Angioedema

Angioedema

Overview
* Self-Limited, subcutaneous edema resulting from increased vascular permeability
* Generally resolves over 24-48 hours
* Mast Cell / Kinin related etiologies
* Involvement of the lips, pharynx and bowel common (potentially life-threatening)
* Treated with CCS and H1/H2 blockers

Etiology
* Immunologic / IgE mediated
* Hereditary and Acquired (non-mast cell)
Ace-Inhibitors
* ACE (Kininase II) degrades bradykinin
* ACE-I results in inc levels bradykinin
* Pts with genetic deficiencies in bradykinin degradation could be at higher risk
* 0.1-0.7% of patients tx with ACE-I
* Intestinal edema may develop

ACE-I
Hereditary/Acquired
* Kinin-mediated angioedema that may be unmasked with use of ACE-I
* C1-Inh deficiency (level or fx) - Inc BKinin
Summary

* Angioedema is potentially life-threatening
* Associated pruritis and hives points to anaphylaxis
* Absence of pruritis and hives think ACE-I and/or C1-Inh deficiency
* Use caution when switching from an ACE-I to an ARB

Angioedema

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Congestive Heart Failure

Congestive Heart Failure
By:Chris Hague, PhD
Technical Advisor: Seth Goldenberg, PhD

Outline

1. What is congestive heart failure?
2. Cardiac Glycosides
3. Phosphodiesterase inhibitors
4. Beta-adrenergic receptor antagonists
5. Sympathomimetics
6. ACE inhibitors/angiotensin receptor antagonists
7. Vasodilators
8. Diuretics
9. Aldosterone antagonists

Congestive Heart Failure
Patient Classification
* Class I (asymptomatic)
* Class II (mild)
* Class III (moderate)
* Class IV (severe)

Factors contributing to CHF
* Ischemic Heart Disease: most prevalent
* CAD: less blood flow to heart, increased damage
* Myocardial Infarct: damaged tissue
* Hypertension: “overworked” heart
* Diabetes
* Lung Disease
* Cardiomyopathies: heart muscle disease
o dilated - enlarged chambers (ventricle/atria)
o hypertrophic - thickened ventricle walls
* Abnormal heart valves: inefficient pumping
o causes are genetic, infection or disease
* Congenital heart defects: present at birth
* Severe Anemia
* Hyperthyroidism
* Cardiac Arrhythmia

Effect on Cardiac Output
Overall decrease in Frank-Starling curve with CHF
Examples of CHF factors
Hypertrophic Cardiomyopathy
Congenital Heart Defects
Types of Heart Failure

* include left, right or both sides
* left ventricular heart failure
* right ventricular heart failure
Onset of disease

* chronic disease: can take years to develop
* endogenous compensatory mechanisms

Compensatory Mechanisms
Symptoms of CHF
* shortness of breath
* persistent coughing/wheezing
* edema (or excess fluid buildup in body tissues)

Symptoms of CHF
* tiredness/fatigue
* lack of appetite/nausea
* confusion/impaired thinking
* increased heart rate

Problems
* Reduced force of contraction
* Decreased cardiac output
* Increased TPR
* Inadequate organ perfusion
* Development of edema
* Decreased exercise tolerance
* Ischemic heart disease
* Sudden death

Therapeutic Overview
Goals
* alleviate symptoms
* improve quality of life
* arrest cardiac remodeling
* prevent sudden death
Drug
* Chronic heart failure
o ACE inhibitors
o Beta-blockers
o ATII antagonists
o aldosterone antagonists
o digoxin
o diuretics
* Acute heart failure
o diuretics
o PDE inhibitors
o vasodilators

Therapies
Non-drug
* Reduce cardiac work
* Rest
* Weight loss
* low Na+ diet
Cardiac Glycosides
* discovered by William Withering
* published “An Account of Foxglove and some of Its Medical Uses” in 1785
* Foxglove plant
Cardiac Glycosides
* derived from plants
o Strophanus - Ouabain
o Digitalis lanata - Digoxin, Digitoxin
* increase force of myocardial contraction
* alters electrophysiological properties
* toxic side-effects
* Digoxin most common used in USA

Digitalis lanata
Mechanism of Action
* inhibitor of Na+/K+ ATPase pump
* increased [Na+]i
* increased Ca2+ influx through Na+/Ca2+ exchanger
* new Ca2+ steady-state: increased Ca2+ release during cardiac action potential
Electrophysiological Effects
* Direct effects
o spontaneous depolarization of atrial cardiomyocytes at high doses

