08b - Anti-Hypertensive Drugs

hypertension

chronically elevated blood pressure that can damage blood vessels, kidneys, heart, brain, and eyes

• prevalence increases strongly with age

• defined as BP > 140/90 or receiving antihypertensive treatment

• dangerous because it can be silent while causing organ damage

anti-hypertensive drug classes

• first-tier → diuretics, renin-angiotensin inhibitors, calcium channel blockers

• second-tier → β-adrenergic blockers, sympathoplegics, direct vasodilators, ⍺₁-adrenergic blockers

  • add-on drugs for when first-tier is not enough or when patient has special conditions

recommended treatment scheme

JNC 8 panel and ASH guidelines

• non-African-American population:

  • any of the following → thiazide diuretics, ACE inhibitors, ARBs, calcium channel blocker (except in heart failure)

• African-American population:

  • thiazide or calcium channel blocker; or thiazide + ACE inhibitor / ARB as initial therapy

• stage 2 hypertension:

  • start with two drugs, with one being a diuretic

diuretics for hypertension

diuretics lower BP by inhibiting sodium reabsorption, causing diuresis to reduce blood volume and venous pressure for reduction of cardiac output and blood pressure

• furosemide (loop agents) work on thick ascending limb

• thiazides work on distal convoluted tubule

  • initially reduces cardiac output by reducing ECF and plasma volume

  • chronic use will cause ECF volume return to baseline

  • at steady state, predominant effect is reduction of peripheral vascular resistance rather than reduced blood volume

  • may be combined with potassium-sparing drugs, since thiazides can waste potassium

    • aldactazide = sprionolactone + hydrocholorothiazide

    • dyazide/maxzide = triamterene + hydrocholorothiazide

    • moduretic = amiloride + hydrocholorothiazide

• aldosterone antagonists work on collecting duct

RAAS inhibitors — ACE inhibors + ARBs

RAAS inhibitors lower blood pressure by blocking angiotensin II formation or action

• angiotensin converting enzyme (ACE) inhibitors:

  • oldest class and most generic choice

  • decreases production of vasopressor peptide angiotensin II

• angiotensin receptor blockers (ARBs):

  • second class of RAAS inhibitors, generally more expensive

  • blocks angiotensin I vascular receptor, where angiotensin II acts

• direct renin inhibitors (DRIs):

  • ALISKIREN → single drug in class that blocks production of angiotensin I

ACE inhibitors

inhibit conversion of angiotenin I to angiotensin II; have same effectiveness in lowering BP, but some may be more effective than others in preventing/delaying adverse renal, cardiac, and vascular remodeling

• benazepril (lotensin), captopril (capoten), enalapril (vasotec), fosinopril (monopril), LISINOPRIL (prinivil, zestril), moexipril (univasc), perinodopril (aceon), quinapril (accupril) RAMIPRIL (altace), trandolapril (mavik)

  • lisinopril → most widely used (generic)

  • ramipril → best effect of remodeling

• adverse reactions:

  • cough → common in 25% of patients due to increased bradykinin in lungs

  • angioedema → swelling of lips and eyelids due to accumulation of bradykinin in tissues

  • hyperkalemia with potassium-sparing diuretics, increased creatinine or blood urea nitrogen, symptomatic hypotension

• contraindications:

  • history of angioedema, bilateral renal-artery stenosis, pregnancy

angiotensin I receptor blocers (ARBs)

block vasoconstrictor and aldosterone-secreting efects of angiotensin II by blocking angiotensin I receptor where angiotensin II acts

• candesartan (atacand), eprosartan (teveten), irbesartan (avapro), LOSARTAN (cozaar), olmesartan (benicar), TELMISARTAN (micardis), VALSARTAN (diovan)

  • losartan → most widely used (generic)

  • telmisartan / valsartan → best effect of remodeling

• will increase angiotensin II levels above baseline due to angiotensin 1 blckade, due to uncoupling a negative feedback loop

• adverse reactions:

  • headache, dizziness, hyperkalemia (if used with K-sparing diuretic), orthostatic hypotension, increased creatinine or blood urea nitrogen

• contraindications:

  • history of angioedema (although it does not increase bradykinin), bilateral renal-artery stenosis, pregnancy

summary of RAAS inhibitor side effects

• hyperkalemia → serum potassium concentration > 5.5 mEq/L

  • consequence of decreased aldosterone secretion and secondary renal potassium secretion into urine

  • dual RAAS inhibitors → increase frequency and severity

  • loop diuretics → can reduce hyperkalemia tendency

• pregnancy → absolute contraindication due to likelihood of fetal malformations (limbs) and defects (kidneys)

• angioedema and cough → unique to ACE inhibitors due to bradykinin, with angioedema occurring more common with ACE inhibitors

• kidney failure → possible with all agents, especially when renal blood flow and GFR (<50%) are compromised

calcium channel blockers

reduce systemic vascular tone by inhibiting Ca²⁺ influx through voltage-gated L-type calcium channels, causing less smooth muscle contraction

• non-dihydropyrimidines (major cardiac effects):

  • DILTIAZEM (benzothiazepine) → slows SA node firing to reduce heart rate, slows AV node conduction, modest negative inotropy

  • VERAPAMIL (phenylalkylamine) → slows SA node firing to reduce heart rate, moderate negative inotropy

    • not suitable for heart failure

  • half-lives of 2.5-7 hours; special formulations for once daily dosing

  • side effects:

    • heart failure → exacerbated from negative inotropy

    • constipation → major side effect of verapamil

    • reduce elimination / increased blood levels of carbamazepine (tegretol), simvastatin, atorvastatin, lovastatin

