Pharm Flashcards
what mediators does cyclooxygenase produce?
prostacyclin (anti-platelet)
prostaglandin E (pain, erythema, edmea)
prostaglandin F (uterine contraction)
thromboxane (platelet aggregation)
what mediators does the lipoxygenase pathway produce?
leukotrienes
what part of the arachadonic pathway do glucocorticosteroids inhibit?
phospholipase A making arachadonic acid from phospholipids
what part of the arachadonic pathway do NSAIDs inhibit?
cyclooxygenase 1 and 2
info for COX1
expressed in most tissues generating low levels of prostaglandins
responsible for protective measures (gastric mucosa), vasodilation (restricting kidney flow), blood clotting, uterine contraction, muscle growth, and synaptic transmission
info for COX2
inducible form of enzyme that is expressed in high concentrations after induced by inflammatory mediators producing high concentrations of prostaglandins and thromboxanes leading to inflammation
constitutively on in kidneys and some parts of brain (local inflammation, wound healing, resistance to infection)
what compound do cyclooxygenases require?
molecular oxygen!
what other mediator is critical for inflammatory conditions?
NFkB
info on NFkB
activated by many signals and induces expression of cytokines (IL-1,6), INFB, cell adhesion molecules, enhancing inflammatory process
what signals activate NFkB
infection (LPS, dsDNA)
antigen receptors (TCR, BCR)
cytokines (TNFalpha, IL-1)
genotoxic stress (UV, gamma-radiation, ROS)
COX1 predominant..?
platelets to make thromboxane causing vasoconstriction and platelet aggregation
gastric mucosa to provide protection via prostaglandins E and I
COX2 predominant…?
joints - where prostaglandins E and I produce pain and inflammation
endothelial cells - where prostacyclins decrease platelet aggregation and increase vasodilation
what is aspirin?
acetyl salicylic acid which is an irreversible, non-selective cox inhibitor via acetylation
what are the reversible, non-selective COX inhibitors?
ibuprofen, naproxen, indomethacin
what is salicylate
also a non-selective, reversible COX inhibitor but it is a weak one that may be more important in NFkB inhibition
what is acetaminophen?
an analgesic and antipyretic and weak anti-inflammatory; it is a weak inhibitor of COX
often used in babies for headache and fever
what do glucocorticoids block?
phospholipase A (block arachadonic acid production), inhibit NFkB, COX2, inflammatory cytokine production
what are some things we treat with COX inhibitors?
headache, dental pain, muscle pain, menstrual cramps, osteoarthritis, ankylosing spondylytis, RA, gout, tendonitis, bursitis - provide symptomatic relief
problem with aspirin?
patients can sometimes not tolerate its gi toxicity
NSAID toxicity?
gi ulcers, inflammation, gastric erosion
decreased GFR, renal edema, necrosis, nephritis
hypertension, allergic hypersensitivity reaction, CNS toxicity
what should you give kids?
acetaminophen, not aspirin which can cause Reye’s syndrome (liver and brain swelling)
why take daily does of aspiring?
decreases risk of MI and ischemic stroke; long term use can decrease cancer incidence
why take other NSAIDs with daily dose of aspirin?
to attenuate the anti-platelet affects of aspirin (i.e. make them less effective)
what is bartter’s syndrome and what do we use for it?
renal problems - NSAIDs reverse symptoms
what is patent ductus arteriosus? and what is used for it?
improper duct closure - NSAIDs allow ducts to close in premature babies without surgical intervention
what is aspirin metabolized to?
salicylate
what are the NSAIDS with short half-lives?
aspirin, ibuprofen, indomethacin
what are the NSAIDs with long half-lives?
naproxen, salicylate
why are acetaminophen and chronic alcohol use a problem?
because ethanol induces CYP2E1 which causes acetaminophen to turn into NAPQI which normally combines with glutathione, but once that is used up it reacts with liver proteins and becomes heptatoxic and necrotic
where are most NSAIDs normally located?
albumin
which COX is needed for normal renal development and function?
