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