Angiotensin converting enzyme inhibitors (ACEi), Angiotensin receptors blockers (ARBs) are used to lower blood pressure, treat heart failure, renal failure, patients with chronic kidney disease and slow renal disease progression in patients with type2 diabetes [1]. National statistics indicates that almost 1% of emergency department visits and 2%of hospitalization for hyperkalemia ends in death [2]. The aim of this text to review the present understanding of hyperkalemia due to angiotensin converting enzyme inhibitors (ACEi) or Angiotensin receptor blockers (ARBs). This includes the pathophysiology of how those agents increases the potassium levels within the body, risk factors for hyperkalemia, signs and symptoms, treatment approach for antagonizing the hyperkalemia.

Potassium

Potassium is an essential nutrient and most abundant cation in the body [3]. It plays a major role in maintaining fluid and electrolyte balance, blood pressure, helps nerves to function, muscles to contract, and move nutrients in to cells and waste products out of the cells. Reducing bone loss and risk of kidney stones. Normal serum potassium levels in the body ranges from 3.5-5.0mEq/L. Diet is the primary source of potassium which include fruits and vegetables, dairy products, meat, nuts and dried peas. Potassium concentration is higher in fruits and vegetables than in cereals and meat, like kiwi, banana, orange juice, potatoes, avocados, turnips, apricots, parsnips [4].

Renin- Angiotensin- Aldosterone System

The renin- Angiotensin- Aldosterone system is one of the most important hormonal mechanism by regulating blood pressure, fluid volume and sodium, potassium balance [5]. Renin is synthesized by the juxta glomerular cells in the walls of the kidneys as an inactive form and released in the blood circulation in response to low levels of sodium, hypotension in the afferent arterioles , In the blood stream pro renin is converted in to active form by the proteolytic and non- proteolytic mechanisms[6]. The active renin converts angiotensinogen in to angiotensin-1, and angiotensin-1 is converted into angiotensin-2 in the presence of angiotensin converting enzyme (ACE) [7]. Aldosterone released from the adrenal cortex by the stimulation of Angiotensin-2. Aldosterone secretion is influenced by both angiotensin-2 and plasma potassium [8]. 

Aldosterone is the major mineralocorticoid, which increases potassium secretion from the body by stimulating an increase in liminal reabsorption of sodium [9]. Aldosterone binds to the receptors present in the collecting duct cells and increases sodium reabsorption across the luminal membrane through sodium channel thus increases potassium secretion through a potassium channel [10]. 

Effect of ACEI and ARBS on the Raas System

Angiotensin converting enzyme inhibitors or Angiotensin receptor blockers are inhibiting the formation of circulating angiotensin-2 or blocking the binding of angiotensin-2 to the adrenal receptors, and also interfere with the stimulatory effect of an aldosterone secretion in the adrenal gland that impair kidney excretion of potassium [11]. Some drugs and disease conditions also can contribute to impaired potassium excretion along with the ACEi/ ARBs and increase the risk of hyperkalemia. The main mechanism include decreased aldosterone concentration, decreased delivery of sodium to the distal nephron, abnormal functioning of collecting tubules and excessive intake of potassium [12]. Dry cough also one of the most common side effect of ACE inhibitors, it may develop in around 10% of the patients using ACE inhibitors. The exact mechanism of ACE inhibitors induced dry cough remains not clear. Degradation or suppression of kininase-II activity by the ACE inhibitors leads to accumulation of kinins, prostaglandins and substance P in upper and lower respiratory tracts. This causes constriction of airway smooth muscles leading to bronchospasm and cough [13, 14].

Risk Factors

The major risk factors for hyperkalemia are increased age due to impaired renin release with subsequent hyperaldosteronism, diabetes, renal impairment either acute kidney disease (AKI) and chronic kidney disease (CKI), heart failure, volume depletion, cell destruction eg: trauma, hemolysis, burns. Excessive potassium intake like through diet, salt substitutes, certain herbal products, due to some drugs antimicrobial drugs, other drugs like Alisacrin, potassium sparing diuretics, beta- blockers, NSAIDS, heparin, digoxin[15].

Table: 1 Treatment of Hyperkalemia due to ACEI and ARBS Therapy [22]

Signs and Symptoms of Hyperkalemia

Hyperkalemia can be classified in to mild (5.5- 6.5mmol/L), moderate (6.5- 7.5mmol/L) and severe hyperkalemia (>7.5mmol/L) based on serum potassium levels in the body [16]. Hyperkalemia may cause cardiac dysfunction and neurological alterations. Cardiovascular dysfunction includes ECG changes, cardiac dysrhythmias. ECG changes mainly peak T waves, widening PR interval, loss of P wave, ST segment changes and widening QRS complex. The elevated potassium levels may cause neurological conditions like fatigue, irritability and mental confusion. A neuromuscular symptom includes muscle cramps, weakness, speech problems, paresthesia, tetany and paralysis. Also cause gastrointestinal manifestations like nausea, diarrhea, and abdominal cramps [17-20].

Treatment of ACEI or ARBS Induced Hyperkalemia

Treatment approach for ACEi and ARBs induced hyperkalemia includes: Antagonizing the cardiac effects of potassium, redistributing potassium in to the cells and removing excess potassium from the body. When a patient with hyperkalemia due to ACEi or ARBs therapy, the first priority is to determine whether the serum potassium is greater than 6mmol/L and any ECG changes are present. If either is detected acute hyperkalemia management should be started and continued until the serum potassium levels below 5mmol/L and reduces ECG abnormalities (Table 1) [21].

ACEi and ARBs are effective therapeutic agents which will rarely cause mild to severe hyperkalemia, particularly among patients with chronic renal disorder. To reduce the risk of hyperkalemia in patients using ACEi/ARB therapy, obtaining baseline eGFR, serum potassium concentration and other concomitant drugs, diet, supplements that can increase hyperkalemia should be assessed. If hyperkalemia occurs, prompt administration of definitive therapy to antagonize the adverse cardiac effects of potassium and maintain normal level of serum and body potassium and optimize the outcomes.

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