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Estrogen & Androgens
Practice Questions
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Pharm. Practice Questions
1 – A 47-year-old Caucasian female is
diagnosed with metastatic breast cancer,
and begins treatment with anastrozole.
Soon after initiating therapy, she
experiences relief of her bone pain, and her
primary tumor substantially decreases in
size. Which of the following best explains
the effect of the therapy in this patient?
Answer
A.
B.
C.
D.
E.
Decreased follicular cell stimulation
Decreased androgen synthesis
Decreased androgen aromatization
Impaired ligand-receptor interaction
Impaired second messenger action
Pharm. Practice Questions
2 – A 38-year-old Caucasian female
presents to your office for a routine checkup, and requests a simple and reliable
method of contraception. She has no
significant past medical history, and does
not take any medications other than a daily
multivitamin. Which of the following
factors would most affect your decision to
prescribe oral contraceptives to this
patient?
Answer
A.
B.
C.
D.
E.
F.
Diet
Physical activity level
Smoking status
Parity
Glucose intolerance
Serum HDL level
Pharm. Practice Questions
3 – A 33-year-old Caucasian female begins
treatment with the abortifacient
mifepristone six weeks after her last
menstrual period. She experiences
abdominal cramps, nausea and vaginal
bleeding soon after initiating therapy.
Which of the following effects is most
likely responsible for this patient’s
symptoms?
Answer
A.
B.
C.
D.
E.
F.
Anti-progestin
Inhibition of progesterone synthesis
Prostaglandin agonist
Inhibition of cell division
Anti-glucocorticoid
Anti-mineralocorticoid
Pharm. Practice Questions
4 – A 23-year-old mildly obese woman is
treated for infertility. Her menstrual cycles are
irregular, occurring once every two to three
months. Examination shows hirsutism. Once
treatment is started, her serum progesterone
level increases sharply and secretory changes
are noted on endometrial sampling. Which of
the following agents has been most likely used
in this patient?
Answer
A.
B.
C.
D.
E.
Progesterone antagonist
Estrogen antagonist
Androgen antagonist
Aromatase inhibitor
GnRH antagonist
PAIN
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Our Goal
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ANALGESIC
&
ANTI INFLAMMATORY
DRUGS
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PAIN




Pain is always a subjective experience
Everyone learns the meaning of “pain” through
experiences usually related to injuries in early life
As an unpleasant sensation it becomes an
emotional experience
Pain is a significant stress physically, emotionally
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TYPES



Somatic pain: caused by the activation of
pain receptors in cutaneous (the body surface)
or deeper tissues (musculoskeletal tissues).
Visceral pain: pain caused by activation of
pain receptors from infiltration, compression,
extension or stretching of the thoracic,
abdominal or pelvic viscera (chest, stomach
and pelvic areas).
Neuropathic pain: caused by injury to the
nervous system due to a tumor compressing
nerves or the spinal cord, or cancer actually
infiltrating into the nerves or spinal cord.
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Various Descriptors of Pain

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
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
Mild
Moderate
Severe
Acute
Chronic
Malignant
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Treatment
Non – opioid analgesics
 Salicylates , NSAID’s, Cox 2 inhibitors
Opioid analgesics – Morphine, Pethidine..
Both can be used in combined therapy.
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

Most of the drugs used as analgesics have
the property of anti inflammatory actions
also.
Some of these drugs have anti-pyretic
property also.
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Anti-Inflammatory Drugs

Non steroidal Anti-inflammatory
Drugs
(NSAID’s)

Steroidal agents
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ROLE OF PROSTAGLANDINS
Cell Membrane (phospholipids)
phospholipase A2
Arachidonic acid
cyclooxygenase aspirin, indomethacin
(COX1 & COX2)
Cyclic endoperoxides (PGG2, PGH2)
Prostacyclin
synthetase
Prostacyclin
PDX, PGI2
(vasodilator,
antiaggregating)
Prostaglandin
synthetase
PGE2 PGF2
(erythma
(vasodilator
edema, pain,
uterus
fever)
contractor)
thromboxane
synthetase
Thromboxane A2
(vasoconstriction
platelet
aggregation)
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NSAID’s (Nonselective COX Inhibitors)

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
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Salicylic acid derivatives: Aspirin, Diflunisal
etc
Para-aminophenol derivatives:
Acetaminophen
Indole and indene acetic acids: Indomethacin
Heteroaryl acetic acids: Tolmetin, Ketorolac
Propionic acids: Ibuprofen, Naproxen,
Ketoprofen etc
Anthranilic acids (Fenamates): Mefenamic
acid, Meclofenamate
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NSAIDs
Selective COX 2 Inhibitors




Rofecoxib (Vioxx)
Celecoxib (Celebrex)
Valdecoxib (Bextra)
Etoricoxib (Arcoxia)
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Salicylates

Aspirin: prototype

Aspirin uniquely inactivates COX
by irreversibly acetylating the
enzyme.
Uses
 Pain (analgesic): moderate dose
 Fever (anti pyretic): moderate dose
 Anti inflammatory: high dose
 Anti platelet: low dose
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
Therapeutic uses: Control of Rheumatoid
Arthritis, Gout, Osteoarthritis, Ankylosing
spondylitis and prophylaxis against platelet
aggregation. & other pains.

