**5. Antihypertensive and antiinflammatory agents**

#### **5.1 Nonsteroidal antiinflammatory agents**

Nonsteroidal antiinflammatory drugs (NSAID) may block the antihypertensive effects of thiazide and loop diuretics, β-adrenergic blockers, α-adrenergic blockers and angiotensin-

Alpha 2-adrenergic blockers and beta-blockers may result in increased risk of sinus bradycardia; exaggerated clonidine withdrawal response (acute hypertension). Monitor heart rate when clonidine and atenolol are given concurrently. Patients to be withdrawn from clonidine who are concomitantly receiving a beta blocking agent, such as atenolol, should be withdrawn from the beta blocker several days before the gradual discontinuation of clonidine to avoid an excessive rise in blood pressure. In the case of a hypertensive crisis following discontinuation of clonidine, IV phentolamine or oral clonidine can be used to reverse the excessive rise in blood pressure. Patients to be withdrawn from clonidine who are concomitantly receiving a beta blocking agent should be monitored carefully for hypertension.

The severity of the most frequent used drugs in ICU is moderate to minor. However, the combination of catecholamine synthesis or release blockers with oxazolidinone is contraindicated because it may result in hypertensive crisis, causing headache, palpitation and neck stiffness. Hypertension due to drugs can cause increase of blood pressure level, reduction

Linezolida is an antibiotic used to treat infections caused by gram-positive bacteria but this drug is also a non-selective and reversible inhibitor of monoamine oxidase (MAO). The inhibitors of this enzyme block the oxidative deamination of three biogenic amines which are norepinephrine, dopamine and 5-hydroxytryptamine. When monoamine oxidase inhibitors (MAOI) are associated with sympathomimetic drugs or foods containing tyramine, hypertensive crisis may occur (Fuzikawa et al., 1999). The hypertensive crises are life-threatening and can also cause damage to susceptible organs as heart, brain and kidneys

The co-administration of calcium channel blockers and some histamine H2-antagonists, as cimetidine, result in increased concentrations of calcium channel blockers and possible cardiovascular toxicity. This effect happens because of Cytochrome P (CYP) 450 inhibition. The Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids and many drugs. Many agents used for management of cardiovascular diseases are substrates, inhibitors or inducers of CYP450 enzymes. When two agents that are substrates, inhibitors or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur (Cheng et al., 2009). Monitoring cardiovascular response is necessary when the patient is in use of cimetidine and a calcium channel blocker. Dose reductions of up to 35% to 40% may

Nonsteroidal antiinflammatory drugs (NSAID) may block the antihypertensive effects of thiazide and loop diuretics, β-adrenergic blockers, α-adrenergic blockers and angiotensin-

**3. Catecholamine synthesis or release blockers and oxazolidinone** 

of antihypertensive drug effectiveness or the worsening of a pre-existing hypertension.

**4. Calcium channel blockers and histamine H2-antagonists** 

be needed for diltiazem or nifedipine if co-administered with cimetidine.

**5. Antihypertensive and antiinflammatory agents** 

**5.1 Nonsteroidal antiinflammatory agents** 

(Plavnik, 2002).

converting enzyme inhibitors. It seems to happen by NSAID interference with prostaglandins synthesis which may thus limit the ability of antihypertensive drugs to control blood pressure.

When concomitant use of loop diuretics and NSAID is required, patient should be monitored for diuretic efficacy and for signs of renal failure.

Potassium-sparing diuretics and NSAID co-administration may also result in hyperkalemia or possible nephrotoxicity. If this combination is necessary, patient should be monitored for blood pressure, weight changes, urine output, potassium levels, creatinine levels, decreased effectiveness of the diuretic and hyperkalemia.

In same way, when concurrently administration of thiazide diuretics and NSAID is necessary, blood pressure and weight should be monitored. It is important to follow the patient for signs of renal failure, including decreases in urine output and increased edema.

Caution is recommended when prescribing NSAID to patients taking ACE inhibitors. When concomitant use is required, patient should be monitored for ACE inhibitor efficacy and for signs of renal failure. NSAID may also promote the development of hyperkalemia in association with ACE inhibitors as a result of deterioration of renal function. They are also responsible for reducing the antihypertensive effects of ACEI by interfering in the synthesis of prostaglandins. Probenicid reduces captopril renal excretion and increases its plasma concentration. On the other hand, aspirin and antiacids may decrease or abolish the antihypertensive efficacy of captopril (Gonzaga et al., 2009).

