The term glucocorticoid is used interchangeably with corticosteroids. The word “glucocorticoid” implies that they have a fundamental action on glucose metabolism, they do but it turns out that the corticosteroids used in therapeutics are really anti-inflammatory steroids.


Obvious uses for glucocorticoids are when pts have adrenal insufficiency (such as Addison’s Disease). Very rarely will you find such a pt, who has to have exogenous cortisol-type drugs taken daily. Overwhelmingly, the use in medicine and dentistry is as an anti-inflammatory agent. They are not like NSAIDs; they have a totally different mechanism. They also are used for immunosuppression, for pts who have had an organ transplant or who have some autoimmune disease. There are myeloproliferative diseases in which a variety of steroids are used. Drugs such as triamcinolone and dexamethasone particularly, have a particularly useful role in dentistry.


Forget about the mineralocorticoids, we don’t use these in dentistry.


Steroid synthesis inhibitors could theoretically be used in Cushing’s-like diseases where you want to suppress the production of steroids. Notice the drug ketoconazole, this is a prominent anti-fungal agent with a side effect against the synthesis of steroids.


Another class is that which blocks the steroid receptor, we see spironolactone, which blocks aldosterone action on the kidney. Also we see other drugs such as the controversial RU 486, which is the controversial contraceptive/abortion pill.

Remember the synthesis of endogenous corticosteroids the precursor is cholesterol. In the adrenal cortex, there’s the zona glomerulosa and zona fasciculata. The zona fasciculata makes the androgens, the sex hormones. The product of importance of the zona glomerulosa are the hormone corticosterone, from which we get the term corticoid. Cortisol (another term) was originally designated compound F and initially was used in treatment of severe arthritis.


If a pt has insufficient cortical production and becomes stressed, as in a dental procedure, hypotensive shock can occur because of their lack of endogenous glucocorticoids. In normal pts the hypothalamus takes care of this by making ACTH (secreted through the pituitary) which acts on the adrenals and cortisol is secreted. However, if a pt is taking an exogenous steroid the negative feedback is to turn off this hypothalamic-pituitary pathway and ACTH is turned off. So whenever your pt is taking an exogenous steroid as an anti-inflammatory or immunosuppressant drug, they don’t have this pathway and cant produce the normal amount of cortisol under stress.


When you look at the variety of agents available, we rarely utilize the endogenous substance cortisol. A very prominent one used in medicine and dentistry is dexamethasone (Decadron), it is the most potent glucocorticoid and is very long acting. It is used in oral surgery and also has a role in general dentistry. Betamethasone is used to treat asthma; asthma is considered an inflammatory disease. Prednisone is given by mouth and is very effective; many pts with arthritis or autoimmune diseases or other diseases with an inflammatory component will be taking this drug. Cortisone is weak and is the natural corticosteroid. Methylprednisolone is potent and can be given by injection – all can be given by injection, but of those discussed methylprednisone and dexamethasone are most often given by injection.


Some of these compounds have fluorine atoms in the molecule, these enhance the potency of the drug.


The route of administration is important. The choice of any agent is based on route of administration and duration of action. Dexamethasone (Decadron) can be given orally, IM, topically, or IV. Betamethasone is given orally and usually in the inhalational mode. Triamcinolone has an important role in dentistry as a topical agent. In some instances, intraarticular administration is used… the physician will inject the steroid right into the synovial space to reduce swelling and pain. When the steroids are used this way its NOT because they are analgesics (steroids are not analgesics!) it is because they reduce the swelling which reduces the pain.



The primary metabolic action that gives them the name “glucocorticoids” is the fact that they increase glycogenolysis and gluconeogenesis. So there tends to be hyperglycemia, usually in acute settings in dentistry this is not a problem. But if a person takes the corticosteroids chronically they will have elevated blood sugar, this is of concern to diabetics especially. They increase protein catabolism and decrease protein synthesis, this leads to a peculiar type of body mass, there tends to be a loss of muscle protein. There is a decreased osteoblast formation and activity, when given chronically. There is decrease of thyroid-stimulating hormone secretion. These metabolic effects are side effects of the drug.


Their anti-inflammatory action is local and systemic. They decrease the production of prostaglandins, cytokines and interleukins. They are not COX-1 or COX-2 inhibitors, this distinguishes the steroids from the NSAIDs. They decrease proliferation and migration of lymphocytes and macrophages, and therefore slow the healing process.

The major problems, caused mainly by high concentrations over a long period of time, include development of cushingoid habitus. Particularly in women, pts will developtrunkal obesity, moon facies, and buffalo hump. Salt retention and hypertension can also occur. The immune system is markedly suppressed, this can be advantageous in treating an autoimmune disease or for a transplant patient to ward off rejection of the new tissue, but the pt becomes vulnerable to opportunistic infections. Osteoporosis caused by chronic steroid use can render pts vulnerable to fractures. Peptic ulcers can result from gastric hemorrhages or intestinal perforation, if you throw in an NSAID on top of the pt’s corticosteroid dose the ulcer can be severely aggravated. Corticosteroids can suppress growth in children. Also, corticosteroids can cause CNS problems and psychoses. Finally, if a pt is on any of these steroids (not by inhalation) they have suppression of they hypothalamic-pituitary-adrenal axis after drug discontinuation.

