MD Notes

creation date: 2025-05-29 15:39
status: note
tags: Pharmacology

Antihypertensives

First-line

Angiotensin-converting enzyme inhibitors

Note: electrolytes and renal function should be tested shortly after prescribing

Mechanism of action

Inhibits ACE which reduces conversion of angiotensin I to angiotensin II. Decreased angiotensin II levels results in:

  • Decreased aldosterone and ADH secretion (less fluid retention)
  • Decreased peripheral vasoconstriction
Special indications
  • Nephroprotective (patients with diabetes or renal disease)
  • Heart failure with reduced ejection fraction
Adverse effects
  • Dry cough
  • Angioedema
  • Hyperkalemia
  • Pemphigus vulgaris (autoimmune blisters)
Contraindications
  • C1 esterase inhibitor deficiency
  • Pregnancy
    Relative:
  • Bilateral renal artery stenosis
  • Solitary kidney
Examples

Prils:

  • Lisinopril
  • Ramipril
  • Captopril

Angiotensin-receptor blockers

Note: electrolytes and renal function should be tested shortly after prescribing

Mechanism of action

Inhibits angiotensin II receptor type 1 resulting in:

  • Decreased aldosterone and ADH secretion (less fluid retention)
  • Decreased peripheral vasoconstriction
Special indications
  • Same as ACEi (if ACEi not tolerated)
Adverse effects
  • Same as ACEi
Contraindications
  • Same as ACEi
Examples

Sartans:

  • Candesartan
  • Valsartan

Thiazide diuretics

Mechanism of action

Inhibits Na+Cl- cotransporters in early distal tubule (which physiologically reabsorbs Na+ and Cl-) and increased Ca2+ reabsorption.

Special indications
  • Chronic edema (eg. with CHF, cirrhosis)
  • Nephrogenic diabetes insipidus
Adverse effects
  • Hypokalemia
  • Metabolic alkalosis
  • Hyponatremia
  • Hypomagnesemia
  • Hyperglycemia
  • Hyperuricemia
  • Hypercalcemia
  • Hyperlipidemia
  • Megaloblastic anemia
  • Thrombocytopenia
Contraindications
  • Gout
  • Anuria
  • Severe hypokalemia
Examples
  • Hydrochlorothiazide

Calcium channel blockers

Dihydropyridines

Mechanism of action

Binds and block L-type calcium channels primarily in vascular smooth muscle.

  • Decreases Ca2+ channel opening frequency with cell membrane depolarization and thus Ca2+ influx
  • Vascular smooth muscle relaxation and vasodilation (decreases TPR)
  • Minimal myocardial depression
Special indications
  • Angina pectoris
  • Raynaud phenomenon
  • Hypertensive emergency (nicardipine, clevidipine)
  • Subarachnoid hemorrhage (nimodipine)
Adverse effects
  • Headache
  • Peripheral edema
  • Flushing
  • Reflex tachycardia
  • Gingival hyperplasia
Contraindications
  • Acute coronary syndrome
  • Symptomatic hypotension
  • Hypertrophic obstructive cardiomyopathy
  • Severe stenotic heart valves
Examples

Short-acting:

  • Nifedipine
  • Clevidipine
  • Nimodipine
    Intermediate-acting:
  • Nitrendipine
  • Nicardipine
  • Lercanidipine
    Long-acting:
  • Amlodipine
  • Felodipine

Non-dihydropyridines

Mechanism of action

Binds and blocks L-type calcium channels primarily in cardiac smooth muscle cells.

