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CARDIOVASCULAR SYSTEM / RENAL SYSTEM
Glomerulus- all small filtrates get filtered (except large proteins like albumin). NaCl is most
prevalent.
Diuretics work by blocking reabsorption of NaCl
∆ excreting water (prevents the passive reabsorption of water)
∆ increased urine is directly related to NaCl reabsorption it blocks.
∆ Block the most NaCl reabsorption = most profound dieresis.
Rationale: since at the end of the tubule, most is reabsorbed, if you catch it earlier, you will
block more. Diuretics at the end have the least impact.
Greatest impact are the ones that work at the proximal tubule (Osmotic diuretics= rarely used).
*** But loop diuretics are the most effective (high ceiling)
Drug Excretion: by the kidneys via
1. Glomerular filtration: (all small molecules go through here, no pumps/passive
process)
electrolytes, amino acids, drugs, metabolic wastes
large molecules remain in the blood (proteins/lipids)
Nonselective process
2. Active tubular secretion and/or Reabsorption **ACTIVE Processes
Reabsorption - proximal convoluted tubule, loop of henle, distal convoluted tubule
- most diuretics act to inhibit this process!
Selective process (active transport)
Greater than 99% of the filtrate undergoes reabsorption
Reabsorption is an active process (water is passive)
Secretion - proximal convoluted tubule
Selective pumps for organic acids and organic bases
Wastes, drugs, toxins
Can pump drugs from blood to filtrate
3. Passive, flow dependent, diffusion
** Give a drug to inhibit the secretion of another drug. This will allow less drug to be eliminated
and the concentration of the drug will be higher in the blood for longer. ∆↑ half life
Aldosterone (Retain Na, Excrete K)
Mineralocorticoid of adrenal cortex (estrogens/testosterone, glucocorticoids,
mineralocorticoids)
Stimulates Na reabsorption from the distal nephron
Causes a loss of K+ (loss of K because excreted)
ADH (anti diuretic hormone) (Retain sodium, Reabsorb water)
Acts @ collecting duct – regulates H2O conservation
o Makes it more permeable to H2O
o Without ADH the collecting duct is impermeable to H2O
Can affect “concentration” of urine
o ADH deficiency – e.g. DI (dilute urine)
o ADH excess – e.g. SIADH (concentrated urine) **anti diuretic hormones concentrate urine
Diuretics
Treat hypertension (high blood pressure)
Mobilize fluid in edematous states (heart failure, cirrhosis, renal disease)
This class of drug can have numerous indications!!
Common mechanism:
Blocking SODIUM and CHLORIDE reabsorption
More solute in the nephron – creates osmotic pressure and prevents the passive
reabsortion of water
Most diuretics act on luminal surface of tubular cells
Classes:
1. Loop diuretics (high ceiling diuretics)
furosemide (Lasix™) (IV or PO) (thick segment –ascending limb of henle’s loop)
Can keep giving large doses without reaching a peak
Good in those with renal impairment (don’t need ↑GFR)
• Ascending loop of Henle
• 20% of filtered Na+ & Cl- load = more profound diuresis
• Rapid onset
• IV for urgent use
• Oral* - potential for ↓efficacy in edematous states and in patients with renal
dysfunction and uremia.
Uses:
1. Edematous states (A = poor)
2. Pulmonary edema
3. HTN
Adverse Effects:
Hypotension
Hypokalemia (can be severe)
Hyponatremia
Hypochloremia
Ototoxicity (rare)- IV, rapid infusion, caution with other drugs that cause this effect
Hyperglycemia
Hyperuricemia
Hyperlipidemia
Hypocalcemia (different than thiazides) but not usually significant because Ca+ is
actively reabsorbed at the distal convoluted tubule
2. Thiazide diuretics (low ceiling diuretics)
Hydrochlorothiazide (early distal convoluted tubule)
Maximal effects occur at low doses (Clinically this means that titrating the dose above a
certain point will not provide more diuresis)
Caution in those with allergy to sulfonamides
Not good in those with renal impairment. Need ↑GFR to work!!