Electrophysiological Effects
Overall Effect on Cardiac Function

Foxglove
Therapeutic Uses
* only orally effective inotropic agent approved in US
* also for CHF secondary to ischemic heart disease
* contraindicated in patients with Wolff-Parkinson-White syndrome
* does not stop disease progression or prolong life in CHF patients

Pharmacokinetics
* long half-life (24-36 h): once daily dosing
* high bioavailability from oral dosing
* large volume of distribution
* digoxin excreted in kidneys
* digitoxin metabolized in liver, active metabolites
* intestinal flora cause variations in toxicity

Side Effects
* extremely low therapeutic index (~2)
* most effects caused by inhibition of Na+/K+ ATPase in extracardiac tissues
* CNS: malaise, confusion, depression, vertigo, vision
* GI: anorexia, nausea, intestinal cramping, diarrhea
* Cardiac: bradycardia, arrhythmias
* anti-digoxin antibody in toxic emergencies

Serum Electrolytes affect Toxicity
* Ca2+
* hypercalcemia: increases toxicity
* K+
* digitalis competes for K+ binding site on Na+/K+ ATPase
* contraindicated with K+ depleting diuretics or patients with hypo/hyperkalemia
* hypokalemia: increased toxicity
* hyperkalemia: decrease toxicity

Example of cardiac side effects
* action potential recordings from purkinje fiber cells
* toxic doses produce oscillatory after depolorizations
* leads to ventricular tachycardia (C)

Vision Effects
* yellow-tinted vision or yellow corona-like spots

Phosphodiesterase Inhibitors
* primarily used for management of acute heart failure
* positive inotropic effects
* increase rate of myocardial relaxation
* decrease total peripheral resistance and afterload

Mechanism of Action
* inhibitor of type III cAMP phosphodiesterase
* increased [cAMP]
* increased PKA phosphorylation of Ca2+ channels in cardiac muscle
* increased cardiac contraction
* relaxes vascular smooth muscle

Therapeutic Use
* Amrinone (Inocor) and Milrinone (Primacor)
* administered IV
* milrinone is ~1o fold more potent
* T 1/2 = 2.5 h for amrinone and 30-60 min for milrinone
* effective in patients taking Beta-blockers
* does not stop disease progression or prolong life in CHF patients
* prescribed to patients non-responsive to other therapies

Side Effects
* sudden death secondary to ventricular arrhythmia
* hypotension
* thrombocytopenia
* long term clinical trials associated with increased adverse effects and increased mortality
* now only prescribed for acute cardiac decompensation in patients non-responsive to diuretics or digoxin

β-adrenergic receptor antagonists
* “β-blockers”
* standard therapy for treatment of CHF
* cheap!
* reduce sudden death caused by other drugs
* Propranolol: prototype
* Carvedilol: combination effects

Propranolol
Carvedilol
Mechanism of Action
* mechanism still unclear
* antagonizes β-adrenergic receptors on cardiac myocytes
* counterbalances increased SNS activity in CHF
* prevents development of arrhythmias
* reduces cardiac remodeling
* prevents renin release

Therapeutic Use
* administered orally
* usually given in conjunction with other therapy
* effective in patients with chronic systolic heart failure in Class II (mild) to Class III (moderate)
* prevents remodeling and cardiac damage

Side Effects
* cardiac decompensation
* bradycardia
* hypoglycemia
* cold extremeties
* fluid retention
* fatigue

Direct acting sympathomimetics
* cause immediate increases in cardiac inotropy
* goal: to increase cardiac output but not effect total peripheral resistance
* used in treatment of acute life-threatening CHF

Dopamine
Dobutamine
Mechanism of Action
* Norepinephrine/epinephrine: increase CO, increase TPR
* Dopamine:
* Dobutamine:

Therapeutic Use
* administered IV, very short T 1/2
* Dopamine
o used in cardiogenic, traumatic or hypovolemic shock
o used with furosemide in diuretic resistant patients (volume overload)
* Dobutamine
o used in patients with low cardiac output and increased left ventricular end-diastolic pressure
o not for use in hypotensive patients

Side Effects
* restlessness
* tremor
* headache
* cerebral hemorrhage
* cardiac arrhythmias
* used with caution in patients taking β-blockers
* can develop dobutamine tolerance

ACE inhibitors/AT1 receptor antagonists
* Goal: to reduce afterload/preload, reduce workload on heart
* generates positive cardiac inotropy
* used in treatment of chronic CHF

ACE inhibitors/AT1 receptor antagonists
* orally active
* ACE inhibitors
* Captopril
* Enalopril
* AT1 antagonists
* Losartan
* Valsartan

