Ch 36: Non-Steroidal Anti-Inflammatory Drugs Flashcards
what are some examples of eicosanoids?
prostaglandins, thromboxanes, leukotrienes
what are eicosanoids?
- hormones & molecules that activate receptors (PLA2)
- formed from membrane phospholipids
what does phospholipase A2 cleave?
an essential fatty acid (arachidonic acid)
- which then cleaves to form lipoxogenase & cyclooxogenase
Lipoxygenase
- forms leukotrienes
* * released in an autocrine & paracrine fashion
Zileuton
lipoxygenase inhibitor
Montelukast & Zaphirlukast
leukotriene receptor blocker
What are the effects of LOX
LTC4 & LTD4 = bronchoconstrictors
- can lead to anaphylaxis
COX
- activated by hormones & biomolecules when acting at receptors
- forms PGG2, converts to PGH2, then to various prostaglandins & thromboxanes
- consists of 2 isoforms
- COX-1 & COX-2
COX-1
- produced in tissues for normal tissue function
- (produces prostaglandins & activates platelets and protect the stomach & intestinal lining)
COX-2
-induced by inflammatory cells
used to treat inflammation, pain & fever
(release IL-6, IL-1B, and TNF-a)
What parts of the body does COX products play key roles?
Smooth muscle Platelets Kidneys CNS Inflammation
smooth muscle
Vascular:
- can be constrictor (TXA2 & PGF2a) or dilator (PGI2 & PGE2)
GI:
- mostly constrictors
Airways:
- PGI2 & PGE2 relax, and others constrict
Reproductive:
- PGF2a + oxytocin = parturition
- PGE2 & PGI2 = relax
platelets
- aggregation that’s mostly inhibited by PG’s
- TXA2 can be released which can lead to aggregation
Kidney
- TXA2 lead to renal vasoconstriction
- elevated renal inflammation
- PGI2 & PGE2 help w/ renal blood flow & function
Inflammation
- PGE2 & PGI2 (prominent) inflam. agents
* * increase B.F. = edema & leukocyte infiltration
CNS
- can lead to fever (PGE2)
- sleep (PGD1)
- regulation of neurotransmission
prostaglandins & thromboxanes cause?
pain (sensitize pain receptors to bradykinin…)
inflammation (increased vascular permeability)
fever (hypothalamic effect)
thrombus formation (clotting)
– vasoconstriction, vasodilation, dysmenorrhea, etc
what are some NSAID effects?
analgesia –> mild-mod pain
anti-inflammation –> corticosteroids
anti-pyretic –> reducing temperature in fever
anti-coagulant –> platelet aggregation
some NSAIDS
aspirin indomethacin naproxen oxaprocin etodolac flurbiprofen ibuprofen diflunisal celecoxib
NSAID adverse effects
CNS -- headaches, tinnitus, dizziness CV -- fluid retention, edema GI -- pain, nausea, vomiting, ulceration Hematologic -- rare (thrombocytopenia) Hepatic -- abnormal liver function Pulmonary -- asthma Rash -- pruritus Renal -- insufficiency to even failure
aspirin
- acetylsalicylic acid
- cheap/ inexpensive
- irreversible inhibitor of COX1 & COX2 (esp. on platelets)
- effective due to COX2 action
- side effects due to COX1 activity
Aspirin side effects
GI
(irritates upper GI)
— so take w/ meals. PG’s = mucous formation
CNS
(tinnitus, vertigo)
– possible kidney/ liver damage
Reye’s Syndrome
- children & teens
- after influenza/ chicken pox
(high fever, vomit, liver dysfunction, unresponsive, delirium, convulsions, coma, death)
Ibuprofen
- similar to aspirin
- less GI side effects
- more potent
Side effects on ibuprofen
- GI
- Rash, pruritis, tinnitis
- nephrotoxic
What area of the body is affected due to the toxicity of Ibuprofen
Stomach
Kidneys
why?
