Salim Soyinka LO's Flashcards
What is rheumatic fever (ARF)?
Delayed inflammatory complication of group A beta streptococcal pharyngitis that usually occur within 2-4 weeks of acute infection
What is the epidemiology of Acute rheumatic fever?
- Peak incidence 5-15 years
- more prevalent in resources limited countries
What are the causes (aetiology) of rheumatic fever?
- Previous infection with group A beta hemolytic streptococcus (GAS) also referred to as streptococcus pyogenes
- usually acute tonsilitis or pharyngitis (strep throat)
Clinical feature of ARF
- Fever
- malaise
- fatigue
- migratory polyarthritis
- Pancarditis (endocarditis, myocarditis, pericarditis)
- Valvular
- Sydenham chorea
- Subcutaneous nodules
- Erythema marginatum
Pancarditis
- rare condition with a poor prognosis combining endocarditis, myocarditis with abscess formation and purulent pericarditis
Endocarditis
- rare and potentially fatal inflammation of the inner lining of the heart chambers and valves and is usually caused by bacteria
Myocarditis
- Inflammation of heart muscle
Pericarditis
- inflammation of the pericardium/ thin sac that surrounds the heart
High pressure valves
- aortic
- mitral
Mitral valve and ARF
- 65 % of cases
- early mitral regurgitation
- late mitral stenosis
Most common cause of mitral stenosis
Rheumatic fever
Aortic valve and arf
- 25 % of cases
Tricuspid valve and ARF
- 10% of cases
Sydenham chorea
- involuntary, irregular, nonrepetitive movements of the limbs, neck, head and/or face
Clinical features sydenham chorea
- 1-8 months after infection
- sometimes asymmetrical or confined to one side
- speech disorders
- ballismus
- muscle weakness
- neuropsychiatric symptoms ( inappropriate laughing/crying, agitation, anxiety, apathy, OCD behaviour)
Ballismus
- severe movement disorder
Pathophysiology of sydenham chorea
- streptococcal antigens lead to Ab production–> Abs cross-react with structures of the basal ganglia and cortical structures –> reversible dysfunction of cortical and striatal circuits
Erythema marginatum
- expanding pink or light rash with a well defined outer border and central clearing
JONES criteria for diagnosis rheumatic fever
- Joints
- Pancarditis
- Nodules
- Erythema marginatum
- Sydenham chorea
Pathophysiology ARF
- Exact pathogenesis not entirely understood but most common
- Acute tonsilitis/ pharyngitis caused by GAS without antibiotic treatment –> development of antibodies against streptococcal M protein–> cross reaction of antibodies with nerve and myocardial proteins (most commonly myosins) due to molecular mimicry–> type II hypersensitivity reaction –> acute inflammatory sequela
Molecular mimicry
- similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign derived antigen in a susceptible individual
Pathology of ARF
- Aschoff bodies
- Anitschkow cells
Aschoff bodies
- nodules found in the hearts of individuals with rheumatic fever
Anitschkow cells
- cardiac histiocytes appearing in Aschoff bodies
- ovoid nucleus containing wavy, caterpillar like bar of chromatin
Histiocytes
- macrophages found in tissue not in blood
Investigations for ARF
- Full blood counts (leukocytosis)
- May show normochromic normocytic anemia of chronic inflammation
- Elevated CRP/ESR
- Tests to show recent GAS infection ( increased antistreptolysin O titer and antistreptococcal DNAse B titer
- Positive throat culture
- Positive rapid GAS carbohydrate antigen detection test
- Confirmed ARF: ECG and echocardiogram
Prognosis ARF
- ## Early death due to myocarditis rather than valvular defects
Advantages of antibiotic prophylaxis
- non-invasive method of preventing future medical issues/infections eg at surgical site infection
- Prevention of bacteremia (spread of bacteria to blood)
Disadvantages of antibiotic prophylaxis
- Resistance: bacteria become resistant to the low dose of antibiotics over time so that the antibiotics are no longer effective
- Cost of therapy can be high
- Abuse by public and GP’s
- Toxicity and adverse reactions
- Interactions with other drugs
Why would additional antibiotics be needed to during surgery/dentistry in rheumatic heart disease?