  • Decreases Ca2+ channel opening frequency with cell membrane depolarization and thus Ca2+ influx
  • Decreases cardiac muscle contractility (decrease CO)
  • Decreases SA node discharge rate (decrease HR)
  • Decreases AV node conduction (stops supraventricular arrhythmias)
Special indications
  • Supraventricular tachyarrhythmias
  • Angina pectoris
  • Hypertrophic obstructive cardiomyopathy
  • Migraine (verapamil)
Adverse effects
  • Decreased contractility
  • Bradycardia
  • AV block
  • Gingival hyperplasia
  • Constipation and hyperprolactinemia (verapamil)
Contraindications
  • Acute coronary syndrome
  • Symptomatic hypotension
  • Preexisting cardiac conduction disorders (WPW syndrome, sick sinus syndrome, systolic dysfunction (CHF), bradycardia, 2nd or 3rd degree AV block)
  • Beta-blocker use
Examples

Benzothiazepines (moderate vasodilator, moderate myocardial depressant):

  • Diltiazem
    Phenylalkylamines (moderate vasodilator, potent myocardial depressant):
  • Verapamil
  • Gallopamil

Second-line

Beta blockers

Cardioselective (β1)

Mechanism of action

Selective binding to beta-1 receptors (primarily found in the heart). Antagonism causes:

  • Decrease in heart rate, contractility, AV node conductivity
  • NO-mediated vasodilation (nebivolol only)

Intrinsic sympathomimetic activity (ISA) refers to partial agonist activity while still blocking epinephrine and norepinephrine. This causes:

  • Less bradycardia and less peripheral vasoconstriction
  • More favourable lipid profile
Special indications
  • Coronary heart disease
  • Compensated heart failure
  • Cardiac arrhythmias
Adverse effects
  • Bradycardia
  • Bradyarrhythmia
  • β2 receptor antagonism at higher dose (cardioselectivity is dose dependent)
Contraindications
  • Symptomatic bradycardia
  • Cardiogenic shock and hypotension
  • Pheochromocytoma
  • Decompensated heart failure
  • CCB use
  • Sick sinus syndrome, heart block >1st degree
    Relative:
  • Asthma/COPD (less important with cardioselective)
  • Psoriasis
  • Raynaud phenomenon, peripheral artery disease
  • Pregnancy (except labetalol)
Examples

Cardioselective beta blockers begin with letter A-M (first half of alphabet), with exception to nebivolol.

With ISA:

  • Acebutolol
  • Celiprolol
    Without ISA:
  • Atenolol
  • Metoprolol
  • Bisoprolol

Nonselective (β1, β2, β3)

Mechanism of action

Blocks β1, β2, β3 receptors.

β1: heart and kidneys (see cardioselective)
β2:

  • Smooth muscles - vasoconstriction and bronchoconstriction
  • Ocular ciliary body - reduce aqueous humour production reducing intraocular pressure
  • Pancreatic beta cells - reduce insulin release
  • Skeletal muscles - reduce glucose uptake
  • Liver - reduce hepatic glycogenolysis
  • Lipoprotein lipase enzyme - inhibition resulting in hyperlipidemia
    β3:
  • Adipose tissue - reduce lipolysis causing weight gain
Special indications
  • Essential tremor, portal hypertension, migraine prophylaxis, thyroid storm (propranolol)
  • Cardiac arrhythmias (sotalol)
  • Glaucoma (timolol)
Adverse effects
  • Bronchoconstriction (exacerbation of asthma/COPD)
  • Vasoconstriction
  • Hypoglycemia and hyperglycemia
  • Bradycardia/syncope
Contraindications

Same as cardioselective β-blockers

Examples

Nonselective beta blockers begin with the letters N-Z.

With ISA:

  • Pindolol
  • Penbutolol
  • Oxprenolol
    Without ISA:
  • Propanolol
  • Nadolol
  • Sotalol
  • Timolol
  • Tertalol
Additional alpha-blocking action
Mechanism of action

In addition to nonselective beta blocking mechanism, also has α-receptor antagonism.

  • Vasodilation resulting in decreased peripheral vascular resistance
  • Reduced portal hypoertension
  • Improved endothelial function and vascular remodeling
Special indications
  • Gestational hypertension (labetalol)
  • Prophylaxis for esophageal variceal bleeding
Adverse effects
  • Same as nonselective beta blockeres
  • Orthostatic hypotension
Contraindications

Same as cardioselective ß-blockers

Examples
  • Labetalol
  • Bucindolol
  • Carvedilol

Loop diuretics

Mechanism of action

Inhibits Na+-K+-2Cl- cotransporters in the thick ascending loop of Henle and reduces calcium reabsorption.

