Final Flashcards
We get cholesterol from what 2 ways:
Diet or we make it ourselves
Cholesterol 3 part synthesis in cells:
1) Mevalonate from Acetyl-CoA
2) Conversion of mevalonate to squalene
3) Cyclization of squalene to cholesterol
Plaque formation
LDL becomes oxidized in the interstitium–>
Macrophages go into swallow up fatty build up–>
they become foam cells–>
foam cells crystalize, die then calcify –>
increased inflammation over time
4 main Lipoproteins:
Chylomicrons
VLDL
LDL
HDL
Chylomicrons:
Lipoproteins
- Formed in intestine (dietary)
- Carry triglycerides and cholesterol
- Degraded by cells, final in liver
- Transported to liver where they are converted to VLDL
- Should not be in blood. only lymphatic system.
VLDL
Lipoprotein
- Secreted by liver
- Travel to peripheral tissues
- Converted to LDL
LDL
Lipoprotein
- Main transport mechanism throughout body
- Transport to cells
- Uptake through LDL-R
- Excessive amounts will deposit into arteries
HDL
Lipoprotein
- Takes extra cholesterol out from cells/lipoproteins, transports it to liver for degradation
- Decreased levels associated with atherosclerosis
Total Cholesterol level
<200
LDL level
<130
HDL level
> 40-50
Triglycerides level
<120
the number one fat in our body
Cholesterol drug classes:
- Statins (HMG-CoA Reductase Inhibitors)
- Niacin
- Fibrates
- Binding Resins
- Absorption Inhibitors
- PCSK9 Inhibitors
Statins: MOA
-Inhibits HMG-CoA Reductase which decreases cellular cholesterol synthesis
- Decreases LDL (-40%)
- Increases LDL-R
- Modest decreases in triglycerides
- increase in HDL (+10%)
Statins: considerations
- Better at night
- Enhanced with food
- 10-80mg
- Restricted use in children, pregnant/lactating
Statins: toxicity
- Elevated liver enzymes (asian descent)
- CK elevations (muscle pain/weakness)
Niacin: MOA
- Blocks the production of VLDL
- Decreases VLDL, LDL (-20%)
- Increases HDL (+25%)
- Decrease Triglycerides
Niacin: considerations/toxicity
2-6g daily
cutaneous vasodilation/flushing
Fibrates: MOA
-PPAR mediated lipolysis
- Decrease VLDL
- Modest decrease in LDL (-10%)
- Increase HDL (+15%)
- Decrease triglycerides
- Increase lipolysis in liver
Fibrates: Toxicity
Rare: GI upset arrhythmias elevated liver enzymes potentiation of coumarin myopathy
Bile Acid Binding Resins: Drug names
Colestipol
Cholestyramine
Bile Acid Binding Resins: MOA
- Surrounds dietary fat/biliary acids and prevents their reabsorption
- Decrease total cholesterol
- Isolated increases in LDL
- may increase VLDL
Bile Acid Binding Resins:
considerations
- usually given with statins
- Granular preparation
- 5-30g per day
Inhibitors of intestinal sterol absorption: Drug
Ezetimibe (Zetia)
Inhibitors of intestinal sterol absorption: MOA
Prevents reabsorption of dietary fat/biliary acids by inhibiting NPCT1
PCSK9
a protein that binds to LDL-R and will cause it to break down.
PCSK9 inhibitors: MOA
Monoclonal antibody binds to PCSK9 which prevents breakdown of LDL-R
PCSK9 inhibitors: considerations
New
Expensive
Injections 1-2x wk
autocoid groups
histamine serotonin bradykinin prostoglandin leukotrienes
Chronic inflammation mediators
Interleukins GM-CSF TNF Interferons PDGF
Cox-1
"good" "housekeeping" always on Protects GI tract Renal tract Plt fx
Cox-2
“bad”
induced during inflammation
NSAIDS: MOA
- Inhibition of COX (decreases inflammation)
- Decreases sensitivity of vessels to bradykinin/histamine (reverse vasodilation in brain to relieve HA)
- Inhibit plt aggregation (Cox-1)
NSAIDS: precautions
all can cause GI upset, nephrotoxicity, and heptotoxicity
ASA:
MOA
Irreversible block of Cox.
Cox1 > Cox2
Celecoxib:
MOA
use
SE
Cox2 selective
use: arthritis
black box warning for cardiac events, sulfa allergy
Ibuprofen:
MOA
SE
Cox1=Cox2
less GI upset than ASA
Indomethacin:
MOA
Use
SE
Cox and Lox (may inhibit phospholipase A and C)
Use: arthritis, gout, patent ductus arteriosis
SE: GI upset 1/3 patients
Acetaminophen:
MOA
Cox2
no anti-inflammatory effect
Glucocorticoids:
Acute action
Suppress inflammation
Mobilize energy stores
Improve cognitive fx
Salt and water retention
Glucocorticoids:
Chronic use problems
Immunosuppression
DM, obesity, muscle wasting
depression
HTN
Glucocorticoids:
MOA
Blocks transcription/translation:
- Suppresses pro-inflammation mediators.
- Up regulate anti-inflammatory mediators.
4 main proteins that are upregulated with glucocorticoids:
- Annexin-1 (lipocortin-1)
- Secretory leukoprotease inhibitor (SLPI)
- IL-10
- Inh-NFkB
Secretory leukoprotease inhibitor (SLPI)
decrease inflammation by blocking protease
IL-10
Immunosuppressive enzyme
Inh-NFkB
protein that directly inhibits the NFkB
Annexin-1 (lipocortin-1)
- suppresses phospholipase A2
- Inhibits leukocyte response
Methotrexate:
non-biologic DMARD
blocks adenosine production
Cyclophosphamide:
non-biologic DMARD
B&T cell suppression
Cyclosporine:
non-biologic DMARD
Inhibition of interleukins
Abatacept (Orencia)
Biologic DMARD
Blocks Tcell activation
Rituximab (Rituxan)
Biologic DMARD
Depletes B-lymphocytes
Adalimumab (humira)
Biologic DMARD
Anti-TNF-alpha
Hierarchical system
stimulus travels down neuron, sends neurotransmitter, causes excitatory or inhibitory action
Diffuse system
Release Neurotransmitter throughout brian
A-beta fibers
touch and pressure
A Delta fibers
sharp fast pain/heat
C fibers
slow dull pain
noxious chemical/ heath
Mu receptors
Most of the effects from this receptor
Delta and kappa receptors
less side effects but can cause dysphoric reactions
Full agonist of Mu receptors:
Morphine
fentanyl
Partial agonist of Mu receptors:
codeine
oxycodone
Morphine metabolism
More active after phase 2
Heroin metabolism
tissue esterases to morphine
2 main metabolic pathways for opioids:
CYP3A4
CYP2D6
Opioids: MOA
- Reduce neurotransmitter release (glutamate, ACh, NE, serotonin, substance P)
- Hyperpolarize postsynaptic neurons
3 classes of opioids:
phenanthrenes
phenylheptylamines
phenylpiperidines
Strong agonist Phenanthrenes: drugs
Morphine
Dilaudid
Heroin
Codeine, oxycodone
Strong agonist Phenylheptylamines: drugs
Methadone:
(half life 25-50hrs, CYP3A4)
Propoxyphene (Darvon)
Strong agonist Phenylpiperidine: drugs
Fentanyl
Meperidine (demerol)
Loperamide (diarrhea)
Meperidine (demerol)
antimuscarinic effects (tachycardia)
(-) inotorpe
seizures
