Cardio/Pulm/Renal

Comp 2
1 – Embryology Genitourinary System
 Embryology
 Intermediate mesoderm  kidneys
 Pronephros  mesonephros  metanephros
 Pronephros = primitive and never develops into functional structures
 Caudal end of mesonephric duct fuses with cloaca
 Mesonephric kidney is functional in weeks 6-10
 Intermediate mesoderm of mesonephros connects to mesonephric duct
 Wolffian duct = mesonephric duct
 Mullerian duct = paramesonephric duct
 Metanephric kidney (day 28)
 Ureteric buds branch from mesonephric ducts  interact with metanephric
blastema
 Metanephric blastema signals  ureteric buds branch/grow  blastema
forms tubules
 Ureteric bud (collecting portion) = ureter, renal pelvis, major/minor calyces,
collecting ducts, collecting tubules
 Metanephric blastema (excretory) = bowman’s capsule, PCT, loop of Henle, DCT
 Functional in week 10
 Mesonephric kidney is incorporated in repro system of males
 Female embryo stages:
 Early:
 Distal urinary, repro, and GI tracts have common opening
 Anterior out pouching towards genital tubercle = allantois
 Later:
 Urogenital system is separated from distal GI tract by urorectal septum
 Cloaca = urogenital sinus + anorectal canal
 Urogenital sinus = urethra and bladder
 Distal portion of mesonephric ducts become incorporated into posterior wall of
cloaca (extrophy)  trigone of bladder
 Pathologies
 Imperforate anus
 Dysfunction of urorectal septum
 Rectum opens into urinary or repro tract; or ends in blind pouch
 VACTERL: vertebral anomalies, anal atresia, CV abnormalities,
tracheoesophageal fistula, esophageal atresia, renal anomalies, limb defects
 Hydronephrosis
 Fluid filled enlargement of kidneys
 Obstruction most commonly in ureteropelvic junction of ureters
 Renal Agenesis
  Ureteric bud fails to contact the metanephric blastema  kidney does not
form
 Unilateral  remaining kidney hypertrophies
 Bilateral  severe oligohydramnios
 Oligohydramnios
 Insufficient amounts of amniotic fluid
 Potter sequence: deformed limbs, dry skin, abnormal facies
 Pulmonary hypoplasia
 Polyhydramnios
 Excess accumulation of amniotic fluid
 Caused by lack of fetal swallowing or maternal diabetes mellitus
 Horseshoe Kidneys
 Fusion of right and left metanephroi near midline
 Prevented from reaching abdominal location (b/c of inferior mesenteric artery)
 Inc. risk for UTIs and kidney stones
 Pelvic Kidney
 Ectopic kidney
 Failure of one kidney to ascend
 Functions normally

