HMG-CoA reductase inhibitors
adverse effects
-relatively free of adverse effects
-may elevate serum levels of _____ enzymes and cause ______
less frequent adverse effects are:
______, ______, _______: destruction of muscle cells releasing myoglobin leading to ____ failure
-increase in ALT/AST (liver homeostasis)
-hepatic toxicity with concurrent ____ use
hepatic hepatitis myalgia, myopathy, rhabdomyolysis renal alcohol
bile acids-binding resin
Cholestyramine & Colestipol
-Cationic ____ molecular weight polymers containing ___
-chloride ion is exchanged for ____ acids in the gut: forming ___________
-resin bile complex cannot be reabsorbed in the distal ______
-to obtain max effect, they must be taken before each ____ and at ____
-the bile acid resin complex is excreted via the _____
-bind to digoxin, levothyroxine, warfarin
moderately effective
reduce LDL by 28%
excellent safety record bc it is not _______ and there is no ______
these drugs cause an decreased absorption of ___ soluble vitamins
-these drugs should NOT be used in pts with ___
large chloride bile bile acid-resin complex ileum meal, bedtime feces absorbed hepatic first effect fat IBD
fibric acids
- activated _____ results in change in lipid metabolism
- increased ____ activation of lipoprotein lipase
- increased uptake of _____ rich lipoproteins
- reduce serum ____ and ____ levels
- -reduction in triglyceride levels is accompanoied by an increase in ____ and ______
adverse effects GI: constipation, fecal impaction -allergic reactions blood cell deficiences -\_\_\_\_\_\_\_ and \_\_\_\_\_\_ (do not administer with \_\_\_\_)
PPAR-alpha muscle triglyceride VLDL triglyceride HDL, cholesterol rhabdomyolysis myalgia
dyslipidemias cause:
- _______
- _______
- ____
- ____
- peripheral __________ disease
- elevated ___/low ____
- elevated ______
atherosclerosis hypertension MI stroke arterial occlusive LDL, HDL triglycerides
Proprotein Convertase Subtilisin/Kexin type 9 Inhibition
- PCSK9 is an enzyme that degrades the _______ on hepatocytes
- it decreases the number of LDL receptors on surface of liver cells
- increases plasma conc of ____
- overexpression increases susceptibility to atherosclerotic lesion development
- _____ results in major reduction in the plasma conc of LDL-C
LDL receptor
LDL-C
inhibition
cholesterol balance
-cholesterol is converted in liver to ____ and secreted in the _____
-____ elimination occurs but most cholesterol is recycled by high affinity transport proteins in the distal ileum back to the liver and back into bile
this is called ____________
bile acids
bile
fecal
enterohepatic circulation
HDL formation
HDL formation occurs in the _____ and _______
- _____ HDL particles are disc shaped and are bound to _______
- this binding converts cholesterol into _________
- these esters migrate to the core of the molecule called ________ particles which is spherical in shape
- HDL serves as a reservoir for exchangeable ________ and plays a role in cholesterol _______
- HDL removes excessive _____ from cells and transports it to the ____
- cholesterol efflux occurs when _______ cholesterol molecules from plasma membrane of cells bind to HDL particles
- this extrahepatic cholesterol is carried by HDL to the liver and this _______ explains HDL’s protective role
liver small intestine pre beta PLTP (phospholipid transfer protein) cholesterol esters alpha HDL apolipoproteins homeostasis cholesterol liver unesterified reverse transport
drugs for hypercholesteremia 1 2 3 4
HMG coA reductase inhibitors (statins)
bile acid binding resins
fibric acid derivatives
misc drugs & natural compouds
therapies that target high-density lipoprotein
- the concentration of _____ is a robust inverse predictor of the risk of having an ASCVD event
- infusion of a preparation of reconstituted HDL reduces coronary _____
- HDLs also have several potentially cardioprotective proprteies including promotion of efflux of _____ from macrophages and inhibition of vascular ______. HDLs also have ____ and ____ effects
