Hypertension Treatment
Primary (essential) hypertension
● Thiazide diuretics
● ACE inhibitors
● Angiotensin II receptor blockers (ARBs)
● Dihydropyridine Ca²⁺ channel blockers
Hypertension with heart failure
● Diuretics
● ACE inhibitors/ARBs
● β-blockers (compensated HF)
● Aldosterone antagonists
β-blockers must be used cautiously in decompensated HF and are contraindicated in
cardiogenic shock.
In HF, ARBs may be combined with the neprilysin inhibitor sacubitril.
Hypertension with diabetes mellitus
● ACE inhibitors/ARBs
● Ca²⁺ channel blockers
● β-blockers
ACE inhibitors/ARBs are protective against diabetic nephropathy.
β-blockers can mask hypoglycemia symptoms.
Hypertension in asthma
● ARBs
● Ca²⁺ channel blockers
● Thiazide diuretics
● Cardioselective β-blockers
Avoid nonselective β-blockers to prevent β₂-receptor–induced bronchoconstriction.
Avoid ACE inhibitors to prevent confusion between drug or asthma-related cough.
Hypertension in pregnancy
● Nifedipine
● Methyldopa
● Labetalol
● Hydralazine
New moms love hugs
Nitrates
Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.
MECHANISM
● Vasodilate by ↑ NO in vascular smooth muscle
● ↑ cGMP and smooth muscle relaxation
● Dilate veins >> arteries → ↓ preload
CLINICAL USE
● Angina
● Acute coronary syndrome
● Pulmonary edema
ADVERSE EFFECTS
● Reflex tachycardia (treat with β-blockers)
● Methemoglobinemia
● Hypotension
● Flushing
● Headache
“Monday disease” (in industrial nitrate exposure):
● Development of tolerance for the vasodilating action during the work week
● Loss of tolerance over the weekend → tachycardia, dizziness, headache upon
reexposure
Contraindicated in:
● Right ventricular infarction
● Hypertrophic cardiomyopathy
● Concurrent PDE-5 inhibitor use
Calcium Channel Blockers
Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine (dihydropyridines, act on vascular
smooth muscle); diltiazem, verapamil (nondihydropyridines, act on heart).
MECHANISM
● Block voltage-dependent L-type calcium channels of cardiac and smooth muscle → ↓
muscle contractility
Potency by Target Tissue:
● Vascular smooth muscle: amlodipine = nifedipine > diltiazem > verapamil
● Heart: verapamil > diltiazem > amlodipine = nifedipine
CLINICAL USE
● Dihydropyridines (except nimodipine):
○ Hypertension
○ Angina (including vasospastic type)
○ Raynaud phenomenon
○ Mainly dilates arteries
● Nimodipine:
○ Subarachnoid hemorrhage (prevents delayed ischemia)
● Nicardipine, clevidipine:
○ Hypertensive urgency or emergency
● Nondihydropyridines:
○ Hypertension
○ Angina
○ Atrial fibrillation/flutter
ADVERSE EFFECTS
● Gingival hyperplasia
● Dihydropyridine:
○ Peripheral edema
○ Flushing
○ Dizziness
● Nondihydropyridine:
○ Cardiac depression
○ AV block
○ Hyperprolactinemia (verapamil)
○ Constipation
Hydralazine
MECHANISM
● ↑ cGMP → smooth muscle relaxation
● Vasodilates arterioles > veins → afterload reduction
CLINICAL USE
● Severe hypertension (particularly acute)
● Heart failure (with organic nitrate)
● Safe to use during pregnancy
● Frequently coadministered with a β-blocker to prevent reflex tachycardia
ADVERSE EFFECTS
● Compensatory tachycardia (contraindicated in angina/CAD)
● Fluid retention
● Headache
● Angina
● Drug-induced lupus
Hypertensive Emergency
Treat with:
● Labetalol
● Clevidipine
● Fenoldopam
● Nicardipine
● Nitroprusside
Nitroprusside
● Short acting vasodilator (arteries = veins)
● ↑ cGMP via direct release of NO
● Can cause cyanide toxicity (releases cyanide)
Fenoldopam
● Dopamine D1 receptor agonist
● Coronary, peripheral, renal, and splanchnic vasodilation
● ↓ BP, ↑ natriuresis
● Also used postoperatively as an antihypertensive
● Can cause:
○ Hypotension
○ Tachycardia
○ Flushing
○ Headache
○ Nausea
Antianginal Therapy
Goal is reduction of myocardial O₂ consumption (MVO₂) by ↓ one or more of the determinants of
MVO₂: end-diastolic volume, BP, HR, contractility.
Nondihydropyridine calcium channel blockers (verapamil, diltiazem) are similar to β-blockers in
effect.
