Konorev Flashcards
What are the alpha-1 adrenergic antagonists - types (generations) used to treat BPH?
What adverse reaction to both types cause?
second generation and third generation blockers
Both cause nasal congestion and flu-like symptoms.
What are the alpha-1 adrenergic antagonists - SECOND GENERATION blockers (3) used to treat BPH?
What are the adverse effects of these?
DAT (zosin) Doxazosin Alfuzosin Terazosin Causes syncope, dizziness, hypotension.
What are the alpha-1 adrenergic antagonists - THIRD GENERATION blockers (2) used to treat BPH?
What are the adverse effects of these?
TS (osin)
Tamsulosin
Silodosin
Causes ejaculatory dysfunction.
What are the 5-alpha reductase inhibitors used to treat BPH?
DUTe, that’s FINA (asteride)
Dutasteride
Finasteride
What is the normal MOA of alpha-1 AR (in BPH)?
What is the result?
Activation of a-1 AR results in IP3 and DAG accumulation, resulting in CONTRACTION of SMOOTH MUSCLE.
What is the result of alpha-1 adrenergic antagonists (in BPH)?
Inhibition of contraction of smooth muscle in vasculature, prostate, and other organs.
What is the first choice tx for BPH?
Does it reduce prostate size?
A-1 adrenergic antagonists
Does NOT REDUCE prostate size.
Are 5a-reductase inhibitors or alpha-1 antagonists more:
Faster acting and more effective.
Associated with less sexual dysfunction.
Faster acting - alpha-1 antagonist
Less sexual dysfunction - alpha-1 antagonist
What three receptors do second generation a-1 antagonists block?
Potently does what?
alpha-1A AR
alpha-1B AR
alpha-1D AR
Potently relax sm muscle in vasculature and prostate.
What second generation a-1 antagonists cause S/E of orthostatic hypotension, first-dose syncope, dizziness?
Terazosin and Doxazosin
What second generation a-1 antagonist is more UROSELECTIVE? Why is it uroselective?
What does it not require?
Alfuzosin is uroselective because of its pharmacokinetics, not AR subtype selectivity
It does not require dose titration.
What is dose titration?
Performed over several weeks after initiation of therapy.
Is Tamulosin more selective for alpha-1A AR or alpha-1B AR?
Where are they preferentially located?
greater selectivity for alpha-1A AR
alpha-1A AR located in PROSTATIC SMOTH MUSCLE
alpha-1B AR located in VASCULATURE
Tamulosin used to BPH patients with what condition?
Orthostatic HYPOTENSION
What third generation a-1 antagonist is a HIGHLY SELECTIVE inhibitor of alpha-1A AR?
What does this drug NOT CAUSE?
Silodosin
DOES NOT CAUSE ORTHOSTATIC HYPOTENSION
What are the drug interactions of alpha-1 antagonists with:
PDE5 inhibitors?
Cimetidine, Diltiazem?
Carbamazepine, PHT?
PDE5 inhibitors - marked systemic hypotension
Cimetidine (ulcers), Diltiazem (HTN) - DECREASED METABOLISM of alpha-1 antagonists
Carbamazepine, PHT - INCREASED alpha-1 metabolism
Which 5a-reductase inhibitor is nonselective?
Which is selective?
And for what types?
Finasteride is SELECTIVE, Type 2 (only) reductase inhibitor
Dutasteride is NON-SELECTIVE, (Type 1 and 2) reductase inhibitor.
MOA of 5a-reductase
TESTOSTERONE and other adrenocortical androgens CONVERTED TO DHT by 5a-reductase
Is DHT or testosterone a more potent androgen?
DHT is more potent than testosterone
MOA of 5a-reductase inhibitor.
- Inhibit formation of DHT in the prostate tissue by PREVENTING ANDROGEN RECEPTOR ACTIVATION
- SHRINK PROSTATE by 20%
Is type 1 or 2 5a-reductase responsible for epithelial tissue enlargement in the prostate?
Type 2!
Where are Type 1 and 2 5a-reductase localized to?
Localization:
Type 1 - skin, hair follicles, liver
Type 2 - prostate, genital tissue, scalp. RESPONSIBLE FOR EPITHELIAL TISSUE ENLARGEMENT IN PROSTSATE
Is 5a-reductase inhibitor or a-1 antagonist considered second-line BPH treatment, and what about its effect makes it this?
5a-reductase, because its effect is due to actual reduction in size of prostate and blockage of further enlargement.
5a-reductase epithelial volumes (cc) and timeline
Baseline
Intermediate
Endpoint
Baseline - 6cc
Intermediate, 6-18mo - 3.3cc
Endpoint, 24-30mo - 2cc
What class should be used for a patient with:
- Enlarged prostate of 40g or MORE.
