Case 36:

LO 5:
Is there any advantage in selecting COX-2-selective drug over a traditional NSAID in this patient? Explain
your answer?
- No because the patient has hypertension and mild heart failure. If we give COX-2 selective
drugs, there will be an increased risk of cardiovascular events like MI and stroke.
- Since the mild gastric irritation experienced by the patient can be controlled by occasional doses
of antacids, then I think it is rational to continue with NSAIDs rather than switch to COX-2
selective drugs.

Case 37:
LO #4:
Which medications are used for the treatment of acute gout? Discuss the mechanism of action of
allopurinol?
- Acute gout is treated with nonsalicylate NSAIDs particularly indomethacin, or with colchicine,
and corticiosteroids.
- Allopurinol inhibits the synthesis of uric acid by inhibiting xanthine oxidase, an enzyme that
converts hypoxanthine to xanthine, and xanthine to uric acid. Allopurinol is metabolized by
xanthine oxidase to alloxanthine which also inhibits xanthine oxidase. Allopurinol also inhibits
purine de novo synthesis.

Case 38:
LO #2:
What are the different Disease Modifying AntiRheumatic Agents used for Rheumatoid Arthritis and their
mechanisms of action?
ABATACEPT
1. Mechanism of action: Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells (see
also Chapter 55). After a T cell has engaged an antigen-presenting cell (APC), a second signal is produced by CD28
on the T cell that interacts with CD80 or CD86 on the APC, leading to T-cell activation. Abatacept (which contains
the endogenous ligand CTLA-4) binds to CD80 and 86, thereby inhibiting the binding to CD28 and preventing the
activation of T cells.

AZATHIOPRINE
1. Mechanism of Action: Azathioprine is a csDMARD that acts
through its major metabolite, 6-thioguanine. 6-Thioguanine
suppresses inosinic acid synthesis, B-cell and T-cell function,
immunoglobulin production, and IL-2 secretion (see Chapter 55).

CHLOROQUINE &
HYDROXYCHLOROQUINE
1. Mechanism of Action: Chloroquine and hydroxychloroquine
are nonbiologic drugs mainly used for malaria (see Chapter 52)
and in the rheumatic diseases as csDMARDs. The following
mechanisms have been proposed: suppression of T-lymphocyte
responses to mitogens, inhibition of leukocyte chemotaxis,
stabilization of lysosomal enzymes, processing through the
Fc-receptor, inhibition of DNA and RNA synthesis, and the
trapping of free radicals.
CYCLOPHOSPHAMIDE
1. Mechanism of Action: Cyclophosphamide is a csDMARD. Its
major active metabolite is phosphoramide mustard, which
cross-links DNA to prevent cell replication. It suppresses T-cell and B-cell function by 30–40%; T-cell suppression
correlates
with clinical response in the rheumatic diseases. Its pharmacokinetics
and toxicities are discussed in Chapter 54.

CYCLOSPORINE
1. Mechanism of Action: Cyclosporine is a peptide antibiotic but
is considered a csDMARD. Through regulation of gene transcription,
it inhibits IL-1 and IL-2 receptor production and
secondarily inhibits macrophage–T-cell interaction and T-cell
responsiveness (see Chapter 55). T-cell–dependent B-cell function
is also affected.

LEFLUNOMIDE
1. Mechanism of Action: Leflunomide, another csDMARD,
undergoes rapid conversion, both in the intestine and in the
plasma, to its active metabolite, A77-1726. This metabolite
inhibits dihydroorotate dehydrogenase, leading to a decrease in
ribonucleotide synthesis and the arrest of stimulated cells in the
G1 phase of cell growth. Consequently, leflunomide inhibits
T-cell proliferation and reduces production of autoantibodies
by B cells. Secondary effects include increases of IL-10
receptor mRNA, decreased IL-8 receptor type A mRNA,
and decreased TNF-α–dependent nuclear factor kappa B
(NF-κB) activation.

METHOTREXATE
Methotrexate, a synthetic nonbiologic antimetabolite, is the
first-line csDMARD for treating RA and is used in 50–70% of
patients. It is active in this condition at much lower doses than
those needed in cancer chemotherapy (see Chapter 54).
1. Mechanism of Action: Methotrexate’s principal mechanism of
action at the low doses used in the rheumatic diseases probably
relates to inhibition of amino-imidazolecarboxamide ribonucleotide
(AICAR) transformylase and thymidylate synthetase.
AICAR, which accumulates intracellularly, competitively
inhibits AMP deaminase, leading to an accumulation of AMP.
The AMP is released and converted extracellularly to adenosine,
which is a potent inhibitor of inflammation. As a result,
the inflammatory functions of neutrophils, macrophages,
dendritic cells, and lymphocytes are suppressed. Methotrexate
has secondary effects on polymorphonuclear chemotaxis.
There is some effect on dihydrofolate reductase and this affects
lymphocyte and macrophage function, but this is not its principal
mechanism of action. Methotrexate has direct inhibitory
effects on proliferation and stimulates apoptosis in immuneinflammatory
cells. Additionally, it inhibits proinflammatory
cytokines linked to rheumatoid synovitis.

