Download COX-1

Nonsteroidal Anti-inflammatory
Drugs (NSAIDs) and Analgesics
Dr. Alia Shatanawi
4-3-2013
There are steroidal anti inflamatory drugs :mainly
glucocoticoid cortisone .
Q: Why do we use such drugs ?(common charectaristics
of these drug):1) To reduce inflamation.
2) Pain Relief .
3)To reduce fever .
• Recall that :
Inflammation :is the body response to a foreign
body/microorganism , it does not mean
infection(microorganism) . it’s the body
response to any stimuli whatever is it.
Inflammatory pathways
• Cyclooxygenase (COX) pathway of arachidonate metabolism
produces prostaglandins
• Effects on blood vessels, on nerve endings, and on cells involved in
inflammation. (Different kinds of prostaglandins with different
effects on different tissues :for example >prostaglandin 1 has
dilatory effect on bronchi ,another has constrictory effect on them
.also in different conditions >in pregnancy it has retraction effect
on utetrine muscles )
• The lipoxygenase pathway of arachidonate metabolism yields
leukotrienes (intermediate in inflamatory rxn specially allergic rxn
[histamine release] so leukotriene inhibitor pathway used to treat
certain conditions such as asthma
• have a powerful chemotactic effect on eosinophils, neutrophils, and
macrophages and promote bronchoconstriction (initiating asthma
)and alterations in vascular permeability.
`
Leukotrien
antagonists
,lipooxygenase
inhibitors used
to treat
asthmatic
conditions .
ASA: aspirin
acetylsalicylic
acid
sometimes
considered
NSAID Or
considered
out of this
group
Prostaglandin
modulates
the action of
leukotriens in
asthmatic
condition
mainly
• Zileuton: (trade name ZYFLO) is an orally active inhibitor of
5-lipoxygenase, and thus inhibits leukotriens (LTB4, LTC4,
LTD4, and LTE4) formation. Zileuton is used for the
maintenance treatment of asthma[ from wikipedia ].
• Colchicine : inhibiting the phagocytosis ,how does it work ?
Actin gets polymerized forming long actin tubules to help in
phagocytosis process by macrophages so by inhibiting
polymerization of actin in the macrophages we can inhibit
their action so inhibiting inflamatory mediating action in
inflamatory site .
Notes …
• Uses of aspirin >> used mainly as pain killer to releive
the pain & inflamation.
• Thrombaxane >>needed for platelet aggregation
,aspirin works to inhibit platelet aggregation .
• It is also used as prophylactic treatment to decrease
the risk of myocardiac infarction but the dose is
lower than that used to treat the pain :
1 mlg -> myocardiac infarction
325 mlg -> as pain killer
Corticosteroid :part
of endocrine system
We’ve 2 different COX
enzymes >> COX 1 & COX 2
These anti inflammatory drugs
used mainly to treat rheumatoid
arthritis(RA) >>very important
Notes about the previous figure …
Constitutive >>available under physiological condition .
Inducible >>it doesn’t act unless there is stimulus .
Synoviocytes >>cells surrounding synovial fluid .
Physiologic functions >>to maintain homeostasis and
integrity of the immune system .
 W e concern that there are cox1 & cox2,,coz of making drug
,,sometimes you want to target specific isoform of the
enzyme coz sometimes the isoform can be associated with
many side effects thus when you target another isoform that
is not present in the body ,you can inhibit the side effects
associated with present cox1 .
 cox 1
Prostaglandin, in the stomach PG acts to inhibit
acid secretion, increase mucus secretion, thus inhibition cox
1 by aspirin will lead to peptic ulcer so the major side effect
of NSAID is :Peptic Ulcer and increasing stomach acidity .
 We give Cox 2 inhibitors to decrease side effects associated
with cox 1 inhibitors
Cyclo-oxygenase (COX)
• Exists in the tissue as constitutive isoform (COX-1).
• At site of inflammation, cytokines stimulates the
induction of the 2nd isoform (COX-2).
• Inhibition of COX-2 is thought to be due to the antiinflammatory actions of NSAIDs.
• Inhibition of COX-1 is responsible for their GIT
toxicity.
