**2. DDI of major severity**

124 Antihypertensive Drugs

Thiazide diuretics Glucocorticoids Moderate Delayed Fair Hypokalemia and

Moderate Not

Beta-blockers Moderate Delayed Fair Hyperglycemia,

specified

Lopp diuretics Moderate Rapid Good Postural hypotension

Thiazide diuretics Moderate Rapid Good Postural hypotension

Oxazolidinone Contraindicated Rapid Good Hypertensive crisis

specified

Direct vasodilators Lopp diuretics Minor Rapid Good Enhanced diuretic response

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

Beta-blockers Major Not

Beta-blockers Moderate Rapid Fair Exaggerated hypertensive

**knowledge**

Minor Rapid Good Enhanced diuretic response

Moderate Delayed Good Reduced diuretic

Moderate Delayed Good Hyperkalemia

Moderate Delayed Fair Hyperkalemia

Moderate Delayed Good Decreased diuretic and

**DDI Outcome** 

to loop diuretic

subsequent cardiac arrhythmias

antihypertensive efficacy

hypertriglyceridemia

Excellent Decreased antihypertensive efficacy

(first dose)

(first dose)

stiffness)

Fair Increased risk of sinus

response

to loop diuretic

response, tachycardia, or arrhythmias during physiologic stress or exposure to exogenous catecholamines

(headache, palpitation, neck

bradycardia; exaggerated clonidine withdrawal

(acute hypertension)

effectiveness, hyperkalemia, or possible nephrotoxicity

**Antihypertensives Drug Classes Severity Onset Scientific** 

Direct vasodilators

agents

Nonsteroidal antiinflammatory

Angiotensin converting enzyme inhibitors

Angiotensin II Receptor Blockers

Nonsteroidal antiinflammatory

Nonsteroidal antiinflammatory

agents

agents

Potassium-sparing diuretics

Angiotensin converting enzyme inhibitors

Catecholamine synthesis or release blockers

Alpha 2 adrenergic blockers

adult inpatients in ICU

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 to either medication should be made carefully.

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 required.

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 monitored when clonidine and verapamil or diltiazem are given concurrently.

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

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 (Goodman & Gilman, 2011).

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

Drug Interaction Exposures in an Intensive Care Unit: Population Under Antihypertensive Use 127

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

When concomitant use of loop diuretics and NSAID is required, patient should be

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

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

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.

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.,

monitored for diuretic efficacy and for signs of renal failure.

antihypertensive efficacy of captopril (Gonzaga et al., 2009).

effectiveness of the diuretic and hyperkalemia.

control blood pressure.

(Houston**,** 1991).

2008).

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.