COX2 - prostaglandin synthesis is important for autoregulation of renal blood flow - so non-selective and selective COX2 inhibitors may affect renal efficiency
which mediator modulates vascular tone?
prostaglandins
which NSAID can cause asthma?
aspirin in sensitive people
drug interactions with NSAIDs?
drugs bound to albumin (warfarin, phenytoin, sulfonylureas, methotrexate) - makes them more potent
inhibition of drug metabolism of phenylbutazone
inhibits acids transport in kidneys - probenecid
increased GI bleeding after alcohol
hypotensive effects reduced for beta-adrenergics, ARBs, ACEi, diruetics
lithium clearance inhibition (increases toxicity)
postassium-sparing diuretics
RA and phospholipids?
the phospholipids get released and are converted to the endoperoxidase precursors and then into prostacyclin, prostaglandin, and thromboxanes - make inflammatory process worse
what are DMARDs?
disease-modifying anti-rheumatic drugs
do not immediately decrease symptoms, take a long time to decrease symptoms becuase they delay they disaease
DMARDs are often taken with…?
NSAIDs - they provide rapid relief for symptoms
what are the DMARDs that are immunosuppressive agents?
glucocorticoids, gold sodium, methotrexate, leflunomide
what are the DMARDs that are TNFalpha blockers?
enteracept, infliximab, adalimumab
what are other DMARDs?
anakinra (IL-1 receptor antagonist)
tocilizumab (IL-6 mAB)
what are some side effects of methotrexate?
anorexia, vomiting, abdominal cramps, infection, lymphomas, mucosal ulcers, leukopenia
how do methotrexate and leflunomide work?
they prevent B cell proliferation/maturation (maybe?) and block IgM/Rheumatoid factor release
what does leflunomide specifically inhibit?
dyhydroorate dehydrogenase which is important in lymphocyte proliferation
what is entercept?
a TNF alpha-trap; it binds to TNF alpha preventing it from stimulating TNF-alpha receptors
what is infliximab?
a TNF-alpha mAB that binds to free TNF-alpha
what is anakinra?
naturally occurring IL-1 receptor antagonist completely inhibiting inflmmatory actions of IL-1
side effects of TNF-alpha inhibitors?
increased incidence of serious infections, allergic reactions
what is rilanocept?
an IL-1 Receptor trap
what does estrogen do in bone?
it stimulates osteoclast apoptosis, suppresses osteoblast apoptosis
what does reduced estrogen levels post-menopause lead to?
decrease in bone mass because you lose the blockage of osteoclasts by estrogen
what is the relationship between OPG and estrogen?
as you decrease estrogen, you decrease OPG, and so more RANKL binds to RANK, more osteoclast activity
what are anti-resorptive/anticatabolic drugs?
they block maturation of osteoclasts or induce apoptosis in osteoclasts, inhibiting bone reporption
what are some antiresorptive/anticatabolic drugs?
bisphosphonates, SERMs, denosumab, calcitonin
what do bisphosphonates do?
they bind to hydroxyapatite crystal during bone remodelling and then when osteoclasts go to resorb bone, they are released, bind to osteoclasts and induce apoptosis - have long term effects because deposited in bone
what can you use bisphosphonates for?
osteoporosis, paget’s disease, metastatic bone disease
what are some bisphosphonates?
alendronate and zoledronic acid
what are side effects of bisphosphonates?
GI side effects, osteonecrosis of jaw rare, after 5 year small increased risk in femur fractures???not clear
why don’t we use estrogen replacement therapy?
because it is linked to increased risk of breast cancer
what are SERMS?
selective estrogen receptor modulators - they act beneficially in some tissue (bone, brain, liver) and antagonistically in others - they decrease ER in breast cancer, agonists in bone, this is due to the different availability of TxFs in different tissues
what is an example of a SERM?
raloxifene, bazedoxifene, iasofoxifene
what are TSECs?
tissue selective estrogen complexes - combine SERM with estrogen - to give a little estrogen back but blocking its negative effects
what does denosumab do?
binds to RANKL, its a mAB, prevents osteoclast maturation
bad thing about anti-resportion drugs?
there is no buildup of bone either
what are osteoanabolic drugs?
they induce osteoblast maturation and decrease osteoblast apoptosis
what are the osteoanabolic drugs?
