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  • RAAS disturbances can play a large role in hypertension development
    • Beta-1 blockers inhibit sympathetic activation of kidney
    • Renin is produced in the JG cells of the kidney in response to hypoperfusion, B1 stimulation, renal artery stenosis, and diuretic use
      • Direct Renin inhibitors stop renin
    • Renin leaves the kidney to cleave angiotensinogen (made in the liver) into angiotensin I
    • Angiotensin Converting Enzyme (ACE) in the pulmonary capillary endothelium converts angiotensin I into angiotensin II and inactivates Bradykinin
      • Site of ACE Inhibitor action
    • Angiotensin II is a potent vasoconstrictor, also promotes aldosterone production in the adrenal cortex
      • Angiotensin II blockers inhibit Angiotensin II from working on the type 1 receptor on the vascular bed and the adrenal cortex
      • This prevents aldosterone production and vasoconstriction
    • Aldosterone acts on the principle cells of collecting ducts in the nephron to increase renal sodium and water absorption
      • Mineralocorticoid Receptor Antagonists prevent this
    • Therefore, any drug that blocks angiotensin II or aldosterone promotes natriuresis
      • Sodium resorption and vasoconstriction blockade decreases hypertension
    • The end result of RAAS activation is increased blood pressure, total body sodium and water, and blood volume

Angiotensin Converting Enzyme Inhibitors (ACEIs)

  • MOA: Inhibit the conversion of Angiotensin I to Angiotensin II
    • ATII (vasoconstrictor, stimulates aldosterone release)
    • Systemic arteriolar dilation, urine sodium loss, intravascular volume loss
  • Also inhibit bradykinin degradation, induce vasodilatory prostaglandin production, reduce SNS activity
    • Chronic nonproductive chough within 1 week of initiation or dosage increase (will be more delayed)
  • Reduce systemic BP and directly modify the permeability of the glomerular epithelium (decrease protein loss)
    • Lowering intraglomerular pressure and reducing protein excretion
      • Great for Hypertension + Protein CKD
    • Reduce the amount of aldosterone acting on DT, sodium loss
  • Slow the progression of diabetic nephropathy
  • Cardioprotective and reduce ventricular remodeling after ischemia
  • Use: Hypertension, decreasing urate load
  • SE: Cough, Hyperkalemia, Potential GFR reduction, Angioedema, skin rash
    • May decrease ATII-mediated constriction of the efferent arteriole
  • Lisinopril
  • Captopril
    • SE: Membranous glomerulonephritis
  • Enalapril
    • Useful in scleroderma renal crisis
    • CI: Pregnancy, acute MI, bilateral renal artery stenosis

Alpha-Adrenergic Blockers

  • General
    • Direct vasodilators used to treat hypertension, but do not affect angiotensin II or aldosterone concentrations or induce natriuresis
    • Alpha receptors are found on the distal ureter, base of the detrusor, bladder neck, and urethra
      • Activation stimulates them to maintain high muscular tone for normal urinary continence
  • Tamsulosin
  • Phentolamine

Angiotensin II Receptor Blocker (ARBs)

  • General
    • Bind zona glomerulosa receptors in the kidney to prevent angiotensin II from inducing expression of aldosterone on angiotensin receptors
    • Do not decrease Angiotensin II levels, but do cause natriuresis and decreased aldosterone production
  • Valsartan (Diovan)

Beta-Adrenergic Receptor Blockers (BBs, Beta Blockers)

  • MOA:
    • Beta-1 blockers block sympathetic stimulation of the JG apparatus in the kidney
    • Reduce BP by decreasing sympathetic stimulation of the heart
      • Decreases HR, lowers SV, reduces arterial pressures
  • Use: Should be given to all patients who have had an MI or who have HF
    • Reduce ischemia-induced remodeling by lowering HR and thus myocardial oxygen demand
    • Also used in AFib for rate control
  • Metoprolol
    • Cardio-selective BB used In CHF
    • SE: asthma, impotence, masks hypoglycemia, heart block
  • Beta-Blocker Toxicity (BB Toxicity)
    • Symptom Onset: 2-6 hours after ingestion
    • Hypotension, Bradycardia, Bronchospasm, AMS, Seizures
      • Wheezing is relatively specific
      • 1st degree AV block
    • Hypoglycemia, Prolonged PR, Bradycardia, Normal Pupils
    • Management
      • Secure airway, GI decontamination, IV Fluid boluses, IV Atropine, IV Glucagon
      • IV Calcium, epinephrine or norepinephrine, IV lipid emulsion all can be used in conjunction

Direct Renin Inhibitors

  • Aliskiren
    • Increases natriuresis and decreases serum angiotensin II, decreasing aldosterone production

Calcium Channel Blockers (CCBs)

  • Vasodilation occurs as a result
  • 2 groups:

Non-Dihydropyridine (NDHP) CCBs

  • Do not have the same peripheral vasodilatory properties
  • Verapamil
  • Diltiazem

