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Non-opioid analgesics
analgesics-antipyretics
non-steroid antiinflammatory
drugs
l analgesics-antipyretics (A-A) drugs
decrease fever and pain
l non-steroid antiflogistics (NSAID) acting
against inflammation, pain and
fever
A-A and NSAID categories partially overlap
l antiuratics – drugs against gout
Cyclooxygenase isoforms
l COX-1 – constitutive – prostanoids providing
physiological and homeostatic functions
(gastroprotective, platelets functions)
l COX-2 – inducible – synthesis via proinflammatory
factors (IL-1, IL-2, TNF-α,
oncogens,..)
l prostanoids ⇒ inflammation, fever, pain
l COX-3 – central mechanism of analgesic and
antipyretic effects (localisation: heart + CNS)
Glucocorticoids
Phospholipase A2
Membrane phospholipids
Arachidonic acid
lipooxygenase
cyclooxygenase
LEUCOTRIENS
PROSTAGLANDINES
PROSTACYKLINES
TROMBOXANES
inflammation
Mobilization of fagocytosis
Changes in vessels permeability
Inflammation
A-A
NSAID
Inh. 5-LOX
Classes
1. Salicylates
2. Anilin derivates
3. Pyrazolones
4. Derivates of propionic acid
5. Derivates of acetic acid
6. Fenamates
7. Oxikams
8. Preferential inhibitors of COX-2
9. Coxibs
1. Salicylates
Effects
l analgesic
l antiflogistic
l antipyretic
l antirheumatic
l antitrombotic
l prophylaxis of myocardial infarction and brain
stroke
l inhibition of platelets functions (antiaggregant)
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Drugs
l ASA – prodrug metabolised to salicylic acid, the
only drug affecting COX irreversibly
l selective inhibition of platelets functions by
irreversible acetylation of COX (for the whole life-time
of thrombocyte)
l Aloxiprin – is degredated in GIT → ASA and
aluminium oxide, slower absorption, safer
l Natrium salicylate – inj. In rheumatic fever,
paliative care
ASA (acetylsalicylic acid)
cholinsalicylate
lysinsalicylate
diflunisal (↑ analgesic and antiflog. effect,
urikosuric, no antipyretic effect)
sulfasalasin (⇒sulfapyridin +
5-aminosalicylic acid)
mesalazin
Derivates of salicylic acid
AE
l Salicylism (↑d.) – hearing impairment, tinnitus, deafness,
vertigo
l Alergies - bronchospasms, itching, rash, anaphylactic
shock, bronchoconstriction
l GIT - nausea, dyspepsia, bleeding, ulcer disease
l Nephropathy – reversible decrease of GF
l Hepatopathy
CAVE
l Gravidity – according to trimester
l Children - Reye syndrome
l Elderly – more sensitive to AE
Contraindications
l haemophilia and other disorders of haemostasis
l before surgery
l ulcer disease
l gastritis
l children under 12 years
l Reye syndrome (hyperpyrexia, acidosis, cramps,
vomiting, neuropsychiatric disorders, hepatopathy)
l gravidity (according to trimester)
l asthma, allergies, nasal polyp
Usual dosing
l antipyretic effect 500 mg
l analgesic effect 500 mg (4 - 6 h)
l antiflogistic,-rheumatic,-uratic 3,6 – 4 g/day
l antiaggregant 30 –100 mg
2. Anilin derivates
Paracetamol (acetaminophen)
l Analgesic, antipyretic
l No antiinflammatory effect!!!
l No effect on aggregation and urikemia
l central mechanism on COX-3
l Indirect influence on 5-HT3 rp in spinal cord
l Fastens peripheral metabolisation of PGG2 to
PGH2
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Pharmacokinetics
l p.o. well absorbed, maximum in 30-60min, low
binding to proteins, hepatic metabolisation
l hepatotoxic mtb.- bound to glutathion
l overdose (10-15g)⇒ antidotum: N-acetylcystein
AE, CI
l Allergies
l Gravidity
l Trimester?
l Co-morbidity
l Alkohol abuse
l Nephropathy
l Hepatopathy
l Phenylketonuria – aspartam is used as korrigens in
paracetamol preparations
Usual dosing
l Effects are comparable with ASA but is safer!!
l 1st choice for ↓ fever and pain in children
under 12
l pain in adults
l 300 to 500 mg each 3-4 h
l 650 mg each 4 to 6 h
l 1000 mg each 6 h
l DTD to 4g
2. Anilin derivates
Phenacetin
l Analgesic, antipyretic
l strongly nephrotoxic, negatively inotropic
l in some countries used in combined analgesic
preparations
l Metabolised to paracetamol
3. Pyrazolones
phenylbutazon
l good antiinflammatory effect, less analgesic
l concentrates in joints and effective concentration
remains for 3 week after last administration
l AUV
propyphenazon
l less toxic
l in combinations (with paracetamol and caffeine)
metamizol
l antiflogistic and antipyretic effect
l AE – allergies, nausea, vomitus,
nephrotoxicity, inhibition of hematopoiesis
l Usually combined with spasmolytics (eg.