- commensals can be introduced into bloodstream
- Harmless for most people but in those. with rheumatic heart disease bacteria can settle on damage endocardium and become surrounded by platelets and fiblin and begin to destroy heart valves
- Phagocytes cannot reach through due to protective fibrin
Why are prophylaxis antibiotics stopped in adulthood?
- Adults less likely to get streptococcal throat infections
Why are prophylaxis antibiotics given in rheumatic fever?
- Patients with RF have a higher incidence of recurrent s.pyogenes infection than others and each new episode causes a new episode of RF
Drugs affecting bacterial cell wall
- Beta lactams (penicillins, cephalosporins, monobactams, carbapenems)
- Glycopeptides
- Cyclic lipopeptides
- Polymixins
- Phosphoric acid derivatives
MOA beta lactams (ring)
- bind to penicillin binding proteins (PBP)/ transpeptidation enzymes
- Inhibits the transpeptidases (cannot cross link peptide chains) and cell cannot maintain its transmembrane osmotic gradient
- cell swelling rupture and death
MOA glycopeptides
vancomycin
- Binds to D-Ala-D-Ala sequence on peptide chain preventing peptidoglycan polymerase from binding single subunits to form a peptidoglycan chain
- Transpeptidation is also inhibited
MOA cyclic lipopeptides
daptomycin
- lipophilic tail of daptomycin is inserted into the bacteial cell membrane
- Causing rapid membrane depolarisation and potassium ion efflux
- DNA, RNA and protein synthesis are inhibited and cell death occurs
MOA polymixins
colistin: polymixin E, polymixin B
- initial target is LPS of outer membrane
- bind to phospholipid in OM leading to cell membrane permeability changes, osmotic barrier lost and cell death occurs due to leakage of cell content
MOA phosphoric acid derivatives
fosfomycin
- Taken into bacterial cell and inhibits synthesis of peptidoglycan by blocking the formation of NAM disrupting cell wall synthesis
List drugs affecting bacterial DNA
- Quinolones
- Nitroimidazole
- Nitrofuran
- Sulphonamides
- Diaminopyrimidines
Quinolones MOA and eg
- Ciprofloxacin, moxifloxacin, levofloxacin
- inhibit DNA gyrase and topoisomerase IV
- Gyrase introduces negative superhelical twists in the bacterial DNA diuble helix
- Topoisomerase IV: responsible for segregating newly formed DNA into two new chromosomes
Nitroimidazole MOA and eg
- metronidazole
- converted to a toxic metabolite by an oxidoreductase enzyme
- Active against anaeobic bacteria as they possess the oxidoreductase enzyme
- Toxic metabolite acts as an electron acceptor (reduced)
- Resulting free radical intermediates damage DNA
- Bactericidal
Nitrofuran MOA and example
- eg nitrofurantoin
- reduced by nitrofuran reductase to unstable reactive metabolites which disrupt ribosomal RNA, DNA and other cell processes
- Bactericidal
Sulphonamides MOA and example
- Sulfamethoxazole
- structurally similar to PABA and inhibits enzyme dihydropteroate synthetase
PABA
bacteria use PABA to synthesise folate to manufacture purines in folic acid pathway
Diaminopyrimidines MOA and example
- Trimethoprim
- Inhibition of dihydrofolate reductase
Co-trimoxazole
- Sulfamethoxazole and trimethoprim
Drugs affecting protein synthesis
- Macrolides
- Aminoglycosides
- Tetracyclines
- Glycylcycline
- Amphenicols
- Lincosamides
- Fusidane
- Oxazolidinones
Bacterial ribosome
70s (30s and 50s)
Macrolides MOA and example
- azithromycin, clarithromycin, erythromycin
- inhibit RNA-dependent protein synthesis by binding reversibly to the 50s subunit
- Binding inhibits translocation of the peptide chain from the acceptor site (A) to the P site (donor site) blocking protein synthesis
- bacteriostatic
Lincosamides MOA and example
- Clindamycin
- Binds 50s subunit, similar to macrolides
Amphenicols MOA and eg
- chloramphenicol
- Binds reversibly to 50s subunit and inhibit peptide bond formation preventing elongation of the peptide chain
Oxazolidinones MOA and eg
- linezolid
- Bind to 50s ribosomal subunit and prevent initiation of tRNA transcription
Aminoglycosides MOA and eg
- Gentamicin, tobramycin, amikacin
- bind irreversibly to the 30s ribosomal subunit inhibiting translation from mRNA to protein, also cause misreading of mRNA
- Bactericidal
Tetracyclines MOA and eg