• Most currently used NSAIDs are somewhat selective
for COX-1, but selective COX-2 inhibitors are
available.
Non -steroidal Anti-Inflammatory Drugs
•
•
•
•
Analgesic
pain.
Antipyretic
Anticoagulant platelet aggregation .
Anti-inflammatory (at higher doses)
Opiods are strong
analgesics that work on
CNS
May lead to addiction .
Comparison of Analgesics
Feature
Narcotic (Opioids) Nonnarcotic
(nonopioid)
Efficacy
Strong
Weak
Prototype
Morphine
Aspirin
Pain Relieved
Any Type
Musculoskeletal
Site of Action
Central
Peripheral and Central
Mechanism
Specific Receptors [in PG Synthesis
the brain] inhibition
inhibition
Danger
Tolerance &
Dependence
G.I irritation
Anti-inflammatory
No
Yes
Antipyretic
No
Yes
Antiplatelets
No
Yes
14
In this table the dr said
that you already know
:
ibuprofen [propionic
acid ]
Aspirin [salicylate.
And it’s important to
focus on selective cox2
inhibitors .
Notes about the previous figure ….
Diclofenac : voltarine .
They work by the same mechanism of action but they classified as
they differ in : potency ,efficacy ,duration of action .
Indomethacin: the most drug causes adverse effect on GIT , then there
is ibuprofen with less severity .
 Also Aspirin has high GI side effect .
Selective Cox-2 inhibitors (Rofecoxib) where heavily prescribed in
inflammatory conditions such as RA and GI irritation, then Rofecoxib
drug was no more present in the market coz of its association with
adverse effects :myocardiac infarction , stroke (cerebrospinal attack ).
 Mechanism of action of cox -2 inhibitors is not clear but they are
mainly responsible to decrease platelet aggregation so they
supposed to have beneficial effect on myocardic infarction but
this promising effect was not detected so they stop selling this
drug [Rofecoxib] in the markets .
 Celecoxib is still present in market however it’s not advised to use
for those who complain from heart diseases.
Common Pharmacological Effects
• Analgesic (CNS and peripheral effect) may involve non-PG
related effects
• Antipyretic (CNS effect) -> associated with hypothalmic
pathway in controlling body temperature
• Anti-inflammatory due mainly to PG inhibitionexcept
acetaminophen is same as paracitamol >>inhibiting Cox2,but it does not have much anti-inflammatory action ,it’s
mainly analgesic &antipyretic }.
Some shown to inhibit activation, aggregation, adhesion of
neutrophils & release of lysosomal enzymes
• Some are Uricosuric [related to excretion of uric acid ,,we’ll
talk about them in Gout ]
Mechanisms of Action
• Antipyretic actions – Fever, heat stroke, incr T°
are hypothalamic problems.
- So, NSAIDs do not decr body T°.
- Fever  release of endog pyrogens (e.g.,
interleukin-1) released from leucocytes  acts
directly on the thermoregulatory centers in
hypothalamus  incr body T°.
- This is assoc with incr in brain PGs (pyrogenic).
- Aspirin prevents the T°-rising effects of
interleukin-1 by preventing the incr in brain PGs.
Pharmacological Effects (cont’d)
• Diverse group of chemicals, but all inhibit
cyclooxygenase.
• Resultant inhibition of PG synthesis is largely
responsible for their therapeutic effects.
• But, inhibition of PG synthase in gastric
mucosa  GIT damage (dyspepsia, gastritis).
NSAID
Mechanism of Action:
• Inhibition of PG synthesis
– Cyclooxygenase (COX) Enzyme:
• COX-1 or Constitutional form of COX.
• COX-2 or Induced form of COX.
21
 Cardiovascular
 • Platelets: Inhibition of platelet COX-1-derived TxA2 with the
net effect of increasing bleeding time (inhibition of platelet
aggregation) mainly cox1 enzyme is responsible to
thrombaxane production.
 • Endothelial COX-2 derived PGI2 can inhibit platelet
aggregation (inhibition augments aggregation by TxA2).
The process of inhibition cox 2 platelet aggregation maybe more
powerful than cox1.
