Antipyretic analgesic
Nonsteroidal anti-inflammatory
drugs
Anton Kohút
Pain perception
Analgesics
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Salicylates- Aspirin
Paracetamol
Other nonsteroidal antiinflammatory drugs
(NSAIDs)
IV. Opioid analgesics
Aspirin
Salicin from Willow Bark.
Biosynthesis of eicosanoids
COX1 and COX2
Mechanism of action of aspirine
Salicylates
Drugs
 Acetylsalicylic acid
(aspirin)
 Diflunisal
 Methylsalicylate
 Sulfasalazine
 Sodium salicylate
Pharmacological actions
 Analgetic
 Antipyretic
 Antiinflammatory
 Antiagregatory
 Anticancerogenic
Side effects of salicylates
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Gastrointestinal effects.
Hepatic and Renal Effects
Neurological effects (high doses stimulation followed
by depression.
Acid-Base balance
Respiration. Salicylates stimulate respiration
Uricosuric Effects. Low doses may decrease urate
excretion. Large doses induce uricosuria.
Small doses of salicylate can block the effects of
probenecid and other uricosuric agents
Side effects of salicylates - cont.
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Oxidative phosphorylation - the uncoupling of oxidative
phosphorylation
Carbohydrate metabolism- large doses hyperglycemia and
glycosuria and deplete liver and muscle glycogen.
Nitrogen metabolism - in toxic doses cause a significant
negative nitrogen balance.
Fat metabolism - reduce lipogenesis
Endocrine effects- large doses of stimulate steroid secretion.
Pregnancy- uses for long periods - reduced weights of babies.
Pharmacokinetics of salicylates
Absorption after p.o. are absorbed rapidly, After oral
administration, the nonionized salicylates are
passively absorbed from the stomach and the small
intestine.
Appreciable concentrations are found in plasma in less
than 30 minutes; a peak value is reached in about 2 hours
 Rectal absorption is slower than after p. o. and is
incomplete and unreliable;
 Salicylic acid is rapidly absorbed from the intact skin,
especially when applied in oily liniments or ointments.
Pharmacokinetics (cont.)
Distribution - distributed throughout most
body tissues and most transcellular fluids,
primarily by pH- dependent passive
processes, readily crosses the placental
barrier and BBB (not diflunizal).
 The volume of distribution 13 l;. at high
doses, increases to about 35 l
 80% to 90% of the salicylate is bound to
plasma proteins.
Pharmacokinetics of salicylates (cont.)
Elimination
The biotransformation takes place in many tissues,
but particularly in the liver.
Are excreted in the urine as free salicylic acid
(10%), salicyluric acid (75%), salicylic phenolic
(10%) and acyl (5%) glucuronides, and gentisic
acid (<1%).
 Half-life for aspirin is 15 minutes; that for
salicylates is 2 to 3 hours in low doses and about 12
hours at usual antiinflammatory doses
Effect of dose on the half-life of aspirin
Aspirin
(low dose)
10
9
8
(according to Lippincott´s
Pharmacology, 2006
11 12 1
7
5
Aspirin
(high dose)
2
3
4
t1/2 = 3 hours
12 1
11 12 1 2
10
2 3
9
3
4
8
7 6 5
t1/2 = 15 hours
Therapeutic uses:
a. Antipyretics and analgesics:
Aspirin, sodium salicylate, choline salicylate, choline
magnesium salicylate - used as antipyretics and analgesics:
- headache, arthralgia, myalgia,
- in the treatment of gout, rheumatic fever, and rheumatoid
arthritis.
Note: Salicylates are the drugs of choice in the treatment of
rheumatoid arthritis.
b. Diflunisal, a derivate of salicylic acid, is not metabolized to
salicylate - it cannot cause salicylism. Diflunisal is 3-4 times
more potent than aspirin as an analgesic and an antiinflammatory agent, but it does not have antipyretic
properties.
Note: Diflunisal does not enter the central nervous system
(CNS) and therefore cannot relieve fever.
Cardiovascular applications: inhibition
of platelet aggregation.
 Low doses of aspirin are used prophylactically to
decrease the incidence of transient ischemic
attack and unstable angina in men as well as that
of coronary artery thrombosis. Aspirin also
facilitates Aspirin also facilitates closure of the
patent ductus arteriosus (PGE2 is responsible for
keeping the ductus arteriosus open).
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d. Colon cancer: Chronic use of aspirin may
reduce the incidence of colorectal cancer.
Therapeutic Uses of salicylates
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(dose depends on the wanted effect)
Analgesia - headache, arthritis, dysmenorrhea,
neuralgia, and myalgia. in the same doses and
manner as for antipyresis
Antipyretic- in the same doses and manner as for
analgesia
Rheumatoid arthritis - 2 to 6 g daily),
Other uses - treatment or prophylaxis platelet
hyperaggregability (dose of aspirin is 40 to 325 mg per
day).
Inflammatory Bowel Disease - mesalamine (5amino-salicyclic acid)
Aspirin
Usual dose
Effect
80 – 160 mg
Antiplatelet
325 – 1000 mg
Analgesic, antipyretic
325 mg – 6 grams
Antiinflammatory,
tinnitus
6 – 10 grams
Respiratory alkalosis
10 – 20 grams
Fever, dehydration,
acidosis
> 20 grams
Shock, coma
Dose-dependent
effects of salicylate
Vasomotor collapse; Coma; Dehydration
Plasma concetration of
salicylate (mg/dL)
150
100
50
Severe Intoxication
Mild
Tinnitus
Central hyperventilation
Anti-inflammatory
10
0
(according to Lippincott´s
Pharmacology, 2006
Lethal
Analgesic
Antipyretic
Antiplatelet
Gastric bleeding
Impaired blood clotting
Hypersensitivity reactions
Preventive use of aspirine
Paracetamol (acetaminophen)
Paracetamol
Pharmacological properties
analgesic and antipyretic effects
 is only a weak inhibitor of COX.
 no effects on platelets, or the excretion of uric acid.