2 – Anatomy and Histology Genitourinary System

 Renal Cortex
 90% of blood supply
 Renal corpuscles, convoluted tubules, straight tubules, collecting tubules, blood
vessels
 Renal Medulla
 10% blood supply (hypoxic)
 Straight tubules, collecting tubules, vasa recta
 Renal columns separate pyramids
 Apex of Medulla
 Aka papilla
 Empty into calyx
 Nerve Supply
 Sympathetic fibers form renal plexus  contraction of vascular smooth muscle
 Lymphatics
 Two networks:
 Along outer regions of cortex  drains into larger lymph vessels in capsule
 Deeper in kidney  drains into larger lymph vessels in renal sinus
 Renal Corpuscle
  Glomerulus, visceral epithelium (podocytes), parietal layer (lines bowman’s
capsule), and mesangial cells
 Glomerular Filtration
 3 components:
 Endothelium – fenestrated
 Glomerular basement membrane
 Lamina rara interna (vascular endothelium side), lamina densa, lamina
rara externa (podocyte side)
 Podocytes – slit diaphragm acts as sieve
 Mesangial Cells
 Phagocytosis/endocytosis
 Structural support
 Secretion (IL-1, PGE2, PDGF)
 Nephron Segments
 Proximal Convoluted Tubule
 Reabsorption: Na+/K+ ATPase pumps, AQP1
 Also glucose, aa’s, small polypeptides, bicarb
 Cuboidal epithelium with brush border
 S1, S2, S3 (susceptible to kidney injury)
 Proximal Straight Tubule
 Less developed brush border and not as specialized for reabsorption
 Thin segment of Loop of Henle
 Thin descending: highly permeable to H2O, no active transport, less
permeable to Na+ and urea, isosmotic ultrafiltrate
 Thin ascending: mostly impermeable to H2O, highly permeable to Na+ and Cl,
hyposmotic ultrafiltrate
 Distal Straight Tubule
 Ion transport
 Reabsorbs Mg2+ and Ca2+
 Contains macula densa cells; meets back up with glomerulus
 Macula densa and Juxtaglomerular Apparatus
 Macula densa monitor Na+ and filtrate volume
 JGA cells contain renin
 Renin-angiotensin-aldosterone system (RAAS)
 Distal Convoluted Tubule
 Highest Na+/K+ ATPase activity in nephron
 Relatively impermeable to H2O
 Reabsorbs: Na+, Cl-, bicarb
 Secretion: K+, ammonium, H+
 Collecting Tubules and Ducts
  Cuboidal epithelium
 Principle (light) cells: predominant cell type
 AQP2 regulated by ADH
 Intercalated (dark) cells
 Secrete H+ or bicarbonate; no cilia
 Ureter and Urinary Bladder Layers
 3 layers:
 Mucosa (transitional epithelium; impermeable to salt and H2O)
 Muscularis
 Adventitia
 Ureter Anatomy
 Transitional epithelium
 Peristalsis
 3 sites of constriction  risk of kidney stones
 Urinary Bladder
 Below peritoneum
 Trigone: triangular regions of openings
 2 ureteric orifices and one internal urethral orifice
 Distension: relaxed  10 cell layers; distended  3 cell layers
 Urethra Anatomy/Histology
 Males (~20cm)  3 segments: prostatic, membranous, spongy
 Females (3cm)

3 – Physiology Renal Function

 Endocrine of Kidney
 Erythropoietin (EPO) = regulator of proliferation of erythroid progenitors
 90% produced in peritubular interstitial cells
 Renin = initiates enzymatic cascade generating angiotensin peptides
 Rate limiting enzyme of RAAS
 Produces angiotensin II from angiotensin I
 Ang II = powerful vasoconstrictor
 JGA cells = primary site of renin storage/release
 Associated with afferent arteriole
 Vitamin D = promotes Ca2+ conservation in body by increasing intestinal Ca2+
absorption and reducing urinary Ca2+ loss
 Produced by action of UV on skin
 Active form = 1,25(OH)2 vit D (calcitriol)
 Synthesis in proximal tubules
 Conversion is under control of PTH
 Nephron Segments
  Cortical nephrons: 85% of total #
 Juxtamedullary nephrons: 15% of total #
 Salt and water reabsorption
 Filtration Barrier
 3 layered glomerular filtration barrier:
 Endothelial cells
 Capillary basement membrane
 Podocytes
 Renal Blood and Plasma Flow
 Kidneys receive approx. 25% of cardiac output
 Glomerulus filters about 15-20 of renal plasma flow
 Renal Blood Flow (RBF):
 One of primary determinants of GFR
 RBF = (cardiac output) x (% to kidney (25%))
 Renal Plasma Flow (RPF)
 Fraction of plasma filtered by glomeruli
 RPF = RBF x (1 – Hct)
 Glomerular Filtration Rate (GFR)
 Determinant of renal function
 Determined by:
 Hydraulic permeability of capillaries
 Surface area (SA)
 Net filtration pressure (NFP)
 GFR = hydraulic permeability x SA x NFP
 NFP = (PGC – PBS) – (πGC – πBS)
 Filtration of Proteins and Peptides
 Filtrate not truly free of all protein
 Smaller proteins (insulin, GH)
 Larger proteins movement is limited (albumin)
 Large proteins  endocytosis at apical membrane of proximal tubules
 Small peptides  catabolized into aa’s by BB peptidases
 Aa’s reabsorbed into PCT cells
4 – OMM ANS, Vicerosomatic Reflexes, and
Chapman’s Points
***SEE SLIDES