Algifen = metamizol + pitofenazon +
fenpiverin)
3. Pyrazolones
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4. Propionic acid derivates
ibuprofen
l good analgesic and antiflogistic effect
l Often used in therapy of acute pain
l low AE, probably best tolerated NSAID, indicated also in
children
ketoprofen - Ketonal crm, Fastum gel, Ketobene
flurbiprofen - Strepfen
tiaprofenic acid – well penetrates to synovial fluid
⇒ diseases of joints
naproxen - Napsyn
5. Acetic acid derivates
l Effective drugs with different AE
diclofenac (Voltaren, Apo-diclo, Inflamac, Fector gel, Olfen)
l antiinflammatory, analgesic, mild antipyretic ef.
l PK: bioavailability 30-70%, short half-life ⇒ retarded forms
l DTD 50-150 mg
l more AE than ASA, but less than indometacin
l mild: headache, insomnia, irritability, GIT disorders, photosensitivity
Indications: aching muscles, headache, after surgery, painful
menstruation…
indometacin (Indometacin supp, Indobene, Vonum cutan)
l Powerful non-selective COX inhibitor with urikosuric
effects
⇒ used in gout attacks
l toxic ⇒ only short-term administration in acute
conditions
l AE in 30% of patients
l GIT, headache, depression, confusion, hallucinations,
damage of haematopoiesis and cartilage
5. Acetic acid derivates 5. Acetic acid derivates
sulindac
l prodrug – metabolite is 500x more effective
l apart from COX inhibition probably can
reduce the growth of polyps and
precancerous lesions in the colon
l is effective tocolytic
l AE: relatively less irritating to the stomach,
skin lesions, toxic to liver and pancreas
6. Fenamates
l Highly potent
l often AE ( vomiting, headache, diarrhea, hematemesis,
hematuria, skin problems, fever)
→ only for acute conditions (migraine,
menstruational or joint pain)
l tolfenamic, mefenamic, meklofenamic,
flufenamic acid
l etofenamate
7. Oxicams
piroxicam
l Well tolerated in most of the patients
l 20 mg once a day
- Pro-roxikam, Flamexin, Reumador
meloxicam
l COX-2 more selective
l less AE
- Movalis, Recoxa
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8. Preferential inhibitors of COX-2
nabumeton
l prodrug
l Relifex, Rodanol
nimesulid
l scavenger
l Inhibits cartilage-degradating enzymes
(elastase, kolagenase)
l Aulin, Coxtral, Mesulid, Nimesil, Zolan
9. Coxibs
l 100 x more specific to COX-2
l less AE in GIT, no effects on aggregation or kidney
blood flow
l AE – increase in thrombembolic cardiovask. and
cerebrovask. attacks (AMI, brain stroke) after
chronic treatment
l rofe- and valdecoxib were withdrawn
l expensive – prescription only by rheumatologist
l for problematic patients with rheumatoid arthritis
l celekoxib has very safe profile (CVS, GIT)
l Good for treatment of morbus Bechterev (spondylitis ankylosa)
l Celebrex, Onsenal
l parekoxib
l etorikoxib
l rofekoxib, valdekoxib
l increased CVS risk
l both were withdrawn
l AE:
l thromboembolic cardio- and cerebrovaskular complications
9. Coxibs Safety of NSAIDs
l Generally NSAIDs must be prescribed and
recommended with caution, especially to
elderly/children
l Risk/benefit of selective NSAIDs is still
discussed
l When patient asks for common analgesic,
paracetamol is the 1st choice (possibly
with co-analgesics)
Often AE of NSAIDs
l Type A – Augmented – dose dependent
l GIT toxicity
l Nephrotoxicity
l Bronchospasms –salicylates and others
NSAIDs, (not after paracetamol)
l Inhibition of platelets functions
l Type B – Bizzare – unpredictable
l Allergies
l Reye syndrome
l rash …
Adverse effects of NSAIDs
l Results of COX-1 inhibition :
l GIT - ↓ cytoprotektive PGE2, PGI2
⇒ erosions, ulcerations
l thrombocytes - ↓ TXA2: inhibition of aggregation
⇒ bleeding
l PGE2, PGI2 autoregulate renal functions
⇒ renal insufficiention
l ↑ LT production causes bronchoconstriction in
predisposed individuals
⇒ asthmatic attack
l uterus - ↓ PGE/F: inhibition of contractions
⇒ elongation and complications of labor
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AE solution
l Dose reduction or change of drug form
l Combination with protective drugs
l proton pump inhibitors (lansoprazol, omeprazol)
l H2 antihistaminics – (cimetidin ranitidin, famotidin)
l antacids
l prostaglandin analoges (substitution)
l possibly COX-2 selective drugs?
