Download NSAIDs

Pharmacotherapy of pain
Types of pain 1
Acute pain
preventive function
localised
has vegetative
sympthomatology and
doesn´t cause severe
psychological changes
clearly defined beginning and
ending
analgesics are usually
effective in treatment
Chronic pain
without preventive
function
lasts 3-6 months
often associated with
severe psychological
changes
without clearly defined
beginning
malignant (caused by
cancer)or non-malignant
Types of pain 2
Nociceptive
somatic
• superficial
• deep
visceral (diffuse)
Neuropatic
central
• deafferentational
peripherial
• neuropaties
Idiopatic
Psychogenic
Therapy of pain
Analgesics and co-analgesics
Non-opioid analgesics
• Analgesics/antipyretics
• Non-steroidal anti-inflammatory drugs
(NSAIDs)
Opioid analgesics
• Natural (morphine, dihydrocodeine)
• Synthetic (fentanyl, buprenorphine)
Co-analgesics
(Antidepressants, Anxiolytics, Myorelaxants, Anticonvulsives,
Neuroleptics, Glucocorticoids, Anesthetics,
2 sympaticomimetics, H1 antihistamines)
Non-opioid analgesics
Analgesics/antipyretics
aspirin (acetylsalicylic acid- ASA)
paracetamol (USA- acetaminophen)
metamizole (textbooks from the US say it´s an NSAID)
Non-steroidal anti-inflammatory drugs (NSAIDs)
Non-selective inhibitors of COX-1 and COX-2
(ibuprofen, diclofenac, ASA)
Preferential inhibitors of COX-2 (nimesulide,
meloxicam)
Selective inhibitors of COX-2
(celecoxib, rofecoxib (dereg.))
Analgesics/antipyretics
Paracetamol
Derivate of anilin
Mechanism of action – unknown, possibly
inhibition of COX-3 (variant of COX-1) in CNS
Good absorption from GIT
Biological half life - 1,5-3 h
Only a small percentage of the drug binds on plasma
proteins (10%)
Elimination – through the kidnies in the form of
glukuronides and sulfates
In doses over 5 g/day can cause hepatal damage
In the world, approximately 200 different preparates
containing paracetamol are being used.
Metamizole
Derivate of pyrazolone
Synonyms Noramidopyrín, Dipyrón
has spasmolytic properties.
Serious adverse effect is
depression of bone marrow leading to agranulocytosis.
Good absorption in the case of both peroral and rectal
administration.
More than 50 % binds onto plasmatic proteins
Plasmatic halflife is short (i.v. metamizole - 14 min)
Elimination- mostly through kidnies.
Non-steroidal anti-inflammatory
drugs
(NSAIDs)
Properties
Cyklooxygenase 1
Cyklooxygenase 2
Localisation
cytoplasmatic in ER
perinuclear
Regulation
constitutional
inducable /
constitutional
Presence in
tissues
GIT mucosa, renal
parenchyma,
endothelium, Tr
Mf, Mo, CNS,
kidneys, uterus,
seminiferous
Predicted
function
Integrity of stomach
mucosa, kidney
perfusion, Tr function
Patogenesis of
inflammation
and genesis of pain
Non-steroidal anti-inflammatory
drugs
Division according to COX selectivity:
Selective inhibitors of COX-1:
Acetylsalicylic acid (ASA)- in a dose of 30- 300
mg/day
Non-selective inhibitors of COX: Acetylsalicylic acid- in a dose of 500 mg/day or
more, ibuprofen, diclofenac, ketoprofen,
tiaprofen, indomethacin and many more
Preferential inhibitors of COX-2: nimesulide, meloxicam etc.
Selective inhibitors of COX-2:
celecoxib, rofecoxib, etoricoxib, valdecoxib etc.
Effects of NSAIDs
1. Analgesic effect
2. Antipyretic effect
3. Antiflogistic effect (mainly higher doses)
4. Antiaggregatory effect (not every NSAID, most
important is ASA because of irreversible blocade of
COX-1- be careful with combination of ASA for
anti-aggregation and other NSAIDs- mostly
ibuprofen)
5. Other effects- for example reduced incidence of
some tumors (for example colorectal carcinoma),
NSAIDs
– one of the most widely used drug
groups→ their ADRs represent a serious
medical / public health / economical
problem
there are big differences between various
NSAIDs in the level risk of particular
possible ADRs
Adverse effects of NSAIDs
 GIT- erosions and ulcers of the gastric mucosa (also in other
localisations in the GIT), nausea, vomitus, meteorism,
diarrhoea, constipation... (mainly inhibition of COX-1)
 kidney- reduction of glomerular filtration, retention of Na and
fluids, edema, hyperkaliemia, kidney failure, interstitial
nephrits... (inhibition of COX-1 and 2)
 CVS- thrombotic events, increase of blood pressure, heart
failure... (mainly COX-2 (mostly in thrombotic events))
 CNS- cephalea, weakness, sleap disorders, dizziness, epileptic
seizures...
