Lecture 25+26 Flashcards
Type IIB Familial combined hyperlipidemia
high LDL and high VLDL
Overproduction of VLDL by liver
Type IV Familial hypertriglyceridemia
high VLDL
Overproduction and/or impaired catabolism of
VLDL
Type I Familial hyperchylomicronemia
increase in chylomicrons
deficiency in LPL or ApoCII
Type IIA Familial hypercholesterolemia
high LDL
Decreased or no functional LDL receptor
expression
Type III Familial dysbetalipoproteinemia
high IDL
Abnormal apoE
Type V Familial mixed hypertriglyceridemia
increase in chylomicrons and high VLDL
Increased production or decreased clearance of
VLDL & chylomicrons.
MOA of statins
Statins are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes the first committed step of cholesterol biosynthesis
By inhibiting cholesterol synthesis statins
deplete intracellular supply of cholesterol
Depletion of intracellular cholesterol leads to
upregulation of HMG-CoA reductase, and upregulation
of the LDL receptor
Upregulation of LDL receptors results in increased clearance of LDL from the blood
The uses of statins
• Drugs of choice for LDL reduction.
• Reduce cardiovascular mortality.
• Lower LDL levels in all types of hyperlipidemias.
• Homozygotes for familial hypercholesterolemia
lack functional LDL receptors and thus benefit much less from treatment with statins.
• Contraindicated in pregnancy
AE of statins
Elevation of aminotransferases
Myopathy and rhabdomyolysis
Niacin
Decreases VLDL, LDL and Lp(a) levels.
It increases HDL levels
Most effective agent for increasing HDL and the only agent that may reduce Lp(a).
MOA of niacin
Niacin inhibits adenylyl cyclase in adipocytes. Leading to inhibition of hormone-sensitive lipase
In the liver niacin inhibits synthesis and
esterification of fatty acids. VLDL production is
decreased
increases LPL activity
uses of Niacin
• Niacin is the most effective drug for raising HDL.
• Particularly useful in patients with combined
hyperlipidemia and low HDL levels.
• Effective in combination with statins
AE of niacin
Intense cutaneous flush after each dose of niacin when the drug is started or the dose increased
taking aspirin before will decrease the flushing
Pruritus, rashes, dry skin. Acanthosis nigricans. Nausea and abdominal discomfort hepatotoxicity hyperglycemia elevate uric acid levels
Fibrates examples
Gemfibrozil
Fenofibrate
Fibrates lower VLDL levels and increase HDL
levels
MOA of fibrates
Fibrates activate peroxisome proliferator activated receptor-alpha (PPAR-alpha).
• PPAR-alpha receptors are expressed primarily in
liver and brown adipose tissue.
• Activation of PPAR-α by fibrates leads to a decrease in plasma TG levels and increase in plasma HDL levels due to the increase LPL and decreased expression of apoC-III
increase HDL and decrease TG
uses for the fibrates
DOC in severe hypertriglyceridemia
Reasonable consideration in moderate
hypertriglyceridemia.
As monotherapy, fibrates offer the highest TG reduction, followed by niacin, W-3-fatty acids, statins, and ezetimibe.
AE of fibrates
Mild GI disturbances.
Myositis
Lithiasis
drug interactions with fibrates
Gemfibrozil inhibits hepatic uptake of statins, thus more statin in blood
(Gemfibrozil competes for the glucuronosyl transferases that metabolize most statins)
increased risk for rhabdomyolysis
fenofibrate does not interfere with interact with statin metabolism
bile acid binding resins
Cholestyramine
Colestipol
Colesevelam
Useful only in hyperlipidemias involving isolated
increases in LDL
MOA of bile acid binding resins
Bind to anionic bile acids in the intestinal lumen and prevent their reabsorption.
The resin-bile acid complex is excreted in the feces, thus preventing bile acids from returning to the liver by the enterohepatic circulation
The reduction in bile acid concentration causes
hepatocytes to increase conversion of cholesterol
to bile acids. This leads to up-regulation of LDL receptors in the liver
decrease in LDL levels
modest increase in HDL
increase synthesis of cholesterol
uses of bile acid binding resins
Used with statins or niacin to increase LDL
reduction.
Drugs of choice for pregnant women and for
children.
Little effect in individuals who completely lack
functional LDL receptors
AE of bile acid binding resins
GI adverse effects: bloating, nausea, cramping
and constipation.
Colesevelam produces fewer GI adverse effects
than cholestyramine or colestipol.
They may increase TG: contraindicated in
hypertryglyceridemia
bile acid binding resins: drugs interactions
Cholestyramine and colestipol reduce absorption
of several drugs and liposoluble vitamins
Ezetimibe
cholesterol absorption inhibitor
Inhibits intestinal absorption of cholesterol and
phytosterols.
Its primary clinical effect is to lower LDL
MOA of ezetimibe
Ezetimibe inhibits an intestinal transport protein
(NPC1L1), which takes up cholesterol from the
lumen
This triggers a compensatory increase in cholesterol synthesis (which can be inhibited with a statin).
upregulation of LDL receptors, which enhances LDL clearance from plasma
uses of Ezetimibe
Useful in combination with a statin in patients unable to reach their LDL goal on statin monotherapy.
First non-statin drug that should be considered as an adjunct to a statin.
Ezetimibe is only used as monotherapy in patients who do not tolerate statins.
AE of ezetimibe
Low incidence of reversible impaired hepatic
function.
Small increase in incidence when ezetimibe is given with a statin.
Myositis has been reported rarely
ezetimibe drug interactions
Bile-acid sequestrants inhibit absorption of
ezetimibe.