Special indications
  • Edema (cardiac, renal, hepatic)
  • Forced diuresis
Adverse effects
  • Hypokalemia
  • Metabolic alkalosis
  • Hyponatremia
  • Hypomagnesemia
  • Hyperglycemia
  • Hyperuricemia
  • Ototoxicity
  • Hypocalcemia
  • Dehydration/hypovolemia
Contraindications
  • Anuria
Examples

Sulfonamides:

  • Furosemide
    Ethacrynic acid

Aldosterone antagonists (potassium-sparing diuretics)

Mechanism of action

Competitively binds to aldosterone receptor in late distal convoluted tubule resulting in inhibition of aldosterone effects such as:

  • Reduces renal reabsorption of water and sodium
  • Reduces secretion of potassium and hydrogen ions
Special indications
  • Hypokalemia
  • Ascites/edema
  • PCOS
Adverse effects
  • Hyperkalemia
  • Metabolic acidosis
  • Endocrine disturbances (antiandrogenic effects in men, amenorrhea in women) - spironolactone
Contraindications
  • Anuria and/or renal insufficiency
  • Pre-existing hyperkalemia
  • Addison disease
Examples
  • Spironolactone
  • Eplerenone

Direct renin inhibitors

Mechanism of action

Inhibition of renin, which converts angiotensinogen to angiotensin I, resulting in downstream effects similar to ACEi and ARBs.

Special indications

RAAS inhibition if ACEi and ARBs not tolerated.

Adverse effects
  • Hyperkalemia
  • Angioedema
Contraindications
  • Pregnancy
  • Current ACEi or ARB use
Examples
  • Aliskiren

Direct arteriolar vasodilators

Mechanism of action

Increases the release of cGMP causing:

  • Relaxation of smooth muscles
  • Subsequent vasodilation

Hydralazine: affects arterioles > veins
Sodium nitroprusside: affects arteries = veins

Special indications
  • First-line for pregnancy (hydralazine)
  • Hypertensive emergency (sodium nitroprusside)
Adverse effects
  • Angina
  • Sodium and water retension
  • Drug-induced lupus erythematosus
  • Peripheral neuritis (hydralazine)
  • Cyanide toxicity (sodium nitroprusside)
Contraindications

Hydralazine:

  • Coronary artery disease
    Sodium nitroprusside:
  • Decreased cerebral circulation
  • Leber optic atrophy
Examples
  • Hydralazine
  • Sodium nitroprusside

Alpha-1 blockers

Mechanism of action

Inhibits alpha-1 receptors which results in:

  • Decreased vasoconstriction
  • Relaxation of bladder neck muscles
  • Reduced alpha-1 mediated CNS stress responses (only if can cross blood-brain barrier eg. prazosin)
Special indications
  • Symptom control in BPH
  • PTSD-related nightmares
Adverse effects
  • Orthostatic hypotension
  • Retrograde ejaculation
  • Dizziness, headache
  • Peripheral edema, hypotension
  • Nausea, constipation
  • Intraoperative floppy iris syndrome
  • Urinary frequency
  • Priapism (prazosin)
Contraindications
Examples
  • Doxazosin
  • Terazosin
  • Prazosin

Note, tamsulosin, alfuzosin, and silodosin are indicated for BPH but not hypertension.

Alpha-2 agonists

Mechanism of action

Activates alpha-2 receptors in presynaptic sympathetic neurons resulting in:

  • Decreased norepinephrine release (and unopposed GABA activity resulting in sedation)
  • Centrally-mediated vasodilation
Special indications
  • Sedation
  • Opiate dependence
  • Alcohol withdrawal
Adverse effects
  • Orthostatic hypotension, hyppotension
  • Side effects can vary and are dependent on medication.
Contraindications
Examples
  • Clonidine
  • Guanfacine
  • Methyldopa

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