Pharmacology: GU Agents
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| What are the most frequently encountered organisms in a lower UTI and where do they originate from? | E. coli (80%) from GI. Staphylococcus saprophyticus (4%) from skin. Klebsiella pneumonia from GI. Proteus mirabilis from GI.
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| Risk factors of lower UTI (9) | 1) Recent sexual intercourse, 2) urinary catheter, 3) delayed micturition, 4) diabetes, 5) spinal cord injury, 6) pregnancy 7) Immunodeficiency 8) elderly 9) lack of circumcision
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| Urinalysis: how it is performed and what is can be positive for | performed on clean catch midstream. Picks up blood, leukocyte esterase, nitrates, protein
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| Most specific and sensitive test for UTI | Urine Cx w/ sensitivity. IDs infecting organism which enables modification of Tx based on antibiotic susceptibility. Used for pyelonephritis and recurrent UTI
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| Uncomplicated UTI case Tx | Trimethoprim/Sulfamethoxazole (Septra/Bactrim) 3-7 days. If allergies, 3-7 days of a fluoroquinolone (Cipro). Cefpodoxime (3rd gen cephalo; can turn urine blue). Adjunct: phenazopyridine: urinary anesthetic w/ adverse of orange urine (Hemolysis in G6PD)
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| Sulfamethoxazole and Triethoprim MOA and Clinical Applications | Sulfa: inhibits dihydropteroate synthase. Tri: inhibits dihydrofolate reductase. Each is bacteriostatic, together bactericidal. CA: DOC for pneumocystics carinii pneumonia; used in skin/soft tissue MRSA infxs, acute or chronic UTIs
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| TMP-SMZ Adverse: | GI, Hematologic (leukopenia, thrombocytopenia, eosinophilia), hypersensitivity (rash->Stevens-Johnson), CNS, Hemolysis if G6PD deficiency
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| Fluoroquinolones: static or cidal? Absorption, Distribution, Efficacy | concentration-dependent bactericidal activity (inhibit DNA topoisomerases), good oral bioavailability, extensive tissue distrubtion, 96% success rate but adverse are stronger than Septra
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| Fluoroquinolones: Adverse | General GI, General CNS (seizures common in elderly), hepatotoxicity, prolongation of QT interval, tendon rupture (don't use below 16 or over 60), hyperglycemia
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| Nitrofurantoin: Absorption, Adverse, Use, MOA | crosses placental barrier and into breast milk, ^ bioavailability w/ food; GI, brown urine, Hemolysis in G6PD deficiency; DOC in pregnancy; inhibits formation of acetyl CoA from pyruvic acid inhibiting energy absorption in bacteria
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| Phenazopyridine: Use, Adverse | Sx relief (topical analgesic effect); Azo dye rapidly excreted in urine; ORANGE URINE, methemoglobinemia follows massive overdose, animal carcinogen.
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| Complicated cystitis: 2 infx possibilities and respective Txs | 1) Indwelling catheter- get rid of it ASAP, only Tx Sx pts. 2) Candiduria: again, Tx Sx pts, fluconazole or amphotericin if resistant
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| Complicated UTIs | Fluoroquinolone for 7-14 days, phenazopyridine for Sx, Nitrofurantoin 7 days for preg (all else CONTRA in pregnancy).
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| Pyelonephritis: Sx, Dx, Tx, Complications | Infx of kidney; constitutional Sx; Dx: urinalysis, urine Cx, CBC, chemistry; Tx: 14 days of Septra or fluoroquinolone; Complications: perinephric/renal abscess, nephorlithiasis
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| Prostatitis: Sx, Dx, Tx, RF | Sx: pain in perineum, lower abdomen, testicles, penis, ejaculation, bladder irritation, obstruction, blood in semen. Dx: clinical Hx, increased PSA, urinalysis/urine Cx. Tx: 4-6 weeks of Septra/fluoroquinolone. RF: trauma, sex abstinence, dehydration.
