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BIOP211
www.endeavour.edu.au
Session 6
Pharmacology
Drugs Affecting Body
Defences (Anti-inflammatory
anti-gout and
immunosuppressive agents)
Department of Bioscience
© Endeavour College of Natural Health www.endeavour.edu.au 2
BIOP211 - Pharmacology
Session Overview
o Introduction to drugs affecting Body Defences.
o Anti-inflammatory, immuno-modulating drugs.
o Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
o Antihistamines.
o Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
o Drugs used for gout.
© Endeavour College of Natural Health www.endeavour.edu.au 3
Drugs affecting the way the body resists disease
Anti-inflammatories
Non-steroidal anti-inflammatories NSAIDs
Steroids
Anti-pyretics
Drugs used to treat gout
Disease-modifying anti-rheumatic drugs
DMARDs
Analgesics
Anti-histamines &
immunomodulating &
immunosuppressive drugs
© Endeavour College of Natural Health www.endeavour.edu.au 4
Joint Diseases
Drug treatment for inflammatory/non inflammatory joint
diseases may be prescribed to:
o Reduce pain.
o Reduce stiffness.
o Increase mobility.
o Minimise disability.
o Prevent / minimise progression of deformity.
o Improve quality of life.
© Endeavour College of Natural Health www.endeavour.edu.au 5
Treatment Goals
Goals of treatment may include:
o Immunosuppression.
o Inhibition of inflammatory-cell migration (“chemotaxis”).
o Inhibition of inflammatory enzyme release.
o Inhibition of prostaglandin synthesis (PGs are one group
of the many “inflammatory-mediators” or “cytokines”
elicited by the various white blood cells that initiate and
regulate inflammation).
© Endeavour College of Natural Health www.endeavour.edu.au 6
Drug Treatment Strategies
o While the aetiologies of the various inflammatory joint
diseases (e.g. gout, RA & OA) differ, there are a number
of common characteristics.
o Same drugs, though different disease processes.
o E.g. NSAIDs, oral corticosteroids, paracetamol,
DMARDs.
© Endeavour College of Natural Health www.endeavour.edu.au 7
Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)
o One of the most commonly administered groups of drugs
worldwide.
o Are generally prescribed or purchased OTC for their
analgesic, anti-inflammatory and antipyretic effects.
© Endeavour College of Natural Health www.endeavour.edu.au 8
NSAIDs
Mechanism of Action:
o Inhibit the biosynthesis of prostaglandins, and thus
reduce the inflammatory response.
o There are least two enzymes involved in the synthesis of
prostaglandins, cyclo-oxygenase (COX) 1 and 2.
o Inhibition of the COX-1 pathway is the cause of most of
the adverse effects, whereas the COX-2 pathway
addresses most of the inflammatory processes.
© Endeavour College of Natural Health www.endeavour.edu.au 9
© Endeavour College of Natural Health www.endeavour.edu.au 10
NSAIDs - Classes
The NSAID classes include:
• Salicylates (aspirin)
• Coxibs
- Celecoxib (Celebrex® )
• Propionic acid derivatives
- Ibuprofen (Nurofen®, Advil®,) Naproxen (Femme-free®, Naprosyn®)
• Indoleacetic acids
- Indomethacin (Arthrexin®, Indocid®), Diclofenac (Voltaren®),
• Fenamates
- Mefenamic acid (Ponstan®)
• Oxicams
- Piroxicam (Feldene®,Mobic ®)
© Endeavour College of Natural Health www.endeavour.edu.au 11
NSAIDs - Formulations
o Available in several different dosage forms including oral
(usually enteric coated), parenteral, suppository and
topical.
o Suppositories may cause significant local irritation and
upper GIT adverse effects are still reported by some
patients.
o Topical formulations (creams/gels etc) have some
limitations in terms of efficacy, although these products
are intended to deliver local anti-inflammatory action at
the site of pain (e.g. joint, soft tissue).
© Endeavour College of Natural Health www.endeavour.edu.au 12
NSAIDs - Indications
Indications
• Mild to moderate pain.