- tetracycline, minocycline, doxycycline
- bind reversibly to 30s subunit and block tRNA binding to the A site on the mRNA ribosome complex
- bacteriostatic
Glycylcycline MOA and eg
- tigecycline
- bind reversibly to 30s subunit and block tRNA binding to the A site on the mRNA ribosome complex (same as tetracyclines)
Fusidane MOA and eg
- fusidic acid
- inhibits protein synthesis by preventing the translocation of elongation factor G from the ribosome
- Elongation factor G is a catalyst for the translocation of tRNA and mRNA down the ribosome
- bactericidal
Risk factors for acute rheumatic fever
- Age 5-14 –> initial episodes rare in older teens and young adults
- Family hx: HLA class II genes appear to be strongly associated
- certain strains of group A strep are more likely to contribute ( serotypes)
- Environmental: crowding, poor hygiene lead to rapid transmission of strep
Medical options in treatment of valvular heart disease
- prophalyaxis antibiotics
- Regular check ups at the dentist
- Antibiotics during any surgical/dental procedures
- Diuretics ( excess fluid)
- ACE inhibitors (BP)
- Antiarrythmic medications
- Vasodilators
- Beta blockers (BP)
- Antithrombotic drugs
- Anticoagulants
Surgical options in treatment of valvular heart disease
- Valve reconstruction (annuloplasty)
- Valve replacement
- Percutaneous balloon valvuloplasty for stenosis (balloon in stenotic valve to widen)
Types of valve replacement and advantages/disadvantages
- biological: anticoagulants only needed for 3 months but 10 year life span
- prosthetic: life long span but anticoagulants always needed
Antibiotics used for GAS infection
- first line penicillin V
- cephalosporins or macrolides if penicillin allergy
Rheumatic heart disease vs infective endocarditis
- infective endocarditis: infection of the endocardium that typically affects one or more heart valves, usually a result of bacteremia, which is most commonly caused by dental procedures, surgery, distant primary infections, and nonsterile injections
- Rheumatic heart disease:: does not involve bacterial infection, heart valves have been left damaged by rheumatic fever and are susceptible to bacterial infection
What does left sternal edge heave indicate?
- heel of hand lifted off chest during each systole
- Aortic stenosis
Aetiology of infective endocarditis
- Staphylococcus aureus: 35-45% IE cases, drug users, prosthetic valves, pacemakers
- Viridans streptococci: 20% cases, most common cause subacute IE especially in predamaged native valves (mitral), dental procedures, produce dextrans which facilitate binding of fibrin-platelet aggregates on heart valves
- Staphylococcus epidermis: less than 15% of cases, bacteremia from infected peripheral venous catheters, subacute IE in patients with prosthetic heart valves, pacemakers, ICD’s
- Enterococci (especially enterococcus faecalis): 10%, multiple drug resistance, cause of IE after nosocomial UTI’s. native and prosthetic valves IE
- Streptococcus gallolyticus: less than 10% cases, colorectal cancer
- GRAM negative HACEK group: less than 5% of cases, poor dental hygiene/peridontal infection
- Fungal endocarditis ( candida, aspergillus fumigatus): less than 5%, immunosuppressed patients, IV drug abusers, cardiosurgical interventions, long-dwelling IV catheters
- Coxiella burnetii Bartonella species: less than 5% of native valve IE cases, Gram-negative pathogens responsible for culture-negative endocarditis
Pathology of infective endocarditis
- Damaged valvular endothelium–> exposure of the subendothelial layer–> adherence of platelets and fibrin–> sterile vegetation (microthrombus)
- localised infection or contamination –> bacteremia–> bacterial colonization of vegetation–> formation of fibrin clots encasing the vegetation–> valve destruction with loss of function
Valves involved in infective endocarditis (in order most frequent)
- mitral
- aortic
- tricuspid (most common IV drug users)
- pulmonary
Clinical consequences of IE
- bacterial vegetation–> bacterial thromboemboli–> vessel occlusion–> infarctions
- emboli can lead to metatstatic infections of other organs
- formation of immune complexes and antibodies against tissue antigens –> glomerulonephritis, oslers nodes
Atrial septation
