Estrogen & Androgens Practice Questions

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 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 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?

Answer 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 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 Progesterone antagonist Estrogen antagonist Androgen antagonist Aromatase inhibitor GnRH antagonist

PAIN

Our Goal

ANALGESIC & ANTI INFLAMMATORY DRUGS

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

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.

Various Descriptors of Pain Mild Moderate Severe Acute Chronic Malignant

Calor, Rubor, tumour, dolor, function laesa

Treatment Non – opioid analgesics Salicylates , NSAID’s, Cox 2 inhibitors Opioid analgesics – Morphine, Pethidine.. Both can be used in combined therapy.

Most of the drugs used as analgesics have the property of anti inflammatory actions also. Some of these drugs have anti-pyretic property also.

Anti-Inflammatory Drugs Non steroidal Anti-inflammatory Drugs (NSAID’s) Steroidal agents Most of the nonsteroidal antiinflammatory agents are overlapping with analgesics and antipyretic functions.

ROLE OF PROSTAGLANDINS Cell Membrane (phospholipids) phospholipase A2 Arachidonic acid cyclooxygenase aspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG2, PGH2) PGE2 PGF2 Prostacyclin synthetase Prostaglandin synthetase thromboxane synthetase COX-1 is a constitutive enzyme and functions in platelet and stomach, renal homeostasis COX-2 is an inducible enzyme that functions in inflammation, brain, kidney Prostacyclin PDX, PGI2 (vasodilator, antiaggregating) (erythma edema, pain, fever) (vasodilator uterus contractor) Thromboxane A2 (vasoconstriction platelet aggregation)

NSAID’s (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 General consideration for anti-inflammatory agents: - palliative not curative - nonspecificity - reduces body’s defensive mechanisms - adverse and toxic effects

NSAIDs Selective COX 2 Inhibitors Rofecoxib (Vioxx) Celecoxib (Celebrex) Valdecoxib (Bextra) Etoricoxib (Arcoxia) Etodolac (Lodine) provides postoperative analgesia that typically lasts for 6-8 hrs. It also is effective in the treatment of osteoarthritis and rheumatoid arthritis.

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 Reye’s syndrome: characterized by acute encephalopathy and fatty infiltration of the liver and possibly of the pancreas, heart, kidney, spleen and lymphnodes.

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 ASA – more selective for COX1… only irreversible inhibitor…

Pharmokinetics 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

Treatment: no specific antidote 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 Please note : aspirin toxicity presents very similar to Quinidine induced Cinchonism (quinism) – flushed sweaty skin, diplopia, tinnitus, headache, nausea, vomiting, vertigo… high dose = skin rash, anaphylactic shock, blindness

A patient presents with the following symptoms: nausea, vomiting, light-headedness & dizziness. Which of the following drugs can have the above side effects? Quinidine Aspirin Digoxin Quinidine – visual disturbances, GI, CNS excitation Aspirin – seizure, cerebral edema, respiratory & metabolic pH Digoxin – anorexia, hyper-salivation, yellow or green halos, diarrhea

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. As an antiinflammatory agent, diflunisal has limited use in dentistry. As a postoperative analgesic, however, it offers advantages when a nonopioid analgesic effect against moderate pain is required.

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 Indomethacin 0.17 (IC50 of COX inhibition) Phenybutazone 7.25 Aspirin 37 Acetaminophen 660 Indomethacin adverse effects: GI irritation, hypersensitivity, leukopenia Sulindac: a sulfoxide form

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.

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. Ketoprofen: Oxaprozin:- unique among propionic acid derivatives because it can be administered once daily. Fenoprofen Flurbiprofen Ibuprofen and naproxen: In patient with rheumatoid arthritis, these drug reduce joint swelling, pain, and morning stiffness, and they improve mobility as measured by an increase in walking time. Naproxen appears to be especially effective in reducing leukocyte activity in inflammation. Ketoprofen appears to prevent lysosomal enzyme release by stabilizing the membranes of lysosomes. 25-50 mg of ketoprofen being about equivally effective for mild to moderate pain as 400 mg ibuprofen. Fenoprofen: recommended dose of 200 mg every 4-6 hrs is likely to be superior to 650 mg of aspirin. Flurbiprofen: intermediate half life (6 hrs), 50-100 mg of flurbiprofen being equal in effectiveness to 400 mg ibuprofen.

Selective COX-2 inhibitors Celecoxib (Celebrex) Rofecoxib (Vioxx) Valdecoxib (Bextra) Etoricoxib (Arcoxia) Rofecoxib – no longer used for fear of increased risk of thrombosis & MI due to increased TXA2 poduction

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. Less antiplatelet action unlike aspirin and some of the other NSAIDs. They may affect the kidneys, and should be used with care by people with kidney disease, high blood pressure, or congestive heart failure.

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.

Others Acetaminophen 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

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

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 Post operative pain – keto…. Sul = has no renal effect

Rheumatoid Arthritis 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 Ig G mediated AID Systemic Inflammation + general osteoporosis Treatment: Cyclosporine - Calcineurin inhibitor; binds cyclophilin. Blocks T-cell activation by preventing IL-2 transcription 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

DMARDS These drugs are relatively toxic, and they are reserved for patients with progressive disease, refractory cases or patients unable to tolerate standard medications. 1. Gold compounds must be injected intramuscularly.

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.

Miscellaneous agents for rheumatoid 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 Azathioprine - Antimetabolite precursor of 6-mercaptopurine. Inhibits lymphocyte proliferation by blocking nucleotide synthesis…. 6-MP degraded by xanthine oxidase; toxicity  by allopurinol 1. Penicillamine, a breakdown product of penicillin can also be used in the treatment of heavy metal poisoning. 2. Antimalarial agents useful fo rRA and Lupus erythematosus, and usually administered in conjunction with steroid hormones or salicylates. Clinical improvement is very slow, requiring 3-6 months. Serious ocular toxicity, retinopathy of dose related. Methotrexate (MTX - Folic acid analog that competitively inhibits dihydrofolate reductase →↓dTMP Ž →↓DNA synthesis

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

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 Rituximab – bind CD20 B-cells Etanercept is a decoy - TNF-α receptor and not a monoclonal antibody

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. Adenine -------hypoxanthine--X---xanthine Guanine--------xanthane-----X------uric acid----allantoin---- ------------------allantoic acid-----2 urea + glyoxylate X: xanthine oxidase

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 GOUT Overproduction of uric acid Under excretion of uric acid

Therapeutic goal of treatment Interfering with uric acid synthesis Increasing uric acid excretion Inhibiting leukocyte entry into the affected joint Administration of NSAIDs

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

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

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.

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 During therapy: maintain an alkaline diuresis Both probenecid and sulfinpyrazone are initially given in low doses, which are gradually increased until the desired serum urate concentration is obtained.