• Dentist, with MD, should establish dose supplementation needed in a pt taking corticosteroids chronically… Rule: dose is increased temporarily, with subsequent decrease back to regular dose levels. E.g., dentist may administer 60mg of Prednisone to a SLE (systemic lupus erythematosus) pt taking the steroid regularly. This dose approximates the physiological amount of steroid released during “dental stress” in a normal subject
• Procedures associated with mild-moderate stress require dentist to supplement steroid (inject dexamethasone to pre treat the pt, as anti-inflammatory agent to prevent swelling).
• Usually, have pt take double their usual dose of steroid on the day of surgery or other stressful procedure, and decrease back to original dose within 2 days.
• For more severe surgical procedures, pt should be given 60mg of Prednisone (or an equivalent) on day of surgery, then taper dose by 50% daily until reqular dose is reached. (A med consult will make this decision about tapering)
• Pts who are immunosuppressed because of chronic use of steroids or because of medical conditions may also require antibiotic prophylaxis because of risk of infection.
• Low risk pts: these are pts taking steroids intermittently; no recommendations as to steroid supplementation. However, best to do dental procedures on the day pt has taken their steroid, not on the steroid-free day.

Dexamethasone: active, untreated infections

Prednisone: serious infections (exceptions: TB meningitis and septic shock); systemic fungal infections; Varicella

Hydrocortisone (Cortisol): children under 2 yrs; systemic funal infections

Triamcinolone (Kenalog, Aristocort): no contraindications when used intralesional (as in dental application); systemic fungal infections (when used IM).


In general, don’t give pts steroids if they have candidiasis – they will exacerbate fungal conditions.

Therapeutic: Decrease neutrophil adherence to vascular endothelium; decrease in neutrophil chemotaxis to site of injury or inflammation; suppress T-cell helper function (this is the rationale in use for transplant pts); inhibit synthesis or secretion of inflammatory mediators and cytokines: interleukins (IL-1 by macrophages, IL-2 by T-lymphocytes), prostanoids (leukotrienes), antibody production by B-lymphocytes; suppression of phagocytosis; suppression of bacteriocidal activity (this will increase the risk of infection).

Other: decrease in growth hormone from anterior pituitary; inhibition of somatomedin C activity (results in impaired growth); catalyze conversion of norepinephrine to epinephrine in adrenal medulla; stabilize lysosomal membranes; induce eosinopenia (decreased number of circulating eosinophils); produce reversible atrophy of spleen and thymus.

High-dosing IM studies have shown significant and sustained anti-inflammatory effects with a single dose administered either pre- or post-operatively… not both. Oral surgery usually gives 10mg i.v. corticosteroid pre-operatively, not post-operatively. Why not pre-treat with 800 mg Ibuprofen? This would be a good therapy because it avoids pituitary effects.

Hypokalemic alkalosis; diabetes mellitus; hyperosmolar nonketotic diabetic state; hypertension; sodium and water retention; mood disorders; cerebral edema; proximal myopathy; glaucoma; pancreatitis; peptic ulceration and gastrointestinal hemorrhage; increased serum urea nitrogen


Studies that have investigated the effects of glucocorticoids on the inflammatory sequelae following third molar surgery show that the effects are variable!


Nasonex (mometasone furoate monohydrate) is a new drug given via a nasal spray for prophylaxis of seasonal allergic rhinitis and perennial allergic rhinitis. No HPA-axis suppression has been detected.

1. clinical presentation of acute MI

Pain

• resembles anginal pain but usually more severe, lasts longer, and may radiate more widely

• may result from release of mediators like adenosine and lactate onto nerve endings

• often referred to C7-T4 dermatomes (neck, shoulders, arms)

• little response to nitroglycerin

• 25% will be asymptomatic (especially diabetics—neuropathy)

Sympathetic NS Response

• combo of pain and hypotension (if present) trigger catecholamine release

• diaphoresis (sweating), tachycardia, cool and clammy skin (vasoconstriction)

Dyspnea

• decreased LV contractility, increased diastolic LV volume and pressure, conveyed to LA and pulmonary veins

• the resultant pulmonary congestion stimulates J receptors which effect a reflex of rapid, shallow breathing

Other Physical Findings

• S4 sound

• S3 sound

• pericardial friction rubs (if inflammation extends to pericardium)

• systolic murmurs (if papillary muscle involvement causes vavular insufficiency or if infact ruptures IV septum)

• systemic responses to inflammation (IL-1, TNF) like low-grade fever and leukocytosis

