DRUG
MECHANISM/USE
PHARMACOKINETICS
 Block COX1 and 2 to inhibit PG synthesis
1. ANALGESIA-PGE2 and PGI2 sensitize nerves to pain
2. ANTIPYRESIS-LPS, TNFa, and IL-1 induce COX2 in the hypothalamus to make
PGE2, which raises the set point for temp
3. ANTIINFLAMMATORY-PGs contribute to vasodilation and pain/tenderness (need
higher doses to tx inflamm)
4. ANTITHROMBOSIS – block COX1 dependent thromboxane synthesis
5. CLOSURE OF DA-indomethacin or ALPROSTADIL to keep it open
6. TOCOLYSIS-delay onset of labor by blocking PGE2 synthesis.
DINOPROSTONE=PGE2 vag suppository for 2nd trimester abortion
ASPIRIN
IRREVERSIBLY INHIBITS PLATELET
 Oral, binds
COX1 for the life of the platelet
albumin(can displace
warfarin)
 Lipid soluble weak
acid – crosses
membranes
 T1/2=15 min but
salicylate also active
 90%reabsorbed
 Kinetics become 0
order at high doses,
longer T1/2
SALICYLATES
 METHYLSALICYLATE
=bengay
 SALSALATE=fewer GI
and no platelets, no
fever
 DIFUNISAL=no
antifever, no
auditory, less GI and
platelets
NSAIDS
SE
OTHER
 GI – bleeding d/t increased H and pepsin and decreased HCO3 and
mucus
 RENAL-decreased renal blood flow
 REYES-hepatic and brain damage in kids with influenza or varicella
with aspirin and other salicylates
 URIC ACID SECRETION-decreased at low and increased at high
 CLOSE DA
HYPERSENSITIVITY – to aspirin but not acetaminophen
OVERDOSE –
 Tinnitus
 Vomiting
 Hyperventilation – resp
alkalosis
 Uncoupler – hyperthermia
 Hypoglycemia
 Metabolic acidosis
 Then resp acidosis
Compared to aspirin, salicylate:
 Lower GI
 Less hypersensitivity
 NO platelet
TX of OD:
 Tx sx with fluids,
tepid water
 Do blood analysis
 Charcoal and
sorbitol
 IV INFUSION OF
NaHCO3 to
alkanalize urin
 Hemodialysis is
above 1mg
ACETIC ACID DERIVATIVES
 INDOMETHACIN
Potent inhibitor of COX1
1. Close DA
2. Tocolysis
3. Acute Gouty Arthritis
Worse GI effects than aspirin
Short term use only

SULINDAC
Prodrug converted to active in liver

DICLOFENAC
Osteoarthritis and RA

KETOROLAC
Shortterm tx of postop pain
PROPIONIC ACID
DERIVATIVES
 IBUPROFEN
 NAPROXEN = longer
t1/2
 KETOPROFEN
LONG HALF LIVES
 PIROXICAM
 OXAPROZIN
Pain, fever, dysmenorrhea, and
inflammation
LOW COX1 ACTIVITY
 NABUMETONE
 ETODOLAC
 MELOXICAM
COX2 SELECTIVE
Anti-inflamm for RA and osteoA

CELECOXIB

ROFECOXIB
REMOVED
VALDECOXIB
REMOVED

COX2>>>COX1
Similar efficacy to ibu
RA, and osteoA
Menstrual pain
FAP to reduce polyp #
SULFONAMIDE
NON SULFA
SULFONAMIDE
Enterohepatic cycling so
prolonged action of 16hr
Rapid release, Delayed
release and ophthalmic
forms
Parental IV or IM for
short term
Less GI toxicity than aspirin
GI tox=aspirin
Worse GI tox
GI tox=aspirin
Once/day dosing
(t1/2=50hr)
But take 7-12 to reach
steady state
COX2>COX1
Worse GI tox
Less GI
Minimal GI
Similar Renal
NO platelet
CYP2C9 metabolism
CYP2d6 inhibitor
T1/2=11.2 so once/day
DRUG INTERACTIONS by cyp2c9
inhibitors (cimetidine, omeprazole,
zarfirlucast, sulfas, ketoconazole)
SERIOUS CV EFFECTS
Stevens-Johnson syndrome
Serious CV effects
Arthrotec = diclofenac
+misoprostol
ACETAMINOPHEN
=NOT AN NSAID!








