Antihypertensives

Categories: Cardiovascular-Renal

  • Physiology
    • RAAS disturbances can play a large role in hypertension development
      • Beta1 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, diuretic use
        • Direct Renin inhibitors stop renin
      • Renin leaves the kidney to cleave angiotensinogen (made in the liver) into angiotensin I
      • Angiotensin Converting Enzyme in the pulmonary capillary endothelium converts angiotensin I into angiotensin II and inactivates Bradykinin
        • ACE Inhibitors
      • 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
    • Tamsulosin
    • Phentolamine
    • 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
  • Angiotensin II Receptor Blocker (ARBs)
    • Drugs: Valsartan
    • 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
  • Beta-Adrenergic Receptor Blockers (BBs, Beta Blockers)
    • MOA:
      • Beta1 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
        • Does 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
      • Hydrochlorothiazide
      • Chlorothiazide (Diuril)
      • 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)
    • 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

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