Lecture 17+18+20 Flashcards
all patients with systolic HF take?
ACEi + Beta blocker + diuretic
drugs types for diastolic HF
diuretics
ACEi / ARB
ca channel inhibitors
beta blockers
DO not use positive inotropes
PDE III inhibitor examples
Inamrinone and Milrinone
MOA of PDE inhibitors
Inhibit myocardial cAMP PDE activity → increased cAMP
levels
reduce preload and afterload
increase AV conduction slightly
used for short-term HF treatment
dopamine
stimulates dopaminergic and adrenergic
• Lower doses = mainly dopaminergic stimulating
(produce renal and mesenteric vasodilation)
• Higher doses = both dopaminergic & b1 stimulating
(produce cardiac stimulation & renal vasodilation)
• Large doses = stimulate a receptors
(vasoconstriction)
used for: cardiogenic shock
Dobutamine
At therapeutic levels the stimulation of b1 -receptors
predominate
potent inotropic effect and mild vasodilation
Used to increase cardiac output in acute management
of heart failure
glucagon
Stimulates adenylyl cyclase to produce increased cAMP (by binding to GPCR), leading to potent inotropic and chronotropic effects
produces similar effect as beta agonists
Used as a cardiac stimulant in management of severe
cases of b-blocker over dosage
myocardial AP phases
phase 0: rapid upstroke and depolarization
Na channels open (Na into cell)
phase 1: initial repolarization
Na channels close, and K open ( K goes out)
phase 2: Plateau
voltage sensitive Ca channels open
slow inward current (balances with K)
phase 3: repolarization
Ca channels close
K channels open (outward)
phase 4: resting potential
increase depolarization due to increase Na permeability
pacemaker AP
phase 0: upstroke
Ca channels open (slow velocity)
phase 3:
Ca channels inactivate; increase in K activation
phase 4:
slow repolarization due to If
treatment for abnormal automaticity
decrease the slope of phase 4 depolarization
raise the threshold of discharge
treatment for re-entrant circuits
slow conduction
increase the refractory period
treatment for afterdepolarizations
slowing conduction
increase the refractory period
Class I anti-arrhythmic drugs
class I are fast channel blockers for Na
IA: Quinidine, procainamide, disopyramide
(IB) Lidocaine, mexiletine
(IC) Flecainide, propafenone
Class II anti-arrhythmic drugs
Beta blockers (Ca)
Propranolol, metoprolol, esmolol
Class III anti-arrhythmic drugs
- inhibitors of repolarization (K+)
Amiodarone, sotalol, dofetilide
Class IV anti-arrhythmic drugs
calcium channel blockers (Ca2+)
Verapamil, diltiazem
miscellaneous anti-arrhythmic drugs
Digoxin, adenosine, magnesium, atropine
Class I MOA
block fast inward Na channels
decrease Na entry; slow raise of phase 0
cause decrease in excitability
Use/state dependence = cells discharging at
abnormally high frequency are preferentially blocked
Class IA MOA
slow rate the change in phase 0
prolong phase 3 (inhibit K)
prolonged repolarization
Quinidine
Class IA anti-arrhythmic
CA: Suppression of supraventricular and ventricular
arrhythmias
Inhibits CYP 2D6, 3A4 & P-glycoprotein
AE of Quinidine
Arrhythmias (torsades de pointes) SA & AV block or asystole Nausea, vomiting & diarrhea (30-50%) Thrombocytopenic purpura Cinchonism
toxic dose = tachy
contraindications of Quinidine
cannot use in those with Heart block
caution in those with heart issues
MOA of procainamide
Similar actions to quinidine
• Blockade of Na+ channels in activated state
• Blockade of K+ channels
• Antimuscarinic properties
CA: Suppression of supraventricular and ventricular
arrhythmias
metabolized by CYP2D6
Partly acetylated to N-acetylprocainamide (NAPA) which prolongs duration of action potential
AE of procainamide
Reversible lupus-like syndrome (25-30%)
Toxic doses: asystole, induction of ventricular
arrhythmias
CNS effects (depression, hallucination, psychosis)
Weak anticholingeric effects
Hypotension
more prevalent in chronic use
contra of procainamide
hypersensitivity, SLE, heart issues (heart block)
MOA of Disopyramide