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| Fosfomycin: MOA, use, General | Novel ABX inhibits enolpyruvyl transferase to block first step in bacterial cell wall synthesis. Distributed to kidneys, bladder wall, seminal vesicles, prostate, 77% effective in uncomplicated Tx of E. Coli and other enterococcus UTIs
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| Pregnancy Categories (A, B, C) for Pharmaceuticals | Category A: adequate and well controlled studies have failed to demonstrate risk (hardly any human studies here). Category B: Animal reproduction studies have failed to demonstrate risk to fetus (most common). Category C: Adverse effect on animal fetuses
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| Pregnancy Categories (D, X) for Pharmaceuticals | Category D: positive evidence of human fetal risk based on marketing or investigational experience or studies in humans. Category X: Studies in animals/humans have demonstrated fetal abnormalities, risks >>>benefits.
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| Short background on G6PD. Who expresses it? | Some survival advantage during malaria infx. Sex-linked genetic disorder w/full expression in males and partial expression in females. Risk for hemolytic anemia w/ exposed to certain drugs/oxidizing agents.
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| 2/400 G6PD Genetic Variants | A-: variant affects 10-% of AAs, most common form of G6PD deficiency, smaller risk of hemolysis, still some enzyme activity. B-: most common in Mediterranean descent. More severe w/ higher likelihood of severe hemolysis...almost no enzyme activity.
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| Clinical implications of hemolysis of G6PD deficiency; Complications of hemolysis; Tx; which variant is more severe? More common? | life threatening; -> acute renal failure and HF; Tx: blood transfusion and hemodialysis; B- is more severe and A- is more common.
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| Drugs that should be avoided w/ G6PD deficiency (just a few common ones) | Sulfa drugs, nitrofurantoin, methylene blue, nalidixic acid, phenazopyridine
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| Complicated UTI cause and Tx in men | abnormal anatomy, BPH, catheter-associated, stones, anal intercourse, STD-related urethritis; Tx: fluoroquinolone 7-14 days.
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| Recurrent disease (what to eval and Tx) | evaluate for UT abnormalities; ABX prophylaxis: low dose septra or nictrofurantoin daily/postcoital (resistance will eventually form); hygiene and urination timing education.
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| Cranberries | High dose of cranberry taken in form of pill/concentrates shown to have modest (30%) decrease in incidence: contain proanthocyanidins that inhibit attachment of fimbriae to bladder wall.
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| T/F: Consuming citric acid will make urine more acidic, making it less favorable of an environment for bacteria. | False. Citric acid will actually make urine more alkaline! Formanic acid, which is in cranberries, actually acidifies urine, making it less favorable of an environment for bacteria.
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| Stress Incontinence: definition, cause, Sx, Dx pearl | loss of urine w/increases in abdominal pressure caused by pelvic floor damage or weak sphincters, Sx: loss of urine w/ cough, laugh, sneeze, running, lifting etc. Dx Pearl: pt will cross legs or adduct thighs when sneezing/coughing.
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| Urge Incontinence: definition, Sx, Cause | loss of urine due to involuntary bladder contractions/spasms; Sx: urgency, frequency (56 times/week), inability to reach toilet in time, nocturia. Multiple triggers cause (not single event).
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| Chronic Urinary Retention: Cause, Sx | (Overflow) Outlet obstruction or bladder underactivity presenting w/ Sx of urge/stress incontinence and continuous leakage. Caused by previous surgery, aging, poor bladder habits, neurologic disorders, medications (tricyclics: anti-cholinergic activity)
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| Functional/Transient Incontinence: | Mostly in elderly (neurogenerative conditions, medications, psych deficiency, constipation, restricted mobility)or with a UTI
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| Muscarinic Receptor Destribution | Only way to treat bladder is to block entire muscarinic system so we must balance between bladder and adverse effects (blurred vision, dry eyes/mouth, tachycardia, dyspepsia, constipation)
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| Main categories for Tx urinary retention | 1) Direct Acting: stimulate cholinergic receptors: choline esters (acetylcholine) and alkaloids (pilocarpine). 2) Indirect-acting: choinesterase inhibitors: Carbamates and Phosphates
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| Single drug used most for urinary retention? | Bethanechol
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| Pilocarpine: what does it do? | stimulates muscarinic system, isolated in 1875 and methacholine/carbachol studies were done in 1911.
