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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Anaphylaxis Urticaria Angioedema

Anaphylaxis Urticaria Angioedema
By:Niraj Patel, MD, MS
Section of Allergy and Immunology
Texas Children’s Hospital & Baylor College of Medicine

Objectives
* Know the clinical presentation, diagnosis and treatment of anaphylaxis.
* Understand the pathophysiology of urticaria and angioedema
* Outline an approach for evaluation and treatment of patients with urticaria and/or angioedema

What is anaphylaxis?
* Affects > 1 organ system: skin, respiratory, cardiovascular, GI symptoms
* 100,000 episodes per year in U.S.
* 1% fatality rate: shock, larnygeal edema
* IgE vs nonIgE mechanisms

Histamine
IgE-Mediated
IgE-receptor
* Protein digestion
* Antigen processing
* Some Ag enters blood

Mast cell
APC
B cell
T cell
Non-IgE Mediated
Pathophysiology: Immune Mechanisms
Causes of Anaphylaxis
* Foods – peanuts, egg, milk, shellfish, wheat, fish, soy
* Insect stings
* Drugs – PCN, NSAIDs
* Contrast media
* Opiods

Clinical Features and Diagnosis
* Skin: Erythema, pruritis, hives, angioedema
* Respiratory: laryngeal edema, wheezing, rhinitis, itching of palate, conjunctivitis
* Cardiovascular: LOC, fainting, palpitations, sense of impending doom
* GI: N/V/D, abdominal pain
* Diagnosis

Management of Systemic Reactions
Stabilize Epinephrine, IV, airway, O2 antihistamine, steroids
Observe 3 hours (mild reaction) 6 hours (severe reaction)
Prevent Epinephrine self administration Referral to an allergist

EpiPen
* EpiPen
o Injection carried with the patient at all times.
o Self-injection to lateral thigh.
o Use EpiPen, Jr. for children < 20kgs.
Urticaria
* Urticaria = Hives
* Common condition, 15-25% at some time in their lives
* Type I hypersensitivity reaction
* Causes: foods, drugs (no identifiable cause in 50%)
Urticaria vs. Angioedema
* Urticaria – superficial dermis
o Characterized by intense pruritis due to histamine effect
* Angioedema – deeper dermal and subcutaneous layers
o May be pruritic but often is a deeper and dull discomfort – burning quality

Chronic Urticaria/Angioedema (Mast cell driven)
Acute vs. Chronic Urticaria
* Acute Urticaria – lasts 6-8 weeks or less
o Viral syndromes (especially in young children)
o Insect bites or stings (fire ants, scabies)
o Food induced reactions (eat this - get that)
o Medication related (antibiotics, NSAIDs, narcotics, angioedema due to ACE inhibitors)
* Chronic Urticaria – lasting longer than 8 weeks
o Physical urticarias (dermographism, cholinergic, cold)
o Urticarial vasculitis
o Urticaria/angioedema associated with autoimmunity
o Autoimmune urticaria
o Idiopathic urticaria

Urticaria - Mechanisms
* Immunologic
* Non-Immunologic
Underlying Mechanisms of Urticaria
Physical Urticarias
Symptomatic Dermatographism
Cholinergic Urticaria
Cold-Induced Urticaria
Delayed Pressure Urticaria
Solar and Aquagenic Urticaria
Schnitzler’s Syndrome
Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
Therapeutic Options
* Antihistamines for most with acute short-lasting urticaria
o Start with non-sedating, long-acting second generation H1 antagonists (Allegra, Zyrtec, Claritin) and supplement

with short-acting, sedating H1 antagonists prn.
* Combination therapy if H1 antagonists do not suffice (30% of cases)
* Steroids and other immunosuppressants reserved for severe urticaria associated with angioedema of oropharnyx or other

systemic signs, moderate to severe drug reactions, urticarial vasculitis, and refractory cases of CIU
H1 Antagonists
* Previously felt to be only histamine receptor blockers
* Recent research now reveals that most of the second generation antihistamines have some mild anti-inflammatory

properties
* Although less expensive, first generation antihistamines have potential for sedation and impaired performance

Why Add an H2 Antagonist?
Immunomodulation Cyclosporine / Tacrolismus
Cyclosporine
ANGIOEDEMA

* Inhibits C1r and C1s of the complement system
* Inhibits activated factor XIIa and kallikrein
* An inhibitor of factor XIa and plasmin
* Inhibits activation of C1
C1 Inhibitor Functions
Hereditary Angioedema
* Autosomal dominant with incomplete penetrance.
o Spontaneous mutations in 50%
o Diminished C4 between attacks
o Very low C4 during attacks
* HAE I
o Low levels of C1 esterase inhibitor
* HAE II
o Dysfunctional C1 INH
* HAE III (estrogen-dependent angioedema)
o Normal C1 INH amount and function
o Normal complement levels
Acquired Angioedema (AAE)
Drug Induced Angioedema
ACE Inhibitor Angioedema
Treatment of Hereditary Angioedema
* Patient education very important; test family
* No regular medication needed in many cases
* Prophylactic stanozolol or danozol
* Epsilon aminocaproic acid (EACA) an option
* Fresh frozen plasma before emergency surgery
* C1 inhibitor
* Symptomatic treatment during attacks
* Steroids and antihistamines are NOT effective!!!
Summary
* Through several mechanisms a variety of mediators may lead to urticaria or angioedema
* Clinically, a causative agent is much more often identified in acute than in chronic urticaria/angioedema
* A number of medications are available to control chronic urticaria while awaiting a spontaneous remission
* Patients with angioedema without urticaria should be tested for C1 inhibitor deficiency

Questions
Anaphylaxis Urticaria Angioedema

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