Strong negative inotropic effect (> quinidine & procainamide) Strong antimuscarinic properties causes peripheral vasoconstriction Blocks K+ channels
CA: Suppression of supraventricular and ventricular
arrhythmias
AE of disopyramide
Pronounced negative inotropic effects
Severe antimuscarinic effects
May induce hypotension & cardiac failure without preexisting myocardial dysfunction
pathogenesis of nephrotic syndrome
damage to glomerular cells which then increases the permeability of the capillaries to proteins
loss of proteins leads to a decreased plasma oncotic pressure… which then leads to the loss of fluid
edema and increased lipoproteins
risks of having membranous nephropathy
thrombosis: can be venous or arterial
patho:
1. Hypercoagulability due to Urinary loss of endogenous anticoagulants (anti thrombin III)
Hypoalbuminemia → stimulation of protein synthesis in liver → increased production of coagulation factors
Intravascular volume depletion → increased blood viscosity
- Endothelial dysfunction due to pro inflammatory cytokines
symptoms of nephrotic syndrome
heavy proteinuria
edema
lipiduria
hyperlipidemia
infection and embolism
Minimal Change Disease
benign disorder is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes)
most common cause of nephrotic syndrome in children (2-6)
can sometimes follow a respiratory infection or immunization
eitopath:
some immune dysfunction that results in the elaboration of factors (“glomerular permeability factors”) that damage visceral epithelial cells and cause proteinuria
no immune deposits are seen
histo of minimal change disease
electron microscopy = will see effaced/ fused foot processes
light = everything looks norm
immuno = no depositions
clinical features of minimal change disease
- Disease typically manifests with abrupt development of the nephrotic syndrome in an otherwise healthy child
- No hypertension
- Renal function is preserved in most of these patients
- Periorbital edema and generalized edema (anasarca)
- Protein loss usually is confined to smaller plasma proteins, chiefly albumin (selective proteinuria)
- Prognosis for children with this disorder is favorable – no tendency to develop into a chronic renal failure/end stage kidney disease
- More than 90% of children respond to a short course of corticosteroid therapy
Focal Segmental Glomerulosclerosis
can be primary (idiopathic) or secondary
primary = most common cause of nephrotic syndrome
disorder of the podocytes
secondary:
HIV, obesity, cancer, drug use
patho of secondary FSGS
reduction in renal mass due to a renal disease
will lead to compensatory hypertrophy and hyperfiltration
will have Intraglomerular hypertension
Focal and segmental sclerosis in glomeruli
micro of FSGS
light:
Collapse of capillary loops, increase in matrix, and
segmental deposition of plasma proteins along the
capillary wall
immuno:
Negative/ or non-specific granular deposits of IgM and
C3
electron:
Diffuse effacement of foot processes, and there may also be focal detachment of the epithelial cells and denudation of the underlying GBM
Clinical features that differ MCD from FSGS
- Higher incidence of microscopic hematuria, reduced GFR (renal insufficiency) and hypertension
- Proteinuria is more often non-selective (more than just albumin)
- Poor response to corticosteroid therapy
- Progression to chronic kidney disease (50% develop end stage renal disease within 10 years
proteinuria:
insidious in onset
non-selective
more than 3.5
Membranous Nephropathy
characterized by diffuse thickening of the glomerular
capillary wall due to the accumulation of deposits containing Ig along the subepithelial side of the basement membrane
epi: 30-50 more common in males most common cause of nephrotic syndrome in elderly really rare in kids
etio: most cases are primary
Autoimmune disease caused in most cases by antibodies to a renal autoantigen; most commonly PLA2R (phospholipase A2 receptor) on podocytes
secondary:
1. endogenous (SLE, cancer, other Autoimmune conditions)
- exogenous
drugs and infections
patho of membranous nephropathy
direct and indirect?