HDL-C atheroma cholesterol inflammation antioxidant antithrombotic
HMG-CoA reductase inhibitors
- reduced levels of liver cholesterol compensate by synthesizing (up-regulating) ____ receptors to draw cholesterol out of circulation
- _____ cleave membrane-bound sterol regulatory element binding proteins (SREBP), which then migrate to the _____ and bind to the sterol response elements (SRE) which increase transcription of various proteins, most notably _______
- the ldl receptor is transported to the ____ cell membrane and binds to passing LDL and VLDL particles, mediating their uptake into the liver (____)
- this results in ____ LDL circulating in blood
LDL receptors proteases nucleus LDL receptors liver bile less
fibric acid derivatives
- indicated for familial _______ and marked ___ deficiency
- fibrates bind to and activate ___ alpha receptor in hepatocytes, skeltal muscle, macrophages and heart tissue
-derivatives of fibric acid or fibrate
_____: first drug in this class, not used clinically due to numerous side effects
-_____
-______
hypertriglyceridemia HDL PPAR clofribate fenofibrate gemfibrozil
LDL particles
- LDL particles not taken up by LDL receptors in tissues migrate into the _____ of blood vessels and bind to _______
- they are subject to ______ resulting in lipid _________
- this modified LDL is internalized by _______ receptors in phagocytic monocytes
- continued accumulation of oxidized LDL results in the formation of _______ which are _____ rich phagocytes
- foam cells may undergo _____ and release ______
- this promotes local inflammatory response
- _______ is initiated
- there is release of matrix _________ which may destabilize atherosclerotic plaques
intima peptidoglycans oxidation perioxidation scavenger foam cells cholesterol apoptosis free radicals atherosclerosis metalloproteinases
niacin
- _______
- ___ soluble B3
- substrate in the synthesis of ___ and ___
- decrease ___ and ___ levels
- decrease production of hepatic ___ due to fall in production of triglycerides
- VLDL are precursors of ___, thus a fall in VLDL leads to a decerase in LDL production
- increases the conc of ___
- decreased breakdown of ____ lipids causes a decrease in ____ cholesterol availability
- pharmacological action needs ___ doses
nicotinic acid water NAD, NADP VLDL, LDL VLDL LDL HDL complex free high
Lipids
- Lipids serve as energy sources, ______ precursors and signal molecules and are packed within _______
- lipoproteins are macromolecular aggregates that transport ______ and ______ in the blood
- ______: large, not dense, high lipid content
- ____: smaller, less dense, moderate-high lipid content
- ____: very small, very dense, low lipid content
- _________ which deliver fatty acids to muscle for ___ synthesis and for storage in _____ tissue/______
- -________
- –component of cell membrane/precursor to ______ and steroid compounds
–______: main storage form of fuel
-elevation of both cholesterol & triglycerides play an important role in ________ and other disorders
hormone lipoporteins triglycerides & cholesterol chylomicrons LDL HDL apolipoproteins ATP adipose hepatocytes cholesterol steroid triglycerides heart diseases
HMG-CoA reductase inhibitors
- statins act by _______ inhibiting HMG-CoA reductase (rate limiting enzyme of the ______ pathway)
- because statins are similar in structure to HMG-CoA on a molecular level, they will fit into the enzymes active site and compete
- this reduces the rate HMG-CoA is able to produce ________, the next molecule in cascade that eventually produces cholesterol
by inhiting HMG-CoA reductase, statins block pathway for synthesizing _____ in the liver
- most circulating cholesterol comes from ______ manufacture rather than diet
- lowered ___ production results in lower blood _____ levels
- cholesterol synthesis appears to occur mostly at _____
