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Note: anything additional from the lecture is in italics.
Pain is a major problem and a symptom in many diseases. Drugs that relief
pain are known as analgesics. Analgesics, along with steroids, are used in
dealing with Rheumatoid arthritis (RA).
RA is very common, it is a chronic progressive inflammation of joint lining with
an autoimmune background against synovial membranes that can lead to joint
destruction
Affects approximately 1% of world population
Causes pain, swelling, stiffness and loss of function in the joints
Generally occurs in a symmetrical pattern and it is polyarticular > 3 joints
May also attack other tissues like skin, lungs, eyes, and blood vessels.
Those numbers provide and idea about the burden of the disease. Right now
there’s no cure available but management is possible.
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Small joints of hands and feet are affected first, larger joints later
It begins during the most productive years (30 – 60 yrs)
Occurs much more frequently in women than in men (women: men=3:1)
Causes are not yet known, however infectious agents, such as viruses and bacteria,
may trigger RA in people with an inherited tendency to develop the disease.
Management of RA:
:Goals
- Relieve pain.
- Reduce swelling.
- Slow down or help prevent joint damage.
- Increase ability to function.
- Improve sense of well-being.
:Approaches in the management of RA
: General
- Exercise or physiotherapy as it is essential for the joints.
- Stress reduction
.Drugs
In some cases, surgery (joint replacement and tendon (not that common): Surgery
reconstruction) two types of surgery available to patients with severe joint damage.
Drugs in RA
Research efforts focus on developing drugs that can reduce inflammation and slow or stop
progression of the disease with few side effects.
Reagents that blunt inflammation but don’t have effects on disease progression:
- Nonsteroidal anti-inflammatory drugs (NSAIDs).
- Steroids (Cortisone, Hydrocortisone, Prednisone-->widely used).
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Disease Modifying Anti-Rheumatic Drugs (DMARDs), that relief and limit the
progression of the disease:
:Broad Acting(immunosuppressants)
Methotrexate
Hydroxychloroquin
Azathoprine
Cyclophosphamide
Cyclosporin
:More selective biologics
TNF antagonists
Intravenous Immunoglobulin (IV Ig)
Anti-inflammatory drugs
1. Steroidal.
2. Nonsteroidal.
- Aspirin.
- Newer NSAID’ s.
3. Disease modifying antirheumatic drugs (DMARD’s).
All what’s mentioned next is on slide no.6
Arachidonic Acid Pathway.
Arachidonic Acid(A.A) pathway is an extremely important pathway in the process of
inflammation. A.A is present in the cell membrane of all cell types and is released
from there by the action of an enzyme known as Phospholipase A2. After its release
A.A undergoes two pathways: Cyclooxygenase(COX) pathway which is involved in the
synthesis of Prostaglandins(PGs) and Lipoxygenase pathway, involved in the
synthesis of Leukotrienes(LTs).
PGs are very important substances with great clinical significance and are widely
used in medicine. Both PGs and LTs are major mediators of inflammation.
In the lipoxygenase pathway, a substance known as Slow Reactant Substance of
Anaphylaxis (SRS-A) is produced. It is made of a number of leukotrienes: LTB4, LTC4,
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LTD4. This substance is responsible for most of the bronchoconstriction experienced
by patients of bronchial asthma and anaphylaxis.
In the cyclooxygenase pathway (also known as PG synthase pathway) prostaglandins
are synthesized, which are-again- important mediators of inflammation. In the
beginning those PGs are defensive; for example, if you experience joint trauma, PGs
are quickly released in order to counteract the effect of the trauma. However, if they
persist they will result in the manifestations of inflammation: redness, hotness,
swelling, fever etc.
We have to manage such manifestations; either by inhibiting the synthesis of PGs or
by using specific antagonists that will inhibit their action.
PGs have many biological and physiological functions, such as: induction of labour,
contraction of the uterus, bronchodilation and constriction, vasodilation and
constriction, stimulating and inhibiting platelet aggregation.
Obviously, PGs are very important, and we synthesize them as needed, but in the
cases where they’re causing damage (as in prolonged inflammation) we have to
inhibit their synthesis or their actions.
Cyclooxygenase enzyme actually has many isozymes, what do we mean by that?
Isozymes are enzymes that originate from different genes but produce similar effects.