 other- hepatotoxicity, bleeding, provocation of asthmatic
attack, Ray´s syndrom, prolonged childbirth, urticaria,
decreased number of white blood cells...
Gastrointestinal ADRs
most serious – ↓ production of
prostaglandins in the gastric mucosa →
peptic ulcer (most often in the stomach and
duodenum; the mucosa can get damaged by
NSAIDs also in other places in the GIT)
roughly 25 % of chronic NSAID users might
develop erosions and ulcers, in 2-4 % perforation
or bleeding can occure
Kidney ADRs
Decreased production of prostanoids →
negative effect on the perfusion of the
kidneys, glomerular filtration, excretion of
sodium and water and on production of
renin → circulation overload, oedemas,
hypertension ; hyperkalemia ; in severe
cases symptoms of acute kidney failure
serious complication– interstitial nephritis
(immunological reasons)
Incidence of kidney ADRs is poughly 18%,
Cardiovascular ADRs
 Increased blood pressure- mostly in hypertensive patients
treated with antihypertensives (mainly ACEIs, ARBs, beta
blockers), there are big differences between various NSAIDs
 Development/worsening of heart failure- the risk is highest
during the first weeks of treatment, mainly in patients with
preexisting congestive heart failure; possibly 19% of all cases
of congestive heart failure could be caused (at least partially)
by NSAID therapy
 Thrombotic events- acute myocardial infarction, stroke,
thromboembolic disease
Opioid analgesics
Dampen strong somatic and visceral pain – strongest
analgesics, without roof effect, can cause addiction
Dampen algognostic (perception and localisation) and
algotymick(psychical and emotional) part of pain
Strong agonists: morphine, fentanyl
Weak agonists: tramadol, codeine
Partial agonists: buprenorphine
Agonists/antagonists: butorfanol, pentazocine
Antagonists: naloxone, naltrexone
Pharmacological effects
Depressory
Analgesia
Depression of breathing
Antitussive effect
Decreased secretion and
motility in the GIT –
constipation
Sedation
Stimulatory
Vomiting
Miosis
Increased tonus of
smooth muscles,
sphincters
Induction of histamine
release
Euphoria
Adverse effects of opioids
Neuropsychiatric
Sedation, clouded consciousness, euphoria, sleep disorders
Cardiopulmonal
Depression of breathing, Bronchoconstriction (high doses)
Orthostatic hypotension, Bradycardia (high doses)
Gastrointestinal
Nausea, vomiting, constipation, gastrointestinal or gallbladder
colics
Urinary system
Retention of urine
Endocrine
Decreased levels of testosterone, problems with menstrual cycle
Allergic and immunologic
Pruritus, immunosupression
Morphine
Prototypical opioid
Isolated from sap from unriped skulls of poppy (1803)
Fast resorption after p.o. application, bioavailability
is only 30% (significant first pass effect)
Most common adverse effects- nausea, vomiting,
constipation, gallbladder and uretral spasms
Depression of breathing is the most common cause of
death in case of intoxication.
Most common signs of intoxication – unconstiousness,
bradypnoea a miosis
Fentanyl
Synthetic derivate of phenylpiperidine
Strong agonist of  receptors
80-100 times more potent than morphine
Lipophilic character – rapid onset of action, but the effect
lasts only for a short time
Contraindicated in pregnancy
Derivates of fentanyl- sufentanyl and alfentanyl are used in
anesteziológii
Big advantage – availability of fentanyl in the form of
transdermal patches – „Durogesic“
The second most widely used opioid
Tramadol
Atypical opioid
Intermediate analgesic effect
High bioavailability is an advantage.
In therapeutic doses lacks most of the adverse effects of
opioids.
The most common adverse effects are sweating, nausea and
dry mouth.
Suitable for treatment of mild to severe pain in adults and
children.
Available in different drug forms.
It is cheap.
In case of long term
treatment, analgesics
should be administered
regularly, not only
when the patient feels
pain.