• Fever.
• Inflammation.
• Prevent platelet aggregation (esp. aspirin anti-platelet
aggregation).
• Rheumatoid arthritis (main indications / chronic) RA.
• Osteoarthritis (main indications /chronic use) OA.
• Various acute and chronic musculoskeletal and soft
tissue inflammations.
© Endeavour College of Natural Health www.endeavour.edu.au 13
NSAIDs - Pharmacokinetics
Pharmacokinetics
• Oral absorption very good.
• Food may delay absorption but does not change the
total amount of drug absorbed.
• High protein binding (>90%).
• Metabolised by the liver.
• Excreted by the kidneys.
© Endeavour College of Natural Health www.endeavour.edu.au 14
NSAIDs – Adverse Effectso Adverse effects include:
• Gastro-intestinal (dyspepsia, nausea, vomiting,
diarrhoea, constipation, gastritis, and may all
potentially lead to ulceration and haemorrhage.
• Skin reactions, rash.
• Sodium retention.
• Renal damage due to inhibition of vasodilator
prostaglandins. This can result in heart failure and
hypertension in some patients.
• NSAIDs may precipitate asthma attacks.
• There are also additional drug-specific adverse
effects.
© Endeavour College of Natural Health www.endeavour.edu.au 15
NSAIDs - Contraindications
Contraindications/Cautions:
o Asthma.
o Caution in the elderly, debilitated patients.
o Caution in people with compromised cardiac function
and/or hypertension.
o Avoid use in persons with a history of hypersensitivity or
a severe allergic reaction to aspirin.
o Severe renal or liver disease.
o Active ulcer disease or GI bleeding.
© Endeavour College of Natural Health www.endeavour.edu.au 16
NSAIDs - Interactions
o Antihypertensives, diuretics (pharmacodynamic).
o Cyclosporin and other nephrotoxic drugs
(Pharmacokinetic).
o Lithium (pharmacokinetic).
o Methotrexate (pharmacokinetic).
o Probenecid (higher plasma concentration of NSAIDs).
o Warfarin (pharmacodynamic).
© Endeavour College of Natural Health www.endeavour.edu.au 17
Salicylates e.g. Aspirin
Aspirin
o Mechanism of Action:
– Suppression of the production of prostaglandins and
thromboxanes due to its irreversible inactivation of
the cyclooxygenase (COX) enzyme which leads to a
long lasting functional deficit in platelets.
– Analgesic, antipyretic, anti-inflammatory and anti-
platelet activity.
© Endeavour College of Natural Health www.endeavour.edu.au 18
Aspirin –Effects
o Analgesia, reducing the amount of PGs available (esp.
PGE1and 2, somatic and CNS). For treatment of pain of
low to moderate intensity. In somatic areas of the body,
in some types of headache, and in uterine spasm.
o Aspirin and aspirin-like drugs inhibit the synthesis of
prostaglandins in the hypothalamus, suppressing higher
setting of the body temperature control.
o Aspirin inhibits cytokines (thromboxane and prostacyclin)
that are normally “pro-platelet-aggregators” in primary
haemostasis. Aspirin makes platelets less ‘sticky”, retard
clot formation, especially within arterial circulation.
© Endeavour College of Natural Health www.endeavour.edu.au 19
Aspirin - Formulations
o Available in multiple forms e.g. slow release, enteric
coated etc and multiple doses usually ranging from
100mg-300mg per tablet.
o The most appropriate will depend on the indication (e.g.
anti-platelet or anti-inflammatory).
o Buffered or soluble dosage forms cause less gastric
irritation and are therefore usually recommended.
o Activity appears enhanced when combined with caffeine.
© Endeavour College of Natural Health www.endeavour.edu.au 20
Aspirin - Indications
o Treatment of pain and fever.
o Headaches.
o Rheumatoid and osteoarthritis.
o Prevention of acute MI *.
o Prevention of stroke*.
