نام خدا به فارماكوويژيلانس و عوارض ناخواسته داروها دي ماه 1393
Drug-Induced cardiovascular disease Parastoo Mirzabeigi, Clinical Pharmacist
Hypertension Hypertension is a chronic medical condition that is characterized by persistent increases in systolic or diastolic blood pressure, or both. Prehypertension is a term used to identify patients with elevated blood pressures that are not high enough to be classified as hypertension, but are higher than normal. Most patients (90 95%) with hypertension have primary (also called essential ) hypertension. The remainder have secondary hypertension, which includes patients with drug-induced causes.
CAUSATIVE AGENTS Drug-induced hypertension is defined as high blood pressure caused by using or discontinuing the use of a chemical substance, drug, or medication. These medications may cause hypertension, exacerbate previously well-controlled hypertension, or antagonize the effects of antihypertensive pharmacotherapy
MECHANISMS Arterial blood pressure is regulated by several factors: the adrenergic nervous system, The renin angiotensin aldosterone system, kidney function and blood flow, hormonal regulatory systems (adrenal cortical hormones, vasopressin, thyroid, insulin), the vascular endothelium (nitric oxide, bradykinin, prostacyclin, endothelin). The various mechanisms by which drugs may induce hypertension are broadly categorized as: fluid-volume expansion, stimulation of sympathetic nervous system activity, interference with the action of antihypertensive drugs, paradoxical responses to antihypertensive agents, and unknown mechanisms.
CLINICAL PRESENTATION/ Elevated blood pressure and the development of hypertension are nearly always asymptomatic. The clinical significance of elevated blood pressure associated with the use of a drug is variable, depending on an individual s baseline blood pressure. It is important to note that the threshold blood pressure for the diagnosis of hypertension varies. Drug-induced blood pressure elevations, if persistent, may be clinically significant even if the blood pressure is not increased to above an individual s goal value.
Risk Factors for Drug-Induced Hypertension
Hypotension Drug-induced hypotension is a clinically important and potentially disabling problem that may lead to syncope, falls and injury, or sustained lack of organ perfusion resulting in ischemia, infarction, or both. The majority of episodes of drug-induced hypotension involve a drop in blood pressure after a patient assumes an upright position. This is known as orthostatic hypotension and has also been referred to as postural hypotension. Orthostatic hypotension is defined as a reduction in systolic blood pressure of at least 20 mm Hg or diastolic pressure of at least 10 mm Hg within 3 minutes of standing
Orthostatic hypotension may result from two different disorders in autonomic cardiovascular control: autonomic failure and neurally mediated syncope. Autonomic failure involves chronic debilitation of sympathetic efferent activity such that vasoconstriction is impeded. Drug-induced orthostatic hypotension is primarily due to autonomic failure in which the causative agent affects central or peripheral autonomic pathways.
ANTIHYPERTENSIVES ACE Inhibitors Captopril, Enalapril Angiotensin-Receptor Blockers Losartan, Olmesartan, Telmisartan, Valsartan Peripheral -ɑ blockers β-adrenergic Blockers (particularly with IV) Atenolol, Esmolol, Propranolol, Metoprolol Carvedilol, Labetalol Calcium-Channel Blockers Centrally acting α- adrenergic agonists Clonidine Methyldopa Peripheral-acting arterial vasodilators Duretics Amiloride,Chlorothiazide, Chlorthalidone, Furosemide, Hydrochlorothiazide Mannitol Inhibition of angiotensin II with increase in bradykinin concentrations Inhibition of angiotensin II at the receptor level Blockade of -adrenoreceptors Blockade of β-and α1-adrenoreceptors Blockade of L-type calcium channel Direct stimulation of -receptors in the vasomotor center of the medulla leading to: Reduction in peripheral vascular resistance Decreased heart rate (secondary to increased vagal tone). Direct arteriolar vasodilatation Inhibition of renal sodium reabsorption thereby leading to intravascular volume depletion Intravascular volume depletion