2. diagnosis of acute MI

Based on:

characteristic history and presentation

• see above

typical EKG changes

• Q wave MI: ST elevation, T wave inversion, Q waves evolve over infarcted areas

• non Q wave MI: ST depression, T wave inversion

serum markers

Marker	Appears	Peaks	Normal	Other
CKMB	4-8 hrs	24 hrs	48-72 hrs	Gold standard, highly sensitive and specific
Myoglobin	2 hrs	12 hrs	24 hrs	Rapid renal clearance, low specificity for MI
Troponins	3 hrs	24 hrs	~5 days	Highly specific and sensitive
LDH	~48 hrs	3-5 days	~8 days	LDH1 most specific for MI

other

• echocardiography: demonstrate contraction or mechanical abnormailties

• nuclear scans: technetium-99m (collects in necrotic myocardium)

3. treatment strategies in acute MI

   1. thrombolysis

• most Q wave Mis occur as a result of occlusive thrombus formation w/in a coronary artery

• can use streptokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), or recombinant plasminogen activator (t-PA)

• all function by activating plasmin which lyses fibrin clots

• contraindicated in those susceptible to hemorrhage

• matters less which agent is given, compared to how soon it is administered

• generally followed by IV heparin

2. coronary revascularization – role of PTCA

• alternative to thrombolytic therapy

• some centers unable to provide angioplasty

3. adjuvant medical treatment

• bed rest

• oxygen

• aspirin (decreases platelet adhesiveness, should be started upon presentation of MI and continued indefinitely)

• B-blockers (decrease sympathetic drive to myocardium, reduce work, contribute to electrical stability)

• Nitrates (relieve pain, work by venodilation which lowers oxygen demand by lowering preload)

• Morphine (eliminate pain and anxiety thereby reducing oxygen demand, also venodilate)

• Anticoagulants (heparin)

• ACE inhibitors (limit post-MI ventricular remodeling and heart failure, begun early and continued indefinitely)

Causes - rheumatic heart disease (isolated mitral stenosis in 25% of all cases of rheumatic h.d., mixed mitral stenosis and regurgitation in 40 % of all cases of rheumatic h.d., two third of patients - women);

in about 50% of patients with mitral stenosis the rheumatic fever may be unrecognised;

viral carditis - very rare cause of mitral stenosis;

two thirds of cases occur in women;

Pathophysiology:

- the mitral valve orifice

• - normally about 5 cm² (in diastole)

• - moderate stenosis (approx 2cm²) - patients remain asymptomatic

• - 1cm or less in severe mitral stenosis

- in mitral stenosis cardiac output may be maintained by rise pressure in LA, pulmonary venous and capillaries - it results in the loss of lung compliance and the development of exertional dyspnoea

• - mild stenosis - atrial pressure rises only on exercise

• - severe stenosis - raised atrial pressure is reqiured to maintain CO even at rest

- the raised atrial pressure - enlarged diameters of LA (LA dilatation in 80% os cases) - atrial fibrillation (sometimes the first sign of clinical deterioration) - loss of atrial contraction contricute to diminished ventricular filling

- risk of atrial thrombosis and systemic thromboembolism (particulary those with AF)

- sudden onset of atrial fibrillation - sudden increase in pulmonary venous pressure - sometimes pulmonary oedema

- the long-termed mitral stenosis and more gradual rise in pressure - the increased pulmonary vascular resistance, which protects against pulmonary oedema

- right ventricular hypertrophy and pulmonary hypertension (results from : passive back-pressure, arterioral constriction, obliterative changes in pulmonary vessels)

SYPMTOPMS (most common in the third or fourth decade of life)

1. Exertional dyspnoea, nocturnal dyspnoea, cough, hemoptysis

2. Leg, ankle oedema, abdominal swelling (right ventricular failure)

3. Symptoms of acute pulmonary oedema (AF, pregnancy)

4. Symptoms secondary to arterial (rare venous) emboli

5. Symptoms of diminished CO (fatique, tiredness)

Asymptomatic mitral stenosis - the phisical signs of mitral stenosis are found before symptoms develop

SIGNS

1. Atrial fibrillation

2. Mitral facies

3. Auscultation

• Loud first heard sound (the stenotic valve prolonges atrial emptying, leaflets remain open at the onset of diastole and are closed suddenly)

• Opening snap (the opening snap gets colser to the second sound as the stenosis becomes more severe, may be inaudible if the valve is heavily calcified)

• Mid-diastolic murmur (the turbulent flow causes the low pitched diastolic murmur, and often a thrill; murmur is accentuated by exercise and during atrial systole-presystolic accentuation; il is heard best at the cardiac apex with the petients in the left lateral decubitus position)

4. Signs of raised pulmonary capillary pressure (crepitations, pulmonary oedema, effusions)

5. Signs of pulmonary hypertension (abnormal pulsation felt to the left of the sternum, due to either to righ ventricular hypertrophy or to forward displacement of the heart by dilated LA; loud the pulmonary component of the second heart sound; tricuspid regurgitation secondary to right ventricular dilatation causes the systolic murmur and systolic waves in the venous pulse)

