Download Pharmacotherapy of the rheumatoid arthritis

Pharmacotherapy of
the rheumatoid arthritis
Dr. Erika Pintér
2016
Polyarthritis chronica progressiva (PCP)
Multifactorial , immunologic disorder that causes significant
systemic effects
Chronic and progressive
Causes deformation of the joints
Symptoms:
Pain
Started in MCP and PIP joints, symmetric
Morning hand and joint stiffness
Laboratory factors ( We, rheumatoid factor, CRP)
Prevalence: 1%
The aims of the therapy:
-Inhibition of the disease activity
-improvement of the physical condition
-slow-down of the development of
structural damages
Drug therapy:
NSAID-s
steroids
DMARD-s disease modifying antirheumatic
drugs
other additional agents
DMARD-s
1.methotrexate
2. cyclophosphamide
3. cyclosporine
4. chloroquine
5. leflunomide
6. gold
7. sulfasalazine
8. penicillamine
9. Monoclonal antibodies –(anti-TNF-α therapy)
infliximab, adalimumab, etanercept
NSAID-s, streroids: symptomatic, anti-inflammatory therapy.
They have no any effect on the progression of the disease.
DMARD-s: disease modifying antirheumatoid drugs.
Long-lasting anti-inflammatory effect, clinical remission
1. Methotrexate
First choice (60% of the patients)
It is active in this condition at much lower doses than those needed in
cancer chemotherapy.
Mode of action (in low dose):
Inhibition of aminoimidadazolecarboxamide ribonucleotide (AICAR)
transformylase, and also thymidilate synthetase, which secondary effects
on PMN chemotaxis.
Some effects on the dihydrofolate reductase (inhibited lymphocyte and
macrophage function).
Kinetics:
70% oral absorption
It is metabolized to a less active hydroxylated metabolite.
Both compounds are polyglutamated within cell and stay for prolong period
in the body.
T1/2: 6-9 h but sometimes 24 h
Excretion: 70% in the urine
30% in the bile
Dose: 15-25 mg/week
Adverse effects: nausea, mucosal ulcers, dose related hepatotoxicity.
The incidence of GIT and liver function abnormalities can be reduced by
the use of leucovorin 24h after each weekly dose, or by daily folic acid.
Contraindicated in pregnancy.
2. Cyclophosphamide
Mode of action: Its major active metabolite is
phosphoramide mustard, which cross-links DNA to
prevent cell replication. It suppress T and B cell
functions by 30-40%.
Dose: 2 mg/kg/day orally
Side effects: dose related bone marrow suppression,
alopecia, haemorrhagic cystitis
3. Cyclosporine
Mode of action: See: immunopharmacology
Kinetics: new microemulsion formulations have 20-30%
oral bioavailability
grape fruit juice increases CS bioavailability by as much
as 62%
metabolisms by CYP3A
Interactions!!!
Dose: 3-5 mg/kg/day
Toxic effects: nephrotoxicity
(interactions with drugs inhibiting CYP3A (diltiazem,
potassium-sparing diuretics)
Serum creatinin should be monitored!
4.Chloroquine
See: malaria
Mode of action: unclear
The following mechanisms have been proposed:
-suppression of T cell responses to mitogens
-decreased leukocyte chemotaxis
-stabilization of lysosomal enzymes
-decrease DNA and RNA synthesis
-trapping of free radicals
Kinetics:
Rapid absorption
50% plasma protein binding
extensively tissue-bound, particularly in melanin-containing tissue
such as the eyes.
T1/2: 45 days
Side effects: ocular toxicity (over 250 mg/day), ophthalmologic
monitoring is advised.
Dyspepsia, nausea, abdominal pain, rashes, nightmares
Relatively safe in pregnancy.
5. Leflunomide
Mode of action: It undergoes rapid conversion in the intestine and plasma 
A77-1726
A77-1726 inhibits dihydroorotate dehydrogenase leading to a decrease of
ribonucleotid synthesis and arrest of stimulated cells in the Gi phase of cell
growth.
It inhibits T cell proliferation antibody production of B cells.
It increases of IL-10 receptor mRNA,
decreases of IL-8 receptor, type A mRNA,
decreases of TNF-α-dependent NFB activation
Kinetics:
Completely absorbed,
T1/2 : 19 days, enterohepatic circulation
Adverse effects:
Diarrhoe 25%, elevation of liver enzymes, might alopecia, weight gain, elevated
blood pressure,
Contraindicated in pregnancy.
6. Gold compounds (only history)
They were first proved to be effective in a clinical trial (1960)
i.m. formulas –aurothiomalate
- aurothioglucose
contain 50% elemental gold
oral: auranoffin (29% elemental gold)
Mode of action: gold alter the morphology and functional capabilities of human
macrophages, monocyte chemotactic factor 1, IL-8, IL-1b, VEGF are inhibited
i.m. gold: inhibited lysosomal enzyme activity, histamine release, complement
system, phagocytic activity of PMN,
oral gold: inhibits PGE1, LTB4 synthesis
Kinetics:
i.m. gold tends to concentrate synovial membrane, liver, kidney, bone marrow,
spleen, lymph node
T1/2 1 year
Dose: i.m. 50 mg/week for 20 weeks
Adverse effects: pruritic skin rashes (15-20%), eosinophilia, stomatitis, metallic
taste int he mouth, thrombocytopenia, leukopenia, pancytopenia (1-10%)
enterocolitis, jaundice
7. Sulfasalazine
Mode of action: it is metabolized to sulfapyridin and 5aminosalicylic acid. It is thought that sulfapyridin is
probably the active molecule against RA. (???) (See:
ulcerative colitis and Crohn’s disease.) It decreases IgA
and IgM rheumatoid factor production.
Kinetics:
10-20% oral absorption, enterohepatic circulation
intestinal bacteria  liberation of 5-aminosalicylic acid
(remains in the gut)
sulfapyridin (is well absorbed)
Adverse effects:
30% stop of treatments
nausea, vomiting, headache, rash, haemolytic anaemia,
methaemoglobinaemia
8. Penicillamine (rarely used)
It is penicillin metabolite, dimethylcysteine. D-isomer is used
against RA. 75% responder patients.
Mode of action: inhibition of IL-1 generation and prevention of
the maturation of newly synthesised collagen. The drug has a
highly reactive thiol group and also has meta-chelating
properties (treatment of Wilson disease)
Kinetics:
It is given orally, 50% is absorbed. Dosage is started low and
increased only gradually to minimise unwanted effects.
Side effects:
Occur in 40% of patients. Anorexia, vomiting, fever, taste
disturbances. Proteinuria (20% of patients). Rashes,
stomatitis, dose-related thrombocytopenia, leukopenia,
aplastic anaemia
9. TNF-a blocking agents
1. adalimumab
Mode of action: is a fully human IgG1 anti-TNF monoclonal antibody.
Adalimumab complexes with soluble TNF-a and prevents its interaction
with p55 and p75 cell surface receptors.
Kinetics: s.c. , t1/2: 10-20 days, dose: 40 mg every other week
Side effects: macrophag-dependent infections (tuberculosis,
opportunistic infections).
Increases incidence of malignancies
2. infliximab
See: immunopharmacology
3. etanercept
See: immunopharmacology