NON-ANTIHYPERTENSIVES Alzheimer s Agents Galantamine, Donepezil Anesthetic Agents Propofol Antiarrhythmic Agents Antidepressant Agents Amitriptyline, Clomipramine, Desipramine, Doxepin, Imipramine Trazodone Aripiprazole, Chlorpromazine Clozapine, Doxazosin, Haloperidol Olanzapine, Pimozide, Prazosin Quetiapine, Risperidone, Tamulosin Terazosin, Thioridazine, Thiothixene Trifluoperazine, Ziprasidone Chemotherapy Agents Dacarbazine, Carmustine, Vincristine Vinblastine, Magnesium Overactivation of muscarinic and nicotinic sites of autonomic and somatic nerves Direct vasodilatation of venous smooth muscle Reduced systemic vascular resistance due to α- adrenoreceptor blockade Blockade of central and/or peripheral - adrenoreceptors Calcium chelation by citric acid in the preparation, Vasodilation due to alcohol content of the diluent, Neurotoxicity- Inhibition of norepinephrine secretion, Neurotoxicity, Opposition of calciumdependent arterial constriction Atracurium, Codeine, Fentanyl, Mivacurium, Morphine, Succinylcholine, Vancomycin Release of histamine
Signs and Symptoms Associated with Drug-Induced Hypotension
Risk Factors for Drug-Induced Hypotension
Approaches to Help Prevent Drug- Induced Hypotension
Myocardial Ischemia and Acute Coronary Syndromes Myocardial ischemia occurs as a result of increased myocardial demand, decreased myocardial oxygen supply, or both, and most commonly occurs in patients with atherosclerotic coronary artery disease. Acute myocardial infarction is a clinical syndrome associated with the development of a prolonged occlusion of a coronary artery leading to decreased oxygen supply, myocardial ischemia, and irreversible damage to myocardial tissue
MYOCARDIAL OXYGEN SUPPLY AND DEMAND The oxygen demand of the heart is determined by its workload. The major determinants of myocardial oxygen consumption are heart rate, contractility, and intramyocardial wall tension during systole. Of the many factors that affect oxygen supply to the heart, coronary blood flow and oxygen extraction are most important. Complex factors that determine coronary blood flow include duration of diastole and coronary vascular resistance. A drug may cause myocardial ischemia i simply by modifying i any one of these factors.
CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS Drug-Induced Myocardial Ischemia The clinical presentation of a patient with drug induced ischemia is similar to that of any ypatient with angina or ischemia associated with atherosclerotic coronary artery disease. The most apparent difference is that drug-induced ischemia The most apparent difference is that drug-induced ischemia may occur in individuals who do not have, or who are not at risk for, coronary artery disease.
Drug-Induced Acute Coronary Syndrome In most situations, the clinical presentation of a patient with drug-induced acute coronary syndrome is similar to that of any patient with non drug-induced acute coronary syndrome. However, there are several exceptions to this generalization. like myocardial ischemia, acute coronary syndromes are relatively unusual in young populations (<45 years of age). Approximately 25% of all acute myocardial infarctions in individuals 18 to 45 years of age have been associated with frequent cocaine use
Drug-Induced Heart Failure Heart failure is a major cause of morbidity and mortality Drug-induced heart failure in patients without preexisting left ventricular dysfunction is quite rare; however, drug induced exacerbation of symptoms of heart failure occur more frequently in those with established heart failure.
Drug-induced HF is mediated by three basic mechanisms: - inhibition of myocardial contractility (negative inotropic agents and direct toxins), - proarrhythmic effects, - expansion of plasma volume
The most recognized negative inotropic agents are the β- blockers,calcium-channel blockers (CCB), most notably verapamil and diltiazem, antiarrhythmic agents, especially disopyramide, quinidine, flecainide The anthracyclines (daunorubicin and doxorubicin) have a direct, dose-related cardiotoxicity that can be minimized by limiting total cumulative doses to 500 to 600 mg/m Drugs that increase the QT interval induce proarrhythmic effects in some patients. Worsening of HF occurs if the disturbed rhythm compromises cardiac functioning.
Drugs that induce sodium and water retention are NSAIDs (via prostaglandin inhibition), certain antihypertensive drugs, glucocorticoids, androgens, estrogens Thiazolidinedione antidiabetic drugs pioglitazone and rosiglitazone. Worsening of HF appears to be dose-dependent dependent and is presumed to be at least partly caused by fluid retention. they not be administered to patients with NYHA class III or IV HF and that they be used cautiously in earlier stages of HF.
