Week 8 Flashcards
Corticosteroids
– Glucocorticoids (cortisone, cortisol)
• Immune response
– Mineralocorticoids (aldosterone)
• Salt balance, blood pressure
Sex hormones
– Estrogens (estrone, estradiol)
• Secondary sexual characteristics, menstrual cycle
– Progestogens/progestins (progesterone)
• Maintaining pregnancy, menstrual cycle
– Androgens (testosterone, DHT)
• Secondary sexual characteristics, spermatogenesis, muscle mass
What are steroids chemically based on?
cholesterol • Same fused 4-ring structure • Various OH and =O groups – binding/recognition by different protein receptors, in the nucleus of cells
Are steriods polar or nonpolar?
fairly nonpolar
Estrogens and progestins
are used in:
contraceptives
and in post-menopausal HRT
(Hormone Replacement Therapy)
Premarin
– (polar) metabolites of estrogens that are readily
converted back into actual estrogens
• Mainly used as post-menopausal HRT
– Treatment for hot flashes,
vaginal discomfort/dryness
– Oral & vaginal cream forms (also IV)
• Lawsuits over possible link to breast cancer
– Manufacturer has prevailed in most of those suits
• Synthetic forms now available
ethinyl estradiol
Synthetic derivative of estradiol – Much longer half-life – Readily absorbed orally – Component of many combined oral contraceptive pills • By itself, formerly used as HRT, but discontinued (2004) due to increased endometrial cancer risks • Classed as a xenoestrogen – Excreted in urine, feces – Persists in environment, may affect fish development
Combined hormonal
contraceptives
Use an estrogen + a progestin
– Eg. ethinyl estradiol + levonorgestrel
• Work by preventing ovulation
– Also thickens cervical mucus, blocks sperm
• Placebo (or iron supplement) for 4-7 days
causes withdrawal bleeding similar to menses
• Monophasic, multiphasic versions
– Multiphasic varies dose 2-3x during the month
• Side-effects:
– Negative: Weight gain, breast tenderness,
possible increase in clotting risk (DVT, heart disease)
– Positive: protection vs ovarian cancer,
used off-label to treat PCOS, endometriosis, acne
Extended cycle pill
Monophasic, take continuously for 3 months
– Eg. Seasonale (ethinylestradiol + levonorgestrel)
– Fewer periods,
some irregular bleeding in 20-40% of women
– Same efficacy, risks as traditional COCP
• Progestin-only “mini pills”
– Taken continuously
– Stricter time requirement (+/- 3h vs +/- 12h)
– Light bleeding/spotting, sometimes at irregular intervals
– Ok for breastfeeding (estrogens suppress milk production)
Birth control implants
Release etonogestrel continuously from a
matchstick-sized subcutaneous implant
– etonogestrel is another progestin
– Typically in upper arm, lasts 3-5 years
– >99% effective
– Must be placed (& removed) by medical provider
• cost up to $800 (may be covered by insurance)
– Fewer, lighter periods, safe while breastfeeding
– Fertility returns soon after removal
– Trade names Implanon, Nexplanon
• Formerly Norplant, no longer marketed in U.S.