- ___ half life statins work at night best
competitively mevalonate .mevalonate cholesterol internal liver cholesterol night short
HMG-CoA reductase inhibitors
Drug causing -myopathies/rhabdomyolysis: _____ & _____
-inhibit metabolism of HMG-CoA inhibitors: _____________
-Warfarin: increase in warfarin blood levels
-_______: may increase serum conc of HMG-CoA
-______: INCREASE serum conc of simvastatin
-______: DECREASE serum conc of simvastatin
_______: increase the serum conc of HMG-CoA reductase inhibitors
fibric acid/niacin macrolide antibiotics cochicine diltiazem efavirenz grapefruit juice
inhibitors of cholesterol absorption
- reduce cholesterol absorption by small intestine
- includes both ____ and ____ cholesterol
- also inhibit production of hepatic. ____
- available: plant sterols (_____: present in fruits and veggies)
_______: decreases cholesterol transport from the _____ into ______ reducing absorption by 50%
-does not reduce absorption of _____ and ____ or ___ soluble vitamins
-decreased plasma LDL, decreased chylomicron cholesterol, decreased liver LDL decreased VLDL production
very effective in combo w ______
dietary, biliary VLDL stanons ezetimibe micelles enterocytes fatty acids, triglycerides, fat statin
OMEGA 3 FATTY ACIDS
____ & ____
-‘___ oils’
-reduce plasma _____ by up to 50%
-regulate nuclear transcription factors such as _____
-decrease triglyceride biosythesis and increased fatty oxidation by the liver
Lovaza: OTC 4 gms/day
EPA, DHA
fish
triglycerides
PPAR
pharmacological consequences of HMG-CoA
- decreased ______: decreased C-reactive protein
- reversal of endothelial dysfunction: improved _____ response to NO
- decreased ______/_____ formation
- improved _____ of atherothrombotic plaque
- decrease in cardiovascular morbidity and mortality
- _____ is least potent
- ________/_____ most potent
inflammation vasodilator thrombosis/atheroma stability fluvastatin atorvastatin/rosuvastatin
niacin adverse effects
-skin: mild to severe cutaneous ____; _____; hyperpigmentation; ___ skin
-_____ effects mediated by prostaglandins
-cardiovascular: atrial fib; hypotension
GI: dyspepsia, vomiting, diarrhea, jaundice
-hyperuricemia
-impaired ____ sensitivity
-potentiation of ___ induced myopathy with HMG coa reductase inhibitors
flushing pruritus dry vasodilating insulin statin
CAUSES of hyperlipidemia
- _____
- _____
- chronic ____ failure
- _____thyroidism
- _______ storage disease
- ______
- physiological ____
- ______ excess
- ________
- ____ hormone replacement therapy
- ________, ______, ______, ______ inhibitors
diet diabetes renal hypo glycogen sepsis stress alcohol lipodystrophy oral beta blockers, dieuretics, glucocorticoids, protease
HMG-CoA reductase Inhibitors
Statins
-enable more ___ to be delivered to the liver resulting in a 60% _____ in serum LDL cholesterol (70% liver uptake/30% other tissues)
-low _______/ good safety profile
-large _________ metabolism
-lovastatin and. simvastatin are ______
-other statins are active compounds
-metabolized via CYP450 therefore drug interaction with other drugs metabolized by same enzyme
-very effective in treatment of __________
LDL reduction bioavailability extensive first pass prodrugs hyperlipidemia
-
Clinical Trials and New Drug Development4
-
Pharmacokinetic Principles of Pharmacology54
-
Autonomic Pharmacology42
-
Respiratory39
-
GI49
-
Respiratory 222
-
Cardiovascular System and Drugs34
-
Part 2 CVS drugs27
-
Heart Failure22
-
Antiarrythmics24
-
Hyperlipidemias22
-
extra17
-
Anticancer Drugs49
-
chemotherapy part 114
-
chemotherapy part 1 (2)14
-
chemotherapy part 1 (3)10
-
chemotherapy part 1 (4)15
-
chemotherapy part 221
-
CNS: ANTIPSYCHOTICS18
-
CNS: ANTI-SEIZURE DRUGS17
-
Parkinson's Disease16
-
Diabetes22
-
CNS affective disorders part 218
-
CNS disorders part 125
-
Pain, Inflammation and Anti-Inflammatory43
-
ANTICOAGULANTS, ANTIPLATELET DRUGS, FIBROLYTIC AGENTS PART 217
