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Person 1

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Alan Shaw

on 22 November 2016

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Transcript of Person 1

Mariam- Immunosuppresant Drugs
Laura Henderson
Biopharmacuticals, anticytokine drugs and future developments
Chapter 26 - Anti-inflammatory & Immunosuppressant Drugs
Future of anti-inflammatory
Future developments
Arthritic disease
Disease Modifying Antirheumatic drugs (DMARDs)
Methotrexate: Immunomodulator
Gold compounds I
Antimalerial drugs
Cyclo-oxygenase Inhibitors
What is Cyclo-oxygenase?
Celecoxib & Etoricoxib
One of commonest chronic inflammatory diseases

1:3 Likely to become severely disabled

Autoimmune reaction
Involves inflammation
Proliferation of synovium
Erosion of cartilage and bone

Heterologous group
Unrelated chemical structures
Different mechanisms of action

Can be Initiated on definitive diagnosis
slow onset- so NSAID also used in early stages
some can be used in other Chronic inflammatory diseases

Common 1st choice drug: Rapid onset
Superior to many other DMARDs
Cytotoxic and immunosuppressant
Folic acid antagonist
Potent antirheumatoid action:
Common 1st choice DMARD
complex of sulfonamide and salicylate
Acts by: 5- aminosalicylic acid scavenging toxic oxygen metabolites produced by Neutrophils
Also used in : chronic inflammatory bowel diseases -
Many side effects:
bone marrow suppression, leucopenia, folic acid absorption inhibition, headaches, anaphylactic type reactions, GI upset, , skin reactions, sperm count reduction - (reversible)
Precise mechanism of action unknown- may modify
rheumatic disease by reducing immune response, IL-1 generation, +/- effect collagen synthesis
Oral administration-Cmax 1-2h (only 1/2 oral dose absorbed)
Low starting dose, dose increase dependent on side effects used in severe disease
75% response rate-therapeutic effects show in weeks/ plateau in months
20% proteinuria
40% unwanted effects- inc Thrombocytopenia Haemtological monitoring req.
Metal chelating properties- not to be given with gold compounds
Absolute contraindications
- Leucopenia or aplastic anemia and auto immune conditions
Poorly absorbed after oral ingestion
Split in to component parts by colon bacteria
(organic compounds)
Effects occur over 3-4 months- Pain and joint swelling subside, progression of bone and joint damage diminishes
Sodium aurothiomalate- IM administration
Auranofin- Oral
Mechanism of action unclear -but auranofin inhibits induction
of IL-1 and TNF_alpha.
: Compounds concentrate and after treatment cessation, remain in tissues, liver cells, kidney tubules, adrenal cortex and systemic macrophages
Excretion mostly renal-some GI tract elimination
t1/2 -7 days increases with treatment so administered weekly then at monthly intervals
Often used with anticytokines
Must be closely monitored due to potential blood dyserasias
Gold compounds II
Side effects
Aurothiomalate -side effects in 33%
-toxic effects in 10%
Auranofin - side effects less frequent/severe-
Stopping therapy in early symptoms
can reduce serious toxic effects
Skin rash-can be severe, non specific flu like symptoms
Proteinuria, thrombocytopenia, blood dyscrasias, hepatitis,
peripheral neuropathy
4 amino quinoline drugs
Chloroquine- used when all else fails
Contraindicated in psoriatic arthroapathy
Important to screen for ocular toxicity

Inflammation forms a significant component of most diseases
Consequently anti inflammatory drugs are employed in almost all areas of medicine

Difficult to produce
interference with immune function
Cannot be given orally
COX-2 inhibitors and coronary thrombosis
Development of nitric oxide

potential to reduce the ulcerogenic events of NSAIDs
Currently in clinical trials