Rheumatic diseases – strategies of
treatment
1. NSAID
2. DMARDs + Biolog. treatment
3. Others antirheumatics
l steroid antiflogistics (= glucocorticoids)
l cytostatics and antimetabolites
l imunosupressants
l proteolytic enzymes
Chronic treatment !
DMARDs
l According to current czech guidelines:
l Most often used DMARDs – antimalarics,
sulfasalazin, metotrexate, leflunomid
l Less often used –
gold salts, azathioprin, cyklosporin A,
cyklofosfamid
DMARDs
l chlorochin
l hydroxychlorochin
l antiinflammatory and imunomodulant effects
l inhibition of leukocytar chemotaxis
l In less severe form of disease
l AE: skin problems, damage of retina
antimalarics
DMARDs
sulfasalazin
l Slow incerase in dosing → onset of effects in 1-2-
months
soli Au
l Natrium aurothiomalate (i.m.), auranofin (p.o.)
l inhibit fagocytosis and thus also immune response
l 30-40% AE: skin and mucosal problems, damage of
haematopoiesis, hepatotoxicity, nephrotoxicity
DMARDs
Leflunomid
imunomodulans (inhibition of pyrimidin
synthesis)
USA – approved as a drug preventing
rejection of organs in allotransplantation
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DMARDs
Biological treatment
l targeted on immune cells and mediators taking
part in development of RA
l anti-TNF drugs:
l fast onset of effect, stop progression of disease but
relapse happens after stopping the medication
l risk of infections, CI vaccination with attenuated agents
AE: GIT, weakness, changes of blood pressure,
infections, allergies
Infliximab, adalimumab
l rekombinant monoclonal Ab
l create a complex with TNF-α
l suitable combination with methotrexate
etanercept
l rekombinant protein of TNF receptor subunit +
fragment of IgG = solubile TNF receptor
Others – rituximab, abatacerp
Other antirheumatics
1. Steroid antiinflammatory drugs
l glucocorticoids
2. Cytostatics and antimetabolites
l metotrexate
l azathioprin
l cyklofosfamid
3. Immunosupressants
l cyklosporin A
4. Proteolytic enzymes
l bromelain
l papain
l trypsin
Gout
Ethiology of gout
primary
l Genetically conditioned impairment in uric acid
metabolism
⇒ Deposit of urates in cartilage and joints
secondary
l Excessive degradation of purines (eg. in cancer)
l Insufficient excretion of uric acid (kidney problem)
l Increased intake of uric acid in food (sea fruit, alcohol…)
l Problematic drugs
l Low doses of ASA inhibit excretion
l thiazid diuretics (hydrochlorothiazid)
l immunosupressants
drugs used in gout
Acute attack
Therapy of hyperurikemia / prevention of attack
Therapy of acute attack
supression of inflammation, pain
inhibition of leucocytes migration into joint
Therapy of hyperurikemia / prevention of attack
excretion of uric acid
decrease in synthesis
diet
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Acute attack
l 1st aid – fast relief form pain and supression of
inflammatory processes
l NSAID
l diclofenac, indometacin, kebuzon
l kolchicin (Colchicum autumnale) (autumn crocus, meadow saffron)
l Mitotic toxin
l Inhibits fagocytosis and migration of leucytes
l AE – severe diarrhea –rehydratation!!
Chronic therapy
Urikosurics
probenecide
l Sometimes is used with ATB (antivirotics) to decrease
their renal excretion and elongate half-life
l interactions:
l salicylates
l heparin - probenecid increase bleeding
l probenecide can influence levels of these drugs:
l Indometacin, ketoprofen
l methotrexate
l nitrofurantoin – chemoterapeutic
l zidovudin – antiretrovirotic
Chronic therapy
Urikosurics
Benzbromaron
inhibition of uric acid reabsorption in proximal tubulus
Hepatotoxic, withdrawn
Antiuratics
l Hypoxantin ⇒ xantin ⇒ uric acid
l Allopurinol
l isomer of hypoxantin, competitive inhibition of
xanthinoxidase (XO)
l Should not be co-administered with drugs with purinderived
molecule (e.g. azathioprin, 6-merkaptopurin)
XO XO
Chronic therapy