* anti-platelet aggregations dose to reduce MI & stroke –
75-150 mg/day i.e. ¼ - ½ tablet.
© Endeavour College of Natural Health www.endeavour.edu.au 21
Aspirin - Pharmacokinetics
o Rapidly absorbed orally
partly from stomach (acidic
properties) and also from
intestines.
o Peak serum levels reached
within 20-40 minutes.
o Distributed throughout most
body tissues.
o 50-90% protein bound.
o Hepatic metabolism.
Adme.jpg, n.d. Absorption
(Laura) viewed
http://insertmedia.office.micr
osoft.com
© Endeavour College of Natural Health www.endeavour.edu.au 22
Aspirin - Adverse Effects
o May cause minimal gastric bleeding or ulceration at low
doses due to a reduction in PG-induced protective
mucous production in the stomach.
o GIT adverse effects including nausea and vomiting are
more common at higher doses, and also in those with a
high level of alcohol consumption.
o May prolong bleeding time.
o May cause tinnitus , dizziness, deafness( large doses).
o Allergic reactions (bronchospasm, urticaria, hayfever) –
rare.
o Renal damage (large doses over long term).
o Aspirin is associated with many drug interactions.
© Endeavour College of Natural Health www.endeavour.edu.au 23
Aspirin - Contraindications
o Contraindications/warnings
• Heart failure and hypertension.
• Renal and hepatic impairment.
• During surgery and those predisposed to bleeding.
• Peptic Ulcer Disease.
• Asthma.
• Late pregnancy.
• In children under 18 years of age (Due to Reye’s
syndrome).
© Endeavour College of Natural Health www.endeavour.edu.au 24
Paracetamol
o Paracetamol has analgesic and antipyretic properties, but little to no
anti-inflammatory activity. (known as acetaminophen in U.S.A.).
o Panadol ™ or Panadol Plus ™ (combined with caffeine for enhanced
analgesia).
Indications
o Fever, mild to moderate pain such as headache (migraine and
tension) and some joint conditions e.g. osteoarthritis (OA).
Mechanism of Action:
o Not yet completely understood.
o It appears to act within the central nervous system, CNS, by
inhibiting prostaglandin synthesis (thus reducing pain and fever).
o Does appear to have some activity in cyclo-oxygenase, COX,
inhibition (although no anti-inflammatory benefits) .
© Endeavour College of Natural Health www.endeavour.edu.au 25
Paracetamol - Pharmacokinetics
o Taken orally, rapidly
absorbed.
o Reaches peak serum
levels in 15-60 minutes.
o Elimination half-life 1-3
hours.
o Metabolised in the liver.
o Glucuronide and sulphate
metabolites excreted by
the kidneys (when taken in
recommended doses).Graph demonstrating bioavailability of paracetamol in an adult. n.d.
viewed http://insertmedia.office.microsoft.com
© Endeavour College of Natural Health www.endeavour.edu.au 26
Paracetamol – Adverse effects
o At therapeutic doses, adverse effects of paracetamol are
minimal and generally very mild in nature.
o Paracetamol is not associated wit the gastric side effects
of NSAIDs as it does not inhibit gastro-intestinal
prostaglandin synthesis (which would lead to excess
production of HCl and pepsin).
o Paracetamol is also not associated with a high incidence
of drug-interactions.
o Although paracetamol has an excellent safety profile,
there is still a small incidence of significant adverse
effects e.g. nausea and rash.
© Endeavour College of Natural Health www.endeavour.edu.au 27
Paracetamol Toxicityo Liver toxicity, but this is seen very rarely and appears to
be linked to the concomitant use of excessive quantities
of alcohol, or overdose.
o Important safety concern with the use of paracetamol,
especially in high doses.
o Overdose can cause serious damage to liver, kidneys,
and hypoglycaemia and may lead to death
o A dose of 10-15 g (i.e. 20-30 tablets) paracetamol may
cause severe liver damage due to depletion of
glutathione, and possibly lead to death.
o A dose of about 50 tablets is usually fatal unless the
patient can be given acetylcysteine, an antidote quickly
enough.