*Mast cells and basophil granules
*Exocytosis during inflammatory and allergic reactions
*Acts on H1, H2, H3, (H4)
*Stimulates gastric secretion (H2)
*Contracts smooth muscle (H1)
*Cardiac stimulation (H2)
*Vasodilation (H1)
*Increased vascular permeability (H1)
*Receptor antagonists H1, H2, H3
*Anti histimine - H1 receptor antagonist
*Inflammation and allergic conditions
*H2- inhibits gastric secretion
*H3 receptor agonists & antagonists- currently being explored
Systemic H1 receptor antagonists
*Cetirizine-non sedating- H,U
*Loratidine-non sedating-H,U
*Chlorphenamine-sedating- H,U,AE
*Promethazine-sedating-H,U,AE,S-motion sickness
*Cyclizine-sedating-nausea,vomiting,motion sickness
H-hives,U-urticaria,AE-Allergic emergency,S-sedation
Pharmacological actions
*1st generation- cross blood brain barrier & sedating
*2nd generation- some cardiac toxicity (torsade de pointes)
*3rd generation- cardio safe drugs
Clinical uses
*Allergic reactions (cetirizine)
-topical preparation
-Injectable formulations
*As antiemetics (cyclizine)
-prevent motion sickness
-nausea & labyrinthine disorders
*For sedation (promethazine)
*Well absorbed-orally
*Remain effective 3-6 hours
*Widely distributed
*Metabolised in the liver & excreted in the urine
Unwanted effects
*Dry mouth*Blurred vision*Constipation*urine retention*GI disturbances*Allergic dermatitis


Long Term Preventer Drugs



Mechanism Therapeutic Features
of Action
Side Effects/ Warnings

Uricolytics (Uricose)

Therapeutic Features

Mechanism of Action Side Effects/

Alan Shaw
Antirheumatoid Drugs
Laura Henderson, Amanda Tiller,
Louise Haddock, Rayma Murphy
Mariam Ahmed, Alan Shaw, Leeanne Orban

Chapter 26 Anti-inflammatory and
immunosuppressant drugs

Wellington Campus

Due 7th September 2015
Histimine Antagonists
Leeanne Orban
to treat Rheumatiod arthritis
Soluble receptor (etanercept)
Antibody (infliximab)

receptor antagonist (anakinra)
Usually prescribed along side
Biopharmacuticals and the treatment of chronic inflammation
Greatest technological breakthrough for decades (Roubille et al 2015)
Engineered recombinant
They can be used in patients who have not responded to conventional therapy
Can be targeted at different aspects of the disease process
Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: A systematic review and meta-analysis. Ann Rheum Dis 2015; 74: 480–489

Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2011; 63: 522–529.

Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005; 32: 1213–1218.
Yogeeswari P. Discovery of fused triazolo-thiadiazoles as inhibitors of TNF-alpha: Pharmacophore hybridization for treatment of neuropathic pain. Pain Ther 2012; 1: 3.
Liu X, Fang L, Guo TB, Mei H, Zhang JZ. Drug targets in the cytokine universe for autoimmune disease. Trends Immunol 2013; 34: 120–128.
Treatment can be targeted
to specific aspects of the
disease process in rheumatoid arthritis
and other inflammatory diseases
Design and synthesis of nitric
Immunosuppressants are used in the therapy of auto-immunes disease and prevent ot treat transplant rejection.
Impair immune responses
Drugs that inhibits purine or pyrimidine synthesis
Decrease responds to infection
Facilitate the emergency of malignancy cells lines
Drugs that inhibits 1L-2 production or action
They can be characterised as:
Ciclosporin is a strong immune suppressant drug
the main agent used to prevent the rejection of transplanted organs.
Naturally occurring compound first found in fungus.

