Pharmacology of Drug use to manage disease of vascular ageing Flashcards
What happens to the vaculature as we age?
Atheroma acculates beneath the endothelial lining of larger vessels
Arterial tree becomes less compliant as walls start to calcify —> BP increases
Hypertension predisposes to futher atheroma development predisposed to by smoking, obesity, high intake of inorganic phosphates
Many risk factors for vascular disase relate to endothelial cell dysfunction
What is the function of endothelial cell?
Tonic release of vasodilator mediators counter-balances sympathetic nervous system mediated arteriolar tone
Flow across the surface of the endothelium sensed and activates endogenous vasdilator systems
NO and EDHF are responsible for tonic vasodilation
Also inhibit platlet and leucocyte adhesion- protect against atheroma development
Give 4 examples of vasodilator mediators released by the endothelium?
NO
CNP
Prostacyclin
EDHF
Give 3 examples of vasoconstrictor mediators released by the endothelium?
Endothelin-1
PGH2 or PGG2
Angiotensin II
What are the sex differences in modulation of myogenic tone in arterioles when its inhibited by release of factors from the endothelium?
Female mice are more effective at inhibiting myogenic tone than male mice
Is EDHF more important in resistance arterioles modulating myogenic tone, in females or males?
Females
What happens in amles when NO activates guanylare cyclase?
Cyclase modulates the response to increasing pressure
What does Oestrogen do to SM guanylate cyclase and hyperpolarising pathways?
Down regualtes SM guanylate cyclase
Upregulates Hyperpolarising pathways which can be activated by NO
What is Flow mediated vasodilation? What is the method?
Method for measuring endothelial cell function in vivo
Image the brachial artery and measure diameter
Apply blood pressure cuff to the forearm and inflate to occlude blood flowof r 5 mins
Release and measure increase in artry diameter as resistance vessels downstream of the brachial artery are dilated
Can examine diff interventions or diseases that influence endothelial cell function. More direct measure than markers released from the endothelium
What does High iPhosphate intake do to endothelial cell function?
Acutely high phosphate intake is associated with albuminuria
Oral phosphate loading impairs endothelial function increasing filtered albumin
High intake impairs function
What does Atherogenesis involve?
Endothelial cell dysfunction (NO reduced synthesis)
Endothelial cell injusy and increase adhesion molecule expression
Monocyte migration into intima
LDL cholesterol tranport into vessel where it - oxidised
OcLDL uptake into macrophages—>foam cells; release cytokines
Subendothelial accumulation of foam cells and T cells—> fatty streaks
Smooth mm proliferation- due to growth factor release from platelets, macrophages and endothelial cells
Plaquw rupture—>thromosis and myocardial infarction
Give an example of lipid lower drugs?
Statins
Bempedoic acid
PCSK9 inhibitors
Fibrates
Inhibitors of cholesterol absorption
Small molecule inhibitors
What is the mode of effect of statin?
Inhibit HMG-CoA reductase
Decreased hepatic sythesis of cholesterol leads to up regulation of LDL receptor in live
This increases liver clearance of LDL from plasma (reduces plasma LDL cholesterol)
Simvastatin- example of selective reversible competitive inhibitor of HMG-CoA reductase
Atorvastatin- long lasting inhibitors
What are othe beneficial effects of statins?
Products of the mevalonate pathway protein lipidation
Addition of prenyl moieties to membrane bound enzymes–> including NOS
leads to desired and undesired effects
Desired effects include:
improved EC function, reduced vasculat inflammation, reduced platelet aggregability, Stabilisation of atherosclerotic plaque
What are the mild adverse effects of statins?
Muscle pain
GI disturbance
Insomnia
What are the serious adverese effects of statins?
Myositis—>rhabdomyolysis (skeletal mm damage)
Angio-oedema
Type 2 diabetes (progression towards)
What do fibrates do?
Reduce VLDL (decrease secretion)
10% reduction in LDL and 10% increase in HDL
agonists at PPARa receptor
What are the adverse effects of fibrates?
Rhabdomyolysis
Cause myoglobinuriaand acute kidney injury
Patients with kidney disease more susceptible:
-Reduced palsma protein binding, reduced drug excretion
Because statins can cause myositis- combining statins with fibrates needs care
What do bile acid binding resin do?
Sequester bile acids in the intestine:
Prevent their reabsorption
Decrease exogenous cholesterol absorption from gut
Increase endogenous cholesterol incorporation into bile acids—>increase LDL uptake into hepatocytes
What is Ezetimibe?
More specific blocker of a transport protein in the duodenum
Better tolerated than bil acid binding resins, does not interfere withabsorption of fat sol vitamins
What are the adverse effects of cholesterol absorption inhibitors?
Interfere with absorption of fat soluble vitamins and drugs
Bulky to take and cause diarrhaea
Largely replaced by statins
What is MTP?
Key role is assembly and release of apoB-containing lipoproteins into blood
Significantly lowers plasma lipid levels by reducing hepatic LDL secretion
All other lipid lowering drugs work by increasing LDL uptake
What inhibits MTP?
Lomitapide