**If one gene produces multiple enzymes they’re known as “alloenzymes”, they will be slightly similar
to one another.
Cyclooxygenase isozymes are: COX1 present in the stomach, platelets and kidneys.
COX2 present in other tissues and COX3 present mainly in the CNS.
There’re two important PGs: PGI2 “prostacyclin” and TXA2 “thromboxane A2".
PGI2 is formed in blood vessels; phospholipase A2 releases A.A from cellular
membrane, then it undergoes COX pathway to produce PGI2 by the enzyme
prostacyclin synthase. It’s a strong vasodilator and inhibitor of platelet aggregation.
We use it in cases of clotting, ischemic heart diseases, coronary artery
vasoconstriction and myocardial infarction (in all these cases we need vasodilation
and to prevent the formation of clots).
TXA2 is formed in platelets by thromboxane synthase enzyme. It’s a very strong
vasoconstrictor and activator of platelets aggregation.
: Inhibitors of PGs and LTs
Steroids act on phospholipase A2, so it inhibits both pathways. NSAIDs usually act on
COX alone so it inhibits PG synthesis only.
Which is more potent in having an anti-inflammatory effect? Steroids or NSAIDs?
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Steroids as they inhibit both pathways.
:Contraindications
PGs are protective of the stomach and the GI tract. And so, any drug that inhibits PG
synthesis usually leads to ulceration and the possible development of peptic ulcer
disease.
Consequently, steroids and non-steroidal drugs are absolutely contraindicated in
patients with history of peptic ulcer disease (current or healed).
What happens to the lipoxygenase pathway when COX pathway is inhibited?
A shift happens that favours LTs formation, and so more SRS-A is produced. As a
result, bronchial asthma is an absolute contraindication of NSAIDs as they could lead
to immediate death (by suffocation).
However, steroids are not contraindicated in patients with bronchial asthma because
they inhibit both pathways, so there’s no shift and no increased production of SRS-A.
in fact we have cases that depend in their management on steroids, those cases are
known as steroid dependant asthma.
COX1 is present in the stomach, kidneys and platelets and it provides protection for
the GI tract. COX2 is present in other tissues, and both are activated during
inflammation. If we were to give a non-selective drug it would inhibit both enzymes,
and that would cost us the protection of the GI tract. However, if we use a COX2
selective inhibitor, then we can reduce the unwanted effects of PGs while still
maintaining the GI protection they provide.
However, even with this added selectivity, steroidal and non-steroidal drugs are still
not prescribed to patient diagnosed with peptic ulcer disease. They’re only given to
other individuals to reduce stomach and GI irritation “reducing ulcerative effect”.
Back to the slides:
:poxygenaseLi
Present in lungs; WBC’s and platelets
:Cyclooxygenase (COX)
Present in all tissues
COX1: present mainly in kidneys, stomach and platelets.
COX2: present in other tissues.
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Last 3 drugs act on Phospholipase A2
but are not widely used in
inflammatory conditions (used more
for other reasons).
This explains the vasodilation
effect of these drugs, they inhibit
TXA2 which is a vasoconstrictor.
PG synthesis inhibitors
- Phospholipase inhibitors.
Glucocorticoids (cortisol; cortisol synthetic analogs).
Phenothiazines.
Antimalarial drugs.
Local anaesthetics…
- COX-inhibitors NSAID’ s
a. Non-selective (inhibit COX1 & COX2 ) Aspirin; Diclofenac (Na+, K+);
Indomethacin, Iboprofen; Naproxen...etc
b. Selective (inhibit selectively COX2 ) Meloxicam; Celecoxib; Rofecoxib;
Etoricoxib; Etodolac; Valdecoxib; Nabumetone…etc. Recent reports suggest
those drugs are protective against colonic cancer(provide 80% protection). This
makes sense when we remember that some inflammatory processes occur in
cancer.
- Thromboxane synthase inhibitors
Dazoxiben, Hydralazine, Diazoxide
- Leukotriene synthesis inhibitors
* Lipoxygenase inhibitors
Zileuton
* Leukotriene antagonists
Zafirlucast; Montelucast...