INVESTIGATIONS

1. The ECG:

• The left atrial hypertrophy - P mitrale (the bifid P waves) or atrial fibrillation

• Right ventricular hypertrophy (the earliest sign - reduction in the size of the usual QS complex in the lead V1)

2. CXR:

• enlarged left atrium

• signs of pulmonary venous hypertension (enlargement of the upper pulmonary veins, horizontal linear shadows in the costophrenic angles)

3. Echocardiography: thickened immobile cusps, enlarged size of the left atrium, reduced valve area, reduced rate of diastolic filling

4. Cardiac catheterisation: pressure gradient between LA and LV

AETIOLOGY

1. Mitral valve prolapse

2. Dilatation of the mitral valve ring (e.g. rheumatic fever, myocarditis, cardiomyopathy)

3. Damage to valve cusps and chordae (rheumatic heart disease - is coexisting mitral stenosis and/or aortic valve disease; endocarditis)

4. Damage to papillary muscle

5. Myocardial infaction

SYMPTOMS of REGURGITATION:

• chronic - produces volume overload of the left atrium and ventricle - dilatation

• exertional dyspnoea, nocturnal dyspnoea, palpitations

• symptoms of pulmonary oedema

• symptoms of diminished cardiac output (tiredness, fatique)

• symptoms of right ventricular failure

• acute - rapid rise of left atrial and pulmonary venous pressure, rapid decrease of stroke volume - pulmonary oedema and symptoms of reduced cardiac output

SIGNS of MITRAL REGURGITATION

• atrial fibrillation/flutter

• cardiomegaly

• apical holosystolic murmur (it is heard best in the apex, radiates into axilla, may be accompanied by a thrill)

• quiet first heart sound (abnormal valve closure), loud third sound sometimes accompanied by short mid-diastolic murmur (the increased forward flow through the mitral valve)

• apex beat displaced to the left (result of dilatation of the left ventricle)

• signs of rised pulmonary capillary pressure (crepitations, pulmonary oedema, effisions)

• signs of pulmonary hypertension

In practice, the usual problem lies in deciding the extent to which cardiac failure is due to mitral regurgitation and extent to which it reflects impaired left ventricular function.

INVESTIGATION IN MITRAL REGURGITATION

1. ECG - left atrial hypertrophy (AF), left ventricular hypertrophy

2. CXR - enlarged left atrium, enlarged left ventricle, signs of pulmonary venous hypertension, signs of pulmonary oedema

3. Echocardiography - dilated LA, LV, dynamic LV (unless LVF predominates), regurgitation detectable on Doppler

4. Cardiac caheterisation - dilated LA, LV, mitral regurgitation, pulmonary hypertension (chronic MR)

• common cause of mild mitral regurgitation (congenital abnormality or degenerative myxomatous changes)

• common in women, who exhibits some features, such as sternal abnormalities, tall, thin stature

• may be inherited as an autosomal dominant phenotype

• symptoms - asymptomatic or associated with atypical chest pain, palpitations, anxiety, neuropsychiatric symptoms (neuroendocrine and autonomic disfunction occurs in some patients and may contribute to the symptoms)

• mitral valve usually is large, floppy, and redundant

• mid-systolic click - in the mildest forms (valve remain competent but bulges into the atrium during systole)

• the click is followed by a late systolic murmur in the presence of regurgitation (the murmurs lengthens as regurgitation becomes more severe)

• prolongation of chordae tendineae increase mitral regurgitation (chordal rupture - regurgitation becomes severe) - complications after fifth or sixth decade (loose myxomatous connective tissue, along with collagen dissolution

• increased incidence of arrhythmias (usually benign)

• haemodynamically significant mitral prolapse can predispose to infective endocarditis

• the long - term prognosis is good

CAUSES of AORTIC STENOSIS

1. Infants, children, adolescents - congenital aortic stenosis, congenital subvalvular aortic stenosis, congenital supravalvular aortic stenosis

2. Young adults to middle-aged - calcification and fibrosis of congenitally bicuspid aortic vavlve, rheumatic aortic stenosis

3. Middle-aged to elderly - calcification of bicuspid valve, senile degenerative aortic stenosis, rheumatic aortic stenosis

Aortic stenosis-

-increased gradient across the aortic valve (critical obstruction - peek systolic pressure gradient > 70 mmHG with abnormal cardiac output, or an effective aortic orifice <>

-hypertrophy of the left ventricle (coronary blood flow may become inadequate)

-outflow obstruction - limited the increase in cardiac output required in exercise

-complications - angina, left ventricular failure, arrhythmias

SYMPTOMS of AORTIC STENOSIS (mild and moderate aortic stenosis - asymptomatic; development of any of cardinal symptoms indicates substantial mortality risk)

1. Exertional dyspnoea (due to diastolic dysfunction associated with increased afterload uncompliant hypertrophied LV)

2. Exertional syncope (inability of the left ventricle to increase its output and maintain the cerebral flow during exercise)