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| Bethanechol: how it works, Antidote, CONTRAs, Adverse | stimulant of smooth muscle of GI tract/urinary system (expels urine). Atropine/epinephrine can antidote overdoses/poor responses. CONTRA: asthma hyperthyroidism (AFib), HF, PUD, coronary insufficiency; Adverse: SWEATING, bladder tightness
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| Deadly Nightshade | natural anti-muscarinic; pupil dilation, poison, related to chili peppers, potatoes, tobacco, jimson weed; atropine was purified from this in 1831
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| Main difference between the original muscarinic antagonists: | Atropine doesn't cross BBB; Scopolamine crosses BBB super easy
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| What 3 glands are most sensitive to atropine? Intermediately? | Salivary, bronchial, sweat; smooth muscle and heart
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| 4 qualities an ideal muscarinic receptor agonist would have if it were to exist. | 1) Efficacious (inhibit involuntary bladder contrations w/o effecting urination 2) Organ selective 3) Durable effects 4) Clinical effectiveness
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| Oxybutynin: Duration, Adverse, Effectiveness, Contra | comes in intermediate and long lasting forms; EXTENSIVE first pass metabolism. Adverse: COGNITIVE impairment, tachycardia, U. retention (66% reduction in incontinence episodes per week. CONTRA in obstructive uropathy and angle-closure glaucoma
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| Oxybutynin Transdermal: Benefit, Adverse, Effectiveness/Summary | avoids first pass metabolism; Adverse: less dry mouth (parotid), 15% site pruritis but lower adverse including cognitive; 50% reduction in weekly incontinence. Sum: Good 24 relief over 24 hours, but not quite as effective. Good for those that forget.
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| Oxybutynin Gel: Benefit, Use, Effectiveness, Adverse | avoids first pass metabolism; q24 hours; reduced urinary incontinence by less than 50% (not as effective as others); Adverse: similar to transdermal product
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| Tolterrodine: Adverse, CONTRA, Effectiveness | Adverse similar to oxybutynin (dry mouth, HA, somnolence (COGNITIVE IMPAIRMENT, constipation), QT prolongation; CONTRA: angle-closure glaucoma, obstructive uropathy; Expect 50% reduction of incontinence (same as oxybutynin transdermal)
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| Solifenacin: Benefit, Adverse, Effectivness | Benefit: less cognitive impairment! Adverse: constipation/obstruction, dry mouth all dose dependent and at similar rate to oxbutynin. 30-50% reduction in incontinence episodes a week.
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| Trospium Chloride: Difference in MOA, Benefit, Effectiveness | Quaternary amine as opposed to tertiary amine. Benefit: Theoretically harder to pass through BBB -> fewer adverse. Not metabolized by liver so ideal for those w/liver disease. 50% reduction in incontinence episodes a week.
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| Darifenacin: Benefit, Adverse, Effectiveness | Greater affinity for M3 (targets visceral receptors) therefore having less CNS effects. Adverse: constipation and dry mouth dose dependent. 30-50% reduction in incontinence/week.
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| Fesoterodine Fumarate: What it treats, Benefit, Adverse, Summary | Tx of overactive bladder (urge incontinence), prodrug of Tolterodine but DOESN'T have the QT prolongation. Adverse: similar antimuscarinic adverse as others but more dry mouth. Sum: $$$ and not very effective, increasing dose -> effect other receptors
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| Mirabegron: MOA, Effectiveness, Adverse | Beta 3 agonist, relaxes detrusor smooth muscle during storage phase, increases bladder capacity relieving urge incontinence (50%). Low activity on B1 and B2 except at high doses. Adverse: Lowest anticholinergic effects, so beast if adverse unbearable.
