What medications for hypertension and diabetes have potential drug-drug interactions or adverse effects, such as hyperkalemia (elevated potassium levels) or hypoglycemia (low blood sugar)?

Drug-Drug Interactions and Adverse Effects in Hypertension and Diabetes Management

Critical Drug Combinations to Avoid

Never combine ACE inhibitors with ARBs, or combine either with direct renin inhibitors—these combinations lack cardiovascular benefit and significantly increase risks of hyperkalemia, syncope, and acute kidney injury. 1

Hyperkalemia Risk

High-Risk Combinations

• Adding mineralocorticoid receptor antagonists (spironolactone, eplerenone) to ACE inhibitors or ARBs substantially increases hyperkalemia risk 1
• This combination is reserved for resistant hypertension (BP ≥140/90 mmHg despite three medications including a diuretic) 1

Monitoring Requirements

• Check serum creatinine/eGFR and potassium within 7-14 days after starting or changing doses of ACE inhibitors, ARBs, or diuretics 1
• Monitor at least annually thereafter 1, 2
• Patients with reduced glomerular filtration are at highest risk 1

Hypoglycemia Risk

Insulin and Sulfonylurea Interactions

• Metformin combined with insulin secretagogues (sulfonylureas) or insulin increases hypoglycemia risk and requires dose reduction of the insulin or secretagogue 3
• ACE inhibitors may potentiate hypoglycemic episodes when combined with sulfonylureas or meglitinides through pharmacodynamic interactions 4

Drugs That Worsen Glycemic Control

Thiazide diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid can cause hyperglycemia and loss of glucose control 3

Electrolyte Disturbances

Hypokalemia

• Thiazide diuretics cause dose-dependent hypokalemia, especially with doses >25 mg hydrochlorothiazide or >12.5 mg chlorthalidone 1, 5
• Risk increases with concurrent corticosteroids or ACTH 5
• Hypokalemia and hypomagnesemia increase ventricular arrhythmias and digitalis toxicity 5

Other Electrolyte Issues

• Thiazides can cause hyponatremia, hypochloremic alkalosis, and hypomagnesemia 5
• Monitor for weakness, lethargy, muscle cramps, hypotension, oliguria, tachycardia, nausea, and vomiting 5

Metabolic Adverse Effects

Diabetes Development

• Thiazide diuretics increase new-onset diabetes risk (11.8% with chlorthalidone vs 8.1% with lisinopril at 4 years) 1
• Beta-blockers increase insulin resistance with chronic treatment 6
• These metabolic effects are dose-dependent for thiazides 6

Lipid Effects

• Thiazides at high doses can increase LDL cholesterol 1
• Beta-blockers may adversely affect lipid profiles 6

Specific Drug-Drug Interactions

Metformin Interactions

• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) increase lactic acidosis risk with metformin 3
• OCT2/MATE inhibitors (ranolazine, vandetanib, dolutegravir, cimetidine) increase metformin levels and lactic acidosis risk 3
• Alcohol potentiates metformin's effect on lactate metabolism 3

Gemfibrozil Interactions

• Gemfibrozil drastically increases repaglinide plasma concentrations and hypoglycemia risk—avoid this combination 4
• Gemfibrozil also increases rosiglitazone levels to a lesser extent 4

Diuretic Interactions

• Cholestyramine and colestipol reduce hydrochlorothiazide absorption by 85% and 43% respectively—separate administration times 5
• NSAIDs reduce diuretic, natriuretic, and antihypertensive effects of thiazides 5
• Lithium should generally not be given with diuretics due to reduced renal clearance and lithium toxicity risk 5

Acute Kidney Injury Risk

ACE inhibitors, ARBs, and diuretics can all cause acute kidney injury 1

• Monitor serum creatinine within 7-14 days of initiation or dose changes 1
• In patients with eGFR <30 mL/min/1.73 m², continuation of ACE inhibitors or ARBs may provide cardiovascular benefit without significantly increasing end-stage kidney disease risk 1

Other Significant Adverse Effects

Cardiovascular

• Beta-blockers and calcium channel blockers (verapamil, diltiazem) can cause AV block 1
• Beta-blockers may mask hypoglycemia symptoms in diabetic patients 7

Orthostatic Hypotension

• Alcohol, barbiturates, and narcotics potentiate orthostatic hypotension with thiazides 5
• Adrenergic agents and vasodilators have high prevalence of orthostatic hypotension in diabetics 7

Sexual Dysfunction

• High-dose thiazides (>50 mg hydrochlorothiazide or >25 mg chlorthalidone) increase erectile dysfunction risk 1
• Beta-blockers and diuretics can cause sexual dysfunction in men 7

Skin Cancer

• Hydrochlorothiazide increases non-melanoma skin cancer risk—instruct patients on sun protection and regular skin screening 5