- Patients with contraindications to adrenergic antagonists.
5a-reductase inhibitors be used
What combo therapy should be used when person has large prostate and a PSA of more than 1.4ng/ml?
Reductase inhibitors and a-1 antagonist
Adverse effects of 5a-reductase inhibitors (4)
- SEXUAL DYSFUNCTION (disorder of ejaculation, erectIle dysfunction, decreased libido)
- TERATOGENIC AFFECT
- Reduce prevalence of prostate cancer, but INCREASE RISK OF HIGHER GRADE, INVASIVE PROSTATE CANCER
- Gynecomastia, muscle weakness, abdominal pain
What drugs exacerbate BPH manifestations (3)?
- Testosterone replacement therapy (because you increase amount of possible DHT that can be made)
- a-adrenergic AGONISTS - oral and nasal decongestant (phenylephrine, ephedrine, pseudoephedrine)
- Drugs with ANTIMUSCARINIC ACTIVITY (decrease sympathetics)
What drugs have anti-muscarinic activity?
Antihistamine drugs
Tricyclic antidepressants
Phenothiazine antipsychotic drugs
Atropine and other muscarinic antagonists
Anti-parkinson’s cholinergic antagonist drugs
Types of erectile dysfunction (ED) (3).
Psychogenic
Drug induced
ORGANIC ED
What percent of pts with ED have organic type?
What are types of organic ED?
70-80%
Hormonal - low Testosterone
Neurologic - nerve impulse impairment
Vascular - atherosclerosis, diabetes, HTN
When do you use testosterone replacement regiments for organic ED?
When do you NOT use testosterone replacement regiments for organic ED? What should you use instead?
Use for patients with DECREASED LIBIDO and LOW SERUM TESTOSTERONE levels - these patients have primary or secondary HYPOGONADISM.
Never use testosterone replacement in patients with normal gonadal function. Use drugs that RELAX the corpus cavernosum SMOOTH MUSCLE.
Drugs used for ED - phosphodiesterase type 5 inhibitors.
Mode of delivery and names (3).
Onset and duration of action.
Oral
(-afil)
SILDENAFIL, VARDENAFIL - onset in 1 hour, 5-6 hour duration
TADALAFIL - DELAYED ONSET (mroe than 2 hours), but PROLONGED DURATION (36 hours)
Drugs used for ED - PGs
Mode of administration and names (1). And what is it an analogue of?
Intracavernosal injection (caverject) or intrauretheral delivery (MUSE) Alprostadil, PGE1 analog
Drugs used for ED - unapproved agents. Name and mode of delivery: 1. alpha antagonist 2. Nonspecific phosphodiesterate inhibitor 3. Antidepressant
- Phentolamine, intracavernosal injection
- Papaverine, intracavernosal injection
- Trazodone, oral
MOA of erection (normal)
MOA of phosphodiesterase type 5 inhibitors (for ED)
Normal erection: Sexual stimulation»_space; Nitric Oxide from NANC NEURONS or endothelial cell»_space; (smooth muscle) GC»_space; cGMP»_space; sm m relaxation»_space; erection
PDE-5 Inhibitor prevents PDE-5 from breaking cGMP down into GMP so that cGMP can go on to stimulate erection
What are adverse affects of all PDE-5 inhibitors?
Hypotension HA, dizziness Facial flushing Priapism Sildenafil and Vardenafil - visual defects (blue/green discrimination and vision loss)
Adverse effects of Sildenafil and Vardenafil? Due to inhibiton of what?
Visual defects - loss of blue/green discrimination, vision loss.
PDE-6 inhibition
Adverse effects of Tadalafil? Due to inhibition of what?
Muscle pain in lower back and limbs due to PDE-11 inhibiton
- Combination of what two things cause possible severe hypotension and MI?
- Combination of what two things cause possible orthostatic hypotension?
- Use caution with what else in combo with PDE-5 inhibitor?
- NITRATES and PDE-5 inhibitors
- Ethanol and PDE-5 inhibitor
- alpha-1 antagonists (Prazosin and Doxazosin)
MOA of Alprostadil (PGE1 analogue) - acts via what receptor to do what?
Acts via EP2 receptor (GPCR) to initiate smooth muscle relaxation.
When do you use alprostadil?
Efficacy?
Lower or higher potential for priapism?
Use when PDE-5 inhibitors are NOT EFFECTIVE.
70-90% effective
Lower potential for priapism
Adverse effects of alprostadil (4).
PAIN and BURNING SENSATION at injection site.
Formation of FIBROTIC PLAQUES at injection site.
Hematomas and bruising at injection site.
Priapism
Algorithm for tx of patients with ED, but normal serum testosterone.