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| Stress Incontinence: 1st 2 steps in Tx approach | 1) Kegals/water intake management/lifestyle changes 2) Medications: Pseudoephedrine (^urethral contraction; Advse: HA, tachycardia, ^BP; CONTRA in CVD/PVD) Intravaginal Estrogen (strengthens periurethral tissue; Advse: ^ endometrial Ca and DVT)
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| Stress Incontinence: Next steps to Tx approach after exhausting 1st 2. | Surgery (pelvic mesh, Adverse: ->inflammation -> infx); Equipment: Pessary (useful in prolapse, elevates bladder neck correcting vesicourethral angle), Occlusive Devices: Most effective non-surgical Tx: 80-84% cure rate. For SIGNIFICANT stress incont.
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| Periurethral bulking agents: | Injection of collagen or beads under cystoscopy restablishing correct alignment of urethra. 40% cure rate, 67% improved.
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| Artificial Sphincter | 3 piece device includes a cuff encircling urethra, pump controlling the device, pressure reservoir placed inside pelvis.
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| What works best for each type of incontinence | Urge/Overactive Bladder: anti-muscarinic and Beta 3 agent. Stress: bulking or surgery unless you can gain control w/ exercises for pelvic floor or w/ psudos.
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| T/F: Benign Prostatic Hyperplasia (BPH) is the main cause of lower urinary tract Sx (LUTS) in older men. | True
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| T/F: By the age of 90 yo, disease is almost universal in men | True
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| Clinical Presentation of BPH (7) | 1) Interruptions in stream 2) Hesitation beginning 3) Terminal dribbling 4) Urgency 5) Weak stream 6) Tenesmus 7) Nocturia
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| Complications of BPH (4) | 1) Urinary retention: inability to void, bladder stones, frequent UTIs. 2) Urinary incontinence 3) Renal failure due to obstructive uropathy (hydroureter/hydronephrosis (fluid back up) 4) Hematuria
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| 2 components of Bladder Outlet Obstruction | 1) Dynamic: due to smooth muscle tone in bladder neck, capsule and stoma of prostate, regulated by alpha receptors. 2) Static: due to mechanical compression from increased prostate size regulated by DHT (dihydrotestosterone)
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| 2 General BPH Tx options | 1) Alpha blockers: Sx relief for BPH by relaxing smooth muscle in prostate, bladder neck, and prostatic urethra. (can cause significant hypotension). 2) 5a reductase inhibitors: inhibit conversion of testosterone to dihydrotestosterone (DHT)
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| Alpha Blockers | DOC as it relieves Sx in one day. Agents end w/ -osin. Adverse: orthostatic hypotension, tachycardia, edema, chest pain, CNS Sx, GI Sx, Intraoperative floppy iris syndrome (IFIS) (Tamulosin implicated 80% of time). Selective blockers minimally effect BP.
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| T/F: All Alpha Blockers reduce hypertension. | False: non-selective blockers like Doxazosin and Terazosin are indicated in Tx of HTN. Careful w/first-dose phenomenon. Selective blockers like Alfuzosin, Tamsulosin, Sildosin are not indicated for HTN Tx and act mainly on urethral muscle.
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| Alfuzosin HCL (Uroxatral) | Adverse: HA, dizziness, fatigue, URI. Take immediately after same meal each day. Avoid use with other Ablockers. Improves U. voiding Sx by decreasing post void residual urine. Very useful in acute U. retention. More specific for urinary tract receptors.
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| Tamsulosin HCL (Flomax) | Side effects include: Headache, dizziness, somnolence, diarrhea, fatigue, back pain. May have lower probability of orthostatic hypotension - More specific for urinary tract receptors. doesn’t have to be taken at a specific time.
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| Doxazosin mesylate (Cardura) | non-selective. Adverse: HA, dizziness, orthostatic hypotension, somnolence, edema, fatigue. Dose titration required and bedtime dosing may decrease orthostatic hypotension. Higher incidence of CHF in men with hypertension and cardiac risk factors.
