 95.0% of potential drug interactions occurrence (Sierra et al., 1997; Meneses & Monteiro, 2000). New drugs availability and prescription of fixed drug combinations difficult potential interactions identification (Trato, 2005). Thereby, this study aimed to discuss the risk of DDI in medical prescriptions of adult inpatients in ICU under use of antihypertensive drugs.

Commonly used drugs in ICU are vasoconstrictors and cardiotonic agents, antimicrobials, coronary vasodilators, direct vasodilators, antisecretory drugs, anticoagulants, sedatives-

 \* Corresponding Author

Drug Interaction Exposures in an Intensive Care Unit: Population Under Antihypertensive Use 123

Major Not

**knowledge**

Moderate Rapid Good Toxicity (headache,

Major Rapid Good Increased risk of

Moderate Rapid Fair Hypotension

Moderate Rapid Good Hypotension and/or

Moderate Rapid Good Exaggerated hypotensive

Moderate Delayed Fair Increased risk of

Lopp diuretics Moderate Rapid Fair Hypotension, bradycardia

Fluoroquinolone Minor Delayed Fair Bradycardia, hypotension

Moderate Delayed Good Decreased diuretic and

Moderate Rapid Fair Hypotension, bradycardia

Thiazide diuretics Moderate Delayed Fair Hyperglycemia,

Glucocorticoids Moderate Delayed Fair Hypokalemia

specified

Sympathomimetics Major Rapid Excellent Hypertension, bradycardia

Hypoglycemic Moderate Delayed Good Hypoglycemia,

Glucocorticoids Moderate Rapid Good Increased glucocorticoids

**DDI Outcome** 

concentrations and enhanced adrenalsuppressant effects

peripheral edema, hypotension, tachycardia)

disturbances

Good Increased incidence of sinus bradycardia requiring hospitalization and insertion

of a pacemaker

and resistance to

hyperglycemia or hypertension

the alpha blocker

epinephrine in anaphylaxis

response to the first dose of

propranolol adverse effects (bradycardia, fatigue, bronchospasm)

hypertriglyceridemia

antihypertensive efficacy

bradycardia

hypotension, bradycardia, atrioventricular conduction

**Antihypertensives Drug Classes Severity Onset Scientific** 

Calcium channel blockers

Beta-blocker drugs

Alpha 1 adrenergic blockers

Alpha 2 adrenergic agonistic drug

blockers

Alpha 1 adrenergic blockers

Direct vasodilators

antiinflammatory

Beta-blocker drugs

agents

Lopp diuretics Nonsteroidal

Beta-blockers Calcium channel

hypnotics agents, antiemetics, antidiabetics agents, analgesics-antipyretics and antiinflammatory drugs.

Micromedex® DrugReax® System (Klasco, 2011) is one of the most used database to describe interactions. The DrugReax System contains a dictionary of more than 8,000 unique drug terms. This system distinguishes trade names from equivalent generic names and it analyses specific drug instead of drug class. This database provides information about clinical consequences or adverse drug reactions that could result from a DDI, describe the interaction mechanism and classifies onset, severity and scientific knowledge of adverse reactions caused by the DDI.

*Onset* is classified as rapid (effects expected within 24 hours of drug administration), delayed (effects not expected to appear within the first 24 hours following drug administration) or unknown (effects expected to appear any time after drug administration).

*Severity* is classified as minor (limited clinical effects including increased frequency or severity of adverse effects and generally no major alteration in therapy), moderate (exacerbation of patient's condition and/or an alteration in therapy), major (life-threatening interaction and/or medical intervention to minimize or prevent serious adverse effects) or contraindicated (life-threatening interaction).

*Scientific knowledge* is classified considering how well DDI is documented in the literature that means excellent (controlled studies clearly established the existence of the interaction), good (documentation strongly suggests the interaction exists but well-controlled studies are lacking), fair (available documentation is poor but pharmacologic considerations lead clinicians to suspect about interaction existence or documentation is good for a pharmacologically similar drug) or unknown (no documentation about the interaction).

Table 1 presents the classification of DDI involving antihypertensive and the most frequent used drugs in ICU.


hypnotics agents, antiemetics, antidiabetics agents, analgesics-antipyretics and

Micromedex® DrugReax® System (Klasco, 2011) is one of the most used database to describe interactions. The DrugReax System contains a dictionary of more than 8,000 unique drug terms. This system distinguishes trade names from equivalent generic names and it analyses specific drug instead of drug class. This database provides information about clinical consequences or adverse drug reactions that could result from a DDI, describe the interaction mechanism and classifies onset, severity and scientific knowledge of adverse

*Onset* is classified as rapid (effects expected within 24 hours of drug administration), delayed (effects not expected to appear within the first 24 hours following drug administration) or unknown (effects expected to appear any time after drug administration). *Severity* is classified as minor (limited clinical effects including increased frequency or severity of adverse effects and generally no major alteration in therapy), moderate (exacerbation of patient's condition and/or an alteration in therapy), major (life-threatening interaction and/or medical intervention to minimize or prevent serious adverse effects) or

*Scientific knowledge* is classified considering how well DDI is documented in the literature that means excellent (controlled studies clearly established the existence of the interaction), good (documentation strongly suggests the interaction exists but well-controlled studies are lacking), fair (available documentation is poor but pharmacologic considerations lead clinicians to suspect about interaction existence or documentation is good for a pharmacologically similar drug) or unknown (no documentation about the interaction).