Pharmacokinetics
 is rapidly and completely absorbed from the gastrointestinal
tract.
 peak concentration in plasma in 30 to 60 minutes, and the
half-life in plasma is about 2 hours
 After large doses of paracetamol, the metabolite (Nacetyl-benzoquinoneimine) is formed -and hepatic
necrosis can result.
HNCOCH3 HNCOCH3 HNCOCH3
Metabolism of paracetamol
Sulfate
OH
Glucuronide
Paracetamol
Cytochrome P-450
mixed function
oxidase
Glutathione
NCOCH3
Nucleophilic
hepatic cell
proteins
Toxic doses
Therapeutic doses O
HNCOCH3
OH
Glutathione
Mercapturic acid
(nontoxic)
(according to
Lippincott´s
Pharmacology, 2006
Toxic
intermediate
HNCOCH3
OH
Cell macro-molecules
Cell death
Paracetamol (cont.)
Therapeutic Uses
 is a suitable substitute for aspirin for analgesic or
antipyretic uses;
Toxic Effects
In therapeutic dosage is usually well tolerated.
 acute overdosage ( 2-3 g) is a dose-dependent,
potentially fatal hepatic necrosis. Renal tubular
necrosis and hypoglycemic coma also may occur.
Toxicity is potentiated by ethanol
 antidot - N-acetylcysteine.
Nonsteroidal antiinflammatory
drugs
NSAIDs
Inflammation represents a series of
homeostatic events that have evolved to aid
in our survival in the face of pathogens and
tissue injry.
NSAIDs
NSADS act as :
 1. cytokine inhibitors ( IL-1, TNF, IL-8), antibodies or
antibody fragments. Antagonists to various peptides that
contribute to cytokine-mediated responses (e.g., substance P,
bradykinin) also are in development.
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2. inhibitors of cell adhesion molecules (these include
soluble fragments of receptors to bind cell adhesion molecules
and use of antibodies, peptides, and carbohydrate moieties to
block cell adhesion molecules.
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3. phospholipase A2 inhibitors - glucocorticoids but whose
toxicity will be less frequent and severe than that of the steroids).
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4. inhibitors of lipooxygenase and leukotriene receptors,
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5. isoform specific inhibitors of cyclooxygenase
(meloxicam).
Classification of NSAIDs
Indomethacin
Pharmacological properties
has prominent antinflammatory and
analgesic-antipyretic properties, is
more potent than aspirin.
 effects of indomethacin are evident
in patients with rheumatoid and
other types of arthritis, including
acute gout.
 is evidence for both a central and a
peripheral action; it also is an
antipyretic.
 is also inhibitor of
polymorphonuclear leukocytes.
Pharmacokinetics
After p. o. oral ingestion the peak
concentration within 2 hours.
Its concentration in synovial fluid is
equal to that in plasma within 5
hours.
Indomethacin is converted primarily
to inactive metabolites, including
those formed by O-demethylation
(about 50%), conjugation with
glucuronic acid (about 10%), and
N-deacylation.
10% - 20% of the drug is excreted
unchanged in the urine, in part by
tubular secretion.
The half-life averages about 3 hours.
Indomethacin
Therapeutic uses
Analgesic-antipyretics
Treatment of ankylosing
spondylitis and osteoarthrosis,
treatment of acute gout
 in obstetrics and neonatal
medicine. - as a tocolytic
agent to suppress uterine
contractions.
 - cardiac failure in neonates
caused by a patent ductus
arteriosus
Side effects
about 20% must discontinue its
use. Most adverse effects are
dose-related.
GIT
 some fatal cases of hepatitis and
jaundice have been reported.
 most frequent is severe frontal
headache.
hematopoietic reactions include
neutropenia, thrombocytopenia,
and, rarely, aplastic anemia.
diclofenac, felbinac, ibuprofen, ketoprofen, piroxicam,
naproxen, flurbiprofen and others.
Gout is a form of arthritis
Development of gout
Antirheumatic Drugs
(drugs used to treat rheumatoid
arthritis)
The major classes of antirheumatic drugs
include:
1. Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs: ibuprofen naproxen
indomethacin .
2. Corticosteroids: prednisone and
dexamethasone.
Is classified as an auto-immune
disease
Physicians now use Disease Modifying AntiRheumatic Drugs (DMARDs) and Slow-Acting
Antirheumatic Drugs (SAARDs).
The major classes of antirheumatic drugs include:
1.
Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs: ibuprofen (Motrin, Nuprin or Advil),
naproxen (Naprosyn, Aleve) indomethacin
(Indocin).
2.
Corticosteroids: prednisone and dexamethasone.
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DMARDs influence the disease process itself and do
not only treat symptoms
-Antimalarials DMARDs include chloroquine (Aralen)
and hydroxychloroquine (Plaquenil).
- Immunosuppresive cytotoxic drugs: methotrexate,
mechlorethamine, cyclophosphamide,
leflunomide, cyclosporine A, chlorambucil, and
azathioprine.
- Slow-Acting Antirheumatic Drugs (SAARDs): are a
special class of DMARDs and the effect of these
drugs is slow acting and not so quickly apparent as
that of the NSAIDs. Example is aurothioglucose
(gold salt).
- Monoclonal antibody: etanercept, infliximab antiTNFdrugs
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Anakinra (recombinant interleukin-1 receptor
antagonist)
Monoclonal antibody:
anti-TNF drugs: Adalimumab, etanercept,
infliximab, leflunomide, Remicade