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| Terazosin HCL (Hytrin) | non-selective. Adverse: Asthenia (lack of strength/energy), postural HypoTN and syncope initially, dizziness, dyspnea, somnolence, nausea, peripheral edema, thrombocytopenia, Afib. Dose titration required and bedtime dosing may decrease O HypoTN.
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| 5a reductase: General | Converts testosterone -> dihydrotestosterone (DHT).
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| DHT: | active and stronger metabolite of testosterone, main androgen regulating prostate fn and size.
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| 5a Reductase inhibitors: General, use, CONTRA | 6-12 months before Sx improvement noticeable. Synergistic w/ alpha blocker. CONTRA: handling in pregnant women
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| Prostate function is primarily in in type I 5a-reductase. | False, primarily Type II. Type I: skin, liver, adrenal. Type II: Hair, liver, seminal vesicles, prostate, epididymis, genital tissues
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| T/F: To attain near complete DHT suppression requires inhibiting both types of 5a-reductase isoenzymes. | True, this suppresses DHT enough to reduce prostate volume. This is actually not ideal though as suppressing both types will have adverse effects.
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| Finasteride: General, Time to reach steady state, Use, Adverse | Suppresses 5a-reductase type II, reducing DHT by 70%. Takes 3 weeks to reach steady state. Small dose improved flow rate and decreased prostatic volume. Adverse: gynecomastia, impotence, decreased libido, possible increase in male breast Ca.
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| Dutasteride: General, Time to reach steady state, Use, Adverse | Inhibits both isoenzymes of 5a-reductase reducing levels of DHT by 95%. Steady state reached in 3 months. Adverse: P450 inhibitors greatly ^ blood levels of this. Prostate volume decreased 26%, flow rate 2x. Adverse: ED, gynecomastia, "don't feel good"
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| T/F: Combining Alpha blockers and 5a-reductase inhibitors has a null effect on outcome. | False, there is a substantial synergistic effect on BPH outcome.
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| T/F: Pts taking Finasteride prophylatically had a lower incidence of prostate cancer but a higher grade tumor if they did get it. | True; Finasteride can mask tumor
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| Alternative BPH Tx | Saw Palmetto: appears to possess 5a-reductase activity and inhibitory effects on androgen receptors. Study of 5666 men saw that even at 2x or 3x usual dose, no improvement was found
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| PDE5 Inhibitors | Inhibitors of phosphodiesterase-5 break down cGMP enhancing smooth muscle relaxation. Tadalafil (cialis) is only FDA-approved agent at this time. Less likely to cause any sexual impact, in fact, it's indicated for ED. Adverse: occur w/nitrates, $$$
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| Erectile Dysfunction: General and some physical causes | 19-64% of 40-65 yo experience on long term basis. Alcohol and tobacco use, fatigue, CNS injuries, hypogonadism, liver/kidney failure, MS, Parkinson's, Radiation therapy of testicles, stroke, prostate/bladder surgery
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| Top 4 Reasons for ED | 1) Psychogenic 2) Physical 3) Alcohol 4) Fatigue
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| Penis Vasculature | Arterial Supply: derived from pudendal artery; cavernosal arteries run down center of each corpus cavernosum. Venous Drainage: compressed during erection.
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| Penis Neuroanatomy: PNS, SNS | PNS: responsible for vasodilation and penile arteries/erection. SNS: maintains flaccidity.
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| Mechanics of Erections (6) | 1) Sexual stimulation 2) Decreased peripheral resistance (NO release) 3) Increased arterial blood flow 4) Raised intracavernosal pressure 5) Relaxation of vascular smooth muscle (cGMP) 6) Lacunar engorgement and erection
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| Losing an erection | PDE5 breaks down cGMP, preventing relaxation of smooth muscle -> pressure on veins released, allowing outflow from corpora cavernosae
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| Possible tests for investigation of ED (4) | Rigiscan (nocturnal tumerscence monitoring- determines whether physiological erection is possible). Doppler Ultrasound (for vascular ED). Cavernosography: venous leak detection, uses injected contrast media :(. Postage Stamp method.