3. Sudden death (arrhythmias, acute ischaemia)

4. Pulmonary oedema

5. Angina (disparity between oxygen supply and myocardial oxygen requirements)

SIGNS of AORTIC STENOSIS

1. Ejection systolic murmur (it is heard best at the aortic area, radiates into the base of the neck, its duration is related to the obstruction severity; intensity may decrease in advanced cases with reduced CO)

2. Slow rising carotid pulse, reduced pulse pressure (prolonged in duration and reduced in amplitude - pulsus parvus et tardus)

3. Left ventricular hypertrophy

4. Thrusting left ventricle

5. Signs of left ventricular failure

INVESTIGATIONS in AORTIC STENOSIS

1. ECG - left ventricular hypertrophy and ST changes (downsloping ST segment and T invrsion - strain pattern in leads reflecting the left ventricle), sometimes LBBB; in the elderly, ECG may be normal despite severe stenosis

2. CXR - P-A frequently normal; sometimes left ventricular enlargement and post-stenotic dilatation of ascending aorta; valve calcifications

3. Echocardiography - abnormal aortic valve (calcified and disorganised), hypertrophied left ventricle, the systolic gradient across the aortic valve
   Valve gradient indicative of moderate or severe stenosis- >60mm mercury

4. Cardiac catheterisation - systolic gradient between LV and aorta, post-stenotic dilatation of aorta, regurgitation of AV may be present

CAUSES of AORTIC REGURGITATION

1. Congenital - bicuspid valve, or disaproportionate cusps

2. Acquired - rheumatic disease, infective endocarditis, trauma, aortic dilatation (Marfan syndrome, atheroma, syphilis, ankylosis spondylitis)

Pathophysiology:

• the stroke volume is increased, as the LV ejects both the forward output and the blood that regurgitates during diastole (hypertrophy end dilatation of the left ventricle) - marked regurgitation

• pulsative arteries

• increased left ventricular diastolic pressure

• increased pulmonary vascular pressure (breathlessness)

SYMPTOMS of AORTIC REGURGITATION

1. Mild to moderate AR - often asymptomatic, awareness of heart failure, palpitations

2. Severe AR - symptoms of heart failure, angina (reduced diastolic coronary perfusion gradient)

SIGNS of AR

1. Pulses - large volume and collapsing pulse, bounding peripheral pulses, capillary pulsation in nail-beds (Quincke's sign), femoral bruit (pistol shot - Durozier's sign), heart nodding with pulse (de Musset's sign)

2. Murmurs - early diastolic murmur, systolic murmur of increased stroke volume, Austin Flint murmur at the apex (soft mid-diastolic that reflects relative mitral stenosis related to increased ventricular diastolic pressure on the mitral valve)

3. Other signs - thrusting apex, 4th heart sound, enlarged LV, signs of heart failure

INVESTIGATIONS

1. ECG - marked regurgitation-left ventricular hypertrophy and ST changes

2. CXR - cardiac and aortic dilatation; features of left ventricular failure

3. ECHO - dilated ventricle with vigorous contraction (until heart failure ensures); fluttering anterior mitral leaflet in the regurgitant jet vegetations in infective endocarditis;

4. Cardiac catheterisation - may not be required
   

AETIOLOGY - rheumatic origin (in association with mitral and aortic valve disease; uncommon - <5%>

CLINICAL FEATURES

• gradually progressive, more common in women

• symptoms of associated mitral or aortic stenosis;

• symptoms of right ventricular failure;

• raised JVP (may be present presystolic hepatic pulsation);

• mid-diastolic murmur (best heard at the lower left or right sternal edge, increased by inspiration);

• CXR - enlarged RA;

• ECHO - dilated RA, fused, thickened tricuspid valve, relativelly smal gradient across the tricuspid valve (5mm)-indicate the significant mitral stenosis

AETIOLOGY - (common valve disease) the most frequent "functional" (dilatation of the tricuspid annulus related to right ventricular dilatation, e.g. following pulmonary hypertension or cor pulmonale); rheumatic disease, tricuspid valve prolapse, Ebstein,s anomaly, carcinois syndrome, intracardiac tumors, infective endocarditis

SYMPTOMS - nonspecific, relate to reduced forward flow and venous congestion (tiredness, oedema, hepatic enlargement); functional TR may regress after associated lesions are corrected and pulmonary hypertension resolves

AETIOLOGY - usually cogenital (isolated or associated with other abnormalities), occasionaly occurs in an acquired form with hypertrophic cardiomyopathy or secondary to the pericardial tumor involment in the area

CLINICAL FEATURES:

• ejection systolic murmur, loudest to the left of upper sternum, radiating towards the left shoulder, and increased on inspiratin; may be thrill, best felt when the patients leans forward and breathes out; preceded by an ejection sound; delay in right ventricular ejection may cause wide splitting of the second heart sound

• the post-stenotic dilatation in the pulmonary artery on the CXR

• ECG - right atrial and right ventricular hypertrophy

• ECHO - abnormal PV, outflow gradient

• mild and moderate isolated PS - common, does not usually progress, and does not required treatment