CLINICAL PRESENTATION The clinical presentation of patients with drug induced heart failure is not different from that from other causes. Symptoms may occur gradually following initiation of a culprit drug. For most drugs that induce heart failure, worsening symptoms of heart failure begin shortly (within days) after initiation of therapy with the drug or increasing the dose. For those drugs causing fluid retention, ti plasma volume expansion may take several days to manifest in symptoms of dyspnea. The onset of anthracycline-induced heart failure has been well characterized. Von Hoff et al. reported an average time of onset of symptoms of heart failure of 33 days
Risk Factors for Drug-Induced Heart Failure Antiarrhythmic Agents Preexisting left ventricular dysfunction Glitazones Preexisting left ventricular dysfunction History of myocardial infarction History of symptomatic coronary artery disease Hypertension Left ventricular hypertrophy Significant aortic or mitral valve disease Advanced d age (>70 yr) Long-standing diabetes (>10 yr) Preexisting edema Current treatment with loop diuretics Development of edema or weight gain Insulin coadministration Chronic kidney disease Anthracyclines Cumulative doxorubicin dose (550 mg/m2) Three-week schedule of administration Advancing age (adults) Concomitant cardiac irradiation Concomitant use of cyclophosphamide, fluorouracil, dactinomycin, mithramycin, mitomycin, or vincristine Trastuzumab Older age Higher body-mass index Antihypertensive therapy Lower pre-trastuzumab left ventricular ejection fraction Concurrent anthracycline use Cumulative anthracycline dose
Arrhythmias
SINUS BRADYCARDIA Sinus bradycardia is defined as a sinus rate <60 bpm. Drugs that inhibit sinus node function resulting in sinus pauses or sinus arrest will also be included d in this section.
ATRIOVENTRICULAR (AV) NODAL BLOCKADE AV nodal blockade occurs when conduction of impulses from the atria to the ventricles through the AV node is inhibited AV nodal blockade is classified as first, second, or third degree. First degree AV nodal blockade is defined as prolongation of the PR interval to >0.2 seconds on an electrocardiogram (ECG). Second degree AV block is a progression of AV nodal dysfunction to the point at which some impulses are not conducted from the atria to the ventricles. Thi d d AV d l bl k d f f d l Third degree AV nodal blockade, often referred to as complete heart block or AV dissociation, is defined by the absence of a relationship between atrial and ventricular depolarization
Mobitz type I second degree AV nodal blockade associated ated with phenylpropanolamine. p o a e.
Mobitz type II second degree AV nodal blockade associated with amiodarone
Third degree AV nodal g blockade associated with carbamazepine.
MECHANISMS Drug-induced sinus bradycardia may be caused by inhibition of automaticity of the node, slowing of sinus node conduction, or prolongation of sinus node repolarization AV nodal blockade may be caused by agents that inhibit AV node conduction or prolong AV node repolarization Both the sinus node and the AV node are heavily influenced by sympathetic and parasympathetic nervous system activity. The action potentials of both the sinus node and the AV node depend primarily on calcium and sodium flux, and calcium or sodium channel inhibitors may cause sinus bradycardia, AV nodal blockade, or both
CLINICAL PRESENTATION First degree AV nodal block is a common electrocardiographic phenomenon that is almost always asymptomatic. Second or third degree AV nodal blockade may result in bradycardia, with heart rates in the range of 40-60 bpm. Symptoms of second or third degree AV nodal blockade are the same as those associated with sinus bradycardia Dizziness Light-headedness Fatigue Weakness Syncope Chest pain Symptoms of heart failure
Risk Factors for Drug-Induced Sinus Bradycardia or Atrioventricular (AV) Nodal Blockade Sinus bradycardia Pretreatment heart rate <60 bpm Underlying sinus-node dysfunction (may occur with advancing age) Concomitant use of >1 sinus-node node inhibiting drug Elevated plasma drug concentrations due to organ dysfunction or drug interactions Atrioventricular nodal blockade Concomitant use of >1 AV nodal blocking drug Pretreatment PR interval >0.2 sec Underlying AV nodal disease (may occur with advancing age) Elevated plasma drug concentrations due to organ dysfunction or drug interactions Hypothyroidism y (may be a risk factor for amiodarone-induced AV block)
Approaches to Help Prevent Drug- Induced Sinus Bradycardia and Atrioventricular (AV) Nodal Blockade For all drugs that may cause sinus bradycardia, AV block, or both Patient should take pulse daily, report if <50 bpm. Do not exceed maximum daily doses. Use combinations of drugs that may cause sinus bradycardia or AV block only when necessary and when the benefits likely outweigh the risks. Avoid sinus or AV node inhibiting drugs in patients with underlying sinus node dysfunction, unless a functioning pacemaker is present (in the case of AV node inhibiting drugs, there must be a functioning ventricular pacemaker).