5 – Physiology Regulation of Renal Filtration

 Role of SNS and RAAS
 Afferent and efferent arterioles are supplied with sympathetic neurons
 Vascular  alpha1 recepter
 Large increases in SNS activity  constriction   GFR   Na+ and H2O
excretion
 3 primary regulators of renin
 SNS: beta1 receptors  stimulate renin release
 Pressure in AA
 Macula densa
 Regulation of GFR and RPF
 Afferent arteriole
 Constriction   RPF, PGC, GFR
 Dilation  RPF, PGC, GFR
 Efferent arteriole
 Constriction  RPF, PGC, GFR
 Dilation  RPF, PGC, GFR
 Afferent and efferent constricted (resistance )
 PGC does not change, GFR, RPF
 Afferent and efferent dilated (resistance )
 PGC does not change, GFR, RPF
 Autoregulation
 Hypertensive damage of glomerular capillaries if pressure is too high
 Change in arterial pressure  change in resistance
 Myogenic Mechanism:
 Fast acting, protects glomeruli short term
 Increase stretch  contraction of VSM
 GFR, RPF
 blood pressure  resistance
 Tubuloglomerular feedback (TGF)
 High GFR  flow and Na+ delivery to macula densa
 Ca2+IC  renin
 Low flow/Na+  release of NO/PG’s
 Renal Clearance
 Removal of substance from plasma and excreted in the urine
 Possible to have greater renal clearance than GFR
 Ex: PAH is filtered 20% and secreted 80%
 Clearance > GFR  net secretion
 Clearance < GFR  net reabsorption
 GFR and Creatinine
 Body produces creatinine at constant rate
  Filtered 90%, secreted 10%
 Plasma creatinine is used as indicator of GFR

6 – Physiology Proximal Tubule 1

 Transepithelial Transport
 Crossing 2 cell layers: tubular epithelium and vascular epithelium
 Cortex  fenestrated endothelium; medulla  some regions are fenestrated
 Crossing tubular epithelium:
 Paracellular transport = Goes substances around cells
 Transcellular transport = 2 step process through cells
 Epithelial Cell Properties
 Diffusion:
 Requires concentration gradient; paracellular and transcellular
 Channels: small pores
 Symporters: cotransporters, same direction
 Uniporters: single species; requires solute to bind to specific site
 Antiporters: exchangers; different directions
 Primary active transporters: against electrochemical gradients
 Structures
 Apical membrane: microvilli
 Basolateral membrane: membrane infoldings
 Direct link between ATP-generating mitochondria and ATP-utilizing
membrane Na+/K+-ATPase
 Tight junctions: leaky; allows substantial paracellular water and solute movement
 Epithelial Transport Basics
 Primary active transporters (ex: Na+/K+-ATPase)
 Saturation kinetics (Vmax)
 Secondary active transporters (ex: Na+/glucose)
 Saturation kinetics (Vmax)
 Passive transporters (fascilitated)
 Saturation kinetics
 Filtration and simple diffusion
 Linear kinetics, no saturation
 Proximal Convoluted Tubule
 Major reabsorptive segment of nephron
 S1 (early PCT), S2 (late PCT), and S3 (proximal straight tubule)
 Early PCT (S1):
 Na+ reabsorbed with phosphate or organic solutes
 Impermeable to Cl-
 Large electrochemical (negative) gradient
  Late PCT (S2):
 Paracellular Cl- permeability increases
 Loss of negative gradient, generation of positive gradient
 Enhances paracellular Na+ reabsorption
 Proximal Tubule Transport
 Lumen to intercellular  multiple secondary transporters mediate Na+
reabsorption
 Intercellular to interstitial  Na+/K+-ATPase
 Drive reabsorption of water down osmotic gradient by transcellular (primary) and
paracellular routes
 Regulation of Sodium Excretion
 Angiotensin II binds to AT1 receptor  Na+ reabsorption
 NE binds to receptor  Na+ reabsorption