The mechanism of the hypertensive effects caused by NSAID seems primarily to be related to their ability to block the cyclo-oxygenase pathway of arachidonic acid metabolism which results in decrease of prostaglandin formation. The prostaglandins are important in normal modulation of renal and systemic vascular dilatation, glomerular filtration, tubular secretion of salt and water reabsorption, adrenergic neurotransmission and the renin-angiotensinaldosterone system. Blockade of benef3ic effects of prostaglandins by NSAID results in complexes events which culminate in attenuation of many antihypertensive agents effects. The risk is greatest in the elderly, blacks and patients with low-renin hypertension. (Houston**,** 1991).

Pharmacologically, it is thought that NSAID interact differently with antihypertensive drugs. However, the NSAID effects on newly initiated antihypertensive drug therapy remain unclear because few studies have included patients who were initially administered NSAID and then antihypertensives. Physiologically, the effects of renal prostaglandins on salt and water transport in the kidney are complementary to the actions of diuretics. Therefore, it is likely that the blocking of prostaglandins synthesis by NSAID attenuates the effect of diuretics. angiotensin-converting enzyme (ACE) inhibitors produce vasodilatation and lower blood pressure by inhibiting ACE which promotes the formation of angiotensin-2 and aldosterone. Bradykinin is an autacoid that produces vasodilatation and further reduces blood pressure. Blocking ACE decreases the inhibition of bradykinin-induced vasodilatation. However, the vasodilatory properties of bradykinin that contribute to the antihypertensive properties of ACE inhibition appear to be mediated through local release of prostaglandins and are therefore susceptible to interference by NSAID (Ishiguro et al., 2008).

Drug Interaction Exposures in an Intensive Care Unit: Population Under Antihypertensive Use 129

consequences of these interactions should be considered in order not to endanger ICU

The presence of drug interactions is a permanent risk in the ICU and not all DDI can be prevented. The use of software is mentioned in the literature as an important toll in reviewing prescriptions to identify interactions and reduce adverse events. Also, the continuing education of professionals involved in the processes of prescribing, dispensing and administering medicines as the main risk factors for drug interactions, the dissemination of information regarding the more frequent and important in clinical practice

[1] AHFS Drug Information 2006. American Society of Health-System Pharmacists. Editor

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[3] Brown, S.A. (2005) Pathophysiology of systemic hypertension. In: ETTINGER, S.;

[4] Cheng, JWM; Frishman, W & Aronow, WS. (2009). Updates on Cytochrome P450-

[5] Correr, CJ; Pontarolo, R; Ferreira, LC & Baptistão, SAM. (2007). Riscos de problemas

[6] Cruciol-Souza, JM; Thomson ,JC & Catisti, DG. (2008). Avaliação de prescrições

[7] Diener, JRC; Prazeres, CEE; Rosa, CM; Alberton, UC & Ramos, CCS. (2006). Avaliação da

[8] Dukes, J. (1992).Hypertension: A review of the mechanisms, manifestations and management. *Journal of Small Animal Practice*, v.33, n.3, p.119-129, ISSN 00224510. [9] Ferreira Sobrinho, F; Nascimento, JWL; Greco, KV & Menezes FG. (2006). Avaliação de

[10] Fuzikawa, CS; Hara, C; Glória, MBA & Rocha, FL. (1999). IMAO e Dieta: Atualizaçäo -

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**8. References** 

## **5.2 Steroidal antiinflammatory agents**

Glucocorticoids may increase blood pressure by increasing the concentration of sodiumpotassium adenosine triphosphate in the cell membrane which could increase the concentration of extracellular sodium and therefore expand the plasma volume. Cortisol also stimulates the synthesis of mineralocorticoid aldosterone leading to sodium and water retention and, consequently, increased blood volume and cardiac output (Ortega et al., 1996; Brown, 2005). It also increases the sensitivity of the myocardium to endogenous catecholamine and increases the vascular response to endogenous vasopressors such as angiotensin II and norepinephrine (Ortega et al., 1996). In addition, glucocorticoids induce hepatic production of angiotensinogen resulting in an exacerbated response of the reninangiotensin-aldosterone system (Dukes, 1992).
