biop211 sn06 lecture drugs affecting body defences · o paracetamol is not associated wit the...

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.


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


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.


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).


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.


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.


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.


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 ®)


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).


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.


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.


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.


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.


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).


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.


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.


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.


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.


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


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.


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).


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).


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) .


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


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.


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.


Corticosteroids – M of Ao Management of rheumatoid arthritis, do not appear to

alter the progression of the disease.


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.


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).


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


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


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


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.


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.


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.


Gold SaltsIndications

o Rheumatoid arthritis.

o Juvenile RA.


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.


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.


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.


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


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.


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)


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).


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.


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.


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.


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


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

https://www.ebs.tga.gov.au/

https://www.mimsonline.com.au/


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