 Hyponatremia
 Isotonic hyponatremia
 Increase in plasma solids (excess in lipids or proteins)
 Hypertonic hyponatremia
 Hyperglycemia causes water to move from ICF to ECF (plasma osmolarity
does not increase)
 Hypotonic hyponatremia
 Hypovolemic
 Decrease in ECV causes increase in ADH
 Non-renal: vomiting, diarrhea, sweating, burns
 Renal: inappropriate loss of Na+ or Cl-
 Euvolemic
 Ectopic ADH (SIADH), CNS disorders, head trauma, pulmonary disease,
drug side effects
 Hypervolemic
 Edematous disorders
 Renal failure

36 – Diuretics Part 1
 Carbonic Anhydrase Inhibitors
 Acetazolamide
 PK: IV, oral, crosses BBB, secretion in proximal tubule (site of action)
 MOA: inhibitor of carbonic anhydrase
 Effects:
 Na+, bicarbonate, and water excretion
 Weak diuretic b/c increased Na+ Cl- to loop of henle  reabsorption
 Increased solutes to macula densa  triggers TGF  afferent arteriole
resistance  RBF and GFR
 Loss of bicarb  hyperchloremic metabolic acidosis
  Uses: open angle glaucoma (intraocular pressure), urinary alkalinization,
metabolic alkalosis, acute mountain sickness, epilepsy, edema (low efficacy)
 AEs: metabolic acidosis, calcium phosphate renal stones (precipitates in alkaline
urine), hypokalemia, sulfonamide allergies
 Contraindications: hypersensitivity, cirrhosis
 Drug interactions: topiramate and zonisamide have weak CA inhibitory actions 
contributes to acid/base disorders and renal stones
 Loop Diuretics
 Furosemide and Ethacrynic Acid (used if there is sulfa allergies)
 MOA: NCCK2 inhibitors (in TAHL)
 Highly efficacious diuretics
 Effects:
 NaCl excretion, Mg2+ and Ca2+ excretion, K+ excretion, uric acid
excretion (hyperuricemia  gout)
 Diuretic Braking Phenomenon: Na+ to macula densa and volume depletion
 renin release  Na+ reabsorption  diuretic resistance
 Uses: acute pulmonary edema, HF, nephrotic syndrome, CKD, ascites of liver
cirrhosis, hypertension, hypercalcemia, drug overdose
 AEs: hyponatremia, hypokalemia, metabolic alkalosis, hypomagnesemia, sulfa
allergies, hyperuricemia, ototoxicity (more for ethacrynic acid)
 Avoid in pregnancy