Can be found in combination products
• Commonly with ACE-I (angiotensin converting enzyme inhibitor)
Uses:
1. Hypertension (**drug of choice. Many can be tx with this alone)
2. Edematous states – mild to moderate edema
Mechanism:
↑excretion of Na+, CL-, K+ and H2O (blocks R of NaCl/Water E K)
By blocking reabsorption Na+ & Cl- in the early segment of the distal convoluted
tubule (10% of filtered Na load)
Adverse Effects:
Hypokalemia – most common cause
Dehydration (uncommon)
Hyperglycemia (diabetics)
Hyperuricemia (↑gout, ↑uric acid)
Hyponatremia
Hypomagnesemia
Hypercalcemia (not usually
significant, in contrast to loops which
causes hypoglycemia)
Ottotoxicity – not a factor, can be
combined with ottotoxic drugs
3. Potassium sparing diuretic AKA Aldosterone antagonists (Gets rid of Na, retains K)
spironolactone (late distal convoluted tubule/collecting duct)
can cause synthesis of Na+/K+ pumps
Aldosterone normally: • increases reabsorption of Na+ and H2O along with the excretion of K+ in the distal tubules
•Is the main Na+ retaining hormone from adrenal gland
Uses:
1. Hypertension edematous states (delayed, minor diuresis) Delay in onset of effect - due to time required to synthesize Na+/K+ transporters
Diuresis – minimal because filtered Na+ load remaining
2. Severe heart failure
Adverse Effects:
Hyponatremia
Hyperkalemia
Endocrine Effects- because of its steroid like structure. The body mistakes it for other
hormones. (Gynecomastia, menstral irregularities, hirsutism, deepened voice)
4. Osmotic diuretics (Proximal tubule) & carbonic anhydrase inhibitors (used less often)
Diuretics – Adverse Effects Grouped
1. Hypovolemia – decreased blood volume
2. Acid base imbalance
3. Electrolyte imbalances
Cardio/Renal II
**RAAS (renin-angiotensin-aldosterone system) help regulate blood pressure blood volume,
fluid & electrolyte balance
Promotes- Remodeling, Cardiac fibrosis and myocyte death
Angiotension Converting Enzyme (ACE inhibitors) – renal elimination
• Many: captopril, enalapril, quinapril, ramipril
• Reduces preload and afterload
Uses:
• Congestive heart failure (CHF)
• Hypertension
• Post MI (reduces mortality following an MI)
• Nephropathy (slows progression of renal disease)
Adverse Effects
1. First dose hypotension (titrate slowly especially in those with overactive RAAS),
caused by widespread vasodilation)
2. Cough (5-10% or more)
3. Angioedema (life threatening)
4. Hyperkalemia (especially in those with K+ sparing diuretics or supplements (need to
monitor this!) Caused by inhibition of aldosterone release
5. Increase in serum creatinine
6. Fetal injury (pregnancy category x)
7. Renal impairment
CI for those with bilateral renal artery stenosis
Caution for those with renal impairment
In those with severe impairment, consult nephrology
Decreased Renal Perfusion
Angiotensin II Receptor Blockers - The ―sartans‖ or ―ARBs‖
• Blocks receptors for angiotensin II and therefore the actions of angiotensin II
E.g. valsartan, candesartan, losartan
• Similar pharmacologic effects as ACE Inhibitors
• Similar side effects- Potentially less cough as does not lead to increased production of bradykinin
RAAS
Digoxin
Used for “inotropic” properties in CHF
May decrease hospitalizations and improve exercise tolerance
Problems with toxicity
Controversy regarding use in certain populations (has a narrow therapeutic index)
Inotropic agent- Inhibits Na+-K+-ATPase:
o This causes increase in intracellular Ca2+
o Increase myocardial contractility
“Parasympathomimetic”:
o Increases vagal impulses and increases response of SA node to acetylcholine
o Result = decrease automaticity of SA node and conduction through AV node
Has a long half life
Monitor serum level if suspected toxicity, changes to drug regimen, changes in renal fx
Mechanism of Action: Inhibiting the Na+/K+ ATPase promotes calcium accumulation
myocytes which prevents myocytes from restoring proper ionic composition following an action
potential
Adverse Effects
1. Dysrrhythmia
Hypokalemia (caution with non K+sparing diuretics!)