For digoxin Measure serum digoxin concentrations: If kidney function is changing. If a drug that interacts with digoxin is added to therapy. Every 6 mo if there is no organ dysfunction or concomitant use of interacting drugs.
Torsades de point
Torsades de pointes is a potentially life-threatening ventricular tachyarrhythmia associated with prolongation of the QT interval QT interval prolongation and torsades de pointes may be congenital or acquired. Acquired torsades de pointes is most often caused by drugs Torsades de pointes associated with intravenous haloperidol
Drug induced Tdp Antiarrhythmic drugs associated with torsade include the following: Class IA - Quinidine, disopyramide, procainamide Class III - Sotalol, amiodarone (rare), ibutilide, dofetilide Nonantiarrhythmic agents can also exhibit potassiumchannel inhibitory properties and can prolong the QTc interval. Most of these drugs, including erythromycin, clarithromycin, fluoroquinolones, azole antifungals, methadone, tricyclic antidepressants, and antipsychotics, cause QTc interval prolongation by inhibiting the inwardly rectifying potassium ion channel, just like quinidine and sotalol
Guidelines suggest that the risk ofqtc prolongation is greater with certain antipsychotic agents, such as thioridazine, ziprasidone, and risperidone, haloperidol (when given parenterally or in high doses) QTc prolongation with perphenazine, clozapine, olanzapine, Q p g p p, p, p, quetiapine, aripiprazole appears to be minimal
Symptoms associated with torsades de pointes are similar to those of other tachyarrhythmias y and are related to heart rate and resulting effects on blood pressure and cardiac output. Although torsades de pointes is sometimes transient, self-limiting, and spontaneously terminating, it can degenerate into ventricular fibrillation and cause sudden cardiac death.
Diagnosis The diagnosis of torsades de pointes is dependent on the ECG. Torsades de pointes is a specific polymorphic ventricular tachycardia associated with prolongation of the QTc interval in the sinus beats that precede the arrhythmia Torsades de pointes, or twisting of the points, is characterized by the apparent twisting of the wide QRS complexes around the isoelectric baseline. A characteristic feature of torsades de pointes is a long short initiating sequence
Prevention of Drug-Induced Torsades de Pointes Avoid use of QTc interval prolonging drugs in patients with pretreatment QTc intervals >450 msec Reduce dose or discontinue QTc interval prolonging agent if QTc increases >60 msec from pretreatment value Discontinue QTc interval prolonging agent if QTc increases to >500 msec Maintain i serum potassium concentrations ti within normal range Maintain serum magnesium concentrations within normal range When possible, avoid use of QTc interval prolonging drugs in patients with left ventricular systolic dysfunction, especially in patients with LVEF <20% who have been diagnosed with one of the
Adjust doses of renally eliminated QTc interval prolonging drugs in patients with kidney disease Avoid use of hepatically metabolized QTc interval prolonging drugs in patients with advanced liver disease Avoid drug interactions involving QTc interval prolonging drugs that are substrates of the cytochrome P-450 enzyme system and cytochrome P-450 enzyme inhibitors Avoid concomitant administration of QTc interval prolonging drugs Avoid use of QTc interval prolonging drugs in patients with a history of drug-induced torsades de pointes Avoid use of QTc interval prolonging drugs in patients
Intravenous erythromycin doses of 1g every 6 hours should be avoided, unless Legionella pneumophila infection is documented. The maximum daily dose of intravenous haloperidol should not exceed 35 mg all patients on methadone therapy should undergo a pretreatment ECG for determination of the QTc interval, a follow-up 12-lead ECG for determination of the QTc interval within 30 days of the initiation of methadone treatment, and a 12-lead ECG for QTc interval determination annually. More intensive QTc interval monitoring is recommended for patients who require daily methadone doses greater than 100 mg, and for those that experience unexplained syncope or seizures