Renal 2 Pharmacology Flashcards
Male Disorder A1 adrenergic antagonist drugs
Doxazosin Terazosin Alfuzosin-BPH only Tamsulosin-BPH only Silodosin-BPH only
Male Disorder 5a-reductase inhibitor drugs
Finasteride
Dutasteride
Erectile Dysfunction Drugs
-phosphodiesterase-5 (PDE5) inhibitors Sildenafil Vardenafil Tadalafil -can also tx ysubg PGE1
Benign Prostatic Hyperlasia (BPH)–what is it? Treatment?
- enlargement obstructs bladder outlet
- Tx using alpha 1 adrenergic antogonists, steroid 5alpha reductase inhibitors, PDE5 inhibitor
Lower Urinary Tract Symptoms (LUTS)
- interrupted stream
- hesitation
- frequency
- dribbling
- fullness
- urgency
- weak stream
Drugs for symptomatic relief of LUTS
- antagonists of a1 receptors
- Terazosin, Doxasozin, Tamsulosin, Silodosin, Alfuzosin
- Drug class to relax muscle tone
- dynamic remedy
- rapid relief of symptoms ~days
a1 adrenoreceptors in blood vessels
a1B more than a1A
A1 receptors in prostate
- smooth muscle contraction
- a1A
a1 receptors in detrusor
instability
a1D>a1A
A1 receptors in spinal cord
- control of urinary function
- a1D
Stimulation of genitourinary a1-receptors
mediate bladder outlet obstruction
Detrusor instability caused by =
a1D receptors + NE
Muscle contraction caused by=
a1A receptors + NE
a1 antagonists
- compete with NE
- this mechanism reduces spasm, promotes muscle relaxation and improves urine flow
Non-specific a1 antagonists
- Terazosin
- Doxazosin
- Alfuzosin
a1 antagonists specific for a1A and/= A1D
- Tamsulosin
- Silodosin
Terazosin and Doxazosin
- no uroselectivity
- adverse effects: postural hypotension, titrate 1st dose; fatigue
- Drug interaction with PDE-5 inhibitors
Alfuzosin
- uroselective (functional) (doesn’t discriminate between subtypes but tends to accumulate in prostate!)
- a1 antagonist
- adverse effects: QT prolongation
- drug interaction with CYP450
- take immediately after meal every day
Tamsulosin and Silodosin
- uroselective for a1A and a1D (a1 antagonist)
- adverse effects: reduced ejaculation; intraoperative floppy iris syndrome (IFIS)
- drug interaction with CYP450
Avoid alfuzosin in
hepatic impairment
Steroid 5a reductase inhibitors (SARI, 5ARI)
- Finasteride
- Dutasteride
- drug class that prevents enlargement and shrinks prostate
- structural remedy (slow BPH progression)
- delayed action–>shrinkage and symptoms relief ~3-6 months
Why is the prostate enlarging?
-aging puls dihydrotestosterone
Enable prostate epithelium survival and growth
- androgenic steroids, testosterone and dihydrotestosterone (DHT)
- DUT potency ~10x >testosterone
- T converted to DHT via SAR (steroid alpha reductase) types I and II
- hypertrophic prostate has ecess SARII
Steroid 5a-reductase (SAR) types I and II convert
serum testosterone to DHT in cells
Hypertrophic prostate has excess
SAR-II
DHT ‘starvation’ may cause
epithelial atrophy, shrinkage, gradual relief of LUTS
DHT starvation can be caused by
inhibiting SAR II
Direct Effects of SAR II Inhibition (Finasteride or Dutasteride)
- testosterone accumulation
- DHT depletion
Indirect Effects of SAR II Inhibition
- AR receptor less occupied
- no gene transcription
Finasteride Selectivity
-specific inhibitor of SAR II
Dutasteride selectivity
-dual inhibitor of SAR I and II
Both finasteride and dutasteride
take about 3 months for a measurable effect
- have similar efficacy
- improved LUTS, reduced prostate volume and serum PSA
- reduced need for surgery
- no dosage adjustment needed for age or renal insufficiency
- no established clinically significant drug interaction (CYP3A metabolism)
- caution with liver abnormalities
Adverse Effects of Finasteride and Dutasteride
-Erectile dysfunction, gynecomastia, depressed libido, ejaculation disturbances
Tadalafil
- phosphodiesterase-5 inhibitor
- approved for use BPH
Erectile (endothelial) Dysfunction associated conditions
-Hypertension, CAD, depression, alcohol abuse, drug abuse, endocrine disorders, diabetes, hypogonadism, trauma to pelvis or spine, hperlipidemia, LUTS, PVD, vascular surgery, smoking, anemia
Corporus cavernosum
- relaxed smooth muscle–>blood in sinusoids–>rigid organ
- neuronal input (NANC) and endothelial lining modulate smooth muscle tone
Corpus spongiosum
-NOT prominent in erectile dysfunction
Nitric Oxide and cGMP
-No interacts directly with guanylate cyclase which activates cGMP which causes smooth muscle relaxation (vasodilation) and erection
Phosphodiesterase-5
-metabolizes cGMP back into GMP
PDE-5 inhibitors
-enhance cGMP signaling by blocking metabolism of cGMP -Sildenafil, Vardenafil, Tadalafil
PDE-5 Inhibitor onset
~15 minutes (take 1 hour before)
PDE-5 Inhibitor span of efficacy
- sildenafil: 3-4 hours; t1/2 4 hrs
- vardenafil: 4-5 hours; t1/2 4 hours
- tadalafil: ~36 hours ; t1/2 18 hours
PDE-5 inhibitors clearance by
hepatic CYP3A4
PDE5 expressed in
corpus cavernosum
PDE6 expressed in
retina
- Sildenafil, vardenafil)
- adverse effect is blue vision disturbance
- take about 10fold to cause this affect
PDE1 expressed in
vasculature, heart, brain
- would take about 80 fold to cause affect
- little clinical significance
PDE11
- heart pituitary testes
- 800 fold to cause affect
PDE3
heart
-negligible effect
PDE-5 related inhibitor side effects
- headache
- dyspepsia
- nasal congestion
- sidlenafil, vardenafil, tadalafil
Tadalafil other side effects
-back pain, myalgia, limb pain
PDE-5 inhibitors contraindications
- do not use with organic nitrates!
- use of PDE-5 inhibitors concurrently with nitrates (e.g. glyceryl trinitrate) may induce extreme hypotension
- drops of 25 mm Hg have been reported, with syncope
Vardenafil and nonspecific a-receptor antagonists
- patients should be hemodynamically stable prior to initiating therapy
- initiate vardenafil at the lowest recommended dose
Tadalafil and nonspecific a-receptor antagonists
-when tadalafil is used for treatment of BPH, concurrent alpha1-blockers are not recommended.
Sildenafil and nonspecific a-receptor antagonists
-alpha-blockers should be initiated at the lowest recommended dose in patients currently receiving sildenafil
Intracavernosal injection of vasoactive drugs
- effective for treating eternal dysfunction
- papaverine, phentolamine, prostaglandin E1
- relaxed smooth muscle–>blood in sinusoids–>rigid organ
PGE1
-interacts with GPCR which activates Adenylate cyclase and activates cAMP–> smooth muscle relaxation