PDE Inhibitors, then if ineffective»_space; INTRACAVERNOSAL tx, then if ineffective»_space; INTRAURETHRAL Alprostadil
FLIBANSERIN - Dx, MOA (what part of NS and what receptor agonist/antagonist), and Clinical Use (indicated for what disorder)
Dx - enhanced sexual desire
MOA - acts on CNS, 5HT1A receptor agonist, 5HT2A receptor antagonist
Clinical - indicated for HSDD - hypoactive sexual desire disorder
FLIBANSERIN - adverse effects
dizziness, nausea, sleepiness, fainting (esp with alcohol use)
FLIBANSERIN - contraindications
USe with alcohol
Live damage
Concomitant use of strong CYP3A4 inhibitors.
What would you use CYP3A4 inhibitors for?
antiviral protease inhibitors, macrolide antibiotics, antifungal azoels
(UI)
Detrusor muscle controlled by what part of the NS and what receptor type?
ANS
Cholinergic M3 Receptor
(UI)
Intrinsic sphincter controlled by what part of the NS and what receptor type?
ANS
alpha-1 AR
(UI)
External sphincter is what and controlled by what?
Skeletal muscle
Under conscious control
What are the types of UI (2)? Under/over activity of what?
(1) (SUI) Stress Urinary Incontinence - underactivity of urethra. Occurs during PHYSICAL EXERTION.
(2) (UUI) Urge Urinary Incontinence - overactivity of bladder. DETRUSOR MUSCLE OVERACTIVE and contacts inappropriately.
What drugs aggravate UI manifestations?
**LOOK AT NEURO NOTES FOR MUSCARINIC LIST
durietics
AChE Inhibitors (result in increased ACh)
Muscarinic agonists
alpha-1 antagonists
alpha-2 agonists (clonidine, methyldopa, guanfacine, guanadrel)
ACE inhibitors - incessant cough leads to stress UI
UUI - what is the goal and what drug classes are used?
Goal is to RELAX the overactive detrusor muscle.
Use MUSCARINIC ANTAGONIST and indirect anticholinergic drugs.
SUI - what is the goal and what drug classes are used?
Goal is to improve function of the intrinsic sphincter.
Use ALPHA1-AGONIST, antidepressants, estrogens (in females)
Types of muscarinic antagonists used for UUI:
Non-selective muscarinic antagonists (2)
M3R selective antagonists (4)
Non-selective muscarinic antagonists (2):
OXYBUTYNIN - most commonly used UI drug
Trospium
M3R selective antagonists (4):
Darifenacin, Solifenacim, TOLTERODINE (drug of choice), Fesoterodine
Fesotoerodine yields the same metabolite as what other M3R selective antagonist?
Which metabolizes faster?
Tolterodine
Tolterodine
Adverse actions of muscarinic antagonists
Dry mouth, constipation, dry eyes, tachycardia, cognitive impariment/confusion/memory loss, vision impairment
Types of Indirect Anticholinergic drugs used for UUI
BOTOX
What is MOA of Botox?
What is the result of botox injection?
Botox clinical use - What muscle and what type of injection, length of action?
MOA - Inhibits release of ACh form presynaptic terminal,
Result - paralyses both sk and sm muscle.
Clinical - local injections into detrusor muscle, paralysis lasts 3-9 months
What causes detrusor underactivity and urinary retention?
Botox overdose
What type of agonist is ephedrine and what is its MOA (what NT is released, direct/indirect, selective/non)?
NE releasing agent and weak, direct, non-selective adrenergic receptor agonist.
What type of agonist is Midodrine and what is its MOA (i.e. what sphincter does it affect, what does it cause in smooth muscle of urethra and bladder base)?
alpha-1 AR selective agonist
MOA - improves function if INTRINSIC SPHINCTER, causes CONTRACTION of sm m of urethra and bladder base
Adverse effects of Midodrine
insomnia, elevated BP, Myocardial ischemia exacerbation, cardiac arrhythmias
Antidepressant drug used for SUI (2) and their MOA (increased or decreased tone of what sphincter by enhancing/inhibiting sypmathetic effect of the bladder)
Impiramine (tricyclin antidepressant) - block reuptake of NE, antimuscarinic efect
Duloxetine - blocks NE and 5HT reuptake
MOA - INCREASED tone of INTERNAL SPHINCTER by ENHANCING sympathetic effect on the bladder.
Estrogen used for SUI (1)
Name
MOA (increases/decreases proliferation of urethral epithelium, increases/decreases blood circulation, increases/decreases expression and function of what receptors)
Clinical use - what route of administration? Especially effective in women with what in addition to SUI?
Estradiol
MOA is increased proliferation of urethral epithelium, increased blood circulation, increased expression UROGENITAL alpha1-AR
Clinical - ONLY TOPICAL FORMULAS, women with vaginits or urethritis