• severe pulmonary stenosis (resting gradient>50mmHG with a normal cardiac output) - needs treatment

ASD classiefied by their location:

1. Ostium secundum defect - in the region of fossa ovalis

2. Ostium primum defect - inferior portion of the septum; may be associated with other endocardial abnormalities (e.g. split anterior leaflet, VSD)

PATHOPHYSIOLOGY: the left-to-right shunt in the atria determined by the size of the defect and the relative compliance of RV - gradual enlargement of the right size of the heart and of pulmonary arteries - pulmonary hypertension and sometimes shunt reversal

CLINICAL FEATURES:

• patients often asymptomatic during childchood and early adulthood

dyspnoea, chest infections, cardiac failure, arrhythmias (e.g. FA) - modes of presentations

• the characteristic physical signs: wide fixed splitting of the second heart sound (wide-delay in right ventricular ejection, increased stroke volume and RBBB; fixed-ASD equalises left and right atrial pressures throughout the respiratory cycle)

• a systolic flow murmur over the pulmonary valve (the left and right atrial pressure are similar, and the flow across the defect does not directly contribute the murmur)

• a diastolic flow murmur over the tricuspid valve (in children with a larged shunt)

• CXR - enlargement of the heart, the pulmonary artery, and pulmonary plethora

• ECG - IRBB (RV depolarisation is delayed as a result of ventricular dilatation), with a left axis deviation in a primum ASD

• patients with ASD and pulmonary-to-systemic shunt rations greather than 1.5 are referred for surgical repair

Normally, the ductus arteriousus functionally closes several hours after birth, and anatomically within 4 to 8 weeks.

In the presence of PDA, there is a continuous arteriovenous shunt between the aorta and pulmonary artery, the volume of which depends on the size of the ductus (50% of the LV output may be recirculated through the lungs-volume overload of LV and pulmonary congestion). Persistance of a large PDA can be complicated by pulmonary changes and Eisenmenger's physiology.

CLINICAL FEATURES:

• small shunts - asymptomatic

• large PDA - retarded growth and development

• sometimes cardiac failure (dyspnoea - first symptom)

• continous machinery murmur with late systolic accentuation, maximal in the second left intercostal space, accompanied by thrill

• CXR - enlargement of the pulmonary artery

• considerable rise in pulmonary artery pressure

• ECG - usually normal

• Eisenmenger's pathology - central cyanosis, more apparent in the feet and toes than in the upper part of the body; the murmur becomes quieter, may be confined to systole, or may disappear; ECG - right ventricular hypertrophy

AETIOLOGY - narrowing of the aorta commonly occurs in the region where the ductus arteriosus joins the aorta (i.e. just below the origin of the left subclavian artery); often associated with other abnormalities (i.e. bicuspid aortic valve, aneurysm of the circle of Wilis); acquired coarctation - rare (i.e. follow trauma, Takayasu's disease)

CLINICAL FEATURES

sometimes it is a cause of cardiac failure in the newborn

often asymptomatic until the adulthood

coarctation is suspected when a patients with systemic hypertension is found to delayed femoral pulse (radial-femoral pulse lag) and 30mmHG or greater systolic pressure difference between the right arm and the legs

other signs: headaches, weakness or cramps in the legs, the upper extremities and thorax may be more developed than lower extremities, abnormally large arterial pulsations in the neck

sometimes systolic murmur posteriorly, over the coarctation, ejection systolic murmur in the aortic area (due to bicuspid valve)

collaterals involving the periscapular and intercostal arteries (systolic or continous murmurs over the lateral thoracic wall

CXR - changes in the contour of the aorta ("3 sign"), notching of the under surfaces of the ribs from collaterals (due to erosion by dillated vessels)

1. RV outflow obstruction (pulmonary stenosis - subvalvular, valvular, supravalvular)

2. VSD

3. overriding of the VSD by the aorta

4. RV hypertrophy

CLINICAL FEATURES:

1. cyanosis - in spite of: cyanosis may be absent in the newborn, or in patients with mild right ventricular outflow obstruction ("acyanotic tetralogy of Fallot")

2. the subvalvular component of the RV outflow obstruction is dynamic (may increase under adrenergic stimulation) - sudden cyanosis, often after feeding or a crying attack, sometimes with unconsious and apnoea ("Fallot's spells")

3. in older children cyanosis becomes apparent, with stunting of growth, digital clubbing and polycythemia (relief by squatting after exertion)

4. loud ejection systolic murmur in the pulmonary area

5. polycythemia in some patients

6. ECG - right ventricular hypertrophy

7. CXR - abnormal small pulmonary artery, "boot-shaped" heart

the tricuspid leaflets do not attach normally and are displaced downward into the right ventricle (atrialized right ventricle) - tricuspid regurgitation, impaired right ventricular function; sometimes there is associated ASD or patent foramen ovale - RA to LA shunt and arrhythmias