Table 1 presents the classification of DDI involving antihypertensive and the most frequent

Benzodiazepinics Moderate Rapid Good Increased/prolonged

Opioid analgesics Major Rapid Good Severe hypotension and an

Antifungals Moderate Delayed Good Increased calcium channel

**knowledge**

Moderate Rapid Good Increased concentrations of

**DDI Outcome** 

toxicity

sedation

depression

edema).

calcium channel blockers and possible cardiovascular

increased risk of respiratory

blockers concentrations and toxicity (dizziness, hypotension, flushing, headache, peripheral

**Antihypertensives Drug Classes Severity Onset Scientific** 

antiinflammatory drugs.

reactions caused by the DDI.

used drugs in ICU.

Calcium channel blockers

contraindicated (life-threatening interaction).

Histamine H2 antagonists (cimetidine)


Drug Interaction Exposures in an Intensive Care Unit: Population Under Antihypertensive Use 125

The combination of calcium channel blockers with opioid analgesics is classified as major severity because it may result in severe hypotension and an increased risk of respiratory depression caused by fentanyl toxicity. For example, diltiazem is a moderate CYP3A4 inhibitor and fentanyl is a CYP3A4 substrate. The concurrent use may result in increased fentanyl plasma levels and fatal respiratory depression. Caution is necessary if these agents are given concurrently and use the lowest possible fentanyl dose. Patient should be carefully monitored for an extended period of time for fentanyl adverse events. Any dosage increases

Calcium channel blockers and beta-blocker drugs co-administration is also classified as major severity because it may result in an increased risk of hypotension, bradycardia, atrioventricular conduction disturbances. If concurrent therapy is required, cardiac function and blood pressure should be carefully monitored, particularly in patients predisposed to heart failure. A dosage adjustment for hepatically metabolized beta blockers may be

The combination of calcium channel blockers with alpha 2-adrenergic agonistic drug is classified as major severity because it may result in increased incidence of sinus bradycardia requiring hospitalization and insertion of a pacemaker. Therefore, heart rate should be

The abrupt discontinuation of vasodilators may lead to a hyper-adrenergic attack causing acute myocardial infarction, stroke and/or other complications due to rebound vasoconstriction. This effect is known as antihypertensive drugs withdrawal. The most commonly drugs involved in this effect are the beta-blockers, centrally acting agents, direct

Concomitant use of beta-blockers and clonidine provide the rebound effect after abrupt withdrawal of therapy. Clonidine by an agonistic effect on presynaptic alpha-2 receptors decreases noradrenaline release from postganglionic sympathetic neurons. It is an excess of catecholamines in the synaptic clefts when the administration of clonidine is interrupted and this catecholamines are available for binding to the alpha and beta receptors. However, if the beta receptor, auxiliar in vasodilation, is blocked, the alpha effects are not counterbalanced. The result is vasoconstriction, rebound hypertension and risk of coronary and cerebral vasospasm. It is recommended that in patients who are on beta blockers and clonidine, the drug should be withdrawn gradually to avoid this adverse drug reaction. Moreover, the use of clonidine and beta-blocker raises the risk of sinus bradycardia

The concurrent use of beta-blocker and sympathomimetic drugs should be avoided because it may result in hypertension, bradycardia and resistance to epinephrine in anaphylaxis. However, if concomitant therapy is necessary, patient should be carefully monitored for severe and prolonged hypertension. Glucagon has positive inotropic and chronotropic effects that are independent of adrenergic receptors. The use of this agent is of great importance in patients on beta blockers which are affected by an anaphylactic reaction. Glucagon increases cardiac output and coronary perfusion, decreasing myocardial hypoxia

monitored when clonidine and verapamil or diltiazem are given concurrently.

vasodilators and calcium channel blockers (Kirk & Johnson, 1995).

and a possible secondary cardiogenic shock (Lieberman, 1998).

**2. DDI of major severity** 

(Goodman & Gilman, 2011).

required.

to either medication should be made carefully.


Table 1. Classification of DDI involving antihypertensive drugs in medical prescriptions of adult inpatients in ICU
