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Practice Questions

Estrogen & Androgens

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. Decreased follicular cell stimulation

B. Decreased androgen synthesis

C. Decreased androgen aromatization

D. Impaired ligand-receptor interaction

E. Impaired second messenger action

Pharm. Practice Questions2 – A 38-year-old Caucasian female presents to your office for a routine check-up, 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?

AnswerAnswer

A. Diet

B. Physical activity level

C. Smoking status

D. Parity

E. Glucose intolerance

F. Serum HDL level

Pharm. Practice QuestionsPharm. 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?

AnswerAnswer

A. Anti-progestin

B. Inhibition of progesterone synthesis

C. Prostaglandin agonist

D. Inhibition of cell division

E. Anti-glucocorticoid

F. Anti-mineralocorticoid

Pharm. Practice QuestionsPharm. Practice Questions4 – 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?

AnswerAnswer

A. Progesterone antagonist

B. Estrogen antagonist

C. Androgen antagonist

D. Aromatase inhibitor

E. GnRH antagonist

PAINPAIN

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Our Goal

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ANALGESIC ANALGESIC & &

ANTI INFLAMMATORY ANTI INFLAMMATORY DRUGSDRUGS

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PAINPAIN

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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TYPESTYPES 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 PainVarious Descriptors of Pain

Mild Moderate Severe Acute Chronic Malignant

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Treatment 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 DrugsAnti-Inflammatory Drugs

Non steroidal Anti-inflammatory Drugs

(NSAID’s)

Steroidal agents

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ROLE OF PROSTAGLANDINSROLE OF PROSTAGLANDINS Cell Membrane (phospholipids) phospholipase A2

Arachidonic acid cyclooxygenase aspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG2, PGH2)

PGE2 PGF2

(erythma (erythma edema, pain, edema, pain, fever)fever)

Thromboxane AThromboxane A22

(vasoconstriction (vasoconstriction platelet platelet aggregation)aggregation)

ProstacyclinProstacyclinPDX, PGIPDX, PGI22

(vasodilator, (vasodilator, antiaggregating)antiaggregating)

(vasodilator (vasodilator uterus uterus contractor)contractor)

ProstacyclinProstacyclinsynthetasesynthetase

thromboxanethromboxanesynthetasesynthetase

ProstaglandinProstaglandinsynthetasesynthetase

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NSAID’s (NSAID’s (Nonselective COX Inhibitors)Nonselective COX Inhibitors)

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 NSAIDs Selective COX 2 InhibitorsSelective COX 2 Inhibitors

Rofecoxib (Vioxx) Celecoxib (Celebrex) Valdecoxib (Bextra) Etoricoxib (Arcoxia)

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SalicylatesSalicylates 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

Pharmokinetics 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

A patient presents with the following symptoms: nausea, vomiting, light-headedness & dizziness. Which of the following drugs can have the above side effects?

A. Quinidine

B. Aspirin

C. Digoxin

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Salicylates (continued)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 AcidsIndole 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 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 DerivativesPropionic 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.

Ketoprofen: Oxaprozin:- unique among propionic acid

derivatives because it can be administered once daily.

Fenoprofen Flurbiprofen

Celecoxib (Celebrex) Rofecoxib (Vioxx) Valdecoxib (Bextra) Etoricoxib (Arcoxia)

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Selective COX-2 inhibitorsSelective COX-2 inhibitors

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Selective COX-2 inhibitorsSelective 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.

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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OthersOthersAcetaminophen 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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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 N-

acetylbenzoiminoquinone 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

Summary Summary

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Rheumatoid Arthritis

Systemic Inflammation + general osteoporosis

Ig G mediated AID

• HLA DR4• RAF & Anti-CCP• RA nodules• Anti-IgG antibodies• Il-1, IL-6, IL-8, TGF• Type III & IV hypersensitivity• Morning stiffness > 30 mins &

improving with use

Hands & feet joints: Knees, hip, elbow, wrist, PIP, MCP, bilateral Affects ↑ female > male

DISEASE MODIFYING DISEASE MODIFYING ANTIRHEUMATIC DRUGS(DMARDS)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 42

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DMARDSDMARDS

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 Miscellaneous agents for rheumatoid arthritis (continued)arthritis (continued)

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

Anticytokine therapies in RAAnticytokine 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 arthritisGouty 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

CAUSES OF GOUTCAUSES OF GOUT

Overproduction of uric acid Under excretion of uric acid

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Therapeutic goal of treatmentTherapeutic 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 goutDrugs 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 TREATMENT OF CHRONIC GOUTGOUT 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 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