- less stomach protection (mucous production)
- less renal B.F. (nephrotoxicity)
symptoms of Ibuprofen toxicity
vomiting (w/ or w/o blood) abdominal pain diarrhea black/tarry stool loss of appetite increased drinking increased urination lethargy dehydration seizures
Naproxen
similar to ibuprofen ( but long lasting)
sulindac
less toxicity for kidneys
has greater GI affects than aspirin & ibuprofen
oxaprozin
50 hr half life
- take once a day
acetaminophen
- inhibits cox enzymes
- anti-pyretic & analgesic (NOT a NSAID)
- less anti-coagulant * anti-inflammatory
side effects of acetaminophen
hepatotoxic at high doses (can be fatal)
- no GI effects & nor Reye’s
indomethacin
- reduce pre-term labor (under 32 weeks)
- manage patent ductus arteriosus
COX-2 meds
celecoxib (Celebrex)
Rofecoxib (Vioxx)
** but removed due to strokes and MI
(for arthritis, dysmenorrhea)
COX-2 inhibitors
- reduce GI side effects (ulceration)
- increased thrombosis, MI, and stroke which lead to retraction of VIOXX
Rheumatoid Arthritis
- chronic, systemic disorder
- synovitis, joint destruction
- morning stiffness
- arthritis in 3+ areas
- affects about 1% of population
- most often women (20-40 yrs)
- auto-immune
* * initiated from previous. infections
* * (IL’s PG’s LK’s cause synovial proliferation, cartilage & bone destruction)
Treating Rheumatoid Arthritis
NSAIDS (treat inflammatory)
Corticosteroids (treat inflammatory)
DMARDS (slow disease)
What are some goals for Rheumatoid Arthritis
- decrease joint inflammation
2. arrest disease progression
Glucocorticoids
- naturally cortisol (hydrocortisone) produced in adrenal cortex
- bind to receptors in cytosol (orphan receptors)
- bound to heat shock proteins
NOTE:
- once steroid binds to receptors, HSP releases receptors, it dimerizes, then moves into the nucleus
- while in nucleus, receptor/ steroid complex acts like a txn factor to initiate mRNA txn
- leads to lipocortin-1 inhibits PLA2 activity
corticosteroid effects
physiologic metabolic catabolic stimulate acid & pepsin in stomach anti-inflammatory/immunosuppressive better than NSAIDS (inhibit leukotrienes) efficacious limiting side effects
when are corticosteroids used?
ONLY when NSAIDS are no longer effective
side effects of corticosteroids
peptic ulcer formation
muscle wasting
osteoporosis
Name some corticosteroids
Betamethasone
cortisol (hydrocortisone)
prednisolone
triamcinolone
DMARDS
disease modifying anti-rheumatic drugs
- takes 6 weeks to 6 months to work
methotrexate
immunosuppressive
one that’s most effective
best for toxicity ratio
side effects to methotrexate
hepatotoxicity
GI
pulmonary effects
hair loss
what does methotrexate inhibit?
thymidylate synthetase
chloroquine, hydroxychloroquine
anti-malaria drugs
- takes 12-24 wks to work
- used when NSAIDS stop working
side effects to chloroquine, hydroxychloroquine
safest DMARDS
ocular damage
headaches
gold therapy (auranofin)
- given orally w/ less side effects
- given early on (don’t reverse previous. damage)
- accumulates in lysosomes of synovial tissue (decrease lysosome & macrophages)
side effects of gold therapy
GI
oral irritation
common rashes, pruritis
blood disorders
Azathioprine
- immunosuppressant to prevent tissue damage
- FOR SEVERE CASES (cases that prevent other treat.)
- anti-metabolyte
- TOXIC & NOT well tolerated
- ** fever, sore throat, fatigue, vomiting
Penicillamine
- chelates heavy metals
- used for lead poisoning
- used for arthritis incase GOLDS don’t work
- immunosuppressant (reduce T cell function)
side effects of Penicillamine
moderately toxic (fever, joint pain, pruritis)
Leflunomide
- NEW
- well tolerated
- works within first month
blocks RNA synthesis in lymphocytes to reduce their activity
side effects of Leflunomide
GI
allergy
hair loss
hepatotoxic (need monitoring)
Etanercept
- new & effective (binds/blocks TNF binding action)
- successful to patients unresponsive to DMARDS
- given by sub-cutaneous injection (2x weekly)
side effects of etanercept
risk of infections (TNF = key part of immune system)
osteoarthritis
- Increase viscosity of synovial fluid
1. Hyaluronan: polysaccharides injected into joints for long lasting relief - Joint tissue precursors
1. glucosamine & chondroitin sulfate: used to reverse damage by providing precursors
Autonomic Pharmacology
CNS
- brain
- spinal cord
PNS
- somatic (skeletal muscle function)
- autonomic (body functions) –> HR, rest rate, etc
- sympathetic (thoracolumbar)
- parasympathetic (cranial sacral)
sympathetic division
1st thoracic to 3rd lumbar
pre-ganglionic neuron–> cord (ventral root) to ganglia
post-ganglionic neuron–> ganglion (dendrite & cell body) to organ
parasympathetic inervation
from brainstem (3,4,9,10 & vagus) to sacral cord Two neurons reach the end of the organ - ganglia found in end organ or tissue - longer pre-gang & shorter post-gang - 1:1 ratio of pre- to post-
Both pre and post neurons release ACh onto smooth muscle, cardiac muscle or glands
What are some ways that drugs can interfere?