• Also Nuvaring vaginal ring; progestin-containing IUDs
Aromatase
Estrogens have an aromatic (benzene) ring on one end – Oxidized (loss of electrons), loss of methyl group • Produced by enzyme aromatase from androgens – Aromatase is a CYP450 enzyme – estradiol from testosterone, (estrone from androstendione)
Aromatase inhibitors
Inhibit production of estrogens,
used in treatment of breast cancers
– About 70% of breast cancers overexpress
estrogen receptor (a nuclear receptor protein)
– Low estrogen levels can cause osteoporosis
• anastrozole (Arimidex)
• letrozole (Femara)
– Also off-label use (since ~2003) as a fertility drug,
to stimulate ovulation
• PCOS—polycystic ovary disorder / androgen excess syndrome
• https://www.nih.gov/news-events/news-releases/new-treatment-increases-pregnancy-rate-women-infertility-disorder 2014
• aromatase inhibitors are NOT steroids themselves
tamoxifen
Tamoxifen is used to treat breast cancer
– Blocks estrogen receptor in breast tissue
• Antagonist
– Does not prevent estrogen production
(unlike aromatase inhibitors)
• May be less effective than aromatase inhibitors
– Usually taken long-term (10 years)
• Partial agonist of estrogen receptors in other tissues
• In bone, it can prevent osteoporosis
• It can increase risk of endometrial cancer
• Tamoxifen is a prodrug,
– metabolized by CYP2D6 and CYP3A4 into its active form
anabolic-androgenic
steroids (AAS)
Some medical uses – Growth stimulation • Today, synthetic growth hormone is used more – Chronic wasting (AIDS, cancer) – Hormone replacement, gender dysphoria • More performance-enhancing uses – Sometimes illegal, usually banned by sports organizations – Estimated 1-3 million people are thought to have misused AAS in the United States • Majority are middle-class males, noncompetitive bodybuilders
Some examples of anabolic-androgenic
steroids (AAS)
• Typically, these drugs are Schedule III, but
there are few medically needed uses
testosterone esters
• nandrolone (esters)
• stanozolol
• metadienone (Dianabol)
• trenbolone
– Used in veterinary medicine to accelerate muscle
gain in cattle & pigs
• “stacking” is use of several drugs together
Risks and Side-effects of anabolic-androgenic
steroids (AAS)
Acne, oily skin, hair loss
• Liver or kidney disease, heart disease
• Altered mood, irritability, aggression, depression
• Gynecomastia, aka “man-boobs” or moobs
– Due to conversion of androgens into estrogens by aromatase!
• Side-effects may be overstated to discourage use
– Often dose-dependent
– Non-medical issues about fairness in sports!
• Detection (in urine or blood)
– GC-MS (gas chromatography + mass spectrometry)
• Difficulty distinguishing metabolites, natural compounds
• LC-MS too (liquid…)
– Immunological assays (often for confirmation)
Delivery of anabolic-androgenic
steroids (AAS)
Oral pills, often of modified synthetic steroids
to keep liver from breaking them down quickly
• Transdermal patches
– Continuous dosing
• Nonpolar = readily absorbed through skin
– Topical creams (may wash/sweat off)
• IM Injections
– Ester of the drug is slowly broken down
to release the active (& more polar) drug
Corticosteroids
• Technically, glucocorticoids
Examples: cortisone, cortisol
• Released naturally in response to stress
• Receptors have both short-term and longer-term effects
– Cell nucleus receptors affect gene transcription
• Suppress inflammation, pain, swelling
• Suppress immune system
– (or for autoimmune treatment, transplants)
• Can also cause hyperglycemia, insulin resistance,
osteoporosis
Glucocorticoid drugs
Hydrocortisone is cortisol
– Oral, injected and topical forms all available
– Topical cream up to 1% is available OTC
• Higher topical doses (or covering the applied area)
can increase systemic absorption
• Most synthetic drugs have higher potency than
hydrocortisone
– Prednisone (and methylprednisolone) ~4x more potent
• Also has a small mineralocorticoid effect, but less than hydrocortisone
– Dexamethasone (and betamethasone) >25x more potent
• No mineralocorticoid effects with these
Inhaled glucocorticoids
Egs. Fluticasone, mometasone
- oral thrush (oral
candidiasis) a risk
Aphthous stomatitis
Non-contagious mouth canker sores • Kenalog Orabase (prescription) – Triamcinolone acetonide (corticosteroid) in a dental paste • Also Orabase (with benzocaine, OTC, no steroid) • Can sometimes become infected if left untreated
Peptic ulcers