PTH (terapatide) and strontium ranelate (not in use)
bad thing about osteoanabolics?
as you increase OBs, you increase RANKL which increases OCs
what does teriparatide do?
it is the active portion of PTH and it stimulates osteoblasts and increases bone mass, but may lead to osteosarcoma
what do bone morphogenetic proteins do?
they promote osteoblast maturation specifically by causing recruitement of mesenchymal stem cells to promote bone healing - often used in surgery
what increases serum calcium?
PTH, vit D
what decreases serum calcium?
calcitonin
what does PTH do?
increases skeletal resorption and deposition depending on situation, decreases calcium excretion, increases vit D synthesis
how can PTH stimulate resorption AND deposition?
at low concentrations it stimulates bone growth, at high concentrations (which occurs when Ca levels are low) it stimulates bone resorption
what does PTH stimulate in the kdiney?
1alpha-hydroxylase which hydroxylates Vit D
what does vit d do?
1,2dihydroxycholecalciferol (aka calciferol) stimulates synthesis of calcium-binding transport proteins in mucosal cells of gut - which increases absorption of calcium
what is calcitonin
it is made by C cells of thyroid and it inhibits osteoclast activity and decreases calcium resorption in the kidney
how do you treat paget’s disease?
calcitonin - it inhibits osteoclasts, or bisphosphates
what is the nicotinic ACH receptor composed of?
5 subunits, 2 alphas which are where the ACh binds - so need 2 molecules to activate receptor
NMJ blockers and brain?
cannot pass thru BBB - so no affect
when ach binds to receptors what happens?
get influx of Na, efflux of K (more Na than K), but it then gets densitized quickly after opening
what are the two types of NMJ blocking agents?
non-depolarizing and depolarizing NMJ blockers
what is a non-depolarizing NMJ blocker?
an antagonist that competes with ACH for binding pocket, when it binds, it prevents depolarization; causes flaccid paralysis
**direct muscle stimulation causes muscle contraction
what are some non-depolarizing NMJ blockers?
**tubocurarine
pancuronium, vacuronium, rocuronium, atracurium, mivacurium
how do you surmount non-depolarizing NMJ blockers?
increase ACH (via ACE inhib)
what is a depolarizing NMJ blocker?
succinylcholine
how do depolarizing NMJ blockers work?
they activate, open, and desensitize the ACH receptor and then persist at NMJ because they are resistant to ACE
what is phase I of depolarizing NMJ blocker?
brief disorganized muscle excitations that lead to fasciculation and then flaccid paralysis due to persistant muscle depolarization because voltage gated sodium channels get inactivated
**muscle contraction cannot be directly stimulated
how can you enhance phase I blockde?
increaseing ACh by adding ACE inhibitors or neostigmine
what ist he phase II blockade?
mechanism unknown but get flaccid paralysis
end-plate depolarization decreases and muscle repolarizes and becomes similar to non-depolarizing blockade
when do you get the phase II blockade?
with high doses or prolonged administration
what is a risk of succinylcholine?
hyperkalemia due to prolonged K efflux (especially patients with trauma, burns, nerve damage due to denervation supersensitivity)
prolonged apnea from decreased plasma cholinesterase activity
malignant hypothermia
what is malignant hypothermia?
muscle rigidity and elevated body temp that can occur when give succinylcholine and halothane
how do you treat malignant hypothermia?
dantrolene which acts on muscle to decrease calcium release from SR to inhibit excitation-contraction coupling
when giving ACEs…what else can you give and what should you also give?
you can give edorphonium or neostigmine instead of ACEs and you should give a muscarinic AChR inhibitor to prevent bradycardia (like atropine)
what is the train of four stimulation paradigm?
non-depolarizing: fade
depolarizing phase I: no fade, but diminished
depolarizing phase II: fade
how do inhaled anesthetics interact with NMJ blockers?
non-depolarizing NMJ potentiation - can use less anesthetic
how do local anethetics and calcium channel blockers interact with NMJ blockers?
potentiate non-depolarizing and depolarizing ones
NMJ blockers can cause bronchospasm how?
affecting histamine release
which blocker binds to nicotinic and muscarinic?
succinylcholine
how do you diagnose myasthenia gravis?
electrophysio test
give edrophonium and see if get better (a short acting ACE)
how do you treat myasthenia gravis?
pyridostigmine