Mechanism of Action
* ACE inhibitors
* AT1 receptor antagonists
* selectively inhibits ATI receptor activation
* decreased preload
* decreased afterload
* decreased cardiac remodeling
* decreased SNS effects

Therapeutic Uses
* drugs of choice in heart failure
* increase survival in long term CHF
* ACE inhibitors
* AT1 receptor antagonists
Side Effects
* ACE inhibitors
+ cough
+ angioneurotic edema
+ hypotension
+ hyperkalemia
* ACE inhibitors and ATI receptor antagonists are both teratogenic

Vasodilators
* Goal: reduce TPR without causing large decrease in BP
* reduce preload
* reduce afterload
* relieves symptoms
* increase exercise tolerance

Drugs Used
* NO Donors
o Nitroglycerin
+ acute ischemia or acute heart failure
+ orally active
+ also administered I.V. for peripheral vasodilation
+ quick onset for acute relief
o Isosorbide dinitrate/hydralazine
+ chronic administration for long-term symptom relief
+ administered I.V.

Drugs Used
* Nesiritide
o recombinant brain-natriuretic peptide (BNP)
o BNP is secreted from ventricular myocytes in response to stretch
o vasodilator: increases cGMP in SMCs
+ decrease afterload/preload
o inhibits cardiac remodelling
o suppresses aldosterone secretion
o administered IV for acute decompensated CHF
o adverse effects: hypotension, renal failure (?)

Diuretics
* used in CHF to reduce extracellular fluid volume
* primarily used in patients with acute CHF with volume overload
* IV infusion causes immediate and predictable diuresis for immediate relief
* Goal: reduce preload/afterload
* overdosing can result in excessive reduction in preload, overreduction in stroke volume
* thiazide and loop diuretics (i.e. Furosemide) commonly used as adjunct therapies in CHF

Aldosterone Antagonists

* elevated AngII levels increase production of aldosterone in the adrenal cortex (~20X increase)
* aldosterone activates mineralocorticoid receptors in renal epithelial cells in kidney
* aldosterone promotes
o Na+ retention, Mg2+ and K+ loss
o increased SNS activity
o decreased PSNS activity
o myocardial/vascular fibrosis

Therapeutic Use
* Goal: inhibit aldosterone negative effects in CHF
* aldosterone receptor antagonists
o spironolactone
o eplerenone
* both antagonists reduce mortality in patients with moderate to severe CHF
* only use in patients with normal renal function and K+ levels
* use with K+ sparing diuretic

Side Effects
* hyperkalemia
* agranulocytosis
* anaphylaxis
* hepatoxicity
* renal failure
* Spironolactone: gynecomastia, sexual dysfunction
* Eplerenone: arrhythmia, myocardial infarct/ischemia

Congestive Heart Failure

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Heart Failure

Heart Failure
By:S. Soliman MD

Definition:
* A state in which the heart cannot provide sufficient cardiac output to satisfy the metabolic needs of the body
* It is commonly termed congestive heart failure (CHF) since symptoms of increase venous pressure are often prominent
Etiology
-Inappropriate work load (volume or pressure overload)
-Restricted filling
-Myocyte loss

Causes of left ventricular failure

• Volume over load: Regurgitate valve
• Pressure overload: Systemic hypertension

Outflow obstruction
• Loss of muscles: Post MI, Chronic ischemia
Connective tissue diseases Infection, Poisons
(alcohol,cobalt,Doxorubicin)
• Restricted Filling: Pericardial diseases, Restrictive
cardiomyopathy, tachyarrhythmia

Pathophysiology
* Hemodynamic changes
* Neurohormonal changes
* Cellular changes

Hemodynamic changes
Neurohormonal changes
Cellular changes
Symptoms
Physical Signs
Framingham Criteria for Dx of Heart Failure
* Major Criteria:
o PND
o JVD
o Rales
o Cardiomegaly
o Acute Pulmonary Edema
o S3 Gallop
o Positive hepatic Jugular reflex
o ↑ venous pressure > 16 cm H2O
* Minor Criteria
LL edema,
Night cough
Dyspnea on exertion
Hepatomegaly
Pleural effusion
↓ vital capacity by 1/3 of normal
Tachycardia 120 bpm
Weight loss 4.5 kg over 5 days management

Forms of Heart Failure
* Systolic & Diastolic
* High Output Failure
o Pregnancy, anemia, thyrotoxisis, A/V fistula, Beriberi, Pagets disease
* Low Output Failure
* Acute
* Chronic
* Right vs Left sided heart failure:

