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LP10-11, Lipoprotein Transport and Atherosclerosis Pathophysiology,…

- - - - Control Sites
        
        CO and PVR Regulation
        
        Arterioles
        
        Capacitance vessels
        
        Heart
        
        Volume of intravascular fluid Regulation
        
        Kidney
      - Renin-Angiotensin-Aldosterone System (RAAS)
        
        Regulation of blood volume and systemic vascular resistance
        
        BP decreases
        
        Juxtaglomerular cells (kidneys)
        
        Increased Renin
        
        Conversion of Angiotensinogen to Angiotensin I
        
        1 more item...
      - Baroreceptors
        
        Baroreceptor Reflex
        
        BP decreases
        
        Decreased baroreceptor activity
        
        Decreased number of afferent impulses towards VC
        
        Decreased PNS activity Increased SNS activity
        
        1 more item...
        
        BP increases
        
        Increased baroreceptor activity
        
        Increased number of afferent impulses towards VC
        
        Increased PNS activity Decreased SNS activity
        
        1 more item...
        
        Aorta and Carotid artery
        
        Sense changes in BP in vascular system Provide inputs to Vasomotor Center
        
        Input travels from VC to arteries, heart and adrenal gland
        
        Arteries: Contraction/Relaxation of smooth muscles
        
        Heart: HR and CO Regulation
        
        Adrenal Gland: Regulation of Epinephrine/Norepinephrine and Aldosterone
      - Stimulate release of Anti-diuretic Hormone (ADH), a vasopressin, from hypothalamus
        
        Increased expression of aquaporins on collecting duct of nephron
      - Vasorelaxant Substances
        
        Endothelium-derived relaxing factor
        
        From vascular endothelium
        
        PVR Regulation
    - - Diastolic BP
        
        Minimum pressure in arteries during ventricular diastole
      - Symptoms
        
        Throbbing headache
        
        Nausea/vomitting
        
        Giddiness
        
        Blurred vision
      - Systolic BP
        
        Highest pressure in arteries during ventricular systole
      - Blood Pressure Calculation
        
        Cardiac Output (CO) x Peripheral Vascular Resistance (PVR)
        
        Cardiac Output: volume of blood ejected from left side of the heart in 1 minute
        
        CO = Heart Rate (HR) x Stroke Volume (SV)
        
        Stroke Volume: volume of blood pumped by a ventricle in 1 beat
        
        Heart Rate: cardiac activity (beats/min)
        
        Peripheral Vascular Resistance: vascular resistance to the blood flow in peripheral arterial vessels
        
        Internal vessel diameter
        
        Vessel length
        
        Blood viscousity
  - - - Diuretics
        
        increase in the amount of urine produced by the kidneys. increase the excretion of Na+ (natriuresis) and H2O (reducing blood volume) by decreasing the reabsorption of Na+ and (usually) Cl− from the filtrate
        
        Loop diuretics
        
        Target: distal tubular Na+/Cl− co-transport system; re-absorption of Na+ and Cl- ions is inhibited
        
        Thiazide diuretics
        
        Target: thick ascending limb,
        inhibiting Na+/K+/2Cl− carrier in the lumenal membrane
        
        Potassium-sparing diuretics / aldosterone antagonists
        
        Compete with aldosterone for its intracellular receptor, Impairs the synthesis of Na+/K+ ATPase and Na+ channels, thereby inhibiting distal Na+ retention and K+ secretion
      - Calcium Channel Blockers
        
        Ca2+ antagonists block Ca2+ entry to cells by preventing opening of voltage gated L-type calcium channels.
        
        ↓contractility, ↓the conductivity of the heart; ↓O2 demand
        
        Intracellular Ca2+ concentration: impt as a regulator of cell function by binding to proteins such as calmodulin, which in turn activates MLCK; latter phosphorylates myosin-LC which initiates interaction with actin smooth muscle cell contraction.
        
        Dihydropyridines: Amlodipine, Nifedipine
        
        Non-dihydropyridines: Verapamil, Diltiazem
      - Beta Blockers
        
        Beta 1 (β1) receptors: Found primarily in heart muscles and their activation results in an increase in HR, contractility.
        
        β1 blockade: Reduces heart rate, renin secretion and vascular smooth muscle contraction.
        