© Endeavour College of Natural Health www.endeavour.edu.au 28
Corticosteroids – M of Ao Management of rheumatoid arthritis, do not appear to
alter the progression of the disease.
Mechanism of Action:
o Exhibit both anti-inflammatory and
immunosuppressive properties and may be used
throughout the various stages of the RA disease
process.
o Inhibit the synthesis of prostaglandins and leukotrienes
and a wide variety of cytokines.
o Corticosteroids also impair migration of monocytes,
lymphocytes and neutrophils and release of proteolytic
enzymes to the affected area, thereby blunting
inflammatory and autoimmune responses.
© Endeavour College of Natural Health www.endeavour.edu.au 29
Corticosteroids
o Suppress vascular and cellular events in the
inflammatory response, both immediate and late
processes (including wound healing and repair).
o Cause atrophy of the thymus and decrease number of
lymphocytes, plasma cells and eosinophils in blood.
o Interfere with the roles of T & B lymphocytes,
macrophages and monocytes in immune and allergic
responses (by blocking production and release of
immune mediators).
© Endeavour College of Natural Health www.endeavour.edu.au 30
Corticosteroids – Adverse Effects
• Gastro-intestinal
effects e.g. peptic
ulceration, dyspepsia
• Increased appetite
• Weight gain
• Atherosclerosis
• Glaucoma and
cataract formation
• Osteoporosis
• Fluid retention
• Acne
• Development of
Cushingoid facies
• Hypertension
• Diabetes
• Vascular necrosis
• Increased
susceptibility to
infection
• Impaired wound
healing
© Endeavour College of Natural Health www.endeavour.edu.au 31
Drugs affecting the way the body resists disease
Anti-inflammatories
Non-steroidal anti-inflammatories NSAIDs
Steroids
Anti-pyretics
Drugs used to treat gout
Disease-modifying anti-
rheumatic drugs DMARDs
Analgesics
Anti-histamines &
immunomodulating &
immunosuppressive drugs
© Endeavour College of Natural Health www.endeavour.edu.au 32
Rheumatoid Arthritis, RA
o Pathology:
• Classical progressive autoimmune disease.
• Involves both humoral and cell mediated immunity.
o Causes – still not fully understood.
o Accumulation of autoantibodies in/around joint results in:
• Platelet aggregation and degranulation.
• Activation of complement – causes histamine release and
increases inflammation.
• Neutrophil infiltration results in phagocytosis and degranulation.
– Results in even more inflammation
© Endeavour College of Natural Health www.endeavour.edu.au 33
Treatment strategies, RA
o Reduce inflammation and autoimmune attack
o Treatment options
• Analgesics + NSAIDs.
– Relieve symptoms but do not slow progression of disease.
• Disease Modifying Anti-rheumatic drugs, DMARDs.
– Gold salts.
– Methotrexate.
• corticosteroids – last option.
© Endeavour College of Natural Health www.endeavour.edu.au 34
DMARDs
o Main goal – intervene before the disease progresses to
severe damage of joints.
o DMARDS have slow onset of action – 1-6 months before
evidence of clinical response is demonstrated.
o Potentially severe adverse effects.
o Slightly different properties, mechanisms of action and
toxic effects, Methotrexate, Gold salts.
o Selection of a DMARD for a patient is RA is made on a
patient specific basis, taking into account:
• Adverse effects and toxicity, dosing schedules, concomitant
disease states and therapies, patient age.
© Endeavour College of Natural Health www.endeavour.edu.au 35
Methotrexate
o Methotrexate (MTX), a folic acid antagonist.
o DMARD of choice for patients with severe disease (positive
rheumatoid factor (RF), erosions or extra-articular manifestations).
o Mechanism of Action: MTX close chemical similarity to folate, so
competitively inhibits the enzyme dihydrofolate reductase, which
subsequently prevents the reduction of folic acid to tetrahydrofolate;
Demonstrated benefit in RA within 3-4 weeks, max. at 6 months.
o ADR stomatitis, nausea, diarrhoea and alopecia. Give folate
supplementation to reduce ADR without loss of efficacy (in RA).
o NSAIDs may be used between pulse doses of methotrexate but
lethal drug interactions with MTX if used together.
o The disadvantages to MTX include cost and the need for laboratory
monitoring.
