Lecture 10,11,12: Erectile Dysfunction, Chem of Sildenafil and BPH Flashcards
What is erectile dysfunction?
- Constant inability to maintain or attain penile erections at sufficient quality for satisfactory sex
What are 2 important parts of the penis for erections?
- Corpus spongiosum: Column surrounding urethra (the tube for urine and semen)
- Prevents compression of urethra in erection
- Corpus cavernosum: spongy column on top of penis that fills w/ blood in erection
- Vascular sinusoids expand & compress veins & trap blood = erection
What are the phases of an erection?
- Flaccid phase
- Latent (filling) phase
- Tumescent phase
- Full erection phase
- Rigid erection phase
- Detumescene phase
What are the different causes and classifications of erectile dysfunction?
- Organic: Usually men over 50, w/ vascular/arterial/anatomical structure issue’
- Psychogenic: Men under 35 w/ bad experience
- Other: Riding bike = nerve compression + drugs: alcohol, beta blockers, alpha blockers
What are the different investigations that can be done for erectile dysfunction?
- Serum lipids
- Fasting glucose
- Hormonal test
- Ultrasound
- International Index of erectile dysfunction
What are the different services that patients with erectile dysfunction can be referred to?
- Urology: Urinary tract and reproductive system
- Endocrinology: hormones and glands
- Cardiology: Rehab after MI
- Mental health
What are the different non-pharmacological management strategies for erectile dysfunction?
- Weight loss
- Exercise
- Diet
- Cessation of smoking
- Moderate alcohol consumption
What are the different pharmacological management strategies for erectile dysfunction?
- Implants
- Vacuum device: pump that pulls and fills w/ blood
- Prosthesis surgery: mechanical cylinder
- Injections: 2nd line alprostadil (side of penis) causes vasodilation and relax
- Tablets: Sildenafil (short acting) and tadalafil (long acting)
What are some side effects of sildenafil and contraindication?
- Transient headache
- Flushing’
- Indigestion
- Disturbances in colour vision
- Nitrates are contraindicated - life threatening hypotension
- Risk of CV problems (ischaemic heart disease)
How many doses of sildenafil do you need with no effect to be classed as a non-responder?
- 6-8 doses at maximum dose w/ stimulation and to see no effect
What is sildenafil indicated for and what did it use to be indicated for?
- ED and pulmonary hypertension (high BP in blood vessels that supply lungs
- Used to be for Angina due to coadministration with nitrates
What is the purpose of vasodilation?
- Opens blood vessels
- Enhances blood flow
- Relaxes muscles in arteries and veins
- Stops muscles tightening and walls narrowing
What types of molecules are cAMP and cGMP, how is each produced?
- 2nd messengers. Are intracellular signalling molecules released in response to extracellular signalling from first messengers (hormones and neurotransmitters interacting w/ receptor)
- ATP -Adenylate cyclase –> cAMP
- GTP -Guanylate cyclase->cGMP
What are the differences in functions between cGMP and cAMP?
- cAMP is often involved in regulating metabolism, cell growth, and gene expression
- cGMP is primarily associated with smooth muscle relaxation and blood vessel dilation. Common regulator of ion channel conductance + reduces calcium
What are smooth muscles and ion channels?
- Smooth Muscle: Walls of blood vessels, lymph vessels and of hollow organs (stomach/SI/uterus)
- Line resp, urinary and reproductive tracts
- Ion channels: Pore forming membrane proteins that allow ions to pass
What molecule regulates cGMP and cAMP production?
- Nitric oxide: produced from sexual arousal which activates cyclase enzymes
- Causes activation of intracellular protein kinases (phosphorylation)
What is the function of phosphodiesterases and what does sildenafil do?
- Breaks phosphodiester bond in cGMP
- Sildenafil inhibits PDE which increases cGMP -> reduces Ca2+ -> increases vasodilation
What are the subtypes of PDE and which catalyse the breakdown of cAMP and cGMP?
- 1,2,3,10,11 = both
- 4,7,8 = cAMP
- 5,6,9 = cGMP
- Type 5 is important selective inhibition of PDE type 3
What is the mechanism of action of cGMP production and how it causes muscle relaxation?
- NO diffuses in
- Interacts w/ soluble guanylate cyclase which produces cGMP and its gated ion channels which regulates conductance
- cGMP binds to cGMP binding protein
- Which activates Protein Kinase G
- Serine/ Threonine proteins are phosphorylated
- Which reduces Ca2+ levels
How does Calcium cause muscle contraction?
- Calcium binds to calmodulin and increases the activity of myosin light chain kinase
- This phosphorylates MLC which interacts with actin and produce muscle contraction in smooth muscle cells
Which tissues does PDE5 act on?
- Corpus cavernosum
- Platelets
- Skeletal muscles
- Smooth muscle
- Airways
- Retina (due to weak inhibition of PDE6 - see green)
What was the process of producing cGMP PDE inhibitors?