        β2 blockade: Bronchoconstriction (↑ airway resistance) and vasoconstriction (↑ vascular resistance)
        
        Non-selective between β1- and β2-adrenoceptor antagonists: propranolol
        
        should be avoided in patients with a history of asthma as they can precipitate bronchospasm
        
        β1 selective antagonists: atenolol, bisoprolol, metoprolol
        
        Both α and β-adrenoceptor blockers + Vasodilating effects (by inducing endothelial nitric oxide production): carvedilol
      - Drugs acting on renin-angiotensin aldosterone system
        
        Angiotensin II Receptor Blockers
        (ARB)
        
        block all effects of Angiotensin II by antagonizing AT1 receptors in arteriolar smooth muscle and in the adrenal gland causing BP to fall.
        
        Adverse effects: Angioedema, Hyperkalaemia, Low incidence of dry cough
        
        Eg, Valsartan
        Losartan
        
        Renin Inhibitors
        
        What is renin?
        
        an enzyme secreted by specialized cells in the kidneys when BP falls or when there is decrease in Na+ flowing through the kidney tubules.
        
        In a series of enzymatic steps, peptidases sequentially cleave amino acids from angiotensinogen to angiotensin I and then angiotensin I to angiotensin II
        
        increase in sympathetic activity
        
        Tubular Na+, Cl- reabsorption and K+ secretion, H2O retention
        
        Arteriolar vascularconstriction, an increase in blood pressure
        
        ADH secretion, hence H2O reabsorption in collecting duct
        
        stimulates secretion of Aldosterone from adrenal gland that increases Na+ (and therefore H2O) reabsorption in the kidney
        
        Angiotensin Converting Enzyme Inhibitors
        (ACE-I)
        
        Adverse effects: - Angioedema
        
        persistent dry cough
        
        hyperkalaemia
        
        Eg, Enalapril
        Lisinopril
        
        ACE inhibitors decrease Angiotensin II production but still allow effects of Angiotensin II synthesized via non-ACE pathways (cardiac chymase system)
        
        Reversible competitive inhibition of ACE blocks conversion of inactive decapeptide angiotensin I to active vasopressor angiotensin II
      - Other vasodilators
        
        Reduce pressure by relaxing arteriole smooth muscles thus reducing peripheral vascular resistance
        
        Postural hypotension, Tachycardia, fluid retention and lupus-like syndrome
        
        Hydralazine
- - - - Hypertriglyceridemia
        
        Elevated concentration of triglyceride (TG) of >4.5 mmol/L :red_cross:
      - Hypercholesterolemia
        
        Elevated concentration of low density lipoprotein (LDL) :red_cross:
        
        Elevated concentration of total cholesterol (TC) :red_cross:
      - Treatment
        
        Statin/HMG-CoA reductase inhibitors
        
        Inhibits cholesterol synthesis
        
        Synthesis of LDL receptor for increase LDL-C uptake
        
        Decrease secretion of VLDL
        
        Mixed Dyslipidemia
        
        Increased LDL-C (LDL + Cholesterol) uptake = Decreased LDL and TC levels :check:
        
        Inhibition of cholesterol synthesis = Decrease TC levels :check:
        
        Decrease secretion of VLDL = Decrease TG levels :check:
        
        Hypercholesterolemia
        
        Increased LDL-C (LDL + Cholesterol) uptake = Decreased LDL and TC levels :check:
        
        Inhibition of cholesterol synthesis = Decrease TC levels :check:
        
        If lipids still not at target
        
        Ezetimibe/Cholesterol Absorption Inhibitor
        
        Blocks NPC1L1 in Enterocytes for inhibition of cholesterol absorption
        
        Side Effects
        
        Diarrhoea
        
        Abdominal pain
        
        Headache
        
        Myalgia
        
        Hypercholesterolemia
        
        Inhibition of cholesterol absorption = Decrease TC levels :check:
        
        Mixed Dyslipidemia
        
        Inhibition of cholesterol absorption = Decrease TC levels :check:
        
        ezetimibe
        
        Side Effects
        
        Myopathy
        
        Rhabdomyolysis
        
        Raised liver enzymes
        
        Jaundice : : :
        
        Simvastatin, Atorvastatin, Lovastatin, Rosuvastatin
        
        Bile Acid Sequestrants (Resins)
        
        Binds and sequester bile acids to stimulate bile acid catabolism from cholesterol
        