Potassium competes with digoxin for binding to Na+/K+ ATPase- decreased K+
increases dig induced inhibition of the pump
2. Digoxin levels
Narrow therapeutic index- Toxicity can occur within the therapeutic range
Toxicity – if suspected, good to do a digoxin level (some have toxicity despite
normal blood level/therapeutic range)
3. GI- Nausea, vomiting, diarrhea, anorexia
4. CNS - Confusion, drowsiness, dizziness, blurred vision, hallucinations
5. CVS- Arrhythmias, AV conduction blocks, ventricular extrasystole, SVT, junctional
rhythms, VT
Case Example
68 yo male with hypertension X 15 years and has had 2 MIs in the last 4 years (the most recent
being 1.5 months ago). As a result of the 2nd MI he sustained LV systolic dysfunction and
symptoms of CHF. He has COPD (C.P. continues to smoke 0.5-1 PPD).
His current medications include:
furosemide 20 mg po once daily (titrated to symptoms)
spironolactone 12.5 mg po once daily
ramipril 10 mg po once daily
metoprolol 50 mg po bid
ASA 325 mg po once daily
simvastatin 20 mg once daily
nitroglycerin spray prn angina
atrovent 2 puffs QID
salbutamol 1-2 puffs bid to qid for shortness of breath
Renal/Cardio III Case Study:
ID: 46-year-old woman, SD
CC: presented to the ED with palpitations and syncope.
HPI: She noted the onset of the complaints approximately 12 hours before arrival. The patient was taking
multiple medications, including
furosemide,
atenolol,
enalapril,
risperidone
sertraline.
PMHx: hypertension, myocardial infarction, congestive heart failure, and bipolar disorder.
The examination demonstrated an alert woman in no apparent distress
On exam: BP: 145/80 mm Hg, P: 60 bpm RR: 16/min
Laboratory studies: low serum potassium and magnesium values.
EKG ordered
Generation of Dysrhythmia
1. Disturbances of impulse formation
• automaticity – cells that spontaneously generate APs (SA, AV nodes, His-Purkinje
system will cause a dysrhythmia if the rate of discharge changes)
2. Disturbances of conduction
• AV block (e.g. 1st degree, 2
nd degree, 3
rd degree)
• Reentry (a localized self sustaining cicuit)
3. Problems with both 1 and 2
Cardiac action potentials – Slow Potentials
4
2
3
Depolarization
0
-60mV
Class II:Beta blockersClass IV:Calcium channel BlockersAdenosine
Ca++
?
Class II:Beta blockersClass IV:Calcium channel blockers
SA node, AV node
Classification of agents (Vaughan Williams classification)
Class I – Blocks sodium channels (phase 0) *slows conduction in atria/ventricle/ HIS Perj
Class II – Beta blockers *SA/AV/ Atria and Ventricles, reduces Ca entry ↓depolarization
Class III – Potassium channel blockers (phase 3) * delay of repolarization of fast K
Class IV – Calcium channel blockers (phase 2)
Others – digoxin, adenosine
** All drugs that treat dysrhythmias have proarrhythmic affects!!!
Fig. 1 A, Electrocardiographic rhythm strip with NSR and long QT interval. B, Twelve-lead ECG with NSR, inverted T waves in leads V2 and V3, and a single premature ventricular contraction. Importantly, the QT interval is prolonged to approximately 500 milliseconds. C, Polymorphic ventricular tachycardia is noted in this patient. This form of PVT is suggestive of torsade de pointes, a subtype of PVT seen in patients with abnormal repolarization—as manifested by the prolonged QT interval on the sinus rhythm ECGs in panels A and B.
Christopher Delk , Christopher P. Holstege , William J. Brady
Electrocardiographic abnormalities associated with poisoning
The American Journal of Emergency Medicine Volume 25, Issue 6 2007 672 - 687
http://dx.doi.org/10.1016/j.ajem.2006.11.038
The rhythm strip demonstrated sinus rhythm with a long QT interval (Fig. 1A). The 12-lead ECG (Fig. 1B) revealed normal sinus rhythm (NSR) at a rate of approximately 60 bpm
with a prolonged QT interval (520 milliseconds).
Antianginals- Drugs for chronic, stable, angina
1. Nitrates - Acute relief with spray and SL tabs
2. Symptom control (chronically):
Calcium channel blockers (CCBs)
Beta blockers
Long acting nitrates
Agents used - Based on the theory of decrease O2 supply in light of increase metabolic demand
1. Increase delivery - drugs to increase coronary blood flow
2. Decrease demand –
o Drugs to decrease cardiac work
o Decrease: HR, Ventricular volume, Blood pressure, Contractility
Nitrates (nitro-glycerine) @ therapeutic doses has selective dilation of veins
1. Decreases O2 demand
Increased venous capacitance
- pooling of the blood in the peripheral veins - reduces the force which blood
returns to the heart (decreases ventricular fillign)
- ↓ Cardiac Preload (degree of stretch prior to contraction), this ↓ force of
contraction, ↓CO and tissue perfusion.