Adverse effects: Gastrointestinal irritation,
Peptic ulcer, Hypersensivity, ↑ bleeding time ,
renal dysfunction (chronic use), Samter’s Triad,
bronchospasm, hyperuricemia, hyperthermia at
large doses (cause of death).
 Reye syndrome: encephalopathy, fatty
infiltration of the liver, kidney, spleen
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Pharmokinetics
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Oral administration
Un-ionized salicyclates passively
absorbed from stomach & small intestine
Salicyclates should be avoided in kids
with viral infection esp: chickenpox
At low doses = ↓↓ uric acid secretion
At high doses = ↑↑ uric acid secretion
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
Salicylism: due to toxic doses causes tinnitus,
vertigo, ↓ hearing, confusion, hallucination,
delirium, coma and death from respiratory
failure
 Treatment: no specific antidote
 ↑ urinary Ph, gastric lavage +/- activated
charcoal, dialysis
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A patient presents with the following
symptoms: nausea, vomiting, lightheadedness & dizziness. Which of the
following drugs can have the above side
effects?
A. Quinidine
B. Aspirin
C. Digoxin

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Salicylates (continued)

Diflunisal: difluorophenyl derivative of
salicylic acid.

Diflunisal is more potent than aspirin in
analgesic & anti-inflammatory actions.
However, it is largely devoid of antipyretic
effects.
 Longer duration (half-life:8-12 hrs vs. 2.5
hrs for salicylates).
 Fewer and less intense gastrointestinal and
antiplatelet effects than does aspirin.
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Indole and Indene Acetic Acids

Indomethacin:



•
Indomethacin is a potent reversible inhibitor of
the COX.
The toxicity limits use in ankylosing spondylitis,
gouthy arthritis and osteoarthritis.
SE: Thrombocytopenia, agranulocytosis
Sulindac: an indene derivative



It must be reduced to sulfide metabolites to
become active form of NSAID.
Sulindac has been used mainly for the
treatment of rheumatoid arthritis,
osteoarthritis, and ankylosing spondylitis.
SE: stevens-johnson syndrome, hematotoxicity
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Phenyl Acetic Acid Derivatives

Diclofenac: phenyl acetic acid derivative

It is a COX inhibitor, and its potency is
substantially greater than that of indomethacin.

Diclofenac sodium (Voltaren) is approved for the
long-term symptomatic treatment of rheumatoid
arthritis, osteoarthritis, and ankylosing spondylitis.

It can also be used for short-term treatment of
acute musculoskeletal injury, acute painful
shoulder, postoperative pain and Dysmenorrhea.

Toxic effects: gastrointestinal effects are the most
common.
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Propionic Acid Derivatives
Propionic acid derivatives used for symptomatic
treatment of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis and acute
gouty arthritis.
Ibuprofen:
 Naproxen:
The half-life of naproxen in plasma is about 14 hrs.

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Ketoprofen:
Oxaprozin:- unique among propionic acid
derivatives because it can be administered once
daily.
Fenoprofen
Flurbiprofen
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Selective COX-2 inhibitors




Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Valdecoxib (Bextra)
Etoricoxib (Arcoxia)
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Selective COX-2 inhibitors
Celecoxib (celebrex): It has been
approved for the treatment of
osteoarthritis and rheumatoid
arthritis. The recommended dose for
treatment osteoarthritis is 200 mg
per day as a single dose or as two
100-mg doses.
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

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Causes less GIT toxicity
Less antiplatelet action
Potential cardiotoxicity which resulted in its
withdrawal from the market (rofecoxib)
SE: abdominal pain, diarrhea, dyspepsia
CI: pts allergic to aspirin, chronic renal
insufficiency, severe heart disease, volume
depletion and hepatic failure.
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Others
Acetaminophen

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Inhibits mainly PG in CNS – antipyretic
& analgesic action
No anti inflammatory action
No anti platelet action
No effect on uric acid
Not known to cause Reye syndrome
Not bronchospastic
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
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Good for pt’s with aspirin SE.
Analgesic and antipyretic in viral infections in
children
Conjugated in the liver to form sulfated
metabolite
A portion is hydroxylated to form Nacetylbenzoiminoquinone a highly reactive and
potentially dangerous metabolite that reacts with
sulfhydryl groups.
At normal doses, it reacts with the sulfhydryl grp
of glutathione, forming a nontoxic substance
which is excreted in urine
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SE:
 Not much with normal doses,
 High doses –N acetyl benzoiminoquinone
reacts with sulfhydryl groups of hepatic
proteins.
 Can lead to hepatic necrosis and also
renal tubular necrosis.
 Anti dote – N - acetylcysteine
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Summary
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Rheumatoid Arthritis
•
•
•
•
•
•
•
HLA DR4
RAF & Anti-CCP
RA nodules
Anti-IgG antibodies
Il-1, IL-6, IL-8, TGF
Ig G mediated AID
Type III & IV hypersensitivity
Morning stiffness > 30 mins &
improving with use
Systemic Inflammation + general osteoporosis
Hands & feet joints: Knees, hip,
elbow, wrist, PIP, MCP, bilateral
Affects ↑ female > male
DISEASE MODIFYING
ANTIRHEUMATIC DRUGS(DMARDS)