 Aspirin (acetylsalicylic acid) covalently modifies and,
irreversibly inhibits platelet COX[v.imp in the exam]. The
enzyme is inhibited for the lifetime of the platelet (~8 -11
days). Effect achieved at very low dose.
 • Basis of therapeutic efficacy in stroke and MI (reduces
mortality and prevents recurrent events).
Additional Cardiovascular Considerations
• Blood vessels/smooth muscle
COX-2 derived PGI2 can antagonize
catecholamine- and angiotensin II-induced
vasoconstriction (NSAIDs can elevate bp).
• Atherosclerosis
Inhibition of COX-2 can destabilize
atherosclerotic plaques (due to its antiinflammatory actions)
Notes about atherosclerosis plaques …
Using cox2 inhibitor drugs leads to mobilizing of the
atherosclerosis plaques this may help in myocardiac infarction,
these plaques will be ruptured to smaller ones that may go to
small artery[in the brain] leading to stroke or coronary artery
leading to myocardiac infarction .
Atherosclerosis plaques : Those who suffer from Angina
pectoris usually have predisposing factors mainly high
concentration of cholesterol ,lipoprotein in the blood stream
,this cholesterol will adhere [deposit] to the internal wall of
artery this will lead to initiating the inflammatory process
>>macrophages will come forming atherosclerosis plaques that
composed of fibroblasts, inflammatory cells , the core of it
formed by lipid finally constriction of the blood vesseles
• also hypertension considered as predisposing
factor, constriction of blood vesseles ,
different factors related to collagen and
thickening of smooth muscles will increase .
Renal
PG important in controlling the blood flow in the kidney (
Dilation afferent Arterioles ,so if we block production we will
impair the kidney circulation )
• COX-1 and COX-2 – generated PGs (TxA2, PGF2 , PGI2 (glom),
PGE2 (medulla), powerful vasodilators) can both incr and decr
Na+ retention (natriuresis predominates), usually in response
to changes in tubular Cl-, extracellular tonicity or low bp.
• NSAIDs tend to promote Na+ retention and can therefore
increase bp. Can counteract effects of many antihypertensives (diuretics, ACE inhibitors and -AR antagonists ).
• PGs have minimal impact on normal renal blood flow, but
become important in the compromised kidney. Patients
(particularly elderly and volume depleted) are at risk of renal
ischemia with NSAIDs.
It’s important to notice ……
Cox 1 cox 2 produce pg powerful vasodilator
Na+ retention & H2O retention thus regulates
BP .
If we inhibit pg ..constriction of afferent
arterioles we will have
Na+ retention &
H2O retention thus BP.
Gastrointestinal
• PGs (generated via COX-1)
1) inhibit stomach acid secretion,
2) stimulate mucus and HCO3- secretion, vasodilation
and therefore,
3) are cytoprotective for the gastric mucosa.
• Therefore, NSAIDs with COX-1 inhibitory activity will
produce opposite effects, leading to:
• Gastric distress, gastric bleeding, sudden acute
hemorrhage {it’s developed also due to the fact that
these drugs are antiplatelet } (effects are dosedependent)
Gestation
PGs (generated from COX-2) are involved in the initiation and
progression of labor and delivery. Therefore, inhibition of their
production by NSAIDs can prolong gestation.{these drugs not
recommended to be taken in the 3rd trimester of pregnancy coz of
their association with early closure of ductus artreosum: an open
btn right & left ventricles ,it’s closed when the baby born}.
They noticed that aspirin may associate with abortion coz it’ll cause
platelet dysfunction(dysaggregation) specially in the early months
of pregnancy .
Respiratory system
High doses (salicylates) cause partial uncoupling of oxidative
phosphorylation with increased CO2 production (COX-independent
effects). Increase in plasma CO2  hyperventilation. Even higher
doses cause depression of respiration.
Other uses of NSAIDs (mechanisms less understood) - Decreased risk
of fatal colon carcinoma
Common Adverse Effects
• Platelet Dysfunction
• Gastritis and peptic ulceration with bleeding
(inhibition of PG + other effects)
• Acute Renal Failure in susceptible
• Sodium+ water retention and edema
• Analgesic nephropathy
• Prolongation of gestation and inhibition of labor.