Analgesic and antipyretic
but diff from aspirin:
NO anti-inflamm
NO CNS effects
No reyes
No CV or resp
No gastric irritation
NO platelets
NO uric acid effects
Similar pharm to aspirin.
Normally glucuronidated
or sulfated and excreted
by kindey.
Small % oxidated to
substance that reacts
with –SH groups, but at
normal doses this reacts
with GLUTATHIONE to
yield a nontoxic product
OVERDOSE
 >7.5g, death at >20g
 Hepatotox at 10-15g
 Glutathione depleted at
high doses and
IRREVERSIBLY reacts with –
SH of proteins
 Alcohol also depletes
glutathione
 TX: NACETYLCYSTEINE =
thiol that provides alt. SH
groups but can’t reverse
damage done. IV bc its gross
 RUMACKMATTHEWNOMOG
RAM to determine risk.
Toxic levels increase t1/2
Vicadin=hydrocodone
+acetaminophen
 STAGE1=0-24hrs-GI
and sweat
 2=24-48hrs-nothing
 3=71-96hrs-more
sever stage 1 and
maybe coma. LFT
and bilirubin
elevated. Decreased
clotting
 4=4d-weeks –
survive w/NO
damage or die
IMMUNOSUPPRESANT:
CYTOTOXIC DRUGS
METHOTREXATE*
Folic acid analong
AZATHIOPRINE*
LEFLUNOMIDE
GOLD COMPOUNDS
 AURANOFIN = oral
 AUROTHIOGLUCOSE =
IM
HYDROXYCHLOROQUINE
=antimalarial
D-PENICILLAMINE
=chelating agent for Cu, Hg, Pb,
Zn
MYCOPHENOLATE MOFETIL*
=specific for T and B cells bc
they have no salvage pathway
MECHANISM/USE
=DMARDS
NOT analgesics or antipyretics
RA, asthma, crohns, MS, psoriasis
 Inhibits DHFR (DHFTHF)so
blocks purine synthesis
 No THF blocks
dUMPdTMP so no DNA,
RNA, or protein
 SO inhibits cell proliferation
Prevents renal transplant rejection
RA, IBD, lupus, nephritis, wegeners
 Blocks DNA and RNA
synthesis
RA
 Inhibits Dihydroorotate
dehydrogenase to block
pyrimidine synthesis
Only for nonresponsive
 Mech unknown.
 Inhibit macrophages?
PHARMACOKINETICS
Take several weeks
AE
Serious and limit duration
OTHER
Taken up by folate
transporter and gets
polyglutamated
LEUCOVORIN Rescue
=N-formylTHF, competes with
metho for uptake N5N10methylene THF
So bypasses need for DHFR
(also helps block thymidylate
synthesis with FLOROURACIL)
BM tox
GI tox
DOC for RA
Antiinflamm at high doses
LUPUS and nonresponsive RA
 Mech unknown
Unresponsive RA, Wilsons, Cystinuria
Max effect may take 3-6mo
Kidney, heart, and liver transplants
 Inhibits DE NOVO synthesis
of dGMP and hence RNA and
DNA
 Reversible, noncompetitive
block of IMP dehydrogenase
Prodrug hydrolyzed
immediately
prodrug6mercaptopurine
(=analog of hypoxanthine)
Prodrug converted in gut or
liver
LONG t1/2 d/t CYLCING
LIVER TOX!
Teratogenic
Long t1/2:
Blood=26days
Tissue=80days
 Diarrhea
 Rash
 Stomatitis
 Renal tox
 Thrombocytopenia
IRREVERSIBLE RETINAL DAMAGE
More toxic than golds
 Cutaneous lesions
 BM tox
 Autoimmune syndromes
FEW
 Some GI
 LESS BM tox than aza
 Minial renal tox (so
better than CSA)
 PREG D
ALLOPURINOL blocks
xanthine oxidase so
causes accum. Of
azathioprine->tox
Cholestyramine (resin)
can be used to shorten
t1/2 from 2wks to 1 day
IM injection can cause
gray/blue pigment to
skin
IMMUNOSUPPRESANT:
CORTICOSTEROIDS
IMMUNOSUPPRESANT:
TNFa and IL-1 TARGETERS
ETANERCEPT*
INFLIXIMAB*
ADALIMUMAB
CERTOLIZUMAB
GOLIMUMAB
ANAKINRA
IMMUNOSUPPRESANT:
T-CELL TARGETERS
CYCLOSPORINE*
TACROLIMUS
=similar to CSA
SIROLIMUS*
=blocks IL2 ACTION
MECHANISM/USE
Switch on synthesis of IKB, inhibit
PLA2
MECHANISM/USE
PHARMACOKINETICS
AE
OTHER
PHARMACOKINETICS
AE
OTHER
TNFa receptor attached to Fc portion
of human IgG
Chimeric monoclonal Ab against
TNFa
SC 2x/week
+/- methotrexate
Human-human
Conjugated to pegol
Anti TNFa human
Recombinant human IL1 Receptor
Antagonist
RA if DMARDS don’t work
MECHANISM/USE
SC every 2 weeks
SC every 4 weeks
SC every 4 weeks
SC ONCE A DAY
 Immunosuppression: Tb,
opportunistic, infections, no
vaccines, demyelinating,
lymphoma
 Autoimmunity – can get lupuslike syndrome
 Ab against drug itself
Prevent Renal, Liver, Heart Rejection
RA, IBD, MG
 Binds CP to prevent
CALCINEURIN from
activating NF-AT (stops Tcell
prolif)
Hydrophobic
Variable absorption
High first pass
Need to assay blood levels



ABATACEPT
=inhibits Tcell prolif
Also blocks CALCINEURIN
but via FKBP25 receptor
Binds FKBP12 but does NOT
block calcineurin or IL2
production
BLOCKS MTOR (a cell cycle
kinase)
Non responsive RA
 CTLA4 soluble B7 receptor
attached to Fc of IgG
 Binds B7 20x stronger than
IV infusions every 8 wks
PHARMACOKINETICS
Don’t use with TNFa blockers
 Infections
 Neutropenia
AE





NEPHROTOXICITY (hard
to tell from kidney
rejection)
HTN
Hypercholesterol
Hirsuitism
LITTLE EFFECT ON BM
+ methotrexate in RA to
limit Ab production
against infliximab
+/+/With MTX
OTHER
INTERACTIONS
-w/drugs that inhibit
P450 3A4
=Antifungals, grapefruit
-Drugs that induce
it=phenobarbitol,
carbamazepine,
rifampin, st jons wort,
nephrotoxics, lovastatin
hydrophobic
hydrophobic
Also CYP3A4 metabolism (see
interactions)
So give 4hrs after CSA
 NOT liver. hepatic a thrmosis
 LITTLE nephrotox (but makes
CSA’s worse)
 High TG and chol
 HTN
 Thrombocytopenia
Don’t use with TNFa blockers or
anakinra
Renal transplant with
CSA or GCs
DACLIZUMAB
BASILIXIMAB
CD28 does
For ACUTE renal rejection
 Monoclonal Ab against IL2 R
IV before surgery
Use with CSA and GCs