© Endeavour College of Natural Health www.endeavour.edu.au 36
Gold SaltsIndications
o Rheumatoid arthritis.
o Juvenile RA.
Mechanism of Action:
o Inhibition of sulphydryl systems and various
enzyme systems thereby suppressing of
phagocytic action of macrophages and leucocytes.
o Alteration of the immune response.
Adverse Reactions include allergic skin reactions,
sore, irritated tongue or gums, mouth ulcers, fungal
infections.
© Endeavour College of Natural Health www.endeavour.edu.au 37
Gold Salts – C/I and Drug-Drug
Interactions
Contraindications
o Inflammatory bowel disease.
o Diabetes.
o Heart failure.
o Renal/hepatic impairment.
Interactions
o Concurrent use with Penicillamine (another DMARD)
increases the risk of serious blood dyscrasias.
o Oral gold preparations have a better safety profile but
injectable dosage forms more efficacious.
© Endeavour College of Natural Health www.endeavour.edu.au 38
GOUTo Gout is caused by an accumulation of urate crystals in
the soft tissues of the body.
o Urate crystals can form when Urate concentrations rise
due to
• Increased production through purine metabolism by xanthine
oxidase.
• Decreased excretion through kidneys.
o Accumulation of Urate crystals in soft tissue stimulate
inflammatory response and migration of white blood cells
to site of crystal formation.
• Inflammatory response causes damage to joint tissue.
© Endeavour College of Natural Health www.endeavour.edu.au 39
Drug Treatment in Gout
Treatment Goals
o Halting an acute attack as soon as possible.
o Prevention of recurrent acute gout attacks.
o Prevention of uric acid stone formation in the kidneys.
o Reducing or preventing disease complications that result
from sodium urate deposits in joints and kidneys.
Two treatment approaches
o Treatment of acute attack
o Prophylactic treatment
© Endeavour College of Natural Health www.endeavour.edu.au 40
Management of Acute Attacks
o There are three treatments available for patients with
acute gouty arthritis i.e.: -
o Colchicine.
o Non-steroidal anti-inflammatory drugs (NSAIDs), most
commonly indomethacin, treatment of acute gout
attacks, and provides pain relief within 2-4 hours.
o Corticosteroids – administered either intra-articularly or
parenterally.
© Endeavour College of Natural Health www.endeavour.edu.au 41
Colchicine for Acute Gout Attacks
o Mechanism of action: may inhibit leukocyte migration; neutrophils
are unable to ingest urate crystals and consequently do not attract
more leukocytes to the area. Decreased lactic acid production
increases the pH in joints; and further deposition of urate crystals is
prevented.
o If colchicine is administered within 12 hours of the onset of acute gout
pain, 75-95% of patients will respond favourably, inflammation
subsiding in 75-80% of patients after about 48 hours
o Administered until pain relief, or until the development of
gastrointestinal symptoms such as diarrhoea, nausea or vomiting, or
the patient has taken a maximum of 8 tablets.
o ADR worse in people with renal or hepatic dysfunction, or are elderly
and frail (risk of dehydration and loss of electrolytes, therefore careful
monitoring is recommended)
© Endeavour College of Natural Health www.endeavour.edu.au 42
Gout Prophylaxis
o After the first acute gout attack, the decision must be
made whether or not to commence prophylactic therapy,
with drugs that lower serum urate concentration.
o Several factors are taken into account in this decision,
including the severity of the attack, whether it was the
first, or a recurrent attack.
o There are two different classes of drugs available for
prophylactic therapy, namely: -
• Xanthine oxidase inhibitors (allopurinol).
• Uricosuric drugs (e.g. probenecid, benzbromarone).