Dihydropyridine (DHP) CCBs

  • Peripherally in arteries to decrease BP
    • No effect on heart, may cause reflex HR increase
    • Peripheral Vasodilation
    • Peripheral edema
      • due to preferential dilatation of precapillary vessels (arteriolar), increases hydrostatic pressure
    • May cause reflex tachycardia and enhance ventricular contraction increasing aortic wall stress (give BB first)
  • Amlodipine
  • Clevidipine
    • CI: Severe Aortic Stenosis, Soy allergy, egg allergy, hyperlipidemia, lipoid nephrosis, acute pancreatitis
  • Nicardipine
    • CI: Severe Aortic Stenosis
  • Nifedipine
    • SE: headache, peripheral edema, bradycardia, constipation, flushing
      • Amiodarone Pulmonary Fibrosis
    • Calcium Channel Blocker Toxicity
      • Bradycardia, hypotension, Hyperglycemia
      • No AMS (unlike BB Toxicity)
      • Treatment
        • IV Glucagon

Sulfonamide Diuretics

Carbonic Anhydrase Inhibitors

  • Acetazolamide (Diamox)
    • Works on proximal tubule of the kidney
      • Inhibits the production and reabsorption of filtered bicarbonate
    • Use: Diuretic, urinary alkalization, metabolic alkalosis, glaucoma, intracranial hypertension, altitude sickness
    • SE: Sulfa allergy, hyperchloremic metabolic acidosis, hypokalemia
      • Ammonia Toxicity, Neuropathy

Loop Diuretics

  • MOA: Blocks Na+-K+-2Cl- symporter in the thick ascending loop of Henle
    • Induce natriuresis, but decreased blood volume stimulates renin release that increases angiotensin II and aldosterone
    • Decrease urate excretion by increasing net urate reabsorption
      • Either enhanced reabsorption or reduced secretion
    • Use: Volume overload, CHF, edema
    • SE: Gout
  • Furosemide (Lasix)
    • Loop diuretic used in pulmonary edema, hypertension, nephrotic syndrome and congestive heart failure
    • SE: Gout (elevated uric acid), ototoxicity, allergy (sulfa), hypokalemia, alkalosis, dehydration, hypocalcemia, hypomagnesemia, interstitial nephritis
  • Bumetanide (Bumex)
    • SE: Allergy (sulfa)
  • Etacrynic Acid (Edecrin)
    • Not a sulfonamide, only loop diuretic that isn't
  • Indacrinone
    • Decreases reabsorption of uric acid
    • Uses: Gout, hypertension
  • Torsemide (Demadex)

Thiazide Diuretics

  • MOA: Inhibit the reabsorption of Na+ and Cl- from the distal convoluted tubule, blocks Na-Cl symporter
    • Intravascular volume depletion via diuresis reduces peripheral vascular resistance
    • Indirectly increases the basolateral Na+/Ca2+ antiporter
    • Use: essential hypertension, edema, CHF, Nephrogenic DI, osteoporosis
    • SE: hyperGLUC (glucose, lipids, uric acid, calcium), Allergy, Gout
      • Dose-dependent hypokalemia, hyponatremia, Metabolic Alkalosis
      • Give oral potassium supplements or potassium sparing diuretic (spironolactone)
  • Hydrochlorothiazide
  • Chlorothiazide (Diuril)

Thiazide Like Diuretics

  • MOA: Primarily work on the DCT
  • Clopamide
    • Selectively binds chloride binding site of Na-Cl symporter in the PCT on the luminal side
    • Equi-osmolar excretion of water with NaCl
  • Chlorthalidone
  • Indapamine
  • Metolazone
    • Remains active even when GFR ≤30-40

Potassium-Sparing Diuretics

  • General
    • Work on the Collecting Tubule of the nephron

Epithelial Sodium Channel Blockers (ENaC Channel)

  • Amiloride
  • Triamterene
  • Benzamil

Mineralocorticoid (Aldosterone) Receptor Antagonists

  • MOA: Renal Cortical Collecting Duct aldosterone receptor blocker
    • Competitive inhibitors of aldosterone receptors, only active in the presence of aldosterone
    • Therefore aldosterone, renin, angiotensin I and II will be elevated
    • SE: Hyperkalemia, gynecomastia, decreased libido, breast tenderness, menstrual irregularities
  • Spironolactone (Aldactone)
    • Spironolactone also blocks progesterone and androgen receptors
    • More side effects, but preferred
    • SE: Hyperkalemia, Gynecomastia, Amenorrhea, Other anti-androgen effects
  • Eplerenone (Inspra)
    • Very selective mineralocorticoid antagonist
    • Low affinity for progesterone or androgen receptors
    • Fewer side effects, less effective

Osmotic diuretics

  • Mannitol
    • Increases tubular fluid osmolarity (increasing urine flow)
    • Use: Intracranial pressure
    • SE: Pulmonary edema, intravascular dehydration
  • Glycerol
  • Urea

Vasopressin Receptor Inhibitors

  • Vaptans
  • Demeclocycline

Direct Arterial Vasodilators

  • Hydralazine
    • May increase myocardial contractility
    • SE: Hypotension, reflex tachycardia, palpitations, dyspnea, hemolytic anemia, diaphoresis, lupus-like reaction, Drug associated autoimmune vasculitis
    • CI: Mitral valve rheumatic heart disease
  • Minoxidil

Peripheral Selective Alpha 1- blockers

  • Doxazosin (Cardura)
  • Prazosin