Similar to what happens with NSAIDs, here we have a shift too; however, this
time it favours the synthesis of PGs. We should utilize such drugs in the
management of peptic ulcer disease (they reduce inflammatory mediators
while maintaining PGs which provide protection for the GI tract).
These drugs could be administered orally in the
management of asthma
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NSAIDs
Inflammatory process involves enzymes (collagenases; hyaluronidase…);
biologically derived oxidants generated by neutrophils and macrophages;
coagulation system; fibrinolytic and complement systems and many mediators
(prostaglandins; kinins; leukotrienes…etc)
Available NSAID’ s
Aspirin
Choline salicylates
Magnesium; Na+ salicylate
Meclofenamate
Mefenamic acid
Etodolac
Diclofenac (Na+; K+)
Ibuprofen Celecoxib
Fenoprofen Valdecoxib
Ketoprofen Meloxicam
Naproxen Azapropazone
Ketorolac
*** Acetaminophen (paracetamol): this is the most widely used analgesic.
Although it is mentioned as an NSAID, it is devoid of any inflammatory effect.
The reason it is listed however is to emphasize the analgesic and antipyretic
effects which are controlled centrally by inhibition of PG synthesis by COX3, the
effects of paracetamol then is central instead of peripheral.
:NSAID’s pharmacokinetics
- Orally, some parenterally effective.
- Differ in potency and are highly bound to plasma proteins.
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- Have small AVD.
- Have similar efficacy and even toxicities.
- t 1/2 and duration of action differ according to available dosage forms.
:NSAID’s general effects
NOTE: Analgesics are divided into two: narcotic and non-narcotic.
Narcotic are like morphine and pethidine and are used in cases of severe pain.
They are effective in mild to moderate pain but they cause addiction and so we
refrain from using them in these cases.
NSAIDs are examples on non-narcotic analgesics.
- Analgesia Effective in mild to moderate pain (headache,
toothache,backache,dysmenorrhea...etc))(unlike narcotic analgesics, they’re
not that effective in severe pain, we say this as a general rule, however,
there’re certain exceptions: voltaren is effective in cases of renal colic because
it has good analgesic effect and also relaxes the ureter, it could also work for
patients with renal stones. But if you’re asked in the exam whether they’re
effective in severe pain or not you should answer with no,they’re not.)
-Highly effective analgesics associated with relatively fewer side effects, most
are OTS drugs and do not require a prescription.
-Unlike narcotic analgesics, they do not lead to addiction
-In patients with RA they provide symptomatic relief, improved function but
no change in disease progression
:The choice of a particular NSAID depends on
Availability; cost; pharmacokinetic properties & side effect profile
NSAID’s undergo great variation among pts with respect to their analgesic and
side effects
It is common that in many cases switching from one NSAID to another could
be to the side of the pt (e.g. one NSAID leading to a side effect could not be
observed with another).
: Effects
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- Anti-inflammatory effect by inhibition of COX.
- Antipyretic effect
- Antiplatelet effect (significant with Aspirin, not significant with selective
COX2 inhibitors)
Why is it significant with aspirin? Because aspirin, and not other NSAIDs, leads
inhibition of irreversible vascular cyclooxygenase andto reversible inhibition of
platelet cyclooxygenase, meaning if we wanted to produce TXA2 we need a
new platelet from the bone marrow that carries a new functional enzyme. (All
other NSAIDs inhibit COX reversibly only.)
- Patency of ductus arteriosus: it is a duct between the pulmonary artery and
aorta during fetal life, maintained by PG’s (Indomethacin has been used
successfully to close it)
- Prolongation of labour(as they are good contractors of the uterus) and
gestation (possible use in premature labour).
- Contraceptive effect especially with selective COX2 inhibitors (inhibit
ovulation).
Acetyl salicylic acid (Aspirin)
: Actions
- Analgesic Effective in mild to moderate pain.
- Antipyretic.
- Anti-inflammatory.
- Antiplatelet, aspirin leads to irreversible inhibition of platelet COX and
reversible inhibition of vascular COX. Individuals older that 50 are advised to
take it daily or every other day(depending on the dose) since they’re at a
higher risk of atherosclerosis, ischemic heart disease and myocardial
infarction.