1. Pathophysiology of Congestive Heart Failure

2. Therapeutic Classes

1. Cardiac glycosides

   1. Agents

      1. digitoxin

      2. digoxin

   2. Pharmacodynamics

   3. Pharmacokinetics

   4. Uses

      1. congestive heart failure: all degrees

      2. atrial fibrillation

      3. atrial flutter

      4. paroxysmal atrial tachycardia

      5. cardiogenic shock

   5. Adverse effects

      1. gastrointestinal

      2. central nervous system

      3. cardiac

      4. other

      5. treatment

2. Amrinone lactate

   1. Pharmacokinetics

   2. Use

   3. Adverse effects

3. Group III

   1. bretylium

   2. amiodarone

   3. Pharmacodynamics: increases prolongation of phase 3

4. Group IV: verapamil

   1. Pharmacodynamics

      1. depresses automaticity

      2. depresses A-V conduction

1. Brief review of cardiac electrophysiology and generation of arrhythmias

2. Cardiac action potential

   1. Phase 0

   2. Phase 1

   3. Phase 2

   4. Phase 3

   5. Phase 4

3. Therapeutic Classes

   1. Group I-A

      1. Agents

         1. quinidine

         2. procainamide

         3. disopyramide

      2. Pharmacodynamics

         1. depresses automaticity

         2. depresses phase 0

         3. depresses conduction velocity

   2. Group I-B

      1. Agents

         1. lidocaine

         2. phenytoin

         3. tocainide

         4. mexiletine

      2. Pharmacodynamics

         1. depresses automaticity

         2. depresses phase 0 slightly

   3. Group I-C

      1. Agents

         1. flecainide

         2. encainide

         3. propafenone

      2. Pharmacodynamics

         1. depresses automaticity

         2. marked depression of phase 0

   4. Group II

      1. Agents

         1. propranolol

         2. esmolol

         3. acebutolol

      2. Pharmacodynamics

         1. depresses automaticity

         2. depresses A-V conduction

Schizophrenia represents a major mental illness, or possibly a group of illnesses, manifested chiefly by disordered thought processes. The thinking disturbance leads to difficulties in communication, in interpersonal relationships, and in reality testing.

Primary symptoms:

1. Affective disturbance

2. Associative disturbance

3. Autism

Main accessory symptoms:

1. Delusions

2. Hallucinations

Schizophrenia is found 4 times more frequently among biological relatives than in the general population.

Biochemical Hypotheses of Schizophrenia

1. Endogenously formed psychotogens:

2. Dopamine hyperactivity

a. All neuroleptics antagonize dopamine receptors: dopamine - sensitive cyclase; receptor binding

b. Prolactin release by neuroleptics

c. Post-mortem receptor changes

d. Sensitivity to dopamine agonists

e. Resemblance of paranoid schizophrenia to amphetamine psychosis

Correlation between Clinically Effective Doses of Antipsychotic Drugs and D₂ Receptor Binding

I
ncreased D₂-like Receptors in Schizophrenic Brains

Typical Antipsychotics: Blockers of Dopamine D₂ Post-synaptic Receptors

Phenothiazines – chlorpromazine, fluphenazine, trifluoperazine, thioridazine

Chlorpromazine α₁ = 5-HT₂ > D₂ > D₁

Thioxanthines – chlorprothixene, thiothixene

Butyrophenones – haloperidol, droperidol

Haloperidol: D₂ > D₁ = D4 > α₁ > 5-HT₂

Others – loxapine, molindone, pimozide

Atypical Antipsychotic Drugs: Lower relative blockade of D₂ receptors, no or low EPS

Clozapine Antagonizes D₄ = a₁ > 5HT₂ > D₂ = D₁; no EPS; agranulocytosis and seizure in 2% of patients

Risperidone D₂ and 5HT₂ antagonist; antipsychotic > EPS

Olanzapine Most like clozapine in receptor profile, S₂ > D₂, high M₁ and D₁ receptor blockage

Quetiapine Similar to clozapine, S₂ > D₂

Sertindole: Similar to resperidone (5HT and DA antagonist) also a₁ antagonist.

Type	Manifestations	Mechanism
Autonomic nervous system	Loss of accommodation, dry mouth, difficulty urinating, constipation Orthostatic hypotension, failure to ejaculate Hypotension, arrhythmia	Muscarinic cholinoceptor blockade Alpha adrenoceptor blockade Antiadrenergic
Central nervous system	Parkinson’s syndrome, acute akathisia, acute dystonia Tardive dyskinesia, tardive dystonia Toxic-confusional state Sedation	Dopamine receptor blockade (Acute) Supersensitivity of dopamine receptors (Chronic) Muscarinic blockade Antihistaminergic (H1)
Endocrine system	Amenorrhea-galactorrhea, infertility, impotence	Dopamine receptor blockade resulting in hyperprolactinemia
Miscellaneous	Neuroleptic malignant syndrome Photosensitivity, heat sensitivity, cholestatic jaundice, retinal pigmentation