37 – Diuretics Part 2
 Thiazide Diuretics
 Hydrochlorothiazide
 MOA: NCC inhibitors (in DCT)
 Moderate diuretic efficacy
 Effects:
 Ca2+ excretion (vs. loop diuretics), Mg2+ excretion
 Urinary dilution
 Uses: HF, hepatic cirrhosis, nephrotic syndrome, chronic renal failure, acute
glomerulonephritis, hypertension, nephrolithiasis (Ca2+ excretion),
nephrogenic diabetes insipidus, osteoporosis (proposed)
 AEs: hypotension, hyponatremia, hypokalemic metabolic alkalosis,
hypomagnesemia, hypercalcemia, hyperuricemia/gout, hyperglycemia,
hyperlipidemias, sulfa allergies
 Drug interactions:
 risk of digitalis with hypokalemia (arrhythmia)
 Na+ excretion  Li+ reabsorption  lithium toxicity
 Vitamin D  hypercalcemia
 Potassium Sparing Diuretics
 ENaC inhibitors  amiloride, triamterene
 Pharmacogenomics: T594M polymorphism in ENaC  sensitivity to
amiloride
 Used with thiazide diuretic to enhance diuresis and counteract K+ loss by
thiazides (rarely used alone for edema or hypertension)
  Uses: Li+ induced nephrogenic DI, Liddle syndrome
 AEs: hyperkalemia (also with hypoaldosteronism and NSAIDs)
 Mineralocorticoid receptor inhibitors (aldosterone antagonists)  spironolactone,
eplerenone
 Uses: edema, hypertension, HF following MI, hepatic cirrhosis
(spironolactone is drug of choice), hirsuitism in women, hyperaldosteronism
 AE: hyperkalemia, gynecomastia, impotence, avoid in 1st trimester of
pregnancy
 Osmotic Diuretics
 Mannitol
 Uses: acute increase in intracranial pressure w/ edema or intraocular pressure,
adjunct to cisplatin (minimize nephrotoxicity)
 AEs: HF, hyponatremia, dehydration, nephrotoxicity (stress on nephrons),
pulmonary edema

38 – Abnormal Pulmonary Exam

 Chronic Obstructive Pulmonary Disease (COPD)
 Distal spaces enlarge and lungs become hyperinflated
 Destruction of alveolar septa and obstruction (limitation of expiratory air flow)
 Barrel chest
 Emphysema = caused by smoking or alpha1 antitrypsin deficiency; pursed lip
breathing
 Chronic bronchitis = productive cough >3 months in a year for >2 years
 Chest Shapes
 Pigeon chest
 Funnel chest
 Thoracic kyphoscoliosis  restrictive lung disease
 Barrel chest  COPD
 Traumatic flail chest  multiple rib fractures
 Terminology
 Retraction = chest wall drawing back
 Pleurisy = inflammation of pleura
 Pitch = highness or lowness of sound
 Resonant = producing a loud, clear, deep sound
 Hyper-resonant = very loud resonant
 Percussion  flatt, dull, tympanic
 Pneumothorax
 When air leaks into pleural space u/l  lung recoils from chest wall
 Pleural air blocks transmission of sounds
 Could hear pleural rub (crackles on both inspiration and expiration)
 Tension pneumothorax = deviated trachea; emergency
 Auscultation
 Egophany  normal is EE, abnormal is AA
 Bronchophony  normal is ninety nine transmitted muffled
 Whispered pectoriloquy  normally heard faintly
 Vesicular, broncho-vesicular, bronchial, tracheal
 Bacterial Pneumonia
 Acute inflammation of bronchioles to alveoli
 Chills, high fever, dyspnea, and chest pain
 Tactile fremitus increased
 Late inspiratory crackles
 Consolidation = alveoli will fill with fluid or blood cells
 Abnormal bronchophony
 Pneumonia, pulmonary edema, pulmonary hemorrhage
 Adventitious Sounds
 Crackles/Rales = when small airways that are deflated in expiration open during
inspiration; air bubbles flowing through secretions of mild closed airways
 Discontinuous
 Fine: soft, high-pitched
 Coarse: louder, lower in pitch
 Early inspiratory  chronic bronchitis, asthma
 Late inspiratory  pneumonia, heart failure
 Wheezes = air flows rapidly through narrowed bronchi
 Asthma, COPD, bronchitis
 Typically heard in expiration
 Continuous, musical
 High pitched with hissing/shrill quality
 Rhonchi = secretions in larger airways
 Chronic bronchitis
 Continuous
 Low pitched with snoring quality
 Stridor = partial obstruction of larynx or trachea
 Typically heard in inspiration
 Emergency
 Asthma
 Widespread narrowing of tracheobronchial tree
 Air flow decreases further and lungs hyperinflate
 Reversible obstruction
 Pleural Effusion
 Dull percussion, decreased tactile fremitus
 Fluid in the pleural space
 Fluid blocks transmission of sounds
 Spirometry
 Forced vital capacity (FVC) = volume of air exhaled from a full lung to maximal
expiration
 Reduced in restriction
 Forced expiratory volume 1sec (FEV1) = amount of air exhaled forcefully in the
first second
 Reduced in obstruction
 Restrictive Lung Disease
 Caused by effort, structural abnormality (obesity, scoliosis), interstitial lung
diseases
  Short shallow breathing