: Aspirin clinical uses
- Minor pain (headache, toothache, backache) Dose 300-600 mg
- Rheumatoid arthritis; dose 900 mg
- Rheumatic fever; dose 3-5 g/day
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- Antiplateletprotection/thrombosis (many doses were evaluated, 81 mg:
this dose is very effective against myocardial infarction including patients who
have undergone ventral bypass surgery, 100mg and 300mg daily or every
other day).
Aspirin is available in nearly all dosage forms, oral & parenteral
:Aspirin side effects
- Gastric irritation
- Bleeding and anemia
- Bronchoconstriction
Aspirin toxic effects: Salicylism (dizziness, tinnitus, nausea and vomiting and
reversible deafness)
:Aspirin contraindications
- Peptic ulcer disease: absolute contraindication as with other NSAIDs.
- Bronchial asthma
- Reye’s syndrome: brain and liver damage in children with viral infection that
was detected after administration of Aspirin.
Is the aspirin responsible for the damage then? It doesn’t matter we don’t give
to children as a precaution.
** Buffered aspirin: aspirin with antidote; aluminium hydroxide, calcium
carbonate, magnesium hydroxide etc. this formula however is not designed for
patients with peptic ulcer disease, but for individuals who have some irritating
effects on the stomach.
Again remember: peptic ulcer disease is an absolute contraindication for
NSAIDs.
: Aspirin MOA
Inhibition of prostaglandin synthesis
Aspirin doesn’t lead to addiction
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: Acetaminophen (Paracetamol)
Analgesic (effective in mild to moderate pain) and antipyretic.
: MOA
Inhibition of prostaglandin synthesis centrally.
Has no anti-inflammatory or antiplatelet activity.
Not contraindicated in patients with peptic ulcer or bronchial asthma.
Paracetamol is not contraindicated during pregnancy (100% safety; no reports
on teratogenicity) or in patients with Reye’ s syndrome.
Large doses > 10g → liver damage
Chronic use could also lead to toxicity (but it takes a very long time to develop,
>20 years).
: Management of toxicity
.tablets from the stomach unabsorbedgets rid of Gastric lavage: -
- NaHCO3: weak acid that enhances excretion of absorbed tablets (done
through alkylation)
- Specific antidote: N-Aceylcysteine (Mucomyst®) I.Vshould be given within
a maximum 24 hours of toxicity.
What’s the difference between antidotes and antagonists?
Antidotes reverse the action of a certain drug by non-receptor mechanisms.
Next is said about slide 28:
Paracetamol is usually absorbed by two conjugation reactions to Glucuronide
and Sulfate, and even if the dose is large the enzymes involved in these
reactions have high capacity in metabolizing paracetamol.
However, if the dose exceeds this capacity, paracetamol undergoes MFO
pathway or Mixed Function Oxidase pathway which produces toxic
metabolites. Luckily these metabolites could be dealt with by Glutathione; the
detoxifying agent present and formed in the liver, it detoxifies the metabolites
and then excretes them outside the body.
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But if the dose is large and exceeds glutathione’s capacity, those metabolites
will bind to DNA and form DNA adducts. This will lead to necrosis of liver cells,
which can be reversed within a maximum of 24 hours, after that it becomes
irreversible.
:NSAIDs side and toxic effects
synthesis inhibition related-I. PG
- GIT bleeding and ulceration (commonest) Most severe with Piroxicam,
Naproxen and Azapropazone
- Prolonged bleeding time, GIT blood loss (antiplatelet effect).
- Delayed parturition (delayed delivery).
- Allergic reactions (bronchospasm, urticaria..)
- Renal effects (Na+ & H2O retention, ↑ BP( not contraindicated in patients
with hypertension thought), hyperkalemia, renal failure…)
synthesis inhibition unrelated-II. PG
- Hepatotoxicity
- CNS effects (headache, dizziness, tinnitus, deafness, drowsiness,
nervousness...)
- Dermal effects
- Retinal and visual disturbances
- Nephropathy (renal papillary necrosis, acute interstitial nephritis, acute renal
failure...)
Nephropathy is more common with combined analgesic therapy and chronic
use (analgesic nephropathy)
:drug interactions-NSAID’s most important drug
+ Warfarin(coagulant) → bleeding
+ 4-quinolone antibacterial agents → convulsions
+ Phenytoin; Sulfonylurea → ↑ phenytoin and sulfonylurea toxicity