• dihydropyridines (negligible cardiac effects):

  • block L-type channels on vascular smooth muscle and cardiac myocytes to prevent excitation-contraction coupling and to decrease vasoconstriction (and HR/contractility)

  • direct vasodilation, minimal negative inotropy and heart rate effects

  • AMLODIPINE, felodipine, isradipine, NICARDIPINE, NIFEDIPINE, nisoldipine

    • amlodipine (generic) most commonly used, in combination formulas; gradual BP lowering with mild sympathetic stimulation

  • side effects:

    • leg edema → prominent with amlodipine, dose-dependent

      • mechanism — pre-capillary arteriolar dilation without venous dilation that increases capillary pressure

      • not treatable with diuretics, but ameliorated with concomitant ACE inhibitors / ARB

    • tachycardia → varies with degree of reflex sympathetic stimulation causing increased oxygen consumption

• side effects → ankle edema, headache, orthostatic hypotension

• contraindications:

  • cardiogenic shock, ventricular dysfunction, SA node or AV conduction disturbances, Wolfe-Parkinson-White arrhythmia

beta-blockers for hypertension (tier 2)

beta-blockers lower blood pressure by decreasing cardaic output and renin release

• selectivity:

  • selective → β₁ >> β₂ receptor blockade

    • ATENOLOL (tenormin), betaxolol (kerlone), bisoprolol (zebeta), METOPROLOL (lopressor, toprol XL)

  • non-selective → β₁ = β₂ receptor blockade

    • nadolol (corgard), PROPRANOLOL (inderal), timolol (blocadren)

• intrinsic sympathomimetic activity (ISA):

  • ISA → partial agonist and blocker, blunts bradycardia

  • non-ISA → majority of drugs, induces bradycardia

• vasodilating:

  • ⍺₁-receptor blockade → labetalol, CARVEDILOL (coreg; non-selective β)

  • nitric oxide stimulation → NEBIVOLOL

• side effects:

  • fatigue, exercise intolerance → major due to prominent effect on heart rate

  • dyspnea → at higher doses, β₁-cardiac specific drugs spill over onto β₂-bronchial receptors causing bronchospasm

  • heart block → most likely when given with non-dihydropyridines (verapamil, diltiazem) that also affect nodal function

  • peripheral vasoconstriction → ischemia in pre-existing peripheral vascular disease

  • metabolic → non-vasodilating beta-blockers impair glucose tolerance and may mask the effects of hypoglycemia

  • depression, insomnia, and nightmares → occur with use of propranolol; should switch to atenolol

    • less lipophilic and does not get into brain as well

• contraindications:

  • AV conduction block (with verapamil/diltiazem), bradycardia, cardiogenic shock, asthma/COPD

alpha-blockers for hypertension (tier 2)

• selective ⍺₁ blockers → PRAZOSIN, DOXAZOSIN, TERAZOSIN

  • mechanism — specific ⍺₁-receptor blockade to inhibit NE-mediated vasoconstriction

  • ancillary action — block smooth muscle contraction in prostate (⍺_1A), reducing symptoms of hypertrophy

    • tamsulosin is selective for ⍺_1A receptor but is ot used for treating hypertension; less likely to cause orthostatic hypotension because used to treat benign prostatic hyperplasia

  • side effects — postural hypotension (marked with first dose)

• non-selective ⍺ blockade → PHENTOLAMINE, PHENOXYBENZAMINE

  • usage — specifically for pheochromocytoma-associated hypertension from NE production (adrenal tumor)

direct vasodilators for hypertension (tier 2)

• HYDRALAZINE has exclusive arterial effect (opens arteries), with no venodilation

  • mechanism — inhibits IP₃-dependent Ca²⁺ release from vascular smooth muscle sarcoplasmic reticulum

  • co-therapy:

    • beta-blockers to blunt tachycardia

    • diuretic (often loop) to control ECF volume

  • target population:

    • blacks → high response rate

    • pregnancy → proven safety to fetus

  • side effects:

    • quick development of tolerance due to reflex sympathetic nerve activation that causes tachycardia (increased cardiac output) and ECF volume increase

    • lupus-like syndrome → complication related to high dose

• MINOXIDIL is most powerful anti-hypertensive drug used in resistant hypertensive as fourth or fifth drug

  • mechanism — inhibits IP₃-dependent Ca²⁺ release from vascular smooth muscle sarcoplasmic reticulum

  • side effects:

    • fluid accumulation → causes peripheral edema

      • pleural and pericardial effusions

    • hypertrichosis → hair growth; problematic in women of dark complexion

  • co-therapy:

    • must treat with loop diuretic and often with beta-blocker

central sympathoplegics for hypertension (tier 2)

lower blood pressure by decreasing sympathetic nervous system output

• ⍺₂ receptor agonist inhibits presynaptic NE release by decreasing presynaptic Ca²⁺, decreasing NE binding to smooth muscle ⍺₁ receptor that mediates vasoconstriction

• CLONIDINE is an ⍺₂ agonist (should never be used as first line therapy)

  • mechanism — decrease of NE discharge by central ⍺₂ receptors and imidazoline receptors

    • reduction in peripheral sympathetic tone → lowers arterial tone and BP

    • increase in peripheral parasympathetic tone → lowers heart rate

  • side effects:

    • rebound hypertension → sudden and sever rise in BP after missed doses of drug (administration by cutaneous patch)

    • drowsiness → very common

• METHYLDOPA is similar to clonidine but have high side effect profile

  • very common use in pregnancy due to high safety profile

  • side effects — dry mouth, dizziness, headache, GI distress, weight gain, joint swelling