39 – Antihypertensive Agents 1
 Angiotensin Receptors
 AT1 receptors: Gq  PLC activation  cytosolic Ca2+ and stimulates PKC
 AT2 receptors: Gi  cAMP  antagonize growth effects, open K+ channels,
close T-type Ca2+ channels, NO production  cGMP  vasodilation
 JNC8 Recommended Initial Monotherapy
 Thiazide diuretics
 Calcium channel blockers (long acting  dihydropyridine)
 ACE inhibitors
 ARBs
 Angiotensin Converting Enzyme Inhibitors (ACEIs)
 Captopril, enalapril/enalaprilat, lisinopril
 Enalaprilat is an active IV form (enalapril in inactive oral)
 ACE inhibitors are prodrugs (except captopril and lisinopril); peptides
 MOA: competitive inhibition of ACE
 PKs: hepatic esterases activate prodrugs (exception is captopril  50%
metabolized by CYP2D6)
 Renal excretion of unchanged active drug
 Mechanisms:
 Lower blood pressure by:
 Inhibit AngII direct vasoconstriction  peripheral vascular resistance
 Na+ and water excretion and aldosterone secretion
 Renal effects:
 Vasodilation of afferent and efferent renal arteriole  GFR
 Severe GFR  acute kidney injury
 Reduced aldosterone secretion  K+ reabsorption
 Hyperkalemia risk factors: renal insufficiency, diabetes, elderly, K+ sparing
drugs
 ACE inhibition  bradykinin  dry coughing
 ARBs don’t affect bradykinin
 ACE reduce effects of AT1 and AT2 receptors
 ARBs are selective for AT1 receptor
 Uses: Hypertension, post-MI, HF w/ reduced EF, CKD, diabetes mellitus type 1
and 2 (slow the rate of diabetic nephropathy progression)
 AEs: hypotension (ARBs more severe), reduced GFR, hyperkalemia, cough
(ARBs less severe), angioedema (assoc. w/ bradykinin  vasodilation),
enteropathy
 Absolutely contraindicated in all trimesters of pregnancy
 fetal lung function  oligohydramnios
 Drug interactions:
 ACEI and ARB concominant therapy not recommended
 Aliskiren  hyperkalemia and hypotensive effects
 Hyperkalemia associated with diuretics and NSAIDs
 Angiotensin II AT1 Receptor Blockers (ARBs)
  Losartan, valsartan
 Non-peptides
 PK: 1x daily dosing for most ARBs; losartan has renal and biliary excretion,
valsartan has only biliary excretion
 MOA: selective competitive inhibitors of AT1; unblocked AT2 receptors 
augmented hypotensive effect
 Lowers blood pressure same way
 Same renal effects
 Same uses
 Same AEs (ARBs have more hypotension and less cough)
 Contraindicated in pregnancy
 Direct Renin Inhibitor
 Aliskiren
 PK: 3% bioavailability, but potency maintains duration of effect
 MOA: potent competitive inhibitor of renin
 Uses: Hypertension (JNC8 does not recommend for initial treatment)
 AEs: same as ACEIs and ARBs
 Contraindicated in pregnancy
 Drug interactions: strong CYP3A4 inhibitors, p-gp inhibitor increase aliskiren
systemic levels (itraconazole and cyclosporine)
 Contraindicated in patients with diabetes mellitus taking ACEI or ARB 
renal impairment, hypotension, hyperkalemia

