Pharmacology Flashcards
What are two critical mediator pathways of inflammatory conditions?
- Nuclear Factor Kappa B (NF-kB)
- Arachidonic Acid Cascade
What are stimuli and target genes for NF-kB?
What is the arachidonic acid cascade?
Arachidonic acid is cleaved from membrane phospholipids by Phospholipase A2
It is used to in the lipoxygenase pathway to make leukotrienes and the Cyco-oxygenase pathway to make prostaglandins, prostacyclin, and thromboxane A2
Pathways are determined by the tissue/cell
What pathway do NSAIDs inhibit?
COX-1 and COX-2 pathways
What are characteristics of the COX-1 pathway?
- Constitutively expressed in many tissues
- generates thromboxanes
- Generates low levels of prostaglandins
What are characteristics of the COX-2 pathway?
- Most responsive for inflammatory response
- Inducible form of enzyme; expressed in high levels after induction by inflammatory mediators
- Generates high levels of prostaglandins and thromboxanes
Functions:
local inflammation
wound healing
resistance to infection
What are functions of prostaglandins?
- protective (i.e. gastric mucosa)
- maintains local blood flow / vasodilation (i.e. kidney)
- platelet aggregation
- uterine contraction
- muscle growth
- modulation of synaptic transmission
Thromboxanes are dependent on which enzyme for their synthesis?
COX-1
What are some non-selective COX inhibitors?
aspirin (irreversible)
ibuprofen
naproxen
What are some toxic side effects of NSAIDs?
- Gastrointestinal tract
- Renal effects
- Hypertension
- Impaired hemostasis
- Allergic hypersensitivity rxns
- CNS toxicity
What are some GI side effects of NSAIDs?
Dyspepsia
Ulcers
Inflammation
Gastric erosion, hemorrhage
What are some renal side effects of NSAIDs?
Glomerular filtration rate reduced
Edema
Necrosis
Nephritis
Hyperkalemia
What are some pharmacokinetic interactions of NSAIDs that increase NSAID toxicity?
potentiation of drugs bound to plasma proteins
(warfarin, phenytoin, sulfonylureas, methotrexate)
Inhibition of drug metabolism
(phenylbutazone)
Inhibition of acid transport in kidney
(by probenecid)
What are some pharmacodynamic intereactions of NSAIDs that increase their toxicity?
Increased risk of bleeding after alcohol
Reduced effects of anti-hypertensive agents
(beta-adrenergic antagonists, ACE inhib., diuretics)
Inhibition of renal clearance of Lithium
Sudden hyperkalemia with K+-sparing diuretics
What are the half lives of NSAIDs?
Short half-life (< 6 hr)
aspirin
ibuprofen (Motrin, Advil)
indomethacin
Long half-life (> 6 hr)
naproxen (Aleve)
salicylate
phenylbutazone
What are COX-2 selective inhibitors?
celecoxib (celebrex)
What are other analgesic/anti-inflammatory (non-NSAID) agents?
Glucocorticoids
Acetaminophen (tylenol)
What are characteristics of glucocorticoids?
- effective anti-inflammatory agents
- inhibit Phospholipase A2, reduce arachidonic acid levels
- inhibit production of inflammatory cytokines (IL-1, TNFalpha, IFNgamma)
- inhibit NF-kB signaling and thus inhibit COX-2 inhibition
- significant side effects limit use
What are characteristics of aceteminophen?
- analgesic, antipyretic agent
- less effective anti-inflammatory agent
- a weak inhibitor of COX-1 and COX-2
- exact mechanism unknown
- drug of choice for fever, headache in infants
What about COX-2 specific inhibitors has led to their removal from the market?
They have increased cardiovascular risk, thought to be because they alter the balance between thromboxanes and prostacyclins, by inhibiting pathways leading to prostacyclin synthesis
What are possible drug treatment options for arthritic conditions?
Relief of symptoms:
NSAIDs
Disease modifying anti-rheumatic drugs (DMARDs)
What are the different categories of DMARDs?
Synthetic Drugs:
Immunosuppresant agents
Biologics:
TNFalpha Blockers
IL-6 mAb
IL-1 Receptor antagonist
Immune Modulators
What are some notable Immunosuppressant DMARDs?
Methotrexate
Leflunomide
What are some notable TNFalpha blockers?
etanercept
infliximab
What are some notable IL-1 receptor antagonists?
anakinra
What are some notable immune modulator DMARDs?
abatacept
rituximab
What are characteristics of methotrexate?
- Immunesuppressant:
dihydrofolate reductase inhibitor - Effectiveness is dose-related
- Slow onset of effects
- Side effects:
anorexia, vomiting, abdominal cramps
mucosal ulcers, hepatotoxicity
mild leucopenia, thrombocytopenia - may be used in combination with other disease modifying drugs
What are characteristics of leflunomide?