- septum primum forms and extends down towards endocardial cushions to split atria in 2
- ostium/foramen primum is a hole present before septum primum completes fusion with endocardial cushions
- before ostium primum closes, ostium secondum appears within septum primum
- septum secondum grows with a hole known as foramen ovale present
- presence of ostium secondum and foramen ovale allows a right to left shunt to be present in developing heart
Ventricular septation
- muscular ventricular septum grows up from the floor of ventricles towards fused endocardial cushions
- small gap in interventricular septum remains which i filled with membranous portion of ventricle
Heart formation
- Blood islands condenses to form 2 heart tubes
- lateral folding to form primitive heart tube
- Sinus venosus: RA
- primitive atrium
- primitive ventricle: left ventricle
- bulbus cordis: right ventricle
- truncus arteriosis : ascending aorta and pulmonary trunk
- cardiac looping
LaPlace law (heart work and mural tension)
T= PR/2 T= wall tension P= pressure R= radius - dilation: increased radius, T has to rise to generate given pressure in systole S= Pr/2h S=stress, 2h wall thickness
Dilated ventricle: increased radius, muscle stretched thin, stress increases more than tension
Ventricular stretch makes AV valves incompetent as papillary muscles and chordae tendinae no longer span gap between ventricular walls and mitral and tricuspid valves
Blood is forced back into atria, squanders part of cardiac work
Leaky valves and undue stress on ventricular muscle mean that beyond a certain point, rises in cardiac pressure are self- defeating
Starlings Law of the heart (normal and failing ventricle)
- stroke volume of left ventricle will increase as the left ventricular volume increases due to myocyte causing a more forceful systolic contraction
S2
- closure of aortic and pulmonary valves
- higher pitch and shorter than S1
- beginning of diastole
S3
- can be normal in some people but can also be pathogenic
- low pitch
- mid diastolic
- gallop rhythm
S4
- always pathological
- late diastolic
- higher pitch than S3
Stenosis
narrowing of vessel/valve
Regurgitation
backflow of blood
systolic murmur
- ASMR
- Aortic stenosis
- Mitral regurgitation
- pulmonic stenosis
- atrial septal defect
- tricuspid regurgitation
- VSD
- mitral valve prolapse
diastolic murmur
- Aortic regurgitation
- Mitral stenosis
diastolic murmur
- Aortic regurgitation
- Mitral stenosis
- pulmonic regurgitation
- tricuspid stenosis
- patent ductus arteriosus
aortic stenosis
mid systolic
crescendo-decrescendo
Mitral regurgitation
holosystolic
high pitch
blowing
Aortic regurgitation
early diastolic
high pitch
blowing
crescendo
Mitral stenosis
mid-late diastolic
opening snap
rumbling
how are murmurs graded
1-5 where 1 is very faint and 5 is very loud, may be heart with stethoscope entirely off chest
P wave
atrial depolarisation
0.12 seconds
QRS wave
ventricular depolarisation
less than 0.12 sec
ST segment
plateau phase of depolarisation
PR
Transmission of signal from atria to ventricles
0.12 to 0.2
Prolonged blockage
Shortened: extra tissue
T wave
Rapid ventricular repolarisation
QT wave
hypo/hyperkalemia
look at pic of cardiac cycle combination
Calculate axis of heart –> see notes
Warfarin
- Vitamin K is a cofactor for gamma-carboxylation of glutamic acid, which is essential for proper function of coagulation factors II, VII, IX, X.
- Vitamin K is reduced by epoxide reductase and in its reduced form acts as a cofactor for carboxylation.
- Warfarin inhibits expoxide reductase, preventing vitamin K from acting as a cofactor
- Is slow acting, takes about 2-5 days to work and is used for chronic anti-coagulation
- AE – teratogenic, bleeding, skin necrosis, drug-drug interactions
Heparin
- Antithrombin III typically inactivates thrombin and factor Xa, but the process is slow
- Heparin is a long sugar that will bind both ATIII and thrombin, or ATIII and Xa, to increase the speed at which ATIII inhibits these coagulation factors.
- prothrombin to thrombin and fibrinogen to fibrin inhibited
Unfractionated vs LMW heparin
- LMWH Xa activity
- unfractionated Xa and IIa activity
Dabigatran
Direct thrombin inhibitor
Rivaroxaban
Direct Xa inhibitor