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| Routine laboratory tests for ED | Screen for 1) Diabetes 2) liver disease 3) renal disease 4) testosterone levels 5) Fasting Lipids 6) Glucose 7) Androgens
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| Normal Nocturnal Erections | Maintenance erections, 4-5 a night lasting around 10 minutes, testosterone dependent, can occur when bladder is full, don't represent actual sexual activity.
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| Psychogenic vs Organic ED (physiological) | P: Sudden onset, complete/immediate loss, AM erections presents, varies w/circumstance/partner. O: Gradual, progressive, lack of AM erections, lack under most sexually stimulating circumstances
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| Intracavernosal Injections: Products and General | produce cavernosal smooth muscle relaxation. Prostaglandin E1 (Caverject): potent vasodilation. Papaverine: opium alkaloid inhibiting phosphodiesterases. Not as reliable but option. Gen: NO SEXUAL STIMULATION REQUIRED, lasts 30 min, takes 3 min to start.
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| Which ED Tx methods are best for spinal cord injury or diabetic neuropathy? | Intracavernosal injections, intra-urethral pellets, Vacuum devices
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| Intra-urethral pellets | Easy/discreet administration, NO STIMULATION REQUIRED, onset 20 min, lasts 30 min.
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| Adverse of PGE1 use (injections and pellets) | Hypotension/syncope/flushing, urethral bleeding, bleeding at injection site, painful erection, persistent erection, possible overdosing
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| PDE5 Inhibitors: MOA, Onset, Adverse | blocks "off" switch" (cGMP is not broken down); active SEXUAL STIMULATION NECESSARY, 1 hour prior to intercourse, dose balances erection and hypotension. 70-90% effective. A: $$$, blue tinting of vision, incredible HA, mucous membranes edematous, HypoTN
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| Apomorphine: General, Onset, Adverse | not approved for ED in USA; dopamine agonist works in CNS to heighten response to sexual stimulus (WHICH IS NECESSARY), onset: 30 min. Adverse: N/V, PROFOUND HypoTN w/ondansetron.
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| Yohimbine | strongly binds to all alpha receptors, "variable" benefit at best. NARROW margin of safety. Adverse: HTN, panic & anxiety attack, tachycardia, HAs, seizures and renal failure (possible but rare)
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| 4 hour long erection: | Medical emergency due to fibrosis and possible gangrene of corpora. Tx: aspirate 50 mL of blood. Recur? Use phenylephrine alternating btwn taking some blood out and putting phenyl in. Press firmly for 5 minutes to prevent hematoma. Urologist referral.
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| Spanish Fly | actually a beetle indigenous to Europe. Caustic Canthridin causes burning/swelling of UT misconstrued as sexual stimulation. Toxic.
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| Raw Oysters | Would require 50 oysters to obtain low levels of stimulate. Amino acids from those 50 oysters would incrase NMDA and D-Asp which would stimulate testosterone in men (progesterone in women)
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| Zallouh | Middle Eastern plant aphrodisiac reputed to enhance male sexual behavior when ingested. Dose dependent effect on ED, but acute/subacute toxicities have been observed including wt loss, hepatomegaly, testicular atrophy, anemia. Total cholesterol decreases
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| Vacuum devices/pumps | Suction draws blood into penis, band put around penis (can only stay on there for 30 min) maintaining erection above band.
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| Surgical Tx for ED | Last resort. $$$ and permanent. Hydraulic (inflatable cylinders placed in penis w/ inflating bulb. Non-hydraulic: semi-rigid removable rods.
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| Counseling points for pts getting inflation devices | 1) prosthesis not as good as original 2) adequate for penetration, but not full erection 3) small rate of infx 4) penis will be cold 5) ejaculation still possible
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