Ranolazine
MECHANISM
● Inhibits the late phase of inward sodium current
● Reduces diastolic wall tension and oxygen consumption
● Does not affect heart rate or blood pressure
CLINICAL USE
● Refractory angina
ADVERSE EFFECTS
● Constipation
● Dizziness
● Headache
● Nausea
Sacubitril
MECHANISM
● A neprilysin inhibitor
● Prevents degradation of:
○ Bradykinin
○ Natriuretic peptides
○ Angiotensin II
○ Substance P
● → ↑ Vasodilation, ↑ ECF volume
CLINICAL USE
● Used in combination with valsartan (an ARB) to treat HFrEF
ADVERSE EFFECTS
● Hypotension
● Hyperkalemia
● Cough
● Dizziness
● Contraindicated with ACE inhibitors due to angioedema (both drugs ↑ bradykinin)
Lipid-Lowering Agents
Statins (Atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)
● LDL: ↓↓↓, HDL: ↑, Triglycerides: ↓
● Mechanism: Inhibit HMG-CoA reductase → ↓ cholesterol synthesis; ↓ intrahepatic
cholesterol → ↑ LDL receptor recycling → ↑ LDL catabolism. Reduce mortality in patients
with CAD.
● Adverse Effects: Hepatotoxicity (↑ LFTs), myopathy (especially when used with fibrates
or niacin).
Bile Acid Resins (Cholestyramine, colesevelam, colestipol)
● LDL: ↓↓, HDL: slightly ↑, Triglycerides: slightly ↑
● Mechanism: Disrupt enterohepatic bile acid circulation → compensatory ↑ conversion of
cholesterol to bile → ↓ intrahepatic cholesterol → ↑ LDL receptor recycling.
● Adverse Effects: GI upset, ↓ absorption of other drugs and fat-soluble vitamins.
Ezetimibe
● LDL: ↓↓, HDL: ↓/—, Triglycerides: ↓/—
● Mechanism: Prevents cholesterol absorption at the small intestine brush border.
● Adverse Effects: Rare ↑ LFTs, diarrhea.
Fibrates (Fenofibrate, gemfibrozil)
● LDL: ↓, HDL: ↑, Triglycerides: ↓↓↓
● Mechanism: Activate PPAR-α → upregulate LPL → ↑ TG clearance; also induce HDL
synthesis.
● Adverse Effects: Myopathy (↑ risk with statins), cholesterol gallstones (via inhibition of
cholesterol 7α-hydroxylase).
Niacin
● LDL: ↓↓, HDL: ↑↑, Triglycerides: ↓
● Mechanism: Inhibits lipolysis (hormone-sensitive lipase) in adipose tissue; reduces
hepatic VLDL synthesis.
● Adverse Effects: Flushed face (prostaglandin mediated; ↓ by NSAIDs or long-term use),
hyperglycemia, hyperuricemia.
PCSK9 Inhibitors (Alirocumab, evolocumab):
● LDL: ↓↓↓, HDL: ↑, Triglycerides: ↓
● Mechanism: Inactivation of LDL-receptor degradation → ↑ removal of LDL from
bloodstream.
● Adverse Effects: Myalgias, delirium, dementia, other neurocognitive effects.
Digoxin
MECHANISM
● Direct inhibition of Na⁺/K⁺-ATPase
→ Indirect inhibition of Na⁺/Ca²⁺ exchanger
→ ↑ [Ca²⁺]ᵢ → positive inotropy
● Stimulates vagus nerve → ↓ HR
CLINICAL USE
● Heart failure (↑ contractility)
● Atrial fibrillation (↓ conduction at AV node and depression of SA node)
ADVERSE EFFECTS
● Cholinergic effects:
○ Nausea
○ Vomiting
○ Diarrhea
● Blurry yellow vision (“van Glow”)
● Arrhythmias
● Atrial tachycardia with AV block
● Can lead to hyperkalemia, which indicates poor prognosis
Factors predisposing to toxicity:
● Renal failure (↓ excretion)
● Hypokalemia (permissive for digoxin binding at K⁺-binding site on Na⁺/K⁺-ATPase)
● Drugs that displace digoxin from tissue-binding sites
● ↓ Clearance (e.g., verapamil, amiodarone, quinidine)
ANTIDOTE
● Slowly normalize K⁺
● Cardiac pacer
● Anti-digoxin Fab fragments
● Mg²⁺
Antiarrhythmics—Sodium Channel Blockers (Class I)
● Slow or block conduction (especially in depolarized cells)
● ↓ slope of phase 0 depolarization
● ↑ action at faster HR
● State-dependent: ↑ HR → shorter diastole → Na⁺ channels spend less time in resting
state (drugs dissociate during this state) → less time for drug to dissociate from receptor
● Effect most pronounced in IC > IA > IB due to relative binding strength
● Fast taxi CAB
Class IA
Quinidine, procainamide, disopyramide
● “The queen proclaims Diso’s pyramid
MECHANISM
● Moderate Na⁺ channel blockade
● ↑ AP duration, ↑ effective refractory period (ERP) in ventricular action potential
● ↑ QT interval, some K⁺ channel blocking effects
CLINICAL USE
● Both atrial and ventricular arrhythmias, especially reentrant and ectopic SVT and VT
ADVERSE EFFECTS
● Cinchonism (headache, tinnitus with quinidine)
● Reversible SLE-like syndrome (procainamide)
● Heart failure (disopyramide)
● Thrombocytopenia
● Torsades de pointes due to ↑ QT interval
Class IB
Lidocaine, mexiletine
● “I’d Buy Liddy’s Mexican tacos”
MECHANISM
● Weak Na⁺ channel blockade
● INa → ↓ AP duration
● Preferentially affect ischemic or depolarized Purkinje and ventricular tissue
CLINICAL USE
● Acute ventricular arrhythmias (especially post-MI)
● Digitalis-induced arrhythmias
● IB is Best post-MI
ADVERSE EFFECTS
● CNS stimulation/depression
● Cardiovascular depression
Class IC
● Drugs: Flecainide, propafenone
● Mnemonic: “Can I have fries, please?”