- Zaprinist: weak, unselective (this interacted w/PDE in place of cGMP)
- Used an analogue + added 2 CH3 groups which lowered IC50 (min inhib conc that inhibited 50% activity) this represents phosphate binding
- Extending 3-substituent fills space in active site occupied by ribose (added propyl)
- Ethoxy group preferred as H-bond maintains co-polarity however had low solubility
- Added sulfonamides on 5 position which increased enzyme affinity
How was primary metabolism of sildenafil?
- Oxidation, dealkylation and hydroxylation
- N-demethylation removed CH3 group from nitrogen atom of piperazine ring = N-demethyl sildenafil = 50% less potent
What was secondary metabolism of sildenafil?
- Conjugation: sulfonation (-OH added incr excretion), glucuronidation (glucuronic acid = more soluble), Amino acid conjugation
What is benign prostatic hyperplasia?
- Non-cancerous enlargement of prostate gland often affecting men as they age
- Causes urinary symptoms due to compression of urethra. Blocks urine flow
- Prostate located below bladder and in front of rectum
- Driven by incr DHT in prostate which promotes cellular growth and hyperplasia
How would you diagnose BPH and what to ask in consultation?
- Med and drug Hx
- Physical exam of bladder and digital rectal exam
- Urine dipstick: blood glucose, protein, leucocytes, nitrites (bacteria convert from nitrates)
- Urinary freq chart and serum creatinine
- International prostate symptom score (IPSS)
What is the function of the prostate gland?
- Produces about 25% of seminal fluid which includes citric acid, G-proteolytic enzymes and G seminal plasmin
- Maximises likelihood of fertilisation
What is the function of the citric acid and G seminal plasmins in the seminal fluid?
- Citric acid: Provides sperm w/ energy + used in oxidative metabolism
- G-seminal plasmin: Contributes to sperm motility & antimicrobial activity, reducing naturally occuring bacteria in the ejaculate
What is the function of the G proteolytic enzymes in particular the prostate specific antigen?
- Facilitates sperm motility via liquefaction of seminal fluid
- Such as PSA, Pepsinogen, hyaluronidase
- PSA: glycoprotein enzyme secreted by epithelial membranes of prostate cells, helps dissolve cervical muscus + better penetration of sperm
- High levels in blood indicate prostate disease
What are the different causes of BPH?
- Metabolic effects: Diabetes, hypertension, overweight= faster growth of prostate
- Hormonal effects: age increases and more DHT, DHT binds to androgen receptors in prostate triggers growth, more oestrogen = more sensitivity to DHT
- Inflammation: cytokine release and healing. Growth->hypoxia->angiogenesis to perfuse problem (more bv to feed tissue). Mediated by VEGF (vascular endothelial growth factor)
- Tissue Remodelling: Balance between cell growth and apoptosis is disrupted, changes in signalling between stromal and epithelial cells -> abnormal growth pattern. BPH cells = hypertrophic + survive longer
What are the symptoms of BPH?
- LUTS symptoms
- Voiding symptoms: Resistance to urinary flow, incomplete bladder empty + incr time to urinate, weak muscle contractions, terminal dribbling
- Storage symptoms: Urgency, polyuria (excessive production of urine)
- Can lead to acute/chronic urinary retention -> renal failure, hypertension, chronic UTI
What are the pharmacological management strategies of BPH?
- Alpha Blockers: a1 receptors = bladder, a2 receptors = B & cardio. E.g Tamsulosin and Doxasosin. 6 weeks then follow up. Cause muscle relaxation and improve flow
- 5 alpha reductase inhibitors: blocks testrosterone to DHT. Dutasteride inhibits 1 & 2, Finasteride inhibits 2. Reduce liklihood of needing surgery and improves IPSS
- Can be used together and shown to reduce progression + improve symptom score
What are some lifestyle management strategies for BPH?
- Reduces spice & caffeine
- Avoid large vols of fluid. Just have normal
Whgat are some adverse effects of alpha blockers?
- Dizzy (take at night)
- Drowsy
- Headache
- Postural hypotension
What are some adverse effects of 5 alpha reductase inhibitors?
- Breast tenderness
- Ejaculatory dysfunction
- Loss of libido
- Impotence: Found in sperm not to concieve
What are some surgical interventions for the treatment of BPH?
- Laserprostatectomy: Laser vaporioses excess prostate tissue
- Transurethral resection of prostate: Removing part of prostate gland that is blocking the urethra
- Transurethral incision of prostate: small incisions in tissue to relieve blockage
What drugs can worsen BPH?
- P: Promethazine
- R: SNRIs
- O: Drugs w/ anticholinergic effects
- S: Stimulants (caffeine)
- T: Testosterone and androgenic steroids
- A: Alpha agonists (Pseudoephedrine)
- T: TCAs (amitryptiline)
- E: Excessive urinators (diuretics, alcohol)