40 – Antihypertensive Agents 2
 L-Type Calcium Channel Blockers (CCBs)
 PK: CYP3A4
 Non-DHP: verapamil, diltiazem
 DHP: nifedipine, amlodipine (long half life)
 2nd on JNC8 list
 Nifedipine extended release  less reflex tachycardia
 Amlodipine  minimal peaks and troughs
 Less reflex tachycardia
 Bind to main pore-forming (α1) subunit
 MOA: CCBs act from the inner side of the membrane  freq. of opening of
Ca2+ channel in response to depolarization
 DHPs and non-DHPs  long lasting smooth muscle relaxation
 Non-DHPs only  contractility throughout the heart, SA node pacemaker
rate and AV node conduction velocity
 Uses: hypertension (all CCBs), angina (most CCBs), supraventricular
tachyarrhythmias (verapamil, dilitazem), raynaud’s phenomenon, migraine,
subarachnoid hemorrhage, tocolytic
 AEs: peripheral edema (most common; caused by vasodilation), immediate
release effects (headache, flushing, dizziness, reflex symp. activation), GERD
 Non-DHP contraindications: risk of AV block and/or severe depression of
ventricular function
 Nifedipine immediate release not for acute anginal episodes
  Drug interactions:
 Verapamil  digoxin levels and toxicity
 CCB + quinidine  excessive hypotension
 Beta Blockers
 Competitive antagonists of NE and Epi
 β-receptors are Gs
 Blocking cardiac beta1  slows HR and AV conduction
 Blocking renal beta1  inhibits renin release
 Non-selective 1st generation: propranolol
 Beta1 selective: esmolol, metoprolol
 Non-selective w/ additional actions: carteolol, carvedilol, labetalol
 Carteolol: NO production, beta2 agonism
 Labetalol: alpha1 receptor antagonism
 Carvedilol: alpha1 receptor antagonism, Ca2+ entry blockade, antioxidant
activity
 Beta blockers good with hypertensive patients with ischemic heart disease, CHF,
certain arrhythmias, hyperthyroidism, and glaucoma
 MOA for hypertension: CO and BP
 MOA for ischemic heart disease: chronotropic effect, inotropic effect, arterial
blood pressure  myocardial O2 consumption
 MOA for CHF: unstable tachyarrhythmias, attenuation of sustained symp.
activation, and reduced remodeling (LV chamber size and EF)
 MOA for arrhythmias: reduced heart rate, intracellular Ca2+ overload, inhibit
depolarization-mediated automaticity, AV nodal conduction time, prolong AV
nodal refractoriness
 MOA for hyperthyroidism: reduce increased number of beta receptors and
controls pulse rate, hypertension, and atrial fibrillation in thyroid storm
 MOA for glaucoma: intraocular pressure by production of aqueous humor
and ocular blood flow
 Helps situational performance anxiety (stage fright)
 AEs: excessive bradycardia, peripheral vascular insufficiency (b/c of
vasodilation), asthma/COPD exacerbation, delayed recovery from insulin-
induced hypoglycemia (b/c of inhibition of beta2 mediated hepatic glycogenolysis
and gluconeogenesis  less sugar in serum  less ability to recover from
insulin), insulin sensitivity and plasma VLDL/LDL, release of free fatty
acids, CNS effects, libido
 Withdrawal syndrome: nervousness, tachycardia, BP, intensity of angina
 Good for pregnancy