MECHANISM
● Strong Na⁺ channel blockade
● Significantly prolongs ERP in AV node and accessory bypass tracts
● No effect on ERP in Purkinje and ventricular tissue
● Minimal effect on AP duration
CLINICAL USE
● SVTs, including atrial fibrillation
● Only as a last resort in refractory VT
ADVERSE EFFECTS
● Proarrhythmic, especially post-MI (contraindicated)
● IC is contraindicated in structural and ischemic heart disease
Antiarrhythmics—β-blockers (Class II)
● Drugs: Metoprolol, propranolol, esmolol, atenolol, timolol, carvedilol
MECHANISM
● Decrease SA and AV nodal activity by:
○ ↓ cAMP, ↓ Ca²⁺ currents
○ Suppress abnormal pacemakers by ↓ slope of phase 4
● AV node particularly sensitive → ↑ PR interval
● Esmolol is very short acting
CLINICAL USE
● SVT, ventricular rate control for atrial fibrillation and atrial flutter
● Prevent ventricular arrhythmia post-MI
ADVERSE EFFECTS
● Impotence
● Exacerbation of COPD and asthma
● Cardiovascular effects:
○ Bradycardia
○ AV block
○ Heart failure (HF)
● CNS effects:
○ Sedation
○ Sleep alterations
● May mask the signs of hypoglycemia
● Metoprolol can cause dyslipidemia
● Propranolol can exacerbate vasospasm in vasospastic angina
Special Considerations
● β-blockers (except the nonselective α- and β-antagonists carvedilol and labetalol) cause
unopposed α1-agonism if given alone for pheochromocytoma or for cocaine toxicity
(unsubstantiated)
● Treat β-blocker overdose with:
○ Saline
○ Atropine
○ Glucagon
Antiarrhythmics—Potassium Channel Blockers (Class III)
● Drugs: Amiodarone, Ibutilide, Dofetilide, Sotalol
● Mnemonic: AIDS
MECHANISM
● ↑ AP duration, ↑ ERP, ↑ QT interval
CLINICAL USE
● Atrial fibrillation, atrial flutter
● Ventricular tachycardia (amiodarone, sotalol)
ADVERSE EFFECTS
● Sotalol:
○ Torsades de pointes
○ Excessive β-blockade
● Ibutilide:
○ Torsades de pointes
● Amiodarone:
○ Pulmonary fibrosis
○ Hepatotoxicity
○ Hypothyroidism or hyperthyroidism (amiodarone is 40% iodine by weight)
○ Acts as hapten:
■ Corneal deposits
■ Blue/gray skin deposits resulting in photodermatitis
○ Neurologic effects
○ Constipation
○ Cardiovascular effects:
■ Bradycardia
■ Heart block
■ Heart failure (HF)
MONITORING
● Remember to check PFTs (pulmonary function tests), LFTs (liver function tests), and
TFTs (thyroid function tests) when using amiodarone.
ADDITIONAL INFO
● Amiodarone is lipophilic and has class I, II, III, and IV effects
Antiarrhythmics—Calcium Channel Blockers (Class IV)
● Drugs: Diltiazem, verapamil
MECHANISM
● Decrease conduction velocity
● ↑ ERP, ↑ PR interval
CLINICAL USE
● Prevention of nodal arrhythmias (e.g., SVT)
● Rate control in atrial fibrillation
ADVERSE EFFECTS
● Constipation
● Gingival hyperplasia
● Flushing
● Edema
● Cardiovascular effects:
○ Heart failure (HF)
○ AV block
○ Sinus node depression
Other Antiarrhythmics
Adenosine
● MECHANISM:
○ ↑ K⁺ out of cells, hyperpolarizing the cell and ↓ ICa, decreasing AV node
conduction
● CLINICAL USE:
○ Drug of choice in diagnosing/terminating certain forms of SVT
○ Very short acting (~15 sec)
● ADVERSE EFFECTS:
○ Flushing
○ Hypotension
○ Chest pain
○ Sense of impending doom
○ Bronchospasm
● Note: Effects blunted by theophylline and caffeine (both are adenosine receptor
antagonists)
Magnesium
● MECHANISM:
○ Effective in torsades de pointes and digoxin toxicity
Ivabradine
● MECHANISM:
○ Prolongs slow depolarization (phase “IV”) by selectively inhibiting “funny” sodium
channels (If)
● CLINICAL USE:
○ Chronic HFrEF
● ADVERSE EFFECTS:
○ Luminous phenomena/visual brightness
○ Hypertension
○ Bradycardia