MYCOPHENOLATE MOFETIL
1. Mechanism of Action: Mycophenolate mofetil (MMF), a csDMARD,
is converted to mycophenolic acid, the active form of
the drug. The active product inhibits inosine monophosphate
dehydrogenase, leading to suppression of T- and B-lymphocyte
proliferation. Downstream, it interferes with leukocyte adhesion
to endothelial cells through inhibition of E-selectin, P-selectin,
and intercellular adhesion molecule 1. MMF’s pharmacokinetics
and toxicities are discussed in Chapter 55.

RITUXIMAB
1. Mechanism of Action: Rituximab is a chimeric monoclonal
antibody biologic agent that targets CD20 B lymphocytes (see
Chapter 55). Depletion of these cells takes place through cellmediated
and complement-dependent cytotoxicity and stimulation
of cell apoptosis. Depletion of B lymphocytes reduces inflammation by decreasing the presentation of antigens to T
lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral B
cells, although this depletion correlates neither with efficacy nor with
toxicity.

SULFASALAZINE
1. Mechanism of Action: Sulfasalazine, a csDMARD, is metabolized
to sulfapyridine and 5-aminosalicylic acid. The sulfapyridine
is probably the active moiety when treating RA (unlike
inflammatory bowel disease; see Chapter 62). Some authorities
believe that the parent compound, sulfasalazine, also has an
effect. Suppression of T-cell responses to concanavalin and
inhibition of in vitro B-cell proliferation are documented. In
vitro, sulfasalazine or its metabolites inhibit the release of inflammatory cytokines produced by monocytes or
macrophages—eg, IL-1, -6, and -12, and TNF-α.

TOCILIZUMAB
1. Mechanism of Action: Tocilizumab, a newer biologic humanized
antibody, binds to soluble and membrane-bound IL-6
receptors, and inhibits the IL-6-mediated signaling via these
receptors. IL-6 is a proinflammatory cytokine produced by different
cell types including T cells, B cells, monocytes, fibroblasts,
and synovial and endothelial cells. IL-6 is involved in a
variety of physiologic processes such as T-cell activation,
hepatic acute-phase protein synthesis, and stimulation of the
inflammatory processes involved in diseases such as RA and
systemic sclerosis (SSc). In a phase 4 superiority study, tocilizumab
monotherapy was superior to adalimumab monotherapy
for reduction of signs and symptoms of rheumatoid
arthritis in patients with incomplete response to MTX.

TNF-`-BLOCKING AGENTS
Adalimumab
1. Mechanism of Action: Adalimumab is a fully human IgG1
anti-TNF monoclonal antibody. This compound complexes
with soluble TNF-α and prevents its interaction with p55 and
p75 cell surface receptors. This results in down-regulation of
macrophage and T-cell function.
Certolizumab
1. Mechanism of Action: Certolizumab is a recombinant,
humanized antibody Fab fragment conjugated to a polyethylene
glycol (PEG) with specificity for human TNF-α. Certolizumab
neutralizes membrane-bound and soluble TNF-α in a
dose-dependent manner.

Etanercept
1. Mechanism of Action: Etanercept is a recombinant fusion
protein consisting of two soluble TNF p75 receptor moieties
linked to the Fc portion of human IgG1 (Figure 36–4); it binds
TNF-α molecules and also inhibits lymphotoxin α.

Golimumab
1. Mechanism of Action: Golimumab is a human monoclonal
antibody with a high affinity for soluble and membrane-bound
TNF-α. Golimumab effectively neutralizes the inflammatory
effects produced by TNF-α seen in diseases such as RA.

Infliximab
1. Mechanism of Action: Infliximab (Figure 36–4) is a chimeric
(25% mouse, 75% human) IgG1 monoclonal antibody that
binds with high affinity to soluble and possibly membranebound
TNF-α. Its mechanism of action probably is the same
as that of adalimumab.

Case 39:
LO #1:
- Peptic Ulcer Disease secondary to H. pylori infection
- Basis:
o Epigastric pain
 Most common symptom characterized by gwaning and burning ensation and
occurs after meaals
o History of peptic ulcer disease
o Positive result of biopsy for H. pylori
LO #3
Explain the role of Helicobacter Pylori in Peptic Ulcer Disease
- H. pylori colonizes the stomach in ~50% of the world’s human population. Colonization with this
organism is the main risk factor for peptic ulceration
- The H. pylori bacteria weakens the protective mucous coating of the stomach and duodenum,
thus allowing acid to get through to the sensitive lining beneath. Both the acid and the bacteria
irritate the lining and cause a sore, or ulcer.
- H. pylori is able to survive in stomach acid because it secretes enzymes that neutralize the acid.
This mechanism allows H. pylori to make its way to the “safe” area – the protective mucous
lining. Once there, the bacterium’s spiral shape helps it burrow through the lining.
- The gram-negative spirochete H pylori was first linked to gastritis in 1983. Since then, further
study of H pylori has revealed that it is a major part of the triad, which includes acid and pepsin,
that contributes to primary peptic ulcer disease. The unique microbiologic characteristics of this
organism, such as urease production, allows it to alkalinize its microenvironment and survive for
years in the hostile acidic environment of the stomach, where it causes mucosal inflammation
and, in some individuals, worsens the severity of peptic ulcer disease.
Case 40:
LO #1:
Describe the mechanism of action of benzodiazepines?