T Cell that are responsible for cell mediated responses + some reduction of T cell dependent B cell responses
it interaction of antigen with T-helper (Th) cell.
Increased intracellular Ca2, which stimulates a phosphatase , Calcineurin
Poorly absorbed by mouth, can be given orally in a more readily absorbed formation.
Can be given intravenous infusion
Peak plasma concentration usually 3 to 4 hours
Plasma half-life is approximately 24 hours
Metabolism occurs in the liver.
Most of metabolites are excreted in the bile
Accumulates in the most tissues of concentration three to four times that seen in the plasma. some remain in the lymphomyeloid tissue + in the fat depot for sometime after stop.
The unwanted effects of Ciclosporin:
Gastrointestinal disturbances
Gum hypertrophy
Tracrolimus is a macrolide antibiotic of fungal origin. it has a similar mechanism of action to Ciclosporin but higher potency and the main difference is that the internal receptor for this drug is not cyclophilin but a different immunophilin termed .
These mainly used in organ transplantation severe a topic eczema. E.g

Sirolimus is used to prevent organ rejection after transplantation and also in coating on stents to prevent restenosis
Pimecrolimus is used topically for atopic eczema.
Can be given Orally, by Intravenous injection and as an ointment for topical use in inflammatory disease of the skin.
Tacrolimus metabolised by the liver and has a half-a life of approximately 7 hours
Unwanted effects of Tacrolimus are similar to Ciclosporin but are more severe.
Gastrointestinal disturbance
Metabolic disturbances
Azathioprine is widely used for immunosuppression, particularly for control of autoimmune disease such as rheumatoid arthritis and prevent tissue rejection in transplant surgery.
It interferes with purine synthesis +cytotoxic
Skin eruption
A mild hepatotoxicity
Depression of bone marraw

Unwanted effects:
Mycophenolate Mofetil
Is semisynthetic derivative of a fungal antibiotic used for preventing organ rejection.
its converted to mycohenolic acid, which is restrains rapid reproduction of both T cell and B lymphocytes and reduces production of cytotoxic T cells by inhibiting inosis monophophate dehydrogenase. Which is enzyme cruial for novo purine biosynthesis both T cells and B cells.
Can be given orally and well absorbed.
Metabolic of mycophenolic acid undergoes enterohepatic cycling
Elimination by kidneys as the inactive glucuronide
Unwanted effects:
Gastrointestinal effect

Raised liver enzymes
Risk of Hepatic failure
the long half-life increases the risk of cummulative toxicity
unwanted effects:
Glucocorticoids involves both their effects the immune response and their anti-inflammatory action.
Restrain the clonal proliferation of Th cell, through decreasing transcription of the gene for IL-2. decrease the transcription of many other cytokone genes
The synthesis and release of anti-flammatory proteins eg Annexin 1 & Protease inhibitors also increased
The effects are mediated through inhibition of the action of transcription factors, such as activator protein-
Rayma Murphy

Drugs used

Uricosurics Uricolytics (Uricase)

Increase urate

Lowers serum


uric acid


Xanthine Oxidase Inhibitors

Reduce the production of uric acid


Long Term Preventer Drug

Mechanism of Therapeutic Features

Side Effects /

Acute Treatment
Long term
Uric Acid level
Decrease pain/inflammation
Cause &


Figure 1.

Uric Acid Crystals
image. Retrieved from http://www.webmd.com/arthritis/ss/slideshow-gout

Amanda Tiller
Cyclo-oxygenase Inhibitors
Traditional NSAIDS
Coxibs: Selective for Cox 2
Decrease inflammation, relieve pain and decrease fever.
Used for: Chronic joint disease (oesto-& rheumatoid arthritis), fractures, sprains & sport injuries, postoperative pain, headaches, dental and menstrual pain.
Long Term Preventer Drugs

Acute Treatment Drugs

First- line treatment
Corticosteroids Non-steroidal anti-

Mechanism of Action
Narrow Therapeutic Index
Side Effects/

Toxic / Fatal

Best Practice Journal. 37.2011. The medical management of gout revisited. Retrieved from

Best Practice Journal. 51. 2013. An update on the management of gout. Retrieved from