block synthesis block uptake block storage displace transmitter prevent exocytosis agonist mimetic block receptor inhibit breakdown
cholinergic receptor
nicotinic receptors
Nn–> neuronal
- post-ganglionic neurons
- pre synaptic cholinergic terminals
- open Na+ or K+ channels
Nm–> muscle
- skeletal muscle neuromuscular junction
- open Na+ or K+ channels
muscarinic receptors
from a mushroom (amanita muscarina)
G protein coupled receptors
- activate ion channels, adenyl cyclase, PLC
at least 4 subtypes
- agonist: muscarine
- antagonist: atropine
(location: sm muscle, glands, heart, brain)
muscarinic receptors & locations
M1 M2 M3 M4 M5
M1
CNS & Symp. post-gang neurons
M2
heart & smooth muscle
M3
glands, smooth muscle
M4
glands, smooth muscle
M5
?? (cloned?? )
Muscarinic effects
- depolarization of ganglia
- decreased chronotropic & inotropic response
- smooth muscle contraction & glandular secretions
cholinergic stimulants
A. Direct-Acting: active receptors
- choline esters: similar to ACh
- Bethanechol
- Pilocarpine
- Methacholine - Alkaloids: from plants
- muscarine
- nicotine
- pilocarpine
what are the effects of direct acting cholinergics
eye:
pupil constriction, accommodation, increased lacrimation & decreased intraoccqular pressure
CV system:
bradycardia, decreased contractility, relax peripheral vessels
Respiratory System:
airway constriction, increased secretions
GI- increased motility
CNS- hypothermia, tremors, convulsions
Bladder- stim detrussor, relax trigone (urination)
SLUD
poisoning by cholinergics salivation lacrimation urination defecation
indirect- acting cholinergics
inhibit AchE
similar effects as direct acting
Reversible:
edrophpnium, neostigmine, physostigmine
Irreversible:
insecticides (malathion, parathion)
nerve gases
what are cholinergics used for?
glaucoma
GI and bladder
Heart
Atropine intoxication
Glaucoma
pilocarpine, physostigmine
- to reduce intraocular pressure
GI and bladder
bethanechil, neostig
- for post-op atony
Heart
edrophorium
- for tachycardia
Atropine intoxication
physostigmine
side effects/ toxicity of cholinergics
contraindications
- asthma, peptic ulcer, bradycardia, hypotension
SLUD
Cholinesterase inhibitor poisoning
- give heroic doses of atropine
- for organphosphatases, use 2-PAM
muscarinic receptor blockers effect:
heart:
tachycardia by clocking vagal input
resp. system:
bronchodilator & less secret
eye:
dilate & accomodate
Urinary & GI:
reduce activity/motility
CNS:
sedative, then excitement
muscarinic blocker uses
respiratory: Ipratropium (Atrovent)
- for asthma & pre- anesthesia
eye: Cyclopentylate
- for mydriasis & Cyclopegia
urinary/GI: Dicyclomine
- for incontinence or irritable bowel
motion sickness: Scopolamine
heart: Atropine
- for bradycardia
others: mushroom poisoning
muscarinic blockers are contraindicated for
glaucoma patients
prostate hypertrophy patients
anti-depressant patients
Ganglionic blockers
autonomic selective inhibitors
pirenzepine
pirenzepine
- for peptic user
- specific for muscarinic gang.
- have less side effects
autonomic selective inhibitors
- Hexamethonium, trimethaphan: used in hypersensitive emergencies
what does autonomic selective inhibitors cause?
tachycardia, mydriasis, constipation, urinary retention, decreased sweat & saliva