- Leads to Orthostatic hypotension
Reducing systemic and pulmonary arterial pressure(afterload)
2. Coronary vasodilation
Redistributes blood flow along collateral arteries and from epicardial to
endocardial regions
Dilates coronary artery stenosis and narrowed coronary arteries
Relieves coronary spasm
3. Tolerance develops: – cannot swallow, or use constantly (losses their efficiency)
Tachyphylaxis- tolerance
Mechanism of action: depletion of sulfhydryl groups or oxidative injury to
mitochondrial aldehyde dehyrogenase (enzyme needed to convert nitroglycerin
into nitric oxide)
Adverse effects:
1. Headache
2. orthostatic hypotension – due to pooling of blood in the veins (↓Preload)
3. reflex tachycardia
4. facial flushing
Nitrates—Routes of Administration
• Sublingual, Translingual spray, Buccal, Oral sustained-release (once a day), Transdermal
delivery systems, Intravenous
Nitrates – drug interactions
• Consider kinetic and dynamic interactions
E.g. other drugs that reduce BP – dynamic interaction but likely a common combination
with nitrates
• Drugs that inhibit reflex tachycardia
E.g. Beta blockers
E.g. CCBs (some)
Drugs for Angina Pectoris— Calcium Channel Blockers (CCBs) - Prevent calcium ions from entering cells
1. VSM – Ca+2
regulates contraction - Arterioles and arteries
2. Coupled with beta1 receptors (SA, AV node, myocardium)
CCBs
Classification of CCB’s
1. Dihydropyridines- Affect VSM (vasodilatation)
nifedipine
amlodipine
felodipine
nicardipine
2. Non-dihydropyridine - Affect VSM (vasodilatation), heart (reduce heart rate)
verapamil
diltiazem
Adverse effects
• Hypotension
• Reflex tachycardia (> with nifedipine but consider other dihydropyridines)
• Bradycardia (More with verapamil and diltiazem)
• Peripheral edema – due to vasodilatation
Cholesterol
How and where do we get it?
Made intracellulary
HMG reductase is an enzyme that makes cholesterol. -hydroxymethylglutaryl CoA reductase (HMG CoA)
Uptake from systemic circulation
Synthesized in liver & secreted into circulation
Lipoproteins are the carriers
inner lipid core and an outer membrane protein
membrane protein allows interaction with other receptors on cells
Cholesterol Management:
Non-drug therapy
HMG CoA reductase inhibitors- hydroxymethylglutaryl CoA reductase
Bile acid-binding resins
Nicotinic acid
Fibric acid derivatives (fibrates)
Cholesterol absorption inhibitor
―HMG CoA‖ Reductase inhibitors AKA“STATINS”
Mechanism of Action
Inhibiting HMG CoA leads to:
# of high affinity LDL receptors in hepatocytes
Causes in circulating LDL pool & LDL’s catabolic rate
takes 4 – 6 weeks for FULL effect
Benefits:
1. Decreases LDL (range 20 – 60 % reduction) (Dose dependent effect )
2. Increases HDL 3. Nonlipid reduction beneficial effects
1. Promote cholesterol plaque stability
2. Reduce inflammation at the plaque site
3. Slow progression of of calcification
4. Reducing platelet deposition and aggregation
4. Many large clinical trials have shown cardiovascular and mortality benefits for those with
existing CV disease.
Has many drug-”other” interactions (like Substrates &/or inhibitors of CYP450 system, 3A4)
- e.g. do not combine simvastatin with grapefruit juice
Adverse Effects:
1. Hepatoxicity (1-2%) – monitoring LFTs
2. Myopathy – myositis – rhabdomyolysis
Rhabdomyolysis – rare but severe consequence, also leads to acute renal failure
risk for this side effect when combined with fibrates, drugs inhibiting
statin metabolism
Counseling patients
notify if symptoms muscle pain or tenderness
If symptoms – evaluate/assess
Check - CK (d/c when CK to e.g. >10 X ULN)
Assess renal function & urine for myoglobin