- Inhibits pyrimidine synthesis by inhibiting dihydroorate dehydrogenase
- reduces lymphocyte proliferation
- potent immunosuppressant
- pro-drug (active metabolite)
- long half-life
- long-term effectiveness/toxicity unkown
- inhibits CYP2C9
- Adverse Effects:
hepatotoxicity
hypertension
teratogenic
may cause fetal death
What are characteristics of etanercept?
TNF-alpha blocker
- a chimeric TNF receptor, blocks binding of TNF-alpha
- reduces joint swelling
- combined with methotrexate
- long-term effectiveness/toxicity unknown
- increased risk of latent TB activation
What are characteristics of Infliximab?
TNF-alpha antibody - blocks stimulation by TNF-alpha
- combined with methotrexate
- long-term effectiveness/toxicity unknown
What is the target for rituximab?
CD20+ B cells
- rituximab prevents development and proliferation of B cells
What are the two types of cholinesterases?
Acetylcholinesterase
Plasma cholinesterase
What is a cholinesterase inhibitor?
Molecules that look like ACh to AChE, ultimately blocking AChE’s ability to cleave ACh
What are the types of cholinesterase inhibitors?
Quarternary alcohols, Carbamates:
Clinical use; choice depends on desired site and duration of action
Organophosphates:
Slowly reversible or irreversible: few clinical uses (except glaucoma)
Found in insecticides and nerve agents
What are medical uses of anticholinesterases?
Myasthenia Gravis
Anesthesia
Alzheimer’s Disease
Glaucoma
Emergency Medicine
Bladder control
Dry mouth
What’s the difference between carbamates and organophosphates that determines their reversibility?
Both act as intermediates of the AChE rxn, blocking the rxn
Carbamate can be dislodged by H2O as a nucleophile
Organophosphates need nucleophiles stronger than H2O initially, then undergo aging which makes them completely irreversible and new AChE must be produced
What is Edrophonium?
Used for diagnosis of Mysathenia Gravis
and reversal of neuromuscular blockade by non-depolarizing muscle relaxants
Bioavailability: IV or IM injectable
Active for ~30min
Metabolism: renal
Adverse effects minimal due to fast elimination
What is Pyridostigmine?
Myasthenia Gravis treatment
(Also, organophosphate poisoning prophylaxis)
Bioavailability: oral treatment
Peak after 30min
active ~4 hrs
Metabolism: renal
Adverse effects:
GI symptoms of nausea, vomiting or diarrhea
sweating and flushing
increased salvation
tearing and constricted pupils
bronchial secretions
What is Donezipil?
Alzheimer’s treatment
Bioavailability: oral treatment
Peak concentration after 4hrs
accumulates in brain 2x plasma levels
active ~ 80hr
Extreme half life requires increasing dose slowly, including a 1 week titration, to avoid adverse effects
Metabolism: renal
What is cholinergic crisis?
Can occur by overdose of anti-AChE drugs:
SLUDS: Salivation, lacrimation, urination, defication, sweating
- Miosis
- profuse secretion
- bronchial constriction
- defecation/urination
- bradycardia
- hypotension
- muscle twitches
- convulsions
- respiratory failure
What is Physostigmine?
Used for Emergency medical reversal of anticholinergics or antihistamines:
Anticholinergics = atropine, scopolamine
antihistamines = diphenhydramine, dimethylhydrinate
“recreational” Jimson weed
Bioavailability: oral or injectable
peak concentration ~10-30min
Transdermal patch for 24hr exposure
Metabolism: liver metabolism, renal elimination
Adverse effects: S.L.U.D.S.
NOTE: also used to treat xerstoma (dry mouth)
What is the intermediate syndrome of organophosphate poisoning?
May occur for up to 1 week after exposure
modifications in function of nicotinic receptors
Symptoms do not respond to:
atropine
2-PAM
Symptoms resolve on own in week or two
Treatment is supportive (respirator)
What is Organophosphate-induced delayed polyneuropathy (OPIDP)?
Symptoms:
muscle weakness
headaches
psyciatric problems
memory problems
Cause not established; likely chronic exposure to OPs
No established pharmaceutical therapy
What is pralidoxime (2-PAM)?
hydroxylamine derivative with a cationic head that is able to regernate AChE active site after organophosphate exposure
Not indicated for carbamate overdose
What is used to treat organophosphate poisoning?
Remove all sources of agent (clothes, etc)
atropine - immediately to stop secretions
pralidoxime (2-PAM) - immediately to regenerate enzyme
diazepam to reduce convulsions
Supportive measures (i.e. respirator)
What is the current protection to organophosphate poisoning?
Prophylactic opportunity with pyridostigmine:
Inhibit a fraction of AChE with spontaneously reversible anti-AChE before exposure
This is possible b/c poisoning effects appear after > 50% enzyme is inhibited