42 – Antihypertensive Agents 3
 Alpha Blockers
 Prazosin, terazosin, doxazosin
 Alpha1 is Gq  vasoconstriction
 MOA: Selective competitive antagonists of alpha1 receptors  preload and
afterload (venous return and peripheral resistance)
  Diuretics and beta blockers are given with vasodilators to counteract
compensatory responses (salt and water retention and reflex tachycardia)
 Effects: BP, orthostatic hypotension (first dose effect, take at bedtime),
tachycardia
 Non-cardiac effects: miosis, nasal stuffiness, resistance to urine flow (for
benign prostatic hyperplasia)
 Uses: refractory hypertension, urinary retention secondary to prostatic
hyperplasia
 AEs: orthostatic hypotension/syncope, IFIS, blurred vision, nasal congestion,
rhinorrhea, reflex tachycardia
 Centrally Acting Sympatholytics
 Alpha2 agonists  clonidine, methyldopa
 Alpha2 is Gi
 Postsynaptic  inhibits activity of those neurons; presynaptic  reduce NE
release
 Clonidine MOA: directly activates alpha2 receptors
 Methyldopa MOA: taken up into presynaptic vesicles  converted to methyl-NE
 replaces NE in secretory vesicle  false transmitter
 Effects: reduced sympathetic outflow from CNS  HR, myocardial
contractility, renal vascular resistance (maintains RBF, GFR)
 Spinal effect for pain relief (epidural clonidine)
 Clonidine uses: refractory hypertension, ADHD, pain management, glaucoma
(topical), menopause, substance withdrawal
 AEs: sedation, dry mouth, bradycardia, orthostatic hypotension, sexual
dysfunction, CNS depression, vivid dreams
 Methyldopa specific AEs: parkinsonism, hyperprolactinemia, hepatotoxicity,
hemolytic anemia, lupus-like syndrome
 Sudden withdrawal  catecholamine surge
 Direct Vasodilators
 Oral: hydralazine, minoxidil
 Paraenteral: nitroprusside, fenoldopam
 Nitroprusside:
 PK: NO + CN-
 Large exposures  cyanide toxicity
 MOA: activates guanylyl cyclase via release of NO or direct stimulation from
enzyme  cGMP  vascular smooth muscle relaxation
 Uses: acute hypertension, acute decompensated heart failure
 AEs: excessive hypotension, cyanide toxicity (tx: sodium thiosulfate)
 Hydralazine:
 Relaxes vascular smooth muscle, mechanism not defined
 Dilates only arterioles
 Pharmacogenomics:
 Slow acetylators  antinuclear Ab and lupus like syndrome
 Fast acetylators  more prone to inadequate therapeutic response
 Uses: HF with reduced EF, hypertensive emergency in pregnancy and
postpartum
  AEs: lupus like syndrome
 Minoxidil:
 MOA: Mediates opening of KATP channels in smooth muscle membranes of
arterioles  hyperpolarization  relaxation of smooth muscle
 Dilates only arterioles
 AEs: reflex tachycardia, hypertrichosis
 Fenoldopam:
 MOA: dopamine D1 agonist  relaxation of vascular smooth muscle +
natriuresis/diuresis
 Dilates peripheral arterioles
 Uses: severe hypertension
 AEs: excessive hypotension, reflex tachycardia, IOP (avoid in glaucoma)
 Hydralazine and minoxidil (oral) are add ons for refractory hypertension
 Vasodilator therapy works best in combination to oppose compensatory
cardiovascular responses (beta blockers and thiazide diuretics)
 Vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction
 AEs: headache, nausea, anorexia, palpitations, sweating, flushing, reflex
tachycardia, salt and fluid retention  angina exacerbation in patients with IHD
 Sympathetic Nerve Terminal Blockers
 Reserpine
 MOA: blocks VMAT 2 (irreversibly)  biogenic amines are not stored in vesicles
 degraded in cytoplasm  depletion of neurotransmitter
 Effects: CO and TPR
 AEs: orthostatic hypotension, sexual dysfunction, dyspepsia, depression,
sedation, parkinsonism
 Contraindications: active peptic ulcer, hx of mental depression