- antigen-antibody reaction
- complement activation
- insertion of MAC into membrane
can be direct or indirect damage
direct:
• Alteration of cytoskeleton
• Effacement of foot processes
• Detachment of podocyte
indirect:
• Activation of epithelial and mesangial cells
• Proteases, oxidants, cytokines
• Stimulation of GBM growth (“spikes”)
either way it leads to increased permeability of the BM
massive proteinuria
histo of membranous nephropathy
light: thickening of the BM
silver stain: spike and dome appearance
immuno:
Granular IgG and C3 deposits around the glomerular basement membrane
clinical features of membranous nephropathy
nephrotic syndrome, microscopic hematuria (50%), hypertension
some have remission; can develop ESRD or thrombosis
Diabetic Nephropathy
Renal disease follows cardiac causes (myocardial infarction) of mortality in patients with diabetes mellitus
due to the side effects of hyperglycemia
can see:
- Glomerular lesions
- Renal vascular lesions, principally arteriolosclerosis
- Pyelonephritis (tubules and interstitium), including necrotizing papillitis
patho of diabetic nephropathy
systemic hyperglycemia
leads to increased matrix formation, increased type IV collagen, and hyperfiltration
histo of diabetic nephropathy
- GBM thickening (identified on EM first)
- Mesangial widening
- Tubular BM thickening
Kimmelstiel-Wilson nodules will be seen
can see ischemia
hyaline arteriosclerosis
NODULAR GLOMERULOSCLEROSIS
Distinctive glomerular lesion characterized by ball-like deposits of a laminated matrix in the periphery of the glomerulus
the nodules are PAS +
can be seen in those with chronic DM
kidneys will be granular and contracted
clinical features of diabetic nephropathy
initially the hyperglycemia just leads to hyperfiltration
(increased GFR)
after a while microalbuminuria occurs
after there is persistent & progressive proteinuria, hypertension, highly variable decline in GFR 1-24 ml/min/year
renal amyloidosis
kidney will appear to be normal color and shape
in extreme cases they might be smaller
micro:
Amyloid deposited primarily in the glomeruli
Interstitial peritubular tissue, arteries, and arterioles are also affected
will see deposits along the BM
CF of renal amyloidosis
Most common renal presentation: nephrotic syndrome
Renal insufficiency is present in 50% at time of Diagnosis.
Electrolyte abnormalities (Fanconi syndrome)
Nephrotic syndrome
Clinical entity due to glomerular disease characterized by
• Heavy proteinuria (>3.5 g/day)
• Hypoalbuminemia and severe edema
• Hyperlipidemia and lipiduria (lipid in urine)
Acute kidney injury
Rapid decline of GFR (within hours to days)
Dysregulation of fluid and electrolyte balance
Retention of metabolic wastes
Chronic kidney disease
Reduced GFR that it persistently less than 60 mL/minute/1.73 sq. m for at least 3 months from any cause and/or persistent albuminuria
End stage renal disease
GFR is less than 5% of normal
This is the terminal stage of uremia
Renal tubular defects
Polyuria (excessive urine formation) and nocturia
Electrolyte disorders
Disorders directly affecting tubules or cause defects in specific
tubular functions (inherited or acquired)
Urinary tract infections
Bacteriuria and pyuria
May infect kidney (pyelonephritis) or bladder (cystitis)
Nephrolithiasis (renal stones)
Spasms of severe pain (renal colic) and hematuria
Nephritic syndrome
Acute in onset; characterized by Grossly visible hematuria or dysmorphic RBCs and red cell casts in urine
Reduced GFR, mild to moderate proteinuria and hypertension
