General B1 stuff Flashcards
Statins (MOA)
- HMG CoA Reductase Inhibitors
- Structural similarity of all statins to HMG CoA substrate
-Act as reversible competitive inhibitors for the active site on HMG CoA reductase, the initial rate-limiting step in cholesterol biosynthesis;
have a higher affinity for the enzyme than natural substrate, HMG-CoA.
-Inhibition of an early and rate-limiting step in cholesterol synthesis, particularly in the hepatocyte, results in an increased need for exogenous (extracellular) cholesterol; this need is met by increased uptake of LDL particles which are rich in cholesterol
-Increase in LDL receptor gene.
o mechanism: In response to the reduced free cholesterol content within hepatocytes, membrane-bound Sterol Regulatory Element- Binding Proteins (SREBPs) are cleaved by a protease and translocated to the nucleus. The transcription factors then bind the sterol-responsive element of the LDL receptor gene, enhancing transcription and increasing the synthesis of LDL receptors (see fig 3)
-up-regulation of LDL receptor results in increased catabolism of LDL. Plasma concentration of LDL falls and less LDL is available to react with cellular elements in blood and blood vessel walls
Statins (pharmacokinetics)
- first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1
- limits systemic exposure to active compound
- all HMG CoA reductase inhibitors seem to preferentially effect the
liver - lovastatin (and simvastatin) administered as inactive lactone
- on uptake by liver cells, lactone prodrug is hydrolyzed to the beta-
hydroxy acid (which is the active form and principal metabolite) - atorvastatin administered in active, open-ring form
- highly bound to plasma proteins
- plasma concentrations peak at 1-4 hours;
o t1/2 of simvastatin is 12 hours o t1/2 of atorvastatin is 20 hours
all other statins have t 1/2 of 1 to 4 hours; clinical implications of this unclear - liver biotransforms all statins; about 70% of statin metabolites excreted by liver
atorvastatin, simvastatin, lovastatin metabolized by CYP3A4
Intercalated discs (transverse part)
Transmits force
- a modified Z-band (z-line)
- consists of fascia adeherens (N-cadherins) & desmosomes
Intercalated discs (lateral part)
CM-CM signaling
-gap junctions (nexi) & a few desmosomes
Excitation-contraction coupling (electrical)
Excitation (electrical)
- AP: depolarization —> T-tubules
- phase 2 of AP: L-type Cav1.2 —> Ca++ influx (highly enriched in cardiomyocytes
- ryanodine receptors in SR: —>—>—> Ca+++ (CICR….calcium induced calcium release
Monckeberg Arteriolosclerosis
- calcific deposits in media (& internal elastic lamina) of medium-sized muscular arteries (typically radial and ulnar arteries)
- > 50 years of age
- no obstruction to the blood flow
- usually not clinically significant
- unrelated to atherosclerosis
- its cause is not completely understood
Chronology of Heart Attack
1) immediate: myocyte death —> MB-CK and cTnl
2) +15 hours: inflammation
3) +2-3 days: wound healing via cardiac fibroblasts….collagen deposition (fibrosis)
4) +204 days: angiogenesis (clinical enhancement via VEGF, FGF)
5) Scar deposition (due to collagen cross-linking)
can pre-existing myocytes mobilize to fix damaged myocardium?
maybe
proliferation can be induced by…
1) inhibiting p38 MAP kinase
2) pro-proliferative agent
Can adult stem cells in the heart fix damaged heart?
- no, but maybe mobilize
- stem cells ID’s by expression of c-Kit
- treat heart with drugs/growth factors to mobilize and expand c-Kit+ cells within their niches
can c-kit+ adult stem cells be transplanted to fix injured myocardium?
- maybe….phase 1 trial SCIPIO
- some function is resotred and infarcted area is reduced, while no harm is done
can transplanted bone marrow cells fix the heart?
maybe. …
- paracrine effect…functional benefit, but little or no re-muscularization
Transplantation of CM derived from iPSCs
-best bet to re-muscularize
-
Continuous capillary
Where?
- CNS
- heart
- skeletal muscle
- lung
Item transported?
-oxygen
fenestrated capillary
where?
- endocrine glands
- GI tract
- kidneys
item transported?
- hormones
- nutrients
- ions
sinusoidal capillary
where?
- BM
- spleen
- liver
item transported?
-whole cells
Atherosclerosis: clinical syndromes
Elastic arteries
- aorta: aneurysm with rupture
- carotid arteries: occlusion causing stroke*
- iliac arteries: occlusion causing gangrene*
Large/medium sized muscular arteries
- coronary arteries: occlusion causing MI*
- popliteal arteries: occlusion causing gangrene*
- renal artery: narrowing/occlusion causing secondary hypertension*
- mesenteric arteries: narrowing/occlusion causing bowel infarction*
*possibly associated with thrombosis
Advanced/vulnerable plaque
At risk for:
1) Rupture, ulceration, erosion, and hemorrhage
- lead to thrombosis, embolism
- progressive luminal narrowing (leading to critical stenosis)
2) Atheroembolism
3) aneurysm formation
- wall weakening leading to aneurysm and rupture
Atherosclerosis pathogenesis
Hypothesis:chronicinflammatoryresponseof arterial wall to endothelial injury
• Components of process:
– Endothelial injury
– Hemodynamic disturbances – Lipid accumulation
– Inflammation
– Infection
– Smooth muscle proliferation
Chronic endothelial injury/dysfunction: ↑permeability, enhanced leukocyte adhesion – Specific cause unknown – Strongly suspected causes: • Hemodynamic disturbances: plaques occur in areas of disturbed flow patterns (at ostia and vessel branch points) • Hypercholesterolemia • Other possible contributors: – Hypertension – Cigarette smoke toxins – Homocysteine – Infectious agents
• Inflammation:
– Adhesion molecules (from endothelial cells) attract leukocytes
– Monocyte adhesion, migration & transformation to macrophages
• Initially protective response, but ultimately cause lesion
progression
– T lymphs: secretion of cytokines & fibrogenic mediators
Infection: Importance is unclear at present
– Herpes virus
– CMV
– Chlamydia pneumoniae
• Smooth muscle cells: Proliferation and migration into intima with production of matrix proteins
ApoA-I
HDL
-activates LCAT; interacts with ABC transporter
ApoB-48
Chylomicrons
-cholesterol transport/clearance
ApoB-100
VLDL, LDL
-binds to LDL receptor
ApoC-II
Chylomicrons, VLDL, HDL
-activates lipoprotein lipase
ApoC-III
Chylomicrons, VLDL, HDL
-inhibits lipoprotein lipase
ApoE
Chylomicrons, VLDL, HDL
-triggers clearance of VLDL and chylomicron remnants