Caused by a gap in the protective mucosal layer of the stomach or the duodenum – 4.5M/yr in U.S. – 75% duodenal, 25% gastric • Usually NOT due to overproduction of HCl • Usually due to infection with Helicobacter pylori bacteria – or to use of NSAIDs • Aspirin, ibuprofen Other contributing factors: – Smoking (>10 cigarettes/day), alcohol – stress • Symptoms: abdominal pain, especially after meals – blood in vomit, tarry feces
GERD
Gastro-esophageal reflux disease • Results from ineffective closing of the lower esophageal sphincter • Acid reflux erodes, irritates esophagus • Main symptom: frequent heartburn – Also recurrent vomiting, coughing, other respiratory issues
Helicobacter
pylori
Grows in stomach,
creates inflammation
– Burrows into less acidic
mucus lining, colonizes there
• Up to 50% of all people (25% in US) have
H. pylori, but ~85% never experience symptoms
• Effective treatment is with antibiotics (+PPI)
– Clarithromycin + amoxicillin + omeprazole
or metronidazole (Flagyl) + tetracycline + omeprazole
Managing GERD
Dietary changes
– Avoiding fatty foods, alcohol, coffee, smoking
– Smaller meals, at least 2-3h before bedtime
– Elevating head when sleeping
• Medications (more on this soon)
• Surgery to narrow or strengthen the lower
esophageal sphincter
H2 antagonists
Histamine stimulates acid production in the
stomach lining via an “H2” receptor
– Different from histamine receptors in inflammation
• H2 antagonists block this receptor, indirectly
causing less acid production by parietal cells
• Less acid lessens pain due to acid eating stomach
lining, allows ulcer to heal
– Ulcers often heal without any treatment
– Ulcers often recur due to underlying H. pylori infection
– Helps treat GERD too
H2 antagonist
examples
Main current eg: ranitidine (Zantac)
– Available OTC (higher dosages by prescription)
– Often taken hs
• Rest and digest: active acid secretion at night
Proton Pump Inhibitors (PPIs)
More effective than H2 antagonists
• Overall rationale is similar
– Directly block acid secretion
• Greater efficacy, can shut down HCl secretion in 2h
– PPI treatment allows ulcers to heal somewhat faster
• Antibiotics vs H. pylori are better in most cases
• Effective long-term treatment for GERD
– Rebound acid production after discontinuing drug
PPI examples
generic names all end in “-prazole”
– Several egs, but most popular is
omeprazole (Prilosec)
• Also esomeprazole (Nexium), pantoprazole, lansoprazole,
others
• Widely used, available generic, qd dosing
– OTC and prescription forms
• OTC usually lower dosages, but not always
– Rebound acid production after discontinuing drug
– Money-maker for drug company
antacids
Inorganic salts (bases) that neutralize acid that is
already in the stomach (and esophagus)
– Sodium bicarbonate (NaHCO3)
• NaHCO3 + HCl →H2CO3 + NaCl(aq) → H2O + CO2 + NaCl(aq)
– Magnesium hydroxide, calcium carbonate,
aluminum hydroxide too
• Immediate symptom relief
– May need to take several tablets,
depending on how much acid is present
• Effective short-term relief, especially for GERD, heartburn
– May need to be taken frequently as more acid gets secreted
– Does not treat underlying causes
a possible negative side-effect of trenbolone is
gynecomastia
Zantac (ranitidine) is an example of this class of anti-ulcer medication:
H2 antagonist
a possible negative side-effect of prednisone is
insulin resistance
H2 antagonists treat ulcers by
Inhibiting production of histamines in the stomach lining
anastrozole is used off-label to
treat gynecomastia
anastrozole is used primarily to
treat breast cancer
The most effective class of drug for long-term treatment of GERD is
PPI (proton pump inhibitor)
The class of drug for treatment of ulcers with the fastest short-term action is
antacid
levonorgestrel is used sometimes to
?prevent pregnancy, PLAN B?
NOT treat polycystic ovary syndrome
Clarithromycin is an example of this class of anti-ulcer medication:
? antibiotic? NOT PPI (proton pump inhibitor)
dexamethasone is used primarily to
reduce inflammation
a possible negative side-effect of aromatase inhibitors is
osteoporosis
The class of drug for treatment of ulcers whose use is declining is
H2 antagonist
a possible negative side-effect of stanozolol is
oily skin/acne
Sodium bicarbonate is an example of this class of anti-ulcer medication:
antacid
Pantoprazole is an example of this class of anti-ulcer medication:
PPI (proton pump inhibitor)
Long term use of PPIs could
reduce nutrient absorption efficiency due to less denaturation of
nutritional proteins, and poorer absorption of vitamin B-12 and some minerals