        Upregulate LDL receptors for increase LDL-C uptake
        
        Activates phosphatidic acid phosphatase for increase triglyceride (TG) synthesis and very low density lipoprotein particles secretion (VLDL)
        
        Mixed Dyslipidemia and Hypercholesterolemia
        
        Increased LDL-C (LDL + Cholesterol) uptake = Decreased LDL and TC levels :check:
        
        Increase TG synthesis and VLDL secretion = Increased TG and VLDL :red_cross:
        
        Side Effects
        
        Constipation
        
        Diarrhea
        
        Hypertriglyceridemia
        
        Cholestyramine
        
        Fibrates
        
        Binding to PPARα nuclear receptors
        
        Increase transcription of gene for lipoprotein lipase for decrease VLDL
        
        Increase transcription of gene for apoA1 and apoA2 for increase HDL
        
        Decrease transcription of gene for apoC2, apoC3 for decrease VLDL
        
        Increase hepatic LDL uptake
        
        If lipids still not at target after Stattin and Ezetimibe
        
        Mixed Dyslipidemia
        
        Decrease secretion of VLDL = Decrease TG levels :check:
        
        Increased LDL-C (LDL + Cholesterol) uptake and HDL secretion = Decreased LDL and TC levels :check:
        
        If lipids still not at target
        
        Severe hypertriglyceridemia and Hypertriglyceridemia
        
        Decrease secretion of VLDL = Decrease TG levels :check:
        
        If triglyceride concentration remains > 4.5 mmol/L
        
        Omega 3 Fish Oil
        
        Reduce hepatic VLDL production
        
        Increases VLDL clearance
        
        Converts VLDL to IDL and final into LDL
        
        Severe hypertriglyceridemia and Hypertriglyceridemia
        
        Decrease plasma concentration of VLDL = Decrease TG levels :check:
        
        1 more item...
        
        unpleasant taste, bad breath, bad-smelling sweat, headache, and gastrointestinal symptoms such as heartburn, nausea, and diarrhea
        
        Omega 3 Fish Oil ......
        
        Side Effects
        
        Raised liver enzymes
        
        Myopathy
        
        Lithiasis
        
        fenofibrate, gemfibrozil
      - Mixed Dyslipidemia
        
        Elevated concentration of triglyceride (TG) :red_cross:
        
        Elevated concentration of low density lipoprotein (LDL) :red_cross:
        
        Elevated concentration of total cholesterol (TC) :red_cross:
      - Severe hypertriglyceridemia
        
        Elevated concentration of triglyceride (TG) of >10 mmol/L :red_cross:
- - - - vLDL are generated within liver hepatocyte cells. Via the free fatty acid, cholesterol, and glycerol + apoB-100.(Transporter of Triglycerides)
        
        VLDL deposits free fatty acid in adipose tissue which leads to a deficiency of triglycerides(smaller size) --> iLD
        
        iDL(Transient phase) will react with HDH and release more triglycerides and become LDL
        
        LDL's major function is to move the cholesterol to the peripheral(such as adrenal glands) part of the body or back to the liver. Detrimental factor - Deposit cholesterol in the arteries of the heart making it more narrow and can cause inflammation
        
        Cholesterol will be eventually uptake by the liver and recycled, receptors recognize apoB-100 found in LDL. HDL is 40% protein and has a lot of space for taking in triglycerides(Trades proteins for triglycerides and cholesterol) HDL contributes to reverse transport.
- - - - This allows LDL to migrate into the arterial wall and into the intima where macrophages will start to uptake them forming foam cells.
        
        This creates the atheroma which is continually growing. Smooth muscle cells can also be transferred into the tunica intima where apoptosis can occur causing which creates more plaque.
        
        This then leads to arterial narrowing(stenosis) causing a limitation to blood flow and oxygen transport, leading to ischemia. It can even lead to stroke or aneurysms. In the case of a rupture can lead to thrombosis
- - - - Very-low-density lipoprotein(vLDL)
        
        Contains apoB-100 apoC2, has a diameter of 30-80nm, and has a desirable concentration of <2.3mmol/L
      - Chylomicrons
        
        Contains apoB-48, apoC2 has a diameter of 100 -1000nm(largest) and optimal serum concentration is <2.3 mmol/L
    - - Contains apoB-100, diameter 20-30nm and optimal serum level of <2.3mmol/L
    - - Contains apoA1 and apoA2, Diameter of 7 - 20nm. Optimal serum level >1mmol/L