						Side Effects
Drug	Chemical Class	CPZ Equiv	DA2 Affinity	Ch-M Affinity	Adr1 Affinity	Extra-pyramidal	Anticholinergic Sedation Hypotension
Low potency Chlorpromazine Largactil	Aliphatic phenothiazine	100	+	+++	+++
Thioridazine Mellaril	Piperidine phenothiazine	100	+	+++	+++
Midpotency Perphenazine Trilafon	Piperazine Phenothiazine	8	++	++	++
Loxapine Loxapac	Dibenzoxazepine	10	++	++	++
High potency Haloperidol Haldol	Butyrophenone	2	+++	-	+
Fluphenazine Moditen	Piperazine phenothiazine	2	+++	-	+
Atypical Clozapine Clozaril	Dibenzodiazepine	80	+	+++	++	Absent	High
Risperidone		2	++	-	++	Low	Low

1. Evidence for down-regulated 5-HT_2A receptors in frontal cortex of schizophrenic patients.

2. Evidence for up-regulation of the 5-HT_2A receptor by antipsychotic drugs.

3. Evidence for cortical 5-HT_2A receptor regulation of dopaminergic function.

4. Inverse agonism at the 5-HT_2A receptor as a mechanistic explanation for antipsychotic action.

1. Diagnostic Complex

   1. General Info

      1. Bone TMRs = 1% of all malignancies

         1. Many times only find these b/c of pathologic frax, lump, or incidental x-ray finding.

-on x-ray, #1 cause of multiple holes in bones = METS (secondary)

1. Most common malignancy in bone is from METs of another cancer (2º)

1. Symptoms are often very vague.

2. Age (see later)

3. Radiographic findings alone can often determine if lesion is Benign, Aggressive, or Frankly Malignant.

   1. Site: some TMRs only occur at specific sites.

      1. Usually at sites of increased turnover (ex. metaphysis)

-Biggest metaphyses and largest amount of malignancies occur in:

Distal Femur > Proximal Tibia > Proximal Humerus.

1. Ex. Chondroblastoma on subchondral region of epiphysis of 17 year old.

1. Bone reaction to lesion?

   1. is the bone growing around the TMR (indicates a low-grade, slow growing TMR)

   2. is the TMR growing so fast that it has broken through the bone (high grade)

2. What kind of matrix is being formed? Bone? Cartilage?

1. Histology: Only after looking at clinical Sx’s, X-rays and forming a DDx to you do a biopsy.

2. Changes with Aging (important to remember for the DDx)

   1. <>

      1. Most bone TMRs arise from distant METS during this period.

         1. Neuroblastoma

         2. Wilm’s TMR

         3. Rhabdomyosarcoma

   2. Age 5 to 20

-this is a time of increased bone turnover and therefore increasedd risk of TMR formation/growth.

-most benign and malignant bone (of all ages) TMRs occur here.

1. Most TMRs at this age are benign

   1. #1 excised TMR is Osteochondroma (b/c it sticks out from the side of the bone – very noticeable)\

-fig 28-26

1. Most sarcomas occur here b/c of the increase turnover of the bone

   1. #1 is Osteosarcoma (1000-2000/year)

   2. #2 is Ewing’s Sarcoma (~400/year in the U. S.)

2. Primary Bone TMR

   1. b/c of  turnover, this is when most of the primary bone malignancies occur.

1. Age 20-40

   1. Few malignant bone TMRs occur.

   2. Most common is GCT of Bone, Fibrosarcoma/Malignant Fibrous Histiocytoma, Lymphoma

   3. Can immediately r/o Ewing’s, Osteosarcoma, METS (usually)

2. Over 40 Years old - Assume any excessive bone growth is malignant until proven otherwise

   1. #1 TMR is some kind of METS

   2. #1 Primary marrow TMR = Myeloma

   3. #1 Sarcoma = Chondrosarcoma (almost exclusive to older adults)

3. Bone TMR Sites

   1. Bone forming

      1. Metaphysis

      2. Knee

      3. Proximal Humerus

   2. Bone marrow derived/other

      1. Diaphysis

      2. Pelvis

   3. Solitary Bone Lesions (DDx of Holes in bones)

      1. Neoplasm: benign or malignant.

      2. Osteomyelitis: more common and mimics nearly everything.

      3. Cysts: idiopathic or the cystic remnant of a TMR.

      4. Focal Dysplasias: can mimic neoplasms.

      5. Metabolic Diseases: such as Hyperparathyroidism; brown TMR – check blood and look at other bones (is the problem systemic like a metabolic disease would beincreased)

      6. Infarcts: that mineralize and look like cartilaginous lesions.

4. Naming Bone TMRs

   1. Generally

      1. “-oma” = benign

      2. “-sarcoma” = malignant

5. General Prognosis of Bone TMRs

   1. Most are benign and w/o incident. They are usually removed b/c:

      1. They get in the way of a ligament (the growth)

      2. They are deforming (ex. if they are on the face)

      3. Incidental finding on x-ray and the pt or physician is paranoid.

      4. They cause a pathological frax (most common presentation)