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5

Dana Alrafaiah

-

Suhail

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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

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+ Methotrexate → ↓ excretion of methotrexate → ↑ toxicity

+ Indomethacin + ACE inhibitors or K+ sparing diuretics → hyperkalemia