© Endeavour College of Natural Health www.endeavour.edu.au 43
Allopurinol – Xanthine Oxidase Inhibitor
o Allopurinol (e.g. Zyloprim®), mainstay of prophylactictreatment in patients with recurrent gout attacks.
o Reduces both the serum and urinary uric acid levels,thus preventing the formation of calculi.
o Mechanism of action: Allopurinol (and alloxathinemetabolite) decrease or inhibit the body’s production ofuric acid from purines (xanthine oxidase inhibitor, last stepof purine catabolism inhibited).
o Of the two compounds, alloxanthine has the longer half-life (28-44 hours), and thus is chiefly responsible for theinhibition of uric acid formation, and the subsequentalleviation of hyperuricaemia.
© Endeavour College of Natural Health www.endeavour.edu.au 44
Allopurinol Therapy and ADR
o Initiation of preventative therapy: low does, gradual
increase (as crystals mobilise out of the affected joint,
may precipitate a acute attack).
o NSAID therapy or colchicine for acute attacks.
o It is NOT necessary to add urinary alkalinisers to
allopurinol therapy (unlike uricosurics).
o ADR include GIT irritation, leading to nausea, vomiting,
abdominal pain or diarrhoea. Other, less frequent
adverse effects include cataracts, red irritated eyes,
headache, dizziness, drowsiness, alopecia.
o Rarely, bone marrow depression, hypersensitivity
reactions.
© Endeavour College of Natural Health www.endeavour.edu.au 45
Uricosurics - Probenecido Uricosurics (e.g. Probenecid – Pro-cid®)
o Mechanism of action: Drugs which increase the urinary
excretion of uric acid (increase the renal clearance by inhibiting
the renal tubular reabsorption of uric acid). Blood levels of
urate decrease and then uric acid and urate mobilized from
joints.
o Danger of renal stone formation because of urinary overload.
Larger volumes of fluid intake and the use of urinary
alkalinisers for the first few months of therapy can reduce the
risk of renal stone formation.
o ADR with uricosurics , GIT irritation, (risk reduced by increased
fluid intake). Rare, but dangerous adverse effects include
blood abnormalities, renal impairment, hepatic impairment.
© Endeavour College of Natural Health www.endeavour.edu.au 46
Treatment of Gout - overview
Copyright
Elsevier © 2007
© Endeavour College of Natural Health www.endeavour.edu.au 47
Tutorial/Forum Discussion of Drug
Diary
Activities from Session 6 are to be included in your formative Drug Diary, can
be included in your summative, Drug Mini-monograph assignment and all could
potentially be included on the final exam:
Discuss these medications that work on Immune Responses or similar. 10
marks for (i) examples (ii) indications (iii) mechanism of action (iv) efficacy and
limitations or cautions / contra-indications (v) adverse effects. Mark your own
answers using the Pharmacology text or online resources. Alternatively, peer
review each other’s answers, allocating 10 marks per drug class:
Non-selective COX inhibitors, cyclo-oxygenase inhibitors
Selective COX inhibitors
DMARDs (disease-modifying anti-rheumatic drugs
Corticosteroids to treat muskulo-skeletal diseases e.g. RA (rheumatoid
arthritis)
Anti-gout drugs, both prophylactics and those needed to treat the
acute attacks
© Endeavour College of Natural Health www.endeavour.edu.au 48
Acknowledgements Bibliography
• Bryant B, Knights K. 2007. Pharmacology for Health Professionals, 2nd
Edition. Mosby Elsevier
• Therapeutic Goods Administration and Department of Health and Aging,
2013, ‘Information about prescription medicines in Australia’, e-Business,
Commonwealth of Australia, Canberra. https://www.ebs.tga.gov.au
• UBM Medica, 2014. MIMSonline, https://www.mimsonline.com.au
• Many thanks to Navinisha (Nav) Lee (Endeavour College of Natural
Medicine, Melbourne) for her input
© Endeavour College of Natural Health www.endeavour.edu.au 49
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