Decision to fund febuxostat (Adenuric) for treatment-resistant gout.
14 May 2014. Retrieved from

Fasturtec rasburicase.pdf
Retrieved from http://www.medsafe.govt.nz/consumers/cmi/f/fasturtec.pdf

Febuxostat. Retrieved from http://www. nzf.org.nz/nzf_5685

Gout and cytotoxic-induced hyperuricaemia.
New Zealand Formulary
. V38. 01 August 205. Retrieved from
http://nzf.org.nz/nzf_5672?searchterm=Gout%20and %20cytotoxic-induced%20hyperuricaemia

Gout and Hyperuricemia. Retrieved from http://www.aafp.org/afp/1999/0215/p925.html

Gout Pharmac. Retrieved from https://www.pharmac.health.nz/medicines/your-health/gout/

Probenecid medical facts from Drugs.com. Retrieved from http://www.drugs.com/mtm/probenecid.html

Questions and Answers about Gout. June 2015. Retrieved from http://www.naims.nih.gov/Health_Info/Gout/

Safer prescribing of high-risk medicines. Colchicine – extremely toxic in overdose. Retrieved from
http://www.bpac.org.nz/ BPJ/2014/september/docs/BPJ63-safer-prescribing.pdf

Sulfinpyrazone to prevent gout
. Retrieved from http://patient.info/medicine/sulfinpyrazone-to-prevent-gout

Uric Acid-Lowering Drugs Pathway, Pharmacodynamics. Retrieved from

Long Term Preventer Drug
primarily suppress T-cell and B-cell production
Orally it is well absorb from intestinal
its half life 5 hours
Metabolised in liver
excreted via biliary system
Louise Haddock

Non-steroidal anti-inflammatory drugs
(also known as non- narcotic's).
"Non-steroidal" different structure from other anti-inflammatory molecules e.g corticosteroids (released by adrenal gland in the body or made synthetically).
Available over the counter (OTC)
Among the most widely used of all drugs
More than 50 different agents on global market

Therapeutic actions:
anti inflammatory
Mechanism of action
Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzyme (COX) at site of inflammation.
-mainly concerned with tissue homeostasis 'house-keeping' role

mainly inflammatory activated by inflammatory cytokines
Two common isoforms
Traditional NSAID's
Aspirin (
Ibuprofen (
Diclofenac (
Indomethacin (
Naproxen (
Mefenamic Acid (
Uses and potency

One of the earliest drugs synthesised. (introduced clinically 1890's)
Oldest of all NSAID's
-pregnancy category D
-now mainly used as cardiovascular drug
provides prolonged inhibition of platelet cox 1 reducing aggregation.
irrevercibly acetylates cox (proteins), as platelets do not have nucleus they cannot de novo protein synthesis so remain inactivated for the life of the platelet (approx 10 days)
may be beneficial in reducing colorectal cancer,radiation induced diarrhoea and possibly beneficial in treating Alzheimers Disease
Acute Treatment Drug
Figure 2.

Low/narrow/small therapeutic index.
Ram F.S.F; McDonald E.M (Editors). 2015. pg 57. First Edition. Essentials of Clinical Pharmacology For Clinicians and Prescribers.
The Printery, Massey University, Palmerson North, New Zealand
Figure 3. Inhibition of uric acid synthesis by allopurinol. Rang H. P., Ritter J.M., Flower R.J., Henderson G.
pg 331. Eighth Edition.
Rang & Dale's Pharmacology.
Elsevier Churchill Livingstone. London
Not true NSAID due to very limited anti-inflammatory action
One of the most commonly used drugs
-pregnancy catergory A
-cox selective,

-a component of many other the counter (OTC) preparations
absorption is rapid and almost complete from gastointestinal tract
metabolised in the liver and excreted in urine as glucuronide and sulfate.
plasma half life 2-4 hrs
Can be given orally, rectally or intravenously
shown to be selective inhibitor of cox-3 (splice product of cox-1) in the CNS of some species