NSAIDS are commonly used for the initial
management of RA, but require high doses
which generally results in marked adverse
effects
The NSAIDS decrease swelling and pain
but have no effect on the progression of the
joint damage
DMARDS slow disease progression, so
used in combination with NSAIDS
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DMARDS
These drugs are relatively toxic, and
they are reserved for patients with
progressive disease, refractory
cases or patients unable to tolerate
standard medications.
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
Gold compounds: Aurothioglucose,
Gold sodium thiomalate, and auranofin
 Mechanism:
Gold compounds are taken
up by macrophages and suppress
phagocytosis and lysosomal enzyme
activity.
 USES; cannot repair existing damage,
rather can only prevent further injury.
 Toxicity: Lesions of the mucous
membranes include dermatitis,
nephrotoxicity, pharyngitis etc. Severe
blood dyscrasias also may occur.
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Miscellaneous agents for rheumatoid
arthritis (continued)

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
Immunosuppressive agents, : Azathioprine,
Methotrexate
Of the cytotoxic immunosuppressant, only
Azathioprine and low oral doses of
methotrexate have been approved for
treatment of RA.
Penicillamine: orally effective alternatives to
gold in the treatment of patients with early,
mild, and nonerosive disease.
It suppresses T-cell and circulating RF.
Toxicities: various cutaneous lesions, blood
dyscrasias etc.
Antimalarial agents: Hydroxychloroquine
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Anticytokine therapies in RA


IL-1 and TNF-α are proinflammatory
cytokines involved in the pathogenesis
of RA
Secreted by synovial macrophages,
stimulates synovial cells to proliferate
and synthesize collagenase, thereby
degrading cartilage, stimulating bone
resorption and proteoglycan synthesis
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Etanercept: recombinant form of TNF
receptor that binds TNF
Infliximab, Adalimumab: a monoclonal
antibody to TNF
Other uses: infliximab (crohn disease)
Anakinra: a IL-1 receptor antagonist
S.E: infections, reactions at injection sites
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Gouty arthritis
An acute attack of gout occurs as a
result of an inflammatory reaction to
crystals of sodium urate that are
deposited in the joint tissue.
The inflammatory response involves:
 Local infiltration of granulocytes,
which phagocytize the urate crystals.
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

Tophaceous deposit: sodium urate
deposits in and around joints in cartilage,
bone, bursa and subcutaneous tissue.
Uric acid nephrolithiasis: formation of
urate stone
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CAUSES OF GOUT


Overproduction of uric acid
Under excretion of uric acid
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Therapeutic goal of treatment




Interfering with uric acid synthesis
Increasing uric acid excretion
Inhibiting leukocyte entry into the affected
joint
Administration of NSAIDs
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Drugs for acute treatment of gout




Indomethacine: decrease the movement of
granulocytes into the affected area
NSAIDs: to decrease pain and inflammation
Glucocorticoids
Aspirin is contraindicated because it
competes with uric acid for organic acid
secretion by the PCT
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TREATMENT OF CHRONIC
GOUT



Allopurinol: its metabolite, alloxanthine, is
an inhibitor of xanthine oxidase, which is
required to synthesize uric acid.
Adverse effects: GIT distress, peripheral
neuropathy, rash and stone formation
It inhibits the metabolism of 6-MP
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Colchicine:

largely effective only against acute gouty arthritis.
MOA: binds to tubulin causing its depolymerization
which inhibits the migration of granulocytes into the
inflamed area and a decreased metabolic and phagocytic
activity of granulocytes
-
It also blocks cell division by binding to mitotic spindle
SE: nausea, vomiting, diarrhea, and abdominal pain.
Toxic effects: hemorrhagic gastroenteritis, extensive
vascular damage, nephrotoxicity, and muscular
depression.
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Drugs used in the treatment of gout

Uricosuric drugs: Sulfinpyrazone & Probenecid - at
higher doses, block proximal tubular reabsorption of
urate, thus ↑↑ urinary excretion of uric acid & lowering
serum urate concentration.

It is ineffective if GFR is <50mL/min. Normal range??
Probenecid:
-
Liberal fluid intake must be continued throughout
therapy.
-
Uricosuric action of Probenecid, blunted by salicylates
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