Urinary incontinence/retention, bladder cancer pharm

Question 1

Adverse effects and contraindications for antimuscarinics/anticholinergics

Answer 1

AEs: 
Peripheral
-- urinary retention esp w/ BPH, 
-- CV effects (palpitaitons, tachy, prolonged QT), 
-- GI effects (mild constipation to severe obstruction)
Central
-- sedation/slow cognitive function
-- confusion/hallucinations
-- sleep disruption

Contraindications:

• • narrow angle glaucoma
• • need for mental alertness/alzheimer type dimentia
• • urinary/GI obstruction

Question 2

Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, trospium

Answer 2

ANTIMUSCARINIC DRUGS FOR INCONTINENCE

– differences: structure, t1/2, receptor specificity

Question 3

Botox use in incontinence

Answer 3

MOA: blocks proposed excitatory effect on suburothelial affarent and detrusor parasympathetic nerve endings by xSNARE complex dependent proteins

– More direct/non systemic effect!

**more successful in pts w/ GOOD ANTICHOLINERGIC RESPONSE, but intolerance to side effects

Question 4

Sympathomimetics

Answer 4

MOA: activate Beta 3 receptors @ bladder detrusor muscle = increase urine retention

Question 5

Rx used in Urinary Retention:

Answer 5

Bethanechol = muscarinic agonist, poor bioavailability and short half life
*AEs: CV (lightheaded/syncope), diarrhea, miosis/tear production, urgent desire to urinate

Neostigmine = xAcetylcholinesterase ie augments Ach action at M3 receptors, poor bioavailability and short T1/2
*AEs: AV block, bradyarrhythmia, MI, hypoTN (possible tachychardia), syncope, arrhythmias,

Question 6

Types of Incontinence

Answer 6

1. Urge/detrusor overactivity = urgency/frequency day and night, due to strokes/alzheimers/parkinsons
2. Stress / outlet incompetence = minimal urine loss w/ coughing, running, sneezing, laughing, due to urological procedures, multigravida or estrogen deficiency
3. Atonic Bladder = complete loss of bladder control, due to severe diabetic neuropathy or stroke
4. Functional = symptoms vary according to external cause such as, change in mental status, UTIs, medication
5. Mixed! = symptoms of urge/stress/overflow

Question 7

Trospium

Answer 7

MOA: anticholinergic/antimuscarinic

**QUATERNARY STRUCTURE = no BBB = no central AEs

Question 8

Darifenacin

Answer 8

MOA: M3 SPECIFIC antimuscarinic

**receptor specificity = no recorded substantially better profile

Question 9

Why do oxybutynin an tolterodine come in extended release?

Answer 9

they have a short half life (~2hrs) – have to counter short clinical effect

**ANTIMUSCARINIC drugs have very varied T1/2s

Question 10

How are antimuscarinics administered?

Answer 10

Orally – w/ hepatic metabolism to inactive products (cyps)

**EXCEPT TROSPIUM

Question 11

advantages of antimuscarinic incontinence therapies?

Answer 11

antimuscarinics:
– oxybutynin = tolterodine
– solifenacin > tolterodine
– Fesoterodien > tolterodine
…based on dry mouth / withdrawal

Extended release = reduces risk of dry mouth

Question 12

Muscarinic receptors in the bladder

Answer 12

M3 = direct smooth muscle contraction (pelvic nerve)

M2 = indirect, opposes B receptors

Question 13

Mirabegron, pseudoephedrine, ephedra

Answer 13

Sympathomimetrics
– mirabegron = beta 3 specific, cyp3A4&raquo_space; 2D6 metabolism, t1/2 = 50 hours!, HTN/tachy AEs

– psuedophedrine = direct and indirect alpha and beta agonist, minimal cyp metabolism, HTN/tachy/Afib AEs

– ephedra = indirect non selective alpha and beta agonist, HTN/tachy/CHF/MI/insomnia AEs

Question 14

Mehtionine

Bovine Collagen

Answer 14

Methionine: Controls odor in incontinence by acidifying urine = creating ammonia free urine

Bovine collagen: injected into submucosal tissue of urethra and bladder neck –> soft cohesive network of fibers/inc tissu bulk around urethral lumen
AEs: urinary retention, hematuria, injection site reaction, worsening incontinence…

Question 15

Opiate effects on urinary detrusor muscle?

Answer 15

inhibit parasympathetic outflow –> urinary retention

Question 16

CTX used for Bladder Cancer?

Answer 16

**BCG
Cisplatin, doxorubicin, Mitomycin C, Thiotepa
(all DNA alkylators!!)

Question 17

Thiotepa

Answer 17

MOA: polyfunctional DNA alkylator

• • aziridine metabolite alkylates
• • diethylenethiophosphoramide cross links DNA

Structure: small lipophillic molecule –> can penetrate urothelial tissue well

Question 18

Bladder tumor resection and drug systemization

Answer 18

– resection could compromise bladder wall strength –> inc drug systemization

Question 19

BCG

Answer 19

Bacillus Calmette Guerin = mycoplasma strain used to tx bladder cancer

MOA: activates pt’s APCs –> induces production of effector T cells –> peak response @ 6-24 hours but sustained effect for months (w/ periodic cycles of dosing)

**REQUIRES INTACT IMMUNE SYSTEM!!

Question 20

Intravesicular effects of Mitomycin and Thiotepa? DLTs?

Answer 20

intravesicular:
Mitomycin = chemical cystitis + palmar/plantar erythema (probably due to contact during subsequent micturation)
+ Pulmonary infiltrates/dyspnea!!

Thiotepa = dysuria, urinary retention, chemical/hemmorhagic cystitis, renal dysfunction

DLTs: PANCYTOPENIA for both