• Hypersenstivity (not immunologic but due to PG
inhibition)
• GIT bleeding and perforation
The Salicylates - Aspirin
Different effects on
respiratory system
depending on the
dose .
• Effect on Respiration: triphasic
1. Low doses: uncoupling phosphorylation → ↑ CO2
→ stimulates respiration.
2. Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal
compensation
3. Depression of respiratory center and
cardiovascular center → ↓ BP, respiratory
acidosis, no compensation + metabolic acidosis
also
The Salicylates - Aspirin
• Duration of action ~ 4 hr.
• Orally taken.
• Weak acid (pKa ~ 3.5); so, non-ionized in
stomach  easily absorbed.
• Hydrolyzed by esterases in tissues and blood
to salicylate (active) and acetic acid.
• Most salicylate is converted in liver to water
soluble conjugates that are rapidly excreted by
kidneys.
Reye's syndrome
this is specific for aspirin in infants and children below the age
of 6 yrs
• Reye's syndrome is a potentially fatal disease that
has numerous detrimental effects to many organs,
especially the brain and liver, as well as causing a
lower than usual level of blood sugar
(hypoglycemia).[1] The classic features are a rash,
vomiting, and liver damage. The exact cause is
unknown and, while it has been associated with
aspirin consumption by children with viral illness, it
also occurs in the absence of aspirin use.
• Note about the Reye Syndrome :
If you have a baby or a child with viral infection it’s not
recommended to prescribe NSAID for him coz this condition
of unknown cause but it maybe associated with aspirin
consumption by a child who has viral illness , so it’s
preferred to prescribe another analgesic for him like
paracitamol .
Aspirin - Therapeutic Uses
• Antipyretic, analgesic
• Anti-inflammatory: rheumatic fever, rheumatoid arthritis
(joint dis), other rheumatological diseases. High dose
needed (5-8 g/day).
• But many pts cannot tolerate these doses (GIT); so,
proprionic acid derivatives, ibuprofen, naproxen tried first.
• Prophylaxis of diseases due to platelet aggregation (CAD,
post-op DVT){ CAD >>coronary artery disease ,DVT >Deep
pain thrombosis}.
• Pre-eclampsia and hypertension of pregnancy (?excess TXA2)
BUT It maybe associated with platelet dysaggregation
or defects in fetus so aspirin not always advised to
be used during pregnancy .
Aspirin Toxicity - Salicylism
• Headache - timmitus - dizziness – hearing
impairment – dim vision
• Confusion and drowziness
• Sweating and hyperventilation
• Nausea, vomiting
• Marked acid-base disturbances [coz it’s salicylic acid
These complications mainly in pts who
].
take over dose of aspirin ,or have
• Hyperpyrexia
hypersensitivity to it .so you should know
the history of disease for the pts
• Dehydration
• Cardiovascular and respiratory collapse, coma
convulsions and death
Aspirin Toxicity - Treatment
• Decrease absorption - activated charcoal,
emetics, gastric lavage
• Enhance excretion – ion trapping (alkalinize
urine), forced diuresis, hemodialysis
• Supportive measures - fluids, decrease
temperature, bicarbonate, electrolytes,
glucose, etc…
Paracetamol
• Paracetemol(acetaminophen) – no significant
anti-inflammatory effect, but used for its mild
analgesic effect.
• Well-absorbed and without GIT irritation.
• Serious disadvantage: at high doses, severe
hepatotoxicity results [coz it will be converted to a
metabolite that is usually toxic to the liver but the
body has a mechanism to come over with this
problem by reduction glutathione rxn ,if you take
over dose of it the body mechanism can't be able to
tolerate it ] .
Paracitamol >>If it’s considered as NSAID this is
due to its mechanism of action that is based
on PG inhibition ,,but it maybe considered as
different group coz it’s not strongly associated
with anti-inflammatory response .[Be Careful
>>it’s never considered as opiods ]
• Every things written in different color/style or
within boxes are extra notes .
Sorry for late….
Rinad Al-Sa’adi .