Right sided heart failure :
Most common cause is left sided failure
Other causes included : Pulmonary embolisms
Other causes of pulmonary htn.
RV infarction
MS
Usually presents with: LL edema, ascites
hepatic congestion
cardiac cirrhosis (on the long
Differential diagnosis
* Pericardial diseases
* Liver diseases
* Nephrotic syndrome
* Protein losing enteropathy

Laboratory Findings
* Anemia
* Hyperthyroid
* Chronic renal insuffiency, electrolytes abnormality
* Pre-renal azotemia
* Hemochromatosis

Electrocardiogram
* Old MI or recent MI
* Arrhythmia
* Some forms of Cardiomyopathy are tachycardia related
* LBBB→may help in management

Chest X-ray
* Size and shape of heart
* Evidence of pulmonary venous congestion (dilated or upper lobe veins → perivascular edema)
* Pleural effusion

Echocardiogram
* Function of both ventricles
* Wall motion abnormality that may signify CAD
* Valvular abnormality
* Intra-cardiac shunts

Cardiac Catheterization
* When CAD or valvular is suspected
* If heart transplant is indicated

TREATMENT
* Correction of reversible causes
Diet and Activity
* Salt restriction
* Fluid restriction
* Daily weight (tailor therapy)
* Gradual exertion programs

Diuretic Therapy
* The most effective symptomatic relief
* Mild symptoms
* Side Effects
* More severe heart failure → loop diuretics
o Lasix (20 – 320 mg QD), Furosemide
o Bumex (Bumetanide 1-8mg)
o Torsemide (20-200mg)

Mechanism of action: Inhibit chloride reabsortion in ascending limb of loop of Henle results in natriuresis, kaliuresis

and metabolic alkalosis

Adverse reaction:
pre-renal azotemia
Hypokalemia
Skin rash
ototoxicity

K+ Sparing Agents
* Triamterene & amiloride – acts on distal tubules to ↓ K secretion
* Spironolactone (Aldosterone inhibitor)
recent evidence suggests that it may improve survival in CHF patients due to the effect on renin-angiotensin-aldosterone

system with subsequent effect on myocardial remodeling and fibrosis

Inhibitors of renin-angiotensin- aldosterone system

o Renin-angiotensin-aldosterone system is activation early in the course of heart failure and plays an important

role in the progression of the syndrome
o Angiotensin converting enzyme inhibitors
o Angiotensin receptors blockers
o Spironolactone

Angiotensin Converting Enzyme Inhibitors
Side effects of ACE inhibitors
* Angioedema
* Hypotension
* Renal insuffiency
* Rash
* cough
Angiotensin II receptor blockers
* Has comparable effect to ACE I
* Can be used in certain conditions when ACE I are contraindicated (angioneurotic edema, cough)
Digitalis Glycosides (Digoxin, Digitoxin)
* The role of digitalis has declined somewhat because of safety concern
* Recent studies have shown that digitals does not affect mortality in CHF patients but causes significant

Mechanism of Action
* +ve inotropic effect by ↑ intracellular Ca & enhancing actin-myosin cross bride formation (binds to the Na-K ATPase →

inhibits Na pump → ↑ intracellular Na → ↑ Na-Ca exchange
* Vagotonic effect
* Arrhythmogenic effect

Digitalis Toxicity
* Narrow therapeutic to toxic ratio
* Non cardiac manifestations
Anorexia,
Nausea, vomiting,
Headache,
Xanthopsia sotoma,
Disorientation
* Cardiac manifestations

Digitalis Toxicity Treatment
* Hold the medications
* Observation
* In case of A/V block or severe bradycardia → atropine followed by temporary PM if needed
* In life threatening arrhythmia → digoxin-specific fab antibodies
* Lidocaine and phenytoin could be used – try to avoid D/C cardioversion in non life threatening arrhythmia

β Blockers
* Has been traditionally contraindicated in pts with CHF
* Now they are the main stay in treatment on CHF & may be the only medication that shows substantial improvement in LV

function
* In addition to improved LV function multiple studies show improved survival
* The only contraindication is severe decompensated CHF

Vasodilators
Positive inotropic agents
Anticoagulation (coumadine)
* Atrial fibrillation
* H/o embolic episodes
* Left ventricular apical thrombus

Antiarrhythmics
* Most common cause of SCD in these patients is ventricular tachyarrhythmia
* Patients with h/o sustained VT or SCD → ICD implant
* Patients with non sustained ventricular tachycardia

New Methods
* Implantable ventricular assist devices
* Biventricular pacing (only in patient with LBBB & CHF)
* Artificial Heart

Cardiac Transplant
* It has become more widely used since the advances in immunosuppressive treatment
* Survival rate
Prognosis
Heart Failure

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