The two agents should not be administered
together
Hypertension- Nephrosclerosis
associated with sclerosis of renal arterioles and small arteries; it is strongly associated with hypertension
patho:
Medial and intimal thickening, a response to hemodynamic changes, aging, genetic defects
Hyalinization of arteriolar walls, caused by extravasation of plasma proteins through injured endothelium and by increased deposition of basement
membrane matrix
Benign Nephrosclerosis
vascular:
Medial and intimal thickening
Hyaline arteriolosclerosis
glomerular:
Global sclerosis
FSGS – compensatory hyperfiltration due to
nephron loss
tubulointerstitial:
Tubular atrophy
Ischemia mediated interstitial fibrosis
patho of benign nephrosclerosis
hypertension = medial and intimal thickening (arteries)
= luminal narrowing = ischemic injury and decreases pressure transmission
histo of benign nephrosclerosis
gross:
Cortical surfaces have a fine, even granularity that
resembles grain leather
Loss of mass is due mainly to cortical scarring and
shrinking
histo:
Hyaline arteriosclerosis
Microscopic subcapsular scars with sclerotic
glomeruli and tubular dropout, alternating with
better preserved parenchyma
CF of benign nephrosclerosis
- Long-standing history of hypertension
- Slowly progressive elevation in serum Creatinine
- Mild proteinuria (<1 g/day)
- No microscopic hematuria
- Few progressing to ESRD
- Clinically: long-standing hypertension
- Bland urine sediment with mild proteinuria
Malignant Nephrosclerosis
hypertension (malignant HPN)
organ damage and renal lesions
patho of malignant nephrosclerosis
HTN = Medial and intimal thickening and Duplication of BM = luminal narrowing = ischemic injury and fibrinoid necrosis in severe HTN
Renal Artery Stenosis
hypertension secondary to renal artery stenosis is caused by increased production of renin from the ischemic kidney
Ischemic kidney is reduced in size and shows signs of diffuse ischemic atrophy
Crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammatory infiltrates
mild arteriosclerosis
CF of renal artery stenosis
Sudden onset of uncontrolled HTN in previously well controlled patient
Accelerated/ malignant hypertension
Intermittent pulmonary edema with normal LV function
Elevated plasma or renal vein renin
Fibromuscular dysplasia
Thrombotic Microangiopathies (TMA)
refers to lesions seen in various clinical syndromes characterized by microvascular thrombosis accompanied by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
first: known etiology
Shiga toxin mediated hemolytic uremic syndrome (HUS and atypical HUS (complement mediated TMA)
Thrombotic thrombocytopenic purpura (TTP)
secondary:
develop in the background of other diseases or conditions without well-defined etiology like malignant hypertension and scleroderma associated TMA
hemolytic uremic syndrome (HUS)
Caused by diverse insults that lead to thrombi in capillaries and/ or arterioles in various tissue beds, including those of the kidney
- Flow abnormalities → shear and mechanically damage red cells → microangiopathic hemolytic anemia (MAHA)
- Microvascular occlusions that cause tissue ischemia and organ dysfunction
- Widespread “consumption” of platelets lead to thrombocytopenia
usually seen in children and caused by enterohemorrhagic E.coli
More severe renal failure, less pronounced CNS involvement
Associated with other infections: viral, Shigella, Salmonella
Drug-induced: Quinine (tonic water), Gemcitabine, Cyclosporine, Ticlopidine, Oral contraceptives
histo of Thrombotic Microangiopathies
Microangiopathic hemolytic anemia Thrombocytopenia Purpuric rash Acute renal failure fever, headache
Thrombotic thrombocytopenic purpura (TTP)
CNS involvement more pronounced, renal failure less severe
Often associated with SLE, HIV, hematological malignancy
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure
clinically silent; manifests in adulthood
can be the PKD1 gene or PKD2 gene
encodes polycystin 1 and 2
PKD2 is milder
CF is AD polycystic kidney disease
asymptomatic until 40s and 50s
Incidentally diagnosed due to work up form hypertension, abdominal mass, flank or back pain
Renal failure, cardiovascular and infections- common causes of death
manifestations due to cyst formation
HTN hematuria flank pain Nephrolithiasis Gram negative infection
hepatic cysts
AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE
Manifests in neonates, infants and children
Mutation in PKHD1 gene on chromosome 6p21 coding for fibrocystin protein
Kidney is enlarged with a smooth external surface
Dilated elongated channels are present at right angles to the cortical surface, completely replacing the medulla and cortex
Congenital hepatic fibrosis
Renal failure and death may occur in infants
MEDULLARY SPONGE KIDNEY
- Multiple cystic dilations of the collecting ducts in the medulla
- Occurs in adults
- Unknown etiopathogenesis
- Usually discovered radiographically
- Renal function is usually normal
SIMPLE CYSTS
- Can be single or multiple
- Common postmortem findings without clinical significance
- More common with older age
Alport Syndrome
inherited disease of the basement membrane collagen type IV which is crucial for normal function of the lens, cochlea, and glomerulus
most commonly X linked
genes coding for the alpha chains in collagen type IV → COL4A4 and COL4A5
defective assembly of the collagen network → defect in GBM
usually males 5-20 years
gross or microscopic hematuria along with
red cell casts
Other features: nerve deafness, lens dislocation, posterior cataracts and corneal dystrophy
path features of alport syndrome
GBM shows irregular foci of thickening alternating with attenuation (thinning)
Pronounced splitting and lamination of the lamina densa, often producing a distinctive “basket weave appearance”
Immunohistochemistry with antibodies against alpha chains- negative in basement membranes
With progression of disease, focal and diffuse glomerulosclerosis sets in