Non Steroidal Anti-inflammatory Drugs
Adverse effects
All NSAID's share a similar profile of unwanted effects due to prostaglandin involvement in:
gastric cytoprotection
platelet aggregation
renal vascular autoregulation
induction of labour

Cox-1 inhibitors
nausea and vomiting
gastric bleeding and ulceration
rashes are common
mild to severe including fatal
Stevens-Johnson syndrome
Kidney Function
acute renal insufficiency in susceptile patients-reversible (PGE2 and PGI2 prostacyclin)
NSAID abuse-analgesic nephropathy
Hypertension- NSAID's raise blood pressure in patients not taking antihypertensive drugs-increasing risk of stroke and MI
Paracetamol overdose (>200 mg/kg or 10g )causes irreversible liver damage
Salicylism (overdose of aspirin):
decreased hearing
nausea and vomiting
5% of patients exposed to NSAID's exact mechanism unknown.
Rare other effects:
CNS effects
bone marrow disturbances liver disorders

Asperheim MK,Favaro JP, Intoduction to Pharmacology, Elsevier Saunders, Missouri, USA, 12th edition, 2012.
Barber P, Parkes J, Blundell D, Further Essentials of Pharmacology for Nurses, Open University Press Berkshire, England, 2012.
Brack G, Franklin P, Caldwell J,Medicines Management for Nursing Practice, Oxford University Press, UK, 2013.
Paradiso C, Lippincott's Review Series Pharmacology, Lippincott, New York, USA, 1998.
Medsafe Data Sheet retrieved from www.medsafe.govt.nz/profs/datasheet/p/panadoltab.pdf
its orally active and absorbed fron gastrointestinal tract, its has a long plasma half life and active metabolite undergoes enterohepatic circulation.
Both drugs have similar pharmacokinetic profiles.
Used for the treatment of Osteoarthritis & rheumatoid arthritis.
Oral administration.
Peak plasma concentration 1-3hrs.
Metabolised in the liver.
Side effects: GI toxicity, headache, dizziness, skin reactions, long term renal effects & peripheral oedema.
Avoid in patient's with gastric ulers.
Prodrug of Valdecoxib.
Used for post-operative pain management.
Maximum blood levels 30-60 mins.
Plasma 1/2 life of 8hrs
Monitor renal function
Side effects: skin reactions, postoperative anaemia & increase in cardiovascular side effects (MI & stroke).
Cox Inhibition
Cyclo-oxygenase: An enzyme in the biosynthetic pathway that is involved in forming prostanoids & prostaglandins (prostacyclin & thromboxane) from arachodonic acid. Two isoforms Cox 1 & 2 & partial Cox 1A & PCox 1B

Cox 1: "Constitutive enzyme" found in the kidney, stomach and platelets, involved in tissue homeostasis, prostaglandin production, protects gastric mucosa and regulates gastric acid.

Cox 2: Inducible enzyme, found in macrophages, leucocytes & fibroblasts. Main function is the production of the prostanoids which have an inflammatory reaction.
Inhibits the dihyroorotate dehydrogenase (DHODH)
involved in synthesis of pyrimidines.

McCance,K., & Huether,S.(2006).Pathophysiology: The biologic basis for disease in adults and children (5th ed). St Louis, Missouri:Elsevier Mosby
Drug of Choice
Figure 4.
Raburicase mechanism of action retrieved from http://www.bloodjournal.org/content/97/10/2998?sso-checked=true
Try lifestyle
had at least >2 attacks in a year

Asperheim MK,Favaro JP, Intoduction to Pharmacology, Elsevier Saunders, Missouri, USA, 12th edition, 2012.

Medsafe Data Sheet retrieved from www.medsafe.govt.nz/profs/datasheet/p/panadoltab.pdf
- response in about a month (also used in discoid lupus)- but only 1/2 patients respond
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