The angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor (AR) blockers are widely used for the treatment hypertension or heart failure and myocardial infarction.
Examples of ACE inhibitors are:
Alacepril, Benazepril, Captopril, Cilazapril, Delapril, Enalapril, Fosinopril, Idrapril, Ilepatril, Imidapril, Libenzapril, Lisinopril, Moexipril, Omapatrilat, Pentopril, Perindopril, Pivopril, Quinapril, Ramipril, Rentiapril, Sampatrilat, Spirapril, Temocapril, Trandolapril, Zofenopril
Angiotensin II receptor blockers (ARBs) include:
Losartan, Azilsartan, Candersartan, Eprosartan, Irbesartan, Olmesartan, Telmisartan, Valsartan
Mechanism of Toxicity
Angiotensin II is a product of renin-angiotensin-aldosterone system. (formed from angiotensin I by ACE), causes direct vasoconstriction of precapillary arterioles and postcapillary venules; inhibits the reuptake of nnoradrenaline; stimulates the release of catecholamines from the adrenal medulla; reduces urinary excretion of sodium and water; stimulates synthesis and release of aldosterone; and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes.
In addition, Angiotensin II increases force of myocardial contraction and the heart rate
It is this renin-angiotensin-aldosterone system that’s impaired by ACE inhibitors and AR blockers ACE inhibitors, as the name implies, blocks an ACE that converts angiotensin I to angiotensin II. In contrast, ARBs directly inhibit the physiological effects of angiotensin II by selectively blocking the AT1 receptors located in many tissues, (e.g., vascular smooth muscle, adrenal gland).
Decreased synthesis of angiotensin II enhances sodium excretion, lowers arterial and venous pressure (reduces preload and afterload), and prevents remodeling of smooth muscle and cardiac myocytes.
Additionally, decreased conversion of angiotensin I to angiotensin II leads to an angiotensin I accumulation upstream which in turn causes an increase in nitric oxide release and, ultimately, vasodilation.
ACEI’s alalso prevent the breakdown of bradykinin which also results in vasodilation, angioedema and persistent cough.
Among the distinct families of endogenous opioids identified thus far, enkephalins have direct effects on blood pressure, heart rate, and the baroreceptor reflex. ACE inhibitors inhibit the metabolism of these opioids, potentiating their opioid effect, which includes lowering blood pressure and bradycardia.
Clinical manifestations
ACE inhibitor and ARB overdose may occasionally result in severe hypotension and organ failure.The peak effect of is seen, on average, 4hrs post-ingestion.
Unlike the hypotensive effects of other vasodilators, ACE inhibitors do not provoke a reflex tachycardia due to lack of compensatory tachycardia following modification of baroreflexes or cancellation of angiotensin II–mediated vagal inhibition.
clinical consequences of hypotension are usually most severe in patients with preexisting cardiovascular disease, who are less able to compensate for changes in blood pressure.
Bradycardia may rarely occur following ACEI overdose.
Acute renal failure may result from profound hypotension. Monitoring of blood urea nitrogen and serum creatinine is important.
Hyperkalaemia and hyponatremia may occur as a result of impaired renal function and aldosterine synthesis and release. Renal impairment, diabetes, potassium-sparing diuretics elevate s the risk for hyperglycemia.
Angioedema is the most significant adverse effect of ACEi. It may lead to airway obstruction and respiratory distress following edema of the glottis and/or larynx. AR blockers, which do not alter bradykinin elimination is less likely to cause this problem.
Liver toxicity may be observed following ACE inhibitor overdose. Cholestatic jaundice or hepatitis has been reported.
Altered mentation may occur secondary to central hypoperfusion.
Treatment
Despite the potential to cause severe hypotension, the drug overdoses are generally mild, and most patients do not require any specific treatment.
Patients in whom hypotension has not occurred within 6 h of ingestion can be considered for discharge.
Treatment is generally supportive with maintenance of normal blood pressure, organ perfusion and adequate urine output.
If the patient presents within 1 hour of ingestion and is awake and able to protect their airway, activated charcoal can be given (50 g for adults; 1 g/kg for children).
For those with hypotension, intravenous fluid infusion should be the first line of therapy. However, severe hypotension may require the administration of vasopressive amines such as low dose dopamine, adrenaline and noradrenaline.
Naloxone, an opioid receptor antagonist, has been shown to be effective in certain situations, especially in cases of severe hypotension where fluid overload is a concern. It is administered as 1 mg bolus followed by continuous intravenous infusion (0.04mg/kg/h) for 24h to avoid the rebound hypotension
Terlipressin synthetic analog of vasopressin has also been used against unresponsive hypotension.
Atropine may be useful in reversing bradycardia.
Administration of intravenous angiotensin II may reverse bradycardia and hypotension refractory to other pressor agents-norepinephrine, epinephrine, and vasopressin, but it is not expected to be very effective after overdose with an ARB
Angiotensin is administered as an infusion, initially at 10-20 ng/kg/min (adjusted every 5 min according to the response in blood pressure and urine output). The maximum rate in the first three hours of treatment is 80 ng/kg/min, and the maximum maintenance dose is 40 ng/kg/min. Angiotensin II carries an increased risk for arterial or venous thrombosis or thromboembolism, often deep vein thrombosis. Therefore, thromboembolism prophylaxis is recommended.
Hepatic dysfunction can be managed with vitamin K and fresh frozen plasma.
Pressor agents such as noradrenaline that act directly on blood vessels must be used cautiously to avoid exacerbate organ hypoperfusion.
When airway compromise is present, the treatment is always securing the airway with an endotracheal tube that allows ventilation until the edema resolves. bradykinin blocking agents might improve the angioedema, but no literature exists proving that they are better than the other agents.
Since the plasma half-life of ACE inhibitors AR blockers are in several hours (ACEI 6–35 hrs; AR blockers 5–24 hours.),it may be necessary to continue treatment for several days.
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